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Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown.Report long-term outcomes of patients with muscle-invasive BCa treated by CMT.We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2-4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr.Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC-60 for less than CR and 42 for recurrent invasive tumors.Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method.Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3-4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3-4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity.CMT achieves a CR and preserves the native bladder in70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.

Objectives High-dose external radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons. Methods QOL questionnaires were sent at specified intervals to 95 men who received proton radiation. Of these, 87 men reported 3- and/or 12-month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). Symptom scores were calculated at baseline, 3 months, 12 months, and long-term follow-up. Generalized estimating equation models were constructed to assess longitudinal outcomes while accounting for correlation among repeated measures in an individual patient. Men were stratified into functional groups from their baseline questionnaires (normal, intermediate, or poor function) for each symptom domain. Long-term QOL changes were assessed overall and within functional groups using the Wilcoxon signed-rank test. Results Statistically significant changes in all four symptom scores were observed in the longitudinal analysis. For the 73 men reporting long-term outcomes, there were significant change scores for incontinence (ID), bowel (BD) and sexual dysfunction (SD), but not obstructive/irritative voiding dysfunction (OID). When stratified by baseline functional category, only men with normal function had increased scores for ID and BD. For SD, there were significant changes in men with both normal and intermediate function, but not poor function. Conclusions Patient reported outcomes are sensitive indicators of treatment-related morbidity. These results quantitate the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category provides an individualized prediction of long-term QOL scores. High dose proton radiation was associated with small increases in bowel dysfunction and incontinence, with more pronounced changes in sexual dysfunction.

Purpose To report a case-matched analysis comparing high-dose external-beam radiation (EBRT) for prostate cancer delivered on Proton Radiation Oncology Group (PROG) 95-09, a randomized trial, with permanent prostate brachytherapy over the same era. Methods From 1996 to 1999, 196 patients were accrued to the high-dose arm (79.2 Gray equivalent (GyE) using photons and protons) of PROG 95-09 at the Massachusetts General Hospital and Loma Linda University Medical Center. Entry criteria specified T1–2 and prostate-specific antigen ≤15 ng/mL. When Gleason score >7 was excluded, 177 men were left for case matching. At Massachusetts General Hospital, 203 similar patients were treated by a single brachytherapist from 1997 to 2002. Minimum follow-up was 3 years. Case matching, based on T stage, Gleason score, prostate-specific antigen, and age resulted in 141 matches (282 patients). Median follow-up was 8.6 and 7.4 years for EBRT and brachytherapy, respectively. The primary endpoint was biochemical failure (BF). Results Using the Phoenix definition, the 8-year BF rates were 7.7% and 16.1% for EBRT and brachytherapy, respectively ( p = 0.42). A stratified analysis was performed by risk group. In the EBRT group, 113 and 28 patients were low and intermediate risk, respectively. In the brachytherapy group, 118 and 23 were. When stratified by risk group, the BF rates were similar by either technique. Conclusions High-dose EBRT and brachytherapy result in similar BF rates for men with localized prostate cancer. Comparative quality-of-life and cost-effectiveness studies are warranted.

Purpose Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials From 2003–2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.

Purpose Increasing body mass index (BMI) is associated with prostate-specific antigen (PSA) failure after radical prostatectomy and external beam radiation therapy (EBRT). We investigated whether BMI is associated with PSA failure in men treated with brachytherapy for clinically localized prostate cancer. Patients and Methods Retrospective analyses were conducted on 374 patients undergoing brachytherapy for stage T1c–T2cNXM0 prostate cancer from 1996–2001. Forty-nine patients (13%) received supplemental EBRT and 131 (35%) received androgen deprivation therapy (ADT). Height and weight data were available for 353 (94%). Cox regression analyses were performed to evaluate the relationship between BMI and PSA failure (nadir + 2 ng/ml definition). Covariates included age, race, preimplantation PSA, Gleason score, T category, percent of prescription dose to 90% of the prostate, use of supplemental EBRT, and ADT. Results Median age, PSA, and BMI were 66 years (range, 42–80 years), 5.7 ng/ml (range, 0.4–22.6 ng/ml), and 27.1 kg/m 2 (range, 18.2–53.6 kg/m 2 ), respectively. After a median follow-up of 6.0 years (range, 3.0–10.2 years), there were 76 PSA recurrences. The BMI was not associated with PSA failure. Six-year PSA failure rates were 30.2% for men with BMI less than 25 kg/m 2 , 19.5% for BMI of 25 or greater to less than 30 kg/m 2 , and 14.4% for BMI of 30 kg/m 2 or greater ( p = 0.19). Results were similar when BMI was analyzed as a continuous variable, using alternative definitions of PSA failure, and excluding patients treated with EBRT and/or ADT. In multivariate analyses, only baseline PSA was significantly associated with shorter time to PSA failure (adjusted hazard ratio, 1.12; 95% confidence interval, 1.05–1.20; p = 0.0006). Conclusions Unlike after surgery or EBRT, BMI is not associated with PSA failure in men treated with brachytherapy for prostate cancer. This raises the possibility that brachytherapy may be a preferred treatment strategy in obese patients.

