Jane Salodof MacNeil

SANTA FE, N.M. — Physicians at the John Wayne Cancer Institute in Los Angeles have developed a scoring system to help identify the small number of thin melanomas most at risk of nodal recurrence and in need of evaluation by sentinel lymph node biopsy.

The system uses three parameters—Breslow thickness, age, and sex—that emerged as significant predictors in a multivariate analysis of 1,732 patients prospectively followed at the institute after treatment with excision alone within 6 months of their melanoma diagnosis. Patients with clinically evident nodal disease or nodal staging were excluded from the study.

Only 2.9% had regional nodal basin recurrence at a mean follow-up of 13.2 years, Dr. Mark B. Faries reported in a presentation of the system at the annual meeting of the Western Surgical Association. Risk increased with Breslow thickness (odds ratio, 2.5; P less than .0001) and male sex (OR, 3.5; P = .0005), but decreased with age above 50 years (OR, 0.45; P = .0019).

Predicted probabilities of recurrence ranged from 0.1% to 17.4% in the 18-step scoring system shown by Dr. Faries, a surgical oncologist at the institute. The lowest risk would be in a female patient over 70 years old with a melanoma less than 0.5 mm thick. The highest risk was assigned to a hypothetical male patient less than 50 years of age with a melanoma 0.76–0.99 mm in Breslow thickness.

"Most patients can be classified as very low risk, but others have a more substantial risk of nodal disease," he said. "The risk of clinical nodal recurrence can be estimated for patients with thin melanoma based on very simple and reproducible parameters."

Men accounted for slightly more than half, 51%, of the study population. Mean age was 48.5 years; mean Breslow thickness was 0.5 mm. Most melanomas were on the trunk (43%) or extremities (41%); just 16% were on the head or neck.

Ulceration was recorded in only 39 patients—2.3% of the study population (among whom only 1,282 had ulceration data available)—but Dr. Faries reported it greatly increased risk of nodal recurrence. The recurrence rate reached 7.7% in patients with ulceration, vs. 2.7% in the absence of ulceration.

This led Dr. James A. Recaberen of Huntington Memorial Hospital in Pasadena, Calif., to observe from the audience, "The most important thing I take away is that anyone with ulceration should be a candidate for nodal investigation." Dr. Faries concurred that while ulceration is infrequent, it can be cause by itself to proceed with a nodal biopsy.

Another lesson, he said, was the need for long follow-up of thin melanomas. About a third of recurrences occurred after 5 years of follow-up. Mean time to nodal recurrence was 38.3 months.

The small number of recurrences relative to the large number of patients with thin melanomas presents a particularly challenging problem, according to Dr. Faries and other speakers. "Melanoma is increasing in incidence faster than virtually any other solid tumor," he said, noting that about 70% of new lesions are less than 1 mm in thickness.

As with thicker melanoma, lymph node status is the most significant prognostic factor Dr. Faries noted. "However, use of sentinel node biopsy in all cases of thin melanoma is not reasonable," he cautioned, citing the large number of patients involved.

Indeed, in his discussion of the presentation, Dr. Richard Thirlby suggested that indiscriminate use of sentinel node dissection could result in a cost of $1 million to find one nodal recurrence.

Dr. Thirlby of Virginia Mason Medical Center in Seattle praised the analysis; however, he noted that it did not give thresholds for ordering a biopsy. To that end, he called for a decision-tree analysis that could help physicians use the system to decide when to recommend a sentinel node procedure.

Decision-tree and cost analyses are excellent suggestions, Dr. Faries agreed, but "I don't know that we can make a bottom line based on any predictive system."

Dr. Faries reported no relevant conflicts of interest.

SANTA FE, N.M. — Physicians at the John Wayne Cancer Institute in Los Angeles have developed a scoring system to help identify the small number of thin melanomas most at risk of nodal recurrence and in need of evaluation by sentinel lymph node biopsy.

The system uses three parameters—Breslow thickness, age, and sex—that emerged as significant predictors in a multivariate analysis of 1,732 patients prospectively followed at the institute after treatment with excision alone within 6 months of their melanoma diagnosis. Patients with clinically evident nodal disease or nodal staging were excluded from the study.

Only 2.9% had regional nodal basin recurrence at a mean follow-up of 13.2 years, Dr. Mark B. Faries reported in a presentation of the system at the annual meeting of the Western Surgical Association. Risk increased with Breslow thickness (odds ratio, 2.5; P less than .0001) and male sex (OR, 3.5; P = .0005), but decreased with age above 50 years (OR, 0.45; P = .0019).

Predicted probabilities of recurrence ranged from 0.1% to 17.4% in the 18-step scoring system shown by Dr. Faries, a surgical oncologist at the institute. The lowest risk would be in a female patient over 70 years old with a melanoma less than 0.5 mm thick. The highest risk was assigned to a hypothetical male patient less than 50 years of age with a melanoma 0.76–0.99 mm in Breslow thickness.

"Most patients can be classified as very low risk, but others have a more substantial risk of nodal disease," he said. "The risk of clinical nodal recurrence can be estimated for patients with thin melanoma based on very simple and reproducible parameters."

Men accounted for slightly more than half, 51%, of the study population. Mean age was 48.5 years; mean Breslow thickness was 0.5 mm. Most melanomas were on the trunk (43%) or extremities (41%); just 16% were on the head or neck.

Ulceration was recorded in only 39 patients—2.3% of the study population (among whom only 1,282 had ulceration data available)—but Dr. Faries reported it greatly increased risk of nodal recurrence. The recurrence rate reached 7.7% in patients with ulceration, vs. 2.7% in the absence of ulceration.

This led Dr. James A. Recaberen of Huntington Memorial Hospital in Pasadena, Calif., to observe from the audience, "The most important thing I take away is that anyone with ulceration should be a candidate for nodal investigation." Dr. Faries concurred that while ulceration is infrequent, it can be cause by itself to proceed with a nodal biopsy.

Another lesson, he said, was the need for long follow-up of thin melanomas. About a third of recurrences occurred after 5 years of follow-up. Mean time to nodal recurrence was 38.3 months.

The small number of recurrences relative to the large number of patients with thin melanomas presents a particularly challenging problem, according to Dr. Faries and other speakers. "Melanoma is increasing in incidence faster than virtually any other solid tumor," he said, noting that about 70% of new lesions are less than 1 mm in thickness.

As with thicker melanoma, lymph node status is the most significant prognostic factor Dr. Faries noted. "However, use of sentinel node biopsy in all cases of thin melanoma is not reasonable," he cautioned, citing the large number of patients involved.

Indeed, in his discussion of the presentation, Dr. Richard Thirlby suggested that indiscriminate use of sentinel node dissection could result in a cost of $1 million to find one nodal recurrence.

