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Purpose Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. Methods Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. Results From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. Conclusion Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.

BACKGROUND: Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT). METHODS: The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months. RESULTS: At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post-treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL. CONCLUSIONS: Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences. Cancer 2013. © 2013 American Cancer Society.

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.

OBJECTIVE To report outcomes for patients with localized prostate cancer managed using a watchful waiting strategy at an American centre and to explore factors that have triggered intervention. PATIENTS AND METHODS From 1991 to 2005, 218 patients diagnosed with untreated localized prostate cancer were followed at Massachusetts General Hospital with prostate-specific antigen (PSA) monitoring and digital rectal examination (DRE). Re-biopsies were performed in 95 of the patients. The median follow-up was 6.3 years. Clinical outcomes and features predicting intervention were examined. RESULTS At diagnosis, the median PSA level was 5.4 ng/mL. The Gleason score (GS) distribution was as follows: 95% with GS 6, 4% with GS 7, 1% with GS 8. The clinical T-stage distribution was as follows: 6% with T1a–b, 84% with T1c, 10% with T2. The median age was 71 years. At 10 years, the overall survival was 79%, the cause-specific survival was 100%, the rate of distant metastasis was 5%, the rate of salvage androgen deprivation therapy was 15% and the rate of freedom from intervention (FFI) was 70%. There was a PSA velocity of ≥2 ng/mL per year in 16% of patients, and a PSA doubling time of ≤3 years in 15% of patients. Among the 95 re-biopsied men, the GS increased (grade progression) in 25% and the percentage of positive cores increased (volume progression) in 33%. On multivariate analysis, only PSA doubling time and volume progression were independent predictors of FFI. CONCLUSIONS In the present series, watchful waiting was associated with low rates of intervention and cancer progression. As PSA doubling time and volume progression were the main triggers for intervention, these will be incorporated into the centre’s current active surveillance protocol. Keywords: prostate cancer, watchful waiting, active surveillance, PSA INTRODUCTION Most patients diagnosed with prostate cancer in the PSA era have features suggesting low-risk disease. ‘Watchful waiting’ was commonly used in the 1970s and 1980s (the pre-PSA era) and was an approach that deferred treatment, usually hormonal therapy, until the disease became symptomatic, if ever. More recently, this has evolved into the approach known as ‘active surveillance’, where time is used as a prognostic test and curative therapy initiated when predetermined signs of progression become evident. The 1990s and the first half of the last decade were a long period of transition between the two approaches. During that time the uncertainty meant that this approach tended to be reserved for elderly patients and those with substantial co-morbidities. This also represents a period in which differing physician approaches allowed the collection of data on true predictors of progression and on predictors of treatment initiation by physicians. These are not necessarily the same thing. Several series from the UK and Canada have reported low rates of progression and intervention with 20–30% of patients ultimately receiving active treatment [1,2]. Those reported from the USA appear to have higher rates of intervention, on the order of 57–73% [3,4]. Whether this results from a higher progression rate, closer surveillance or a lower trigger threshold for therapy is unclear. In the present study, we report on a single USA institution’s experience with watchful waiting and explore factors that triggered therapeutic intervention. Because the study reaches back to the 1990s, before the concept of active surveillance was formalized, it explores how patients were managed in the ‘PSA era’ before strict criteria for intervention were established.

408 Background: To assess GD or FCT as the chemoradiation (CRT) component of a bladder sparing regimen. Methods: Patients with T2-4a bladder cancer were randomized. Patients had a maximal transurethral resection and induction CRT to 40 Gy followed by cystoscopic assessment. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others were offered cystectomy and no further CRT. Adjuvant gemcitabine/cisplatin chemotherapy was subsequently administered. The primary endpoint was the rate of distant metastasis at 3 years (DM3). Toxicity and other efficacy related endpoints including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3) were also assessed. Using the Clopper-Pearson method, the study required 32 patients per arm, with a benchmark DM3 of 25% and a 1-sided significance level of 0.1. If both arms meet this benchmark, toxicity will be used to select a regimen for future study. This study was not designed to compare arms. Results: From 12/2008 to 4/2014, 70 patients were enrolled; 66 were eligible for analysis (33 per arm). Median follow-up was 4.3 years. DM3 was 22% and 16% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. CR rates were 88% and 78%, respectively. Of 33 patients in the FCT group, 32 (97%) completed induction, 27 (93%) completed induction and consolidation, and 18 (55%) completed the entire protocol. Of 33 patients in the GD group, these figures were 31 (94%), 23 (92%), and 16 (49%), respectively. Of 33 patients in the FCT group, 21 (64%) had grade 3-4 toxicity during protocol treatment with 18 (55%), 2 (6%) and 2 (6%) experiencing hematologic, GI and GU toxicity, respectively. For 33 patients in the GD group, these figures were 18 (55%) overall and 14 (43%), 3 (9%) and 2 (6%), respectively. Conclusions: Both regimens are promising, given DM3 rates < 25%. As there was less toxicity in the GD arm, it would be reasonable to consider a gemcitabine based option as well as a cisplatin based regimen for future trials. Daily radiation may be as effective as twice-daily radiation, which may broaden appeal. Clinical trial information: NCT00777491.

