Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone.

PURPOSE: Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival. METHODS AND MATERIALS: Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated. RESULTS: The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2. CONCLUSIONS: An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Flow cytometric analysis of DNA ploidy, percent S-phase fraction, and total proliferative fraction as prognostic indicators of local control and survival following radiation therapy for prostate carcinoma.

PURPOSE: Treatment recommendations for localized prostate cancer may be improved by the identification of tumor factors prognostic for local control and survival. In this retrospective study, flow cytometric deoxyribonucleic acid (DNA) ploidy analysis and cell cycle analysis were performed on paraffin-embedded biopsy material to determine if additional prognostic factors could be identified in patients treated with radiation therapy. METHODS AND MATERIALS: Seventy patients with T1-4NxM0 tumors were identified in whom the primary treatment had been radical radiation therapy with no prior or concurrent endocrine therapy and in whom sufficient prostatic tissue was available for flow cytometric analysis. There were 40 diploid, 26 aneuploid, and 4 multiploid cases. Aneuploid and multiploid cases were combined for analysis. Cell cycle data were obtained on all diploid and 10 aneuploid cases. RESULTS: The histologic differentiation of the tumor (well or moderate vs. poor) was an independent predictor of overall survival and disease-free survival (p = 0.05 and 0.01, respectively). Local control was worse in the poorly differentiated patients, although this was not statistically significant in a multivariate analysis (p = 0.08). Neither T-stage, deoxyribonucleic acid ploidy (diploid vs. nondiploid), percent S-phase fraction, nor total proliferative fraction (S-phase fraction + G2M) significantly predicted for any of these endpoints. Within the diploid and well or moderately differentiated subgroup (n = 25), S-phase (< 4.2 vs. > or = 4.2) was a significant predictor of local control (100% vs. 51%, p = 0.03). A comparable distinction could be made using total proliferative fraction (< 10% vs. > or = 10%) with local control rates of 100% vs. 56% (p = 0.05). Among the poorly differentiated tumors, no similarly favorable subgroup was identified. CONCLUSIONS: This retrospective and multivariate analysis identifies both histology and percent S-phase or total proliferative fraction as predictors of local control following irradiation, and confirms that histology, but not DNA ploidy, is significant for overall survival. If these previously unreported findings are confirmed by prospective studies, S-phase should be added to histology as a parameter in the evaluation of clinical trials.

Radiation therapy for localized prostate carcinoma: experience at the Massachusetts General Hospital (1973-1981).

The success following irradiation in 370 patients with clinically localized prostate carcinoma was measured by overall patient survival as well as the cumulative incidence with time of treated patients who developed either local tumor regrowth or progression with distant metastases. With a minimum follow-up of 5 years in living patients, we evaluated the cumulative frequency curves using both univariate and multivariate (Cox) analyses. Overall patient survival and probability of progression with distant metastases were significantly influenced by initial tumor stage and the degree of histologic differentiation. The results at 8 years are significantly better for patients with T2 (B) tumors (local regrowth in 8%, distant metastases in 18%) than for patients with T3-T4 (C) tumors (local regrowth in 28%, distant metastases in 60%). Patient tolerance of external-beam radiation therapy was carefully analyzed in 121 consecutively treated patients in 1980 and 1981 for subsequent radiation-related sequelae. Minor transient intestinal and urologic sequelae were observed in 21% and 23% of the patients, respectively. These mild to moderate symptoms resolved in all but 7% of the patients who are continuing with mild symptoms. One patient had a major complication, i.e., a cystectomy required for persistent bleeding. Erectile potency has been maintained in 63% of potent patients. No specific benefit or detriment in outcome was seen in the minority of 51 patients who were irradiated by iodine-125 implantation.(ABSTRACT TRUNCATED AT 250 WORDS)