Jane Salodof MacNeil

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

STOCKHOLM — Clinical studies of two experimental agents—tremelimumab and ipilimumab—have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seeks to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%–29% as second-line therapies.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

▸ Response in baseline lesions.

▸ Stable disease with a slow, steady decline in tumor volume.

▸ Response after increase in total tumor volume.

▸ Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response, compared with overall survival in phase IIItrials.

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15- mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease—a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10-mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29%. Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed.

ELSEVIER GLOBAL MEDICAL NEWS

GÖTEBORG, SWEDEN—Eliminating nodal disease in cervical cancer patients with positive pelvic and para-aortic positive lymph nodes failed to improve survival in a prospective 24-patient phase II study.

The results were presented at the annual meeting of the European Society for Therapeutic Radiology and Oncology.

Investigators at the Mallinckrodt Institute of Radiology in St. Louis used positron-emission tomography (PET) to guide 60 Gy of intensity-modulated radiation therapy (IMRT) to pelvic and para-aortic lymph nodes where metastases had been detected by PET with fluorodeoxyglucose (FDG).

Three months after radiotherapy, 21 patients were screened again by FDG-PET, a timetable the lead investigator, Dr. Perry W. Grigsby, had previously reported to be predictive of survival (JAMA 2007;298:2289-95). Nineteen patients (90%) had negative lymph nodes at this point, suggesting radiotherapy had been successful.

Six of the 19 patients—nearly a third—already had new metastases in other locations, however. By 40 months, nearly all had progressed. Cause-specific survival at that point was about 50%, said Dr. Grigsby, professor of radiation oncology, nuclear medicine, and gynecologic oncology at Washington University, St. Louis.

“Some of these patients have been treated for their recurrences, and will live a few months longer,” he observed.

The 5-year survival rate for cervical cancer with positive lymph nodes is only about 30%, according to Dr. Grigsby. Efforts to deliver more radiotherapy to positive lymph nodes have so far resulted in high toxicity with no improvement in survival.

For the current study, patients had to have positive nodes with no other sites of metastases when enrolled. Half of the 24 patients had stage IIIb disease; nine had stage IIb disease, and three cases were stage Ib2. The majority, 20 patients, had squamous cell histology; 2 patients had adenocarcinoma, and 1 each were classified with clear cell or small cell cervical cancer.

The protocol delivered a clinical target volume-nodal of 50 Gy over 30 fractions to the pelvis and para-aortic lymph node regions, along with a molecular target volume-nodal of 60 Gy directed at the FDG-PET-positive lymph nodes in these areas. In addition, the women were treated with six cycles of brachytherapy (6.5-Gy high dose rate) and weekly cisplatin (40 mg/m

The median treatment time was reported as 53 days, with a median follow-up of 22 months.

Acute toxicity was high, with 58% of patients having grade 3 adverse events, 33% with grade 4, and one patient dying of a chemotherapy-related adverse event. Late toxicity occurred in 13% of patients: two with small bowel obstructions and one with proctitis.

The results show that delivering 60 Gy of PET-guided IMRT to pelvic and para-aortic lymph nodes along with concurrent chemotherapy is feasible and eliminates nodal disease in most patients, Dr. Grigsby said.

Nonetheless, he found survival remains poor due to development of distant metastases.

“These patients are at exceptionally high risk of dying from metastatic disease, and we need to search out improved systemic agents in order to cure this patient population,” he concluded.

Dr. Grigsby stated that he had no conflicts of interest to disclose.

Positive lymph nodes are shown in green on the FDG-PET scan.

In one dose-distribution plan, the blue areas receive 50 Gy of radiation and the positive lymph nodes (orange) receive 60 Gy. Images courtesy Dr. Perry W. Grigsby

GÖTEBORG, SWEDEN—Eliminating nodal disease in cervical cancer patients with positive pelvic and para-aortic positive lymph nodes failed to improve survival in a prospective 24-patient phase II study.

The results were presented at the annual meeting of the European Society for Therapeutic Radiology and Oncology.

Investigators at the Mallinckrodt Institute of Radiology in St. Louis used positron-emission tomography (PET) to guide 60 Gy of intensity-modulated radiation therapy (IMRT) to pelvic and para-aortic lymph nodes where metastases had been detected by PET with fluorodeoxyglucose (FDG).

Three months after radiotherapy, 21 patients were screened again by FDG-PET, a timetable the lead investigator, Dr. Perry W. Grigsby, had previously reported to be predictive of survival (JAMA 2007;298:2289-95). Nineteen patients (90%) had negative lymph nodes at this point, suggesting radiotherapy had been successful.

Six of the 19 patients—nearly a third—already had new metastases in other locations, however. By 40 months, nearly all had progressed. Cause-specific survival at that point was about 50%, said Dr. Grigsby, professor of radiation oncology, nuclear medicine, and gynecologic oncology at Washington University, St. Louis.

“Some of these patients have been treated for their recurrences, and will live a few months longer,” he observed.

The 5-year survival rate for cervical cancer with positive lymph nodes is only about 30%, according to Dr. Grigsby. Efforts to deliver more radiotherapy to positive lymph nodes have so far resulted in high toxicity with no improvement in survival.

For the current study, patients had to have positive nodes with no other sites of metastases when enrolled. Half of the 24 patients had stage IIIb disease; nine had stage IIb disease, and three cases were stage Ib2. The majority, 20 patients, had squamous cell histology; 2 patients had adenocarcinoma, and 1 each were classified with clear cell or small cell cervical cancer.

The protocol delivered a clinical target volume-nodal of 50 Gy over 30 fractions to the pelvis and para-aortic lymph node regions, along with a molecular target volume-nodal of 60 Gy directed at the FDG-PET-positive lymph nodes in these areas. In addition, the women were treated with six cycles of brachytherapy (6.5-Gy high dose rate) and weekly cisplatin (40 mg/m

The median treatment time was reported as 53 days, with a median follow-up of 22 months.

Acute toxicity was high, with 58% of patients having grade 3 adverse events, 33% with grade 4, and one patient dying of a chemotherapy-related adverse event. Late toxicity occurred in 13% of patients: two with small bowel obstructions and one with proctitis.

The results show that delivering 60 Gy of PET-guided IMRT to pelvic and para-aortic lymph nodes along with concurrent chemotherapy is feasible and eliminates nodal disease in most patients, Dr. Grigsby said.

Nonetheless, he found survival remains poor due to development of distant metastases.

