[en] Over the last ten years the RTOG has evaluated, by 5 Phase III trials, (two are ongoing and three have been completed) the potential clinical gains of neoadjuvant Maximal Androgen Blockade (MAB), Zoladex monthly and Flutamide daily, of adjuvant LHRH agonists (Zoladex) therapy and of the sequencing of four months of MAB with radiation (neoadjuvant vs. adjuvant). Two additional Phase III trails for men with locally advanced prostate cancer are soon to open. One will evaluate the potential gains in survival of salvage radiation therapy plus adjuvant anti-androgen therapy, compared to salvage radiation alone, for patients with an elevated PSA following radical prostatectomy for pathologic state T3, NO tumors; and a second Phase III trial to evaluate the potential gain of external beam irradiation added to life-long MAB for patients with pathologically proven metastases to the pelvic lymph nodes from prostatic carcinoma. The endpoints of this trial will be overall and disease-specific survival as well as life long symptomatic local control and other quality of life issues. During our next grant period we anticipate that our accrual of over 2500 patients to randomized trials for patients with prostate cancer will be increased by 20-30% with the addition of many RTOG associate and affiliated members along with the CCOP institutions. the identification of significant increases in freedom from any progression and freedom from distant metastases by androgen suppression of limited duration have been reported already in two of our trials (RTOG 86-10 and RTOG 85-31) although no clear overall survival benefits are yet demonstrated. Nevertheless these impressive results have had a major impact nationally on the treatment of patients with locally advanced prostatic cancer

[en] In the USA the recommended treatment for patients with muscle-invading transitional cell cancer of the bladder is usually radical cystectomy. Conservative surgery irradiation, and cisplatin-based systemic chemotherapy are, however, each effective for some patients. Although they provide the opportunity for bladder preservation, each modality, when used alone, is inferior to radical cystectomy in terms of local control and, perhaps, survival. Many recent publications have now documented the efficacy of combined modality treatment protocols employing all three of these modalities together. All employ a selective approach in which the patients only receive full-dose radiation if they have had a complete response to induction CMT. Overall survival data for T2-T3a patients are certainly as good as any reported cystectomy series of similarly clinically staged and similar aged patients. Radiation adds very significantly to the transurethral resection and systemic chemotherapy to maintain the bladder free of tumor. Substantially higher rates of pathologic confirmation of complete response are found following transurethral surgery and chemoradiation when compared with transurethral surgery and chemotherapy omitting the radiation. Overall survival is as good as cystectomy based approaches at 48-54% and over 80% of these long-term survivors keep their bladders. Following such therapies, 20-30% will subsequently develop superficial tumors. These patients may still be well treated by standard methods using transurethral resection and intravesical drugs. The concern of urologists that the conserved irradiated bladder functions poorly has also been answered by recent reports using modern radiation techniques. The instance of cystectomy for bladder shrinkage is repeatedly below 2%. Furthermore, sexual function is commonly preserved. The systemic morbidity of the chemotherapy is relatively high, but new approached using anti-emetics and GCSF now allow this to be reduced. In many cystectomy series, adjuvant chemotherapy is given, and thus cystectomy patients are at risk for the same morbidity. A selective approach using combined modality therapy therefore represents one treatment option to be presented to patients with muscle invading bladder tumors. This approach is particularly attractive for patients with clinically staged T2 and T3a disease, especially those who can undergo visibly complete transurethral resections and those who did not have an obstructer ureter

[en] In the USA the recommended treatment for patients with muscle-invading transitional cell cancer of the bladder is usually radical cystectomy. Conservative surgery (transurethral resection and partial cystectomy), irradiation, and cis-platinum based systemic chemotherapy are, however, each effective for some patients. Although they provide the opportunity for bladder preservation, each modality, when used alone, is inferior to radical cystectomy in terms of local control and, perhaps, survival. Initial response and local control rates are improved when a multimodality approach is used. Up to 85% of patients selected for bladder sparing therapy on the basis of their initial response to chemo-radiation may keep their bladders. This figure could increase further when other powerful prognostic factors, such as the presence of hydronephrosis or carcinoma in situ, are taken into account in initial patient selection. Deferring the patient from immediate cystectomy does not appear to compromise survival. The most appropriate sequencing of radiation and chemotherapy is yet to be established. Concomitant cis-platinum and irradiation improves local control and bladder preservation when compared with irradiation alone but does not decrease the metastatic rate. It is hoped that the well recognized activity of cis-platinum based combination chemotherapy in advanced disease will translate into effective eradication of micrometastatic disease (known to be present in up to 40% of patients at diagnosis). This has yet to be clearly demonstrated in a randomized trial. The addition of combination chemotherapy to radiation does not increase bladder morbidity but carries a considerable systemic risk. Thus, despite promising phase II studies, until a survival benefit is proven in a randomized trial, neoadjuvant or adjuvant combination chemotherapy in conjunction with irradiation should continue to be regarded as experimental