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 whether failure to maintain local control (LC) of prostate cancer after radiation therapy results in a higher incidence of distant metastasis (DM). PATIENTS AND METHODS: From 1972 to 1999, 1,469 patients with clinically localized prostate cancer were treated with radical radiation therapy. Disease outcome was retrospectively reviewed for all patients with more than 2 years of follow-up. RESULTS: The actuarial 10-year LC rate was 79%. Gleason score ≥ 7, prostate-specific antigen (PSA) more than 15, and T3 to T4 tumors predicted a higher incidence of local failure (LF) (palpable recurrence or positive rebiopsy). The 10-year distant metastasis-free survival (DMFS) was 74%. Gleason score ≥ 7, PSA more than 15, and T3 to T4 tumors predicted a higher incidence of distant failure. LF was the strongest predictor for DM in a multivariate model. The 10-year DMFS for LC and LF patients was 77% and 61%, respectively. Median time to distant failure was prolonged in patients with LF compared with patients with locally controlled disease (54 v 34 months). Hazard rate analysis of the time to DM revealed that patients who maintain LC have a lower rate of DM, which remains constant over time. Patients who ultimately develop LF have a higher initial rate of DM, which increases with time. CONCLUSION: Patients with locally persistent prostate cancer are at greater risk of DM. The higher initial hazard of DM is consistent either with an increased likelihood of subclinical micrometastases before treatment or with posttreatment tumor embolization. The prolonged time to appearance of DM in locally failing patients and the increasing hazard of DM over time is most consistent with a late wave of metastases from a locally persistent tumor.

Background Between April 1963 and July 1991, 18 patients were treated for spermatic cord sarcoma. The histologic subtype distribution was: 7 leiomyosarcoma, 7 liposarcoma, 2 malignant fibrous histiocytoma, and 1 mesothelioma. Methods All patients underwent surgical resection: 16 radical orchiectomy and local excision. Nine were treated with orchiectomy alone, and 9 received adjuvant radiation. The radiation fields encompassed the ipsilateral iliac and inguinal lymph nodes, vas deferens, and hemiscrotum in 7 patients, and iliac and inguinal lymph nodes in 2 patients. Results The actuarial 5 and 8-year disease free survivals for the 18 patients were 77% and 58%, with an overall survival of 78% and 70%, respectively. The 5 and 8-year locoregional control rates were 82% and 61%. Five of 9 patients treated with surgery alone developed locoregional recurrence while none of the nine who had adjuvant radiation relapsed. The median follow-up for the irradiated group, however, was shorter (123 vs 63 months) and staging studies more complete. These potential biases are discussed. Conclusion In this series, relapse was common after orchiectomy alone. Adjuvant radiation therapy may reduce the incidence of locoregional failure.

Purpose: The initial management of stage I nonHodgkin's lymphoma of the testis is by orchiectomy but the role and efficacy of adjuvant strategies are uncertain. We reviewed cases of lymphoma at our institution to determine whether adjuvant treatment was beneficial.Materials and Methods: A retrospective review of outcome was conducted on 26 patients who presented to our institution. Median followup for the group was 54 months. Kaplan-Meier actuarial analyses were performed on the entire group and subsets.Results: Actuarial 5 and 10-year overall survival rates were 79 percent and 63 percent, and relapse-free survival rates were 61 percent and 46 percent, respectively. In patients who received adjuvant combination chemotherapy the 5-year relapse-free survival rate improved (75 percent versus 50 percent) but effect did not achieve statistical significance and was lost by 10 years. No relapse-free survival advantage was noted for patients receiving adjuvant irradiation to the pelvic and para-aortic nod...

Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT).The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months.At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post-treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL.Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences.

PURPOSE This study examines the effect of preoperative irradiation on tumor proliferation in rectal cancer. PATIENTS AND METHODS One hundred twenty-two patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki-67 and proliferating-cell nuclear antigen (PCNA) immunostaining and the number of mitoses per 10 high-power fields (hpf). Preirradiation and postirradiation proliferative activity was determined and correlated to clinical outcome. RESULTS There was an overall reduction in the tumor proliferative activity of rectal cancer after irradiation compared with its preirradiation state. Decreases in the activity of all three markers of tumor proliferation (Ki-67 and PCNA immunostaining, and mitotic counts) were observed in irradiated tumors compared with pretreatment biopsies. Postirradiation tumor proliferative activity was associated with pathologic tumor stage. A high level of proliferative activity was observed in tumors downstaged to the rectal wall (T1-2) compared with tumors that retained transmural penetration (T3-4). Multivariate analysis indicated that postirradiation proliferative activity and stage were independently associated with survival following surgery. Patients with tumors that exhibited elevated proliferative activity postirradiation had improved survival compared with patients with tumors that showed less proliferative activity. CONCLUSION Moderate- to high-dose preoperative irradiation decreases both the tumor size and proliferative activity of rectal cancers. Elevated postirradiation tumor proliferative activity correlates strongly with improved survival. This may aid in identifying high-risk patients following preoperative irradiation and surgery.

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.

