A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma

For most patients with newly diagnosed GBM, postoperative radiotherapy plus TMZ has become the standard of care [2]. Assuming that TMZ is moving rapidly into the first-line setting, the question arises whether it should be given again in relapsed patients.

The choice of chemotherapy depended on whether the patient had previously received chemotherapy as first-line therapy. Frequently, treatment decisions have to be made based on case-by-case evaluation, depending on prior therapy, time to relapse, tumor grade, and performance status [23]. Several phase II studies have shown that chemotherapy approaches can provide some encouraging results in terms of efficacy. Nitrosoureas, PCB, paclitaxel, TMZ, and cisplatin were tested, although the impact on OS was minimal [24‐26]. In a large randomized, multicentre, open-label phase II study that compared TMZ and PCB in 225 patients with GBM at first relapse, Yung et al. [27] demonstrated that the 6-month PFS rate for patients who received TMZ was 21%, with an improvement in patient health-related quality of life. Antiangiogenic therapy has been demonstrated to represent a promising novel approach for treatment of malignant brain tumors. Recent clinical trials targeting vascular endothelial growth factor (VEGF) signaling with bevacizumab plus irinotecan have shown promising radiographic and clinical responses, while also confirming adequate safety in recurrent GBM patients [28]. We have also to consider the high impact on national health systems of the pharmaco-economic aspects of this regimen, as both irinotecan and bevacizumab are extremely expensive agents.

FTM represents an evolution of nitrosourea that was synthesized to facilitate passage through the blood–brain barrier by the addition of a phosphoalanine vector. The use and efficacy of this drug, using the conventional schedule [14] in patients with recurrent GBM, are known but limited by considerable toxicity. Hematological toxicity is observed in nearly 40% of patients receiving FTM, and thrombocytopenia and leukopenia are more frequent and significant in pretreated patients.

Myelosuppression was the most common adverse event that occurred, mainly during the induction phase of treatment. We cannot ignore that the traditional schedule of FTM including the induction phase achieved hopeful clinical results. On the basis of these considerations, we planned a new treatment that maintains the global dosage/time ratio but with different fractionation, similarly to our experience reported for low protracted dose of TMZ [29]. In fact, metronomic administration of cytotoxic drugs is proven to be less toxic than acute administration, causing also important and different biological effects on tumor cells. In the traditional schedule, patients received 400 mg/m² FTM during an 8-week period (days 1, 8, and 15 every 28–35 days), with considerable toxicity that frequently does not allow completion of the schedule. In the present trial, the patients received, during the same period, 400 mg/m² FTM fractionated to days 1, 15, 30, 45, and 60, and we did not observe any serious adverse events that compromised the dose density of this treatment. In our opinion, this could be the explanation for the promising results obtained in our series. The results of the present study show that fractionated FTM monotherapy is able to achieve response in 25% of patients, with an overall DCR of 65%. These results are remarkable, since they were observed in a pretreated population that had received one previous line of chemotherapy. However, our favorable data also have to be interpreted on the basis of “pseudoprogression” occurrence that could overestimate the results obtained in the present trial. We tried to reduce the influence of the occurrence of such a pseudoprogression effect by excluding patients who experienced progression within 3 months from radiation therapy according to NCI of Canada recommendations [30]. Moreover, none of the 14 patients enrolled in the study and who ended adjuvant TMZ treatment in the 3 months achieved an objective response during or after FTM therapy. However, we cannot exclude that some of the recorded responses could be resolution of radionecrosis, since we do not have data from amino-acid positron emission tomography (PET) and/or MRI spectroscopy demonstrating the specific features of tumor tissue. In addition, pretreatment with an alkylating agent could positively select for patients who will respond to alkylating therapy in relapse. The results regarding the activity of our schedule are in line with those reported in the literature with single-agent FTM at the conventional schedule of 100 mg/m² [10, 14]. However, these previous experiences were characterized by important hematological toxicity, as recently confirmed by Brandes et al. [15]. In the present study, we confirmed these results in a larger population of patients, with a better DCR and toxicity profile. Our efficacy data (PFS-6) are similar to those reported in two other trials, by Scoccianti et al. [18] and Fabrini et al. [17], but with a lower rate of grade 3–4 hematological toxicities, likely due to the longer period of rest between each induction phase. This is reasonable if we consider that we use a similar intensive dose for induction phase, and probably it may represent an explanation for the better results than those obtained by Brandes et al. [15], even if comparison across trials is always challenging. The crucial role of the induction phase for the efficacy of this drug was recently shown in two studies exploring FTM in combination with either dacarbazine or PCB [31, 32]. In these two trials the lower observed efficacy, considered as response rate (3–11%), is probably due to the different schedule that, in our case, includes the weekly induction phase. Our data confirmed the absence of cross-resistance between FTM and TMZ, since all responses were observed in TMZ-pretreated patients. PFS-6, the primary endpoint of the protocol, was 61% and represents an encouraging result compared with other experience with this drug or with other chemotherapeutic or targeted agents [33] or using the combination of irinotecan and bevacizumab. The treatment was well tolerated, underlining the lower toxicity than the usual schedule of FTM. In fact, in our series we recorded few grade 3 toxicities, preserving patient quality of life (QoL), which remains a crucial goal for these patients who currently cannot be cured but only palliated. Moreover, the patients who started FTM at least 3 months after completion of TMZ administration had a significantly higher response rate than patients who started FTM immediately after TMZ completion. These findings are in line with similar observations reported by others [15, 33]. MGMT promoter methylation status represents an important prognostic factor in newly diagnosed GBM patients, and it can influence the efficacy of TMZ therapy [4]. However, after primary treatment for newly diagnosed GBM, changes may occur in the status of MGMT promoter methylation [34]. In our study, we found a higher rate of disease control in patients with methylated MGMT, and a trend toward prolonged PFS-6, without achieving statistical significance. This result reflects the limited statistical power due to the relatively small number of cases enrolled in the present trial. To the best of our knowledge, this is the first report specifically dealing with use of protracted low FTM doses for induction phase. The considerable activity and lack of toxicity of this schedule open a new avenue for investigation of the possible use of FTM in combination with targeted therapy agents.