[en] In the USA the recommended treatment for patients with muscle-invading transitional cell cancer of the bladder is usually radical cystectomy. Conservative surgery irradiation, and cisplatin-based systemic chemotherapy are, however, each effective for some patients. Although they provide the opportunity for bladder preservation, each modality, when used alone, is inferior to radical cystectomy in terms of local control and, perhaps, survival. Many recent publications have now documented the efficacy of combined modality treatment protocols employing all three of these modalities together. All employ a selective approach in which the patients only receive full-dose radiation if they have had a complete response to induction CMT. Overall survival data for T2-T3a patients are certainly as good as any reported cystectomy series of similarly clinically staged and similar aged patients. Radiation adds very significantly to the transurethral resection and systemic chemotherapy to maintain the bladder free of tumor. Substantially higher rates of pathologic confirmation of complete response are found following transurethral surgery and chemoradiation when compared with transurethral surgery and chemotherapy omitting the radiation. Overall survival is as good as cystectomy based approaches at 48-54% and over 80% of these long-term survivors keep their bladders. Following such therapies, 20-30% will subsequently develop superficial tumors. These patients may still be well treated by standard methods using transurethral resection and intravesical drugs. The concern of urologists that the conserved irradiated bladder functions poorly has also been answered by recent reports using modern radiation techniques. The instance of cystectomy for bladder shrinkage is repeatedly below 2%. Furthermore, sexual function is commonly preserved. The systemic morbidity of the chemotherapy is relatively high, but new approached using anti-emetics and GCSF now allow this to be reduced. In many cystectomy series, adjuvant chemotherapy is given, and thus cystectomy patients are at risk for the same morbidity. A selective approach using combined modality therapy therefore represents one treatment option to be presented to patients with muscle invading bladder tumors. This approach is particularly attractive for patients with clinically staged T2 and T3a disease, especially those who can undergo visibly complete transurethral resections and those who did not have an obstructer ureter

[en] Purpose: To determine the effect of external beam radiation therapy on serum prostate-specific antigen (PSA) production by the benign prostate. Methods and Materials: We studied a cohort of 24 men receiving treatment for cancer of the bladder or rectum. The radiation fields in all cases encompassed the prostate gland, and none of the patients were known to have prostate cancer. All patients had 2 or more PSA estimations obtained in the years following their radiation treatment. A second group of 46 patients who had undergone radical external beam radiation therapy for prostate cancer and who were clinically disease free 8-22 years later were also observed, with a median of 5.8 years of PSA observations. Results: Only 3 of the 24 patients in the first group showed a significant rise of > 0.2 ng/ml in their serum PSA levels, with a median of 3.3 years follow-up from the first PSA test. Seven of 24 showed progressive declines, and 14 of 24 showed steady levels. The median PSA for this group was ≤ 0.5 ng/ml. Only 6 of the 46 in the second group showed a PSA rise of > 0.2 ng/ml. Thirty-four had stable values, and 6 had further declines. Again, the median PSA for the entire group was ≤ 0.5 ng/ml. Conclusion: Recovery of prostatic secretory function is an uncommon event after external beam radiation. The concern that this might significantly confound new definitions of biochemical failure after radical radiation for prostate cancer that are based on progressively rising PSA values thus appears to be unfounded

