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.

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.

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.

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.

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.

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.

Bladder preservation: optimizing radiotherapy and integrated treatment strategies.

While radical cystectomy (RC) remains the standard of care for muscle-invasive transitional cell carcinoma of the bladder, a series of single-institution and cooperative-group trials with a long-term follow-up have shown that combined modality therapy for bladder preservation can provide selected patients with an excellent chance for long-term survival with an intact, functioning bladder. Strategies for preserving the bladder have developed over the past 20 years, with continued refinements in radiation therapy, chemotherapy and patient selection. The hallmarks of modern bladder-preserving therapy include: (i) careful patient selection; (ii) combined therapy with maximum transurethral resection of bladder tumour, radiation and concurrent chemotherapy; (iii) cystoscopic assessment of the response to therapy with prompt salvage cystectomy for nonresponders; (iv) careful follow-up with cystoscopic surveillance and prompt cystectomy for invasive recurrence. Contemporary bladder-preserving approaches in patients with clinically staged muscle-invasive bladder cancer can achieve complete response rates of 60-85%, 5-year survival rates of 50-60%, and survival rates with an intact bladder of 40-45%. Although there are no randomized studies comparing RC with combined therapies for bladder preservation, long-term data show that overall and disease-specific survival rates in contemporary RC series of clinically staged patients with T2-T4a bladder cancer are comparable to those of bladder-preserving protocols. Thus, combined modality therapy for bladder preservation has become a safe, tested and effective alternative to RC in selected patients with muscle-invasive bladder cancer who desire to keep their bladders. Future work will continue to refine the bladder-preserving approach to improve survival and local control.

Benchmarks achieved in the delivery of radiation therapy for muscle-invasive bladder cancer.

Radiation therapy has a multifaceted role in the treatment of muscle-invasive bladder cancer, from being a component of bladder sparing regimens to adjuvant therapy for patients after partial cystectomy, to palliative treatment in patients with metastatic disease. Here, we review the techniques currently used and the settings in which these techniques are applied. Advances in imaging and radiation delivery have allowed for definition of more precise treatment volumes, permitting the delivery of higher tumor doses and lesser doses to critical targets. Better tumor control, fewer therapeutic complications, and better quality of life outcomes are anticipated. In the United States, the most rapidly growing use of radiation in the treatment of bladder cancer is as a component of selective bladder conservation. It uses trimodality therapy, consisting of a maximal transurethral resection followed by concurrent chemotherapy and radiation. Careful cystoscopic surveillance by an experienced urologist ensures a prompt cystectomy at the fist sign of treatment failure. The majority of patients retain a well-functioning bladder with no survival decrement. Radiation therapy is also used as adjuvant therapy after partial cystectomy in select patients. In this setting, it decreases the risk of local or incisional recurrence. It is also used in patients with pelvic recurrences after cystectomy, often combined with concurrent chemotherapy. Radiation is a very effective palliative agent for patients with locally advanced or metastatic disease. It can palliate bleeding and pain for patients with local progression or alleviate pain from bony metastases.

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.

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).

Selective bladder preservation by trimodality therapy for patients with muscularis propria-invasive bladder cancer and who are cystectomy candidates--the Massachusetts General Hospital and Radiation Therapy Oncology Group experiences.

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.

RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.

To examine combination cisplatin and twice-daily accelerated irradiation (RT) after aggressive transurethral resection of bladder tumor (TURBT) in an attempt to preserve the bladder and to determine the likelihood that patients who complete this regimen could then complete three cycles of methotrexate, cisplatin, vinblastine (MCV) chemotherapy. Between 1998 and 2000, 52 patients with Stage T2-T4aN0M0 disease, from 17 institutions, were entered into the trial. Forty-seven patients were deemed eligible; the planned accrual was 40. Of the 46 patients, 68% were >60 years old, 70% were men, and 96% had a Karnofsky score >/=90. The clinical T stage was T2 in 66%, T3a in 25%, and T3b in 9%. The median follow-up at the time of analysis was 26 months. The protocol required TURBT within 6 weeks of the initiation of induction therapy. Induction treatment involved 13 days of concomitant boost RT, 1.8 Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4-6 h later. For sensitization, cisplatin (20 mg/m(2)) was given on the first 3 days of each treatment week. Three to four weeks after induction, patients were evaluated cystoscopically for residual disease. Patients whose biopsies and cytologic evaluations showed no disease completed consolidation chemoirradiation. Patients with residual tumor went on to cystectomy. After either consolidation or cystectomy, patients were to complete three cycles of MCV chemotherapy. Of the 47 patients, 45% completed all phases of the protocol treatment with minor, or no, deviations. Five patients refused either the postinduction evaluation or cystectomy and 6 refused adjuvant chemotherapy. The CR rate after induction therapy was 74%. For 2 patients, residual disease after induction was limited to positive cytologic findings, and for 8 patients, biopsy of the primary site revealed persistence. Of the 8 cystectomy patients, 2 had no evidence of disease in the bladder at pathologic review of the surgery specimen. Grade 3 toxicity related to chemotherapy was observed in 11% of patients during both induction and consolidation, and in 41% during adjuvant chemotherapy. A total of 8 patients (36% of those receiving adjuvant chemotherapy) went on to develop Grade 4 neutropenia or thrombocytopenia during additional adjuvant chemotherapy. Grade 3 toxicity due to RT was seen in 4% and 0% of patients during induction and consolidation, respectively. One patient developed Grade 4 hydronephrosis during consolidation. The projected 36-month value for locoregional failure, distant metastasis, overall survival, and bladder-intact survival was 27%, 29%, 61%, and 48%, respectively. After aggressive TURBT, twice-daily accelerated RT initiated in concomitant-boost format is well tolerated and results in a rate of complete response (74%) similar to that in previous bladder-sparing trials. The projected 2-year values for locoregional control, bladder-intact survival, and overall survival were also consistent with previously reported trials of bladder-sparing treatment. With only 45% of patients completing three cycles of MCV, this form of adjuvant chemotherapy appears to be poorly tolerated by most patients.