Susan London

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

SAN DIEGO – Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show.

In a retrospective study of 18,534 wait-listed older adults, the rates of posttransplantation complications in septuagenarians were much the same as those in sexagenarians, except that the former were in fact less likely to experience rejection.

And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

"Selected septuagenarians – and I underscore the word selected – with advanced heart failure derive great benefit from heart transplantation," said lead investigator Dr. Daniel Goldstein. "This is not every 70-year-old [who is] going to walk into your office."

The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted.

One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers.

"I don’t see being able to do this without having an alternative list situation. UCLA is the perfect model," asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. "It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it’s a little more palatable."

With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted.

Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that "there is great variability in who we think is too old for transplantation," he said. "It’s clear that more centers are doing away with chronological age criteria."

In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for the years 1987-2010, first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, single-organ heart transplantation.

Results showed that "in the current era, septuagenarians are being transplanted more frequently, without a doubt," Dr. Goldstein reported. The number undergoing transplantation increased almost every year, and their median age was 71 years.

For age-group comparisons, the investigators restricted analyses to the years 1998-2010, a period when the data became robust and contemporary medical and surgical practices were in use, he explained.

Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions.

Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation.

With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older.

In findings that Dr. Goldstein called "quite eye opening," there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%).

In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). And relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs. 9.83 years), although most of the difference between groups appeared to result from a difference in the first year.

"I was rather surprised" by the 8-year value for the septuagenarians. "That’s a very important number," commented Dr. Goldstein. "While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy."

In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged 60-69 years.

Dr. Goldstein said he had no relevant financial disclosures.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

SAN DIEGO – A new allocation algorithm that is designed to improve regional sharing of donor hearts with sicker patients before they are allocated locally to less-sick patients appears to be having the intended effects, according to a national cohort study.

In the study of nearly 12,000 adult patients who were wait-listed for primary heart transplantation in 2004-2009 in the United States, those who were wait-listed after the new algorithm was implemented were 17% less likely to die on the waiting list or to become too sick for transplantation, researchers reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Moreover, this benefit was achieved without any increase in the rate of in-hospital mortality among transplant recipients, even though they were sicker on average.

"The risk of dying on the heart transplant [waiting list] or becoming too sick for transplant has declined [in the United States] since the change in allocation algorithm in 2006," said lead investigator Dr. Tajinder P. Singh, a pediatric cardiologist at Children’s Hospital Boston. And reassuringly, "the shift in hearts to sicker transplant candidates has not resulted in higher early posttransplant mortality."

These findings suggest that the new algorithm has been effective "not only from a utilitarian view, which means most benefit for most people, but even from the fairness or justice perspective," he commented. "By granting the hearts to sicker people, you are taking care of that point of view, too."

An attendee asked whether patterns might differ at the local or regional level vs. the national level, given that some centers in the New York City area, for example, feel they have been hurt by the new algorithm. Dr. Singh replied that because of small patient numbers and regional variations, it was not possible to get a reliable picture at those levels.

"The demand for donor hearts continues to exceed their supply," he said, giving background to the study. "The United Network for Organ Sharing has periodically modified the allocation algorithm in the United States" to improve waiting list outcomes.

The last such modification, implemented in July 2006, expanded the sharing of these scarce organs across a geographic region, making them available first to the sickest patients (those with status 1A or 1B) in a region before allocating them locally to less-sick patients.

"The goal of such a change was to lower national [waiting list] mortality without a concurrent increase in posttransplant mortality, and that consideration is more than theoretical because sicker patients will be at higher risk of dying post transplant," he explained. "The early outcome trends after the allocation change have been supportive, but regional analyses have questioned the merits of the new allocation."

The investigators studied all patients aged 18 years or older who were placed on the waiting list for primary heart transplantation between July 1, 2004, and June 30, 2009, and who were undergoing transplantation of only a heart.

For comparison, the patients were split according to when they were listed into "era 1" (before the date of implementation of the new algorithm) and "era 2" (after that date). Study results were based on 11,864 patients in total; 38% were listed in era 1 and 62% were listed in era 2.

Patients in the two eras were similar with respect to most sociodemographic and medical factors, except that those in era 2 were more likely to be aged 60 years or older (32% vs. 28%), to receive mechanical support (14% vs. 13%), and to be sicker, as indicated by having a transplantation status of 1A (20% vs. 19%) or 1B (38% vs. 32%), for instance.

