Susan London

SAN ANTONIO – Adjuvant bevacizumab does not further improve the already very good outcomes being achieved with contemporary therapy in high-risk HER2-positive breast cancer, according to results of the randomized, phase III BETH trial.

There was little room for improvement on chemotherapy and HER2-targeted therapy with trastuzumab as the standard of care, as an estimated 92% of patients were still alive and free of disease after a median follow-up of about 3 years, lead investigator Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

"The addition of bevacizumab didn’t add any efficacy but certainly added some safety concerns," Dr. Slamon commented in a press briefing. Increased rates of grade 3/4 adverse events, such as hypertension and bowel perforation, were associated with use of bevacizumab.

BETH thus joins a host of trials with negative results for antiangiogenic therapy in breast cancer, he said. "Unless there is a new drug or strategy where we can find the subgroup [that benefits], I think this is not going anywhere. We have gotten a pretty good effect with what we have. We have very little room at the top. We have to think about new strategies for those patients who aren’t getting the benefit that we hope they will with targeted therapy."

In other trial findings, there were consistently high rates of invasive disease–free survival regardless of whether the chemotherapy/trastuzumab regimen used (left up to the treating centers) did not contain an anthracycline (docetaxel, carboplatin, and trastuzumab [Herceptin] – TCH) or did contain an anthracycline (5-fluorouracil, epirubicin, and cyclophosphamide – FEC).

Given the known toxicity of anthracyclines and the availability of an equally effective and safer alternative, their use in HER2-positive breast cancer is no longer justified, according to Dr. Slamon, director of clinical/translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and professor of medicine and chief of the division of hematology/oncology at UCLA.

Acknowledging that the topic is intensely debated, Dr. Slamon noted that "there is no reason to take that risk now that we have more than 4,000 patients treated [with TCH] between BCIRG-006 [which first rigorously tested this regimen] and BETH that show that this gives a pretty favorable outcome. We at our institution do not use these drugs [anthracyclines]. It doesn’t mean they are not effective; they just don’t provide any incremental benefit over other drugs that would give you the same effect without the safety concerns."

While praising the trial as "exceptionally well run" and agreeing on interpretation of the bevacizumab results, press briefing moderator Dr. Jennifer Litton expressed an opposing view.

"I’m totally on the other side of the aisle, that we shouldn’t say that all anthracyclines should go away," maintained Dr. Litton, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "The BETH trial specifically asked the question: Does bevacizumab add anything? And the answer quite clearly is no." It did it compare an anthracycline- and a non–anthracycline-containing arm. "That was not the design or intent," she said.

Additionally, in contrast to other similar trials, almost half of the patients who participated in BETH had stage I disease, raising the possibility of selection bias for who received TCH.

"But I do feel that the Herceptin story and the combination stories to come" with lapatinib, pertuzumab, and TDM1 "are really going to also be the landscape changers in HER2 disease," Dr. Litton concluded. "And we are going to be continuing to find specific strategies and not a one-therapy-fits-all for all HER2 disease because we are learning more and more about the molecular subsets of cancer. How we have broken them up into triple receptors is really going to go by the wayside."

Bevacizumab (Avastin) is an antibody to vascular endothelial growth factor (VEGF). It is approved for use by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer.

The 3,509 women enrolled in BETH (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) had HER2-positive, node-positive, or high-risk node-negative breast cancer; 92% received TCH as their chemotherapy.

With a median follow-up of 38 months in the trial population overall, there was no significant difference between patients randomized to receive bevacizumab and those who did not in terms of the 3-year rate of invasive disease–free survival (92% vs. 92%) and overall survival (97% vs. 96%).

The findings were consistent across subgroups stratified by a variety of patient and disease characteristics, Dr. Slamon noted.

Additionally, the rate of invasive disease–free survival was statistically indistinguishable with or without bevacizumab in both the cohort given TCH (92% vs. 92%) and the cohort given FEC (91% vs. 89%).

In the trial population overall, addition of bevacizumab to chemotherapy tripled the rate of all grade 3/4 adverse events of special interest (27% vs. 8%, P less than .0001), such as hypertension, congestive heart failure, and gastrointestinal perforation.

Dr. Slamon disclosed that he serves as an adviser to Roche/Genentech, which supported the trial.

SAN ANTONIO – Adjuvant bevacizumab does not further improve the already very good outcomes being achieved with contemporary therapy in high-risk HER2-positive breast cancer, according to results of the randomized, phase III BETH trial.

There was little room for improvement on chemotherapy and HER2-targeted therapy with trastuzumab as the standard of care, as an estimated 92% of patients were still alive and free of disease after a median follow-up of about 3 years, lead investigator Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

"The addition of bevacizumab didn’t add any efficacy but certainly added some safety concerns," Dr. Slamon commented in a press briefing. Increased rates of grade 3/4 adverse events, such as hypertension and bowel perforation, were associated with use of bevacizumab.

BETH thus joins a host of trials with negative results for antiangiogenic therapy in breast cancer, he said. "Unless there is a new drug or strategy where we can find the subgroup [that benefits], I think this is not going anywhere. We have gotten a pretty good effect with what we have. We have very little room at the top. We have to think about new strategies for those patients who aren’t getting the benefit that we hope they will with targeted therapy."

In other trial findings, there were consistently high rates of invasive disease–free survival regardless of whether the chemotherapy/trastuzumab regimen used (left up to the treating centers) did not contain an anthracycline (docetaxel, carboplatin, and trastuzumab [Herceptin] – TCH) or did contain an anthracycline (5-fluorouracil, epirubicin, and cyclophosphamide – FEC).

Given the known toxicity of anthracyclines and the availability of an equally effective and safer alternative, their use in HER2-positive breast cancer is no longer justified, according to Dr. Slamon, director of clinical/translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and professor of medicine and chief of the division of hematology/oncology at UCLA.

Acknowledging that the topic is intensely debated, Dr. Slamon noted that "there is no reason to take that risk now that we have more than 4,000 patients treated [with TCH] between BCIRG-006 [which first rigorously tested this regimen] and BETH that show that this gives a pretty favorable outcome. We at our institution do not use these drugs [anthracyclines]. It doesn’t mean they are not effective; they just don’t provide any incremental benefit over other drugs that would give you the same effect without the safety concerns."

While praising the trial as "exceptionally well run" and agreeing on interpretation of the bevacizumab results, press briefing moderator Dr. Jennifer Litton expressed an opposing view.

"I’m totally on the other side of the aisle, that we shouldn’t say that all anthracyclines should go away," maintained Dr. Litton, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "The BETH trial specifically asked the question: Does bevacizumab add anything? And the answer quite clearly is no." It did it compare an anthracycline- and a non–anthracycline-containing arm. "That was not the design or intent," she said.

Additionally, in contrast to other similar trials, almost half of the patients who participated in BETH had stage I disease, raising the possibility of selection bias for who received TCH.

"But I do feel that the Herceptin story and the combination stories to come" with lapatinib, pertuzumab, and TDM1 "are really going to also be the landscape changers in HER2 disease," Dr. Litton concluded. "And we are going to be continuing to find specific strategies and not a one-therapy-fits-all for all HER2 disease because we are learning more and more about the molecular subsets of cancer. How we have broken them up into triple receptors is really going to go by the wayside."

Bevacizumab (Avastin) is an antibody to vascular endothelial growth factor (VEGF). It is approved for use by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer.

The 3,509 women enrolled in BETH (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) had HER2-positive, node-positive, or high-risk node-negative breast cancer; 92% received TCH as their chemotherapy.

With a median follow-up of 38 months in the trial population overall, there was no significant difference between patients randomized to receive bevacizumab and those who did not in terms of the 3-year rate of invasive disease–free survival (92% vs. 92%) and overall survival (97% vs. 96%).

