2012 ASCO Annual Meeting

CHICAGO – Maintenance erlotinib was no more efficacious than observation when given to women with ovarian or related cancers who had no evidence of progression after receiving first-line platinum-based chemotherapy.

The 835 women studied in a randomized, phase III trial had a median progression-free survival of about 1 year and an overall survival median of about 4.5 years regardless of whether they were assigned to erlotinib – an oral inhibitor of the EGFR (epidermal growth factor receptor) tyrosine kinase – or simple observation.

The findings were similar in patient subgroups who were stratified according to a wide range of factors, such as stage and (in preliminary analyses) tumor EGFR positivity, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Maintenance erlotinib after first-line chemotherapy in patients with ovarian, peritoneal, or fallopian tube cancer did not increase progression-free survival nor overall survival," said lead investigator Dr. Ignace B. Vergote. Moreover, a quarter of patients stopped the drug early because of adverse effects.

"At this moment, we cannot identify a subgroup that might benefit from erlotinib maintenance therapy after first-line chemotherapy for ovarian cancer, but we are continuing to look at immunohistochemistry and FISH [fluorescence in situ hybridization] analysis," added Dr. Vergote, chairman of the Leuven (Belgium) Cancer Institute and head of the department of obstetrics and gynecology and gynecologic oncology at the Catholic University of Leuven.

Discussant Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia noted that there was "a compelling body of basic and preclinical evidence that made the advent or launch of this study very logical." For example, research had shown a correlation between high tumor EGFR levels and poor prognosis in ovarian cancer, as well as an association– in various cancers – of EGFR mutations or expression with response to therapies targeting this receptor.

"Unfortunately, the addition of erlotinib as part of a maintenance schedule did not budge progression-free survival or overall survival," he said. "Perhaps now, in 2012, with the value of ... hindsight, one might have made this prediction, in that there have been now numerous negative single-arm studies or nearly negative single-arm studies with both small-molecule inhibitors and monoclonal antibodies" against EGFR.

Women enrolled in the EORTC (European Organisation for Research and Treatment of Cancer) 55041 trial – a joint effort of six cooperative groups – had high-risk stage I, or stages II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and at least stable disease as of the end of first-line platinum-based chemotherapy.

They were assigned to either erlotinib (Tarceva) 150 mg daily for 2 years or observation. Erlotinib is currently approved by the Food and Drug Administration for the treatment of non–small cell lung cancer and pancreatic cancer.

Demographic and clinical data showed that about 62% of patients had serous tumor histology. Nearly all (96%) had received carboplatin and paclitaxel as their first-line therapy. Roughly 70% had had primary debulking surgery, whereas 30% had received neoadjuvant therapy and interval debulking surgery; there was no evidence of disease at surgery in 48% of the former and 62% of the latter.

Overall, 25% of patients in the erlotinib group stopped therapy early because of unacceptable adverse events (mainly rash), Dr. Vergote reported.

Main results showed that with a median follow-up of 4.3 years, erlotinib and observation were statistically indistinguishable in terms of median progression-free survival (12.7 vs. 12.4 months), with progression defined according to RECIST criteria or CA (cancer antigen) 125 levels, and overall survival (51 vs. 59 months). The findings were similar in subgroups stratified by stage, age, performance status, and response at the end of first-line chemotherapy.

Patients in the erlotinib group were more likely to experience grade 3/4 diarrhea (5% vs. 1%) and rash (13% vs. 0%).

Preliminary tumor mutational analysis in 318 patients showed that the most common was PI3KCA mutation (present in about 4% of cases), followed by KRAS mutation (present in about 3%). Only about 1% had an EGFR mutation, and mutations of NRAS and BRAF were similarly uncommon.

Progression-free survival was better for patients having any of these mutations than for those having none (P = .04). But among the former, there was no significant benefit of erlotinib over observation.

Progression-free survival was also similar across subgroups of patients whose tumors were EGFR positive and negative according to either immunohistochemistry or FISH.

Analyses failed to identify any significant relationship between the development of rash during erlotinib therapy and progression-free survival. The investigators plan to analyze quality of life data.

Dr. Vergote disclosed no relevant conflicts of interest. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Maintenance erlotinib was no more efficacious than observation when given to women with ovarian or related cancers who had no evidence of progression after receiving first-line platinum-based chemotherapy.

The 835 women studied in a randomized, phase III trial had a median progression-free survival of about 1 year and an overall survival median of about 4.5 years regardless of whether they were assigned to erlotinib – an oral inhibitor of the EGFR (epidermal growth factor receptor) tyrosine kinase – or simple observation.

