Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial.

BACKGROUND: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88). There are limited data on long-term recurrence risk. OBJECTIVE: To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). INTERVENTION: Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer-specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. RESULTS AND LIMITATIONS: Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43-0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36-0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60-1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58-1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69-1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59-1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, [95% CI 0.31-0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. CONCLUSIONS: Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. PATIENT SUMMARY: We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004).

PURPOSE: To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. METHODS AND MATERIALS: In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). RESULTS: Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT - sRT) was 6.4% (95% confidence interval -7.3%, 16.8%) under an intention to treat analysis and 2.6% (-12.8%, 14.6%) in the "per-protocol" population. CONCLUSIONS: In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.

Endocrine therapy and other targeted therapies for metastatic breast cancer.

The most important change in the treatment of advanced breast cancer that will emerge over the next 10 years is the shift from adjuvant tamoxifen to adjuvant aromatase inhibitors. This will mean an increasing proportion of tamoxifen-naive aromatase inhibitor-resistant breast cancer. Research of the most appropriate methods of optimizing remaining endocrine sensitivity in these patients is needed. The rapid expansion in the understanding of the molecular basis of breast cancer biology provides potential targets for novel therapies. Despite these pivotal developments, resistance to endocrine therapy remains a key limitation in the management of advanced breast cancer. Until recently, the only option following the development of resistance to an endocrine agent was to change endocrine therapy and, on exhaustion of endocrine sensitivity, to move to cytotoxic chemotherapy. Understanding of at least some of the mechanisms underlying the development of endocrine resistance is now emerging. We now have the tools that may allow us to both overcome resistance and restore sensitivity, or to pre-empt certain types of resistance from developing. These tools include the increasing array of signal transduction inhibitors in combination with standard endocrine agents. Correct clinical management strategy can be guided by preclinical modeling but can only be validated by carefully designed clinical trials. These will, at the very least, need to be conducted with correlative translational research elements that will track changes in tumors as resistance emerges and will allow us to select the most appropriate treatment strategy for individual patients. Amongst the myriad of promising drugs there will undoubtedly be some that fail to meet current hopes, but we can be optimistic that a handful will find a useful place in keeping advanced breast cancer at bay for longer than can be achieved at present. However, the holy grail of a cure is likely, in the medium term, to remain elusively at the end of the rainbow for most of these patients. Several other methods for the management of these patients are in development. These include strategies to overcome endocrine resistance and methods to target deregulated endocrine and growth factor signaling pathways using gene and immunotherapy approaches.