ASCO 2017: Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer
Standard of care for management of muscle-invasive bladder cancer (MIBC) remains neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). However, as this continues to be a morbid procedure with significant QOL implications, the promise of bladder sparing therapy for MIBC has always been appealing. However, there has yet to be strong evidence for its safety and oncologic equivalence. Conflicting population-level data3 and institutional data2 in the absence of randomized trial data has made it difficult to determine the feasibility of this approach.
Prior work by this United Kingdom consortium demonstrated that adding radiosensitizing chemotherapy (fluorouracil and mitomycin C) to radiotherapy significantly reduced the need for salvage cystectomy in patients with MIBC. Many of the patients were previously treated with NAC. Primary outcome was locoregional recurrence, as a potential marker for subsequent cancer-specific survival. They found that, with a median follow-up of 69.9 months, at 2 years, rates of locoregional disease–free survival were 67% in the chemoradiotherapy group and 54% in the radiotherapy group. Five-year rates of overall survival were 48% in the chemoradiotherapy group and 35% in the radiotherapy group.
In this study, the consortium adds cetuximab (Cet), an epidermal growth factor receptor (EGFR) inhibitor. While they have previously reported phase 1 safety data, in this report, they combine phase 1 and 2 data to emphasize safety and efficacy.
Study Design:
Over a 4-year period in the UK, 33 patients (7 pts phase I and 26 patients from phase II) to undergo treatment for MIBC.
Treatment entailed: loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5-FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2 on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcome: feasibility and toxicity in phase 1, 3-month pathological complete response (CR) rate in phase II. Secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS).
Results:
In the cohort of 33 patients, median age of pts was 70 (range 46.9-85.6). All patients had MIBC, without evidence of metastatic disease.
Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 33 patients, only 28 had data that was evaluable. Phase II primary outcome data was available for 25 pts at the time of analysis with a 3-month pathological CR rate of 88%. Five local progressions and 4 deaths were reported.
While 12 patients reported at least one significant adverse event, grade 4 toxicities observed were dyspnea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The most common grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria.
Data on PFS and OS has yet to be presented.
Limitations / Discussion Points:
1. This is a very small cohort of patients. Twelve of 28 patients had at least one SAE, suggesting a higher adverse event profile.
2. The 3 month PFS primary outcome may be too premature to make any strong conclusions. As 5 patients already had local progression and there were already 4 deaths, there appears to be a high primary failure rate.
3. Unfortunately, without PFS and OS results, it is difficult to make any strong conclusions.
Further follow-up is warranted, and these early results are to be taken cautiously. Comparison against standard of care is warranted.
Presented By: Syed A. Hussain
Co-Authors: Laura Buckley, Baljit Kaur, Carey Hendron, Anjali Zarkar, Daniel Ford, Richard Viney, Isabel Syndikus, Zafar Malik, Chinnamani Eswar, Amisha Desai, Elizabeth Southgate, Stephen Mangar, Johannes Van Der Voet, Anna Lydon, Nicholas D. James
Institution(s): University of Liverpool, Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom; University of Birmingham, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom; University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; City Hospital, Cancer Centre Queen Elizabeth Hospital, Birmingham, United Kingdom; NHS, Birmingham, United Kingdom; Clatterbridge Cancer Centre, Wirral, United Kingdom; Clatterbridge Cancer Centre, Bebington, United Kingdom; University Hospital Birmingham, Birmingham, United Kingdom; Imperial College Healthcare NHS Trust, London, United Kingdom; South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom; South Devon Healthcare NHS Foundation Trust, Torquay, United Kingdom; Queen Elizabeth Hospital, Coventry, United Kingdom
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
REFERENCES:
1. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators.
Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. doi: 10.1056/NEJMoa1106106.
2. Kulkarni GS, Hermanns T, Wei Y, Bhindi B, Satkunasivam R, Athanasopoulos P, Bostrom PJ, Kuk C, Li K, Templeton AJ, Sridhar SS, van der Kwast TH, Chung P, Bristow RG, Milosevic M, Warde P, Fleshner NE, Jewett MAS, Bashir S, Zlotta AR. Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic. J Clin Oncol. 2017 Apr 14:JCO2016692327. doi: 10.1200/JCO.2016.69.2327. [Epub ahead of print]
3. Seisen T, Sun M, Lipsitz SR, Abdollah F, Leow JJ, Menon M, Preston MA, Harshman LC, Kibel AS, Nguyen PL, Bellmunt J, Choueiri TK, Trinh QD. Comparative Effectiveness of Trimodal Therapy Versus Radical Cystectomy for Localized Muscle-invasive Urothelial Carcinoma of the Bladder. Eur Urol. 2017 Apr 12. pii: S0302-2838(17)30266-X. doi: 10.1016/j.eururo.2017.03.038. [Epub ahead of print]