CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
Dr. Barbara Fisher
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
Dr. Helen Shih
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.