The findings were similar in patient subgroups who were stratified according to a wide range of factors, such as stage and (in preliminary analyses) tumor EGFR positivity, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Maintenance erlotinib after first-line chemotherapy in patients with ovarian, peritoneal, or fallopian tube cancer did not increase progression-free survival nor overall survival," said lead investigator Dr. Ignace B. Vergote. Moreover, a quarter of patients stopped the drug early because of adverse effects.

"At this moment, we cannot identify a subgroup that might benefit from erlotinib maintenance therapy after first-line chemotherapy for ovarian cancer, but we are continuing to look at immunohistochemistry and FISH [fluorescence in situ hybridization] analysis," added Dr. Vergote, chairman of the Leuven (Belgium) Cancer Institute and head of the department of obstetrics and gynecology and gynecologic oncology at the Catholic University of Leuven.

Discussant Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia noted that there was "a compelling body of basic and preclinical evidence that made the advent or launch of this study very logical." For example, research had shown a correlation between high tumor EGFR levels and poor prognosis in ovarian cancer, as well as an association– in various cancers – of EGFR mutations or expression with response to therapies targeting this receptor.

"Unfortunately, the addition of erlotinib as part of a maintenance schedule did not budge progression-free survival or overall survival," he said. "Perhaps now, in 2012, with the value of ... hindsight, one might have made this prediction, in that there have been now numerous negative single-arm studies or nearly negative single-arm studies with both small-molecule inhibitors and monoclonal antibodies" against EGFR.

Women enrolled in the EORTC (European Organisation for Research and Treatment of Cancer) 55041 trial – a joint effort of six cooperative groups – had high-risk stage I, or stages II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and at least stable disease as of the end of first-line platinum-based chemotherapy.

They were assigned to either erlotinib (Tarceva) 150 mg daily for 2 years or observation. Erlotinib is currently approved by the Food and Drug Administration for the treatment of non–small cell lung cancer and pancreatic cancer.

Demographic and clinical data showed that about 62% of patients had serous tumor histology. Nearly all (96%) had received carboplatin and paclitaxel as their first-line therapy. Roughly 70% had had primary debulking surgery, whereas 30% had received neoadjuvant therapy and interval debulking surgery; there was no evidence of disease at surgery in 48% of the former and 62% of the latter.

Overall, 25% of patients in the erlotinib group stopped therapy early because of unacceptable adverse events (mainly rash), Dr. Vergote reported.

Main results showed that with a median follow-up of 4.3 years, erlotinib and observation were statistically indistinguishable in terms of median progression-free survival (12.7 vs. 12.4 months), with progression defined according to RECIST criteria or CA (cancer antigen) 125 levels, and overall survival (51 vs. 59 months). The findings were similar in subgroups stratified by stage, age, performance status, and response at the end of first-line chemotherapy.

Patients in the erlotinib group were more likely to experience grade 3/4 diarrhea (5% vs. 1%) and rash (13% vs. 0%).

Preliminary tumor mutational analysis in 318 patients showed that the most common was PI3KCA mutation (present in about 4% of cases), followed by KRAS mutation (present in about 3%). Only about 1% had an EGFR mutation, and mutations of NRAS and BRAF were similarly uncommon.

Progression-free survival was better for patients having any of these mutations than for those having none (P = .04). But among the former, there was no significant benefit of erlotinib over observation.

Progression-free survival was also similar across subgroups of patients whose tumors were EGFR positive and negative according to either immunohistochemistry or FISH.

Analyses failed to identify any significant relationship between the development of rash during erlotinib therapy and progression-free survival. The investigators plan to analyze quality of life data.

Dr. Vergote disclosed no relevant conflicts of interest. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Maintenance erlotinib was no more efficacious than observation when given to women with ovarian or related cancers who had no evidence of progression after receiving first-line platinum-based chemotherapy.

The 835 women studied in a randomized, phase III trial had a median progression-free survival of about 1 year and an overall survival median of about 4.5 years regardless of whether they were assigned to erlotinib – an oral inhibitor of the EGFR (epidermal growth factor receptor) tyrosine kinase – or simple observation.

The findings were similar in patient subgroups who were stratified according to a wide range of factors, such as stage and (in preliminary analyses) tumor EGFR positivity, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"Maintenance erlotinib after first-line chemotherapy in patients with ovarian, peritoneal, or fallopian tube cancer did not increase progression-free survival nor overall survival," said lead investigator Dr. Ignace B. Vergote. Moreover, a quarter of patients stopped the drug early because of adverse effects.