Purpose Selective bladder preservation by use of trimodality therapy is an established management strategy for muscle-invasive bladder cancer. Individual disease features have been associated with response to therapy, likelihood of bladder preservation, and disease-free survival. We developed prognostic nomograms to predict the complete response rate, disease-specific survival, and likelihood of remaining free of recurrent bladder cancer or cystectomy. Methods and Materials From 1986 to 2009, 325 patients were managed with selective bladder preservation at Massachusetts General Hospital (MGH) and had complete data adequate for nomogram development. Treatment consisted of a transurethral resection of bladder tumor followed by split-course chemoradiation. Patients with a complete response at midtreatment cystoscopic assessment completed radiation, whereas those with a lesser response underwent a prompt cystectomy. Prognostic nomograms were constructed predicting complete response (CR), disease-specific survival (DSS), and bladder-intact disease-free survival (BI-DFS). BI-DFS was defined as the absence of local invasive or regional recurrence, distant metastasis, bladder cancer-related death, or radical cystectomy. Results The final nomograms included information on clinical T stage, presence of hydronephrosis, whether a visibly complete transurethral resection of bladder tumor was performed, age, sex, and tumor grade. The predictive accuracy of these nomograms was assessed. For complete response, the area under the receiving operating characteristic curve was 0.69. The Harrell concordance index was 0.61 for both DSS and BI-DFS. Conclusions Our nomograms allow individualized estimates of complete response, DSS, and BI-DFS. They may assist patients and clinicians making important treatment decisions.

INTRODUCTION AND OBJECTIVES: The choice to terminate active surveillance (AS) for localized prostate cancer in favor of initiating definitive treatment is based on a variety of factors. These may include pathologic change on re-biopsy, progression in PSA or DRE, or patient preference. The relative extent to which each of these factors plays a role in the termination of AS is not clearly established. Our objective was to determine the prevalence of prostate re-biopsy and subsequent pathologic change in an AS cohort. METHODS: Under IRB approved protocol, a historical cohort study of men diagnosed with prostate cancer was performed at a single tertiary-care center between 1991 and 2011. Although AS had been practiced throughout this period, in 2008 our group agreed upon a protocol for repeat biopsy at 12-18 months after diagnosis. Subsequent biopsy was left to the discretion of the treating physician. Only men with active surveillance as the initial management option were included. RESULTS: The median follow-up was 4.5 years for the 623 patients included in the study. Median PSA at diagnosis was 5.1 ng/mL. 96.2% (600/623) of patients were Gleason 6, 3.7% (23/623) were Gleason 7 and 89.9% (561/623) were stage T1c. 378 (60.1%) patients underwent re-biopsy. The number of re-biopsies ranged from 1 – 7 with 125 (33.1%) patients having more than one re-biopsy. Findings on initial re-biopsy revealed prostate cancer in 70.9% (268/378), benign tissue in 21.2% (80/378), PIN in 6.4% (24/378), and atypia in 1.6% (6/378). The Gleason sum increased in 17.9% of patients whose re-biopsy revealed cancer. Cancer volume increased (expressed as percentage of positive cores in quartiles) in 25.7% of patients on re-biopsy. Of 149 patients who required active treatment, 45.0% (67/ 149) was due to pathologic progression. CONCLUSIONS: We identified a significant proportion of Gleason upgrading and volume progression on repeat biopsy in this cohort. Repeat biopsy often resulted in a significant change in management of our AS population. These findings support the critical role of repeat biopsy in an AS protocol.

The primary goal of radical radiation therapy in men with localized prostate carcinoma is cure and a secondary but important goal is to achieve cure without treatment related sequelae, such as loss of continence, rectal injury, loss of potency and the need for castration. A literature review of 2,611 men undergoing irradiation for all stages of localized prostatic carcinoma documented a 0.2% incidence of treatment related mortality, 1.9% severe complications, 0.9% incontinence and 33 to 60% maintenance of full potency 5 or more years after treatment. A separate analysis was made of 331 patients with only early tumors (stages T1 and T2) treated with conventional external beam radiation therapy to doses of 63 to 74 Gy. from 2 individual centers (Massachusetts General Hospital and M.D. Anderson Hospital) and 1 multi-institutional group (Radiation Therapy Oncology Group). Median followup was 6.1 years; however, in 2 series followup ranged to 14 years. This analysis revealed frequencies of treatment associated sequelae of 0% for mortality, 0% severe complications, 0.4% urinary incontinence, 5.4% genitourinary structures (1.2% persisting), 5.1% hematuria (0.9% persisting) and 5.4% rectal bleeding (0.6% persisting). This composite analysis of men undergoing irradiation for stages T1 and T2 tumors with conventional fractionation and doses indicates that acute morbidity is minor and usually transient, severe injury is rare, most late gastrointestinal and genitourinary symptoms of radiation injury are neither permanent nor debilitating, and few symptoms of radiation injury develop beyond 5 years from treatment. These data, combined with the low progression rates (using prostate specific antigen criteria) following irradiation of men with early tumors, further substantiate the primary role of radical radiotherapy in the treatment of surgical risk adversive patients.

