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Doxorubicin Remains First-Line Standard for Metastatic Soft-Tissue Sarcomas
VIENNA – A more aggressive combination of doxorubicin and ifosfamide provided no significant overall survival advantage over single-agent doxorubicin as first-line chemotherapy in advanced soft-tissue sarcoma in a phase III trial.
The European Organisation for Research and Treatment of Cancer (EORTC) 62012 study’s primary end point of median overall survival reached 14.3 months with the combination and 12.8 months with doxorubicin alone (hazard ratio, 0.83; P = .076). One-year survival rates were 60% and 51%, respectively.
As previously observed, the combination of doxorubicin (Adriamycin) and ifosfamide (Ifex) increased response rates and progression-free survival, but at a cost of considerably more toxicity. "The standard treatment remains single-agent doxorubicin," Dr. Winette van der Graaf said during a Presidential Symposium at the European Society for Medical Oncology Congress.
Combination therapy, she added, can be considered if surgery for unresectable tumors or curative metastasectomy is foreseen, and may be an option for highly symptomatic patients without comorbidity, although the pros and cons should be discussed with the patient.
"The advantage of having the results of this study is that it’s easier now to have this discussion with the patient," said Dr. van der Graaf, of Radboud University Nijmegen (Netherlands) Medical Centre.
The EORTC Soft Tissue and Bone Sarcoma Group designed the trial to answer the long-standing question of whether single-agent doxorubicin or doxorubicin plus ifosfamide is the best first-line treatment for metastatic soft-tissue sarcomas. An earlier EORTC phase III trial (J. Clin. Oncol. 1995;13:1537-45) explored the combination at a lower dose of ifosfamide than is used today, with more recent phase II trials suggesting that a higher dose could increase response rates and progression-free survival.
EORTC 62012 investigators at 38 centers in nine countries randomly assigned 455 patients, aged 18-60 years, with locally advanced unresectable or metastatic soft-tissue sarcoma to receive doxorubicin 75 mg/m2 bolus on day 1 or as a 72-hour continuous IV infusion or doxorubicin 25 mg/m2 on days 1-3 plus ifosfamide 2.5 g/m2 on days 1-4 and pegfilgrastim 6 mg subcutaneous on day 5.
Patients were stratified by age, performance status (0 vs. 1), liver metastases, and histological grade. No prior chemotherapy was allowed for advanced disease.
After a median follow-up of 56 months, median progression-free survival increased significantly from 4.6 months with single-agent doxorubicin to 7.4 months with the addition of ifosfamide (HR 0.74, P = .003), Dr. van der Graaf reported on behalf of lead author Dr. Ian Judson of the Royal Marsden Hospital, London.
Subgroup analyses revealed significantly longer progression-free survival among patients aged 40-49 years, but this significance disappeared when all patients under age 50 were included in the analysis. No subgroups had significantly better overall survival.
The complete response rate was very low, at 0.4% in the doxorubicin arm and 1.8% in the combination arm. Remarkably, partial responses doubled with combination therapy from 13.2% to 24.7%, but overall response rates (13.6% vs. 26.5%) were far less than expected from phase II trials, where they ranged from 52% to 66%, she observed.
At first blush, the difference in progression-free survival with combination therapy may not appear that important, but from the perspective of patients with metastatic soft-tissue sarcoma, who typically have a median survival of only 1 year, this means that they’ll spend about 20% of their lifetime longer with disease control, said discussant Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
"The question for us as clinicians is can we target patients who truly would get more benefit from this kind of doubling of tumor response and control, despite the sizable toxicities of the more toxic combination chemotherapy," he said.
Dr. Demetri pointed out that significantly more patients discontinued combination therapy than single-agent doxorubicin due to toxicity (40 patients vs. 6 patients). The most common grade 3 or higher adverse events in the combination and doxorubicin arms were febrile neutropenia (46% vs. 13.5%), anemia (35% vs. 4.6%) and thrombocytopenia (33.5% vs. 0.4%).
Dr. Demetri cautioned that the results should not be blindly extrapolated to clinical practice because patients in the trial were younger and healthier than those typically seen in practice. However, the solid data can be used to make informed choices, he said.
If a patient is asymptomatic, as many metastatic sarcoma patients are, then single-agent doxorubicin, which he described as a strong, aggressive, "truck" of a therapy, "may be sufficient" and "more kind, more humane" to the patient, he said. If the patient is symptomatic or tumor shrinkage is required to improve quality of life because of tumor-related pain, "then perhaps combination therapy, although more toxic, may be more beneficial," he added.
The EORTC sponsored the trial. Dr. van der Graaf and Dr. Judson reported no conflicts of interest. Dr. Demetri reported financial relationships with several pharmaceutical companies.
VIENNA – A more aggressive combination of doxorubicin and ifosfamide provided no significant overall survival advantage over single-agent doxorubicin as first-line chemotherapy in advanced soft-tissue sarcoma in a phase III trial.
The European Organisation for Research and Treatment of Cancer (EORTC) 62012 study’s primary end point of median overall survival reached 14.3 months with the combination and 12.8 months with doxorubicin alone (hazard ratio, 0.83; P = .076). One-year survival rates were 60% and 51%, respectively.
As previously observed, the combination of doxorubicin (Adriamycin) and ifosfamide (Ifex) increased response rates and progression-free survival, but at a cost of considerably more toxicity. "The standard treatment remains single-agent doxorubicin," Dr. Winette van der Graaf said during a Presidential Symposium at the European Society for Medical Oncology Congress.
Combination therapy, she added, can be considered if surgery for unresectable tumors or curative metastasectomy is foreseen, and may be an option for highly symptomatic patients without comorbidity, although the pros and cons should be discussed with the patient.
