The lack of impact of treatment time on the outcome of definitive radiotherapy for carcinoma of the prostate.

The records of 180 patients definitively irradiated for newly diagnosed adenocarcinoma of the prostate between 1970 and 1988 at Duke University Medical Center (107 patients from 1970-1983) and Moore Regional Hospital (73 patients from 1981-1988) were reviewed to determine the impact of overall treatment time on survival, local control, disease-free survival, and time to distant metastases. Using multivariate analysis we controlled for the influence of the following prognostic variables in addition to overall treatment time: age, clinical stage, histologic grade, acid phosphatase, type of biopsy, radiation dose, and use of hormonal therapy. Median follow-up was 46 months. Eighty-three percent of patients had clinical Stage B or C tumors. This is the first study to consider how treatment time might interact with recognized prognostic variables to influence treatment outcomes in prostate cancer and we found that overall treatment time did not significantly influence any of the outcome endpoints. Future research designed to improve local control after radiotherapy for prostate cancer should not focus on altering treatment time, but should explore other avenues such as hyperthermia, chemical modifiers or conformal therapy.

Topical application of WR-2721 to prevent radiation-induced proctosigmoiditis. A phase I/II trial.

Patients undergoing x-ray therapy to the pelvis have intestinal symptoms proportional to the volume treated and the dose delivered. WR-2721, S-2 (3-aminopropylaminoethyl) phosphorothioic acid, is an organic thiophosphate compound that selectively protects normal tissues against radiation effects. A Phase I/II study was done to test the ability of topical application of WR-2721 to protect the mucosa of the rectosigmoid from radiation damage. Thirty-one patients were enrolled in this study, of which, seven were control subjects. Twenty-four patients received WR-2721 daily, in enema form, 45 minutes before treatment. The patients were assigned by groups of three to receive increasing doses of WR-2721 beginning with 100 mg/enema to 450 mg/enema. Rectal mucosal biopsies were obtained within the treated field before, during, and at the end of therapy. The degree of damage to the rectal mucosa was scored on the basis of a 0 to 4 scale (with 0, least damage to 4, most damage) as determined by the percentage of damaged mucosal crypt glands. The patients' symptoms were recorded once a week during the entire course of therapy. The biopsy scores of the control group were slightly higher than those of the treatment groups; however, this difference did not appear to be significant. In the treated groups, there was a slight decrease in the biopsy scores with increasing doses of WR-2721, but this trend was not sustained. There were no differences among any of the groups in the symptoms experienced during the course of therapy. This study showed that WR-2721 could be administered safely in enema form in doses ranging from 100 to 450 mg/enema, but this drug did not protect the rectosigmoid mucosa from radiation damage at the doses administered.

Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990.

From 1984-1990, 143 patients with squamous cell or adenocarcinoma of the esophagus were enrolled in a Phase I/II study of neoadjuvant chemotherapy followed by concurrent chemotherapy plus radiotherapy with or without subsequent esophagectomy. Patients received one cycle of Cisplatin or Carboplatin plus Etoposide for squamous cell carcinoma, or Cisplatin or Carboplatin plus 5FU for adenocarcinoma, followed by two cycles of the same chemotherapy given concurrently with 44-46 Gy over 5 weeks. Operable patients then underwent esophagectomy. Inoperable patients and those with positive surgical margins received additional irradiation (16-18 Gy). Twelve percent of the surgical group received preoperative radiotherapy doses > or = 50 Gy. Seventy-two percent (103) had clinical Stage I-III tumors and 28% (40) were clinical Stage IV (1983 American Joint Committee on Cancer criteria). Only clinical Stage I-III patients were analyzed with respect to patterns of failure. Isolated local failure occurred in 19/103 (18%) of clinical Stage I-III patients. Both local and distant relapse occurred in 15/103 (15%), and distant metastases alone occurred in 25/103 (24%). The 3-year actuarial rates of local and distant failures were 45% and 60%, respectively. Among the clinical Stage I-III patients who underwent surgery (n = 58) versus those who did not (n = 45), the 3-year actuarial local and distant failure rates were 30% versus 60% and 45% versus 45%, respectively. Multivariate analysis was performed to identify significant predictors of local control. For all clinical Stage I-III patients, treatment with surgery (p = 0.001) and with three or more cycles of chemotherapy (p = 0.02) were significant predictors of improved local control. Patients who underwent surgery were significantly younger and had a better performance status than those who did not. The improvement in local control with surgery did not translate into better survival, likely on account of a high operative mortality rate in older patients and those receiving > or = 50 Gy preoperatively. We conclude that local control remains poor with concurrent chemotherapy + radiotherapy for esophageal cancer. The addition of surgery improved local control, but distant metastases remain a problem both in this group of patients as well as those treated without esophagectomy. Efforts to improve local control appear warranted, but it remains to be demonstrated that improved local control translates into improved survival in esophageal cancer because of a high rate of distant metastases in patients whose disease is controlled in the esophagus.