Overall, 13% of the patients studied either died or had a worsening of their condition that prevented transplantation while they were on the waiting list, the study’s primary end point, Dr. Singh reported.

Before statistical adjustment, patients in era 2 were 14% less likely than their counterparts in era 1 to die or worsen while on the wait list (hazard ratio, 0.86; P = .005). And this benefit was evident among both status 1A patients and status 1B patients individually.

After adjustment for numerous potential confounders, patients in era 2 were 17% less likely to die or worsen while on the wait list (HR, 0.83; P = .001). The benefit was similar in most subgroups, except that by race, it was mainly limited to white patients.

Other risk-reducing factors included having an implantable cardioverter defibrillator (HR, 0.87) and having a continuous-flow left ventricular assist device (HR, 0.56).

Overall, 65% of the patients ultimately underwent transplantation. Compared with their counterparts in era 1, era 2 transplant recipients had a shorter median wait time before receiving a heart (55 vs. 63 days; P less than .001) and were more likely to be status 1A at transplantation (48% vs. 37%; P less than .001).

The donor ischemic time was longer for recipients in era 2 (3.3 vs. 3.2 hours; P = .02), but the small difference was probably not clinically important, according to Dr. Singh.

The lack of a greater difference in ischemic time – despite the sharing of organs over larger geographic areas in the latter era – was not surprising, he said. "The way it occurred, it went from local to within 500 miles, say. It may be broader regional sharing, but it’s not long distance to get to [the heart] and bring the heart in to the surgery."

There was no rise in the rate of in-hospital mortality post transplantation with implementation of the new algorithm. In fact, "interestingly, in-hospital mortality was lower rather than higher [in era 2], even though sicker patients were getting transplanted," Dr. Singh commented, with a rate of 5.3% in era 2, compared with 6.3% in era 1.

Dr. Singh reported having no conflicts of interest related to the research.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.

SEATTLE – Vaccinating girls against human papillomavirus at age 11 or 12 years, as is currently recommended, appears to be most appropriate for preventing infection, but barriers persist, according to two studies presented at the annual meeting of the Society for Adolescent Health and Medicine.

In a study among girls as young as age 13 years, one in eight who reported that they had never had sexual intercourse nonetheless had vaginal infection with human papillomavirus (HPV). And more than two-thirds of those who had had sex were infected.

In another study among girls aged 14-17 years and their mothers, the most commonly cited reasons for not vaccinating were fear of side effects, perceived danger of the vaccine, and lack of a recommendation to vaccinate from their health care provider.

Prevalence of HPV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine be targeted to girls aged 11-12 years, with catch-up vaccination in girls and young women aged 13-26 years, noted Dr. Jessica A. Kahn, an associate professor of pediatrics at the University of Cincinnati.

But there is some reluctance among clinicians and parents alike to vaccinate at age 11 or 12, she said. "This is concerning, as HPV is commonly acquired during the teen years, and HPV vaccines are not effective at preventing infections with vaccine types of HPV in young women who are already infected with those types at the time of vaccination."

Data on the prevalence of type-specific HPV infection in girls initiating HPV vaccination are generally lacking, according to Dr. Kahn. "These data are needed in order to estimate the public health impact of HPV vaccination in the catch-up age group, and to guide educational and public health interventions designed to maximize the effectiveness of HPV vaccination."

She and her colleagues studied 259 girls aged 13-21 years who were receiving their first dose of HPV vaccine in a hospital-based adolescent clinic. Clinicians or the girls themselves collected vaginal samples that were tested for 37 HPV types. The girls and their mothers completed questionnaires about factors potentially related to HPV acquisition.

Overall, 27% of the girls were sexually inexperienced, reporting that they had never had vaginal or anal sex. But 13% of this group had had sexual contact, reporting genital skin-to-skin contact only.

The percentage of girls testing positive for any HPV type was 70% in the sexually experienced group and much lower, though not zero, at 12% in the sexually inexperienced group (P less than .001).

The sexually experienced group was also more likely than the inexperienced group to test positive for at least one of the high-risk HPV types in the quadrivalent vaccine – types 6, 11, 16, and 18 (31% vs. 4%, P less than .001) – and for at least one of those in the bivalent vaccine – types 16 and 18 (21% vs. 3%, P less than .001).