"The advantage of having the results of this study is that it’s easier now to have this discussion with the patient," said Dr. van der Graaf, of Radboud University Nijmegen (Netherlands) Medical Centre.
The EORTC Soft Tissue and Bone Sarcoma Group designed the trial to answer the long-standing question of whether single-agent doxorubicin or doxorubicin plus ifosfamide is the best first-line treatment for metastatic soft-tissue sarcomas. An earlier EORTC phase III trial (J. Clin. Oncol. 1995;13:1537-45) explored the combination at a lower dose of ifosfamide than is used today, with more recent phase II trials suggesting that a higher dose could increase response rates and progression-free survival.
EORTC 62012 investigators at 38 centers in nine countries randomly assigned 455 patients, aged 18-60 years, with locally advanced unresectable or metastatic soft-tissue sarcoma to receive doxorubicin 75 mg/m2 bolus on day 1 or as a 72-hour continuous IV infusion or doxorubicin 25 mg/m2 on days 1-3 plus ifosfamide 2.5 g/m2 on days 1-4 and pegfilgrastim 6 mg subcutaneous on day 5.
Patients were stratified by age, performance status (0 vs. 1), liver metastases, and histological grade. No prior chemotherapy was allowed for advanced disease.
After a median follow-up of 56 months, median progression-free survival increased significantly from 4.6 months with single-agent doxorubicin to 7.4 months with the addition of ifosfamide (HR 0.74, P = .003), Dr. van der Graaf reported on behalf of lead author Dr. Ian Judson of the Royal Marsden Hospital, London.
Subgroup analyses revealed significantly longer progression-free survival among patients aged 40-49 years, but this significance disappeared when all patients under age 50 were included in the analysis. No subgroups had significantly better overall survival.
The complete response rate was very low, at 0.4% in the doxorubicin arm and 1.8% in the combination arm. Remarkably, partial responses doubled with combination therapy from 13.2% to 24.7%, but overall response rates (13.6% vs. 26.5%) were far less than expected from phase II trials, where they ranged from 52% to 66%, she observed.
At first blush, the difference in progression-free survival with combination therapy may not appear that important, but from the perspective of patients with metastatic soft-tissue sarcoma, who typically have a median survival of only 1 year, this means that they’ll spend about 20% of their lifetime longer with disease control, said discussant Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
"The question for us as clinicians is can we target patients who truly would get more benefit from this kind of doubling of tumor response and control, despite the sizable toxicities of the more toxic combination chemotherapy," he said.
Dr. Demetri pointed out that significantly more patients discontinued combination therapy than single-agent doxorubicin due to toxicity (40 patients vs. 6 patients). The most common grade 3 or higher adverse events in the combination and doxorubicin arms were febrile neutropenia (46% vs. 13.5%), anemia (35% vs. 4.6%) and thrombocytopenia (33.5% vs. 0.4%).
Dr. Demetri cautioned that the results should not be blindly extrapolated to clinical practice because patients in the trial were younger and healthier than those typically seen in practice. However, the solid data can be used to make informed choices, he said.
If a patient is asymptomatic, as many metastatic sarcoma patients are, then single-agent doxorubicin, which he described as a strong, aggressive, "truck" of a therapy, "may be sufficient" and "more kind, more humane" to the patient, he said. If the patient is symptomatic or tumor shrinkage is required to improve quality of life because of tumor-related pain, "then perhaps combination therapy, although more toxic, may be more beneficial," he added.
The EORTC sponsored the trial. Dr. van der Graaf and Dr. Judson reported no conflicts of interest. Dr. Demetri reported financial relationships with several pharmaceutical companies.
VIENNA – A more aggressive combination of doxorubicin and ifosfamide provided no significant overall survival advantage over single-agent doxorubicin as first-line chemotherapy in advanced soft-tissue sarcoma in a phase III trial.
The European Organisation for Research and Treatment of Cancer (EORTC) 62012 study’s primary end point of median overall survival reached 14.3 months with the combination and 12.8 months with doxorubicin alone (hazard ratio, 0.83; P = .076). One-year survival rates were 60% and 51%, respectively.
As previously observed, the combination of doxorubicin (Adriamycin) and ifosfamide (Ifex) increased response rates and progression-free survival, but at a cost of considerably more toxicity. "The standard treatment remains single-agent doxorubicin," Dr. Winette van der Graaf said during a Presidential Symposium at the European Society for Medical Oncology Congress.
Combination therapy, she added, can be considered if surgery for unresectable tumors or curative metastasectomy is foreseen, and may be an option for highly symptomatic patients without comorbidity, although the pros and cons should be discussed with the patient.
"The advantage of having the results of this study is that it’s easier now to have this discussion with the patient," said Dr. van der Graaf, of Radboud University Nijmegen (Netherlands) Medical Centre.
The EORTC Soft Tissue and Bone Sarcoma Group designed the trial to answer the long-standing question of whether single-agent doxorubicin or doxorubicin plus ifosfamide is the best first-line treatment for metastatic soft-tissue sarcomas. An earlier EORTC phase III trial (J. Clin. Oncol. 1995;13:1537-45) explored the combination at a lower dose of ifosfamide than is used today, with more recent phase II trials suggesting that a higher dose could increase response rates and progression-free survival.
EORTC 62012 investigators at 38 centers in nine countries randomly assigned 455 patients, aged 18-60 years, with locally advanced unresectable or metastatic soft-tissue sarcoma to receive doxorubicin 75 mg/m2 bolus on day 1 or as a 72-hour continuous IV infusion or doxorubicin 25 mg/m2 on days 1-3 plus ifosfamide 2.5 g/m2 on days 1-4 and pegfilgrastim 6 mg subcutaneous on day 5.
Patients were stratified by age, performance status (0 vs. 1), liver metastases, and histological grade. No prior chemotherapy was allowed for advanced disease.