We studied 69 cases of malignant lymphoma of the testis, epididymis, and spermatic cord, including 64 cases in which the tumor involved these sites at presentation and five cases in which lymphoma relapsed in the testis. The patients without prior lymphoma were 16 to 91 (mean, 56) years old. Fifty-two patients had diffuse large-cell lymphomas [seven large cleaved cell (two with follicular areas), 27 large noncleaved, two multilobated, six not otherwise specified (NOS), 10 immunoblastic]; six, small noncleaved cell; two, diffuse mixed small and large cell; one, diffuse small cleaved; one, follicular mixed small cleaved and large cell; and two, high grade, unclassified in the Working Formulation. Twenty-nine cases (55%) were stage I; five (9%), stage II; one (2%), stage III, and 18 (34%), stage IV. Forty patients (73%) achieved a complete remission; 23 had a relapse of tumor at 4 to 274 months (median, 13) and five were salvaged. At last follow-up, 20 (36%) patients were free of disease, six (11%) were alive with disease, and 29 (53%) had died of lymphoma. Features associated with longer disease-free actuarial survival (DFS) included stage I disease (p = 0.0001) and sclerosis (p = 0.0001). Among patients with stage I lymphoma, those with right-sided tumors (p = 0.005) or tumors with sclerosis (p = 0.0017) had longer DFS. Lymphomas with extensive sclerosis were all stage I (p = 0.0057). Four of five patients with secondary testicular lymphoma had extranodal primary sites. They ranged from 13 to 66 years (median, 35). Testicular relapses occurred 13-37 months after initial diagnosis. Three had diffuse large, noncleaved cell type; one, lymphoblastic and one, diffuse mixed small and large cell. Immunophenotyping showed B lineage in 33 cases and T lineage in one case. Most testicular lymphomas are B-lineage large-cell lymphomas, which frequently involve other extranodal sites at presentation and at relapse, and which often have an aggressive clinical course.

PURPOSE This study examines the association between the pathologic response of rectal cancer after irradiation and its pretreatment proliferative state as assayed by proliferating cell nuclear antigen (PCNA) and mitotic activity. PATIENTS AND METHODS Ninety patients with clinical stage T3 and T4 rectal cancer received preoperative irradiation followed by surgery. Pretreatment tumor biopsies were scored for PCNA activity (number of tumor cells staining immunohistochemically with an anti-PCNA monoclonal antibody) and the number of mitoses per 10 high-powered fields (hpf). Postirradiation surgical specimens were examined for extent of residual disease. RESULTS The tumors of 33 of 90 patients (37%) exhibited marked pathologic downstaging (no residual tumor or cancer confined to the rectal wall) after preoperative irradiation. Two features were independently associated with the likelihood of marked pathologic regression after preoperative irradiation: lesion size and PCNA/mitotic activity. When stratified by tumor size, marked tumor regression occurred most frequently in smaller tumors with high PCNA/mitotic activity compared with larger tumors with lower PCNA/mitotic activity. Intermediate downstaging rates were seen for small or large tumors with moderate PCNA/mitotic activity. CONCLUSION Tumor PCNA/mitotic activity predicts the likelihood of response to irradiation, which may aid in formulating treatment policies for patients with rectal cancer.

Purpose To investigate patients’ willingness to participate (WTP) in a randomized controlled trial (RCT) comparing intensity-modulated radiotherapy (IMRT) with proton beam therapy (PBT) for prostate cancer (PCa). Methods and Materials We undertook a qualitative research study in which we prospectively enrolled patients with clinically localized PCa. We used purposive sampling to ensure a diverse sample based on age, race, travel distance, and physician. Patients participated in a semi-structured interview in which they reviewed a description of a hypothetical RCT, were asked open-ended and focused follow-up questions regarding their motivations for and concerns about enrollment, and completed a questionnaire assessing characteristics such as demographics and prior knowledge of IMRT or PBT. Patients’ stated WTP was assessed using a 6-point Likert scale. Results Forty-six eligible patients (33 white, 13 black) were enrolled from the practices of eight physicians. We identified 21 factors that impacted patients’ WTP, which largely centered on five major themes: altruism/desire to compare treatments, randomization, deference to physician opinion, financial incentives, and time demands/scheduling. Most patients (27 of 46, 59%) stated they would either “definitely” or “probably” participate. Seventeen percent (8 of 46) stated they would “definitely not” or “probably not” enroll, most of whom (6 of 8) preferred PBT before their physician visit. Conclusions A substantial proportion of patients indicated high WTP in a RCT comparing IMRT and PBT for PCa.

OBJECTIVE. The purpose of this article is to discuss the information that is important to note in imaging reports of patients with prostate cancer. CONCLUSION. Accurate staging through imaging is an integral part of prostate cancer management. Ultrasound, CT, bone scanning, and MRI are used for prostate cancer patients to assess the primary tumor, lymph node status, and bone metastasis. Accurate reporting of images is crucial for effective cancer treatment.