[en] Purpose: To assess the long-term outcome of conventional external beam radiation therapy in the management of clinically confined prostate cancer and to examine the proposition that radiation accelerates tumor growth in those who fail treatment. Methods and Materials: One thousand and forty-four men with T1-4NxM0 prostate cancer treated by conventional external beam radiation therapy at the Massachusetts General Hospital between 1977 and 1991 were analyzed. Median follow-up was 49 months. Failure was defined as: two sequential rises in serum prostate specific antigen (PSA) level; or a PSA > 1 ng/ml 2 or more years after radiation; or any clinical failure. Kaplan-Meier actuarial analyses were used to assess outcome. Results: At 10 years only 40% of the T1-2 group remained disease free. When subdivided by grade, the well-differentiated tumors (Gleason 1-2) exhibited a 53% actuarial 10-year disease-free survival, moderately differentiated (Gleason 3) 42%, and poorly differentiated (Gleason 4-5) 20%. The corresponding values for the T3-4 men were 33% for Gleason 1-2, 20% for Gleason 3, and 10% for Gleason 4-5. Overall the value for T3-4 tumors was 18% at 10 years. On relapse the median PSA doubling times for the T1-2 patients were predicted by histology: 18.8 months for Gleason 1-2 patients; 11.1 months for Gleason 3; and 9.6 months for Gleason 5. Significant differences were found between the Gleason 3 and the Gleason 4-5 groups (p = 0.04) and the Gleason 1-2 and the Gleason 4-5 groups (p = 0.03). A wide range of doubling times was seen within each grade group. When compared with recently reported data on selected T1-2 patients who were managed by expectant observation there was no advantage over the first decade (and certainly no disadvantage) in terms of metastasis-free survival or disease-specific survival for the irradiated Gleason 1-3 patients. However, a gain was seen for those with Gleason 4-5 tumors. Conclusion: Less than half of the T1-2NxM0 and less than one-fifth of the T3-4NxM0 patients receiving conventional radiation therapy were biochemically disease free at 10 years. The PSA doubling times on relapse show a wide variation. Grade was important in determining the rate of relapse suggesting that radiation does not induce a homogeneous acceleration of prostate tumors. A metastasis-free and disease-specific survival advantage was found for the poorly differentiated tumors when compared with similar patients reported in the literature who were managed initially by observation

[en] Purpose: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes. It explores the dose-volume relationship for NTCP of the rectum, using long-term data on rectal wall bleeding following prostatic irradiation. Methods and Materials: Previously published data were reviewed and updated on 41 patients with Stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost, including dose-volume histograms (DVHs) of each patient's anterior rectal wall and data on the occurrence of postirradiation rectal bleeding (minimum FU > 4 years). Logistic regression was used to test whether some individual combination of dose and volume irradiated might best separate the DVHs into categories of high or low risk for rectal bleeding. Further analysis explored whether a group of such dose-volume combinations might be superior in predicting complication risk. These results were compared with results of the 'critical volume model', a mathematical model based on assumptions of underlying radiobiological interactions. Results: Ten of the 128 tested dose-volume combinations proved to be 'statistically significant combinations' (SSCs) distinguishing between bleeders (14 out of 41) and nonbleeders (27 out of 41), ranging contiguously between 60 CGE (Cobalt Gray Equivalent) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds ratios for each SSC were not significantly different across the individual SSCs; however, analysis combining SSCs allowed segregation of DVHs into three risk groups: low, moderate, and high. Estimates of probabilities of normal tissue complications (NTCPs) based on these risk groups correlated strongly with observed data (p = 0.003) and with biomathematical model-generated NTCPs. Conclusions: There is a dose-volume relationship for rectal mucosal bleeding in the region between 60 and 75 CGE; therefore, efforts to spare rectal wall volume using improved treatment planning and delivery techniques are important. Stratifying dose-volume histograms (DVHs) into risk groups, as done in this study, represents a useful means of analyzing empirical data as a function of heterogeneous dose distributions. Modeling efforts may extend these results to more heterogeneous treatment techniques. Such analysis of DVH data may allow practicing clinicians to better assess the risk of various treatments, fields, or doses, when caring for an individual patient