Dr. Thirlby of Virginia Mason Medical Center in Seattle praised the analysis; however, he noted that it did not give thresholds for ordering a biopsy. To that end, he called for a decision-tree analysis that could help physicians use the system to decide when to recommend a sentinel node procedure.

Decision-tree and cost analyses are excellent suggestions, Dr. Faries agreed, but "I don't know that we can make a bottom line based on any predictive system."

Dr. Faries reported no relevant conflicts of interest.

SANTA FE, N.M. — Physicians at the John Wayne Cancer Institute in Los Angeles have developed a scoring system to help identify the small number of thin melanomas most at risk of nodal recurrence and in need of evaluation by sentinel lymph node biopsy.

The system uses three parameters—Breslow thickness, age, and sex—that emerged as significant predictors in a multivariate analysis of 1,732 patients prospectively followed at the institute after treatment with excision alone within 6 months of their melanoma diagnosis. Patients with clinically evident nodal disease or nodal staging were excluded from the study.

Only 2.9% had regional nodal basin recurrence at a mean follow-up of 13.2 years, Dr. Mark B. Faries reported in a presentation of the system at the annual meeting of the Western Surgical Association. Risk increased with Breslow thickness (odds ratio, 2.5; P less than .0001) and male sex (OR, 3.5; P = .0005), but decreased with age above 50 years (OR, 0.45; P = .0019).

Predicted probabilities of recurrence ranged from 0.1% to 17.4% in the 18-step scoring system shown by Dr. Faries, a surgical oncologist at the institute. The lowest risk would be in a female patient over 70 years old with a melanoma less than 0.5 mm thick. The highest risk was assigned to a hypothetical male patient less than 50 years of age with a melanoma 0.76–0.99 mm in Breslow thickness.

"Most patients can be classified as very low risk, but others have a more substantial risk of nodal disease," he said. "The risk of clinical nodal recurrence can be estimated for patients with thin melanoma based on very simple and reproducible parameters."

Men accounted for slightly more than half, 51%, of the study population. Mean age was 48.5 years; mean Breslow thickness was 0.5 mm. Most melanomas were on the trunk (43%) or extremities (41%); just 16% were on the head or neck.

Ulceration was recorded in only 39 patients—2.3% of the study population (among whom only 1,282 had ulceration data available)—but Dr. Faries reported it greatly increased risk of nodal recurrence. The recurrence rate reached 7.7% in patients with ulceration, vs. 2.7% in the absence of ulceration.

This led Dr. James A. Recaberen of Huntington Memorial Hospital in Pasadena, Calif., to observe from the audience, "The most important thing I take away is that anyone with ulceration should be a candidate for nodal investigation." Dr. Faries concurred that while ulceration is infrequent, it can be cause by itself to proceed with a nodal biopsy.

Another lesson, he said, was the need for long follow-up of thin melanomas. About a third of recurrences occurred after 5 years of follow-up. Mean time to nodal recurrence was 38.3 months.

The small number of recurrences relative to the large number of patients with thin melanomas presents a particularly challenging problem, according to Dr. Faries and other speakers. "Melanoma is increasing in incidence faster than virtually any other solid tumor," he said, noting that about 70% of new lesions are less than 1 mm in thickness.

As with thicker melanoma, lymph node status is the most significant prognostic factor Dr. Faries noted. "However, use of sentinel node biopsy in all cases of thin melanoma is not reasonable," he cautioned, citing the large number of patients involved.

Indeed, in his discussion of the presentation, Dr. Richard Thirlby suggested that indiscriminate use of sentinel node dissection could result in a cost of $1 million to find one nodal recurrence.

Dr. Thirlby of Virginia Mason Medical Center in Seattle praised the analysis; however, he noted that it did not give thresholds for ordering a biopsy. To that end, he called for a decision-tree analysis that could help physicians use the system to decide when to recommend a sentinel node procedure.

Decision-tree and cost analyses are excellent suggestions, Dr. Faries agreed, but "I don't know that we can make a bottom line based on any predictive system."

Dr. Faries reported no relevant conflicts of interest.

SANTA FE, N.M. — A review of discharge data from nearly 1.5 million appendectomies found average hospital charges in nonperforated appendicitis cases were nearly $4,000 higher for laparoscopic procedures than for open procedures, despite similar lengths of stay.

Conversely, charges were comparable for both types of procedures in perforated cases, but hospital stays were 1 day shorter when surgery was done laparoscopically.

“These data indicate that laparoscopic appendectomy should be reserved for perforated appendicitis while open appendectomy should be performed in nonperforated appendicitis,” David Ludlow, a fourth-year medical student at the University of Utah, Salt Lake City, concluded in a presentation of the findings at the annual meeting of the Western Surgical Association.

Mr. Ludlow and senior author Dr. Raminder Nirula, a surgeon at the University of Utah Hospitals, conducted the retrospective cohort study of appendectomies in the U.S. National Inpatient Sample (NIS) from 2001 to 2005. Using ICD-9 diagnosis and procedure codes, they identified 598,384 laparoscopic procedures and 871,605 open procedures.

During the years studied, the number of laparoscopic procedures increased by 24% for nonperforated appendicitis and by 19% for perforated appendicitis, while the number of open appendectomies decreased. By 2005, the discharge data showed nonperforated appendicitis was more likely to be treated laparoscopically than by open surgery. Open appendectomy was still more common in perforated cases (fewer than 30,000 laparoscopic procedures vs. fewer than 25,000 open procedures).

While hospital charges throughout the study period increased for laparoscopic and open procedures, by 2005 they were similar in perforated cases at $26,399 and $25,368, respectively. For nonperforated appendicitis, however, laparoscopic procedures in 2005 averaged $18,479 vs. $14,828 for open appendectomy.

Lengths of stay in nonperforated cases were similar, at 1.7 days for laparoscopic procedures and 2.1 days for open procedures, Mr. Ludlow reported. In perforated cases, however, laparoscopic patients left the hospital after 4.2 days on average vs. 5.1 days after an open appendectomy.

The NIS database is large, includes all kinds of patients from all kinds of hospitals, and is able to stratify data by perforated vs. nonperforated appendicitis, Mr. Ludlow noted. The NIS does not, however, include data on readmissions, wound infections, intra-abdominal abscesses, or return to work.

Addressing these gaps, he cited single-institution studies that have shown similar readmission and wound infection rates for laparoscopic and open procedures, but higher abscess rates by 1%–4% and faster return to work by 1–4 days after laparoscopic appendectomy.

Dr. Fred Luchette of Loyola University Medical Center in Maywood, Ill., praised the research but questioned the recommendations made solely on the basis of evidence from discharge data. While hospital costs in nonperforated cases may be higher with laparoscopic procedures, the cost to society could be lower, he said, noting that such patients usually return to work sooner.

“Society costs vs. hospital costs—this is a philosophical question,” Dr. Nirula responded, emphasizing that the study only addressed the growing concern over hospital costs.