“These patients are at exceptionally high risk of dying from metastatic disease, and we need to search out improved systemic agents in order to cure this patient population,” he concluded.

Dr. Grigsby stated that he had no conflicts of interest to disclose.

Positive lymph nodes are shown in green on the FDG-PET scan.

In one dose-distribution plan, the blue areas receive 50 Gy of radiation and the positive lymph nodes (orange) receive 60 Gy. Images courtesy Dr. Perry W. Grigsby

GÖTEBORG, SWEDEN—Eliminating nodal disease in cervical cancer patients with positive pelvic and para-aortic positive lymph nodes failed to improve survival in a prospective 24-patient phase II study.

The results were presented at the annual meeting of the European Society for Therapeutic Radiology and Oncology.

Investigators at the Mallinckrodt Institute of Radiology in St. Louis used positron-emission tomography (PET) to guide 60 Gy of intensity-modulated radiation therapy (IMRT) to pelvic and para-aortic lymph nodes where metastases had been detected by PET with fluorodeoxyglucose (FDG).

Three months after radiotherapy, 21 patients were screened again by FDG-PET, a timetable the lead investigator, Dr. Perry W. Grigsby, had previously reported to be predictive of survival (JAMA 2007;298:2289-95). Nineteen patients (90%) had negative lymph nodes at this point, suggesting radiotherapy had been successful.

Six of the 19 patients—nearly a third—already had new metastases in other locations, however. By 40 months, nearly all had progressed. Cause-specific survival at that point was about 50%, said Dr. Grigsby, professor of radiation oncology, nuclear medicine, and gynecologic oncology at Washington University, St. Louis.

“Some of these patients have been treated for their recurrences, and will live a few months longer,” he observed.

The 5-year survival rate for cervical cancer with positive lymph nodes is only about 30%, according to Dr. Grigsby. Efforts to deliver more radiotherapy to positive lymph nodes have so far resulted in high toxicity with no improvement in survival.

For the current study, patients had to have positive nodes with no other sites of metastases when enrolled. Half of the 24 patients had stage IIIb disease; nine had stage IIb disease, and three cases were stage Ib2. The majority, 20 patients, had squamous cell histology; 2 patients had adenocarcinoma, and 1 each were classified with clear cell or small cell cervical cancer.

The protocol delivered a clinical target volume-nodal of 50 Gy over 30 fractions to the pelvis and para-aortic lymph node regions, along with a molecular target volume-nodal of 60 Gy directed at the FDG-PET-positive lymph nodes in these areas. In addition, the women were treated with six cycles of brachytherapy (6.5-Gy high dose rate) and weekly cisplatin (40 mg/m

The median treatment time was reported as 53 days, with a median follow-up of 22 months.

Acute toxicity was high, with 58% of patients having grade 3 adverse events, 33% with grade 4, and one patient dying of a chemotherapy-related adverse event. Late toxicity occurred in 13% of patients: two with small bowel obstructions and one with proctitis.

The results show that delivering 60 Gy of PET-guided IMRT to pelvic and para-aortic lymph nodes along with concurrent chemotherapy is feasible and eliminates nodal disease in most patients, Dr. Grigsby said.

Nonetheless, he found survival remains poor due to development of distant metastases.

“These patients are at exceptionally high risk of dying from metastatic disease, and we need to search out improved systemic agents in order to cure this patient population,” he concluded.

Dr. Grigsby stated that he had no conflicts of interest to disclose.

Positive lymph nodes are shown in green on the FDG-PET scan.

In one dose-distribution plan, the blue areas receive 50 Gy of radiation and the positive lymph nodes (orange) receive 60 Gy. Images courtesy Dr. Perry W. Grigsby

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial conducted in obese patients who for the most part were not diabetic.

Participants on four different doses of liraglutide—1.2, 1.8, 2.4, and 3.0 mg—tested in the study lost significantly more weight, compared with a control group on placebo. Those treated at the two highest doses (2.4 and 3.0 mg per day) lost significantly more weight than did those given 120 mg of orlistat (Xenical) three times a day.

The mean weight loss ranged from 4.8 kg with the lowest 1.2-mg dose of liraglutide to 7.2 kg with the 3.0-mg dose, according to the investigators. The mean weight loss for placebo was little more than 2 kg and about 4 kg with orlistat.

Dr. Arne Astrup, the lead author and head of the department of human nutrition at the University of Copenhagen, described results of the six-arm, 564-patient study in an oral presentation at the annual scientific meeting of NAASO, the Obesity Society. Novo Nordisk A/S sponsored the trial.

Nearly two-thirds of the participants in the current study did not have diabetes; most of the rest were classified with prediabetes, leaving about 3% with the disease. About three-quarters of the population were women, and the average age was in the mid-40s (range 18–65 years). Body mass index ranged from 30 kg/m

The proportion of participants who lost 5% or more of body weight was 44% with orlistat but ranged from 54% to 76% with the liraglutide doses; and 28% of those on the highest dose lost more than 10% of their body weight. The most common adverse events were nausea and vomiting.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving support for serving on advisory boards relative to liraglutide. The investigators also included Novo Nordisk employees, one of whom was a shareholder in the company, and other scientists who had received financial support and/or served on advisory boards.

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial conducted in obese patients who for the most part were not diabetic.

Participants on four different doses of liraglutide—1.2, 1.8, 2.4, and 3.0 mg—tested in the study lost significantly more weight, compared with a control group on placebo. Those treated at the two highest doses (2.4 and 3.0 mg per day) lost significantly more weight than did those given 120 mg of orlistat (Xenical) three times a day.

The mean weight loss ranged from 4.8 kg with the lowest 1.2-mg dose of liraglutide to 7.2 kg with the 3.0-mg dose, according to the investigators. The mean weight loss for placebo was little more than 2 kg and about 4 kg with orlistat.

Dr. Arne Astrup, the lead author and head of the department of human nutrition at the University of Copenhagen, described results of the six-arm, 564-patient study in an oral presentation at the annual scientific meeting of NAASO, the Obesity Society. Novo Nordisk A/S sponsored the trial.

Nearly two-thirds of the participants in the current study did not have diabetes; most of the rest were classified with prediabetes, leaving about 3% with the disease. About three-quarters of the population were women, and the average age was in the mid-40s (range 18–65 years). Body mass index ranged from 30 kg/m

The proportion of participants who lost 5% or more of body weight was 44% with orlistat but ranged from 54% to 76% with the liraglutide doses; and 28% of those on the highest dose lost more than 10% of their body weight. The most common adverse events were nausea and vomiting.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving support for serving on advisory boards relative to liraglutide. The investigators also included Novo Nordisk employees, one of whom was a shareholder in the company, and other scientists who had received financial support and/or served on advisory boards.