The findings were consistent across subgroups stratified by a variety of patient and disease characteristics, Dr. Slamon noted.

Additionally, the rate of invasive disease–free survival was statistically indistinguishable with or without bevacizumab in both the cohort given TCH (92% vs. 92%) and the cohort given FEC (91% vs. 89%).

In the trial population overall, addition of bevacizumab to chemotherapy tripled the rate of all grade 3/4 adverse events of special interest (27% vs. 8%, P less than .0001), such as hypertension, congestive heart failure, and gastrointestinal perforation.

Dr. Slamon disclosed that he serves as an adviser to Roche/Genentech, which supported the trial.

SAN ANTONIO – Adjuvant bevacizumab does not further improve the already very good outcomes being achieved with contemporary therapy in high-risk HER2-positive breast cancer, according to results of the randomized, phase III BETH trial.

There was little room for improvement on chemotherapy and HER2-targeted therapy with trastuzumab as the standard of care, as an estimated 92% of patients were still alive and free of disease after a median follow-up of about 3 years, lead investigator Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

"The addition of bevacizumab didn’t add any efficacy but certainly added some safety concerns," Dr. Slamon commented in a press briefing. Increased rates of grade 3/4 adverse events, such as hypertension and bowel perforation, were associated with use of bevacizumab.

BETH thus joins a host of trials with negative results for antiangiogenic therapy in breast cancer, he said. "Unless there is a new drug or strategy where we can find the subgroup [that benefits], I think this is not going anywhere. We have gotten a pretty good effect with what we have. We have very little room at the top. We have to think about new strategies for those patients who aren’t getting the benefit that we hope they will with targeted therapy."

In other trial findings, there were consistently high rates of invasive disease–free survival regardless of whether the chemotherapy/trastuzumab regimen used (left up to the treating centers) did not contain an anthracycline (docetaxel, carboplatin, and trastuzumab [Herceptin] – TCH) or did contain an anthracycline (5-fluorouracil, epirubicin, and cyclophosphamide – FEC).

Given the known toxicity of anthracyclines and the availability of an equally effective and safer alternative, their use in HER2-positive breast cancer is no longer justified, according to Dr. Slamon, director of clinical/translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and professor of medicine and chief of the division of hematology/oncology at UCLA.

Acknowledging that the topic is intensely debated, Dr. Slamon noted that "there is no reason to take that risk now that we have more than 4,000 patients treated [with TCH] between BCIRG-006 [which first rigorously tested this regimen] and BETH that show that this gives a pretty favorable outcome. We at our institution do not use these drugs [anthracyclines]. It doesn’t mean they are not effective; they just don’t provide any incremental benefit over other drugs that would give you the same effect without the safety concerns."

While praising the trial as "exceptionally well run" and agreeing on interpretation of the bevacizumab results, press briefing moderator Dr. Jennifer Litton expressed an opposing view.

"I’m totally on the other side of the aisle, that we shouldn’t say that all anthracyclines should go away," maintained Dr. Litton, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "The BETH trial specifically asked the question: Does bevacizumab add anything? And the answer quite clearly is no." It did it compare an anthracycline- and a non–anthracycline-containing arm. "That was not the design or intent," she said.

Additionally, in contrast to other similar trials, almost half of the patients who participated in BETH had stage I disease, raising the possibility of selection bias for who received TCH.

"But I do feel that the Herceptin story and the combination stories to come" with lapatinib, pertuzumab, and TDM1 "are really going to also be the landscape changers in HER2 disease," Dr. Litton concluded. "And we are going to be continuing to find specific strategies and not a one-therapy-fits-all for all HER2 disease because we are learning more and more about the molecular subsets of cancer. How we have broken them up into triple receptors is really going to go by the wayside."

Bevacizumab (Avastin) is an antibody to vascular endothelial growth factor (VEGF). It is approved for use by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer.

The 3,509 women enrolled in BETH (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) had HER2-positive, node-positive, or high-risk node-negative breast cancer; 92% received TCH as their chemotherapy.

With a median follow-up of 38 months in the trial population overall, there was no significant difference between patients randomized to receive bevacizumab and those who did not in terms of the 3-year rate of invasive disease–free survival (92% vs. 92%) and overall survival (97% vs. 96%).

The findings were consistent across subgroups stratified by a variety of patient and disease characteristics, Dr. Slamon noted.

Additionally, the rate of invasive disease–free survival was statistically indistinguishable with or without bevacizumab in both the cohort given TCH (92% vs. 92%) and the cohort given FEC (91% vs. 89%).

In the trial population overall, addition of bevacizumab to chemotherapy tripled the rate of all grade 3/4 adverse events of special interest (27% vs. 8%, P less than .0001), such as hypertension, congestive heart failure, and gastrointestinal perforation.

Dr. Slamon disclosed that he serves as an adviser to Roche/Genentech, which supported the trial.

SAN ANTONIO – The oral tyrosine kinase inhibitor dasatinib appears to increase the efficacy of first-line aromatase inhibitor therapy in women with advanced breast cancer, suggests a randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.

Adding dasatinib (SPRYCEL) to letrozole (Femara) did not improve the clinical benefit rate – the trial’s primary endpoint – among the 120 postmenopausal women with hormone receptor–positive, HER2-negative locally recurrent or metastatic breast cancer.

But the combination doubled patients’ median progression-free survival from 10 months to 20 months in an intent-to-treat analysis, Dr. Dev Paul of U.S. Oncology and the Rocky Mountain Cancer Centers in Denver reported in a session and a related press briefing at the meeting.

"Dasatinib may be inhibiting the emergence of resistance to aromatase inhibitor therapy," he said.

The researchers were unable to identify factors that explained why the clinical benefit rate was the same, but the progression-free survival was different for the two groups. The study was small, did not use a placebo, and permitted crossover; "all of these things could affect the results, and this is a preliminary exploratory study," Dr. Paul said.

Combining dasatinib with other aromatase inhibitors – fulvestrant or exemestane – has not improved progression-free survival benefit in women with metastatic breast cancer previously treated with a nonsteroidal aromatase inhibitor, Dr. Paul noted; thus, it may be important to give dasatinib the first time that patients are given an aromatase inhibitor. "Putative predictive biomarkers for benefit from dasatinib will be assessed in patients’ archival breast cancer tissues to help inform patient selection for future studies."

In additional findings from the trial, adding dasatinib appeared to attenuate the adverse impact of letrozole on bone health. At the end of the study, patients given the combination therapy were half as likely as their counterparts given letrozole alone to have osteopenia.

The findings on bone density suggest "an on-target effect of the Src inhibitor [dasatinib]," commented Dr. Carlos L. Arteaga, who moderated the press briefing. Dr. Arteaga is president-elect of the American Association for Cancer Research and associate director for translational/clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and a codirector of SABCS.

Dr. Paul noted that the observations occurred in an intent-to-treat analysis that included all patients according to their initial treatment assignment.

During a discussion after the presentation, one session attendee questioned the interpretation that dasatinib was inhibiting the emergence of resistance to letrozole and pointed out that 23% of patients who had progression on letrozole monotherapy had clinical benefit after crossing over to the combination. "You could also interpret the crossover data [as saying] that [dasatinib] simply treats endocrine resistance. So my question is, have you looked at the time to total progression? Have you looked at that 23% clinical benefit in the cross-over group? Because [dasatinib] may not stop resistance, it may just treat it."

Looking at the total time to progression for sequential vs. combined therapy, it may be that the time to progression curves really don’t separate quite so much, the discussant maintained.

Dr. Paul acknowledged that this alternate interpretation was possible and said that such analyses have not yet been done.