After a median follow-up of 56 months, median progression-free survival increased significantly from 4.6 months with single-agent doxorubicin to 7.4 months with the addition of ifosfamide (HR 0.74, P = .003), Dr. van der Graaf reported on behalf of lead author Dr. Ian Judson of the Royal Marsden Hospital, London.
Subgroup analyses revealed significantly longer progression-free survival among patients aged 40-49 years, but this significance disappeared when all patients under age 50 were included in the analysis. No subgroups had significantly better overall survival.
The complete response rate was very low, at 0.4% in the doxorubicin arm and 1.8% in the combination arm. Remarkably, partial responses doubled with combination therapy from 13.2% to 24.7%, but overall response rates (13.6% vs. 26.5%) were far less than expected from phase II trials, where they ranged from 52% to 66%, she observed.
At first blush, the difference in progression-free survival with combination therapy may not appear that important, but from the perspective of patients with metastatic soft-tissue sarcoma, who typically have a median survival of only 1 year, this means that they’ll spend about 20% of their lifetime longer with disease control, said discussant Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
"The question for us as clinicians is can we target patients who truly would get more benefit from this kind of doubling of tumor response and control, despite the sizable toxicities of the more toxic combination chemotherapy," he said.
Dr. Demetri pointed out that significantly more patients discontinued combination therapy than single-agent doxorubicin due to toxicity (40 patients vs. 6 patients). The most common grade 3 or higher adverse events in the combination and doxorubicin arms were febrile neutropenia (46% vs. 13.5%), anemia (35% vs. 4.6%) and thrombocytopenia (33.5% vs. 0.4%).
Dr. Demetri cautioned that the results should not be blindly extrapolated to clinical practice because patients in the trial were younger and healthier than those typically seen in practice. However, the solid data can be used to make informed choices, he said.
If a patient is asymptomatic, as many metastatic sarcoma patients are, then single-agent doxorubicin, which he described as a strong, aggressive, "truck" of a therapy, "may be sufficient" and "more kind, more humane" to the patient, he said. If the patient is symptomatic or tumor shrinkage is required to improve quality of life because of tumor-related pain, "then perhaps combination therapy, although more toxic, may be more beneficial," he added.
The EORTC sponsored the trial. Dr. van der Graaf and Dr. Judson reported no conflicts of interest. Dr. Demetri reported financial relationships with several pharmaceutical companies.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Kaposi's Sarcoma Makes Unwelcome Return
Kaposi's sarcoma is making a comeback in aging HIV patients, even among those with well-controlled disease. Dr. Kieron S. Leslie, an associate clinical professor of dermatology at the University of California, San Francisco, discusses the cancer's return and its implications for patients with HIV.
Kaposi's sarcoma is making a comeback in aging HIV patients, even among those with well-controlled disease. Dr. Kieron S. Leslie, an associate clinical professor of dermatology at the University of California, San Francisco, discusses the cancer's return and its implications for patients with HIV.
Kaposi's sarcoma is making a comeback in aging HIV patients, even among those with well-controlled disease. Dr. Kieron S. Leslie, an associate clinical professor of dermatology at the University of California, San Francisco, discusses the cancer's return and its implications for patients with HIV.
Washington Post Blasts Proliferation of ESAs for Anemia
Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.
The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).
While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.
Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.
Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.
The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).
While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.
Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.
Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.
The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).
While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.
Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.
FDA Warns of QT Prolongation with Ondansetron Dose
Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.
GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.
The updated label will say that ondansetron, a 5-HT3 receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.
The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.
Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.
The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.
It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.
Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.
The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.
Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.
GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.
The updated label will say that ondansetron, a 5-HT3 receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.
The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.
Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.
The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.
It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.
Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.
The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.
Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.
GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.
The updated label will say that ondansetron, a 5-HT3 receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.
The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.
Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.
The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.
It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.
Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.
The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.
FDA Announces Limited Leucovorin Recall
Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.
The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.
To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.
Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.
Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.
Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.
Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.
Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.
Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.
The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.
To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.
Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.
Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.
Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.
Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.
Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.
Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.
The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.
To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.
Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.
Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.
Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.
Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.
Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.
Regorafenib Delays Progression of Refractory Metastatic GIST
CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.
Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).
"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.
"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.
Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.
"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.
Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.
GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.
The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).
Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.
The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.
Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.
Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.
"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.
Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.
Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.
"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."
Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.
The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.
CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.
Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).
"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.
"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.
Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.
"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.
Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.
GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.
The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).
Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.
The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.
Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.
Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.
"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.
Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.
Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.
"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."
Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.
The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.
CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.
Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).
"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.
"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.
Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.
"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.
Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.
GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.
The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).
Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.
The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.
Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.
Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.
"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.
Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.
Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.
"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."
Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.
The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Median progression-free survival was 4.8 months with regorafenib vs. 0.9 months for placebo (HR = 0.27; P less than .0001).
Data Source: The international, multicenter, double-blind, placebo-controlled GRID (GIST–Regorafenib In Disease) trial randomized 199 patients with treatment-refractory, metastatic, unresectable gastrointestinal stromal tumor.
Disclosures: The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.
Laparoscopy Tops Open Resection for Most Gastric Tumors
SAN DIEGO – Patients who underwent laparoscopic resection of gastric submucosal neoplasms had shorter operative times, less blood loss, lower postoperative morbidity, and shorter hospital lengths of stay compared with those who underwent open resection, according to results from a single-center study.
"Numerous reports not only have assessed the feasibility, but confirmed the long-term oncologic efficacy of laparoscopic resection for gastrointestinal stromal tumors [GISTs]," Dr. Sabha Ganai said at the annual Digestive Disease Week.
"However, in 2004, the European Society of Medical Oncology published a consensus report suggesting that laparoscopic surgery may result in a higher risk of tumor rupture and peritoneal seeding, and suggested that laparoscopic resection may be acceptable in cases of small intramural tumors – those 2 cm or smaller," she added (Ann. Oncol. 2005;16:566-78).
