Schomberg, Paula J.

1562 Background: Prior studies have shown additive effects of CPT-11 in combination with BCNU, and radiosensitizing effects of CPT-11 in gliomas. Methods: All pts had GBM by central review prior to registration. With MTD based on a pilot study (Arm A), those not receiving anticonvulsants (non-EIAC, Arm C) received RT with concomitant CPT-11 (125 mg/M2/wk × 4, cycle 1), followed by BCNU (100 mg/M2 q 6 wk) + CPT-11 (75 mg/M2/wk × 4, q 6 wks, cycles 2–5) beginning within 4 wks of RT. Pts on EIAC (Arm B) received CPT-11 (400 mg/M2/wk × 4, cycle 1) during RT, then post-RT BCNU (100 mg/M2 q 6 wk) + CPT-11 (400 mg/M2/wk q 6 wks, cycles 2–5). Dose de-escalations (but no escalations) were allowed. Toxicity was graded by CTC v. 3.0. Primary endpoint was overall survival at 12 mo (OS12), with a interim futility analysis after 12 mos. follow up in the first 35 patients. 18 “successes” (survival > 12 mo) were required to proceed. Results: There were 56 pts treated (20 Arm A, 12 Arm B, 24 Arm C). Six pts on Arm A developed toxicity at the pilot CPT-11 cycle 2–5 dose of 125mg/M2, requiring reduction (75 mg/M2) for the remainder of Arm A and all Arm C pts. The decision rule for the first 35 patients was not met, with inclusion of the 6 Arm A pts (14 successes, 19 failures, 2 incomplete data) or without these pts ( 13 successes, 20 failures, 2 incomplete). In the 35 pts with mature data, the best confirmed response was PR in 2 (6%), REGR in 4 (11%) and stable (>4 wks, STAB) disease in 7 (20%). For the 56 pts (51 with mature data), PR, REGR and STAB were noted in 4%, 16%, and 39% respectively. Reason for end of treatment (N=56) was: completion of study treatment (13%); pt refusal (11%); adverse event (9%); progression (39%); all cause death (9%); too early (13%) or other (7%). In the 51 pts whose data is mature, progression free survival at 6 mos (PFS6) was 29.8% (95% CI: 19.1, 46.3); PFS12 was 16.5% (95% CI: 8.3, 32.9) and OS at 12 mos was 45.4% (95% CI: 32.7, 63). Overall median survival was 10.7 mos (95% CI: 7.8, 14.5). Conclusions: Although limited activity (PR+REGR+STAB) of this combination was demonstrated, the decision rule (minimum OS12 “successes”) was not reached, and tolerability of this regimen was only moderate. We consider the regimen as not superior to results obtained with other regimens in prior NCCTG studies. No significant financial relationships to disclose.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or beta–human chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Purpose In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). Patients and Methods After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). Results Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). Conclusion Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.