As for why an open procedure with longer length of stay would not cost more in perforated appendectomy cases, Dr. Nirula concurred with an audience suggestion that the added cost of equipment for laparoscopy probably was a factor.

SANTA FE, N.M. — A review of discharge data from nearly 1.5 million appendectomies found average hospital charges in nonperforated appendicitis cases were nearly $4,000 higher for laparoscopic procedures than for open procedures, despite similar lengths of stay.

Conversely, charges were comparable for both types of procedures in perforated cases, but hospital stays were 1 day shorter when surgery was done laparoscopically.

“These data indicate that laparoscopic appendectomy should be reserved for perforated appendicitis while open appendectomy should be performed in nonperforated appendicitis,” David Ludlow, a fourth-year medical student at the University of Utah, Salt Lake City, concluded in a presentation of the findings at the annual meeting of the Western Surgical Association.

Mr. Ludlow and senior author Dr. Raminder Nirula, a surgeon at the University of Utah Hospitals, conducted the retrospective cohort study of appendectomies in the U.S. National Inpatient Sample (NIS) from 2001 to 2005. Using ICD-9 diagnosis and procedure codes, they identified 598,384 laparoscopic procedures and 871,605 open procedures.

During the years studied, the number of laparoscopic procedures increased by 24% for nonperforated appendicitis and by 19% for perforated appendicitis, while the number of open appendectomies decreased. By 2005, the discharge data showed nonperforated appendicitis was more likely to be treated laparoscopically than by open surgery. Open appendectomy was still more common in perforated cases (fewer than 30,000 laparoscopic procedures vs. fewer than 25,000 open procedures).

While hospital charges throughout the study period increased for laparoscopic and open procedures, by 2005 they were similar in perforated cases at $26,399 and $25,368, respectively. For nonperforated appendicitis, however, laparoscopic procedures in 2005 averaged $18,479 vs. $14,828 for open appendectomy.

Lengths of stay in nonperforated cases were similar, at 1.7 days for laparoscopic procedures and 2.1 days for open procedures, Mr. Ludlow reported. In perforated cases, however, laparoscopic patients left the hospital after 4.2 days on average vs. 5.1 days after an open appendectomy.

The NIS database is large, includes all kinds of patients from all kinds of hospitals, and is able to stratify data by perforated vs. nonperforated appendicitis, Mr. Ludlow noted. The NIS does not, however, include data on readmissions, wound infections, intra-abdominal abscesses, or return to work.

Addressing these gaps, he cited single-institution studies that have shown similar readmission and wound infection rates for laparoscopic and open procedures, but higher abscess rates by 1%–4% and faster return to work by 1–4 days after laparoscopic appendectomy.

Dr. Fred Luchette of Loyola University Medical Center in Maywood, Ill., praised the research but questioned the recommendations made solely on the basis of evidence from discharge data. While hospital costs in nonperforated cases may be higher with laparoscopic procedures, the cost to society could be lower, he said, noting that such patients usually return to work sooner.

“Society costs vs. hospital costs—this is a philosophical question,” Dr. Nirula responded, emphasizing that the study only addressed the growing concern over hospital costs.

As for why an open procedure with longer length of stay would not cost more in perforated appendectomy cases, Dr. Nirula concurred with an audience suggestion that the added cost of equipment for laparoscopy probably was a factor.

SANTA FE, N.M. — A review of discharge data from nearly 1.5 million appendectomies found average hospital charges in nonperforated appendicitis cases were nearly $4,000 higher for laparoscopic procedures than for open procedures, despite similar lengths of stay.

Conversely, charges were comparable for both types of procedures in perforated cases, but hospital stays were 1 day shorter when surgery was done laparoscopically.

“These data indicate that laparoscopic appendectomy should be reserved for perforated appendicitis while open appendectomy should be performed in nonperforated appendicitis,” David Ludlow, a fourth-year medical student at the University of Utah, Salt Lake City, concluded in a presentation of the findings at the annual meeting of the Western Surgical Association.

Mr. Ludlow and senior author Dr. Raminder Nirula, a surgeon at the University of Utah Hospitals, conducted the retrospective cohort study of appendectomies in the U.S. National Inpatient Sample (NIS) from 2001 to 2005. Using ICD-9 diagnosis and procedure codes, they identified 598,384 laparoscopic procedures and 871,605 open procedures.

During the years studied, the number of laparoscopic procedures increased by 24% for nonperforated appendicitis and by 19% for perforated appendicitis, while the number of open appendectomies decreased. By 2005, the discharge data showed nonperforated appendicitis was more likely to be treated laparoscopically than by open surgery. Open appendectomy was still more common in perforated cases (fewer than 30,000 laparoscopic procedures vs. fewer than 25,000 open procedures).

While hospital charges throughout the study period increased for laparoscopic and open procedures, by 2005 they were similar in perforated cases at $26,399 and $25,368, respectively. For nonperforated appendicitis, however, laparoscopic procedures in 2005 averaged $18,479 vs. $14,828 for open appendectomy.

Lengths of stay in nonperforated cases were similar, at 1.7 days for laparoscopic procedures and 2.1 days for open procedures, Mr. Ludlow reported. In perforated cases, however, laparoscopic patients left the hospital after 4.2 days on average vs. 5.1 days after an open appendectomy.

The NIS database is large, includes all kinds of patients from all kinds of hospitals, and is able to stratify data by perforated vs. nonperforated appendicitis, Mr. Ludlow noted. The NIS does not, however, include data on readmissions, wound infections, intra-abdominal abscesses, or return to work.

Addressing these gaps, he cited single-institution studies that have shown similar readmission and wound infection rates for laparoscopic and open procedures, but higher abscess rates by 1%–4% and faster return to work by 1–4 days after laparoscopic appendectomy.

Dr. Fred Luchette of Loyola University Medical Center in Maywood, Ill., praised the research but questioned the recommendations made solely on the basis of evidence from discharge data. While hospital costs in nonperforated cases may be higher with laparoscopic procedures, the cost to society could be lower, he said, noting that such patients usually return to work sooner.

“Society costs vs. hospital costs—this is a philosophical question,” Dr. Nirula responded, emphasizing that the study only addressed the growing concern over hospital costs.

As for why an open procedure with longer length of stay would not cost more in perforated appendectomy cases, Dr. Nirula concurred with an audience suggestion that the added cost of equipment for laparoscopy probably was a factor.

For a related video with Dr. Cheng, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Patients with severe idiopathic thrombocytopenic purpura were eight times more likely to achieve target platelet counts when treated for 6 months with oral eltrombopag in a randomized, placebo-controlled, phase III trial presented at the annual meeting of the American Society of Hematology.

Eltrombopag (Promacta) reduced the odds of bleeding by 76% and of clinically significant bleeding by 65%, vs. placebo. It also lessened the need for rescue medications and concomitant medications in patients with chronic idiopathic thrombocytopenic purpura (ITP) not responsive to previous therapy.

