Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233.

PURPOSE: To investigate the differences in outcomes among patients with muscle-invasive bladder cancer on NRG Oncology Radiation Therapy Oncology Group protocols 9906 and 0233 who achieved complete response and near-complete response after induction chemoradiation and then completed bladder-preserving therapy with chemoradiation therapy (chemo-RT) to full dose (60-64 Gy). PATIENTS AND METHODS: A pooled analysis was performed on 119 eligible patients with muscle-invasive bladder cancer enrolled on NRG Oncology Radiation Therapy Oncology Group trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose of at least 60 Gy. Bladder recurrence, salvage cystectomy rates, and disease-specific survival were estimated by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method. RESULTS: Among the 119 eligible patients, 101 (85%) achieved T0, and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36 of 101 T0 patients (36%) versus 5 of 18 Ta or Tis patients (28%) experienced bladder recurrence (P=.52). Thirteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, compared with 1 patient among near-complete responders (P=.63). Disease-specific, bladder-intact, and overall survivals were not significantly different between T0 and Ta/Tis cases. CONCLUSIONS: The bladder recurrence and salvage cystectomy rates of the complete and the near-complete responders were similar. Therefore it is reasonable to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy with consolidation chemo-RT to full dose (60-64 Gy).

Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.

PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. PATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. RESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. CONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.

Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.

BACKGROUND: We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. METHODS: In our randomised phase 2 trial, we enrolled patients with T2-4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3-4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. FINDINGS: Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0-6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3-4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3-4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3-4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3-4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3-4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3-4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3-4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3-4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. INTERPRETATION: In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. FUNDING: US National Cancer Institute.

Nomograms predicting response to therapy and outcomes after bladder-preserving trimodality therapy for muscle-invasive bladder 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.

Trimodality therapy for bladder conservation in treatment of invasive bladder cancer.

During the past 25 years, prospective clinical trials have established that bladder preservation therapy for select patients with muscle-invasive bladder cancer is a safe and effective alternative to an immediate cystectomy. Cisplatin-based chemoradiation is the most well-studied and accepted component of trimodality therapy; however, other systemic agents have recently been shown effective in combination with radiation therapy, increasing the range of options to allow for better personalization of care. In this review, the most recent advances in the field of bladder-preserving trimodality therapy are presented, and future directions for improving the outcomes are outlined.

Pooled analysis of phase II trials evaluating weekly or conventional cisplatin as first-line therapy for advanced urothelial carcinoma.

BACKGROUND: Weekly gemcitabine with GC every 3-4 weeks is considered conventional first-line chemotherapy for advanced urothelial carcinoma (UC). Weekly split-dose cisplatin with wGC might be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC and wGC to compare efficacy and safety. PATIENTS AND METHODS: Two trials of wGC and 3 trials of GC were identified. Because the data were not derived from randomized trials, GC and wGC were not formally compared, and exact 95% quasi-binomial confidence intervals (CI), for response rates and grade ≥ 3 toxicities were calculated. RESULTS: The 95% CI overlapped, suggesting agreement between wGC and GC. No clear difference in response rates and grade ≥ 3 toxicities between GC and wGC were observed. CONCLUSION: Gemcitabine combined with day 1 cisplatin and wGC yielded similar responses and grade ≥ 3 toxicities in advanced UC in a hypothesis-generating pooled analysis of phase II trials. Considering the probable lower nephrotoxicity of fractionated cisplatin, prospective evaluation of wGC might be warranted across cisplatin-eligible and -ineligible patients to develop a single chemotherapy template for the development of combinations with biological agents in a broad population of patients.

Immunohistochemistry as an adjunct in the differential diagnosis of radiation-induced atypia versus urothelial carcinoma in situ of the bladder: a study of 45 cases.

Muscle invasive urothelial carcinoma has been treated with cystectomy ± adjuvant therapy. Recently, a bladder-sparing protocol has been offered to selected patients closely followed with surveillance biopsies. In this setting, radiation-induced changes (RAD-Ch) may be very difficult to distinguish from carcinoma in situ, and failing to recognize them may lead to overtreatment. We ascertained the role of immunohistochemistry using cytokeratin (CK) 20, p53, and CD44s in bladder biopsies from 28 patients with a history of bladder radiation and 17 with carcinoma in situ without radiation. Negative or weak multifocal nuclear p53 staining was seen in 24 of 28 RAD-Ch cases, whereas strong and diffuse nuclear p53 staining was found in 8 of 17 carcinoma in situ cases and moderate and focal to multifocal in 3. CK20 showed strong cytoplasmic staining of only umbrella cells in 22 of 28 RAD-Ch cases. In contrast, 11 of 17 carcinomas in situ showed diffuse and strong CK20 positivity and 5 moderate and focal to multifocal positivity. All carcinomas in situ with weak or no p53 showed significant CK20 staining except 1. CD44s displayed diffuse membranous positivity in 7 of 17 RAD-Ch cases and up to mid-third in 8. Only 1 of 17 carcinomas in situ had diffuse membranous CD44s staining. Diffuse and significant CK20 expression was seen in most carcinomas in situ. Strong and diffuse p53 expression was only seen in carcinoma in situ (~50%), whereas diffuse CD44s staining was typically only seen in RAD-Ch. Our data suggest that a CK20(-) p53(-) CD44a panel proves to be very helpful (CK20 more reliable than p53 or CD44s) in the diagnosis of RAD-Ch.

Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience.

BACKGROUND: 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. OBJECTIVE: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MEASUREMENTS: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: 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 p<0.001). 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. CONCLUSIONS: CMT achieves a CR and preserves the native bladder in >70% 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.

Complications and long-term results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer.

PURPOSE: Radical cystectomy has been the standard treatment for muscle invasive bladder cancer. Combined modality therapy involving transurethral bladder tumor resection, external beam radiation and chemotherapy is an effective alternative to cystectomy in selected patients. Salvage cystectomy is reserved for those in whom combined modality therapy fails. We characterized complications associated with salvage cystectomy. MATERIALS AND METHODS: From 1986 to 2007 of 348 patients undergoing bladder sparing therapy 102 (29%) underwent salvage cystectomy, 91 of whom were treated at Massachusetts General Hospital after receiving combined modality therapy for T2-T4aNxM0 bladder cancer. Patients underwent transurethral bladder tumor resection followed by chemoradiation (40 Gy). Early assessment was performed by cystoscopy/re-biopsy. Patients with complete response continued with consolidation chemoradiation (total dose 64 Gy). Immediate salvage cystectomy (50 of 91) was performed for persistent disease, while delayed salvage cystectomy (41 of 91) was performed for an invasive recurrence. Complications were classified using the Clavien system. RESULTS: Median patient age was 69.4 years (range 27.5 to 88.9) and median living patient followup was 12 years (range 0 to 23). Of the patients 99% (90 of 91) underwent ileal diversion. Complications of any grade within 90 days occurred in 69% (63 of 91) of patients and 16% (15 of 91) experienced major complications within 90 days. Of the patients 21% (19 of 91) required hospital readmission within 90 days. The 90-day mortality rate was 2.2% (2 of 91). Significant cardiovascular/hematological complications (pulmonary embolism, myocardial infarction, deep vein thrombosis, transfusion) within 90 days were more common in the immediate than in the delayed cystectomy group (37% vs 15%, p = 0.02). Tissue healing complications (fascial dehiscence, wound infection, ureteral stricture, anastomotic stricture, stoma/loop revisions) were more common in the delayed than in the immediate cystectomy group (35% vs 12%, p = 0.05). CONCLUSIONS: Salvage cystectomy is associated with acceptable morbidity, although complication rates are slightly higher than for other cystectomy series. Immediate cystectomies have more cardiovascular/hematological complications while delayed cystectomies have more tissue healing complications.

Application of a fracture risk algorithm to men treated with androgen deprivation therapy for prostate cancer.

PURPOSE: Osteoporosis causes morbidity and mortality in men. The National Osteoporosis Foundation recommends fracture risk assessment with the online WHO/FRAX tool. Although androgen deprivation therapy for prostate cancer increases fracture risk, there is limited information about which men require preventative drug therapy. We applied the WHO/FRAX tool to men treated with androgen deprivation therapy for prostate cancer. MATERIALS AND METHODS: Information was collected from a practice cohort of men treated with gonadotropin-releasing hormone agonists, and included age, height, weight, history of gonadotropin-releasing hormone agonist treatment, dual energy x-ray absorptiometry results, prior bone targeted therapy and clinical risk factors for fracture. Subjects were evaluated with the WHO/FRAX algorithm (http://www.shef.ac.uk/FRAX/). RESULTS: A total of 363 men treated with androgen deprivation therapy (median age 72 years) were evaluated. By the FRAX algorithm with clinical information (no dual energy x-ray absorptiometry data) the 3% hip fracture risk threshold for treatment was exceeded by 51.2% of the men (median risk 3.1%). When subjects were grouped by age the treatment threshold was reached by 3.3% of those younger than 70 years, 76.6% of those 70 to 79 years old and by 98.8% of those 80 years old or older. Using FRAX with bone mineral density data in the 93 patients who underwent bone mineral density testing the median 10-year hip fracture risk was 0.9% and the treatment threshold was exceeded by 15% of these subjects. CONCLUSIONS: In this cohort of men receiving androgen deprivation therapy the prevalence of risk sufficient to necessitate drug therapy was high and was strongly influenced by age. The WHO/FRAX algorithm identifies a greater proportion of men for treatment than the traditional threshold of T score -2.5 or less.

Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06.

PURPOSE: In selected patients with muscle-invasive bladder cancer, combined-modality therapy (transurethral resection bladder tumor [TURBT], radiation therapy, chemotherapy) with salvage cystectomy, if necessary, can achieve survival rates similar to radical cystectomy. We investigated late pelvic toxicity after chemoradiotherapy for patients treated on prospective protocols. PATIENTS AND METHODS: Between 1990 and 2002, 285 eligible patients enrolled on four prospective protocols (Radiation Therapy Oncology Group [RTOG] 8903, 9506, 9706, 9906) and 157 underwent combined-modality therapy, surviving >or= 2 years from start of treatment with their bladder intact. Rates of late genitourinary (GU) and GI toxicity were assessed using the RTOG Late Radiation Morbidity Schema, with worst toxicity grade (scale 0 to 5) occurring >or= 180 days after start of consolidation therapy reported for each patient. Persistence of toxicity was defined as grade 3+ toxicity not decreasing by at least one grade. Logistic and Cox regression analyses were performed to evaluate relationship between clinical characteristics, frequency, and time to late grade 3+ pelvic toxicity. Covariates included age, sex, stage, presence of carcinoma in situ, completeness of TURBT, and protocol. RESULTS: Median follow-up was 5.4 years (range, 2.0 to 13.2 years). Seven percent of patients experienced late grade 3+ pelvic toxicity: 5.7% GU and 1.9% GI. In only one of nine patients did a grade 3+ GU toxicity persist. Notably there were no late grade 4 toxicities and no treatment-related deaths. None of the clinical variables studied predicted for late grade 3+ pelvic toxicity. CONCLUSION: Rates of significant late pelvic toxicity for patients completing combined-modality therapy for invasive bladder cancer and retaining their native bladder are low.

Bladder cancer.

Bladder cancer is a heterogeneous disease, with 70% of patients presenting with superficial tumours, which tend to recur but are generally not life threatening, and 30% presenting as muscle-invasive disease associated with a high risk of death from distant metastases. The main presenting symptom of all bladder cancers is painless haematuria, and the diagnosis is established by urinary cytology and transurethral tumour resection. Intravesical treatment is used for carcinoma in situ and other high grade non-muscle-invasive tumours. The standard of care for muscle-invasive disease is radical cystoprostatectomy, and several types of urinary diversions are offered to patients, with quality of life as an important consideration. Bladder preservation with transurethral tumour resection, radiation, and chemotherapy can in some cases be equally curative. Several chemotherapeutic agents have proven to be useful as neoadjuvant or adjuvant treatment and in patients with metastatic disease. We discuss bladder preserving approaches, combination chemotherapy including new agents, targeted therapies, and advances in molecular biology.

Lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) identifies occult lymph node metastases in prostate cancer patients prior to salvage radiation therapy.

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.

The results of concurrent chemo-radiotherapy for recurrence after treatment with bacillus Calmette-Guérin for non-muscle-invasive bladder cancer: is immediate cystectomy always necessary?

OBJECTIVES: To report our original experience in patients in whom bacille Calmette-Guérin (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.

Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.

OBJECTIVES: To evaluate the safety, tolerance, protocol completion rate, tumor response rate, and patient survival of chemoradiotherapy for patients with muscle-invasive operable bladder cancer. METHODS: After transurethral resection of the tumor in patients with Stage T2-T4a bladder cancer, twice-daily radiotherapy with paclitaxel and cisplatin chemotherapy induction (TCI) was administered. If repeat biopsy showed less than Stage T1 disease, consolidation with TCI was given. If repeat biopsy showed greater than Stage T1 disease, cystectomy was recommended. Adjuvant gemcitabine and cisplatin were given to all patients. RESULTS: A total of 80 patients met protocol eligibility. TCI resulted in 26% developing grade 3-4 acute toxicity, mainly gastrointestinal (25%). During consolidation TCI, grade 3-4 acute toxicity, all transient, was reported in 8%. Four cycles of adjuvant chemotherapy were completed per protocol or with minor deviations in 70% of the patients. Adjuvant treatment was associated with grade 3 toxicity in 46% and grade 4 in 26%. One patient had a fatal hemorrhagic stroke. Late bladder radiation toxicity was evaluated in 53 patients with > or = 2 years of follow-up. Of these 53 patients, 3 experienced self-limited, late grade 3 bladder toxicity. The postinduction complete response rate was 81% (65/80), 36 of the 80 patients died (22 of bladder cancer). At a median follow-up of 49.4 months, the actuarial 5-year overall and disease-specific survival rate was 56% and 71%, respectively. CONCLUSIONS: These favorable tumor response rates with possible increased bladder preservation rates suggest that this treatment regimen deserves further study.