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial conducted in obese patients who for the most part were not diabetic.

Participants on four different doses of liraglutide—1.2, 1.8, 2.4, and 3.0 mg—tested in the study lost significantly more weight, compared with a control group on placebo. Those treated at the two highest doses (2.4 and 3.0 mg per day) lost significantly more weight than did those given 120 mg of orlistat (Xenical) three times a day.

The mean weight loss ranged from 4.8 kg with the lowest 1.2-mg dose of liraglutide to 7.2 kg with the 3.0-mg dose, according to the investigators. The mean weight loss for placebo was little more than 2 kg and about 4 kg with orlistat.

Dr. Arne Astrup, the lead author and head of the department of human nutrition at the University of Copenhagen, described results of the six-arm, 564-patient study in an oral presentation at the annual scientific meeting of NAASO, the Obesity Society. Novo Nordisk A/S sponsored the trial.

Nearly two-thirds of the participants in the current study did not have diabetes; most of the rest were classified with prediabetes, leaving about 3% with the disease. About three-quarters of the population were women, and the average age was in the mid-40s (range 18–65 years). Body mass index ranged from 30 kg/m

The proportion of participants who lost 5% or more of body weight was 44% with orlistat but ranged from 54% to 76% with the liraglutide doses; and 28% of those on the highest dose lost more than 10% of their body weight. The most common adverse events were nausea and vomiting.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving support for serving on advisory boards relative to liraglutide. The investigators also included Novo Nordisk employees, one of whom was a shareholder in the company, and other scientists who had received financial support and/or served on advisory boards.

PHOENIX — Sibutramine helped people who had lost substantial amounts of weight maintain much of their weight loss for 2 years in a multicenter, double-blind, randomized trial. By 3 years, however, they had regained about as much as a control group on placebo.

In all, 466 participants started the maintenance study after losing an average of 30 kg in nonpharmacologic weight-loss programs. Although everyone had begun to put the pounds back on before entering the trial, they had to have maintained at least half of their peak weight loss for 6 months, said Dr. James W. Anderson, the lead investigator, reported in an analysis at the annual meeting of The Obesity Society.

Indeed, the net weight gain for the two groups was significantly less with sibutramine (Meridia) for the first 2 years—0.6% vs. 3.1% at 6 months, 2.8% vs. 5.6% at 1 year, and 7.1% vs. 9.8% at 24 months. At 3 years, the sibutramine group still had less net weight gain (9.6% vs. 11.7%), but the difference was no longer significant, and both groups appeared to plateau, said Dr. Anderson of the University of Kentucky, Lexington.

Abbott Laboratories became the study sponsor after acquiring sibutramine and decided to curtail follow-up at 36 months, according to Dr. Anderson, who emphasized that he has not received support from Abbott for more than 5 years.

The trial randomized 236 subjects to 15 mg of sibutramine per day and 230 to placebo at 26 sites. Of these, 150 placebo patients and 144 sibutramine patients completed 36 months. Blood pressure and pulse rate were significantly higher with sibutramine. Serious adverse events were more common with placebo (19% vs. 17%), but more people discontinued because of adverse events on sibutramine (15% vs. 7%).

PHOENIX — Sibutramine helped people who had lost substantial amounts of weight maintain much of their weight loss for 2 years in a multicenter, double-blind, randomized trial. By 3 years, however, they had regained about as much as a control group on placebo.

In all, 466 participants started the maintenance study after losing an average of 30 kg in nonpharmacologic weight-loss programs. Although everyone had begun to put the pounds back on before entering the trial, they had to have maintained at least half of their peak weight loss for 6 months, said Dr. James W. Anderson, the lead investigator, reported in an analysis at the annual meeting of The Obesity Society.

Indeed, the net weight gain for the two groups was significantly less with sibutramine (Meridia) for the first 2 years—0.6% vs. 3.1% at 6 months, 2.8% vs. 5.6% at 1 year, and 7.1% vs. 9.8% at 24 months. At 3 years, the sibutramine group still had less net weight gain (9.6% vs. 11.7%), but the difference was no longer significant, and both groups appeared to plateau, said Dr. Anderson of the University of Kentucky, Lexington.

Abbott Laboratories became the study sponsor after acquiring sibutramine and decided to curtail follow-up at 36 months, according to Dr. Anderson, who emphasized that he has not received support from Abbott for more than 5 years.

The trial randomized 236 subjects to 15 mg of sibutramine per day and 230 to placebo at 26 sites. Of these, 150 placebo patients and 144 sibutramine patients completed 36 months. Blood pressure and pulse rate were significantly higher with sibutramine. Serious adverse events were more common with placebo (19% vs. 17%), but more people discontinued because of adverse events on sibutramine (15% vs. 7%).

PHOENIX — Sibutramine helped people who had lost substantial amounts of weight maintain much of their weight loss for 2 years in a multicenter, double-blind, randomized trial. By 3 years, however, they had regained about as much as a control group on placebo.

In all, 466 participants started the maintenance study after losing an average of 30 kg in nonpharmacologic weight-loss programs. Although everyone had begun to put the pounds back on before entering the trial, they had to have maintained at least half of their peak weight loss for 6 months, said Dr. James W. Anderson, the lead investigator, reported in an analysis at the annual meeting of The Obesity Society.

Indeed, the net weight gain for the two groups was significantly less with sibutramine (Meridia) for the first 2 years—0.6% vs. 3.1% at 6 months, 2.8% vs. 5.6% at 1 year, and 7.1% vs. 9.8% at 24 months. At 3 years, the sibutramine group still had less net weight gain (9.6% vs. 11.7%), but the difference was no longer significant, and both groups appeared to plateau, said Dr. Anderson of the University of Kentucky, Lexington.

Abbott Laboratories became the study sponsor after acquiring sibutramine and decided to curtail follow-up at 36 months, according to Dr. Anderson, who emphasized that he has not received support from Abbott for more than 5 years.

The trial randomized 236 subjects to 15 mg of sibutramine per day and 230 to placebo at 26 sites. Of these, 150 placebo patients and 144 sibutramine patients completed 36 months. Blood pressure and pulse rate were significantly higher with sibutramine. Serious adverse events were more common with placebo (19% vs. 17%), but more people discontinued because of adverse events on sibutramine (15% vs. 7%).

