CHICAGO — When temsirolimus (Torisel) is added to chemotherapy in the treatment of rhabdomyosarcoma, the most common soft tissue sarcoma in children, event-free survival is improved, new research shows.
"This is the first time that we have seen a significant benefit in event-free survival in a randomized phase 2 trial," said Jeffrey Toretsky, MD, from the Georgetown University Lombardi Comprehensive Cancer Center in Washington, DC. This is partly because the condition is rare, which makes enrollment in clinical trials a challenge.
Dr. Toretsky spoke during a Highlights of the Day session here at the 2014 Annual Meeting of the American Society of Clinical Oncology®.
In the phase 2 study, temsirolimus or bevacizumab (Avastin) was added to a chemotherapy regimen of vinorelbine and cyclophosphamide in patients with an unfavorable prognosis at first relapse or disease progression.
Event-free survival was better in the temsirolimus group than in the bevacizumab group (65% vs 50%), but there was no difference in overall survival.
However, results from another study presented at the meeting were disappointing. In children with intermediate-risk rhabdomyosarcoma, the addition of irinotecan to the combination of vincristine, dactinomycin, and cyclophosphamide (VAC) did not improve event-free or overall survival.
At 2 years, event-free survival was the same in the group treated with irinotecan plus VAC as it was in those treated with VAC alone (64% vs 64%), and overall survival was similar (86% vs 84%). However, the combination did have a better toxicity profile.
"Part of the clinical dilemma of treating rhabdomyosarcoma is that we too often think of it as a single disease," explained Leonard Wexler, MD, a pediatric oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, who served as discussant for both studies. "It is not. It can arise in almost any part of the body, but the local control and surgical paradigms differ, depending on the tumor's primary site."
Need for Better Therapies
Rhabdomyosarcoma is a relatively rare disease. In the United States, only about 400 people younger than 20 years are diagnosed with it each year. About 100 of these patients have low-risk tumors with an excellent prognosis, but the majority will have unresected and unfavorable site tumors, Dr. Wexler explained.
There is a "striking" difference in survival expectations in the different subgroups. Long-term event-free survival exceeds 80% in patients with low-risk disease, but ranges from 50% to 65% in those with intermediate-risk disease and from 15% to 35% in those with high-risk disease, he reported.
In relapsed disease, long-term survival is uncommon for the vast majority of children, even with maximally intensive multiagent chemotherapy.
"There has been no improvement in outcomes since I finished my fellowship in 1991. Local treatment failure remains the dominant risk for most patients, and late radiation effects remain a source of morbidity," said Dr. Wexler. "Systemic treatment failure remains the dominant risk in most patients with alveolar rhabdomyosarcoma and in all patients with metastatic disease, and curative therapy is infrequent in the setting of recurrent disease."
In a previous study, an intensified 6-drug chemotherapy regimen was used to treat high-risk nonmetastatic rhabdomyosarcoma and other soft tissue sarcomas, as reported by Medscape Medical News. There was no increase in survival or reduction in the intensity of local therapy, but the 6-drug combination was much more toxic than the standard 3-drug regimen of vincristine, dactinomycin, and either cyclophosphamide or ifosfamide.
Temsirolimus Trumps Bevacizumab
The study comparing temsirolimus and bevacizumab was conducted by Leo Mascarenhas, MD, director of the Clinical Trials Office in the Children's Center for Cancer and Blood Diseases and principal investigator for the Children's Oncology Group, funded by National Cancer Institute, at the Children's Hospital Los Angeles, and colleagues.
The cohort involved 87 patients younger than 30 years with an unfavorable prognosis at first relapse or disease progression.
For all patients, intravenous (IV) vincristine 25 mg/m² was administrated on days 1 and 8 and IV cyclophosphamide 1.2 g/m² was administered on day 1.
Patients were randomized to either IV temsirolimus 15 mg/m² on days 1, 8, and 15, or to IV bevacizumab 15 mg/kg daily.
The primary end point was event-free survival at 6 months.
At 6 months, the response rate favored temsirolimus over bevacizumab (47.4% vs 27.5%; P = .12). The number of complete responses also favored temsirolimus (5 vs 4), as did the number of partial responses (13 vs 7).
The rate of progressive disease was better with temsirolimus than bevacizumab (28% vs 10%).
There were no differences in response rates at 6 weeks between the 2 groups, or in rates of 2-year survival.
The treatments were well tolerated, and there were no unexpected toxicities. Febrile neutropenia was the most common adverse event with both regimens. Oral mucositis, hypokalemia, and hypertriglyceridemia were noted primarily in the temsirolimus group — in about 10% of patients — but only during the first 2 courses. There were no toxic deaths in either group.
"Temsirolimus has been selected by Children's Oncology Group for further investigation in newly diagnosed intermediate rhabdomyosarcoma patients," said Dr. Mascarenhas.
No Survival Difference, Better Toxicity Profile
Results from the irinotecan trial were presented by Douglas S. Hawkins, MD, associate hematology/oncology division chief and associate director of the Center for Clinical and Translational Research at Seattle Children's Hospital.
The cohort involved 461 patients with intermediate-risk disease, defined as alveolar rhabdomyosarcoma or incompletely resected embryonal rhabdomyosarcoma arising in an unfavorable primary site (stage II/III), both without distant metastases. "The majority of patients were 1 to 9 years of age and had stage III disease," said Dr. Hawkins.
All patients received a VAC regimen for 42 weeks, consisting of vincristine 1.5 mg/m², dactinomycin 0.045 mg/kg, and cyclophosphamide 1.2 g/m² every 3 weeks.
In addition, 234 patients were randomized to receive IV irinotecan 50 mg/m² per day for 5 days.
Dosing was adjusted for children younger than 3 years and radiation therapy (36.0 to 50.4 Gy) was started at week 4, with individualized local control for children younger than 2 years.
The most common primary tumor sites were parameningeal (44%), extremity (13%), and bladder/prostate (13%).
At 2 years, event-free and overall survival were virtually identical in the 2 groups. "When broken down by histology, they were again virtually identical," Dr. Hawkins reported.
Although there were no differences in survival, there were "striking" differences in toxicity, he noted.
The researchers looked at 3 reporting periods: weeks 1 to 15, weeks 16 to 30, and weeks 31 to 43.
"As anticipated, there was a higher incidence of diarrhea in the VAC plus irinotecan group, especially during the first 2 reporting periods," he said, although it became less common later on. Oral mucositis was more common in the first reporting period for the irinotecan group as well, although this also leveled off.
Surprisingly, hematologic and infectious complications were lower in the irinotecan group than in the group treated with VAC alone.
In future studies by the Children's Oncology Group, VAC plus irinotecan will be used as the comparison group, Dr. Hawkins noted.
Dr. Wexler pointed out that even though there was no difference in outcomes, VAC plus irinotecan was "declared the winner" for the next generation of studies, "based on the more favorable short-term and most likely long-term toxicity profile."
He explained that this is not truly an equivalent study; for that, a much larger population would be needed. "Although it is likely that there is no difference in outcome, we can't say that with confidence at this time."
Both studies were funded by the Children's Oncology Group.
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Cite this: New Drug Combos Promising in Higher-Risk Rhabdomyosarcoma - Medscape - Jun 05, 2014.