"At this moment, we cannot identify a subgroup that might benefit from erlotinib maintenance therapy after first-line chemotherapy for ovarian cancer, but we are continuing to look at immunohistochemistry and FISH [fluorescence in situ hybridization] analysis," added Dr. Vergote, chairman of the Leuven (Belgium) Cancer Institute and head of the department of obstetrics and gynecology and gynecologic oncology at the Catholic University of Leuven.

Discussant Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia noted that there was "a compelling body of basic and preclinical evidence that made the advent or launch of this study very logical." For example, research had shown a correlation between high tumor EGFR levels and poor prognosis in ovarian cancer, as well as an association– in various cancers – of EGFR mutations or expression with response to therapies targeting this receptor.

"Unfortunately, the addition of erlotinib as part of a maintenance schedule did not budge progression-free survival or overall survival," he said. "Perhaps now, in 2012, with the value of ... hindsight, one might have made this prediction, in that there have been now numerous negative single-arm studies or nearly negative single-arm studies with both small-molecule inhibitors and monoclonal antibodies" against EGFR.

Women enrolled in the EORTC (European Organisation for Research and Treatment of Cancer) 55041 trial – a joint effort of six cooperative groups – had high-risk stage I, or stages II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and at least stable disease as of the end of first-line platinum-based chemotherapy.

They were assigned to either erlotinib (Tarceva) 150 mg daily for 2 years or observation. Erlotinib is currently approved by the Food and Drug Administration for the treatment of non–small cell lung cancer and pancreatic cancer.

Demographic and clinical data showed that about 62% of patients had serous tumor histology. Nearly all (96%) had received carboplatin and paclitaxel as their first-line therapy. Roughly 70% had had primary debulking surgery, whereas 30% had received neoadjuvant therapy and interval debulking surgery; there was no evidence of disease at surgery in 48% of the former and 62% of the latter.

Overall, 25% of patients in the erlotinib group stopped therapy early because of unacceptable adverse events (mainly rash), Dr. Vergote reported.

Main results showed that with a median follow-up of 4.3 years, erlotinib and observation were statistically indistinguishable in terms of median progression-free survival (12.7 vs. 12.4 months), with progression defined according to RECIST criteria or CA (cancer antigen) 125 levels, and overall survival (51 vs. 59 months). The findings were similar in subgroups stratified by stage, age, performance status, and response at the end of first-line chemotherapy.

Patients in the erlotinib group were more likely to experience grade 3/4 diarrhea (5% vs. 1%) and rash (13% vs. 0%).

Preliminary tumor mutational analysis in 318 patients showed that the most common was PI3KCA mutation (present in about 4% of cases), followed by KRAS mutation (present in about 3%). Only about 1% had an EGFR mutation, and mutations of NRAS and BRAF were similarly uncommon.

Progression-free survival was better for patients having any of these mutations than for those having none (P = .04). But among the former, there was no significant benefit of erlotinib over observation.

Progression-free survival was also similar across subgroups of patients whose tumors were EGFR positive and negative according to either immunohistochemistry or FISH.

Analyses failed to identify any significant relationship between the development of rash during erlotinib therapy and progression-free survival. The investigators plan to analyze quality of life data.

Dr. Vergote disclosed no relevant conflicts of interest. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.

CHICAGO – The investigational multikinase inhibitor regorafenib continues to produce small but significant improvements in progression-free survival along with a trend toward better overall survival of metastatic colorectal cancer bearing KRAS mutations.

Among patients with wild-type KRAS in the phase III, randomized CORRECT trial, progression-free survival was 2.0 months with regorafenib and best supportive care, compared with 1.8 months with placebo (hazard ratio, 0.475; 95% confidence interval, 0.362-0.623), Dr. Eric Van Cutsem reported at the annual meeting of the American Society of Clinical Oncology.

The respective medians were 1.9 and 1.7 months (HR, 0.525; 95% CI, 0.425-0.649) among patients with KRAS mutations conferring resistance to EGFR (epidermal growth factor receptor) inhibitors, said Dr. Van Cutsem, a professor of gastrointestinal oncology at University Hospital Leuven (Belgium) in Gasthuisberg.

Likewise, the median overall survival favored regorafenib in patients with wild-type KRAS, reaching 7.3 months in the experimental arm vs. 5.0 months among similar patients assigned to placebo (HR, 0.653; 95% CI 0.476-0.895). Among patients with KRAS mutations, the respective medians were 6.2 and 5.1 months (HR, 0.867; 95% CI, 0.670-1.123).

"Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups.

"Side effects are manageable in this patient population, and therefore it’s fair to conclude that regorafenib is a new potential standard of care for patients with chemorefractory metastatic colorectal cancer," Dr. Van Cutsem said.