PHOENIX — Weight loss following bariatric bypass surgery lowered heart rates and resolved most QTc abnormalities in the electrocardiograms of 100 patients in a retrospective study presented at the annual scientific meeting of the Obesity Society.

Dr. Philippe Gilbert reported men and women had significantly slower heart rates at 22 months of follow-up. In men, greater weight loss correlated with reductions in QTc interval. Although women also had shorter QTc intervals as a group after surgery, this did not correlate with weight loss.

Bariatric surgery is associated with improvements in comorbidities associated with metabolic syndrome. Dr. Gilbert, a cardiologist at Hôpital Laval in Quebec City, said he and his coinvestigators decided to look at its impact on electrocardiographic (ECG) abnormalities because obese patients have “a 1.6-fold increase of sudden death caused by cardiac arrhythmias.”

They reviewed 100 consecutive patients who underwent biliopancreatic diversion with a duodenal switch from January 2000 to July 2001. The population comprised 32 men and 68 women, who were on average aged 40 and 43 years, respectively, at baseline. Changes in weight, body mass index, heart rate, and QTc before and after surgery were statistically significant for both genders.

Among the men, heart rate went from 83 to 62 beats per minute and QTc fell from 428 to 411 milliseconds. Among the women, heart rate went from 79 to 62 beats per minute, and QTc from 430 to 410 milliseconds.

The reductions in QTc correlated with the amount of weight loss in men, but not in women. In each sex, Dr. Gilbert noted, only one patient did not have a normal QTc after surgery.

Dr. Gilbert and his coinvestigators said they have no conflicts of interest.

PHOENIX — Weight loss following bariatric bypass surgery lowered heart rates and resolved most QTc abnormalities in the electrocardiograms of 100 patients in a retrospective study presented at the annual scientific meeting of the Obesity Society.

Dr. Philippe Gilbert reported men and women had significantly slower heart rates at 22 months of follow-up. In men, greater weight loss correlated with reductions in QTc interval. Although women also had shorter QTc intervals as a group after surgery, this did not correlate with weight loss.

Bariatric surgery is associated with improvements in comorbidities associated with metabolic syndrome. Dr. Gilbert, a cardiologist at Hôpital Laval in Quebec City, said he and his coinvestigators decided to look at its impact on electrocardiographic (ECG) abnormalities because obese patients have “a 1.6-fold increase of sudden death caused by cardiac arrhythmias.”

They reviewed 100 consecutive patients who underwent biliopancreatic diversion with a duodenal switch from January 2000 to July 2001. The population comprised 32 men and 68 women, who were on average aged 40 and 43 years, respectively, at baseline. Changes in weight, body mass index, heart rate, and QTc before and after surgery were statistically significant for both genders.

Among the men, heart rate went from 83 to 62 beats per minute and QTc fell from 428 to 411 milliseconds. Among the women, heart rate went from 79 to 62 beats per minute, and QTc from 430 to 410 milliseconds.

The reductions in QTc correlated with the amount of weight loss in men, but not in women. In each sex, Dr. Gilbert noted, only one patient did not have a normal QTc after surgery.

Dr. Gilbert and his coinvestigators said they have no conflicts of interest.

PHOENIX — Weight loss following bariatric bypass surgery lowered heart rates and resolved most QTc abnormalities in the electrocardiograms of 100 patients in a retrospective study presented at the annual scientific meeting of the Obesity Society.

Dr. Philippe Gilbert reported men and women had significantly slower heart rates at 22 months of follow-up. In men, greater weight loss correlated with reductions in QTc interval. Although women also had shorter QTc intervals as a group after surgery, this did not correlate with weight loss.

Bariatric surgery is associated with improvements in comorbidities associated with metabolic syndrome. Dr. Gilbert, a cardiologist at Hôpital Laval in Quebec City, said he and his coinvestigators decided to look at its impact on electrocardiographic (ECG) abnormalities because obese patients have “a 1.6-fold increase of sudden death caused by cardiac arrhythmias.”

They reviewed 100 consecutive patients who underwent biliopancreatic diversion with a duodenal switch from January 2000 to July 2001. The population comprised 32 men and 68 women, who were on average aged 40 and 43 years, respectively, at baseline. Changes in weight, body mass index, heart rate, and QTc before and after surgery were statistically significant for both genders.

Among the men, heart rate went from 83 to 62 beats per minute and QTc fell from 428 to 411 milliseconds. Among the women, heart rate went from 79 to 62 beats per minute, and QTc from 430 to 410 milliseconds.

The reductions in QTc correlated with the amount of weight loss in men, but not in women. In each sex, Dr. Gilbert noted, only one patient did not have a normal QTc after surgery.

Dr. Gilbert and his coinvestigators said they have no conflicts of interest.

STOCKHOLM — Adjuvant chemotherapy appears critical to overcoming adverse prognostic factors for recurrence and survival in women with BRCA1 or BRCA2 breast cancer, according to a large prospective study presented at the annual meeting of the European Society for Medical Oncology.

Although BRCA1 and BRCA2 carriers presented at a younger age and with more advanced disease than patients with sporadic breast cancers, those who had adjuvant chemotherapy fared as well overall as comparable patients in the control group.

Hazard ratios for distant disease recurrence and for death were far worse in the absence of adjuvant chemotherapy, however: 1.69 and 1.97, respectively, in BRCA1 carriers; 2.13 and 3.62 (P = .005), respectively, in BRCA2 carriers. That just one of these ratios is statistically significant owes to only a small number of carriers not receiving adjuvant chemotherapy, said study investigator Dr. Pamela J. Goodwin, Marvelle Koffler Chair in Breast Research and professor of medicine at the University of Toronto. In all, 87% of BRCA1 carriers and 79% of BRCA2 carriers had adjuvant chemotherapy. Those who did not have adjuvant therapy were likely treated 10 to 15 years ago, Dr. Goodwin suggested.

“The vast majority [of BRCA1 carriers] receives chemotherapy, and what seems to be happening is that the chemotherapy is overcoming the effect of the adverse prognostic factors,” she said in an interview.

Although adjuvant chemotherapy was slightly less frequent in BRCA2 carriers, the investigators saw a similar pattern. She added: “It seems to overcome the adverse prognosis. … Not getting chemotherapy is a major, major negative.”