• To report outcomes for patients with localized prostate cancer managed using a watchful waiting strategy at an American centre and to explore factors that have triggered intervention.• From 1991 to 2005, 218 patients diagnosed with untreated localized prostate cancer were followed at Massachusetts General Hospital with prostate-specific antigen (PSA) monitoring and digital rectal examination (DRE). Re-biopsies were performed in 95 of the patients. • The median follow-up was 6.3 years. Clinical outcomes and features predicting intervention were examined.• At diagnosis, the median PSA level was 5.4 ng/mL. The Gleason score (GS) distribution was as follows: 95% with GS 6, 4% with GS 7, 1% with GS 8. The clinical T-stage distribution was as follows: 6% with T1a-b, 84% with T1c, 10% with T2. The median age was 71 years. • At 10 years, the overall survival was 79%, the cause-specific survival was 100%, the rate of distant metastasis was 5%, the rate of salvage androgen deprivation therapy was 15% and the rate of freedom from intervention (FFI) was 70%. • There was a PSA velocity of ≥ 2 ng/mL per year in 16% of patients, and a PSA doubling time of ≤ 3 years in 15% of patients. • Among the 95 re-biopsied men, the GS increased (grade progression) in 25% and the percentage of positive cores increased (volume progression) in 33%. • On multivariate analysis, only PSA doubling time and volume progression were independent predictors of FFI.• In the present series, watchful waiting was associated with low rates of intervention and cancer progression. • As PSA doubling time and volume progression were the main triggers for intervention, these will be incorporated into the centre's current active surveillance protocol.

Purpose Chemoradiation for anal cancer yields effective tumor control, but is associated with significant acute toxicity. We report our multi-institutional experience using dose-painted IMRT (DP-IMRT). Patients and Methods Between August 2005 and May 2009, 43 patients were treated with DP-IMRT and concurrent chemotherapy for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. DP-IMRT was prescribed as follows: T2N0: 42 Gy, 1.5 Gy/fraction (fx) to elective nodal planning target volume (PTV) and 50.4 Gy, 1.8 Gy/fx to anal tumor PTV; T3-4N0-3: 45 Gy, 1.5 Gy/fx to elective nodal PTV, and 54 Gy, 1.8 Gy/fx to the anal tumor and metastatic nodal PTV >3 cm with 50.4 Gy, 1.68 Gy/fx to nodal PTVs ≤3 cm in size. Acute and late toxicity was reported by the treating physician. Actuarial analysis was performed using the Kaplan-Meier method. Results Median age was 58 years; 67% female; 16% Stage I, 37% II; 42% III; 5% IV. Fourteen patients were immunocompromised: 21% HIV-positive and 12% on chronic immunosuppression. Median follow-up was 24 months (range, 0.6–43.5 months). Sixty percent completed chemoradiation without treatment interruption; median duration of treatment interruption was 2 days (range, 2–24 days). Acute Grade 3+ toxicity included: hematologic 51%, dermatologic 10%, gastrointestinal 7%, and genitourinary 7%. Two-year local control, overall survival, colostomy-free survival, and metastasis-free survival were 95%, 94%, 90%, and 92%, respectively. Conclusions Dose-painted IMRT appears effective and well-tolerated as part of a chemoradiation therapy regimen for the treatment of anal canal cancer.

Purpose We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer. Methods and Materials A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5–127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34→Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated. Results Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis ( p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis ( p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Conclusions This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.

Purpose To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. Patients and Methods Men with T1b-T2b prostate cancer and prostate-specific antigen ≤ 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes. Results A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade ≥ 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade ≥ 3 GI toxicity. Conclusion This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade ≥ 3 late urinary or rectal morbidity.

Purpose We examined whether rectal dose–volume histogram (DVH) parameters were associated with long-term patient-reported gastrointestinal (GI) quality of life (QOL) after conventional (70.2 GyE) or high-dose (79.2 GyE) radiation for prostate cancer. Methods and Materials Of 64 men with localized prostate cancer alive with a minimum 7-year follow-up after treatment as part of a randomized trial with either 70.2 GyE or 79.2 GyE of external beam radiation at Massachusetts General Hospital, 56 men (88%) returned a QOL questionnaire, and 50 of those men had DVH information. The DVH parameters of the anterior rectal wall were correlated with patient-reported long-term GI QOL using Pearson correlation and t tests. Results There was a trend toward an association between increased long-term GI dysfunction and higher V60 ( p = 0.07), V65 ( p = 0.06), V70 ( p = 0.09), and V75 ( p = 0.09). When dichotomized by their medians, a V60 > 54% ( p = 0.04), V70 > 44% ( p = 0.06), and V75 > 39% ( p = 0.06) were associated with increased long-term GI dysfunction. There was no difference in long-term GI dysfunction between men on the conventional vs. high-dose arms ( p = 0.49). Conclusions Dose–volume histogram parameters of the anterior rectal wall were associated with long-term patient-reported GI QOL after prostate radiation, whereas the dose prescribed to the prostate was not, suggesting that DVH constraints, rather than total prescribed dose, may have the greatest impact on long-term bowel dysfunction, and therefore that continued dose escalation may be feasible if appropriate dose–volume constraints are met.

