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Combined chemotherapy, radiation prolongs PFS, OS in grade 2 gliomas
The addition of combination chemotherapy to radiation extended PFS and OS in patients with grade 2 gliomas, according to long-term study results published in The New England Journal of Medicine.
However, the combination of chemotherapy and radiation led to more adverse events than radiation alone, results showed.
Initial results from this trial showed patients treated with procarbazine (Matulane, Sigma Tau Pharmaceuticals), lomustine (Gleostine, Corden Pharma) and vincristine after initial radiation therapy receipt achieved prolonged PFS compared with patients who received radiation therapy alone. However, early results did not show a significant OS benefit.
Walter J. Curran
“This is the first phase 3 trial to demonstrate conclusively a treatment-related survival benefit for patients with grade 2 glioma," Jan C. Buckner, MD, professor of oncology at Mayo Clinic in Rochester, Minnesota, said in a press release. “Our results indicate that initial therapy of radiation therapy followed by [procarbazine, lomustine and vincristine] is necessary to achieve longer survival in patients with grade 2 glioma and that salvage therapy at relapse after radiation therapy alone is less effective.”
Buckner and colleagues conducted this follow-up analysis after a median of 11.9 years.
The trial included 251 patients with grade 2 astrocytoma, oligoastrocytoma or oligodendroglioma enrolled from 1998 to 2002. Patients aged younger than 40 years underwent subtotal resection or biopsy, whereas patients aged 40 years or older underwent biopsy or resection of any of the tumor.
The researchers randomly assigned patients to radiation therapy alone (n = 126) or with six cycles of combination chemotherapy (n = 125).
At long-term follow-up, 67% of patients had experienced tumor progression and 55% had died.
Patients assigned chemotherapy and radiation achieved a median OS of 13.3 years (95% CI, 10.6-not reached), whereas patients assigned radiation alone achieved a median OS of 7.8 years (95% CI, 6.1-9.8). These data equated a significant reduction in risk for death with combined chemotherapy and radiation (HR = 0.59; 95% CI, 0.42-0.83).
Similarly, median PFS was significantly longer among patients assigned combination therapy (10.4 years vs. 4 years; HR for progression or death = 0.5; P < .001).
More patients in the combination arm also achieved 10-year PFS (51% vs. 21%) and OS (60% vs. 40%).
An exploratory OS analysis based on histologic type showed a benefit of chemotherapy and radiation in all subtypes; however, the difference did not reach statistical significance in patients with astrocytoma.
Further, a subgroup analysis stratified by IDH1 R132H mutations showed patients with this mutation achieved longer OS regardless of treatment group (13.1 years vs. 5.1 years). Patients with IDH1 R132H mutations who received radiation plus chemotherapy had longer OS than those who receive radiation alone (P = .002); however, too few events occurred among patients without the mutation to determine the association of treatment effect in this subgroup.
Results of multivariable analyses identified favorable prognostic variables, including chemotherapy plus radiation after 1 year of follow-up (P = .001 for comparison with radiation alone), oligodendroglioma (P = .001 for comparison with oligoastrocytoma; P = .01 for comparison with astrocytoma) and age younger than 40 years (P = .01 for comparison with patients aged 40 years or older).
The most common toxic effects included fatigue, anorexia, nausea and vomiting, which were primarily low grade. In the combination arm, three patients required red cell transfusions, one patient underwent platelet transfusions and one patient experience febrile neutropenia.
There were no reports of grade 5 toxic events, myelodysplasia or leukemia.
Two-hundred forty-five patients experienced late toxic events attributed to radiation, which were mostly grade 1 (n = 38) or grade 2 (n = 14). Twenty-two percent of late toxic effects occurred in the brain.
“These results provide further clarification about how the histopathologic differences among low-grade gliomas correlate with their biologic behavior and progression,” Walter J. Curran, Jr, MD, executive director of the Winship Cancer Institute of Emory University, NRG Oncology Group chairman, and HemOnc Today Associate Editor for radiation oncology, said in the release. “They also shed light on the most effective role and timing of radiation therapy and chemotherapy in prolonging PFS and OS and minimizing morbidity in the younger age group of patients diagnosed with these brain tumors.”– by Cameron Kelsall
Disclosure: The NCI provided funding for this study. Please see the full study for a list of the researchers’ relevant financial disclosures.
Perspective
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This is a well-designed, practice-changing study that defines a role for procarbazine (Matulane, Sigma Tau Pharmaceuticals), lomustine (Gleostine, Corden Pharma) and vincristine, or “PVC” chemotherapy, for patients with high-risk low-grade glioma (LGG). It is an important study because it is the first to conclusively demonstrate that, for patients aged older than 40 years or with a subtotal resection of tumor, chemotherapy nearly doubles survival time when given after radiotherapy.
However, as with most trials, with one question answered, several others open up.
Although this trial answers the question of how high-risk LGG should be treated, there still remains the question of when. Radiation is effective in treating LGG and seems to work equally well as salvage therapy after progression as it does if offered immediately after surgery. In the current study, the beneficial effect of PVC seems to be contingent upon receiving it immediately after radiotherapy, which in turn was delivered in the postoperative setting for all patients. This leaves open the question: Can postoperatively asymptomatic patients still expect similar benefits if the combined radiochemotherapy regimen were held until time of progression? This is an unknown.
Additionally, there are two standard definitions in use for “high-risk” low-grade glioma. The present study uses an older definition gleaned from analyses of earlier work from the American group. A more recent, and perhaps more commonly used, definition comes from analyses of European data. The question remains: Which is a more useful definition in identifying patients who will most benefit from the addition of chemotherapy?
Further, this study doesn’t fully address the question of optimal chemotherapy. It proved the superiority of PVC, the standard when the trial was designed, added to radiation compared with radiation alone. It remains unanswered if temozolomide — a same-class drug that is the standard of care for high-grade glioma and far less toxic than PVC — is equally effective for LGG patients.
These latter two issues were glanced upon in a study published 1 year ago. RTOG 0424 treated patients with the European definition of high-risk disease with temozolomide in addition to the standard of care. Outcomes were superior compared with historical patients treated without chemotherapy. How this stacks up against the outcomes in the current study remains unanswered.
Finally, it has become clear that traditional classification of gliomas, which is done by assessing tumor appearance under the microscope, is likely inferior to molecular classification — that is, using a tumor’s gene signature to group, prognosticate and plan treatment. Outcomes for ostensibly the same tumor can vary considerably depending upon gene expression.
For instance, although all patients in the current study had so-called high-risk low-grade glioma, patients with tumors harboring mutated IDH had better outcomes regardless of treatment, and the addition of chemotherapy improved outcomes further still. In the future, trials such as RTOG 0424 will investigate the benefits of therapy on lesions defined by molecular signature rather than classic histopathology.
Reference:
Fisher BJ, et al. Int J Radiat Oncol Biol Phys. 2015;doi:10.1016/j.ijrobp.2014.11.012.