Bayer Healthcare announced that it has applied in Europe and the United States for approval of regorafenib for patients with metastatic colorectal cancer based on these results. The company said at the end of June that the Food and Drug Administration granted priority review, which would require a decision in 6 months.

The CORRECT (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) trial randomized 760 patients: 505 to regorafenib plus best supportive care, and 255 to placebo plus best supportive care. More than half had KRAS mutations; nearly half had metastatic disease.

Investigators reported the primary and secondary end points of the study at a symposium on gastrointestinal cancers sponsored by ASCO in January 2012.

Regorafenib added a median benefit of just 1.4 months, compared with placebo plus best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn., said at that meeting. Although the added time was short, he noted, all participants were running out of options after the failure of standard therapies, including bevacizumab (Avastin) and EGFR inhibitors.

In the new presentation at the ASCO annual meeting, Dr. Van Cutsem reiterated those data and gave updated information on response rates and prespecified subgroup analyses.

There were no complete responses for patients on either the active drug or placebo, and only 1% of the 505 patients on regorafenib had a partial response, compared with 0.4% of 255 patients on placebo.

More patients on regorafenib had stable disease (42.8% vs. 14.5%), and fewer progressed while on the drug (49.5% vs. 80.0%). The disease control rate (defined as partial responses and stable disease combined at least 6 weeks after randomization) was significantly better for regorafenib (P less than .000001), Dr. Van Cutsem noted.

Regorafenib was superior to placebo in overall survival among men and women, patients younger than 65 years, those with baseline ECOG (Eastern Cooperative Oncology Group) performance status scores of 0 or 1, and patients with the primary disease site in the colon.

The most frequent grade 3 adverse events with regorafenib were hand-foot skin reactions, fatigue, diarrhea, hypertension, and rash. Drug-related deaths occurred in 1% of patients on regorafenib, compared with none in patients on placebo.

Speaking about the overall trial results, the invited discussant Dr. Chris Garrett of the University of Texas M.D. Anderson Cancer Center in Houston said, "I think [regorafenib] should be an option for patients with chemotherapy-refractory metastatic colorectal cancer who have a good performance status. However, patients should be made aware of the toxicities that may come with it. In the future, hopefully, biomarker studies will help us optimize which patients get the most benefit from this therapy."

The CORRECT trial was sponsored by Bayer HealthCare AG in Leverkusen, Germany. Dr. Van Cutsem has received research funding from the company. Dr. Garrett reported having no relevant financial disclosures.

CHICAGO – The investigational multikinase inhibitor regorafenib continues to produce small but significant improvements in progression-free survival along with a trend toward better overall survival of metastatic colorectal cancer bearing KRAS mutations.

Among patients with wild-type KRAS in the phase III, randomized CORRECT trial, progression-free survival was 2.0 months with regorafenib and best supportive care, compared with 1.8 months with placebo (hazard ratio, 0.475; 95% confidence interval, 0.362-0.623), Dr. Eric Van Cutsem reported at the annual meeting of the American Society of Clinical Oncology.

The respective medians were 1.9 and 1.7 months (HR, 0.525; 95% CI, 0.425-0.649) among patients with KRAS mutations conferring resistance to EGFR (epidermal growth factor receptor) inhibitors, said Dr. Van Cutsem, a professor of gastrointestinal oncology at University Hospital Leuven (Belgium) in Gasthuisberg.

Likewise, the median overall survival favored regorafenib in patients with wild-type KRAS, reaching 7.3 months in the experimental arm vs. 5.0 months among similar patients assigned to placebo (HR, 0.653; 95% CI 0.476-0.895). Among patients with KRAS mutations, the respective medians were 6.2 and 5.1 months (HR, 0.867; 95% CI, 0.670-1.123).

"Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups.

"Side effects are manageable in this patient population, and therefore it’s fair to conclude that regorafenib is a new potential standard of care for patients with chemorefractory metastatic colorectal cancer," Dr. Van Cutsem said.

Bayer Healthcare announced that it has applied in Europe and the United States for approval of regorafenib for patients with metastatic colorectal cancer based on these results. The company said at the end of June that the Food and Drug Administration granted priority review, which would require a decision in 6 months.

The CORRECT (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) trial randomized 760 patients: 505 to regorafenib plus best supportive care, and 255 to placebo plus best supportive care. More than half had KRAS mutations; nearly half had metastatic disease.

Investigators reported the primary and secondary end points of the study at a symposium on gastrointestinal cancers sponsored by ASCO in January 2012.

Regorafenib added a median benefit of just 1.4 months, compared with placebo plus best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn., said at that meeting. Although the added time was short, he noted, all participants were running out of options after the failure of standard therapies, including bevacizumab (Avastin) and EGFR inhibitors.

