A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m 2 /day or 150 mg/m 2 /day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m 2 /day or 125 mg/m 2 /day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% ( P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group ( P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients ( P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity. © 2000 Cancer Research Campaign

To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.

Background:A serious, albeit rare, sequel of therapeutic ionizing radiotherapy is delayed development of a new, histologically distinct neoplasm within the radiation field.Methods:We identified 27 cases, from a 10-year period, of intracranial tumors arising after cranial irradiation. The original lesions for which cranial radiation was used for treatment included: tinea capitis (1), acute lymphoblastic leukemia (ALL; 5), sarcoma (1), scalp hemangioma (1), cranial nerve schwannoma (1) and primary (13) and metastatic (1) brain tumors, pituitary tumor (1), germinoma (1), pinealoma (1), and unknown histology (1). Dose of cranial irradiation ranged from 1800 to 6500 cGy, with a mean of 4596 cGy. Age at cranial irradiation ranged from 1 month to 43 years, with a mean of 13.4 years.Results:Latency between radiotherapy and diagnosis of a radiation-induced neoplasm ranged from 4 to 47 years (mean 18.8 years). Radiation-induced tumors included: meningiomas (14), sarcomas (7), malignant astrocytomas (4), and medulloblastomas (2). Data were analyzed to evaluate possible correlations between gender, age at irradiation, dose of irradiation, latency, use of chemotherapy, and radiation-induced neoplasm histology. Significant correlations existed between age at cranial irradiation and development of either a benign neoplasm (mean age 8.5 years) versus a malignant neoplasm (mean age 20.3; P = 0.012), and development of either a meningioma (mean age 7.0 years) or a sarcoma (mean age 27.4 years; P = 0.0001). There was also a significant positive correlation between latency and development of either a meningioma (mean latency 21.8 years) or a sarcoma (mean latency 7.7 years; P = 0.001). The correlation between dose of cranial irradiation and development of either a meningioma (mean dose 4128 cGy) or a sarcoma (mean dose 5631 cGy) approached significance (P = 0.059).Conclusions:Our study is the first to show that younger patients had a longer latency period and were more likely to have lower-grade lesions (e.g. meningiomas) as a secondary neoplasm, while older patients had a shorter latency period and were more likely to have higher-grade lesions (e.g. sarcomas).

Fifty-one adult patients with recurrent malignant gliomas were treated in a Phase II trial of multidrug chemotherapy (6-thioguanine, dibromodulcitol, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 5-fluorouracil, and hydroxyurea). Thirty-one patients underwent radical tumor debulking, before the administration of chemotherapy. Fifty-seven percent of all patients had either an objective radiographic response or stabilization of disease after the institution of therapy. The overall median survival time (MST) was 40 weeks; it was 79 and 33 weeks for anaplastic astrocytoma and glioblastoma patients, respectively. The overall median time to tumor progression (MTP) was 19 weeks--32 weeks for anaplastic astrocytoma patients and 13 weeks for glioblastoma patients. Serious chemotoxicity occurred in 35% of patients without permanent morbidity or mortality. The factors that affected response (including disease stabilization), MTP, and MST were identified through a multivariate statistical analysis. A longer MTP was associated with higher Karnofsky scores, lower grade initial histology, lack of prior chemotherapy, greater degree of myelotoxicity, smaller postoperative tumor volumes, greater extent of surgical resection, and a local versus diffuse recurrence pattern. A longer MST was associated with higher Karnofsky scores, lower grade histology at the time of recurrence, greater degree of myelotoxicity, and lobar versus deep tumor location. Response (including disease stabilization) correlated with higher Karnofsky scores, lower grade histology (initial and current), prior lower grade histology, smaller preoperative tumor volume, longer intervals from the time of initial diagnosis, and absence of prior chemotherapy. These results suggest that, in addition to established prognostic factors such as Karnofsky scores, other factors including prior chemotherapy administration, patterns of tumor recurrence, and tumor location may be important variables to consider in future Phase II-III clinical trials. Of the treatment variables analyzed, greater surgical debulking and smaller postoperative tumor volumes were associated with prolonged MTP but not MST, and greater myelotoxicity had a positive association with all outcomes. The significance of this latter relationship and its relevance to chemotherapy dosing will require further study. Standardization in the design and reporting of clinical trials and the use of computer-assisted tumor volume calculations to assess the extent of surgical resection and the response to therapy are advocated.

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