Objective To evaluate the efficacy and safety of proton stereotactic radiosurgery (PSRS) for acromegaly that is refractory to surgical treatment and medication. Methods From 1992 to 2003, 22 patients were treated at our institution for persistent acromegaly with use of PSRS. All patients had undergone at least one transsphe-noidal surgical procedure without biochemical cure. The median treatment dose delivered during PSRS was 20 (range, 15 to 24) cobalt gray equivalents. Results Follow-up was available for all patients at a median of 6.3 (range, 2.5 to 14.2) years after PSRS. A response to PSRS was observed in 21 of 22 patients (95%). A complete response (CR), defined as sustained (> 3 months) normalization of insulinlike growth factor-I without medical suppression, was attained in 13 patients (59%). Among patients with CR, the median time to CR was 42 (range, 6 to 62) months. No visual complications, seizures, clinical evidence of brain injury, or secondary tumors were noted on regular magnetic resonance imaging scans. One patient had complete pituitary dysfunction before PSRS and was therefore excluded from evaluation for failure. Of the other 21 patients, 8 (38%) had new pituitary deficits. Conclusion These results demonstrate that PSRS is effective for persistent acromegaly, with 59% of patients attaining normal insulinlike growth factor-I levels without use of any medication after a median of 6.3 years. Our findings indicate that radiosurgery results in an expeditious biochemical response with low morbidity. (Endocr Pract. 2007;13:726-734)

Purpose: To compare intensity-modulated photon radiotherapy (IMRT) with three-dimensional conformal proton therapy (3D-CPT) for early-stage prostate cancer, and explore the potential utility of intensity-modulated proton therapy (IMPT). Methods and Materials: Ten patients were planned with both 3D-CPT (two parallel-opposed lateral fields) and IMRT (seven equally spaced coplanar fields). Prescribed dose was 79.2 Gy (or cobalt Gray-equivalent, [CGE] for protons) to the prostate gland. Dose–volume histograms, dose conformity, and equivalent uniform dose (EUD) were compared. Additionally, plans were optimized for 3D-CPT with nonstandard beam configuration, and for IMPT assuming delivery with beam scanning. Results: At least 98% of the planning target volume received the prescription dose. IMRT plans yielded better dose conformity to the target, whereas proton plans achieved higher dose homogeneity and better sparing of rectum and bladder in the range below 30 Gy/CGE. Bladder volumes receiving more than 70 Gy/CGE (V 70 ) were reduced, on average, by 34% with IMRT vs. 3D-CPT, whereas rectal V 70 were equivalent. EUD from 3D-CPT and IMRT plans were indistinguishable within uncertainties for both bladder and rectum. With the use of small-angle lateral-oblique fields in 3D-CPT and IMPT, the rectal V 70 was reduced by up to 35% compared with the standard lateral configuration, whereas the bladder V 70 increased by less than 10%. Conclusions: In the range higher than 60 Gy/CGE, IMRT achieved significantly better sparing of the bladder, whereas rectal sparing was similar with 3D-CPT and IMRT. Dose to healthy tissues in the range lower than 50% of the target prescription was substantially lower with proton therapy.

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.

Purpose: Regression of rectal carcinoma after preoperative irradiation is variable, likely reflecting differences in the physical and biologic properties of these tumors. This study examines the assocation between the pathologic response of rectal cancer after irradiation and its pretreatment proliferative state as assayed by the activity of the proliferative dependent antigens (Ki-67, PCNA) and mitotic counts. Methods and Materials: One hundred and twenty-two patients with locally advanced rectal cancer received preoperative irradiation followed by surgery. Pretreatment tumor biopsies were scored for the extent of Ki-67 and PCNa immunostaining and the number of mitoses per 10 high-powered fields. Postirradiation surgical specimens were examined for extent of residual disease. Results: The tumors of 38 of 122 patients (31%) exhibited marked pathologic downstaging (no residual tumor or cancer confined to teh rectal wall) after preoperative irradiation. Two features were associated with the likelihood of marked pathologic regression after preoperative irradiation: tumor proliferative activity and lesion size. When stratified by lesion size, marked tumor regression occurred most frequently in smaller tumors with high Ki-67, PCNA, and mitotic activity compared to larger tumors with lower Ki-67, PCNA, and mitotic activity. Intermediate downstaging rates were seen for small or large tumors with moderate Ki-67, PCNA, and mitotic activity. Conclusion: Tumor Ki-67, PCNA, and mitotic activity predicts the likelihood of response to irradiation, which may aid in formulating treatment policies for patients with rectal cancer.