In the new presentation at the ASCO annual meeting, Dr. Van Cutsem reiterated those data and gave updated information on response rates and prespecified subgroup analyses.

There were no complete responses for patients on either the active drug or placebo, and only 1% of the 505 patients on regorafenib had a partial response, compared with 0.4% of 255 patients on placebo.

More patients on regorafenib had stable disease (42.8% vs. 14.5%), and fewer progressed while on the drug (49.5% vs. 80.0%). The disease control rate (defined as partial responses and stable disease combined at least 6 weeks after randomization) was significantly better for regorafenib (P less than .000001), Dr. Van Cutsem noted.

Regorafenib was superior to placebo in overall survival among men and women, patients younger than 65 years, those with baseline ECOG (Eastern Cooperative Oncology Group) performance status scores of 0 or 1, and patients with the primary disease site in the colon.

The most frequent grade 3 adverse events with regorafenib were hand-foot skin reactions, fatigue, diarrhea, hypertension, and rash. Drug-related deaths occurred in 1% of patients on regorafenib, compared with none in patients on placebo.

Speaking about the overall trial results, the invited discussant Dr. Chris Garrett of the University of Texas M.D. Anderson Cancer Center in Houston said, "I think [regorafenib] should be an option for patients with chemotherapy-refractory metastatic colorectal cancer who have a good performance status. However, patients should be made aware of the toxicities that may come with it. In the future, hopefully, biomarker studies will help us optimize which patients get the most benefit from this therapy."

The CORRECT trial was sponsored by Bayer HealthCare AG in Leverkusen, Germany. Dr. Van Cutsem has received research funding from the company. Dr. Garrett reported having no relevant financial disclosures.

CHICAGO – The investigational multikinase inhibitor regorafenib continues to produce small but significant improvements in progression-free survival along with a trend toward better overall survival of metastatic colorectal cancer bearing KRAS mutations.

Among patients with wild-type KRAS in the phase III, randomized CORRECT trial, progression-free survival was 2.0 months with regorafenib and best supportive care, compared with 1.8 months with placebo (hazard ratio, 0.475; 95% confidence interval, 0.362-0.623), Dr. Eric Van Cutsem reported at the annual meeting of the American Society of Clinical Oncology.

The respective medians were 1.9 and 1.7 months (HR, 0.525; 95% CI, 0.425-0.649) among patients with KRAS mutations conferring resistance to EGFR (epidermal growth factor receptor) inhibitors, said Dr. Van Cutsem, a professor of gastrointestinal oncology at University Hospital Leuven (Belgium) in Gasthuisberg.

Likewise, the median overall survival favored regorafenib in patients with wild-type KRAS, reaching 7.3 months in the experimental arm vs. 5.0 months among similar patients assigned to placebo (HR, 0.653; 95% CI 0.476-0.895). Among patients with KRAS mutations, the respective medians were 6.2 and 5.1 months (HR, 0.867; 95% CI, 0.670-1.123).

"Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups.

"Side effects are manageable in this patient population, and therefore it’s fair to conclude that regorafenib is a new potential standard of care for patients with chemorefractory metastatic colorectal cancer," Dr. Van Cutsem said.

Bayer Healthcare announced that it has applied in Europe and the United States for approval of regorafenib for patients with metastatic colorectal cancer based on these results. The company said at the end of June that the Food and Drug Administration granted priority review, which would require a decision in 6 months.

The CORRECT (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) trial randomized 760 patients: 505 to regorafenib plus best supportive care, and 255 to placebo plus best supportive care. More than half had KRAS mutations; nearly half had metastatic disease.

Investigators reported the primary and secondary end points of the study at a symposium on gastrointestinal cancers sponsored by ASCO in January 2012.

Regorafenib added a median benefit of just 1.4 months, compared with placebo plus best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn., said at that meeting. Although the added time was short, he noted, all participants were running out of options after the failure of standard therapies, including bevacizumab (Avastin) and EGFR inhibitors.

In the new presentation at the ASCO annual meeting, Dr. Van Cutsem reiterated those data and gave updated information on response rates and prespecified subgroup analyses.

There were no complete responses for patients on either the active drug or placebo, and only 1% of the 505 patients on regorafenib had a partial response, compared with 0.4% of 255 patients on placebo.

More patients on regorafenib had stable disease (42.8% vs. 14.5%), and fewer progressed while on the drug (49.5% vs. 80.0%). The disease control rate (defined as partial responses and stable disease combined at least 6 weeks after randomization) was significantly better for regorafenib (P less than .000001), Dr. Van Cutsem noted.