No safety concerns emerged in RAISE (Randomized Placebo-Controlled ITP Study With Eltrombopag), a 197-patient trial sponsored by GlaxoSmithKline and designed to evaluate long-term use of the agent. Adverse events were minor and similar with eltrombopag and placebo.

For patients who are “refractory to the conventional therapy or suffering from the side effects, there is now new hope and a new treatment,” principal investigator Dr. Gregory Cheng of the Chinese University of Hong Kong said at a press briefing.

The availability of eltrombopag and romiplostim (AMG-531, Nplate), another new thrombopoietin receptor agonist, represents “a huge change” in thinking about ITP and will greatly benefit patients, according to Dr. Sherrill J. Slichter, an investigator at the briefing, who was not involved in the eltrombopag study and who emphasized that she has no stock in the companies behind these new drugs.

“It has been an enormous boon to the management of these patients to be able to show that some of the ones who fail immunosuppressive therapy in fact respond to an agent that increases platelet production,” said Dr. Slichter of Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network in Seattle. Stopping eltrombopag leads to a reduction in platelet counts, she said: “So it is not a cure, but it is a treatment.”

Still, despite enthusiasm for Dr. Cheng's results, neither Dr. Slichter nor Dr. Kenneth Kaushansky, president of ASH, was ready to use eltrombopag in patients who still have other options. Indeed, Dr. Kaushansky, chair of the department of medicine at the University of California, San Diego, predicted that hematologists would be slow to adopt eltrombopag and romiplostim.

“We have not seen significant side effects so far from thrombopoietin-stimulating agents,” he said. “But we don't have years and tens of thousands of experiences yet. Once we begin to see [that] the side effect profile of those agents is not significant, then I think confidence will grow in those agents, and I think we will see those agents used earlier.”

Dr. Cheng agreed that, in his own practice, he still reserves eltrombopag for chronic patients who have failed to respond to other proven therapies. “My first line of therapy will still be corticosteroids,” he said, concurring that potentially curative treatments, including splenectomy, should be tried before potentially lifelong treatment with eltrombopag.

An exception might be an ITP patient scheduled for surgery, Dr. Cheng suggested. Currently, the patient might be admitted to a hospital for preparation with intravenous immunoglobulin, but 2 weeks of oral eltrombopag therapy could be an outpatient alternative. “Then they have the surgery and can stop the medication afterward,” he said.

RAISE randomized adults with platelet counts below 30,000 mcL who had failed at least one other ITP therapy. While 135 patients received a starting dose of 50 mg of eltrombopag once daily, another 62 patients received a placebo. Depending on response, the trial allowed titration of the eltrombopag dose up or down in a range of 25–75 mg once a day.

Investigators set the primary end point as achieving platelet counts between 50,000 and 400,000 mcL. Dr. Cheng said that 75% of the eltrombopag cohort reached target, vs. 28% of those on placebo. This was true regardless of splenectomy status. The odds ratio for achieving a response with eltrombopag was 8.2.

Median counts were 16,000 mcL in both cohorts before the initiation of treatment, and never went above 30,000 mcL in the placebo group, according to data released by GlaxoSmithKline. In the eltrombopag cohort, it rose to 36,000 mcL after 1 week, and thereafter ranged from 52,000 mcL to 91,000 mcL during the study. The median returned to baseline within 2 weeks of stopping eltrombopag at the end of the study.

Secondary end points favoring eltrombopag included more patients stopping or reducing simultaneous ITP medications (59% vs. 32%) and fewer patients needing rescue therapy (19% vs. 40%).

Dr. Cheng disclosed being a consultant to and receiving honoraria from GlaxoSmithKline. His coinvestigators included employees of the company and holders of equity ownership.

'There is now new hope and a new treatment' for ITP patients refractory to conventional treatment. DR. CHENG

For a related video with Dr. Cheng, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Patients with severe idiopathic thrombocytopenic purpura were eight times more likely to achieve target platelet counts when treated for 6 months with oral eltrombopag in a randomized, placebo-controlled, phase III trial presented at the annual meeting of the American Society of Hematology.

Eltrombopag (Promacta) reduced the odds of bleeding by 76% and of clinically significant bleeding by 65%, vs. placebo. It also lessened the need for rescue medications and concomitant medications in patients with chronic idiopathic thrombocytopenic purpura (ITP) not responsive to previous therapy.

No safety concerns emerged in RAISE (Randomized Placebo-Controlled ITP Study With Eltrombopag), a 197-patient trial sponsored by GlaxoSmithKline and designed to evaluate long-term use of the agent. Adverse events were minor and similar with eltrombopag and placebo.

For patients who are “refractory to the conventional therapy or suffering from the side effects, there is now new hope and a new treatment,” principal investigator Dr. Gregory Cheng of the Chinese University of Hong Kong said at a press briefing.

The availability of eltrombopag and romiplostim (AMG-531, Nplate), another new thrombopoietin receptor agonist, represents “a huge change” in thinking about ITP and will greatly benefit patients, according to Dr. Sherrill J. Slichter, an investigator at the briefing, who was not involved in the eltrombopag study and who emphasized that she has no stock in the companies behind these new drugs.

“It has been an enormous boon to the management of these patients to be able to show that some of the ones who fail immunosuppressive therapy in fact respond to an agent that increases platelet production,” said Dr. Slichter of Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network in Seattle. Stopping eltrombopag leads to a reduction in platelet counts, she said: “So it is not a cure, but it is a treatment.”

Still, despite enthusiasm for Dr. Cheng's results, neither Dr. Slichter nor Dr. Kenneth Kaushansky, president of ASH, was ready to use eltrombopag in patients who still have other options. Indeed, Dr. Kaushansky, chair of the department of medicine at the University of California, San Diego, predicted that hematologists would be slow to adopt eltrombopag and romiplostim.

“We have not seen significant side effects so far from thrombopoietin-stimulating agents,” he said. “But we don't have years and tens of thousands of experiences yet. Once we begin to see [that] the side effect profile of those agents is not significant, then I think confidence will grow in those agents, and I think we will see those agents used earlier.”

Dr. Cheng agreed that, in his own practice, he still reserves eltrombopag for chronic patients who have failed to respond to other proven therapies. “My first line of therapy will still be corticosteroids,” he said, concurring that potentially curative treatments, including splenectomy, should be tried before potentially lifelong treatment with eltrombopag.

An exception might be an ITP patient scheduled for surgery, Dr. Cheng suggested. Currently, the patient might be admitted to a hospital for preparation with intravenous immunoglobulin, but 2 weeks of oral eltrombopag therapy could be an outpatient alternative. “Then they have the surgery and can stop the medication afterward,” he said.

RAISE randomized adults with platelet counts below 30,000 mcL who had failed at least one other ITP therapy. While 135 patients received a starting dose of 50 mg of eltrombopag once daily, another 62 patients received a placebo. Depending on response, the trial allowed titration of the eltrombopag dose up or down in a range of 25–75 mg once a day.

