User login
European Society for Medical Oncology (ESMO): Sarcoma and GIST Conference
Launch of rare-cancer trial spurs many more
MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.
The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.
Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.
"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.
The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.
"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.
The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.
The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."
The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.
Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.
GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.
Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.
On Twitter @mitchelzoler
MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.
The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.
Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.
"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.
The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.
"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.
The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.
The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."
The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.
Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.
GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.
Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.
On Twitter @mitchelzoler
MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.
The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.
Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.
"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.
The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.
"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.
The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.
The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."
The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.
Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.
GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.
Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Pazopanib helps significant minority of sarcoma patients
MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.
"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).
The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.
Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.
A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).
During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.
"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.
The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.
[email protected] Twitter: @mitchelzoler
MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.
"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).
The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.
Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.
A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).
During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.
"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.
The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.
[email protected] Twitter: @mitchelzoler
MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.
"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).
The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.
Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.
A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).
During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.
"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.
The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.
[email protected] Twitter: @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Doxorubicin, ifosfamide combination touted for advanced sarcomas
MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.
"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.
The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).
The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.
The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.
But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.
Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m2. If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m2. He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.
"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."
On Twitter @mitchelzoler
MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.
"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.
The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).
The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.
The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.
But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.
Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m2. If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m2. He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.
"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."
On Twitter @mitchelzoler
MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.
"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.
The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).
The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.
The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.
But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.
Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m2. If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m2. He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.
"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Some consider denosumab standard treatment for unresectable giant cell tumor of bone
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Europe’s latest sarcoma guidelines increase emphasis on genetic profiling
MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.
"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."
The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.
The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.
For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.
One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.
The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.
This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.
For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.
The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.
Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.
On Twitter @mitchelzoler
MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.
"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."
The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.
The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.
For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.
One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.
The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.
This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.
For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.
The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.
Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.
On Twitter @mitchelzoler
MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.
"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."
The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.
The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.
For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.
One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.
The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.
This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.
For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.
The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.
Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Role for GIST genotyping stirs controversy
MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.
"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.
"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."
Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."
In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."
Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."
Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.
"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.
"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.
"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.
Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:
• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.
• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.
• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.
• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.
• The remaining GIST have other, rare mutations.
Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.
"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.
"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."
Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."
In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."
Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."
Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.
"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.
"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.
"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.
Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:
• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.
• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.
• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.
• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.
• The remaining GIST have other, rare mutations.
Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.
"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.
"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.
"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."
Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."
In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."
Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."
Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.
"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.
"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.
"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.
Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:
• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.
• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.
• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.
• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.
• The remaining GIST have other, rare mutations.
Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Liquid biopsies may solve GIST biopsy problem
MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.
"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.
"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.
Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.
The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).
Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).
Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.
Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.
Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.
Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.
"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.
"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.
Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.
The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).
Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).
Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.
Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.
Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.
Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.
"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.
"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.
Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.
The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).
Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).
Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.
Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.
Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.
Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
