Chemotherapy plays an important role in treating patients with malignant gliomas, even though only modest benefits are gained from its use. While new biologic and chemotherapeutic agents are continuously being developed, to date none of these agents has significantly increased survival in patients with malignant gliomas. Until better therapies are available, attempts to optimize currently available agents by overcoming mechanism of resistance is an important therapeutic strategy.
We determined that the MTD of TMZ that could be given over a 28-day period with a fixed dose of BCNU (150 mg/m2) every 8 weeks was 80 mg/m2; the DLT at 90 mg/m2 was grade 4 neutropenia and thrombocytopenia in 1 patient each. The 28-day course of TMZ was chosen because the myelosuppressive effects of BCNU occur approximately 4 weeks after administration, and the 28-day off period allowed hematologic recovery. On the 28-day schedule, the amount of TMZ exposure to the tumor was 1.4 to 2.5 times more, depending on the dose level, than exposure on the standard 5-day schedule of 200 mg/m2. For patients who continued on in therapy, the major toxicity in subsequent cycles was hematologic; most other toxicities were grade 1 or 2, and pulmonary toxicity was not seen. The true benefit of this regimen cannot be assessed, as these patients had just completed RT; hence any responses may have been due to radiation. Additionally, any effects seen from this regimen could be similar to either agent alone or due to the 28-day dosing schedule of TMZ and not necessarily the combination of drugs or AGT depletion.
Two phase 1 studies and one phase 2 study used O6
-benzylguanine to modulate intratumoral AGT, in combination with BCNU, to treat malignant gliomas or other solid tumors (Friedman et al., 2000b; Quinn et al., 2002; Schilsky et al., 2000
). The phase 1 trials were able to use only 40 mg/m2
of BCNU, a dose far lower than typically used (Friedman et al., 2000b; Schilsky et al., 2000
). The DLT was grade 3 or 4 thrombocytopenia and neutropenia. The hematologic toxicity was cumulative and prevented some patients from continuing on therapy, which corresponds to in vitro data that O6
-benzylguanine potentiates BCNU toxicity in hematopoietic stem cells (Westerhof et al., 2001
). In the phase 1 and 2 studies for patients with recurrent or progressive malignant gliomas, myelosuppression was the major toxicity, and pulmonary toxicity was seen in 2 patients in the phase 1 trial (Friedman et al., 2000b; Quinn et al., 2002
). None of the patients in either study responded to therapy, possibly because of the low dose of BCNU, a lack of reversal of AGT activity, or an alternate mechanism of resistance. Brandes et al. (2002)
used procarbazine (100 mg/m2
, days 1–5) to deplete AGT prior to treating with BCNU (80 mg/m2
, days 3–5). They treated 58 chemotherapy-naïve patients with recurrent or progressive GBM post-RT. Several patients required dose reduction because of hematologic toxicity, and 5 patients had partially reversible pulmonary toxicity. Another group (Beith et al., 1997; Slancar et al., 1997
) also used procarbazine to deplete AGT with a slightly different regimen (procarbazine 200 mg/m2
on days 1–5, BCNU 80 mg/m2
on days 3–5, and vincristine 1.4 mg/m2
on day 3). Significant pulmonary, hematologic, and hepatic toxicities were seen. Measurement of AGT levels in peripheral monocytes revealed a 54% decrease after 2 days of procarbazine therapy (Beith et al., 1997; Slancar et al., 1997
A phase 1 trial of BCNU and TMZ was performed through the North American Brain Tumor Consortium, using the knowledge that this combination is synergistic in vitro. In that study, the MTD was BCNU at 150 mg/m2
followed by TMZ at 550 mg /m2
, each as a single dose, every 6 weeks. As in our study, the main toxicity was myelosuppression, but 3 patients had pulmonary toxicity, at least one of which was likely due to BCNU (Schold et al., 2000
). A follow-up study of this combination in patients with AA prior to RT also noted significant myelosuppression preventing 22% of the patients from completing the full 4 cycles prior to receiving RT (Chang et al., 2003
As a phase 1 study, efficacy was not a primary end point. However, our results are comparable to other studies of adjuvant therapy. The Medical Research Council Brain Tumor Working Party (2001)
found a median TTP and OS of 24 and 40 weeks, respectively, in patients with high-grade astrocytomas treated with RT and PCV. Levin et al. (2000)
treated GBM patients post-RT with procarbazine, CCNU, and vincristine ± alpha-difluoromethylornithine and found a median TTP of approximately 18 weeks and OS of 57 to 61 weeks. Brandes et al. (2002)
determined a median TTP of approximately 19 weeks and a PFS at 6 and 12 months of 42.3% and 15.4%, respectively, in chemotherapy-naïve GBM patients with progressive disease.
The combination of TMZ (80 mg/m2) given over 28 days and BCNU (150 mg/m2) given every 8 weeks is feasible. A phase 2 trial of this regimen at the MTD will determine the true efficacy of this regimen when compared to other trials of adjuvant therapy. However, the toxicity seen in our study following cycle 1 raises the issue of whether a lower dose of TMZ or BNCU might be more rational. Dose reductions in BCNU may alter the efficacy of this combination, and the cytotoxic effects of BCNU may decrease at a dose less than 100 mg/m2. Pulmonary toxicity was not a complication in our study and may have been due to the level of AGT reduction. Cumulative myelosuppression from this combination may affect long-term therapy for patients responding to treatment or alternative therapies for patients who have progressed. Post-cycle 1 toxicities should be assessed in all phase 1 studies, as these toxicities may impact present and future therapies.