Investigators set the primary end point as achieving platelet counts between 50,000 and 400,000 mcL. Dr. Cheng said that 75% of the eltrombopag cohort reached target, vs. 28% of those on placebo. This was true regardless of splenectomy status. The odds ratio for achieving a response with eltrombopag was 8.2.

Median counts were 16,000 mcL in both cohorts before the initiation of treatment, and never went above 30,000 mcL in the placebo group, according to data released by GlaxoSmithKline. In the eltrombopag cohort, it rose to 36,000 mcL after 1 week, and thereafter ranged from 52,000 mcL to 91,000 mcL during the study. The median returned to baseline within 2 weeks of stopping eltrombopag at the end of the study.

Secondary end points favoring eltrombopag included more patients stopping or reducing simultaneous ITP medications (59% vs. 32%) and fewer patients needing rescue therapy (19% vs. 40%).

Dr. Cheng disclosed being a consultant to and receiving honoraria from GlaxoSmithKline. His coinvestigators included employees of the company and holders of equity ownership.

'There is now new hope and a new treatment' for ITP patients refractory to conventional treatment. DR. CHENG

For a related video with Dr. Cheng, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Patients with severe idiopathic thrombocytopenic purpura were eight times more likely to achieve target platelet counts when treated for 6 months with oral eltrombopag in a randomized, placebo-controlled, phase III trial presented at the annual meeting of the American Society of Hematology.

Eltrombopag (Promacta) reduced the odds of bleeding by 76% and of clinically significant bleeding by 65%, vs. placebo. It also lessened the need for rescue medications and concomitant medications in patients with chronic idiopathic thrombocytopenic purpura (ITP) not responsive to previous therapy.

No safety concerns emerged in RAISE (Randomized Placebo-Controlled ITP Study With Eltrombopag), a 197-patient trial sponsored by GlaxoSmithKline and designed to evaluate long-term use of the agent. Adverse events were minor and similar with eltrombopag and placebo.

For patients who are “refractory to the conventional therapy or suffering from the side effects, there is now new hope and a new treatment,” principal investigator Dr. Gregory Cheng of the Chinese University of Hong Kong said at a press briefing.

The availability of eltrombopag and romiplostim (AMG-531, Nplate), another new thrombopoietin receptor agonist, represents “a huge change” in thinking about ITP and will greatly benefit patients, according to Dr. Sherrill J. Slichter, an investigator at the briefing, who was not involved in the eltrombopag study and who emphasized that she has no stock in the companies behind these new drugs.

“It has been an enormous boon to the management of these patients to be able to show that some of the ones who fail immunosuppressive therapy in fact respond to an agent that increases platelet production,” said Dr. Slichter of Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network in Seattle. Stopping eltrombopag leads to a reduction in platelet counts, she said: “So it is not a cure, but it is a treatment.”

Still, despite enthusiasm for Dr. Cheng's results, neither Dr. Slichter nor Dr. Kenneth Kaushansky, president of ASH, was ready to use eltrombopag in patients who still have other options. Indeed, Dr. Kaushansky, chair of the department of medicine at the University of California, San Diego, predicted that hematologists would be slow to adopt eltrombopag and romiplostim.

“We have not seen significant side effects so far from thrombopoietin-stimulating agents,” he said. “But we don't have years and tens of thousands of experiences yet. Once we begin to see [that] the side effect profile of those agents is not significant, then I think confidence will grow in those agents, and I think we will see those agents used earlier.”

Dr. Cheng agreed that, in his own practice, he still reserves eltrombopag for chronic patients who have failed to respond to other proven therapies. “My first line of therapy will still be corticosteroids,” he said, concurring that potentially curative treatments, including splenectomy, should be tried before potentially lifelong treatment with eltrombopag.

An exception might be an ITP patient scheduled for surgery, Dr. Cheng suggested. Currently, the patient might be admitted to a hospital for preparation with intravenous immunoglobulin, but 2 weeks of oral eltrombopag therapy could be an outpatient alternative. “Then they have the surgery and can stop the medication afterward,” he said.

RAISE randomized adults with platelet counts below 30,000 mcL who had failed at least one other ITP therapy. While 135 patients received a starting dose of 50 mg of eltrombopag once daily, another 62 patients received a placebo. Depending on response, the trial allowed titration of the eltrombopag dose up or down in a range of 25–75 mg once a day.

Investigators set the primary end point as achieving platelet counts between 50,000 and 400,000 mcL. Dr. Cheng said that 75% of the eltrombopag cohort reached target, vs. 28% of those on placebo. This was true regardless of splenectomy status. The odds ratio for achieving a response with eltrombopag was 8.2.

Median counts were 16,000 mcL in both cohorts before the initiation of treatment, and never went above 30,000 mcL in the placebo group, according to data released by GlaxoSmithKline. In the eltrombopag cohort, it rose to 36,000 mcL after 1 week, and thereafter ranged from 52,000 mcL to 91,000 mcL during the study. The median returned to baseline within 2 weeks of stopping eltrombopag at the end of the study.

Secondary end points favoring eltrombopag included more patients stopping or reducing simultaneous ITP medications (59% vs. 32%) and fewer patients needing rescue therapy (19% vs. 40%).

Dr. Cheng disclosed being a consultant to and receiving honoraria from GlaxoSmithKline. His coinvestigators included employees of the company and holders of equity ownership.

'There is now new hope and a new treatment' for ITP patients refractory to conventional treatment. DR. CHENG

For a related video, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT

For a related video, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT

For a related video, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT

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 they all 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 to be eligible.

“The placebo group steadily gained weight throughout the study. The sibutramine group gained less weight,” Dr. James W. Anderson, the principal 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 statistically significant, and both groups appeared to plateau with no difference from 30 to 48 months.

Dr. Anderson, professor emeritus of medicine and clinical nutrition at the University of Kentucky, Lexington, has been medical director of the HMR Weight Loss Program at the university for 22 years. He said he proposed the study to address the common problem of weight rebound after weight loss and designed the trial to run for 60 months.

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

The trial randomized 236 subjects to receive 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.

The baseline population was about 48 years old on average. More than 90% were white, and three-fourths were women. The participants weighed about 91 kg with a mean body mass index slightly over 32 kg/m

With data on 289 participants, Dr. Anderson estimated that they would have maintained 10.4 kg of weight loss at 5 years—or 35.1% of their initial weight loss before entering the trial.

Blood pressure and pulse rate were significantly higher with sibutramine, said Dr. Anderson, but total adverse events were not. “Sibutramine may be a useful adjunct in selected patients,” he concluded.

'The placebo group steadily gained weight…. The sibutramine group gained less weight.' DR. ANDERSON

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 they all 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 to be eligible.

