Neil Osterweil

October 22, 2014

BOSTON — Patients with newly diagnosed glioblastoma multiforme (GBM) have significantly better overall survival when there is a short delay between surgery and the start of radiation therapy, investigators say.

The optimal time to start radiation in patients with GBM is controversial, with some studies showing worse outcomes among patients for whom therapy is delayed and others suggesting that a short delay may not be harmful or may even be beneficial, said Seunggu Han, MD, a neurosurgery resident at the University of California San Francisco (UCSF), at the Congress of Neurological Surgeons (CNS) 2014 Annual Meeting here.

"With most other malignancies — breast cancer, lung cancer — it's very clear that even if you delay radiation a little bit, outcomes are significantly worse, but it's beginning to look like it's not quite the same for glioblastoma," he said in an interview with Medscape Medical News.

"The initial concern was that delaying any kind of cytotoxic adjuvant therapy for aggressive disease would ultimately lead to tumor regrowth and ultimately worse patient outcomes," he said.

But as the UCSF team found in an analysis of pooled data from four phase 1/2trials, patients with chemoradiotherapy delays of 30 to 35 days after surgery had significantly better progression-free survival (univariate hazard ratio [HR,] 0.59; P = .006) and overall survival (univariate HR, 0.47; P < .001) compared with patients who started receiving radiation within 29 days of surgery. However, no benefit was seen when radiation therapy was delayed by more than 35 days.

In multivariate analysis controlling for treatment protocol, age, Karnofsky performance score, and extent of resection, progression-free survival no longer differed between patients with shorter or longer times to initiation of radiation, but overall survival remained significantly better among patients started on radiation 30 to 35 days after surgery (multivariate HR, 0.6; P = .03).

"It seems there is a window of 30 to 35 days after surgery during which concurrent chemoradiation with temozolomide seems to have the greatest efficacy," Dr Han said.

 
It seems there is a window of 30 to 35 days after surgery during which concurrent chemoradiation with temozolomide seems to have the greatest efficacy Dr Seunggu Han
 

He added that he and his colleagues do not recommend deliberate delays in chemoradiation for patients with newly diagnosed GBM, but rather homogeneity in intervals to the initiation of radiation in clinical trials.

Four Trials

The investigators looked at outcomes for treatment-naive patients with GBM who were enrolled in one of four clinical trials at their center. Each trial assessed the effects of temozolomide with another agent: the experimental antiangiogenic enzastaurin, erlotinib (Tarceva, Astellas Oncology), or bevacizumab (Avastin, Genentech). Protocols for each study called for radiation therapy within 6 weeks of surgery.

They identified 198 patients and grouped them according to whether they started adjuvant chemoradiotherapy within 29 days of surgery, from 30 to 35 days after surgery, or after 35 days.

In multivariate analysis, they found that age, Karnofsky performance score, extent of resection, and time to chemoradiotherapy were significant independent predictors of overall survival.

Potential explanations for their findings, said Dr Han, include the possibility that patients with poor prognosis at baseline were rushed into adjuvant therapy following surgery. Another possibility, supported by work in animal models, is that the tumor resection cavity may shrink, resulting in a reduction of tissue susceptible to radiation injury. A third possibility is that local hypoxia in the surgical bed might decrease the efficacy or radiation or chemotherapy in the short term.

Jay Steven Loeffler, MD, chief of radiation oncology at Massachusetts General Hospital Cancer Center in Boston, Massachusetts, who was not involved in the study, told Medscape Medical News that for most forms of cancer, radiation delayed is therapeutic benefit denied.

"There [are] lots of data that suggest delaying radiation compromises outcome (eg, breast cancer, head and neck cancer, and medulloblastoma). In fact, most prospective clinical trials stipulate the starting time of radiation after surgery to avoid excessive delay. The retrospective data from UCSF suggests a 'window' (30 to 34 days postop) where radiation might be most effective in the treatment of patients with glioblastoma," he said.

Dr Loeffler agrees that postoperative inflammatory changes, including hypoxia, might account for the poorer response to early radiation.

"If treatment is too early, hypoxia might blunt the cytotoxic effect of radiation. If the treatment is beyond the window, tumor repopulation occurs which would have a negative impact on the radiation," he explained.

"This data substantiates what our observation in clinic has historically been," agreed David Reardon, MD, clinical director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute in Boston.

Dr Reardon told Medscape Medical News that in GBM, "the macroscopic part of the tumor is in some ways the tip of the iceberg. Getting that removed surgically makes a big difference for patients, but we still have a lot of tumor to tackle, and I think the sooner we can get on track with that, the better."

The authors did not report the funding source for the study. Dr Han, Dr Loeffler, and Dr Reardon have disclosed no relevant financial relationships.

Congress of Neurological Surgeons (CNS) 2014 Annual Meeting. Abstract 105. Presented October 19, 2014.

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