Proton radiation is an emerging therapy for localized prostate cancer that is being sought with increasing frequency by patients. The physical properties of a proton beam make it ideal for clinical applications; the Bragg peak allows for deposition of dose at a well-defined depth with essentially no exit dose. Thus, high doses can be delivered to a target while largely sparing adjacent normal tissue. Proton radiation has proven effective in dose escalation for prostate cancer. This is important, as high-dose conformal radiation is now the standard form of external radiation for this disease. Intensity-modulated radiation therapy, which uses X-rays, is another means of delivering high radiation doses to the prostate and is currently the most widely used form of external radiation in the US. At present prices, it is probably more cost-effective than proton radiation; this could change. Clear dosimetric superiority of protons in the high-dose region has not yet been demonstrated. A dosimetric advantage may emerge as pencil-beam scanning replaces passive scanning, and intensity-modulated proton therapy becomes possible. This technique would be particularly well suited to partial prostate 'boosts', hypofractionation regimens and stereotactic delivery of radiation, all new approaches to prostate cancer that are being investigated.

OBJECTIVES To report our original experience in patients in whom bacille Calmette-Guerin (BCG) therapy has failed for T1 bladder cancer with subsequent progression to T2 disease treated with chemo-radiotherapy, as the management of recurrent high-grade T1 bladder cancer after failed BCG therapy is challenging, and radical cystectomy is the standard treatment because there are no well established second-line bladder-preserving therapies. PATIENTS AND METHODS From 1988 to 2002, 18 patients with T2 recurrence after failure of BCG therapy for T1 bladder cancer were treated with chemo-radiotherapy at the authors' institution. Patients received a visibly complete transurethral resection of the bladder tumour (TURBT) and concurrent chemo-radiotherapy with a mid-treatment evaluation after 40 Gy. Patients with less than a complete response had a prompt cystectomy; the others completed radiotherapy to 64-65 Gy. The primary treatment outcome was freedom from cystectomy due to recurrence not treatable by conservative measures; secondary outcomes included disease-specific (DSS) and overall survival (OS). RESULTS With a median follow-up of 7.0 years, only one patient had persistent tumour at re-staging TURBT and had an immediate cystectomy. Of the remaining 17 patients, 10 (59%) were free of any bladder recurrence. The actuarial 7-year DSS and OS were 70% and 58%, respectively. At 7 years, 54% of patients were alive with intact bladders and free of invasive recurrence. CONCLUSIONS In this study we specifically evaluated patients with apparently small muscle-invasive recurrences after BCG treatment for T1 bladder cancer. Selective bladder preservation with chemo-radiotherapy is possible, with low morbidity and a high chance of long-term bladder control. If successful in treating T2 recurrences after BCG therapy, it now seems timely to critically evaluate chemo-radiotherapy as an alternative to immediate cystectomy in the management of patients with T1 recurrences after BCG.

Adrenal Cortical Carcinomas 67 Epidemiology 67 Natural History 67 Clinical Presentation 67 Diagnostic Workup and Staging 68 Endocrinology 68 Imaging Characteristics of ACC 68 Pathologic Classification 68 General Management 69 Surgery 69 Chemotherapy 69 Radiation Therapy Techniques 70

Twenty-six patients with prostate cancer status post-radical prostatectomy who were candidates for salvage radiation therapy (SRT) underwent lymphotropic nanoparticle enhanced MRI (LNMRI) using superparamagnetic nanoparticle ferumoxtran-10. LNMRI was well tolerated, with only two adverse events, both Grade 2. Six (23%) of the 26 patients, previously believed to be node negative, tested lymph node positive by LNMRI. A total of nine positive lymph nodes were identified in these six patients, none of which were enlarged based on size criteria.

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.

Although immediate radical cystectomy remains the standard of care for invasive bladder cancer, a large body of international experience from single institutions and cooperative groups has accumulated, suggesting favorable results with bladder-sparing approaches in appropriately selected patients. Modern selective bladder preservation with trimodality therapy, consisting of transurethral resection of the bladder tumor, radiation, and chemotherapy, can achieve complete response rates of 60–80%, 5-year survival rates of 50–60%, and survival rates with an intact bladder of 40–45%. Although no randomized comparisons between cystectomy and trimodality therapy exist, long-term data confirm that the 10-year overall and disease-specific survival rates for patients in bladder-sparing protocols are comparable to outcomes reported in contemporary cystectomy series. In addition, quality of life studies have demonstrated that the retained native bladder functions well. Thus, trimodality therapy with careful cystoscopic surveillance and with prompt cystectomy for invasive recurrences has emerged as a legitimate alternative to extirpative surgery. Future work will continue to optimize the bladder-sparing regimen while limiting toxicity.