“The placebo group steadily gained weight throughout the study. The sibutramine group gained less weight,” Dr. James W. Anderson, the principal 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 statistically significant, and both groups appeared to plateau with no difference from 30 to 48 months.

Dr. Anderson, professor emeritus of medicine and clinical nutrition at the University of Kentucky, Lexington, has been medical director of the HMR Weight Loss Program at the university for 22 years. He said he proposed the study to address the common problem of weight rebound after weight loss and designed the trial to run for 60 months.

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

The trial randomized 236 subjects to receive 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.

The baseline population was about 48 years old on average. More than 90% were white, and three-fourths were women. The participants weighed about 91 kg with a mean body mass index slightly over 32 kg/m

With data on 289 participants, Dr. Anderson estimated that they would have maintained 10.4 kg of weight loss at 5 years—or 35.1% of their initial weight loss before entering the trial.

Blood pressure and pulse rate were significantly higher with sibutramine, said Dr. Anderson, but total adverse events were not. “Sibutramine may be a useful adjunct in selected patients,” he concluded.

'The placebo group steadily gained weight…. The sibutramine group gained less weight.' DR. ANDERSON

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 they all 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 to be eligible.

“The placebo group steadily gained weight throughout the study. The sibutramine group gained less weight,” Dr. James W. Anderson, the principal 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 statistically significant, and both groups appeared to plateau with no difference from 30 to 48 months.

Dr. Anderson, professor emeritus of medicine and clinical nutrition at the University of Kentucky, Lexington, has been medical director of the HMR Weight Loss Program at the university for 22 years. He said he proposed the study to address the common problem of weight rebound after weight loss and designed the trial to run for 60 months.

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

The trial randomized 236 subjects to receive 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.

The baseline population was about 48 years old on average. More than 90% were white, and three-fourths were women. The participants weighed about 91 kg with a mean body mass index slightly over 32 kg/m

With data on 289 participants, Dr. Anderson estimated that they would have maintained 10.4 kg of weight loss at 5 years—or 35.1% of their initial weight loss before entering the trial.

Blood pressure and pulse rate were significantly higher with sibutramine, said Dr. Anderson, but total adverse events were not. “Sibutramine may be a useful adjunct in selected patients,” he concluded.

'The placebo group steadily gained weight…. The sibutramine group gained less weight.' DR. ANDERSON

PHOENIX — Orlistat produced modest weight loss in extremely obese adolescents but failed to reverse comorbidities associated with metabolic syndrome in a randomized, placebo-controlled trial conducted by the National Institutes of Health.

Teenagers treated with orlistat (Xenical) lost more weight than did those on placebo after 6 months of treatment, but measures of blood pressure, cholesterol, insulin resistance, and fat-soluble vitamins were not significantly different—except for triglycerides, which were lower in the placebo group (P = .05).

“Orlistat really cannot be routinely recommended for treatment of obese-adolescents for comorbid conditions associated with obesity,” Dr. Jack A. Yanovski, the principal investigator, concluded during his presentation of the data at the annual scientific meeting of the Obesity Society.

Dr. Yanovski, head of the unit on growth and obesity within the National Institute of Child Health and Human Development, noted that orlistat gained approval for use in obese 12- to 16-year-olds in 2003 after a large randomized trial sponsored by Hoffmann-La Roche Inc. showed a modest but statistically significant reduction in body mass index (BMI) for this population. Only a quarter of participants met metabolic syndrome criteria, however, and changes in lipids, glucose, blood pressure, and insulin resistance were not significant.

Roche contributed orlistat and placebo for the current study, which enrolled 200 overweight black and white teenagers, all of whom had at least one comorbidity associated with metabolic syndrome. The group was evenly randomized: 100 participants to the full adult dose of 120 mg of orlistat three times per day and 100 teens to placebo. All were given a low-calorie diet.

The population was about 65% female and 61% black with an average age of about 14.6 years and average BMI of 41.7 kg/m

The orlistat group lost significantly more weight: −2.9 kg. vs. −0.6 kg for the placebo group. The orlistat group also had a significantly greater reduction in BMI (−1.72 vs. −0.70) and in fat mass (−3.9 kg. vs. −1.4 kg).

Blacks lost significantly less weight on orlistat than did whites, but orlistat was just as efficacious when weight gain in the black placebo group was taken into account. For blacks, the difference between weight loss on orlistat and weight gain on placebo was 2.5 kg. Whites lost whether they were on orlistat or placebo, but they lost more on orlistat with a similar difference of 2.2 kg.

Liver enzymes were significantly and unexpectedly higher with orlistat, he reported. Gastrointestinal side effects also were more common, but described as short in duration and well tolerated.

Although the trial was blinded, Dr. Yanovski reported most participants in the orlistat arm guessed correctly that they were on the study medication—possibly as a result of the GI side effects associated with orlistat.

PHOENIX — Orlistat produced modest weight loss in extremely obese adolescents but failed to reverse comorbidities associated with metabolic syndrome in a randomized, placebo-controlled trial conducted by the National Institutes of Health.

Teenagers treated with orlistat (Xenical) lost more weight than did those on placebo after 6 months of treatment, but measures of blood pressure, cholesterol, insulin resistance, and fat-soluble vitamins were not significantly different—except for triglycerides, which were lower in the placebo group (P = .05).

“Orlistat really cannot be routinely recommended for treatment of obese-adolescents for comorbid conditions associated with obesity,” Dr. Jack A. Yanovski, the principal investigator, concluded during his presentation of the data at the annual scientific meeting of the Obesity Society.

Dr. Yanovski, head of the unit on growth and obesity within the National Institute of Child Health and Human Development, noted that orlistat gained approval for use in obese 12- to 16-year-olds in 2003 after a large randomized trial sponsored by Hoffmann-La Roche Inc. showed a modest but statistically significant reduction in body mass index (BMI) for this population. Only a quarter of participants met metabolic syndrome criteria, however, and changes in lipids, glucose, blood pressure, and insulin resistance were not significant.

Roche contributed orlistat and placebo for the current study, which enrolled 200 overweight black and white teenagers, all of whom had at least one comorbidity associated with metabolic syndrome. The group was evenly randomized: 100 participants to the full adult dose of 120 mg of orlistat three times per day and 100 teens to placebo. All were given a low-calorie diet.

The population was about 65% female and 61% black with an average age of about 14.6 years and average BMI of 41.7 kg/m

The orlistat group lost significantly more weight: −2.9 kg. vs. −0.6 kg for the placebo group. The orlistat group also had a significantly greater reduction in BMI (−1.72 vs. −0.70) and in fat mass (−3.9 kg. vs. −1.4 kg).

Blacks lost significantly less weight on orlistat than did whites, but orlistat was just as efficacious when weight gain in the black placebo group was taken into account. For blacks, the difference between weight loss on orlistat and weight gain on placebo was 2.5 kg. Whites lost whether they were on orlistat or placebo, but they lost more on orlistat with a similar difference of 2.2 kg.