Dr. Ganai, a fellow in surgical oncology and clinical medical ethics at the University of Chicago, noted that concerns exist "regarding the ability to generalize laparoscopic techniques to the spectra of gastric submucosal neoplasms, specifically related to tumor size and location, particularly the GE junction/cardia, the antrum/pylorus, and posteriorly based lesions."
To evaluate patient selection for a minimally invasive approach to resection, Dr. Ganai and her associates compared laparoscopic and open techniques used in the resection of gastric submucosal neoplasms. "We hypothesized that there are predictors of unsuccessful laparoscopic resection, with failures defined by conversions, complications, and recurrences," she said.
The retrospective study involved 106 patients with gastric submucosal neoplasms who underwent operative management at the university from October 2002 to March 2012. There were 79 patients in the laparoscopic group and 27 in the open group. The mean age was 63 years, the mean body mass index was 29 kg/m2, and 57% were male.
There was less preoperative use of ultrasound in the open group vs. the laparoscopic group (67% vs. 87%, respectively), and greater pretreatment lesion size (9.5 cm vs. 3.9 cm). In addition, the open group had a 6-month greater interval from diagnosis to surgery (10.1 months vs. 4.4 months), and more neoadjuvant imatinib was used in the open group (26% vs. 5%).
Most tumors (76%) were GISTs; the rest were leiomyomas (9%), schwannomas (6%), carcinoids (3%), and other types (6%).
There were no significant differences between the groups in terms of tumor location; most were found in the greater curvature (41% open vs. 32% laparoscopic). "There were slightly more posterior lesions in the open group, but this was not statistically significant," she said. "On presentation, patients in the open group had a significantly greater presentation with abdominal pain, while those in the laparoscopic group were more likely to present with GI bleed."
Most patients underwent sleeve or wedge resection, with 11% of patients undergoing transgastric wedge resections. A higher proportion of the open group required a gastroenteric anastomosis (37% vs. 6%) and a multivisceral resection (41% vs. 1%). Overall, operative time was significantly greater in the open group (a mean of 230 minutes vs. 132 minutes), as was the amount of estimated blood loss (a mean of 364 mL vs. 35 mL).
Most GISTs in the laparoscopic group (64%) ranged in size from 2 cm to 5 cm, while the majority in the open group (58%) were greater than 5 cm. In addition, the open group had a higher mitotic index (44% vs. 20%).
Postoperatively, hospital length of stay was significantly shorter in the laparoscopic group (a mean of 3.3 days) than in the open group (a mean of 8.4 days). The laparoscopic group also had significantly fewer surgical site infections (1% vs. 22%), anastomotic leaks (0% vs. 7%), and postoperative arrhythmias (0% vs. 15%).
Overall complications, evaluated on the basis of the Accordion Severity Grading System of surgical complications, were less severe in the laparoscopic group. "However, there was one perioperative death in the laparoscopic group related to a massive myocardial infarction, as well as two reoperations, one related to a port site hernia and one related to a gastric outlet obstruction in an antral lesion," Dr. Ganai said.
On multivariate analysis, conversion was predicted by tumor size greater than 8 cm (odds ratio, 18.48), while recurrence was predicted by having a mitotic rate of greater than 5 mitoses per 50 high-power fields (OR, 4.68). Laparoscopic resection resulted in better perioperative outcomes, with less morbidity, shorter operative times, less blood loss, and shorter lengths of stay (P less than .05). No significant difference was seen in survival; 90% and 81% of patients were alive 3 years after laparoscopic and open resection, respectively (hazard ratio, 0.4; P = .13). "Tumor biology and imatinib may play a greater role in oncologic outcome than technical considerations," Dr. Ganai suggested.
She acknowledged certain limitations of the study, including its retrospective design, the potential for selection bias, and limited follow-up, "especially in the lower-risk tumors."
Dr. Ganai said that she had no relevant financial conflicts to disclose.
SAN DIEGO – Patients who underwent laparoscopic resection of gastric submucosal neoplasms had shorter operative times, less blood loss, lower postoperative morbidity, and shorter hospital lengths of stay compared with those who underwent open resection, according to results from a single-center study.
"Numerous reports not only have assessed the feasibility, but confirmed the long-term oncologic efficacy of laparoscopic resection for gastrointestinal stromal tumors [GISTs]," Dr. Sabha Ganai said at the annual Digestive Disease Week.
"However, in 2004, the European Society of Medical Oncology published a consensus report suggesting that laparoscopic surgery may result in a higher risk of tumor rupture and peritoneal seeding, and suggested that laparoscopic resection may be acceptable in cases of small intramural tumors – those 2 cm or smaller," she added (Ann. Oncol. 2005;16:566-78).
Dr. Ganai, a fellow in surgical oncology and clinical medical ethics at the University of Chicago, noted that concerns exist "regarding the ability to generalize laparoscopic techniques to the spectra of gastric submucosal neoplasms, specifically related to tumor size and location, particularly the GE junction/cardia, the antrum/pylorus, and posteriorly based lesions."
To evaluate patient selection for a minimally invasive approach to resection, Dr. Ganai and her associates compared laparoscopic and open techniques used in the resection of gastric submucosal neoplasms. "We hypothesized that there are predictors of unsuccessful laparoscopic resection, with failures defined by conversions, complications, and recurrences," she said.
The retrospective study involved 106 patients with gastric submucosal neoplasms who underwent operative management at the university from October 2002 to March 2012. There were 79 patients in the laparoscopic group and 27 in the open group. The mean age was 63 years, the mean body mass index was 29 kg/m2, and 57% were male.