"Src is a pleiotropic nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival. Membrane estrogen receptor-alpha complexes with Src and PI3 kinase to drive breast cancer growth and endocrine therapy resistance," Dr. Paul said, giving some background to the trial. "Src also regulates osteoclast-mediated bone turnover."

Dasatinib inhibits Src tyrosine kinase and is currently approved by the Food and Drug Administration for treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia and chronic myelogenous leukemia.

Women enrolled in the trial were allowed to have had prior non–aromatase inhibitor endocrine therapy for metastatic disease; prior adjuvant aromatase inhibitor therapy if completed at least 1 year before study entry; and one prior chemotherapy regimen for metastatic disease.

After stratification by disease-free interval and prior receipt of tamoxifen, patients were randomized to receive letrozole plus dasatinib or letrozole alone on 28-day cycles.

Patients on letrozole alone were allowed to cross over if they experienced progression, and 56% ultimately did so, Dr. Paul reported.

About half of the women in each treatment arm had not received any prior chemotherapy; 60% of those randomized to the combination and 49% of those randomized to letrozole alone had not received any prior endocrine therapy.

The clinical benefit rate – consisting of complete responses, partial responses, and stable disease for at least 6 months – was 71% with dasatinib plus letrozole and 66% with letrozole alone, a nonsignificant difference.

However, in intent-to-treat analyses, median progression-free survival was more than twice as long with the combination (20.1 months vs. 9.9 months; exploratory hazard ratio, 0.69).

In each treatment arm, about one-third of patients had a bone density T score below –1.5 at baseline, and about one-third received bisphosphonates during the study. But, by the end of the study, the proportion of patients with a T score below –1.5 was smaller in those on combination therapy (14% vs. 32%).

"There were no unexpected toxicities associated with dasatinib," Dr. Paul commented. The addition of this agent was associated with higher rates of grade 3 rash, edema, fatigue, anemia, neutropenia, arthralgia, and pleural effusion, but there were no grade 4 toxicities. Overall, one-quarter of patients needed a dasatinib dose reduction.

Dr. Paul disclosed no relevant conflicts of interest. The trial was sponsored by Bristol-Myers Squibb, the makers of SPRYCEL (dasatinib).

SAN ANTONIO – The oral tyrosine kinase inhibitor dasatinib appears to increase the efficacy of first-line aromatase inhibitor therapy in women with advanced breast cancer, suggests a randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.

Adding dasatinib (SPRYCEL) to letrozole (Femara) did not improve the clinical benefit rate – the trial’s primary endpoint – among the 120 postmenopausal women with hormone receptor–positive, HER2-negative locally recurrent or metastatic breast cancer.

But the combination doubled patients’ median progression-free survival from 10 months to 20 months in an intent-to-treat analysis, Dr. Dev Paul of U.S. Oncology and the Rocky Mountain Cancer Centers in Denver reported in a session and a related press briefing at the meeting.

"Dasatinib may be inhibiting the emergence of resistance to aromatase inhibitor therapy," he said.

The researchers were unable to identify factors that explained why the clinical benefit rate was the same, but the progression-free survival was different for the two groups. The study was small, did not use a placebo, and permitted crossover; "all of these things could affect the results, and this is a preliminary exploratory study," Dr. Paul said.

Combining dasatinib with other aromatase inhibitors – fulvestrant or exemestane – has not improved progression-free survival benefit in women with metastatic breast cancer previously treated with a nonsteroidal aromatase inhibitor, Dr. Paul noted; thus, it may be important to give dasatinib the first time that patients are given an aromatase inhibitor. "Putative predictive biomarkers for benefit from dasatinib will be assessed in patients’ archival breast cancer tissues to help inform patient selection for future studies."

In additional findings from the trial, adding dasatinib appeared to attenuate the adverse impact of letrozole on bone health. At the end of the study, patients given the combination therapy were half as likely as their counterparts given letrozole alone to have osteopenia.

The findings on bone density suggest "an on-target effect of the Src inhibitor [dasatinib]," commented Dr. Carlos L. Arteaga, who moderated the press briefing. Dr. Arteaga is president-elect of the American Association for Cancer Research and associate director for translational/clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and a codirector of SABCS.

Dr. Paul noted that the observations occurred in an intent-to-treat analysis that included all patients according to their initial treatment assignment.

During a discussion after the presentation, one session attendee questioned the interpretation that dasatinib was inhibiting the emergence of resistance to letrozole and pointed out that 23% of patients who had progression on letrozole monotherapy had clinical benefit after crossing over to the combination. "You could also interpret the crossover data [as saying] that [dasatinib] simply treats endocrine resistance. So my question is, have you looked at the time to total progression? Have you looked at that 23% clinical benefit in the cross-over group? Because [dasatinib] may not stop resistance, it may just treat it."

Looking at the total time to progression for sequential vs. combined therapy, it may be that the time to progression curves really don’t separate quite so much, the discussant maintained.

Dr. Paul acknowledged that this alternate interpretation was possible and said that such analyses have not yet been done.

"Src is a pleiotropic nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival. Membrane estrogen receptor-alpha complexes with Src and PI3 kinase to drive breast cancer growth and endocrine therapy resistance," Dr. Paul said, giving some background to the trial. "Src also regulates osteoclast-mediated bone turnover."

Dasatinib inhibits Src tyrosine kinase and is currently approved by the Food and Drug Administration for treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia and chronic myelogenous leukemia.

Women enrolled in the trial were allowed to have had prior non–aromatase inhibitor endocrine therapy for metastatic disease; prior adjuvant aromatase inhibitor therapy if completed at least 1 year before study entry; and one prior chemotherapy regimen for metastatic disease.

After stratification by disease-free interval and prior receipt of tamoxifen, patients were randomized to receive letrozole plus dasatinib or letrozole alone on 28-day cycles.

Patients on letrozole alone were allowed to cross over if they experienced progression, and 56% ultimately did so, Dr. Paul reported.

About half of the women in each treatment arm had not received any prior chemotherapy; 60% of those randomized to the combination and 49% of those randomized to letrozole alone had not received any prior endocrine therapy.

The clinical benefit rate – consisting of complete responses, partial responses, and stable disease for at least 6 months – was 71% with dasatinib plus letrozole and 66% with letrozole alone, a nonsignificant difference.

However, in intent-to-treat analyses, median progression-free survival was more than twice as long with the combination (20.1 months vs. 9.9 months; exploratory hazard ratio, 0.69).

In each treatment arm, about one-third of patients had a bone density T score below –1.5 at baseline, and about one-third received bisphosphonates during the study. But, by the end of the study, the proportion of patients with a T score below –1.5 was smaller in those on combination therapy (14% vs. 32%).

"There were no unexpected toxicities associated with dasatinib," Dr. Paul commented. The addition of this agent was associated with higher rates of grade 3 rash, edema, fatigue, anemia, neutropenia, arthralgia, and pleural effusion, but there were no grade 4 toxicities. Overall, one-quarter of patients needed a dasatinib dose reduction.

Dr. Paul disclosed no relevant conflicts of interest. The trial was sponsored by Bristol-Myers Squibb, the makers of SPRYCEL (dasatinib).

SAN ANTONIO – The oral tyrosine kinase inhibitor dasatinib appears to increase the efficacy of first-line aromatase inhibitor therapy in women with advanced breast cancer, suggests a randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.

Adding dasatinib (SPRYCEL) to letrozole (Femara) did not improve the clinical benefit rate – the trial’s primary endpoint – among the 120 postmenopausal women with hormone receptor–positive, HER2-negative locally recurrent or metastatic breast cancer.

But the combination doubled patients’ median progression-free survival from 10 months to 20 months in an intent-to-treat analysis, Dr. Dev Paul of U.S. Oncology and the Rocky Mountain Cancer Centers in Denver reported in a session and a related press briefing at the meeting.