In a multivariate analysis of the sexually experienced group, these girls were significantly more likely to be HPV positive if they had had two to five, or six or more lifetime male partners, compared with one partner (odds ratios 6.2 and 10.3) and if their mother reported not having communicated with them about the HPV vaccine (OR 4.0).

In contrast, in the sexually inexperienced group, none of a variety of factors, including reported sexual contact, were independently associated with the odds of being HPV positive.

"Clinicians and parents should be strongly encouraged to vaccinate 11- to 12-year-old girls and not procrastinate," Dr. Kahn asserted. "It’s difficult to predict the age of sexual initiation, and thus, these recommendations by the ACIP minimize the probability that girls will be infected at the time of vaccination."

The findings also support the recommendation for catch-up vaccination in older girls, she added, as a majority of the sexually active group were still negative for high-risk types of the virus covered by the vaccines.

"I think it’s probably helpful for clinicians to develop some brief talking points for use with parents in terms of HPV vaccination," said Dr. Kahn. "Those would include the fact that HPV is acquired very rapidly after sexual initiation, that the vast majority of people will acquire HPV at some point in their lives, and that the vaccine is only effective in preventing vaccine-type HPVs if given before exposure."

"I think it’s really important for us to get those messages out, and I think it can be done in a pretty concise way," she concluded.

Barriers to HPV vaccination. Understanding barriers to HPV vaccination is important not only for promoting uptake, but also possibly for efforts to address disproportionately high rates of HPV infection in certain population groups, according to Dr. Laura M. Kester, a pediatrician at Indiana University in Indianapolis.

"Positive maternal attitudes toward vaccination have been shown to be associated with higher rates of HPV vaccination," she noted.

Dr. Kester and her colleagues studied a national sample of 501 girls aged 14-17 years and their mothers recruited to an online-based survey in 2010. The mothers and daughters completed surveys asking about number of doses of HPV vaccine the daughter had received, sociodemographic factors, insurance status, and maternal experiences related to HPV infection. The mothers of unvaccinated daughters were asked why they had not had their girls vaccinated. Survey results showed that the mothers were 45 years old on average. The majority were white (76%) and college educated (81%).

According to maternal report, 50% of the daughters had initiated HPV vaccination, defined as having received at least one dose, and 38% had completed vaccination, defined as having received all three doses in the series.

These rates suggest improvement from 2009, Dr. Kester noted, when data from the Centers for Disease Control and Prevention showed an initiation rate of 44% and a completion rate of 27%.

The rate of initiation did not vary significantly with the daughter’s insurance status or according to a variety of maternal factors, such as race/ethnicity, education level, relationship status, geographic location, employment status, or exposure to negative experiences related to HPV (having had an abnormal Pap smear, a colposcopy, or a friend or family member with cervical cancer).

In contrast, the rate of completion differed significantly by maternal race/ethnicity, with about 40% of the daughters of white mothers having completed the series, compared with 25% of daughters of black mothers and 25% of daughters of Hispanic mothers (P less than .001).

Mothers’ most commonly reported reasons for not initiating HPV vaccination for their daughter were concern about vaccine side effects (cited by 36%), fear that it was dangerous (36%), and lack of a recommendation by their provider (34%).

They also cited a belief that the vaccine did not work (13%), not having seen a provider in a long time (12%), concern about eligibility for or cost of the vaccine (11%), and concern that vaccinating would encourage their daughter to have sex (8%).

"There is no evidence from our data that demographic or socioeconomic disparities played a role in vaccination initiation," commented Dr. Kester. "However, we do see that black and Hispanic populations were less likely to complete vaccination."

Taken together, the findings "suggest there is continued need to encourage vaccine uptake as well as need for further educational interventions, at the level of the patient, the provider, and the parent on vaccine benefit, efficacy, and safety," she said. "In addition, this data reminds us that there is a continuing need to evaluate barriers to vaccination initiation and completion, looking at reasons for racial discrepancy of vaccine completion."

Dr. Kahn reported that she is co-principal investigator on two trials in which Merck is providing the vaccine and immunogenicity testing. Dr. Kester reported that some of her coinvestigators are investigators for or receive research funding from Merck.