Dr. Goodwin and her coinvestigators selected participants for the prospective study from population-based cancer registries in Ontario, Canada (1996-98), Northern California (1995-2000), and Australia (1992-1999). DNA samples were required. The population compared in the analyses comprised 92 BRCA1 carriers, 72 BRCA2 carriers, and 1,549 women with sporadic breast cancer.

Another 1,510 women were identified with other familial breast cancers. Although she did not discuss this population, Dr. Goodwin told her audience that “their results were virtually identical to the sporadic group.”

Analysis of the impact of adjuvant hormonal therapy is in progress, she added, and will be presented in December at the San Antonio Breast Cancer Symposium.

Compared with women with sporadic disease, the BRCA1 carriers tended to be younger and have higher-grade disease with negative receptors, Dr. Goodwin said. BRCA2 carriers presented with high-grade disease but had more nodal involvement. Tumor characteristics such as T stage, nodal status, and grade appeared to have similar prognostic effects in carriers and patients with sporadic disease, she said, but “effects of grade were less apparent in carriers.” Carrier status did not appear to have a significant effect on distant disease-free survival or overall status in BRCA1 carriers.

The effect was significant with respect to both in univariate analysis for BRCA2 carriers, but disappeared after adjustment for age and tumor characteristics. The unadjusted prognosis is important when counseling individual patients, Dr. Goodwin advised. “They are more concerned about how they will fare as individuals than whether their outcomes are swayed by age or tumor characteristics,” she said.

“Adjuvant chemotherapy appears to play a particularly important role in mutation carriers,” Dr. Goodwin said, concluding, “understanding the relative efficacy of different chemotherapeutic agents in the adjuvant setting in mutation carriers should be an important priority.”

In a discussion of the study, Dr. Judith Balmaña of the Hospital Universitari Vall d'Hebron in Barcelona cited numerous limitations, including selection bias, short follow-up, and small populations in earlier analyses that compared BRCA1 and BRCA2 carriers with women who had sporadic disease. The current study had a well-documented cohort, she said, and shows that the prognostic effects of BRCA status depend on chemotherapy use.

BRCA deficiency is a predictive biomarker of response to chemotherapy, said Dr. Balmaña, but “there is still no definitive word on the best treatment regimen for BRCA breast cancer.”

'It seems to overcome the adverse prognosis…. Not getting chemotherapy is a major negative.' DR. GOODWIN

STOCKHOLM — Adjuvant chemotherapy appears critical to overcoming adverse prognostic factors for recurrence and survival in women with BRCA1 or BRCA2 breast cancer, according to a large prospective study presented at the annual meeting of the European Society for Medical Oncology.

Although BRCA1 and BRCA2 carriers presented at a younger age and with more advanced disease than patients with sporadic breast cancers, those who had adjuvant chemotherapy fared as well overall as comparable patients in the control group.

Hazard ratios for distant disease recurrence and for death were far worse in the absence of adjuvant chemotherapy, however: 1.69 and 1.97, respectively, in BRCA1 carriers; 2.13 and 3.62 (P = .005), respectively, in BRCA2 carriers. That just one of these ratios is statistically significant owes to only a small number of carriers not receiving adjuvant chemotherapy, said study investigator Dr. Pamela J. Goodwin, Marvelle Koffler Chair in Breast Research and professor of medicine at the University of Toronto. In all, 87% of BRCA1 carriers and 79% of BRCA2 carriers had adjuvant chemotherapy. Those who did not have adjuvant therapy were likely treated 10 to 15 years ago, Dr. Goodwin suggested.

“The vast majority [of BRCA1 carriers] receives chemotherapy, and what seems to be happening is that the chemotherapy is overcoming the effect of the adverse prognostic factors,” she said in an interview.

Although adjuvant chemotherapy was slightly less frequent in BRCA2 carriers, the investigators saw a similar pattern. She added: “It seems to overcome the adverse prognosis. … Not getting chemotherapy is a major, major negative.”

Dr. Goodwin and her coinvestigators selected participants for the prospective study from population-based cancer registries in Ontario, Canada (1996-98), Northern California (1995-2000), and Australia (1992-1999). DNA samples were required. The population compared in the analyses comprised 92 BRCA1 carriers, 72 BRCA2 carriers, and 1,549 women with sporadic breast cancer.

Another 1,510 women were identified with other familial breast cancers. Although she did not discuss this population, Dr. Goodwin told her audience that “their results were virtually identical to the sporadic group.”

Analysis of the impact of adjuvant hormonal therapy is in progress, she added, and will be presented in December at the San Antonio Breast Cancer Symposium.

Compared with women with sporadic disease, the BRCA1 carriers tended to be younger and have higher-grade disease with negative receptors, Dr. Goodwin said. BRCA2 carriers presented with high-grade disease but had more nodal involvement. Tumor characteristics such as T stage, nodal status, and grade appeared to have similar prognostic effects in carriers and patients with sporadic disease, she said, but “effects of grade were less apparent in carriers.” Carrier status did not appear to have a significant effect on distant disease-free survival or overall status in BRCA1 carriers.

The effect was significant with respect to both in univariate analysis for BRCA2 carriers, but disappeared after adjustment for age and tumor characteristics. The unadjusted prognosis is important when counseling individual patients, Dr. Goodwin advised. “They are more concerned about how they will fare as individuals than whether their outcomes are swayed by age or tumor characteristics,” she said.

“Adjuvant chemotherapy appears to play a particularly important role in mutation carriers,” Dr. Goodwin said, concluding, “understanding the relative efficacy of different chemotherapeutic agents in the adjuvant setting in mutation carriers should be an important priority.”

In a discussion of the study, Dr. Judith Balmaña of the Hospital Universitari Vall d'Hebron in Barcelona cited numerous limitations, including selection bias, short follow-up, and small populations in earlier analyses that compared BRCA1 and BRCA2 carriers with women who had sporadic disease. The current study had a well-documented cohort, she said, and shows that the prognostic effects of BRCA status depend on chemotherapy use.

BRCA deficiency is a predictive biomarker of response to chemotherapy, said Dr. Balmaña, but “there is still no definitive word on the best treatment regimen for BRCA breast cancer.”

'It seems to overcome the adverse prognosis…. Not getting chemotherapy is a major negative.' DR. GOODWIN

STOCKHOLM — Adjuvant chemotherapy appears critical to overcoming adverse prognostic factors for recurrence and survival in women with BRCA1 or BRCA2 breast cancer, according to a large prospective study presented at the annual meeting of the European Society for Medical Oncology.