"Dasatinib may be inhibiting the emergence of resistance to aromatase inhibitor therapy," he said.

The researchers were unable to identify factors that explained why the clinical benefit rate was the same, but the progression-free survival was different for the two groups. The study was small, did not use a placebo, and permitted crossover; "all of these things could affect the results, and this is a preliminary exploratory study," Dr. Paul said.

Combining dasatinib with other aromatase inhibitors – fulvestrant or exemestane – has not improved progression-free survival benefit in women with metastatic breast cancer previously treated with a nonsteroidal aromatase inhibitor, Dr. Paul noted; thus, it may be important to give dasatinib the first time that patients are given an aromatase inhibitor. "Putative predictive biomarkers for benefit from dasatinib will be assessed in patients’ archival breast cancer tissues to help inform patient selection for future studies."

In additional findings from the trial, adding dasatinib appeared to attenuate the adverse impact of letrozole on bone health. At the end of the study, patients given the combination therapy were half as likely as their counterparts given letrozole alone to have osteopenia.

The findings on bone density suggest "an on-target effect of the Src inhibitor [dasatinib]," commented Dr. Carlos L. Arteaga, who moderated the press briefing. Dr. Arteaga is president-elect of the American Association for Cancer Research and associate director for translational/clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and a codirector of SABCS.

Dr. Paul noted that the observations occurred in an intent-to-treat analysis that included all patients according to their initial treatment assignment.

During a discussion after the presentation, one session attendee questioned the interpretation that dasatinib was inhibiting the emergence of resistance to letrozole and pointed out that 23% of patients who had progression on letrozole monotherapy had clinical benefit after crossing over to the combination. "You could also interpret the crossover data [as saying] that [dasatinib] simply treats endocrine resistance. So my question is, have you looked at the time to total progression? Have you looked at that 23% clinical benefit in the cross-over group? Because [dasatinib] may not stop resistance, it may just treat it."

Looking at the total time to progression for sequential vs. combined therapy, it may be that the time to progression curves really don’t separate quite so much, the discussant maintained.

Dr. Paul acknowledged that this alternate interpretation was possible and said that such analyses have not yet been done.

"Src is a pleiotropic nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival. Membrane estrogen receptor-alpha complexes with Src and PI3 kinase to drive breast cancer growth and endocrine therapy resistance," Dr. Paul said, giving some background to the trial. "Src also regulates osteoclast-mediated bone turnover."

Dasatinib inhibits Src tyrosine kinase and is currently approved by the Food and Drug Administration for treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia and chronic myelogenous leukemia.

Women enrolled in the trial were allowed to have had prior non–aromatase inhibitor endocrine therapy for metastatic disease; prior adjuvant aromatase inhibitor therapy if completed at least 1 year before study entry; and one prior chemotherapy regimen for metastatic disease.

After stratification by disease-free interval and prior receipt of tamoxifen, patients were randomized to receive letrozole plus dasatinib or letrozole alone on 28-day cycles.

Patients on letrozole alone were allowed to cross over if they experienced progression, and 56% ultimately did so, Dr. Paul reported.

About half of the women in each treatment arm had not received any prior chemotherapy; 60% of those randomized to the combination and 49% of those randomized to letrozole alone had not received any prior endocrine therapy.

The clinical benefit rate – consisting of complete responses, partial responses, and stable disease for at least 6 months – was 71% with dasatinib plus letrozole and 66% with letrozole alone, a nonsignificant difference.

However, in intent-to-treat analyses, median progression-free survival was more than twice as long with the combination (20.1 months vs. 9.9 months; exploratory hazard ratio, 0.69).

In each treatment arm, about one-third of patients had a bone density T score below –1.5 at baseline, and about one-third received bisphosphonates during the study. But, by the end of the study, the proportion of patients with a T score below –1.5 was smaller in those on combination therapy (14% vs. 32%).

"There were no unexpected toxicities associated with dasatinib," Dr. Paul commented. The addition of this agent was associated with higher rates of grade 3 rash, edema, fatigue, anemia, neutropenia, arthralgia, and pleural effusion, but there were no grade 4 toxicities. Overall, one-quarter of patients needed a dasatinib dose reduction.

Dr. Paul disclosed no relevant conflicts of interest. The trial was sponsored by Bristol-Myers Squibb, the makers of SPRYCEL (dasatinib).

SAN ANTONIO – Pathologic complete response is a strong prognostic factor in women with HER2-positive early breast cancer who receive neoadjuvant HER2-targeted therapy, investigators reported at the annual San Antonio Breast Cancer Symposium.

A team led by Dr. Martine Piccart-Gebhart, chair of the Breast International Group (BIG) in Brussels, analyzed data from 455 patients in the randomized NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, who received one or both HER2 therapies, along with chemotherapy.

With a median follow-up of almost 4 years, those who experienced a pathologic complete response (pCR) – meaning no detectable invasive disease in either the breast or axilla at surgery – were 62% less likely to have had events such as recurrences or second primaries, and 65% less likely to have died, she reported in a session and related press briefing.

The benefit of pCR was more pronounced among patients whose tumors were negative for hormone receptors than among their counterparts whose tumors were positive.

The new data should not change the standard of care, trastuzumab and chemotherapy, she cautioned. "But what this trial indicates to us is that it is possible that for this particular subgroup – hormone receptor–negative, HER2-positive – we could potentially use a neoadjuvant model to speed up approval of new agents. And that’s important because we know that adjuvant trials in breast cancer take forever and are very time- and money-consuming, and require thousands of patients."

Thus, the findings would lend support to the Food and Drug Administration’s use of pCR as the bar for accelerated approval of new drugs for this patient subgroup, she said.

Event-free and overall survival did not differ significantly according to the specific HER2 therapy received, although dual therapy tended to have an edge in patients with hormone receptor–negative tumors. However, the trial was not powered to detect moderate differences in these outcomes, according to Dr. Piccart-Gebhart.

"It is the very large ALTTO trial, with the recruitment of 8,300 women, that will provide a robust answer on the effect of dual HER2 blockade on long-term outcomes, and we expect to report these results at ASCO [American Society of Clinical Oncology] next year," she commented.

Analyses of NeoALTTO will be repeated after another 2.5 years, Dr. Piccart-Gebhart added. "It is possible that with longer follow-up, we will also see a bigger treatment effect in the hormone receptor–positive subgroup. But clearly, this trial provides further evidence that HER2-positive, hormone receptor–negative and HER2-positive, hormone receptor–positive groups are two different diseases."

Press briefing moderator Dr. Jennifer Litton of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, Houston, noted that pCR was used to gain initial approval of pertuzumab (Perjeta), another targeted therapy, in the neoadjuvant setting.

The reported data "in my opinion, show that it continues to be a very valid surrogate endpoint, and continues to [address the issue] of how we can develop new drugs, get them to patients quicker, with a smaller number of patients involved and less cost," she said.

Session attendee Dr. Steven E. Vogl, an oncologist in New York, asked whether pCR should be abandoned as a surrogate marker for the hormone receptor–positive subset. "It looks like the benefit of pCR was, at best, tiny in your study for those women, and probably we should think twice about using pCR in deciding which therapy is better – we should wait for event-free and overall survival. What do you think?"

Dr. Piccart-Gebhart replied that a meta-analysis of HER2 neoadjuvant therapy performed by the FDA with a much longer follow-up did find a benefit of pCR in the hormone receptor–positive subset. "It was less striking, but it was there. So I think that we have to be cautious because NeoALTTO is still a relatively small study.

"But I would tend to agree with you that the data look a lot stronger in the hormone receptor–negative subgroup, and there, based on the results I showed today, I feel confident that you could use the neoadjuvant model for accelerated approval of new drugs," she added. "For the hormone receptor–positive patients, I’m a little bit more cautious. I think these are slow actors. The events come later; you need a longer follow-up. And then of course the endocrine treatment is important and you give it after surgery in all these trials, which could be a mistake."