There was less preoperative use of ultrasound in the open group vs. the laparoscopic group (67% vs. 87%, respectively), and greater pretreatment lesion size (9.5 cm vs. 3.9 cm). In addition, the open group had a 6-month greater interval from diagnosis to surgery (10.1 months vs. 4.4 months), and more neoadjuvant imatinib was used in the open group (26% vs. 5%).
Most tumors (76%) were GISTs; the rest were leiomyomas (9%), schwannomas (6%), carcinoids (3%), and other types (6%).
There were no significant differences between the groups in terms of tumor location; most were found in the greater curvature (41% open vs. 32% laparoscopic). "There were slightly more posterior lesions in the open group, but this was not statistically significant," she said. "On presentation, patients in the open group had a significantly greater presentation with abdominal pain, while those in the laparoscopic group were more likely to present with GI bleed."
Most patients underwent sleeve or wedge resection, with 11% of patients undergoing transgastric wedge resections. A higher proportion of the open group required a gastroenteric anastomosis (37% vs. 6%) and a multivisceral resection (41% vs. 1%). Overall, operative time was significantly greater in the open group (a mean of 230 minutes vs. 132 minutes), as was the amount of estimated blood loss (a mean of 364 mL vs. 35 mL).
Most GISTs in the laparoscopic group (64%) ranged in size from 2 cm to 5 cm, while the majority in the open group (58%) were greater than 5 cm. In addition, the open group had a higher mitotic index (44% vs. 20%).
Postoperatively, hospital length of stay was significantly shorter in the laparoscopic group (a mean of 3.3 days) than in the open group (a mean of 8.4 days). The laparoscopic group also had significantly fewer surgical site infections (1% vs. 22%), anastomotic leaks (0% vs. 7%), and postoperative arrhythmias (0% vs. 15%).
Overall complications, evaluated on the basis of the Accordion Severity Grading System of surgical complications, were less severe in the laparoscopic group. "However, there was one perioperative death in the laparoscopic group related to a massive myocardial infarction, as well as two reoperations, one related to a port site hernia and one related to a gastric outlet obstruction in an antral lesion," Dr. Ganai said.
On multivariate analysis, conversion was predicted by tumor size greater than 8 cm (odds ratio, 18.48), while recurrence was predicted by having a mitotic rate of greater than 5 mitoses per 50 high-power fields (OR, 4.68). Laparoscopic resection resulted in better perioperative outcomes, with less morbidity, shorter operative times, less blood loss, and shorter lengths of stay (P less than .05). No significant difference was seen in survival; 90% and 81% of patients were alive 3 years after laparoscopic and open resection, respectively (hazard ratio, 0.4; P = .13). "Tumor biology and imatinib may play a greater role in oncologic outcome than technical considerations," Dr. Ganai suggested.
She acknowledged certain limitations of the study, including its retrospective design, the potential for selection bias, and limited follow-up, "especially in the lower-risk tumors."
Dr. Ganai said that she had no relevant financial conflicts to disclose.
SAN DIEGO – Patients who underwent laparoscopic resection of gastric submucosal neoplasms had shorter operative times, less blood loss, lower postoperative morbidity, and shorter hospital lengths of stay compared with those who underwent open resection, according to results from a single-center study.
"Numerous reports not only have assessed the feasibility, but confirmed the long-term oncologic efficacy of laparoscopic resection for gastrointestinal stromal tumors [GISTs]," Dr. Sabha Ganai said at the annual Digestive Disease Week.
"However, in 2004, the European Society of Medical Oncology published a consensus report suggesting that laparoscopic surgery may result in a higher risk of tumor rupture and peritoneal seeding, and suggested that laparoscopic resection may be acceptable in cases of small intramural tumors – those 2 cm or smaller," she added (Ann. Oncol. 2005;16:566-78).
Dr. Ganai, a fellow in surgical oncology and clinical medical ethics at the University of Chicago, noted that concerns exist "regarding the ability to generalize laparoscopic techniques to the spectra of gastric submucosal neoplasms, specifically related to tumor size and location, particularly the GE junction/cardia, the antrum/pylorus, and posteriorly based lesions."
To evaluate patient selection for a minimally invasive approach to resection, Dr. Ganai and her associates compared laparoscopic and open techniques used in the resection of gastric submucosal neoplasms. "We hypothesized that there are predictors of unsuccessful laparoscopic resection, with failures defined by conversions, complications, and recurrences," she said.
The retrospective study involved 106 patients with gastric submucosal neoplasms who underwent operative management at the university from October 2002 to March 2012. There were 79 patients in the laparoscopic group and 27 in the open group. The mean age was 63 years, the mean body mass index was 29 kg/m2, and 57% were male.
There was less preoperative use of ultrasound in the open group vs. the laparoscopic group (67% vs. 87%, respectively), and greater pretreatment lesion size (9.5 cm vs. 3.9 cm). In addition, the open group had a 6-month greater interval from diagnosis to surgery (10.1 months vs. 4.4 months), and more neoadjuvant imatinib was used in the open group (26% vs. 5%).
Most tumors (76%) were GISTs; the rest were leiomyomas (9%), schwannomas (6%), carcinoids (3%), and other types (6%).
There were no significant differences between the groups in terms of tumor location; most were found in the greater curvature (41% open vs. 32% laparoscopic). "There were slightly more posterior lesions in the open group, but this was not statistically significant," she said. "On presentation, patients in the open group had a significantly greater presentation with abdominal pain, while those in the laparoscopic group were more likely to present with GI bleed."
Most patients underwent sleeve or wedge resection, with 11% of patients undergoing transgastric wedge resections. A higher proportion of the open group required a gastroenteric anastomosis (37% vs. 6%) and a multivisceral resection (41% vs. 1%). Overall, operative time was significantly greater in the open group (a mean of 230 minutes vs. 132 minutes), as was the amount of estimated blood loss (a mean of 364 mL vs. 35 mL).