[en] Objective: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes, with the goal of exploring the dose-volume relationship for NTCP of the rectum, using long-term data of rectal wall bleeding following irradiation for prostate cancer. Comparison is made between these results and those generated by a mathematical model of NTCP. Materials and Methods: Previously published data were updated on 41 patients with stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost. DVHs of each patient's anterior rectal wall were used as well as data on the occurrence of post-irradiation rectal bleeding (minimum FU > 4 yrs). 128 separate dose-volume combinations were analyzed. For a given dose-volume combination, each patient's DVH was classified as low-risk or high-risk, and this classification was evaluated as an independent variable with treatment outcome as the dependent variable in a logistic regression. The odds-ratios derived from the regression coefficients of those combinations that tested significant (p<.05 by Wald Chi-Square) were compared. Combinations of these 'statistically significant discriminators' (SSDs) were analyzed for predictive power. These results were compared with results of the 'critical volume model', a mathematical model based on underlying biophysical assumptions. Results: 9 of 128 dose-volume combinations proved to be SSDs between bleeders ((15(41))) and non-bleeders ((26(41))), ranging contiguously between 60 Cobalt-Gy-equivalent (CGE) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds-ratios between low- and high-risk groups were not significantly different across the SSDs, a result of high correlation among groupings across SSDs. However, analysis combining SSDs allowed segregation of DVHs into three risk groups: low, intermediate, and high. Estimates of NTCPs based on these risk groups correlated strongly with observed data (p=0.003) and with biomathematical model-generated NTCPs. Conclusion: The data show there is a dose-volume relationship for rectal mucosal bleeding, at least between 60 and 75 CGE. The results demonstrate that using combinations of SSDs to stratify risk groups represents a useful means of analyzing empirical data as a function of hetereogeneous dose distributions. Strong correlation of these results with estimates of the biomathematical 'critical volume' model argue for their usefulness in estimating NTCP. Further clinical data is required to confirm these results. Further statistical refinement may be explored with Monte Carlo simulation techniques

[en] Rationale: To assess the likelihood of men clinically free from adenocarcinoma 10 years after radiation therapy, remaining so through the second decade. Method: A retrospective analysis was performed on 33 men clinically disease free 10 or more years after radiation therapy with no androgen suppression. A median follow-up of a further 46 months beyond 10 years was available for this group. Kaplan-Meier actuarial analysis of outcome was used. Biochemical failure was defined as 2 successive PSA rises. Results: Of these 33 men, 17 originally had Gleason Grade 1-2 tumors, 9 Gleason 3, and 7 Gleason 4-5. In 28, serum PSA was available at 10 years. For 13, it was below 0.5 ng/ml; for 5, 0.5-1.0 ng/ml; for 3, 1.1-2.0 ng/ml; for 2, 2.1-4.0 ng/ml; for 6, >4.0 ng/ml. Four of the 8 patients with serum PSA values greater than 2, had had rising profiles prior to 10 years and had thus biochemically failed. They were excluded from further analysis. Subsequent clinical and biochemical disease free survival at 15 years respectively for the whole group was 83% and 54%, respectively. For those with a serum PSA at 10 years below 1 ng/ml, the corresponding figures were 89% and 69%. For those with a serum PSA greater than 1 ng/ml, they were 75% and 32%. Conclusions: A significant rate (31%) of biochemical failure was observed in the second decade after radiation therapy, although clinical failure was infrequently seen. The risk of subsequent biochemical failure was substantially lower for those with PSA values at 10 years of less than 1 ng/ml

[en] Purpose: Combined modality therapy has become the standard oncologic approach to achieve organ preservation in many malignancies. Methods and Materials: Although radical cystectomy has been considered as standard treatment for invasive bladder carcinoma in the United States, good results have been recently reported from several centers using multimodality treatment, particularly in patients with clinical T2 and T3a disease who do not have a ureter obstructed by tumor. Results: The components of the combined treatment are usually transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy and radiation therapy. Following an induction course of therapy a histologic response is evaluated by cystoscopy and rebiopsy. Clinical 'complete responders' (tumor site rebiopsy negative and urine cytology with no tumor cells present) continue with a consolidation course of concurrent chemotherapy and radiation. Those patients not achieving a clinical complete response are recommended to have an immediate cystectomy. Individually the local monotherapies of radiation, TURBT, or multidrug chemotherapy each achieve a local control rate of the primary tumor of from 20 to 40%. When these are combined, clinical complete response rates of from 65 to 80% can be achieved. Seventy-five to 85% of the clinical complete responders will remain with bladders free of recurrence of an invasive tumor. Conclusions: Bladder conservation trials using combined modality treatment approaches with selection for organ conservation by response of the tumor to initial treatment report overall 5-year survival rates of approximately 50%, and a 40-45% 5-year survival rate with the bladder intact. These modern multimodality bladder conservation approaches offer survival rates similar to radical cystectomy for patients of similar clinical stage and age. Bladder-conserving therapy should be offered to patients with invasive bladder carcinoma as a realistic alternative to radical cystectomy by experienced multimodality teams of urologic oncologists