Results of a 2 x 2 Phase III Randomized Trial of Synchronous Chemo-radiotherapy (CRT) Compared to Radiotherapy (RT) Alone and Standard vs. Reduced High Volume RT in Muscle Invasive Bladder Cancer (MIBC) (BC2001 CRUK/01/004)
Authors: N. James1, S. Hussain1, E. Hall2, P. Jenkins3, J. Tremlett4, C. Rawlings5, M. Crundwell6, R. Waters2, R. A. Huddart2
1 University of Birmingham, Birmingham, United Kingdom
2 Institute of Cancer Research, Sutton, United Kingdom
3 Cheltenham General Hospital, Cheltenham, United Kingdom
4 Brighton and Susgender University Hospitals NHS Trust, Brighton, United Kingdom
5 South Devon Healthcare NHS Foundation, Torbay, United Kingdom
6 Royal Devon and Exeter Hospital, Exeter, United Kingdom
- No trials have been undertaken directly comparing cystectomy and bladder-preservation for muscle-invasive bladder cancer.
- Chemo-radiation (bladder preservation) has been advocated for selected patients with muscle-invasive disease.
- ChemoRT regimens have resulted in OS of 50-60% at 5 years, OS with intact bladder of 40% , and 80% alive with intact bladder
- There are 2 main concerns about bladder preservation compared with radical cystectomy:
- Toxicity of radiation therapy on bladder function
- Field cancerization effect, whereby 30-50% of patients experience a local recurrence (~50% invasive and ~50% superficial), either in the area of tumor or in a different part of bladder
- As a result, when bladder preservation is selected, close surveillance is critical.
- BC2001, the trial presented here, tests the hypotheses that 1) synchronous CRT improves loco-regional control (compared to RT alone) and 2) reducing the volume of bladder irradiated to full RTdose reduces late toxicity without compromising tumor control.
- A pilot phase I/II study from the Birmingham group found a pathologic CR rate of 70% at three months and 1 yr PFS of 82% with 5FU/ MMC and concurrent radiation, therefore, the study group went forward with the Phase III trial described here.
Materials and Methods:
- Between August 2001 and April 2008, 458 pts were recruited
- This study is 2x2 factorial design, so is actually two trials in one. Due to the difficulty in accrual, the group decided to look at both chemo randomization for patients getting radiation and RT dose randomization
- Patients could be either double or single randomized to CRT vs. RT alone and/or to standard RT (sRT) vs reduced high-dose volume RT (rvRT)
- sRT: RT to tumor and whole bladder with 1.5cm margin
- rvRT: RT to tumor +1.5cm margin treated to 100 (+/-5)% target dose and remaining bladder to 80% target dose
- Patient eligibility included clinicalT2-T4a N0 bladder cancer, with no age cut-off
- 81% of pts were male, majority PS 0. Most pts were between 70-79; median age 73
- GFR > 25 ml/min
- More pts were randomized to the chemo/no chemo than the RT part of the study: (182 CRT vs. 178 RT; 108 sRT vs. 111 rvRT).
- Neoadjuvant chemotherapy prior to randomization was permitted.
- RT was 64 Gy /32 fx in 6.5 weeks or 55 Gy / 20fx in 4 wks (as per center policy)
- 60% of pts got 64Gy
- Chemotherapy was mitomycin C (12 mg/m2 bolus) day 1 of RT and 5FU continuous infusion at 500 mg/m2 during wk 1 and wk 4 of RT.
- The primary endpoint was loco-regional disease-free survival (LRDFS) with pts censored at second primary, metastasis, and death. Overall survival was not chosen as the endpoint because in this elderly population, the group expected deaths from competing causes
- Secondary endpoints included toxicity, quality of life, salvage cystectomy rate, cystoscopic local control, and overall survival (OS).
- Chemotherapy was administered as per protocol for 91% and 68% of CRT pts at wk 1 and wk 4, respectively.
- 30% received neoadjuvant chemotherapy
- Overall, 49 (11.2%) pts experienced grade 3/4 RTOG toxicity during post-treatment follow-up which did not differ by treatment group:
- CRT: 12 (6.6%) vs. RT: 21 (11.8%), p = 0.07
- sRT: 11 (10.2%) vs. rvRT: 16 (14.4%), p = 0.31
- 95% completed RT as planned, regardless of whether or not they had concurrent chemotherapy. Adding chemo tended to increase grade 1-2 rather than grade 3-4 toxicity.
- There was no evidence of difference in LRDFS or OS between sRT and rvRT.
- With 40 months median follow-up, LRDFS was improved in the CRT group (HR = 0.61, 95% p = 0.01). Two-year event-free rates were 71% for CRT vs 58% for RT with no evidence of heterogeneity by randomized RT treatment group, RT dose/fractionation schedule or by use of neoadjuvant chemo.
- When OS at two years was examined, 63% were alive in the CRT arm, compared to 58% in the RT alone arm, with HR = 0.78. This difference did not meet statistical significance. (CI 0.57 - 1.05), p = 0.10.
- The overall cystectomy rate was 10% (46/458) with no differences between the randomization arms (but trend for lower cystectomy rate in chemo arm)
- CRT: 8.8% vs. RT: 12.4%; sRT 8.3% vs. rvRT 11.7%
- Indications for cystectomy were recurrence (n=35), late side effects of RT (n=2), and other/unknown (n=9).
- In MIBC, CRT using MMC/5FU is well tolerated and significantly improves LRDFS compared to RT alone, providing a good bladder preservation rate
- Reducing the dose to uninvolved bladder has minimal effect on local control and toxicity (authors expected lower toxicity based on prior phase II data)
- Prior neoadjuvant chemotherapy did not affect outcomes in pts who got synchronous chemoRT
- This study shows that T2-T4 TCC is a systemic disease requiring multi-modality treatment.
- This is the largest study of chemoradiotherapy in bladder cancer, and based on these results, concurrent chemoradiotherapy should be the standard treatment for bladder preservation.
- 5 FU and MMC is well tolerated with concurrent daily RT and should be strongly considered, especially in who cannot receive cisplatinum
- These data support the concept that concurrent chemotherapy (given at a lower dose than adjuvant or neoadjuvant chemo), is a successful treatment strategy.
- Organ sparing CRT is appropriate for both non-cystectomy and cystectomy candidates, and early salvage for poor responders is important.
- Considering that the use of neoadjuvant chemotherapy had no effect in patients who received concurrent CRT, it makes sense to treat patients with definitive CRT up-front; the neoadjuvant chemo approach may make sense in patients for whom there are concerns about ability to tolerate CRT