Most GISTs in the laparoscopic group (64%) ranged in size from 2 cm to 5 cm, while the majority in the open group (58%) were greater than 5 cm. In addition, the open group had a higher mitotic index (44% vs. 20%).
Postoperatively, hospital length of stay was significantly shorter in the laparoscopic group (a mean of 3.3 days) than in the open group (a mean of 8.4 days). The laparoscopic group also had significantly fewer surgical site infections (1% vs. 22%), anastomotic leaks (0% vs. 7%), and postoperative arrhythmias (0% vs. 15%).
Overall complications, evaluated on the basis of the Accordion Severity Grading System of surgical complications, were less severe in the laparoscopic group. "However, there was one perioperative death in the laparoscopic group related to a massive myocardial infarction, as well as two reoperations, one related to a port site hernia and one related to a gastric outlet obstruction in an antral lesion," Dr. Ganai said.
On multivariate analysis, conversion was predicted by tumor size greater than 8 cm (odds ratio, 18.48), while recurrence was predicted by having a mitotic rate of greater than 5 mitoses per 50 high-power fields (OR, 4.68). Laparoscopic resection resulted in better perioperative outcomes, with less morbidity, shorter operative times, less blood loss, and shorter lengths of stay (P less than .05). No significant difference was seen in survival; 90% and 81% of patients were alive 3 years after laparoscopic and open resection, respectively (hazard ratio, 0.4; P = .13). "Tumor biology and imatinib may play a greater role in oncologic outcome than technical considerations," Dr. Ganai suggested.
She acknowledged certain limitations of the study, including its retrospective design, the potential for selection bias, and limited follow-up, "especially in the lower-risk tumors."
Dr. Ganai said that she had no relevant financial conflicts to disclose.
FROM THE ANNUAL DIGESTIVE DISEASE WEEK
FDA Approves Pazopanib for Advanced Soft-Tissue Sarcomas
"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."
Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.
Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).
Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.
The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.
The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.
Pazopanib is marketed by GlaxoSmithKline.
"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."
Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.
Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).
Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.
The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.
The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.
Pazopanib is marketed by GlaxoSmithKline.
"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."
Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.
Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).
Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.
The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.
The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.
Pazopanib is marketed by GlaxoSmithKline.
Cixutumumab With Temsirolimus Slows Ewing's Sarcoma
CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.
Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.
Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.
The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.
Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.
To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.
All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.
At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.
In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."
The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).
"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.
"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."
One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.
Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.
The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).
Dr. Naing reported having no relevant financial relationships to disclose.
CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.
Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.
Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.
The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.
Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.
To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.
All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.
At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.
In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."
The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).
"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.
"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."
One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.
Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.
The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).
Dr. Naing reported having no relevant financial relationships to disclose.
CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.
Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.
Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.
The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.
Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.
To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.
All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.
At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.
In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."
The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).
"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.
"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."
One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.
Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.
The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).
Dr. Naing reported having no relevant financial relationships to disclose.
FROM THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION OF CANCER RESEARCH
Major Finding: Five of 17 patients with refractory Ewing’s sarcoma demonstrated partial or complete response to combination therapy with cixutumumab and temsirolimus.
Data Source: Data were taken from a phase I clinical trial of cixutumumab and temsirolimus in 20 heavily pretreated patients with Ewing’s sarcoma family of tumors.
Disclosures: Dr. Naing reported having no relevant financial relationships to disclose.
ASCO: Stop Underdosing Obese Cancer Patients
Chemotherapy doses should be tailored for obese cancer patients based on their actual body weight, not their ideal body weight, according to a new practice guideline from the American Society of Clinical Oncology.
There is no evidence that full-weight-based chemotherapy doses cause greater toxicity than adjusted doses, and concerns about "overdosing" obese cancer patients are unfounded, a panel of experts wrote in a report published online April 2 in the Journal of Clinical Oncology.
A systematic review of the literature showed that many overweight and obese cancer patients continue to receive underdoses of intravenous and oral cytotoxic drugs because of "considerable uncertainty among physicians about optimal dose selection," even though research has confirmed that full-weight-based dosing is both safe and crucial to the patients’ survival.
"Many oncologists continue to use either ideal body weight or adjusted ideal body weight, or to cap the body surface area at, for example, 2.0 m2, rather than use actual body weight to calculate body surface area," said Dr. Jennifer J. Griggs of the University of Michigan, Ann Arbor, and her associates on the expert panel for ASCO’s new practice guideline.
As a result, chemotherapy dosing varies widely in overweight and obese patients, with as many as 40% receiving less than optimal dosing. This "may explain, in part, the significantly higher cancer mortality observed in overweight and obese individuals," they noted.
"With the incidence of obesity at an all-time high in the United States, as well as in other developed and developing nations, oncologists face this issue more than ever before," Dr. Griggs added in a press statement accompanying release of the guideline.
The ASCO guideline panel reviewed all the randomized clinical trials, meta-analyses, and clinical practice guidelines of other organizations concerning cytotoxic oral or IV chemotherapy dosing approaches for overweight or obese patients with cancer, excluding leukemias. Since there have been no prospective randomized studies directly comparing full-weight-based dose selection against other types of dose selection, they had to rely primarily on subgroup analyses and registry data.
Most of the studies concerned breast, ovarian, colon, and lung cancers, the authors said. As little data in the literature addressed dosing for novel agents such as tyrosine kinase inhibitors, immunotherapies such as interleukin-2 or interferon, or monoclonal antibodies, the guideline did not address these agents.
A summary of the guideline (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9436]) lists these key recommendations:
• Actual body weight should be used to select cytotoxic chemotherapy doses, regardless of obesity status. There is no evidence that either short- or long-term toxicity is increased with this approach.