Regorafenib was superior to placebo in overall survival among men and women, patients younger than 65 years, those with baseline ECOG (Eastern Cooperative Oncology Group) performance status scores of 0 or 1, and patients with the primary disease site in the colon.

The most frequent grade 3 adverse events with regorafenib were hand-foot skin reactions, fatigue, diarrhea, hypertension, and rash. Drug-related deaths occurred in 1% of patients on regorafenib, compared with none in patients on placebo.

Speaking about the overall trial results, the invited discussant Dr. Chris Garrett of the University of Texas M.D. Anderson Cancer Center in Houston said, "I think [regorafenib] should be an option for patients with chemotherapy-refractory metastatic colorectal cancer who have a good performance status. However, patients should be made aware of the toxicities that may come with it. In the future, hopefully, biomarker studies will help us optimize which patients get the most benefit from this therapy."

The CORRECT trial was sponsored by Bayer HealthCare AG in Leverkusen, Germany. Dr. Van Cutsem has received research funding from the company. Dr. Garrett reported having no relevant financial disclosures.

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – Olaparib, the novel PARP inhibitor that came up short of a survival advantage in a much-watched trial in ovarian cancer, is again showing positive results in that disease.

Olaparib was effective and well tolerated as an adjunctive targeted therapy in women with platinum-sensitive advanced serous ovarian cancer, regardless of BRCA mutational status, according to new results from a different randomized, open-label phase II trial.

Among the 162 women studied, those treated with olaparib – an oral investigational inhibitor of PARP, or poly(ADP-ribose) polymerase – along with chemotherapy and also as maintenance therapy had a nearly one-half reduction in the risk of progression or death relative to their counterparts treated with chemotherapy alone and no maintenance therapy.

The absolute difference in the risk of events was about 3 months, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"There is an active biomarker analysis program to analyze tumor tissue, and the analysis of samples from this study will be combined with the samples from [a monotherapy maintenance study] to look at potential predictive biomarkers for olaparib efficacy," noted first author Dr. Amit M. Oza of Princess Margaret Hospital in Toronto.

"Olaparib clinical development continues, and the immediate aims are to determine the optimal patient population and to find an acceptable tablet dose and schedule for long-term treatment, to enable the next generation of clinical studies," he added.

Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia cited the earlier study of olaparib maintenance, which showed improved progression-free survival but, at least as of an interim analysis, not overall survival in his invited discussion of the current study (N. Engl. J. Med. 2012;366:1382-92).

"If we as a community are going to bend the survival curves of ovarian cancer upward, we are going to need to find a therapeutic strategy that works in advanced serous carcinoma," he said. Although the study was "positive ... perhaps a bit provocatively, I am going to argue that I suspect this study will ultimately be negative – negative not in that it didn’t meet its therapeutic end point, but in that it will fail to bend the ovarian cancer survival curve upward."

Serous ovarian cancers have extremely diverse genomic aberrations, so it is unlikely that there are large groups of patients with similar tumors, according to Dr. Seiden.

"The genomics of serous carcinoma argue against phase III studies at least of what I would argue are molecularly targeted agents. Bringing new drugs to our patients will require new strategies in clinical trial design, new strategies in genomic stratification, and new strategies in FDA approval," he maintained.

The women studied in the trial were 60 years old on average, Dr. Oza reported at the meeting. In 80% of cases, the cancer’s status regarding mutations of the BRCA genes (which have been associated with greater PARP inhibitor efficacy in some cancers) was unknown. The majority of women had received only a single platinum-containing regimen.

The investigators assigned the women evenly to chemotherapy (paclitaxel plus carboplatin) with concurrent olaparib, followed by olaparib maintenance, or to chemotherapy alone followed by no maintenance therapy. The carboplatin dose was one-third lower in the group given olaparib. "In this study, we used the capsule formulation of olaparib," he noted.

Study results showed that median progression-free survival was 12.2 months with olaparib and 9.6 months without it (hazard ratio, 0.51; P = .001).

"The curves begin to separate at 6 months and after that. So there was no separation of the two curves during the concurrent portion of the treatment," Dr. Oza pointed out.

"There were no specific subgroups that did not seem to benefit from the addition of olaparib," he continued, although benefit was somewhat greater in women who had a progression-free interval exceeding 12 months before the trial as compared with a shorter duration.

Immature data for overall survival showed a rate of about 15% with olaparib and 14% without it. There were no significant differences between the groups in terms of response rate whether assessed with RECIST criteria (64% vs. 58%) or cancer antigen 125 (CA-125) levels (86% vs. 74%).