Liver enzymes were significantly and unexpectedly higher with orlistat, he reported. Gastrointestinal side effects also were more common, but described as short in duration and well tolerated.

Although the trial was blinded, Dr. Yanovski reported most participants in the orlistat arm guessed correctly that they were on the study medication—possibly as a result of the GI side effects associated with orlistat.

PHOENIX — Orlistat produced modest weight loss in extremely obese adolescents but failed to reverse comorbidities associated with metabolic syndrome in a randomized, placebo-controlled trial conducted by the National Institutes of Health.

Teenagers treated with orlistat (Xenical) lost more weight than did those on placebo after 6 months of treatment, but measures of blood pressure, cholesterol, insulin resistance, and fat-soluble vitamins were not significantly different—except for triglycerides, which were lower in the placebo group (P = .05).

“Orlistat really cannot be routinely recommended for treatment of obese-adolescents for comorbid conditions associated with obesity,” Dr. Jack A. Yanovski, the principal investigator, concluded during his presentation of the data at the annual scientific meeting of the Obesity Society.

Dr. Yanovski, head of the unit on growth and obesity within the National Institute of Child Health and Human Development, noted that orlistat gained approval for use in obese 12- to 16-year-olds in 2003 after a large randomized trial sponsored by Hoffmann-La Roche Inc. showed a modest but statistically significant reduction in body mass index (BMI) for this population. Only a quarter of participants met metabolic syndrome criteria, however, and changes in lipids, glucose, blood pressure, and insulin resistance were not significant.

Roche contributed orlistat and placebo for the current study, which enrolled 200 overweight black and white teenagers, all of whom had at least one comorbidity associated with metabolic syndrome. The group was evenly randomized: 100 participants to the full adult dose of 120 mg of orlistat three times per day and 100 teens to placebo. All were given a low-calorie diet.

The population was about 65% female and 61% black with an average age of about 14.6 years and average BMI of 41.7 kg/m

The orlistat group lost significantly more weight: −2.9 kg. vs. −0.6 kg for the placebo group. The orlistat group also had a significantly greater reduction in BMI (−1.72 vs. −0.70) and in fat mass (−3.9 kg. vs. −1.4 kg).

Blacks lost significantly less weight on orlistat than did whites, but orlistat was just as efficacious when weight gain in the black placebo group was taken into account. For blacks, the difference between weight loss on orlistat and weight gain on placebo was 2.5 kg. Whites lost whether they were on orlistat or placebo, but they lost more on orlistat with a similar difference of 2.2 kg.

Liver enzymes were significantly and unexpectedly higher with orlistat, he reported. Gastrointestinal side effects also were more common, but described as short in duration and well tolerated.

Although the trial was blinded, Dr. Yanovski reported most participants in the orlistat arm guessed correctly that they were on the study medication—possibly as a result of the GI side effects associated with orlistat.

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial in obese patients, most of whom 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.

“A very nice dose separation” was how 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 at the annual scientific meeting of NAASO, the Obesity Society.

Novo Nordisk A/S sponsored the trial. It announced in May that it had submitted a New Drug Application for liraglutide to the U.S. Food and Drug Administration and a marketing authorization application to the European Medicines Agency—both seeking an indication for liraglutide in the treatment of people with type 2 diabetes. These were followed in July by a request for marketing approval in Japan.

Liraglutide is a human analogue of glucagon-like peptide-1 (GLP-1). According to the company's Web site, liraglutide inhibits appetite and stimulates insulin production only when glucose levels become too high.

In September, The Lancet published the results of a 1-year phase III trial showing that patients with early type 2 diabetes achieved better glycemic control with liraglutide monotherapy (doi:10.1016/S0140–6736(08)61246–5).

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. Waist circumference also went down significantly relative to placebo at the two highest liraglutide doses.

Pulse rates increased by up to four beats per minute with liraglutide but declined with placebo and orlistat. Mean systolic blood pressure decreased 5.6–8.8 mm Hg in the liraglutide groups, and declined 4 mm Hg with placebo and 5.4 mm Hg with orlistat.

Four patients had hypoglycemic symptoms with liraglutide. None required assistance. The most common events were nausea and vomiting. “In all the doses except the highest, [nausea] came down to the placebo level over time,” Dr. Astrup said. A phase III trial is planned.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving financial 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.

The proportion who lost 5% or more of body weight was 44% with orlistat but 54%–76% with liraglutide. DR. ASTRUP

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial in obese patients, most of whom 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.

“A very nice dose separation” was how 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 at the annual scientific meeting of NAASO, the Obesity Society.

Novo Nordisk A/S sponsored the trial. It announced in May that it had submitted a New Drug Application for liraglutide to the U.S. Food and Drug Administration and a marketing authorization application to the European Medicines Agency—both seeking an indication for liraglutide in the treatment of people with type 2 diabetes. These were followed in July by a request for marketing approval in Japan.

Liraglutide is a human analogue of glucagon-like peptide-1 (GLP-1). According to the company's Web site, liraglutide inhibits appetite and stimulates insulin production only when glucose levels become too high.

In September, The Lancet published the results of a 1-year phase III trial showing that patients with early type 2 diabetes achieved better glycemic control with liraglutide monotherapy (doi:10.1016/S0140–6736(08)61246–5).

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. Waist circumference also went down significantly relative to placebo at the two highest liraglutide doses.

Pulse rates increased by up to four beats per minute with liraglutide but declined with placebo and orlistat. Mean systolic blood pressure decreased 5.6–8.8 mm Hg in the liraglutide groups, and declined 4 mm Hg with placebo and 5.4 mm Hg with orlistat.

Four patients had hypoglycemic symptoms with liraglutide. None required assistance. The most common events were nausea and vomiting. “In all the doses except the highest, [nausea] came down to the placebo level over time,” Dr. Astrup said. A phase III trial is planned.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving financial 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.

The proportion who lost 5% or more of body weight was 44% with orlistat but 54%–76% with liraglutide. DR. ASTRUP

PHOENIX — Liraglutide, an investigational drug given once a day, produced significantly more weight loss than orlistat in a randomized, 20-week, placebo-controlled trial in obese patients, most of whom 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.

“A very nice dose separation” was how 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 at the annual scientific meeting of NAASO, the Obesity Society.

Novo Nordisk A/S sponsored the trial. It announced in May that it had submitted a New Drug Application for liraglutide to the U.S. Food and Drug Administration and a marketing authorization application to the European Medicines Agency—both seeking an indication for liraglutide in the treatment of people with type 2 diabetes. These were followed in July by a request for marketing approval in Japan.

Liraglutide is a human analogue of glucagon-like peptide-1 (GLP-1). According to the company's Web site, liraglutide inhibits appetite and stimulates insulin production only when glucose levels become too high.