In the NeoALTTO study (also known as BIG 1-06), women with HER2-positive early breast cancer measuring at least 2 cm were randomly assigned to 18 weeks of neoadjuvant therapy with dual HER2 blockade using both lapatinib (Tykerb) and trastuzumab (Herceptin), or single HER2 blockade with one of the agents alone – each given along with paclitaxel.

After surgery, they received combination chemotherapy and then more of the same HER2 therapy out to 52 weeks, as well as hormonal therapy if indicated.

Initial results, previously reported, showed that the rate of pCR – the trial’s primary endpoint – was 24.7% with lapatinib alone, 29.5% with trastuzumab alone, and 51.3% with the combination, Dr. Piccart-Gebhart reported.

The new results showed that there were no significant differences between the treatment arms in the adjusted 3-year rates of event-free survival (78%, 76%, and 84%, respectively) or overall survival (93%, 90%, and 95%, respectively). But there was greater separation of the curves in the hormone receptor–negative subset, suggesting a possible treatment effect, according to Dr. Piccart-Gebhart.

In an analysis of all trial arms combined that used a starting point of 30 weeks after randomization, relative to patients who did not have a pCR, those who did were significantly less likely to have events (postoperative recurrence, second primary, or death, or progression in those who did not have surgery) (hazard ratio, 0.38; P = .0003) and to die (HR, 0.35; P = .005).

"There were no surprises" in terms of adverse events, she reported. "The adverse events were consistent with the known safety profiles of lapatinib and trastuzumab."

Over the entire study period, compared with trastuzumab alone, the combination of lapatinib plus trastuzumab led to higher rates of severe diarrhea, hepatobiliary adverse events, and rash, as well as a higher rate of cardiac events.

Dr. Piccart-Gebhart disclosed that she has received consulting fees from Roche, and her institution has received research funding from GlaxoSmithKline PLC and Roche. The trial was sponsored by GlaxoSmithKline.

SAN ANTONIO – Pathologic complete response is a strong prognostic factor in women with HER2-positive early breast cancer who receive neoadjuvant HER2-targeted therapy, investigators reported at the annual San Antonio Breast Cancer Symposium.

A team led by Dr. Martine Piccart-Gebhart, chair of the Breast International Group (BIG) in Brussels, analyzed data from 455 patients in the randomized NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, who received one or both HER2 therapies, along with chemotherapy.

With a median follow-up of almost 4 years, those who experienced a pathologic complete response (pCR) – meaning no detectable invasive disease in either the breast or axilla at surgery – were 62% less likely to have had events such as recurrences or second primaries, and 65% less likely to have died, she reported in a session and related press briefing.

The benefit of pCR was more pronounced among patients whose tumors were negative for hormone receptors than among their counterparts whose tumors were positive.

The new data should not change the standard of care, trastuzumab and chemotherapy, she cautioned. "But what this trial indicates to us is that it is possible that for this particular subgroup – hormone receptor–negative, HER2-positive – we could potentially use a neoadjuvant model to speed up approval of new agents. And that’s important because we know that adjuvant trials in breast cancer take forever and are very time- and money-consuming, and require thousands of patients."

Thus, the findings would lend support to the Food and Drug Administration’s use of pCR as the bar for accelerated approval of new drugs for this patient subgroup, she said.

Event-free and overall survival did not differ significantly according to the specific HER2 therapy received, although dual therapy tended to have an edge in patients with hormone receptor–negative tumors. However, the trial was not powered to detect moderate differences in these outcomes, according to Dr. Piccart-Gebhart.

"It is the very large ALTTO trial, with the recruitment of 8,300 women, that will provide a robust answer on the effect of dual HER2 blockade on long-term outcomes, and we expect to report these results at ASCO [American Society of Clinical Oncology] next year," she commented.

Analyses of NeoALTTO will be repeated after another 2.5 years, Dr. Piccart-Gebhart added. "It is possible that with longer follow-up, we will also see a bigger treatment effect in the hormone receptor–positive subgroup. But clearly, this trial provides further evidence that HER2-positive, hormone receptor–negative and HER2-positive, hormone receptor–positive groups are two different diseases."

Press briefing moderator Dr. Jennifer Litton of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, Houston, noted that pCR was used to gain initial approval of pertuzumab (Perjeta), another targeted therapy, in the neoadjuvant setting.

The reported data "in my opinion, show that it continues to be a very valid surrogate endpoint, and continues to [address the issue] of how we can develop new drugs, get them to patients quicker, with a smaller number of patients involved and less cost," she said.

Session attendee Dr. Steven E. Vogl, an oncologist in New York, asked whether pCR should be abandoned as a surrogate marker for the hormone receptor–positive subset. "It looks like the benefit of pCR was, at best, tiny in your study for those women, and probably we should think twice about using pCR in deciding which therapy is better – we should wait for event-free and overall survival. What do you think?"

Dr. Piccart-Gebhart replied that a meta-analysis of HER2 neoadjuvant therapy performed by the FDA with a much longer follow-up did find a benefit of pCR in the hormone receptor–positive subset. "It was less striking, but it was there. So I think that we have to be cautious because NeoALTTO is still a relatively small study.

"But I would tend to agree with you that the data look a lot stronger in the hormone receptor–negative subgroup, and there, based on the results I showed today, I feel confident that you could use the neoadjuvant model for accelerated approval of new drugs," she added. "For the hormone receptor–positive patients, I’m a little bit more cautious. I think these are slow actors. The events come later; you need a longer follow-up. And then of course the endocrine treatment is important and you give it after surgery in all these trials, which could be a mistake."

In the NeoALTTO study (also known as BIG 1-06), women with HER2-positive early breast cancer measuring at least 2 cm were randomly assigned to 18 weeks of neoadjuvant therapy with dual HER2 blockade using both lapatinib (Tykerb) and trastuzumab (Herceptin), or single HER2 blockade with one of the agents alone – each given along with paclitaxel.

After surgery, they received combination chemotherapy and then more of the same HER2 therapy out to 52 weeks, as well as hormonal therapy if indicated.

Initial results, previously reported, showed that the rate of pCR – the trial’s primary endpoint – was 24.7% with lapatinib alone, 29.5% with trastuzumab alone, and 51.3% with the combination, Dr. Piccart-Gebhart reported.

The new results showed that there were no significant differences between the treatment arms in the adjusted 3-year rates of event-free survival (78%, 76%, and 84%, respectively) or overall survival (93%, 90%, and 95%, respectively). But there was greater separation of the curves in the hormone receptor–negative subset, suggesting a possible treatment effect, according to Dr. Piccart-Gebhart.

In an analysis of all trial arms combined that used a starting point of 30 weeks after randomization, relative to patients who did not have a pCR, those who did were significantly less likely to have events (postoperative recurrence, second primary, or death, or progression in those who did not have surgery) (hazard ratio, 0.38; P = .0003) and to die (HR, 0.35; P = .005).

"There were no surprises" in terms of adverse events, she reported. "The adverse events were consistent with the known safety profiles of lapatinib and trastuzumab."

Over the entire study period, compared with trastuzumab alone, the combination of lapatinib plus trastuzumab led to higher rates of severe diarrhea, hepatobiliary adverse events, and rash, as well as a higher rate of cardiac events.

Dr. Piccart-Gebhart disclosed that she has received consulting fees from Roche, and her institution has received research funding from GlaxoSmithKline PLC and Roche. The trial was sponsored by GlaxoSmithKline.

SAN ANTONIO – Pathologic complete response is a strong prognostic factor in women with HER2-positive early breast cancer who receive neoadjuvant HER2-targeted therapy, investigators reported at the annual San Antonio Breast Cancer Symposium.