• Use the same strategy in obese patients as in other patients for dose reductions, taking into account the type and severity of toxicity, any comorbid conditions, and whether the aim of treatment is cure or palliation. There is no evidence that greater dose reductions are needed for obese patients. Also, consider resuming the full-weight-based dose for subsequent chemotherapy cycles, especially if a possible cause of toxicity (such as impaired renal or liver function) has resolved.
• Consider fixed dosing only with select cytotoxic agents for which maximal dosing limits have been established, such as vincristine, carboplatin, or bleomycin.
• Calculate body surface area using any of the standard formulas currently available. There is no evidence to support using one formula over any other.
• Further research is needed into the pharmacokinetics and pharmacogenetics of chemotherapy dosing for obese patients, who have been excluded from many anticancer drug trials.
The guideline also emphasizes that physicians may need to fully discuss this issue with patients and caregivers, stressing that higher doses are needed in obese patients for the chemotherapy to be effective and reassuring them that toxicity is not expected to be any greater at proportionally higher doses.
"Communication with other health care providers is also warranted. Pharmacists and nursing professionals who are accustomed to limiting chemotherapy doses for obese patients should be informed of the existing evidence. IV and oral doses may be prepackaged for patients of normal weight, but appropriate dosing should be delivered, regardless of doses contained within a given vial. Arbitrary capping based on drug procurement is unacceptable (e.g., 1 vs. 1.5 vials)," the guideline stated.
Clinicians also should be aware that since rates of obesity are higher in black patients, Hispanic patients, and patients of lower socioeconomic status, these groups are harmed the most by underdosing and may benefit the most when full-weight-based dosing is adopted.
"This guideline should ease fears about administering chemotherapy based on actual body weight to otherwise healthy obese patients with cancer," Dr. Gary H. Lyman, cochair of the expert panel that drafted the guideline, said in a press statement.
"While chemotherapy dose for an obese patient may be larger than some physicians are accustomed to, they can rest assured that the risk of toxicity associated with chemotherapy dosing based on actual body weight is no greater in obese patients than in nonobese patients with cancer," said Dr. Lyman, a professor of medicine in the division of medical oncology at Duke University, Durham, N.C.
The full practice guideline, along with additional information on methodology and clinical resources, is available at ASCO’s website. For additional patient information, click here.
No financial conflicts of interest were reported.
Chemotherapy doses should be tailored for obese cancer patients based on their actual body weight, not their ideal body weight, according to a new practice guideline from the American Society of Clinical Oncology.
There is no evidence that full-weight-based chemotherapy doses cause greater toxicity than adjusted doses, and concerns about "overdosing" obese cancer patients are unfounded, a panel of experts wrote in a report published online April 2 in the Journal of Clinical Oncology.
A systematic review of the literature showed that many overweight and obese cancer patients continue to receive underdoses of intravenous and oral cytotoxic drugs because of "considerable uncertainty among physicians about optimal dose selection," even though research has confirmed that full-weight-based dosing is both safe and crucial to the patients’ survival.
"Many oncologists continue to use either ideal body weight or adjusted ideal body weight, or to cap the body surface area at, for example, 2.0 m2, rather than use actual body weight to calculate body surface area," said Dr. Jennifer J. Griggs of the University of Michigan, Ann Arbor, and her associates on the expert panel for ASCO’s new practice guideline.
As a result, chemotherapy dosing varies widely in overweight and obese patients, with as many as 40% receiving less than optimal dosing. This "may explain, in part, the significantly higher cancer mortality observed in overweight and obese individuals," they noted.
"With the incidence of obesity at an all-time high in the United States, as well as in other developed and developing nations, oncologists face this issue more than ever before," Dr. Griggs added in a press statement accompanying release of the guideline.
The ASCO guideline panel reviewed all the randomized clinical trials, meta-analyses, and clinical practice guidelines of other organizations concerning cytotoxic oral or IV chemotherapy dosing approaches for overweight or obese patients with cancer, excluding leukemias. Since there have been no prospective randomized studies directly comparing full-weight-based dose selection against other types of dose selection, they had to rely primarily on subgroup analyses and registry data.
Most of the studies concerned breast, ovarian, colon, and lung cancers, the authors said. As little data in the literature addressed dosing for novel agents such as tyrosine kinase inhibitors, immunotherapies such as interleukin-2 or interferon, or monoclonal antibodies, the guideline did not address these agents.
A summary of the guideline (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9436]) lists these key recommendations:
• Actual body weight should be used to select cytotoxic chemotherapy doses, regardless of obesity status. There is no evidence that either short- or long-term toxicity is increased with this approach.
• Use the same strategy in obese patients as in other patients for dose reductions, taking into account the type and severity of toxicity, any comorbid conditions, and whether the aim of treatment is cure or palliation. There is no evidence that greater dose reductions are needed for obese patients. Also, consider resuming the full-weight-based dose for subsequent chemotherapy cycles, especially if a possible cause of toxicity (such as impaired renal or liver function) has resolved.
• Consider fixed dosing only with select cytotoxic agents for which maximal dosing limits have been established, such as vincristine, carboplatin, or bleomycin.
• Calculate body surface area using any of the standard formulas currently available. There is no evidence to support using one formula over any other.
• Further research is needed into the pharmacokinetics and pharmacogenetics of chemotherapy dosing for obese patients, who have been excluded from many anticancer drug trials.
The guideline also emphasizes that physicians may need to fully discuss this issue with patients and caregivers, stressing that higher doses are needed in obese patients for the chemotherapy to be effective and reassuring them that toxicity is not expected to be any greater at proportionally higher doses.
