Combined Modality Approaches to Glioblastoma
Combined Modality Approaches to Glioblastoma
Abstract & commentary
By William B. Ershler, MD
Synopsis: Temozolomide, administered during and subsequent to radiation therapy for patients with glioblastoma, was shown in this randomized, phase III trial to provide survival benefit when compared to those post-surgical patients treated with radiation alone.
Source: Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459-466.
Randomized trials of radiotherapy vs. no radiotherapy after surgery showed significant survival benefits for radiotherapy,1 but the benefit of additional chemotherapy administered concurrently, or in an adjuvant setting, has been slow to accumulate. A meta-analysis of 12 randomized trials of adjuvant chemotherapy for high-grade glioma showed a 35% one-year survival rate for glioblastoma, an improvement of only 6%.2 In 2004, a randomized, phase III trial by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and two-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy.3 At the time of that publication, it could not be determined whether the apparent survival advantage would be durable over time. Thus, Stupp et al provide a new analysis, with the median follow-up of now more than five years.
The trial included adult patients with newly diagnosed glioblastoma who were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide, followed by up to six cycles of adjuvant temozolomide. Patients were randomly assigned to receive either standard focal radiotherapy or standard radiotherapy plus concomitant daily temozolomide, followed by adjuvant temozolomide. The radiation was a fractionated conformal 3-D approach to a total dose of 60 Gy in 30 daily fractions. Concomitant chemotherapy consisted of oral temozolomide at a daily dose of 75 mg/m2 given seven days per week from the first to the last day of radiotherapy, for no more than 49 days. After a four-week break, patients received up to six cycles of adjuvant oral temozolomide (150-200 mg/m2) for five days every 28 days. Prophylaxis against Pneumocystis jirovecii with either pentamidine or trimethoprim-sulfamethoxazole was prescribed for all patients receiving adjuvant temozolomide.
Between August 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. Of those, 287 (97%) of 286 patients in the radiotherapy-alone group and 254 (89%) of 287 in the combined-treatment group died during five years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at two years, 16.0% (12.0-20.6) at three years, 12.1% (8.5-16.4) at four years, and 9.8% (6.4-14.0) at five years with temozolomide, vs. 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p < 0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years of age.
In the earlier analysis of this trial,3 it was noted that patients whose tumor had a methylated promoter for the gene encoding O-6-methylguaninie DNA methyltransferase (MGMT), were more likely to benefit from the addition of concomitant and adjuvant temozolomide. Upon repeat analysis at five years, it turns out that methylation of the MGMT promoter was the single best predictor for outcome and benefit from temozolomide chemotherapy. However, it is noted that the benefits of combined therapy were reported in all prognostic subgroups, including older patients, and the latter was not clearly present at the time of the initial analysis.
Commentary
Thus, combined initial treatment for glioblastoma with temozolomide and radiotherapy improves survival compared with radiotherapy alone. The survival advantage of combined treatment lasts for up to five years of follow-up. Nevertheless, most patients successfully treated with combined therapy eventually had tumor recurrence and died. Further analysis revealed that most patients treated with radiotherapy alone in the present study received salvage chemotherapy at recurrence or progression, and about half the patients initially treated with temozolomide received further chemotherapy at progression. Nonetheless, survival was better for those who received combined treatment, supporting Stupp et al's conclusion that the addition of chemotherapy early in the disease course, and concomitantly with radiotherapy, is the best strategy when evaluating new chemotherapeutic agents.
Regarding temozolomide, there have been a number of reports that would suggest a synergistic effect with radiation. For example, temozolomide and radiotherapy inhibit cell growth in a glioblastoma cell-line model;4 temozolomide induces an arrest in G2/M in glioblastoma cell lines;5 temozolomide has a radiation-enhancing effect in some glioma cell lines;6 temozolomide inhibits radiation-induced invasion via inhibition of integrins;7 and temozolomide increases radiation-induced DNA double-strand breaks and cell death in a glioblastoma model, but only when the drug is given concomitantly with radiotherapy and not sequentially.8
Thus, although temozolomide has limited activity as a single agent, its role in combination with radiation is now established. Furthermore, the benefits of adjuvant temozolomide with radiotherapy lasted throughout five years of follow-up in the current study. Questions remain about the efficacy of continuing drugs after the completion of radiation, and by which schedule and dose. Current research from EORTC intends to address these and related issues (EORTC CATNON trial). Also, the question of whether MGMT methylation status identifies patients most likely to benefit from the addition of adjuvant temozolomide will be addressed in the ongoing RTOG/ EORTC intergroup trial.
References
1. Rocconi RP, et al. Role of chemotherapy for patients with recurrent platinum-resistant advanced epithelial ovarian cancer: A cost-effectiveness analysis. Cancer. 2006;107:536-543.
2. Stewart LA. Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 2002;359:1011-1018.
3. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.
4. Wedge SR, et al. In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs. 1997; 8:92-97.
5. Hirose Y, et al. p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res. 2001;61:1957-1963.
6. van Rijn J, et al. Survival of human glioma cells treated with various combinations of temozolomide and X-rays. Int J Radiat Oncol Biol Phys. 2000;47:779-784.
7. Wick W, et al. Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res. 2002;62:1915-1919.
8. Chakravarti A, et al. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res. 2006;12: 4738-4746.
Temozolomide, administered during and subsequent to radiation therapy for patients with glioblastoma, was shown in this randomized, phase III trial to provide survival benefit when compared to those post-surgical patients treated with radiation alone.Subscribe Now for Access
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