Objectives To assess whether statin use improves local control (LC) in patients undergoing organ-preserving trimodality therapy for muscle-invasive bladder cancer. Methods We retrospectively analyzed the data from 286 patients with muscle-invasive, transitional cell carcinoma of the bladder treated with maximal transurethral resection of the bladder tumor followed by chemoradiotherapy from 1986 to 2003 at the Massachusetts General Hospital. Patients with a complete response after induction chemoradiotherapy received consolidation chemoradiotherapy and those with an incomplete response underwent cystectomy. Of the 286 patients, 35 (12%) were known to be taking a statin during chemoradiotherapy. LC was defined as freedom from the development of muscle-invasive bladder cancer or superficial bladder cancer necessitating cystectomy. Results The median follow-up time was 2.7 years for all patients and 3.1 years for survivors. The overall 5-year LC rate was 55%. On univariate analysis, tumor stage, completeness of transurethral resection of the bladder tumor, hydronephrosis, chemotherapy type, treatment era, and statin use were significantly associated with LC. The 5-year LC rate for patients taking a statin was 73% versus 52% for patients not taking a statin ( P = 0.04). On multivariate analysis incorporating covariates that were statistically significant ( P P = 0.02) and the absence of hydronephrosis ( P = 0.01) remained significantly associated with LC. Conclusions Statin use was associated with an improvement in LC on univariate analysis but was not found to be independently associated with LC after controlling for known prognostic factors. The potential beneficial interaction between statin use and chemoradiotherapy in bladder cancer warrants further investigation in a prospective study.

Purpose: Phase I–II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. Patients and Methods: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994–2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. Results: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n = 81) or PFT-R (n = 83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). Conclusions: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.

The Massachusetts General Hospital and the Radiation Therapy Oncology Group have been leading the charge for organ conservation in bladder cancer in North America for over two decades. In a series of six successive studies the group has refined the techniques and is now moving toward a translational future in which novel biologic agents will be combined with the best current strategies. The North American approach is characterized by its selective nature, in that it preselects patients likely to do well with a trimodality approach and then further selects according to the response to an induction course of chemotherapy and radiation. Only those who are complete responders move onto full dose. This "check point" allows salvage cystectomy to be performed on incomplete responders before they have had full-dose radiation. This preserves the urinary diversion options open to the surgeon as well as brings forward the time to a salvage procedure should it be needed.

It remains controversial as to whether the administration of chemotherapy prior to radiation following the surgical treatment for localized breast cancer compromises local control.The outcome of 290 patients who received chemotherapy prior to breast or chest wall irradiation following curative breast cancer surgery was retrospectively analyzed to determine if delaying radiation from the time of surgery adversely affects local-regional control. The patients were divided into three groups according to the time interval from definitive surgery to the start of radiation: group 1,5 months; group 2, 5 to7 months, and group 3, 7+ months. Local-regional and distant failure events were analyzed according to the time delay from surgery to radiation.The median follow-up was 6.0 years (range, 7 months to 15 years). Loco-regional failure was observed in 22 patients, 18 of which occurred within the original radiation fields. There was no significant adverse effect on local control or distant failure from delaying radiation for systemic chemotherapy. Univariate and multivariate analyses revealed that positive margins after surgery were associated with increased local recurrence.Delaying radiation therapy for greater than 7 months, in order to administer chemotherapy following curative breast cancer surgery, does not compromise local control. However, positive margins were significantly associated with higher rates of local failure and even an increase in radiation boost dose was not able to fully counteract the increased risk of local failure.

We determine the efficacy of conventional dose, external beam radiation for localized prostate cancer using cohort analysis with maximized followup.A total of 205 men with T1-2 prostate cancer were treated with conventional external beam radiation to a median and modal dose of 68.4 Gy during a 16-month period from 1991 to 1993. Followup was maximized in these patients, and median followup for those alive with or without disease was 114 months.Median patient age at treatment was 72 years, and overall survival at 5 and 10 years was 78% and 53%, respectively. The actuarial risk of local failure was 18% at 10 years as was the risk of metastatic disease. The actuarial risk of being free of biochemical failure at 10 years (American Society for Therapeutic Radiology and Oncology definition) was 49%. That risk was 42% if the definition was used without backdating failure to a time between last low value and first increase. When a crude analysis of 10-year outcome was performed 127 of the 205 treated patients (62%) were still alive, including 59% with no evidence of biochemical failure and a median prostate specific antigen of 1.0 ng/ml. Of the 78 men (38% of total) who died during the 10 years 32 died either of or with recurrent cancer.Mature followup minimizes many of the biases seen in previously published radiation series. This study provides a yardstick against which newer radiation modalities may be measured.

Purpose To estimate the biases inherent in prostate cancer outcome that arise from different failure end points and variations in follow-up time and intensity using a cohort of men with long follow-up. Methods and materials The study cohort consisted of 205 men with T1–T2N0-Nx prostate cancer treated with conventional radiotherapy between 1991 and 1993. The median follow-up was 103 months. Outcome was assessed using different definitions of biochemical failure, including the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria and the "nadir plus two" criteria (any rise of 2 ng/mL greater than the current nadir). Patient subgroups were created according to where patients had received their last 2 years of follow-up. Patients were also stratified according to whether they were initially present in the departmental database (under regular surveillance) or were uncovered after more vigorous investigation (previously "lost to follow-up"). Results In this series with maximized follow-up, the 10-year biochemical disease-free survival rate did not change significantly with varying definitions of failure, 49% and 45% for ASTRO and "nadir plus two" criteria, respectively. Patients followed by outside physicians ( n = 99) were faring better at 10 years than those followed at the treating institution by either their radiation oncologist ( n = 50) or their medical oncologist or urologist ( n = 52). This was by all measures of outcome, including overall survival, and metastasis-free survival. Patients previously lost to follow-up ( n = 43) who were tracked down also appeared to be doing better than those on our database for whom information had been readily available ( n = 161). This, however, may have been an artifact of the ASTRO criteria, which underestimates failure when insufficient prostate-specific antigen values are available. Conclusion The ASTRO definition of failure underestimates late failure. This bias may be compensated for by the use of cohorts with long follow-up or the use of the "nadir plus two" definition of failure. The use of institutional prostate cancer databases may overestimate failure rates because patients followed outside of the treating institution fared better with respect to both survival and biochemical recurrence. Vigorous attempts to obtain follow-up beyond the hospital walls may correct this bias.

