Treatment of recurrent gliomas with eflornithine.

BACKGROUND: Oral eflornithine in combination with intravenous mitoguazone (methylbisguanylhydrazone) has shown activity against recurrent anaplastic gliomas. Eflornithine alone, however, has not been evaluated against recurrent gliomas. PURPOSE: This study compared the antitumor activity of oral eflornithine with that of oral eflornithine combined with intravenous mitoguazone in the treatment of patients with recurrent or progressive glioblastoma multiforme as well as nonglioblastoma anaplastic gliomas. METHODS: During the 1st year of therapy with eflornithine alone, the drug was given at a dose of 3.6 g/m2 on days 1-14, 22-35, and 43-56 every 8 hours; cycles were repeated every 63 days until progression. For the 2nd year, the drug was given on days 1-14, 29-42, and 57-70, with 84 days between cycles. For the 1st and 2nd years of eflornithine-mitoguazone therapy, eflornithine was given at 1.8 g/m2 on the same schedule. Mitoguazone was given intravenously at 200 mg/m2 on the final day of each 2-week sequence of eflornithine therapy. Response was determined by evaluating changes in the size of contrast-enhanced neuroimages. RESULTS: Because of two cases of lethal hepatic necrosis, the initial random allocation of patients to the eflornithine-mitoguazone arm was stopped after 23 patients had been accrued. Ninety-eight patients were entered in the eflornithine arm; 80 patients (36 glioblastoma multiforme patients and 44 anaplastic glioma patients) were assessable for response. Antitumor activity (partial response, minor response, and stable disease) was seen in 45% of the patients with anaplastic gliomas, for a median of 49 weeks, but in only 17% of patients with glioblastoma multiforme (median not attained). Twenty-one (20%) of the patients with anaplastic glioma and 33% of the patients with glioblastoma multiforme were removed from the study before completing the first 8-week course of therapy because of neurological deterioration and tumor progression by the 5th week of treatment. CONCLUSION: This study suggests that eflornithine alone is an effective palliative therapy for recurrent anaplastic gliomas. Additional studies are needed to confirm our finding.

Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas.

PURPOSE: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas. METHODS AND MATERIALS: Between 1988 and 1992, 90 patients received 1.9-2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m(2) carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed. RESULTS: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age (p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis (p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance (p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients. CONCLUSION: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18-33 months).

Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas.

OBJECTIVE: To determine the efficacy of the combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas after failure of either previous radiotherapy alone or previous radiotherapy plus nitrosourea-based chemotherapy. METHODS: Seventy-seven patients with recurrent malignant gliomas were studied. 6-Thioguanine was administered for 4 days before lomustine, and procarbazine was administered for 1 day before and 2 days after lomustine to potentiate lomustine's antitumor effect. Hydroxyurea was initiated 1 day before lomustine and continued for a total of 3 days. RESULTS: Thirty patients with glioblastomas and 47 patients with anaplastic gliomas were eligible for evaluation. In the glioblastoma group, 2 of 30 patients had a partial response and 8 of 30 patients had stable disease. This group of patients who responded and had stable disease included 6 of 10 patients who had not undergone previous chemotherapy but only 4 of 20 who had undergone previous chemotherapy. The overall median time to disease progression for the glioblastoma group was 9 weeks. In the anaplastic glioma group, 11 of 47 patients had a partial response and 25 of 47 had stable disease, including 23 of 30 without previous chemotherapy and 13 of 17 who had undergone previous chemotherapy. The median time to disease progression for the whole anaplastic glioma group was 24 weeks; however, the time to disease progression was 50 weeks for responding patients who had not undergone previous chemotherapy and 25 weeks for those who had undergone previous chemotherapy. CONCLUSION: Our results indicate that chemotherapy with a combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea is active for patients with recurrent anaplastic gliomas and glioblastomas not previously treated with nitrosourea-based chemotherapy but is inactive for patients with glioblastomas previously treated with chemotherapy.

[Kidney transplantation]. / Trasplantectomía renal.

In a consecutive series of 639 Renal Transplants (RT) performed between January 1st 1978 and December 31st 1988, 75 Renal Transplanctectomies (RTX) were carried out. Of those, fifty-seven (76%) were due to immunological causes, 10 (13.3%) to vascular complications, 7 (9.3%) to urological problems and 1 (1.3%) to deep infection. The time elapsed between RTX and RT was as follows: 25 were performed earlier than 6 weeks, 17 between 6 weeks to 6 months, and 33 after 6 months. The higher number of complications did not happened, as it is frequently described, in the first group; on the contrary, it fell in the group that had been transplanted longer. There were 13 immunologically caused renal rhexis, 5 of which were RTX, another 5 were operated on and diagnosed at perioperation, and immediately received the appropriate treatment so they were able to keep their kidney, and finally, 3 patients were diagnosed a rejection with renal rhexis, ecographically confirmed. These patients were given only medical treatment, which was enough to allow jugulation of the picture. RTX techniques used were: extracapsular in 28 cases and intracapsular in 47. Surgical approach, except for 2 cases of simultaneous kidney and pancreas transplantation, was extraperitoneal.

Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma.

Targeting the epidermal growth factor receptor (EGFR) may be effective in a subset of glioblastoma patients. This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response. The primary endpoint was progression free survival (PFS). Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28-day cycle (target AUC of 6 mg x ml/min). Daily erlotinib at 150 mg/day was dose escalated to 200 mg/day, as tolerated. Clinical and MRI assessments were made every 4 and 8 weeks, respectively. Tumor tissue was evaluated for EGFR, AKT and phosphatase and tensin homolog (PTEN) status. One partial response (PR) was observed out of 43 assessable patients. Twenty patients (47%) had stable disease (SD) for an average of 12 weeks. Median PFS was 9 weeks. The 6-month PFS rate was 14%. Median overall survival (OS) was 30 weeks. This regimen was well tolerated with grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. A recursive partitioning analysis (RPA) predicted that patients with KPS >or=90 treated with more than 1 prior regimen had the highest OS. No correlation was observed between EGFR, Akt or PTEN expression and either PFS or OS. Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients. Future trials should be stratified based on optimal molecular or clinical characteristics.