Women known to have BRCA mutations appeared to be scattered evenly throughout a waterfall plot showing the degree of response (or lack thereof), Dr. Oza noted.

The combination regimen "was well tolerated and deliverable," with similar rates of dose modifications and completion of chemotherapy," he said. During the concurrent phase of treatment, "the rates of grade 3 or worse neutropenia and thrombocytopenia are not dramatically different between the two arms, which is reassuring."

During the maintenance phase of treatment, the overall rate of grade 3 or worse adverse events was 29% in the olaparib group and 16% in the control group, and "there were no additional safety concerns or safety signals that emerged related to toxicity of olaparib."

Dr. Oza disclosed that he receives research funding from AstraZeneca. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Olaparib, the novel PARP inhibitor that came up short of a survival advantage in a much-watched trial in ovarian cancer, is again showing positive results in that disease.

Olaparib was effective and well tolerated as an adjunctive targeted therapy in women with platinum-sensitive advanced serous ovarian cancer, regardless of BRCA mutational status, according to new results from a different randomized, open-label phase II trial.

Among the 162 women studied, those treated with olaparib – an oral investigational inhibitor of PARP, or poly(ADP-ribose) polymerase – along with chemotherapy and also as maintenance therapy had a nearly one-half reduction in the risk of progression or death relative to their counterparts treated with chemotherapy alone and no maintenance therapy.

The absolute difference in the risk of events was about 3 months, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"There is an active biomarker analysis program to analyze tumor tissue, and the analysis of samples from this study will be combined with the samples from [a monotherapy maintenance study] to look at potential predictive biomarkers for olaparib efficacy," noted first author Dr. Amit M. Oza of Princess Margaret Hospital in Toronto.

"Olaparib clinical development continues, and the immediate aims are to determine the optimal patient population and to find an acceptable tablet dose and schedule for long-term treatment, to enable the next generation of clinical studies," he added.

Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia cited the earlier study of olaparib maintenance, which showed improved progression-free survival but, at least as of an interim analysis, not overall survival in his invited discussion of the current study (N. Engl. J. Med. 2012;366:1382-92).

"If we as a community are going to bend the survival curves of ovarian cancer upward, we are going to need to find a therapeutic strategy that works in advanced serous carcinoma," he said. Although the study was "positive ... perhaps a bit provocatively, I am going to argue that I suspect this study will ultimately be negative – negative not in that it didn’t meet its therapeutic end point, but in that it will fail to bend the ovarian cancer survival curve upward."

Serous ovarian cancers have extremely diverse genomic aberrations, so it is unlikely that there are large groups of patients with similar tumors, according to Dr. Seiden.

"The genomics of serous carcinoma argue against phase III studies at least of what I would argue are molecularly targeted agents. Bringing new drugs to our patients will require new strategies in clinical trial design, new strategies in genomic stratification, and new strategies in FDA approval," he maintained.

The women studied in the trial were 60 years old on average, Dr. Oza reported at the meeting. In 80% of cases, the cancer’s status regarding mutations of the BRCA genes (which have been associated with greater PARP inhibitor efficacy in some cancers) was unknown. The majority of women had received only a single platinum-containing regimen.

The investigators assigned the women evenly to chemotherapy (paclitaxel plus carboplatin) with concurrent olaparib, followed by olaparib maintenance, or to chemotherapy alone followed by no maintenance therapy. The carboplatin dose was one-third lower in the group given olaparib. "In this study, we used the capsule formulation of olaparib," he noted.

Study results showed that median progression-free survival was 12.2 months with olaparib and 9.6 months without it (hazard ratio, 0.51; P = .001).

"The curves begin to separate at 6 months and after that. So there was no separation of the two curves during the concurrent portion of the treatment," Dr. Oza pointed out.

"There were no specific subgroups that did not seem to benefit from the addition of olaparib," he continued, although benefit was somewhat greater in women who had a progression-free interval exceeding 12 months before the trial as compared with a shorter duration.

Immature data for overall survival showed a rate of about 15% with olaparib and 14% without it. There were no significant differences between the groups in terms of response rate whether assessed with RECIST criteria (64% vs. 58%) or cancer antigen 125 (CA-125) levels (86% vs. 74%).

Women known to have BRCA mutations appeared to be scattered evenly throughout a waterfall plot showing the degree of response (or lack thereof), Dr. Oza noted.

The combination regimen "was well tolerated and deliverable," with similar rates of dose modifications and completion of chemotherapy," he said. During the concurrent phase of treatment, "the rates of grade 3 or worse neutropenia and thrombocytopenia are not dramatically different between the two arms, which is reassuring."