Purpose To evaluate the risk factors for lymphedema in patients receiving breast conservation therapy for early-stage breast cancer. Methods and materials Between 1982 and 1995, 727 Stage I–II breast cancer patients were treated with breast conservation therapy at Massachusetts General Hospital. A retrospective analysis of the development of persistent arm edema was performed. Lymphedema was defined as a >2-cm difference in forearm circumference compared with the untreated side. The median follow-up was 72 months. Breast and regional nodal irradiation (BRNI) was administered in 32% of the cases and breast irradiation alone in 68%. Results Persistent arm lymphedema was documented in 21 patients. The 10-year actuarial incidence was 4.1%. The median time to edema was 39 months. The only significant risk factor for lymphedema was BRNI. The 10-year risk was 1.8% for breast irradiation alone vs. 8.9% for BRNI ( p = 0.001). The extent of axillary dissection did not predict for lymphedema even within the subgroups of patients defined by the extent of irradiation. Most patients underwent Level I or II dissection. In this subgroup, the lymphedema risk at 10 years was 10.7% for BRNI vs. 1.0% for breast irradiation alone ( p = 0.0003). Conclusion Nodal irradiation was the only significant risk factor for arm lymphedema in patients receiving breast conservation therapy for early-stage breast cancer. Our data suggest that this risk is low with Level I/II dissection and breast irradiation. However, even after the addition of radiotherapy to the axilla and supraclavicular fossa, the development of lymphedema was only 1 in 10, lower than generally recognized.

To determine the effect of prostatic irradiation on the production of prostate specific antigen (PSA), serum PSA levels were measured in 36 men who received pelvic irradiation (45 to 65 Gy.) for nonprostatic malignancies, and compared with those of a control group of 79 men of comparable age without prostate cancer or prior pelvic irradiation identified from the records of the Massachusetts General Hospital internal physicians. The median PSA level was lower in the irradiated group than in the control group (0.65 versus 1.1 ng./ml.). Of the irradiated patients 47% had undetectable PSA levels versus 20% of the controls (p = 0.004, Fisher's exact test). A group of 27 prostate cancer patients who received up to 68 Gy. 8 to 16 years (median 10 years) previously and who remained clinically disease-free were also studied. The median PSA level was less than 0.5 ng./ml. The proportion of patients with undetectable PSA levels was significantly higher than that of the controls (p0.001) but it was not significantly different from those irradiated for other pelvic cancers. Of those patients 67% had an undetectable PSA level and 78% had a level of less than 1 ng./ml. Our study suggests that radiation therapy results in a permanent decrease in PSA production by the prostate gland and that patients whose PSA values do not reach less than 1 ng./ml. following radical radiation therapy for prostate cancer are unlikely to be long-term clinical disease-free survivors.

To determine the durability of prostate-specific antigen (PSA) progression-free survival beyond 5 years in patients biochemically free of relapse 5 years after external beam radiotherapy (EBRT).This study identified 328 men treated with EBRT to the prostate who were biochemically (American Society for Therapeutic Radiology and Oncology definition) disease free 5 years after treatment. The median follow-up was 7.4 years. The patients were divided into four groups according to their PSA values 5 years after treatment: PSAor=0.5, 0.5 toor=1.0, 1.0 toor=2.0, and 2.0-4.0 ng/mL. PSA progression-free rates were calculated in each subgroup at 10 years after treatment. Yearly hazard rates of biochemical progression were also calculated for the 5-10 years after treatment.The PSA progression-free survival rate was 87%, 79%, and 67%, respectively, 8, 10, and 13 years after treatment in patients biochemically free of disease 5 years after treatment. The progression-free rates at 10 years after treatment according to the PSA level at 5 years was 92% for PSAor=0.5 ng/mL; 71% for PSA 0.5 toor=1.0 ng/mL; 78% for PSA 1.0 toor=2.0 ng/mL; and 56% for PSA 2.0 toor=4.0. The lower the PSA level at 5 years, the more durable the probability of maintained biochemical disease-free survival (p0.0001). The yearly hazard rates of biochemical progression ranged from 3.1% to 6.6% in the 5-10 years after RT.When PSA levels remain low (2 ng/mL) 5 years after EBRT, the great majority of patients will be biochemically disease free at 10 years. The hazard rates of biochemical progression in the 6-10 years after treatment are low and are comparable to those published for prostatectomy series.