Although BRCA1 and BRCA2 carriers presented at a younger age and with more advanced disease than patients with sporadic breast cancers, those who had adjuvant chemotherapy fared as well overall as comparable patients in the control group.

Hazard ratios for distant disease recurrence and for death were far worse in the absence of adjuvant chemotherapy, however: 1.69 and 1.97, respectively, in BRCA1 carriers; 2.13 and 3.62 (P = .005), respectively, in BRCA2 carriers. That just one of these ratios is statistically significant owes to only a small number of carriers not receiving adjuvant chemotherapy, said study investigator Dr. Pamela J. Goodwin, Marvelle Koffler Chair in Breast Research and professor of medicine at the University of Toronto. In all, 87% of BRCA1 carriers and 79% of BRCA2 carriers had adjuvant chemotherapy. Those who did not have adjuvant therapy were likely treated 10 to 15 years ago, Dr. Goodwin suggested.

“The vast majority [of BRCA1 carriers] receives chemotherapy, and what seems to be happening is that the chemotherapy is overcoming the effect of the adverse prognostic factors,” she said in an interview.

Although adjuvant chemotherapy was slightly less frequent in BRCA2 carriers, the investigators saw a similar pattern. She added: “It seems to overcome the adverse prognosis. … Not getting chemotherapy is a major, major negative.”

Dr. Goodwin and her coinvestigators selected participants for the prospective study from population-based cancer registries in Ontario, Canada (1996-98), Northern California (1995-2000), and Australia (1992-1999). DNA samples were required. The population compared in the analyses comprised 92 BRCA1 carriers, 72 BRCA2 carriers, and 1,549 women with sporadic breast cancer.

Another 1,510 women were identified with other familial breast cancers. Although she did not discuss this population, Dr. Goodwin told her audience that “their results were virtually identical to the sporadic group.”

Analysis of the impact of adjuvant hormonal therapy is in progress, she added, and will be presented in December at the San Antonio Breast Cancer Symposium.

Compared with women with sporadic disease, the BRCA1 carriers tended to be younger and have higher-grade disease with negative receptors, Dr. Goodwin said. BRCA2 carriers presented with high-grade disease but had more nodal involvement. Tumor characteristics such as T stage, nodal status, and grade appeared to have similar prognostic effects in carriers and patients with sporadic disease, she said, but “effects of grade were less apparent in carriers.” Carrier status did not appear to have a significant effect on distant disease-free survival or overall status in BRCA1 carriers.

The effect was significant with respect to both in univariate analysis for BRCA2 carriers, but disappeared after adjustment for age and tumor characteristics. The unadjusted prognosis is important when counseling individual patients, Dr. Goodwin advised. “They are more concerned about how they will fare as individuals than whether their outcomes are swayed by age or tumor characteristics,” she said.

“Adjuvant chemotherapy appears to play a particularly important role in mutation carriers,” Dr. Goodwin said, concluding, “understanding the relative efficacy of different chemotherapeutic agents in the adjuvant setting in mutation carriers should be an important priority.”

In a discussion of the study, Dr. Judith Balmaña of the Hospital Universitari Vall d'Hebron in Barcelona cited numerous limitations, including selection bias, short follow-up, and small populations in earlier analyses that compared BRCA1 and BRCA2 carriers with women who had sporadic disease. The current study had a well-documented cohort, she said, and shows that the prognostic effects of BRCA status depend on chemotherapy use.

BRCA deficiency is a predictive biomarker of response to chemotherapy, said Dr. Balmaña, but “there is still no definitive word on the best treatment regimen for BRCA breast cancer.”

'It seems to overcome the adverse prognosis…. Not getting chemotherapy is a major negative.' DR. GOODWIN

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths in asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients so far treated in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data closed June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort compared with the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year. “Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't.”

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes later this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them.”

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths in asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients so far treated in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data closed June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort compared with the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year. “Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't.”

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes later this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them.”

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths in asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients so far treated in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data closed June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort compared with the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year. “Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't.”

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes later this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them.”

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com

ALBUQUERQUE — A prospective pilot study of 41 children with complaints of nonspecific musculoskeletal pain found their average levels of vitamin D were low even though the youngsters lived in the sunny southwest of the United States.

The mean level of serum 25-hydroxyvitamin D was lower in a group of 35 children with vague pain complaints than in 6 children found to have diagnosable conditions that explained their pain: 28 ng/mL vs. 38 ng/mL. While this difference was statistically significant, average vitamin D levels in both groups of children (aged 2-17 years) met the study's definition of hypovitaminosis D.

Moreover, when eight children were given vitamin D supplements, five had “marked subjective improvement or complete relief” from pain. Those making a recovery included one of two children with documented hip effusion as well as children with back pains and leg pains that had lasted, in some cases, for years.

“I am certainly not saying growing pains are caused by vitamin D deficiency, but it is something we are exploring,” Dr. Elizabeth A. Szalay said in an interview after presenting the data at the annual meeting of the Pediatric Orthopaedic Society of North America.

What was, perhaps, most remarkable, was that the children lived in New Mexico—an area not typically used in vitamin D studies because it has abundant sunshine year round. The National Health and Nutrition Examination Survey III suggests that 3% of healthy adolescents at a higher latitude have vitamin D levels below 25 ng/mL during summer, she said. In the New Mexico study, 30% of the youngsters in pain had vitamin D levels below 25 ng/mL.

Dr. Szalay, an orthopedic surgeon at the University of New Mexico and Carrie Tingley Hospital, both in Albuquerque, and her coinvestigator Elyce B. Tryon used a local laboratory's classification of vitamin D levels in their analysis. Ranges were presented as 0-5 ng/mL for deficiency, 5-20 ng/mL for insufficiency, 20-40 ng/mL for hypovitaminosis D, 40-100 ng/mL for sufficiency, and more than 100 ng/mL for toxicity.

The highest level recorded was 47 ng/mL. It was seen in both subgroups: those with vague complaints and those with objective explanations of their pain (Legg-Calvé-Perthes disease, arthrogryposis, and chondrolysis). The lowest level in the majority with vague complaints was less than half that of the children with diagnoses: 12 ng/mL vs. 25 ng/mL.

Dr. Szalay speculated that the low levels of vitamin D could be attributed to a convergence of factors. Sunlight is a prime source of vitamin D and 15 minutes of exposure a day is sufficient, she said, but many children do not play outside. They don't walk to school and may spend as much as 44 hours a week on electronic media such as video games.

