Flutamide-associated liver toxicity during treatment with total androgen suppression and radiation therapy for prostate cancer.

PURPOSE: To examine the frequency and severity of toxicity associated with flutamide inpatients treated with total androgen suppression before and during pelvic radiation therapy (RT) for prostate cancer. MATERIALS AND METHODS: Sixty-five patients with T2b-T4 prostate cancer received flutamide and goserelin acetate for 4 months, with RT beginning at the 3rd month. Treatment records including liver function test (LFT) results at baseline and during treatment were reviewed and toxicities noted. RESULTS: In 30 (46%) of 65 patients, flutamide was discontinued prematurely. Primary reasons included elevation in LFT levels (n=14); gastro-intestinal toxicity (n=9); decreased hemoglobin level (n=2); patient refusal (n=2); and arthralgia, rash, and malaise (n=1 each). Hepatotoxicity generally was manifest as asymptomatic transaminase level elevation. Grade 3-4 hepatotoxicity was noted in four of 65 patients. Mean aspartase aminotransferase increased from 23 (baseline) to 67 U/L (during flutamide treatment) (P<.02); mean alanine aminotransferase level increased from 26 (baseline) to 94 U/L (during flutamide treatment) (P<.005). CONCLUSION: Flutamide toxicity was common. LFTs should be monitored during flutamide therapy. The role of flutamide in this treatment regimen may need to be reevaluated.

A phase I/II study of intraoperative radiotherapy in advanced unresectable or recurrent carcinoma of the rectum: a Radiation Therapy Oncology Group (RTOG) study.

The Radiation Therapy Oncology Group (RTOG) initiated a phase I/II study of intraoperative radiotherapy (IORT) in advanced or recurrent rectal cancer to assess therapeutic efficacy, toxicity, and establish quality control guidelines prior to beginning a phase III trial. From October 1985 through December 1989, 87 patients with histologically proven adenocarcinoma of the rectum or rectosigmoid with recurrent/persistent disease after surgery or those primarily inoperable were entered by 14 institutions. Of 86 evaluable patients, 42 patients received IORT either alone (n = 15) or in combination with external beam (n = 27). Local control was dependent on the amount of residual disease prior to IORT, with 2-year actuarial local control of 77% if no gross residual disease remained vs. 10% with gross residual disease (P = 0.001). For the recurrent/residual group (n = 33), this observation was also significant with a 2-year actuarial local control rate of 64% if no gross residual remained vs. 10% with gross residual disease (P = 0.004). Local control translated into an improved survival for all patients and the recurrent/residual group with 2-year actuarial survival of 88% and 89% if no gross residual disease remained vs. 48% and 45% with gross residual disease, respectively (P = .0005, 0.006). Six patients (14.6%) experienced four grade 3 and three grade 4 complications as a possible result of IORT during follow-up with a 2-year actuarial risk of major complications of 16%. We conclude that IORT is feasible within a cooperative group and can be performed with acceptable complication rates. A phase III trial to demonstrate a therapeutic advantage for IORT over external beam alone is currently in progress.

Intraoperative radiation therapy of extrahepatic biliary carcinoma: a report of RTOG-8506.

Twenty-three patients with unresected, resected but residual, or locally recurrent biliary duct cancer were entered on a Radiation Therapy Oncology Group (RTOG) Phase I-II study. Of 16 patients who were properly entered and eligible for study, eight patients (50%) completed protocol treatment including intraoperative radiation therapy (IORT). Minor acute complications from therapy were common. There was no early grade 3 or 4 toxicity. Major long-term toxicity (grade 4) was noted in one patient who suffered a perforated viscous related to salvage radiation therapy for a scar recurrence and died of infection 1 month after retreatment. With a median follow up of 10.5 months, two of the eight patients who received IORT are alive. Of the six patients who died, one had persistent disease, one had the tumor recur in the surgical wound and subsequently died of complications related to retreatment with high dose radiation, and one died of intercurrent disease. In addition, two patients died with liver metastasis, and one died with intraabdominal disease outside of the IORT volume. Bulk of disease may be an important determinant of outcome.

Surgical complications of intraoperative radiation therapy: the Radiation Therapy Oncology Group experience.

Intraoperative radiotherapy (IORT) is being used with increasing frequency in many institutions in the United States but little is known about the surgical complication rates. The Radiation Therapy Oncology Group initiated three prospective studies in IORT in 1986 and we report here the experience in advanced malignancies of the stomach, pancreas, and rectum. The incidence and nature of major surgical complications were reviewed and presented with their implications in regard to future IORT trials. Two hundred twenty-seven patients were entered on three studies by 20 participating institutions between 1985 and 1989. One hundred twenty-nine patients received IORT while 98 patients were found to have too advanced disease to be benefited by IORT and underwent palliative surgical procedures only. IORT doses ranged from 12-22 Gy and bowel anastomoses were not irradiated. Wound infection in the IORT group was 6% vs. 2% in the non-IORT patients but this was not significant at the P = 0.05 level. Other complications included anastomotic leak (n = 5), operative bleeding (n = 10), pancreatitis (n = 2), and were not statistically different in the IORT and non-IORT groups. The mortality rate for the IORT and non-IORT groups combined was 1.8%. This large multi-institutional experience in patients with advanced malignancy demonstrates that patients receiving IORT do not have a higher surgical complication rate than those not receiving IORT. Long-term survival data await the implementation of Phase III trials in advanced intra-abdominal malignancy.

Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group.

The Radiation Therapy Oncology Group in 1985 began a study of IORT plus external beam radiation therapy for patients with locally unresected, non-metastatic pancreatic cancer. Patients were treated with a combination of 2000 cGy of IORT and postoperative external beam radiation therapy to 5040 cGy in combination with IV 5-FU (500 mg/m2/day on the first 3 days of the external beam treatment). As patients were registered on study prior to exploration, it was expected that a number of patients would be excluded from further analysis at the time of surgery. Eighty-six patients were entered on study through 6/1/88 and analyzed through 4/90. Fifty-one patients were fully analyzable. Median survival time of the 51 patients was 9 months with an 18-month actuarial survival rate of 9%. Local control could not be adequately evaluated in this multi-institutional study. Major postoperative complications were not excessive and occurred in 12% of patients. Two patients had major late morbidity leading to death, one from duodenal bleeding and the second from biliary obstruction. Although this study does demonstrate the feasibility of IORT in a multi-institutional setting, it does not demonstrate any advantage of IORT over conventional therapy for this disease.

Conventional radiation therapy in the management of arteriovenous malformations of the central nervous system.

Between 1967 and 1981, five patients were treated for vascular malformation of the central nervous system using conventional radiotherapy at Stanford University Medical Center. Two patients had arteriovenous malformations (AVM's) of the spinal cord, two patients had intracranial AVM's, and one patient had a hemangio-epithelioma of the occiput. All patients demonstrated clinical improvement after high dose radiation therapy with follow-up from 5 to 20 years. There have been no complications directly attributable to radiation therapy.

Practical and technical considerations in establishing an intraoperative radiation therapy program in the community practice.

The Radiation Oncology Center in Sacramento, California, has developed a procedure for establishing an intraoperative radiation therapy facility in a community practice. The logistics pertaining to personnel, equipment, physical measurements, and quality assurance are presented. Particular emphasis is given to the most effective means of acquiring the large quantity of data needed to ensure a program of acceptable quality.