To describe the need for treatment and cancer-specific and overall survival in a contemporary active surveillance (AS) cohort.Historical cohort study of men diagnosed with localized prostate cancer between 1997 and 2009 and managed with AS at a tertiary care center. Inclusion criteria were Gleason score ≤ 6 (Gleason score of 7 in select patients),≤ 3/12 cores positive, and prostate-specific antigen (PSA) level20 ng/ml. Survival analyses were conducted using the Kaplan-Meier method.A total of 469 men with median age at diagnosis of 68.1 years (interquartile range [IQR]: 62.5-73.4) were followed up for a median of 4.8 years (IQR: 3.4-7.3). Median PSA level at diagnosis was 5.1 ng/ml (IQR: 4.0-6.9), with 94% of them having PSA level10 ng/ml. Overall, 98.3% (461/469) of patients had a Gleason score of 6 and 1.7% (8/469) had a Gleason score of 3+4 = 7, and 94.0% (441/469) had T1c stage disease. Freedom from treatment was 77% at 5 years and 62% at 10 years. A total of 116 (24.7%) patients received treatment during the course of surveillance. Reasons for treatment included 44.8% (52/116) for pathologic reclassification, 30.2% (35/116) for PSA progression, 12.1% (14/116) for patient preference, 5.2% (6/116) for digital rectal examination progression, and 4.3% (5/116) for metastatic disease. Of the patients treated, 59 (50.1%) received radiation, 26 (22.4%) underwent surgery, 17 (14.7%) received brachytherapy, and 14 (12.1%) received androgen-deprivation therapy. Cancer-specific survival was 100% at 5 and 10 years. Overall survival was 95% at 5 years and 88% at 10 years.In a contemporary cohort of men with low-risk prostate cancer, AS allowed avoidance of treatment most of them. Common reasons for change in management were Gleason upgrading and volume progression on prostate rebiopsy.

Materials/Methods: From 1986 to 2009, 314 patients were managed with selective bladder preservation at MGH. Treatment consisted of maximal transurethral resection of bladder tumor (TURBT) followed by split course chemoradiation. Patients with a complete response at midtreatment cystoscopic assessment completed radiation, while those with a lesser response underwent a prompt cystectomy. For this analysis, BI-DFS was defined as the absence of local invasive or regional recurrence, distant metastasis, bladder cancer related death or radical cystectomy. ACox proportional hazards model was constructed using 7 clinical and treatment variables to build a prognostic nomogram estimating 5 and 10-year BI-DFS. Backward selection was employed such that only variables maintaining a p value of 0.2 or less were retained in the final model.

Purpose/Objective: Biochemical control after external beam radiation has recently been readdressed. A multi-institutional analysis suggested the Houston definition (current nadir 2) is superior to the ASTRO consensus definition. Although ASTRO has been used, biochemical failure is not defined for patients receiving brachytherapy. This analysis explores definitions of biochemical failure and their interactions with PSA bounce after brachytherapy.

at least 50% of the dose there was a lower probability of NVG (p 0.0001). The further away the tumor was from the fovea or from the disc the later NVG occurred (p 0.003, p 0.006) with the 3 year estimates for distances of 0 and 0 mm of 72% and 89% to the fovea and 76% and 88% to the disc. If 100% of the macula and optic disc and less than 29% (upper quartile) of the ciliary body received at least 50% of the dose, the NVG outcome was more favorable (p 0.02, p 0.006 and p 0.0001). Factors in univariate analysis that were not predictors of NVG are age of the patient, gender, or the eye involved. When the factors determined to be significant predictors of NVG with univariate methods are considered simultaneously, the most significant predictor of NVG is when at least 30% of the ciliary body received at least 50% of the dose (LLRT: p 0.0001). There is also a significant association between the macula and optic disc being treated with at least 50% of the dose (p 0.0001). For 50% of the patients 100% of both sites and for 23% of the patients 100% of both sites were treated with at least 50% of the dose. Therefore, using these cut-points, the final predictive model was either ciliary body proportion plus macula or plus disk proportion (LLRT: p 0.003).

The risk of developing lymphedema after axillary dissection and radiation is lifelong. The reported incidence varies, but underrepresents mild or asymptomatic arm edema. We retrospectively analyzed 237 patient records for arm lymphedema (LE). 185 patients had available morbidity data and were free from axillary recurrence. Median f/u was 43 months. Patient complaints and examination with arm measurements were used to assess the LE, which was graded as mild, moderate, or severe. The 5–yr actuarial incidence of LE is 28%. The incidence of developing mild LE was 23%, of moderate or severe LE, 7%. Of 38 events, 28 were mild, 9 moderate, and 1 severe. The 5–year actuarial incidence increased as the level of axillary dissection increased, and as the number of nodes sampled increased: no dissection performed (n = 46) 13%, Level 1 (n = 47) 27%, Level 2 (n = 56) 41%, Level 3 (n = 23) 30%. As it can be difficult to determine high axillary dissection levels retrospectively, arm morbidity was also assessed using the number of lymph nodes dissected. The S-yr actuarial incidence of LE is: None (n = 46) 12%, 1−10 (n = 54) 29%, 11−20 (n = 65) 40%, > 20 (n = 20) 39% (P = 0.05). These differences were more marked in those patients receiving radiation to the axilla or supraclavicular fossa (n = 132): 61% and 53% for a level 2 and 3 dissection vs. 10% and 25% for no dissection or a level one dissection (P = 0.001). Morbidity is reduced with a less extensive dissection of the axilla, especially if the patient receives adjuvant radiation to the axilla. The extent of the axillary dissection should be sufficient only to establish the risk of systemic disease.