Treatment Options for Recurrent Glioblastoma: Pitfalls and Future Trends

Enrico Franceschi; Alicia Tosoni; Stefania Bartolini; Valeria Mazzocchi; Antonio Fioravanti; Alba A. Brandes


Expert Rev Anticancer Ther. 2009;9(5):613-619. 

In This Article

Chemotherapy at Recurrence/progression

Macdonald et al. have attempted to standardize response criteria on the basis of CT/MRI imaging, neurological status and steroid usage.[20] Currently, however, time to progression (TTP) and/or progression-free survival at 6 months (PFS-6) are believed to be more reliable and objective end points in evaluating the efficacy of medical treatment. Indeed, TTP measurement is straightforward and, unlike survival, is not influenced by further treatment.[21] Recently, the prognostic role of PFS-6 in patients with GBM recurrence was confirmed by Ballmann et al., whose findings showed that PFS-6 was correlated with overall survival at 12 months.[22] Chemotherapy, in association with corticosteroids, may often palliate symptoms and improve the quality of life.[23] This is an undeniable, although less objectively measurable, end point of efficacy for medical treatments, and should be assessed in state-of-the-art clinical trials. Chemotherapy is extensively administered to patients with recurrent GBM, although objective response rates remain unsatisfactory and TTP is short (3-6 months).[24] A retrospective analysis of eight Phase II chemotherapy trials conducted on 225 patients with GBM (partly pretreated with one or more chemotherapy regimens) reported a PFS-6 of 15% and a median progression-free survival of 9 weeks,[25] thus representing the benchmark for drug activity in the pre-RT/TMZ era.

Before the European Organisation for the Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) Phase III trial,[1] nitrosoureas, BCNU and lomustine, liposoluble alkylating drugs, were the gold standard for first-line chemotherapy for recurrent GBM after surgery and RT, with a response rate of approximately 30%. However, this may have been an overestimation, with findings being based on criteria that were essentially clinical. Data reported in subsequent studies on chemonaive patients indicated that BCNU treatment was followed by a response rate of 15% and a PFS-6 of 17.5%.[26] Furthermore, many other Phase II trials, conducted before the era of combined RT/TMZ for newly diagnosed GBM, reported PFS-6 rates of up to 39% in patients with recurrent disease receiving TMZ in combination with other agents (i.e., marimastat,[27] cisplatin[28] and 13-cis-retinoic acid[29]). However, it has not yet been proven that multiagent chemotherapy is more effective than single nitrosourea administration.[24,30] Nor has it been demonstrated that TMZ has advantages over a BCNU or procarbazine, lomustine and vincristine regimen, despite the fact that an indirect comparison made between studies suggests that TMZ has a better, noncumulative toxicity profile than other regimens used.

Following the introduction of the current standard of care for newly diagnosed GBM patients with RT and concomitant/adjuvant TMZ, novel first- and second-line treatments are under evaluation. Therefore, even though clear data are not yet available, nitrosourea-based chemotherapy should be considered a reasonable option,[26] as well as a TMZ rechallenge for patients without disease progression during TMZ treatment.[31]

Temozolomide rechallenge was recently investigated also by Perry et al. In their retrospective analysis, the authors showed that TMZ rechallenge with a continuous 50 mg/m2 daily schedule is an intriguing approach, especially for patients with recurrence after completion of TMZ administration concurrent with and adjuvant to RT: GBM patients failing during the first 3-6 months of adjuvant therapy (B1); GBM patients failing after more than 6 months of therapy (B2); and GBM patients who recurred after stopping treatment (B3). The PFS-6 rates were 28.6 (B1), 9.5 (B2) and 30.4% (B3).[32]

Repeat surgery and implantation of chemotherapy (BCNU)-impregnated polymers (Gliadel®) may also prolong survival in selected patients.[16] Recently, a Phase II trial using a thirdgeneration nitrosourea, fotemustine, investigated treatment efficacy in a population treated exclusively with TMZ and RT; MGMT methylation status was also assessed. A PFS-6 of 20.9% was obtained, and the authors suggested that their study findings represented a benchmark of activity at the time of recurrence.[33] The same approach has also been investigated by other groups.[34,35]