In September, The Lancet published the results of a 1-year phase III trial showing that patients with early type 2 diabetes achieved better glycemic control with liraglutide monotherapy (doi:10.1016/S0140–6736(08)61246–5).

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. Waist circumference also went down significantly relative to placebo at the two highest liraglutide doses.

Pulse rates increased by up to four beats per minute with liraglutide but declined with placebo and orlistat. Mean systolic blood pressure decreased 5.6–8.8 mm Hg in the liraglutide groups, and declined 4 mm Hg with placebo and 5.4 mm Hg with orlistat.

Four patients had hypoglycemic symptoms with liraglutide. None required assistance. The most common events were nausea and vomiting. “In all the doses except the highest, [nausea] came down to the placebo level over time,” Dr. Astrup said. A phase III trial is planned.

Dr. Astrup disclosed being a consultant to Novo Nordisk and receiving financial 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.

The proportion who lost 5% or more of body weight was 44% with orlistat but 54%–76% with liraglutide. DR. ASTRUP

PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.

Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were engaged in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.

About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.

The 91 obese patients in the study had a baseline body mass index of 42 mg/m

Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger (average age, 43 years). This cohort started with a baseline BMI of 53 kg/m

In 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks, fell to 30 U/L at 16 weeks, and were below baseline at 40 weeks. Mean peak and final values in this group were 81 U/L and 24 U/L, respectively. Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks, then fell to 34 U/L by 16 weeks. Mean peak and final values in this group were 97 U/L and 28 U/L, respectively. A similar pattern was seen in the obese group, but the changes were not as dramatic. Initial and final ALT values were 33 U/L and 29 U/L, respectively, said Dr. Anderson, who disclosed no conflicts of interest.

PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.

Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were engaged in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.

About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.

The 91 obese patients in the study had a baseline body mass index of 42 mg/m

Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger (average age, 43 years). This cohort started with a baseline BMI of 53 kg/m

In 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks, fell to 30 U/L at 16 weeks, and were below baseline at 40 weeks. Mean peak and final values in this group were 81 U/L and 24 U/L, respectively. Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks, then fell to 34 U/L by 16 weeks. Mean peak and final values in this group were 97 U/L and 28 U/L, respectively. A similar pattern was seen in the obese group, but the changes were not as dramatic. Initial and final ALT values were 33 U/L and 29 U/L, respectively, said Dr. Anderson, who disclosed no conflicts of interest.

PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.

Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were engaged in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.

About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.

The 91 obese patients in the study had a baseline body mass index of 42 mg/m

Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger (average age, 43 years). This cohort started with a baseline BMI of 53 kg/m

In 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks, fell to 30 U/L at 16 weeks, and were below baseline at 40 weeks. Mean peak and final values in this group were 81 U/L and 24 U/L, respectively. Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks, then fell to 34 U/L by 16 weeks. Mean peak and final values in this group were 97 U/L and 28 U/L, respectively. A similar pattern was seen in the obese group, but the changes were not as dramatic. Initial and final ALT values were 33 U/L and 29 U/L, respectively, said Dr. Anderson, who disclosed no conflicts of interest.

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.

STOCKHOLM — The failure of the largest randomized phase III trial ever conducted in stage IV melanoma has left investigators around the globe with a question for which they have no easy answer: What next?

Temozolomide did not improve upon the dismal survival rates achieved by standard therapy with dacarbazine (DTIC) in the disappointing multinational study presented at the European Society for Medical Oncology Congress. And some experimental treatments for advanced melanoma produced objective responses in less than 10% of patients reported upon by phase II investigators at the same meeting.

Moreover, DTIC may not be better than best supportive care—the two have never been tested against each other, according to Dr. Lorenz Jost, who painted a glum picture of melanoma research to date in his discussion of the temozolomide study.

"We don't have any proof that dacarbazine extends survival. Even worse, we don't have any proof that DTIC doesn't shorten survival," Dr. Jost of Kantonsspital Bruderholz in Switzerland told Congress attendees.

Except for the historical failure to compare DTIC to best supportive care, Dr. Jost found nothing wrong with the conduct of the European Organisation for Research and Treatment of Cancer (EORTC) 18032 trial comparing oral temozolomide with DTIC injection. At a median 18-month follow-up, median overall survival was little better than 9 months in both arms of the 859-patient study.

No chemotherapy combination has shown a significant advantage over DTIC, Dr. Jost said, citing a study comparing DTIC with vinblastine, bleomycin, and cisplatin (J. Clin. Oncol. 1984;2:164-8), nor have more aggressive regimens, such as one augmenting DTIC with cisplatin and carmustine (J. Clin. Oncol. 1999;17:2745-51).

Vaccines likewise have produced similar survival rates to DTIC (Ann. Onc. 2006;17:563-70), he continued, and a metaanalysis of 18 trials involving 2,621 patients randomized to biochemotherapies versus chemotherapy yielded an odds ratio of 0.99 for overall survival (J. Clin. Oncol. 2007;25:5426-34).

If DTIC cannot clear large tumors, Dr. Jost asked, can it be better used as an adjuvant therapy? No benefit has been seen with that approach, and boosting DTIC with sorafenib also produced no advantage in a study published earlier this year (J. Clin. Oncol. 2008;26:2178-85).

Maybe investigators should move on to a new class of drugs targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), he suggested, showing a list of about a dozen studies, among which only three trials reported patient responses (J. Trans. Med. 2008;6:22).

Despite all these red lights, Dr. Jost urged his audience not to despair. "Keep putting patients onto trials," he said.

But what trials? Even before Dr. Jost discussed the temozolomide results, an audience member suggested that perhaps it was time to stop doing phase III chemotherapy trials in melanoma.

Indeed, so many phase III trials have failed to improve survival rates in patients with late-stage melanoma that asking "What is your next phase III?" is to pose "a below-the-belt question," according to Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute.

"We don't have an idea in the cooperative groups in the United States. Both the Southwest [Oncology Group] and the ECOG [Eastern Cooperative Oncology Group] are totally waiting for something in a blinding streak of brilliance," said Dr. Kirkwood, an ECOG investigator.

He reported on the investigational anti-CTLA-4 agent tremelimumab in a Pfizer Inc.-sponsored trial during the same session (see related story above). The bottom line seen in trials of tremelimumab and another experimental anti-CTLA-4 agent, ipilimumab, is that "objective response rates are very similar and there are people alive who wouldn't have been without these agents," he said in an interview. The main obstacle is anti-CTLA-4 therapy is "not efficient," with only a small number of people responding out of hundreds so far treated. The next step is to study proinflammatory cytokines and proteomics to identify factors predictive of response to these agents, Dr. Kirkwood said.

For Dr. Poulam M. Patel of the University of Nottingham (England), and investigator of the temozolomide trial, finding ways to identify molecular targets and subtype patients is likely to be the next direction taken by collaborative groups in melanoma. In his presentation, he also noted that no therapy has been proved more effective than DTIC in 2 decades.