Zosia Chustecka

June 06, 2016

CHICAGO — Elderly patients with glioblastoma multiforme should also be treated with temozolomide added on to radiotherapy, as is the standard of care for this cancer, a new study concludes.

The new study, an international phase 3 trial headed by academics, was conducted specifically in elderly patients (>65 years of age), which better reflects what is seen in the clinic than previous studies.

The median onset of glioblastoma is 64 years of age, noted lead investigator James R. Perry, MD, from the Sunnybrook Health Sciences Centre in Toronto. But previous studies have had a median age of 54 years, and even the trial that established the standard of care excluded patients over 70 years.

In the new trial, only patients over 65 years of age were enrolled; the median patient age was 73 years, and 41% were aged between 71 and 75 years, and nearly 30% were older than 75 years.

The results show that temozolomide added to radiotherapy improved overall survival when compared with radiotherapy alone, and so should be considered a standard of care also in elderly patients, say the researchers.

"Although glioblastoma disproportionately affects older patients, there are no clear guidelines for treating these patients, and practice varies globally," Dr Perry commented.

Dr James Perry

"This study provides the first evidence from a randomized clinical trial that chemotherapy in combination with a shorter radiation schedule significantly extends survival without a detriment to quality of life," he said.

The new results were presented here at the plenary session of the American Society of Clinical Oncology 2016 Annual Meeting.

Important Clinical Question

This study answers an important clinical question, said Andrew Lassman, MD, chief of neuro-oncology at the New York Presbyterian Hospital in New York City, who was commenting to Medscape Medical News on the results after the presentation.

He explained that temozolomide plus radiotherapy has been established as a standard of care for glioblastoma for more than a decade, after the landmark trial by Stupp et al (N Engl J Med. 2005;352:987-996).

But that trial stopped at 70 years of age, and many patients presenting in the clinic are older than that. How to treat them has been unclear; some clinicians have extrapolated the findings from the landmark trial and used chemoradiotherapy, but some have been wary of doing so, as there have been some data from smaller European trials that have suggested that elderly patients may in fact have worse outcomes from chemoradiation compared with radiotherapy alone, he explained.

Brian Michael Alexander, MD, PhD, disease center leader for radiation oncology at the Center for Neuro-Oncology, Dana-Farber Cancer Institute, and associate professor of radiation oncology at Harvard Medical School in Boston, also welcomed the new data.

"Glioblastoma is frequently diagnosed in older individuals, and these are important data showing that our best therapies can work and be tolerable for elderly patients," he said in statement.

"It's good to have an option to offer patients that we know can have a positive impact, though still physicians and their patients need to weigh the benefits of this approach carefully," Dr Alexander added.

Less Intensive Treatment

The international phase 3 trial was led by the Canadian Cancer Trials Group (CCTG), with collaboration from the European Organization for the Research and Treatment of Cancer (EORTC) and the Trans-Tasmin Radiation Oncology Group (TROG).

The trial was conducted in 562 patients 65 years and older who were newly diagnosed with glioblastoma. They were randomly assigned to either short-course radiation therapy (40 Gy in 15 fractions over 3 weeks) or short-course radiation plus 3 weeks of concomitant temozolomide plus monthly adjuvant temozolomide until progression or 12 cycles.

Discussant for the study, Stuart Grossman, MD, from the Sidney Kimmel Comprehensive Cancer Center at John Hopkins in Baltimore, noted that this was less intensive than the standard of care established in 2005, which is radiation at 60 Gy over 6 weeks with concurrent temozolomide for 6 weeks, followed by temozolomide for 6 months.

Although a previous trial has shown that the shorter course of radiotherapy is noninferior to the longer course, there are no data to support the shorter temozolomide treatment course, and so Dr Grossman said he was concerned about "potential undertreatment."

However, Dr Lassman said he felt it was reasonable, as the shorter course of temozolomide would reduce toxicity, some of which could be hard on elderly patients. One of the adverse effects of temozolomide is constipation, "which can be a real issue in the elderly,' he added, while others include nausea and vomiting and thrombocytopenia.

The shorter radiation course "is undoubtedly an advantage" for elderly patients, who may have difficulties with mobility and distance from the radiotherapy center, and in this trial "patients were able to complete the treatment easily, " Dr Perry commented during the press briefing.

Improved Survival, Doubled in Subgroup

The results show significant benefit, with median overall survival of 9.3 months with chemoradiation compared with 7.6 months with radiation therapy (hazard ratio [HR], 0.67; P < .0001) and median progression-free survival of 5.3 months vs. 3.9 months (HR, 0.50; P < .0001).

At a press briefing highlighting the data, Dr Perry commented that "although the difference in median survival seems modest, temozolomide significantly increased the chances of surviving 2 or 3 years. For an individual patient, that can mean being able to be part of another family holiday or celebration."

The 1-year survival rates were 37.8% for chemoradiation vs 22.2% with radiotherapy alone, and the 2-year survival rates were 10.4% vs 2.8% with radiation therapy alone.

As has been seen in previous trials, the benefit was greatest in patients with MGMT promoter methylation, a genetic abnormality linked to better response to chemotherapy and longer survival in this disease

In this trial, 165 patients had MGMT promoter methylation, and in this group, overall survival was doubled by the addition of temozolomide. The median overall survival was 13.5 months with chemoradiation vs 7.7 months with radiation alone (HR, 0.53; P = .0001) .

There was also an improvement in survival in patients who lacked MGMT promoter methylation (n = 189), although in this subgroup, the difference did not quite reach statistical significance (median overall survival was 10.0 months vs 7.9 months, respectively; HR, 0.75; P = .055). Dr Lassman commented that this is probably due to lack of statistical power because of the small numbers involved, and said the results suggest that this subgroup also benefits from the addition of temozolomide, although not as much.

While the methylated status is accepted as a prognosis marker, there has been some debate over whether or not it predicts response to chemotherapy, Dr Alexander told Medscape Medical News. It appears that both groups benefit, although patients with methylation appear to respond better to chemoradiotherapy.

But the benefit in the unmethylated patients is small, so in those patients (who also have worse prognosis), the clinician may decide to omit chemotherapy and try something else, within the context of a clinical trial, he said. This is especially relevant if the patient has poor performance status, and there is concern that they may not be able to tolerate temozolomide too well; in such cases, the unmethylated status adds to the discussion of the risk/benefit equation, as the benefit in these patients is smaller, he commented.

Dr Perry reports stock and other ownership interests with DelMar Pharmaceuticals and VBL Therapeutic. Several coauthors report relationships with pharmaceutical companies, as detailed in the abstract.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA2. Presented June 5, 2016.


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