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PRIORITY PRESS - 15th European Cancer Conference and 34th ESMO Multidisciplinary Congress

Berlin, Germany / September 20-24, 2009

In 2004, a randomized phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) established a new standard of care when concurrent and adjuvant temozolomide (TMZ) with radiotherapy (RT) was shown to significantly improve median and two-year survival over RT alone in patients with newly diagnosed glioblastoma multiforme (GBM).

“This was the first trial to show a statistically significant and clinically meaningful benefit from the addition of TMZ to RT,” Dr. Warren Mason, Medical Director, Pencer Brain Tumor Centre, Princess Margaret Hospital, Toronto, Ontario, told delegates here. At a median follow-up of 61 months, the significant survival advantage seen with additional TMZ at two years has persisted and was especially robust among patients with methylated tumours. It is now known that tumours harbouring MGMT methylation promoters are more sensitive to TMZ than unmethylated tumours.

In reviewing the updated findings, Dr. Mason reminded delegates that in the original trial, 573 patients with newly diagnosed GBM were randomized to either RT alone at a dose of 60 Gy in 30 fractions or the same dose of RT plus concurrent TMZ 75 mg/m²/day for 42 consecutive days, followed by six cycles of adjuvant TMZ 150 to 200 mg/m² day for five consecutive days in 28-day cycles.

At two years, 27.2% of patients in the combination modality arm were still alive vs. 10.9% for RT monotherapy patients. Three- four- and five-year survival rates were 16.0%, 12.1% and 9.8%, respectively, for the RT/TMZ arm vs. 4.4%, 3.0% and 1.9%, respectively, for the RT monotherapy arm (P<0.0001) (Table 1). “Ten years ago, we would never have seen GBM patients living three, four and five years,” Dr. Mason remarked, “so there has been a significant shift in patient demographics as a consequence of this trial.” The most favourable prognostic group in the trial benefitted from the combined approach the most, such that 40% of RT/TMZ recipients were alive at two years vs. 20% in the RT arm; 28% were still alive at five years vs. 6.8% in the RT group. Benefit from the combined modality approach over RT alone was still apparent in less favourable prognostic groups, but it was not as compelling, with fewer patients being alive in either arm at each time point. As might be expected, MGMT methylation status was a strong predictor of response and outcome from chemoradiotherapy with TMZ.

“The prognosis in this disease remains poor but we do have reason to be optimistic as small numbers of patients can now be considered long-term survivors,” Dr. Mason concluded, adding that any new treatments for GBM must be measured against the RT/TMZ combination which remains the “backbone of care” for this difficult patient population.

Table 1.

Exploring Other Formulations

In the pivotal EORTC-NCIC CTG trial, exclusion criteria included patients who had difficulty swallowing, those with impaired gastrointestinal absorption, those with a poor performance status (PS) and the elderly. All of these patients, especially the elderly (among whom GBMs disproportionately occur), could benefit from chemoradiotherapy with TMZ, provided TMZ could be delivered in a form other than the oral formulation used in the pivotal trial.

Recently, an intravenous (i.v.) formulation has become available, as noted by Dr. Andrew Lassman, Director, Fellowship Program in Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York.

In a bioequivalence study, 22 patients were enrolled in an open-label, two-way crossover pilot study, among whom 19 had evaluable pharmacokinetic data. Results showed that both the area under the curve (AUC) and Cmax for TMZ and its active metabolite were well within accepted bioequivalence guidelines for oral and i.v. preparations, provided the i.v. formulation at 150 mg/m2 was infused over 90 minutes. No unexpected toxicities were observed with the i.v. formulation and site reactions were mild, as Dr. Lassman observed.

Pseudoprogression

As was discussed by Dr. Alba Brandes, Chief of Medical Oncology, Bellaria-Maggiore Hospital, Bologna, Italy, concurrent use of TMZ with RT increases the rate of therapy-induced necrosis or “pseudoprogression.” Unfortunately, pseudoprogression is radiologically indistinct from tumour recurrence and it becomes difficult to separate true progressors from pseudoprogressors on first and even second MRI following chemoradiotherapy.

However, it is important to recognize that the incidence of pseudoprogression, at least among patients with methylated tumours, is not inconsequential, occurring in 20% to 40% of this patient group. Confusing pseudoprogressors with true progressors may lead to premature termination of TMZ adjuvant therapy, thereby compromising patient outcome.

In her own study of pseudoprogression, Dr. Brandes and colleagues treated 103 patients with newly diagnosed GBM with concurrent RT/TMZ followed by prolonged maintenance chemotherapy. She reported, “At the end of concomitant therapy, 53 patients had stable lesions or no lesions at all, but 50 patients had enlarged lesions and the question was, was this true progression or not?”

At the second MRI, investigators observed that the enlarged lesions had either stabilized or resolved in 64% of this cohort of 50 patients, while only 36% of the group were true early progressors. Furthermore, “we found that there was a 91% probability of pseudoprogression in patients with methylated MGMT promoter tumours vs. a 59% probability of early progression in unmethylated MGMT promoter tumours,” Dr. Brandes, explained.

The median overall survival for the overall cohort in this study was 20.7 months; again, patients with methylated tumours had a far higher median survival rate at 43 months vs. 16 months for patients with unmethylated tumours. True early progressors also had a median survival of only 10 months vs. pseudoprogressors whose median survival was 38 months.

“In the absence of clear and validated methods to distinguish pseudoprogression from real progression, TMZ, at least in methylated patients, should be continued in our opinion, despite findings at first MRI after concomitant treatment,” Dr. Brandes concluded. She added that this practice could be considered “reasonable” because of the high rate of pseudoprogression in patients with methylated MGMT tumours .

Alkylating Agent Resistance

Resistance to alkylating agents such as TMZ via MGMT-mediated resistance remains a challenge in the management of patients with malignant gliomas. To that end, researchers have sought to determine if dose-dense TMZ might help overcome this resistance. As discussed by Dr. Wolfgang Wick, Chairman of Neuro-Oncology, University of Heidelberg, Germany, results from recent trials suggest that prolonged exposure to TMZ might effectively deplete cells of MGMT activity and increase their sensitivity to alkylating agents.

In one of his own studies, Dr. Wick and colleagues enrolled 21 patients with recurrent or progressive GBM in a phase II study during which they were treated with a one-week-on/one-week-off regimen of TMZ 150 mg/m² on days 1 to 7 and on days 15 to 21 of a 28-day treatment regimen. Two patients achieved a partial response and 17 others had stable disease. The median progression-free survival was five months. “In this uncontrolled trial, results were impressive,” reported Dr. Wick.

Summary

In his concluding remarks, Dr. Wick noted that data from the EORTC-NCIC CTG trial are “even more convincing” after five years of follow-up than they were earlier on, and that the difference between the two arms is even greater with longer-term follow-up. “Very importantly,” he advised delegates not to be too hasty about changing therapies after RT but to continue with established treatment, “as this is potentially in the best interests of your patients.”