A team led by Dr. Martine Piccart-Gebhart, chair of the Breast International Group (BIG) in Brussels, analyzed data from 455 patients in the randomized NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, who received one or both HER2 therapies, along with chemotherapy.

With a median follow-up of almost 4 years, those who experienced a pathologic complete response (pCR) – meaning no detectable invasive disease in either the breast or axilla at surgery – were 62% less likely to have had events such as recurrences or second primaries, and 65% less likely to have died, she reported in a session and related press briefing.

The benefit of pCR was more pronounced among patients whose tumors were negative for hormone receptors than among their counterparts whose tumors were positive.

The new data should not change the standard of care, trastuzumab and chemotherapy, she cautioned. "But what this trial indicates to us is that it is possible that for this particular subgroup – hormone receptor–negative, HER2-positive – we could potentially use a neoadjuvant model to speed up approval of new agents. And that’s important because we know that adjuvant trials in breast cancer take forever and are very time- and money-consuming, and require thousands of patients."

Thus, the findings would lend support to the Food and Drug Administration’s use of pCR as the bar for accelerated approval of new drugs for this patient subgroup, she said.

Event-free and overall survival did not differ significantly according to the specific HER2 therapy received, although dual therapy tended to have an edge in patients with hormone receptor–negative tumors. However, the trial was not powered to detect moderate differences in these outcomes, according to Dr. Piccart-Gebhart.

"It is the very large ALTTO trial, with the recruitment of 8,300 women, that will provide a robust answer on the effect of dual HER2 blockade on long-term outcomes, and we expect to report these results at ASCO [American Society of Clinical Oncology] next year," she commented.

Analyses of NeoALTTO will be repeated after another 2.5 years, Dr. Piccart-Gebhart added. "It is possible that with longer follow-up, we will also see a bigger treatment effect in the hormone receptor–positive subgroup. But clearly, this trial provides further evidence that HER2-positive, hormone receptor–negative and HER2-positive, hormone receptor–positive groups are two different diseases."

Press briefing moderator Dr. Jennifer Litton of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, Houston, noted that pCR was used to gain initial approval of pertuzumab (Perjeta), another targeted therapy, in the neoadjuvant setting.

The reported data "in my opinion, show that it continues to be a very valid surrogate endpoint, and continues to [address the issue] of how we can develop new drugs, get them to patients quicker, with a smaller number of patients involved and less cost," she said.

Session attendee Dr. Steven E. Vogl, an oncologist in New York, asked whether pCR should be abandoned as a surrogate marker for the hormone receptor–positive subset. "It looks like the benefit of pCR was, at best, tiny in your study for those women, and probably we should think twice about using pCR in deciding which therapy is better – we should wait for event-free and overall survival. What do you think?"

Dr. Piccart-Gebhart replied that a meta-analysis of HER2 neoadjuvant therapy performed by the FDA with a much longer follow-up did find a benefit of pCR in the hormone receptor–positive subset. "It was less striking, but it was there. So I think that we have to be cautious because NeoALTTO is still a relatively small study.

"But I would tend to agree with you that the data look a lot stronger in the hormone receptor–negative subgroup, and there, based on the results I showed today, I feel confident that you could use the neoadjuvant model for accelerated approval of new drugs," she added. "For the hormone receptor–positive patients, I’m a little bit more cautious. I think these are slow actors. The events come later; you need a longer follow-up. And then of course the endocrine treatment is important and you give it after surgery in all these trials, which could be a mistake."

In the NeoALTTO study (also known as BIG 1-06), women with HER2-positive early breast cancer measuring at least 2 cm were randomly assigned to 18 weeks of neoadjuvant therapy with dual HER2 blockade using both lapatinib (Tykerb) and trastuzumab (Herceptin), or single HER2 blockade with one of the agents alone – each given along with paclitaxel.

After surgery, they received combination chemotherapy and then more of the same HER2 therapy out to 52 weeks, as well as hormonal therapy if indicated.

Initial results, previously reported, showed that the rate of pCR – the trial’s primary endpoint – was 24.7% with lapatinib alone, 29.5% with trastuzumab alone, and 51.3% with the combination, Dr. Piccart-Gebhart reported.

The new results showed that there were no significant differences between the treatment arms in the adjusted 3-year rates of event-free survival (78%, 76%, and 84%, respectively) or overall survival (93%, 90%, and 95%, respectively). But there was greater separation of the curves in the hormone receptor–negative subset, suggesting a possible treatment effect, according to Dr. Piccart-Gebhart.

In an analysis of all trial arms combined that used a starting point of 30 weeks after randomization, relative to patients who did not have a pCR, those who did were significantly less likely to have events (postoperative recurrence, second primary, or death, or progression in those who did not have surgery) (hazard ratio, 0.38; P = .0003) and to die (HR, 0.35; P = .005).

"There were no surprises" in terms of adverse events, she reported. "The adverse events were consistent with the known safety profiles of lapatinib and trastuzumab."

Over the entire study period, compared with trastuzumab alone, the combination of lapatinib plus trastuzumab led to higher rates of severe diarrhea, hepatobiliary adverse events, and rash, as well as a higher rate of cardiac events.

Dr. Piccart-Gebhart disclosed that she has received consulting fees from Roche, and her institution has received research funding from GlaxoSmithKline PLC and Roche. The trial was sponsored by GlaxoSmithKline.

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

WOODINVILLE, WASH. – The diagnosis of photocontact dermatitis can be challenging and often requires careful photopatch testing, according to Dr. Vincent A. DeLeo.

He reviewed the finer points of diagnosing the two main types of photocontact dermatitis – photoirritant and photoallergic – and differentiating them from other conditions with a similar clinical presentation at the annual Coastal Dermatology Symposium.

Photoirritant contact dermatitis

In photoirritant contact dermatitis, a chemical deposited on the skin absorbs radiation and then causes damage directly, without any immune reaction. The diagnosis is a clinical one, said Dr. DeLeo, chairman of the department of dermatology at St. Luke’s–Roosevelt Hospital Center and Beth Israel Medical Center in New York.

"You as a clinician know it is a photodistributed disease," he said. "You take a good history, you get a history of the patient being exposed topically to the chemical, and that’s how you make the diagnosis," he commented. "This is universal; it will happen to any of us if we get exposed to these photosensitizing chemicals in enough concentration and we get enough light to develop this kind of reaction."

Photos courtesy Dr. Vincent A. DeLeo

Photoirritant contact dermatitis is almost always induced by UVA radiation; therefore, it can occur even if a patient is wearing a sunscreen that protects against UVB light.

The reaction has the appearance of a sunburn, with erythema, edema, and possibly blistering. It usually resolves with hyperpigmentation. "The interesting thing is that a lot of these reactions are subclinical, at least the erythema component that you don’t see. All you do see is the resulting hyperpigmentation," he said at the meeting, presented by the Caribbean Dermatology Symposium.

A common culprit is tar, in which case the condition is known as tar smarts. These cases usually result from occupational exposure in roofers, but can be seen as well in people who use tar shampoos and then go out in the sun.

The furocoumarins (psoralens) also can produce photoirritant contact dermatitis. The most common form is phytophotodermatitis, which involves plant compounds, especially those in the exocorp (green peel) of limes. The hallmark is tiny blisters on involved skin.

"It’s a delayed reaction. So people are squeezing limes into their gin and tonics on the weekend, and then Monday or Tuesday, when they are back at work, all of a sudden they develop these blisters, and they don’t associate it with what they did on weekend," Dr. DeLeo noted.

Phytophotodermatitis also can result from contact with celery that has been bred to have a high psoralen content so that it stays fresh longer. "You see this in grocery workers primarily, people who are exposed to a lot of celery, handling it and then going into the sun and getting the reaction," Dr. DeLeo said.