During the maintenance phase of treatment, the overall rate of grade 3 or worse adverse events was 29% in the olaparib group and 16% in the control group, and "there were no additional safety concerns or safety signals that emerged related to toxicity of olaparib."

Dr. Oza disclosed that he receives research funding from AstraZeneca. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Olaparib, the novel PARP inhibitor that came up short of a survival advantage in a much-watched trial in ovarian cancer, is again showing positive results in that disease.

Olaparib was effective and well tolerated as an adjunctive targeted therapy in women with platinum-sensitive advanced serous ovarian cancer, regardless of BRCA mutational status, according to new results from a different randomized, open-label phase II trial.

Among the 162 women studied, those treated with olaparib – an oral investigational inhibitor of PARP, or poly(ADP-ribose) polymerase – along with chemotherapy and also as maintenance therapy had a nearly one-half reduction in the risk of progression or death relative to their counterparts treated with chemotherapy alone and no maintenance therapy.

The absolute difference in the risk of events was about 3 months, investigators reported at the annual meeting of the American Society of Clinical Oncology.

"There is an active biomarker analysis program to analyze tumor tissue, and the analysis of samples from this study will be combined with the samples from [a monotherapy maintenance study] to look at potential predictive biomarkers for olaparib efficacy," noted first author Dr. Amit M. Oza of Princess Margaret Hospital in Toronto.

"Olaparib clinical development continues, and the immediate aims are to determine the optimal patient population and to find an acceptable tablet dose and schedule for long-term treatment, to enable the next generation of clinical studies," he added.

Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia cited the earlier study of olaparib maintenance, which showed improved progression-free survival but, at least as of an interim analysis, not overall survival in his invited discussion of the current study (N. Engl. J. Med. 2012;366:1382-92).

"If we as a community are going to bend the survival curves of ovarian cancer upward, we are going to need to find a therapeutic strategy that works in advanced serous carcinoma," he said. Although the study was "positive ... perhaps a bit provocatively, I am going to argue that I suspect this study will ultimately be negative – negative not in that it didn’t meet its therapeutic end point, but in that it will fail to bend the ovarian cancer survival curve upward."

Serous ovarian cancers have extremely diverse genomic aberrations, so it is unlikely that there are large groups of patients with similar tumors, according to Dr. Seiden.

"The genomics of serous carcinoma argue against phase III studies at least of what I would argue are molecularly targeted agents. Bringing new drugs to our patients will require new strategies in clinical trial design, new strategies in genomic stratification, and new strategies in FDA approval," he maintained.

The women studied in the trial were 60 years old on average, Dr. Oza reported at the meeting. In 80% of cases, the cancer’s status regarding mutations of the BRCA genes (which have been associated with greater PARP inhibitor efficacy in some cancers) was unknown. The majority of women had received only a single platinum-containing regimen.

The investigators assigned the women evenly to chemotherapy (paclitaxel plus carboplatin) with concurrent olaparib, followed by olaparib maintenance, or to chemotherapy alone followed by no maintenance therapy. The carboplatin dose was one-third lower in the group given olaparib. "In this study, we used the capsule formulation of olaparib," he noted.

Study results showed that median progression-free survival was 12.2 months with olaparib and 9.6 months without it (hazard ratio, 0.51; P = .001).

"The curves begin to separate at 6 months and after that. So there was no separation of the two curves during the concurrent portion of the treatment," Dr. Oza pointed out.

"There were no specific subgroups that did not seem to benefit from the addition of olaparib," he continued, although benefit was somewhat greater in women who had a progression-free interval exceeding 12 months before the trial as compared with a shorter duration.

Immature data for overall survival showed a rate of about 15% with olaparib and 14% without it. There were no significant differences between the groups in terms of response rate whether assessed with RECIST criteria (64% vs. 58%) or cancer antigen 125 (CA-125) levels (86% vs. 74%).

Women known to have BRCA mutations appeared to be scattered evenly throughout a waterfall plot showing the degree of response (or lack thereof), Dr. Oza noted.

The combination regimen "was well tolerated and deliverable," with similar rates of dose modifications and completion of chemotherapy," he said. During the concurrent phase of treatment, "the rates of grade 3 or worse neutropenia and thrombocytopenia are not dramatically different between the two arms, which is reassuring."

During the maintenance phase of treatment, the overall rate of grade 3 or worse adverse events was 29% in the olaparib group and 16% in the control group, and "there were no additional safety concerns or safety signals that emerged related to toxicity of olaparib."

Dr. Oza disclosed that he receives research funding from AstraZeneca. Dr. Seiden disclosed no relevant conflicts of interest.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.