R. Stupp

Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM). Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group

2 Background: Standard therapy of GBM after biopsy or resection is RT. TMZ, a novel methylating agent demonstrated some activity against recurrent glioma. In a phase II trial we observed a potential survival advantage by adding TMZ concomitantly and adjuvant to RT (Stupp et al. JCO 2002). In this randomized trial we tested this novel regimen against RT.nnnMETHODSnPatients (pts) age 18-70 years with histologically proven newly diagnosed GBM (WHO grade IV) were eligible. Pts were randomized between standard RT (60 Gy in 30 daily fractions of 2 Gy) versus the same RT and concomitant (TMZ 75 mg/m2/d, daily up to 42 days) followed by up to 6 cycles of adjuvant TMZ (150-200 mg/m2, daily x 5d, q28 d). Survival (intent to treat) was the primary endpoint aiming at a 30% improvement (log-rank). Pathology was centrally reviewed.nnnRESULTSnFive hundred and seventy-three pts from 85 centers were randomized. Median follow-up is 2 years, 436 patients have died. Median time between histological diagnosis and treatment start was 5 weeks. RT was delivered as prescribed in 93% of pts. Concomitant TMZ was administered without interruption in 76%, temporarily interrupted in 11% and prematurely discontinued in 12%. Adjuvant TMZ was given to 76% of pts, 36% completed all 6 cycles for a total of 924 cycles. The increase in median survival is 3 months. The log-rank test is significant with a p-value of < .0001. The hazard ratio is 0.62 (95% c.i. 0.51-0.75). Grade 3/4 hematotoxicity was observed in 7% of pts during concomitant TMZ/RT treatment, and in 16% (5.2% of cycles) of the adjuvant TMZ. Patients continue to be followed to evaluate long term effects of treatment.nnnCONCLUSIONSnConcomitant and adjuvant TMZ chemotherapy significantly improves PFS and overall survival in GBM pts. This treatment is safe and well tolerated. [Figure: see text] [Table: see text].

CorrespondenceEvidence-based management of adult patients with diffuse glioma – Authors' reply

Authors’ reply We appreciate the interest of our colleagues representing the European Low-Grade Glioma Network in the updated European Association for Neuro-Oncology (EANO) guidelines. Such guidelines often represent a multidisciplinary consensus that aims at providing guidance also in areas where evidence from conclusive clinical studies is limited or absent. Our colleagues miss a specific reference to the value of radiological growth rates. If we did not think that the assessment of tumour growth by neuroimaging was important, we would not have recommended regular MRI scanning to determine benefit from treatment and the need for re-intervention. However, no prospective systematic outcome study informs us on how to integrate radiological growth rates into clinical decision making, notably about timepoints of interventions. Furthermore, our colleagues are at odds with our assessment of the scientific literature on the role of surgery for adult patients with glioma. Yet, our assessment of the evidence, which is a result of multidisciplinary consensus involving leading neurosurgeons in Europe, is fully consistent with the current Cochrane review, which reinforces the need for randomised controlled clinical trials in this situation. We agree that the recent long-term followup on the Norwegian cohort study is suggestive of a benefit of early surgical intervention in patients with low grade gliomas across the major molecular subtypes and might in fact be the best evidence for a role of early surgery in this population published so far. Yet, this cohort study cannot be considered as conclusive evidence about the value of resection. Moreover, the article was not available in the public domain when we prepared the EANO guideline. Finally, it is incorrect to state that cognitive function and quality of life assessments are not mentioned: they are in fact mentioned as part of the clinical examination. Furthermore, this was not the main scope of this guideline and the importance of cognitive function and quality of life in the overall management strategies for adult patients with glioma has recently been addressed in a separate EANO guideline.