Diet by itself is unlikely to provide enough vitamin D, she continued. Milk is fortified with vitamin D, but consumption is down, compared with years past. “In 1970, children drank twice as much milk as soda,” she said. “In 2000, children drank twice as much soda as milk.”

While children benefit from the calcium in other dairy products, she added, these do not contain vitamin D and are usually not fortified. “Eggs have vitamin D, if they feed it to the chickens and, even then, it is a very small amount,” she said. “There are only 25 units in an egg. You've got to eat a lot of eggs to get to 800 to a thousand units.”

Children's multivitamins, likewise, do not make up for vitamin D deficiency, according to Dr. Szalay. Some only contain 64 U a day, she said, recommending that children at risk take both a multivitamin and a chewy calcium-plus-D supplement plus two glasses of milk a day. For children without pain, she set the desired daily intake at 800-1,000 U of vitamin D, but added that she recommends 1,000-2,000 U for children with pain.

The investigators have started another study in children without pain complaints, she added. One facet will be to compare those engaged in outdoor sports such as soccer, football, and baseball with those who engage in indoor activities.

ALBUQUERQUE — A prospective pilot study of 41 children with complaints of nonspecific musculoskeletal pain found their average levels of vitamin D were low even though the youngsters lived in the sunny southwest of the United States.

The mean level of serum 25-hydroxyvitamin D was lower in a group of 35 children with vague pain complaints than in 6 children found to have diagnosable conditions that explained their pain: 28 ng/mL vs. 38 ng/mL. While this difference was statistically significant, average vitamin D levels in both groups of children (aged 2-17 years) met the study's definition of hypovitaminosis D.

Moreover, when eight children were given vitamin D supplements, five had “marked subjective improvement or complete relief” from pain. Those making a recovery included one of two children with documented hip effusion as well as children with back pains and leg pains that had lasted, in some cases, for years.

“I am certainly not saying growing pains are caused by vitamin D deficiency, but it is something we are exploring,” Dr. Elizabeth A. Szalay said in an interview after presenting the data at the annual meeting of the Pediatric Orthopaedic Society of North America.

What was, perhaps, most remarkable, was that the children lived in New Mexico—an area not typically used in vitamin D studies because it has abundant sunshine year round. The National Health and Nutrition Examination Survey III suggests that 3% of healthy adolescents at a higher latitude have vitamin D levels below 25 ng/mL during summer, she said. In the New Mexico study, 30% of the youngsters in pain had vitamin D levels below 25 ng/mL.

Dr. Szalay, an orthopedic surgeon at the University of New Mexico and Carrie Tingley Hospital, both in Albuquerque, and her coinvestigator Elyce B. Tryon used a local laboratory's classification of vitamin D levels in their analysis. Ranges were presented as 0-5 ng/mL for deficiency, 5-20 ng/mL for insufficiency, 20-40 ng/mL for hypovitaminosis D, 40-100 ng/mL for sufficiency, and more than 100 ng/mL for toxicity.

The highest level recorded was 47 ng/mL. It was seen in both subgroups: those with vague complaints and those with objective explanations of their pain (Legg-Calvé-Perthes disease, arthrogryposis, and chondrolysis). The lowest level in the majority with vague complaints was less than half that of the children with diagnoses: 12 ng/mL vs. 25 ng/mL.

Dr. Szalay speculated that the low levels of vitamin D could be attributed to a convergence of factors. Sunlight is a prime source of vitamin D and 15 minutes of exposure a day is sufficient, she said, but many children do not play outside. They don't walk to school and may spend as much as 44 hours a week on electronic media such as video games.

Diet by itself is unlikely to provide enough vitamin D, she continued. Milk is fortified with vitamin D, but consumption is down, compared with years past. “In 1970, children drank twice as much milk as soda,” she said. “In 2000, children drank twice as much soda as milk.”

While children benefit from the calcium in other dairy products, she added, these do not contain vitamin D and are usually not fortified. “Eggs have vitamin D, if they feed it to the chickens and, even then, it is a very small amount,” she said. “There are only 25 units in an egg. You've got to eat a lot of eggs to get to 800 to a thousand units.”

Children's multivitamins, likewise, do not make up for vitamin D deficiency, according to Dr. Szalay. Some only contain 64 U a day, she said, recommending that children at risk take both a multivitamin and a chewy calcium-plus-D supplement plus two glasses of milk a day. For children without pain, she set the desired daily intake at 800-1,000 U of vitamin D, but added that she recommends 1,000-2,000 U for children with pain.

The investigators have started another study in children without pain complaints, she added. One facet will be to compare those engaged in outdoor sports such as soccer, football, and baseball with those who engage in indoor activities.

ALBUQUERQUE — A prospective pilot study of 41 children with complaints of nonspecific musculoskeletal pain found their average levels of vitamin D were low even though the youngsters lived in the sunny southwest of the United States.

The mean level of serum 25-hydroxyvitamin D was lower in a group of 35 children with vague pain complaints than in 6 children found to have diagnosable conditions that explained their pain: 28 ng/mL vs. 38 ng/mL. While this difference was statistically significant, average vitamin D levels in both groups of children (aged 2-17 years) met the study's definition of hypovitaminosis D.

Moreover, when eight children were given vitamin D supplements, five had “marked subjective improvement or complete relief” from pain. Those making a recovery included one of two children with documented hip effusion as well as children with back pains and leg pains that had lasted, in some cases, for years.

“I am certainly not saying growing pains are caused by vitamin D deficiency, but it is something we are exploring,” Dr. Elizabeth A. Szalay said in an interview after presenting the data at the annual meeting of the Pediatric Orthopaedic Society of North America.

What was, perhaps, most remarkable, was that the children lived in New Mexico—an area not typically used in vitamin D studies because it has abundant sunshine year round. The National Health and Nutrition Examination Survey III suggests that 3% of healthy adolescents at a higher latitude have vitamin D levels below 25 ng/mL during summer, she said. In the New Mexico study, 30% of the youngsters in pain had vitamin D levels below 25 ng/mL.

Dr. Szalay, an orthopedic surgeon at the University of New Mexico and Carrie Tingley Hospital, both in Albuquerque, and her coinvestigator Elyce B. Tryon used a local laboratory's classification of vitamin D levels in their analysis. Ranges were presented as 0-5 ng/mL for deficiency, 5-20 ng/mL for insufficiency, 20-40 ng/mL for hypovitaminosis D, 40-100 ng/mL for sufficiency, and more than 100 ng/mL for toxicity.

