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Outcomes in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy followed by (chemo)radiotherapy in the BC2001 trial

  • Syed A. Hussain,
  • Nuria Porta,
  • Emma Hall,
  • Abdulazeez Salawu,
  • Rebecca Lewis,
  • Thiagarajan Sreenivasan,
  • Jan Wallace,
  • Malcolm Crundwell,
  • Peter Jenkins,
  • Jean Tremlett,
  • Robert Huddart,
  • Nicholas D. James

Background

BC2001 demonstrated improved local control with the addition of chemotherapy to radiotherapy in 360 patients with muscle-invasive bladder cancer.

Objective

To establish whether such benefit remained in BC2001 patients who received prior neoadjuvant chemotherapy.

Design, setting, and participants

A total of 117 patients (33%) received neoadjuvant chemotherapy and were randomised to radiotherapy with (48%) or without (52%) concomitant chemotherapy. Patients were recruited between August 2001 and April 2008 from 28 UK centres.

Intervention

Platinum-based neoadjuvant chemotherapy, followed by radiotherapy with (cRT) or without (RT) synchronous 5-fluorouracil and mitomycin-C.
Outcome measurements and statistical analysis

Toxicity, locoregional control (LRC), overall survival (OS), and quality of life (QoL) were measured.

Results and limitations

Of the patients, 74% received gemcitabine plus cisplatin or carboplatin. Compliance rates with full-dose radiotherapy were cRT 93% and RT 92%. An excess of grade ≥3 toxicities while on (chemo)radiation occurred for cRT 33% versus RT 22%, although nonstatistically significant (p = 0.16). With 110 mo median follow-up for survival (interquartile range 96–123), cRT showed improved LRC though not statistically significant (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] 0.33–1.23, p = 0.18). No differences in OS (aHR = 0.95, 95% CI 0.57–1.57, p = 0.8) were observed. No significant detriment in QoL was observed between cRT and RT in this subgroup of patients.

Conclusions

Neoadjuvant chemotherapy does not compromise the delivery of radical curative treatment. Although underpowered due to a small sample size, the benefit of chemoradiotherapy to improve local control in this group of patients receiving neoadjuvant chemotherapy is consistent with that observed in the main trial. Although a nonsignificant excess of toxicity was observed, there was no evidence of impaired QoL.

Expert's summary

By Dr. Francesco Soria

The standard treatment for patients with muscle-invasive bladder cancer is represented by radical cystectomy with pelvic lymph-node dissection, eventually preceded by cisplatin-based neoadjuvant chemotherapy in fit patients.

Chemoradiotherapy is the most effective bladder-sparing alternative to surgery, with reported long-term survival rates comparable to those of early cystectomy in selected patients, and bladder preserving rates of 70-90%. In the BC2001 trial, the combination of chemotherapy (fluorouracil + mitomycin-C) and radiotherapy has proven to be superior to radiotherapy alone in achieving disease control. Two-years locoregional disease-free rates and 5-years overall survival rates were 67% and 48% in the chemoradiotherapy group compared to 54% and 35% in patients treated with radiotherapy alone.  

Conversely to the surgical setting, the role of neoadjuvant chemotherapy in patients receiving bladder-sparing treatment remains, to date, mainly unexplored. In this article, Hussain et al. performed a subgroup analysis of patients enrolled in the BC2001 trial who received neoadjuvant chemotherapy before either chemoradiotherapy or radiotherapy alone. Despite the limitations inherent in the nature of the study (not pre-planned analysis, possible unavoidable selection bias, insufficient statistical power), these results demonstrated a possible role for neoadjuvant chemotherapy also in patients undergoing bladder-sparing treatment. These findings pave the way towards new clinical trials aiming to test the efficacy of neoadjuvant chemotherapy and, eventually, neoadjuvant immunotherapy in patients receiving chemoradiotherapy as a radical treatment for muscle-invasive bladder cancer. 

Expert's comment

In this retrospective subgroup analysis of the BC2001 trial, the authors aimed to evaluate the safety, tolerability and efficacy of neoadjuvant chemotherapy before chemoradiotherapy or radiotherapy alone as a bladder-sparing treatment for muscle-invasive bladder cancer. Overall, 117 out of 360 patients received neoadjuvant chemotherapy before chemoradiotherapy (56) or radiotherapy alone (61). The majority of patients received gemcitabine plus either cisplatin or carboplatin as a neoadjuvant regimen. No difference regarding safety, tolerability, quality of life and compliance rates with full-dose radiotherapy was observed between patients who received neoadjuvant chemotherapy and those who did not. Although not significant, the oncologic advantage of chemoradiotherapy over radiotherapy alone was confirmed also in this subgroup of patients. Notably, neoadjuvant chemotherapy seems to confer a long-term oncologic advantage in patients treated with radiotherapy only (5-yr overall survival rate 46% vs 37% in the main trial), but not in those who received chemoradiotherapy (48% vs 49% in the main trial).