"Communication with other health care providers is also warranted. Pharmacists and nursing professionals who are accustomed to limiting chemotherapy doses for obese patients should be informed of the existing evidence. IV and oral doses may be prepackaged for patients of normal weight, but appropriate dosing should be delivered, regardless of doses contained within a given vial. Arbitrary capping based on drug procurement is unacceptable (e.g., 1 vs. 1.5 vials)," the guideline stated.
Clinicians also should be aware that since rates of obesity are higher in black patients, Hispanic patients, and patients of lower socioeconomic status, these groups are harmed the most by underdosing and may benefit the most when full-weight-based dosing is adopted.
"This guideline should ease fears about administering chemotherapy based on actual body weight to otherwise healthy obese patients with cancer," Dr. Gary H. Lyman, cochair of the expert panel that drafted the guideline, said in a press statement.
"While chemotherapy dose for an obese patient may be larger than some physicians are accustomed to, they can rest assured that the risk of toxicity associated with chemotherapy dosing based on actual body weight is no greater in obese patients than in nonobese patients with cancer," said Dr. Lyman, a professor of medicine in the division of medical oncology at Duke University, Durham, N.C.
The full practice guideline, along with additional information on methodology and clinical resources, is available at ASCO’s website. For additional patient information, click here.
No financial conflicts of interest were reported.
Chemotherapy doses should be tailored for obese cancer patients based on their actual body weight, not their ideal body weight, according to a new practice guideline from the American Society of Clinical Oncology.
There is no evidence that full-weight-based chemotherapy doses cause greater toxicity than adjusted doses, and concerns about "overdosing" obese cancer patients are unfounded, a panel of experts wrote in a report published online April 2 in the Journal of Clinical Oncology.
A systematic review of the literature showed that many overweight and obese cancer patients continue to receive underdoses of intravenous and oral cytotoxic drugs because of "considerable uncertainty among physicians about optimal dose selection," even though research has confirmed that full-weight-based dosing is both safe and crucial to the patients’ survival.
"Many oncologists continue to use either ideal body weight or adjusted ideal body weight, or to cap the body surface area at, for example, 2.0 m2, rather than use actual body weight to calculate body surface area," said Dr. Jennifer J. Griggs of the University of Michigan, Ann Arbor, and her associates on the expert panel for ASCO’s new practice guideline.
As a result, chemotherapy dosing varies widely in overweight and obese patients, with as many as 40% receiving less than optimal dosing. This "may explain, in part, the significantly higher cancer mortality observed in overweight and obese individuals," they noted.
"With the incidence of obesity at an all-time high in the United States, as well as in other developed and developing nations, oncologists face this issue more than ever before," Dr. Griggs added in a press statement accompanying release of the guideline.
The ASCO guideline panel reviewed all the randomized clinical trials, meta-analyses, and clinical practice guidelines of other organizations concerning cytotoxic oral or IV chemotherapy dosing approaches for overweight or obese patients with cancer, excluding leukemias. Since there have been no prospective randomized studies directly comparing full-weight-based dose selection against other types of dose selection, they had to rely primarily on subgroup analyses and registry data.
Most of the studies concerned breast, ovarian, colon, and lung cancers, the authors said. As little data in the literature addressed dosing for novel agents such as tyrosine kinase inhibitors, immunotherapies such as interleukin-2 or interferon, or monoclonal antibodies, the guideline did not address these agents.
A summary of the guideline (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9436]) lists these key recommendations:
• Actual body weight should be used to select cytotoxic chemotherapy doses, regardless of obesity status. There is no evidence that either short- or long-term toxicity is increased with this approach.
• Use the same strategy in obese patients as in other patients for dose reductions, taking into account the type and severity of toxicity, any comorbid conditions, and whether the aim of treatment is cure or palliation. There is no evidence that greater dose reductions are needed for obese patients. Also, consider resuming the full-weight-based dose for subsequent chemotherapy cycles, especially if a possible cause of toxicity (such as impaired renal or liver function) has resolved.
• Consider fixed dosing only with select cytotoxic agents for which maximal dosing limits have been established, such as vincristine, carboplatin, or bleomycin.
• Calculate body surface area using any of the standard formulas currently available. There is no evidence to support using one formula over any other.
• Further research is needed into the pharmacokinetics and pharmacogenetics of chemotherapy dosing for obese patients, who have been excluded from many anticancer drug trials.
The guideline also emphasizes that physicians may need to fully discuss this issue with patients and caregivers, stressing that higher doses are needed in obese patients for the chemotherapy to be effective and reassuring them that toxicity is not expected to be any greater at proportionally higher doses.
"Communication with other health care providers is also warranted. Pharmacists and nursing professionals who are accustomed to limiting chemotherapy doses for obese patients should be informed of the existing evidence. IV and oral doses may be prepackaged for patients of normal weight, but appropriate dosing should be delivered, regardless of doses contained within a given vial. Arbitrary capping based on drug procurement is unacceptable (e.g., 1 vs. 1.5 vials)," the guideline stated.
Clinicians also should be aware that since rates of obesity are higher in black patients, Hispanic patients, and patients of lower socioeconomic status, these groups are harmed the most by underdosing and may benefit the most when full-weight-based dosing is adopted.
"This guideline should ease fears about administering chemotherapy based on actual body weight to otherwise healthy obese patients with cancer," Dr. Gary H. Lyman, cochair of the expert panel that drafted the guideline, said in a press statement.
"While chemotherapy dose for an obese patient may be larger than some physicians are accustomed to, they can rest assured that the risk of toxicity associated with chemotherapy dosing based on actual body weight is no greater in obese patients than in nonobese patients with cancer," said Dr. Lyman, a professor of medicine in the division of medical oncology at Duke University, Durham, N.C.
The full practice guideline, along with additional information on methodology and clinical resources, is available at ASCO’s website. For additional patient information, click here.
No financial conflicts of interest were reported.
FROM THE JOURNAL OF CLINICAL ONCOLOGY