ASCO GU 2019: Randomized Phase III Trial of Adjuvant Sequential Chemotherapy plus Radiotherapy versus Adjuvant Radiotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy: Urothelial Carcinoma Subgroup Analysis.

San Francisco, CA (UroToday.com) For patients with muscle-invasive urothelial carcinoma, surgery may provide long term cure for up to 50% of patients. However, a substantial number of patients, especially those with locally advanced disease, will have disease recurrence and the five year overall survival for patients with tumor invasion beyond the bladder is 40%¹. Thus, neoadjuvant chemotherapy is recommended for all patients who are willing and medically fit to receive chemotherapy. For those patients who do not receive neoadjuvant chemotherapy, adjuvant chemotherapy may improve overall survival. A meta-analysis of 940 patients from nine randomized trials showed an improvement in overall survival compared with radical cystectomy alone (HR0.77, 95% CI 0.59-0.99)as well as improvement in disease-free survival, most notably amongst patients with positive nodes². However, the improvement in overall survival was not seen for all patients in the EORTC 30994 study, which found that the 5 year overall survival was 53.6 versus 47.7 percent(HR 0.78, 95% CI 0.56-1.08)³. Thus, this area remains controversial, and ongoing studies including immunotherapy options are being investigated. This study reports on adding radiotherapy in addition to adjuvant chemotherapy for high risk locally advanced bladder cancer patients after cystectomy.

Summary
This abstract provides data from a phase III randomized trial in patients with high risk urothelial carcinoma. Patients were randomized to receive either postoperative radiotherapy (PORT) or PORT plus chemotherapy (cisplatin and gemcitabine). Chemotherapy was split up to two cycles before PORT and two cycles after PORT. Patients must have had at least one high risk feature including ≥pT3b, grade 3, or positive nodes with negative margins after radical cystectomy. The radiation protocol was 45Gy in 1.5Gy BID.

In this study, 81 patients with urothelial carcinoma were enrolled.

ASCO GU 2019 UC baseline characteristics

ASCO GU 2019 UC baseline characteristics

This was a young cohort of patients with a median age of 55. This trial started before neoadjuvant chemotherapy was routinely given for muscle-invasive bladder cancer in Egypt. With 21-month median follow up time, the two year disease free survival was 62% for patients receiving PORT plus chemotherapy compared with 48% receiving PORT alone. PORT plus chemotherapy also improved overall survival at two years, 71% vs 51% (HR 0.45, 95% CI 0.21-0.96, p=0.039)

ASCO GU 2019 OS benefit

In terms of safety, grade III GI toxicity was observed in 7% of patients receiving chemotherapy plus PORT compared to 8% of PORT patients.

Conclusions
For patients who did not receive neoadjuvant chemotherapy, PORT plus chemotherapy improves overall survival compared with PORT alone, with an impressive hazard ratio of 0.45. Interestingly, for patients with non-urothelial bladder cancer, Dr. Zaghloul mentioned that adjuvant chemoradiation was detrimental. Adjuvant chemoradiation in this cohort was well tolerated and contemporary studies should be conducted to confirm the benefit seen here.

Presented by: Mohamed S. Zaghloul, MD, Egyptian National Cancer Institute, Cairo, Egypt

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University. Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

References:
1. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. Journal of clinical oncology 2001;19:666-75.
2. Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. European urology 2014;66:42-54.
3. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. The Lancet Oncology 2015;16:76-86.

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