Photoallergic contact dermatitis

In photoallergic contact dermatitis, the chemical deposited on the skin – most commonly a sunscreen, fragrance, or medication – absorbs radiation and becomes an allergen. Only sensitized people have a reaction.

This dermatitis is exematous and pruritic, and shows a sun-exposed distribution, although it is usually patchy. The reaction is delayed, typically starting 1-2 days after sun exposure.

"The photodistributed eruption will usually be in all photoexposed areas. And this is important in making the distinction between this and other photosensitivities," Dr. DeLeo said. "Usually it will occur on all areas including the face ... and usually it spares upper lids and beneath the chin, although not always," he noted.

"The diagnosis of photoallergic contact dermatitis is confirmed by photopatch testing," he said. "Almost all photosensitive patients with eczematous morphology should be photopatch tested."

However, survey data suggest that only about two-thirds of dermatologists do this testing (Am. J. Contact Dermat. 2003;14:5-11), largely because this dermatitis is uncommon today as most sensitizing agents are identified before products come to market.

Photopatch testing can be done in the office; it requires at least a UVA source, photoantigens, and general patch test supplies. A UVB source is helpful for distinguishing photoallergic contact dermatitis from conditions such as chronic actinic dermatitis.

"If I were to buy four photoantigens, I would probably buy oxybenzone, musk ambrette, padimate O, and avobenzone," Dr. DeLeo said. "You can also test directly to the patient’s products, and usually it’s going to be sunscreens, so you can just have them bring in whatever they are using."

In a study by the North American Contact Dermatitis Group in which 363 consecutive patients with a history of photosensitivity were given a final diagnosis after photopatch testing, the leading diagnosis was allergic contact dermatitis (122 patients), followed by photoallergic contact dermatitis (75 patients) and polymorphous light eruption (72 patients).

The most common photoallergen was oxybenzone. Others included ketoprofen, avobenzone, sulisobenzone, and musk ambrette.

"In the Northwest, mainly in Washington and Oregon, people are compounding ketoprofen, which is a nonsteroidal anti-inflammatory agent, into a topical agent ... that can induce a photoallergic contact dermatitis," Dr. DeLeo explained.

Newer photoallergens include the sunscreen methylene bis-benzotriazolyl tetramethylbutylphenol (bisoctrizole, brand name Tinosorb M) (Dermatitis 2011;22:106-11).

"This [product] is not available in the U.S., but is available in Europe," Dr. DeLeo noted. However, reactions have been seen among patients using Ahava, an Israeli product sold in the United States. The manufacturers "are apparently saying they are not using it as a sunscreen but as a sort of preservative. So you need to watch out for this one," he said.

In fact, the Food and Drug Administration is considering approval of several new sunscreens, and bisoctrizole is among them, so more cases may be seen, according to Dr. DeLeo.

Another emerging photoallergen is the sunscreen octocrylene. "We haven’t seen any positives to this as yet, but it is being reported in Europe as a very important new photoallergic agent. It may be that they are using a lot more of that as a photostabilizer for avobenzone in Europe than we do in our own cosmetics," he said.

Importantly, there is cross-reactivity among oxybenzone, octocrylene, and ketoprofen, said Dr. DeLeo. Therefore, "those of you who live in the Northwest and see this reaction to ketoprofen may want your patients to avoid oxybenzone and octocrylene as well," he added.

Dr. DeLeo disclosed that he is a consultant for Pfizer, Prous Science, L’Oréal, Limited Brands, Goodyear, Estée Lauder, Mary Kay, and La Roche-Posay.

WOODINVILLE, WASH. – The diagnosis of photocontact dermatitis can be challenging and often requires careful photopatch testing, according to Dr. Vincent A. DeLeo.

He reviewed the finer points of diagnosing the two main types of photocontact dermatitis – photoirritant and photoallergic – and differentiating them from other conditions with a similar clinical presentation at the annual Coastal Dermatology Symposium.

Photoirritant contact dermatitis

In photoirritant contact dermatitis, a chemical deposited on the skin absorbs radiation and then causes damage directly, without any immune reaction. The diagnosis is a clinical one, said Dr. DeLeo, chairman of the department of dermatology at St. Luke’s–Roosevelt Hospital Center and Beth Israel Medical Center in New York.

"You as a clinician know it is a photodistributed disease," he said. "You take a good history, you get a history of the patient being exposed topically to the chemical, and that’s how you make the diagnosis," he commented. "This is universal; it will happen to any of us if we get exposed to these photosensitizing chemicals in enough concentration and we get enough light to develop this kind of reaction."

Photos courtesy Dr. Vincent A. DeLeo

Photoirritant contact dermatitis is almost always induced by UVA radiation; therefore, it can occur even if a patient is wearing a sunscreen that protects against UVB light.

The reaction has the appearance of a sunburn, with erythema, edema, and possibly blistering. It usually resolves with hyperpigmentation. "The interesting thing is that a lot of these reactions are subclinical, at least the erythema component that you don’t see. All you do see is the resulting hyperpigmentation," he said at the meeting, presented by the Caribbean Dermatology Symposium.

A common culprit is tar, in which case the condition is known as tar smarts. These cases usually result from occupational exposure in roofers, but can be seen as well in people who use tar shampoos and then go out in the sun.

The furocoumarins (psoralens) also can produce photoirritant contact dermatitis. The most common form is phytophotodermatitis, which involves plant compounds, especially those in the exocorp (green peel) of limes. The hallmark is tiny blisters on involved skin.

"It’s a delayed reaction. So people are squeezing limes into their gin and tonics on the weekend, and then Monday or Tuesday, when they are back at work, all of a sudden they develop these blisters, and they don’t associate it with what they did on weekend," Dr. DeLeo noted.

Phytophotodermatitis also can result from contact with celery that has been bred to have a high psoralen content so that it stays fresh longer. "You see this in grocery workers primarily, people who are exposed to a lot of celery, handling it and then going into the sun and getting the reaction," Dr. DeLeo said.

Photoallergic contact dermatitis

In photoallergic contact dermatitis, the chemical deposited on the skin – most commonly a sunscreen, fragrance, or medication – absorbs radiation and becomes an allergen. Only sensitized people have a reaction.

This dermatitis is exematous and pruritic, and shows a sun-exposed distribution, although it is usually patchy. The reaction is delayed, typically starting 1-2 days after sun exposure.

"The photodistributed eruption will usually be in all photoexposed areas. And this is important in making the distinction between this and other photosensitivities," Dr. DeLeo said. "Usually it will occur on all areas including the face ... and usually it spares upper lids and beneath the chin, although not always," he noted.

"The diagnosis of photoallergic contact dermatitis is confirmed by photopatch testing," he said. "Almost all photosensitive patients with eczematous morphology should be photopatch tested."

However, survey data suggest that only about two-thirds of dermatologists do this testing (Am. J. Contact Dermat. 2003;14:5-11), largely because this dermatitis is uncommon today as most sensitizing agents are identified before products come to market.

Photopatch testing can be done in the office; it requires at least a UVA source, photoantigens, and general patch test supplies. A UVB source is helpful for distinguishing photoallergic contact dermatitis from conditions such as chronic actinic dermatitis.

"If I were to buy four photoantigens, I would probably buy oxybenzone, musk ambrette, padimate O, and avobenzone," Dr. DeLeo said. "You can also test directly to the patient’s products, and usually it’s going to be sunscreens, so you can just have them bring in whatever they are using."

In a study by the North American Contact Dermatitis Group in which 363 consecutive patients with a history of photosensitivity were given a final diagnosis after photopatch testing, the leading diagnosis was allergic contact dermatitis (122 patients), followed by photoallergic contact dermatitis (75 patients) and polymorphous light eruption (72 patients).