The highest level recorded was 47 ng/mL. It was seen in both subgroups: those with vague complaints and those with objective explanations of their pain (Legg-Calvé-Perthes disease, arthrogryposis, and chondrolysis). The lowest level in the majority with vague complaints was less than half that of the children with diagnoses: 12 ng/mL vs. 25 ng/mL.

Dr. Szalay speculated that the low levels of vitamin D could be attributed to a convergence of factors. Sunlight is a prime source of vitamin D and 15 minutes of exposure a day is sufficient, she said, but many children do not play outside. They don't walk to school and may spend as much as 44 hours a week on electronic media such as video games.

Diet by itself is unlikely to provide enough vitamin D, she continued. Milk is fortified with vitamin D, but consumption is down, compared with years past. “In 1970, children drank twice as much milk as soda,” she said. “In 2000, children drank twice as much soda as milk.”

While children benefit from the calcium in other dairy products, she added, these do not contain vitamin D and are usually not fortified. “Eggs have vitamin D, if they feed it to the chickens and, even then, it is a very small amount,” she said. “There are only 25 units in an egg. You've got to eat a lot of eggs to get to 800 to a thousand units.”

Children's multivitamins, likewise, do not make up for vitamin D deficiency, according to Dr. Szalay. Some only contain 64 U a day, she said, recommending that children at risk take both a multivitamin and a chewy calcium-plus-D supplement plus two glasses of milk a day. For children without pain, she set the desired daily intake at 800-1,000 U of vitamin D, but added that she recommends 1,000-2,000 U for children with pain.

The investigators have started another study in children without pain complaints, she added. One facet will be to compare those engaged in outdoor sports such as soccer, football, and baseball with those who engage in indoor activities.

ALBUQUERQUE — Computed tomography imaging with coronal and sagittal reconstructions beat conventional x-rays at diagnosing cervical spine injuries in high-risk pediatric trauma patients in a study.

Dr. Gregory A. Mencio of Vanderbilt University in Nashville, Tenn., reviewed 413 consecutive charts of high-risk patients younger than 18 years at a level I trauma center. All were evaluated by CT scan and conventional five-view x-ray of the cervical spine.

CT scanning detected 71 of 74 cervical spine injuries in the patients, who had an average age of 11 years. Only 50 injuries were detected by x-ray. Combining the two brought the detection rate to 72 cases—just 1 more than diagnosed by CT, Dr. Mencio said at the annual meeting of the Pediatric Orthopaedic Society of North America.

“A lot of these kids have multiple systems injury,” Dr. Mencio said. “Do a CT of the head and neck and torso and total spine. It takes about 10 minutes to scan them from top to bottom, and you have all the information that you need.”

The researchers estimated that the radiation dose was lower with CT, but the costs were higher: $1,800 for CT, vs. $500 for x-rays. For both, Dr. Mencio noted conflicting data appear in the literature.

He offered these recommendations:

▸ CT of the cervical spine with sagittal and coronal reconstructions is the initial imaging modality of choice for high-risk pediatric trauma patients.

▸ Conventional x-ray may be used to elucidate dynamic instability and follow alignment over time.

▸ Magnetic resonance imaging is used to evaluate patients with neurologic injuries and in obtunded patients who risk prolonged immobilization.

ALBUQUERQUE — Computed tomography imaging with coronal and sagittal reconstructions beat conventional x-rays at diagnosing cervical spine injuries in high-risk pediatric trauma patients in a study.

Dr. Gregory A. Mencio of Vanderbilt University in Nashville, Tenn., reviewed 413 consecutive charts of high-risk patients younger than 18 years at a level I trauma center. All were evaluated by CT scan and conventional five-view x-ray of the cervical spine.

CT scanning detected 71 of 74 cervical spine injuries in the patients, who had an average age of 11 years. Only 50 injuries were detected by x-ray. Combining the two brought the detection rate to 72 cases—just 1 more than diagnosed by CT, Dr. Mencio said at the annual meeting of the Pediatric Orthopaedic Society of North America.

“A lot of these kids have multiple systems injury,” Dr. Mencio said. “Do a CT of the head and neck and torso and total spine. It takes about 10 minutes to scan them from top to bottom, and you have all the information that you need.”

The researchers estimated that the radiation dose was lower with CT, but the costs were higher: $1,800 for CT, vs. $500 for x-rays. For both, Dr. Mencio noted conflicting data appear in the literature.

He offered these recommendations:

▸ CT of the cervical spine with sagittal and coronal reconstructions is the initial imaging modality of choice for high-risk pediatric trauma patients.

▸ Conventional x-ray may be used to elucidate dynamic instability and follow alignment over time.

▸ Magnetic resonance imaging is used to evaluate patients with neurologic injuries and in obtunded patients who risk prolonged immobilization.

ALBUQUERQUE — Computed tomography imaging with coronal and sagittal reconstructions beat conventional x-rays at diagnosing cervical spine injuries in high-risk pediatric trauma patients in a study.

Dr. Gregory A. Mencio of Vanderbilt University in Nashville, Tenn., reviewed 413 consecutive charts of high-risk patients younger than 18 years at a level I trauma center. All were evaluated by CT scan and conventional five-view x-ray of the cervical spine.

CT scanning detected 71 of 74 cervical spine injuries in the patients, who had an average age of 11 years. Only 50 injuries were detected by x-ray. Combining the two brought the detection rate to 72 cases—just 1 more than diagnosed by CT, Dr. Mencio said at the annual meeting of the Pediatric Orthopaedic Society of North America.

“A lot of these kids have multiple systems injury,” Dr. Mencio said. “Do a CT of the head and neck and torso and total spine. It takes about 10 minutes to scan them from top to bottom, and you have all the information that you need.”

The researchers estimated that the radiation dose was lower with CT, but the costs were higher: $1,800 for CT, vs. $500 for x-rays. For both, Dr. Mencio noted conflicting data appear in the literature.

He offered these recommendations:

▸ CT of the cervical spine with sagittal and coronal reconstructions is the initial imaging modality of choice for high-risk pediatric trauma patients.

▸ Conventional x-ray may be used to elucidate dynamic instability and follow alignment over time.

▸ Magnetic resonance imaging is used to evaluate patients with neurologic injuries and in obtunded patients who risk prolonged immobilization.