The most common photoallergen was oxybenzone. Others included ketoprofen, avobenzone, sulisobenzone, and musk ambrette.

"In the Northwest, mainly in Washington and Oregon, people are compounding ketoprofen, which is a nonsteroidal anti-inflammatory agent, into a topical agent ... that can induce a photoallergic contact dermatitis," Dr. DeLeo explained.

Newer photoallergens include the sunscreen methylene bis-benzotriazolyl tetramethylbutylphenol (bisoctrizole, brand name Tinosorb M) (Dermatitis 2011;22:106-11).

"This [product] is not available in the U.S., but is available in Europe," Dr. DeLeo noted. However, reactions have been seen among patients using Ahava, an Israeli product sold in the United States. The manufacturers "are apparently saying they are not using it as a sunscreen but as a sort of preservative. So you need to watch out for this one," he said.

In fact, the Food and Drug Administration is considering approval of several new sunscreens, and bisoctrizole is among them, so more cases may be seen, according to Dr. DeLeo.

Another emerging photoallergen is the sunscreen octocrylene. "We haven’t seen any positives to this as yet, but it is being reported in Europe as a very important new photoallergic agent. It may be that they are using a lot more of that as a photostabilizer for avobenzone in Europe than we do in our own cosmetics," he said.

Importantly, there is cross-reactivity among oxybenzone, octocrylene, and ketoprofen, said Dr. DeLeo. Therefore, "those of you who live in the Northwest and see this reaction to ketoprofen may want your patients to avoid oxybenzone and octocrylene as well," he added.

Dr. DeLeo disclosed that he is a consultant for Pfizer, Prous Science, L’Oréal, Limited Brands, Goodyear, Estée Lauder, Mary Kay, and La Roche-Posay.

WOODINVILLE, WASH. – The diagnosis of photocontact dermatitis can be challenging and often requires careful photopatch testing, according to Dr. Vincent A. DeLeo.

He reviewed the finer points of diagnosing the two main types of photocontact dermatitis – photoirritant and photoallergic – and differentiating them from other conditions with a similar clinical presentation at the annual Coastal Dermatology Symposium.

Photoirritant contact dermatitis

In photoirritant contact dermatitis, a chemical deposited on the skin absorbs radiation and then causes damage directly, without any immune reaction. The diagnosis is a clinical one, said Dr. DeLeo, chairman of the department of dermatology at St. Luke’s–Roosevelt Hospital Center and Beth Israel Medical Center in New York.

"You as a clinician know it is a photodistributed disease," he said. "You take a good history, you get a history of the patient being exposed topically to the chemical, and that’s how you make the diagnosis," he commented. "This is universal; it will happen to any of us if we get exposed to these photosensitizing chemicals in enough concentration and we get enough light to develop this kind of reaction."

Photos courtesy Dr. Vincent A. DeLeo

Photoirritant contact dermatitis is almost always induced by UVA radiation; therefore, it can occur even if a patient is wearing a sunscreen that protects against UVB light.

The reaction has the appearance of a sunburn, with erythema, edema, and possibly blistering. It usually resolves with hyperpigmentation. "The interesting thing is that a lot of these reactions are subclinical, at least the erythema component that you don’t see. All you do see is the resulting hyperpigmentation," he said at the meeting, presented by the Caribbean Dermatology Symposium.

A common culprit is tar, in which case the condition is known as tar smarts. These cases usually result from occupational exposure in roofers, but can be seen as well in people who use tar shampoos and then go out in the sun.

The furocoumarins (psoralens) also can produce photoirritant contact dermatitis. The most common form is phytophotodermatitis, which involves plant compounds, especially those in the exocorp (green peel) of limes. The hallmark is tiny blisters on involved skin.

"It’s a delayed reaction. So people are squeezing limes into their gin and tonics on the weekend, and then Monday or Tuesday, when they are back at work, all of a sudden they develop these blisters, and they don’t associate it with what they did on weekend," Dr. DeLeo noted.

Phytophotodermatitis also can result from contact with celery that has been bred to have a high psoralen content so that it stays fresh longer. "You see this in grocery workers primarily, people who are exposed to a lot of celery, handling it and then going into the sun and getting the reaction," Dr. DeLeo said.

Photoallergic contact dermatitis

In photoallergic contact dermatitis, the chemical deposited on the skin – most commonly a sunscreen, fragrance, or medication – absorbs radiation and becomes an allergen. Only sensitized people have a reaction.

This dermatitis is exematous and pruritic, and shows a sun-exposed distribution, although it is usually patchy. The reaction is delayed, typically starting 1-2 days after sun exposure.

"The photodistributed eruption will usually be in all photoexposed areas. And this is important in making the distinction between this and other photosensitivities," Dr. DeLeo said. "Usually it will occur on all areas including the face ... and usually it spares upper lids and beneath the chin, although not always," he noted.

"The diagnosis of photoallergic contact dermatitis is confirmed by photopatch testing," he said. "Almost all photosensitive patients with eczematous morphology should be photopatch tested."

However, survey data suggest that only about two-thirds of dermatologists do this testing (Am. J. Contact Dermat. 2003;14:5-11), largely because this dermatitis is uncommon today as most sensitizing agents are identified before products come to market.

Photopatch testing can be done in the office; it requires at least a UVA source, photoantigens, and general patch test supplies. A UVB source is helpful for distinguishing photoallergic contact dermatitis from conditions such as chronic actinic dermatitis.

"If I were to buy four photoantigens, I would probably buy oxybenzone, musk ambrette, padimate O, and avobenzone," Dr. DeLeo said. "You can also test directly to the patient’s products, and usually it’s going to be sunscreens, so you can just have them bring in whatever they are using."

In a study by the North American Contact Dermatitis Group in which 363 consecutive patients with a history of photosensitivity were given a final diagnosis after photopatch testing, the leading diagnosis was allergic contact dermatitis (122 patients), followed by photoallergic contact dermatitis (75 patients) and polymorphous light eruption (72 patients).

The most common photoallergen was oxybenzone. Others included ketoprofen, avobenzone, sulisobenzone, and musk ambrette.

"In the Northwest, mainly in Washington and Oregon, people are compounding ketoprofen, which is a nonsteroidal anti-inflammatory agent, into a topical agent ... that can induce a photoallergic contact dermatitis," Dr. DeLeo explained.

Newer photoallergens include the sunscreen methylene bis-benzotriazolyl tetramethylbutylphenol (bisoctrizole, brand name Tinosorb M) (Dermatitis 2011;22:106-11).

"This [product] is not available in the U.S., but is available in Europe," Dr. DeLeo noted. However, reactions have been seen among patients using Ahava, an Israeli product sold in the United States. The manufacturers "are apparently saying they are not using it as a sunscreen but as a sort of preservative. So you need to watch out for this one," he said.

In fact, the Food and Drug Administration is considering approval of several new sunscreens, and bisoctrizole is among them, so more cases may be seen, according to Dr. DeLeo.

Another emerging photoallergen is the sunscreen octocrylene. "We haven’t seen any positives to this as yet, but it is being reported in Europe as a very important new photoallergic agent. It may be that they are using a lot more of that as a photostabilizer for avobenzone in Europe than we do in our own cosmetics," he said.

Importantly, there is cross-reactivity among oxybenzone, octocrylene, and ketoprofen, said Dr. DeLeo. Therefore, "those of you who live in the Northwest and see this reaction to ketoprofen may want your patients to avoid oxybenzone and octocrylene as well," he added.

Dr. DeLeo disclosed that he is a consultant for Pfizer, Prous Science, L’Oréal, Limited Brands, Goodyear, Estée Lauder, Mary Kay, and La Roche-Posay.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.