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

San Francisco, CA (  In this study, the authors assess the role of adjuvant sequential chemotherapy and radiotherapy versus adjuvant radiotherapy alone for patients with locally advanced non-metastatic urothelial carcinoma of the bladder (Bladder cancer, BCa) following radical cystectomy (RC).

At this time, the standard of care for localized non-metastatic cM0 muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy and RC. However, loco-regional recurrence (LRR), remains a common and important challenge associated with poor oncologic outcomes. If LRR have a role in the subsequent development of distant disease, then adjuvant therapy is needed to enhance local control. More importantly, the poor prognosis of patients with metastatic disease highlights the importance of locoregional control and potential for cure.

The authors of this study previously established that “adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in locoregional-disease free survival and marginal improvements in disease-free survival” versus chemotherapy alone in patients with locally advanced bladder cancer.1 Indeed, the role of post-operative chemotherapy is controversial – prior trials were closed prematurely or were underpowered, while retrospective studies demonstrated potential benefit. However, the SWOG 8710 and EORTC/MRC studies demonstrated that chemotherapy does not address locoregional failure – and local recurrences are often highly morbid and rarely salvageable. A recent phase II trial by Zaghloul et al. (JAMA Surgery 2018) demonstrated that adjuvant radiation added to chemotherapy significantly improved 2-year local control rates (100% vs. 67% in patients with urothelial histology, p < 0.01).1

In this presentation, the authors assess the use of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy, focusing on patients only with urothelial carcinoma in this post-hoc analysis.

A randomized phase III trial was opened to compare post-operative radiotherapy (PORT) vs. sequential chemo+PORT after RC for locally advanced bladder cancer (LABC). They accrued patients between 2002–2008 at the NCI in Cairo, Egypt. Bladder cancer patients ≤70 with at least one of the following factors (≥pT3b, histologic grade 3, or positive nodes) with negative surgical margins after RC + BPLND were eligible for inclusion.

UroToday ASCOGU2019 Abstract 351 M.Zaghloul
Treatment was as follows:  RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before & after RT.

In terms of outcomes, the primary endpoint was DFS. Secondary endpoints included overall survival (OS) & late GI toxicity.

153 pts were enrolled to these two arms, and of these, 53% had urothelial carcinoma (41 chemo+PORT & 40 PORT). Due to the nature of bladder cancer development in Egypt (ie schistosomiasis and adenocarcinoma of the bladder), this represents a smaller proportion than in most other countries – and likely more reflective of the population likely to be encountered elsewhere.

Importantly, in the cohort as a whole, the study was negative – there was no DFS benefit with the addition of chemotherapy to PORT.

In the urothelial cohort of 81 patients, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) & 15 months for PORT (range 5-70). Full demographic info can be found below:

UroToday ASCOGU2019 Abstract 351 M.Zaghloul 2

The two groups were pretty evenly matched – except for node count. The chemo-RT group had a greater proportion of nodes removed at the time of RC.

There were 2 local failures for PORT & none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) & 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) & 51% (95% CI 40-61%), log-rank p=0.048.

On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039).

In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) & 6 PORT patients (8%). This treatment was generally well tolerated. The rate of late GI complications was quite low, which was reassuring.

Based on these results, the authors conclude that the addition of adjuvant chemo to PORT improved DFS & OS for patients with high-risk locally advanced bladder urothelial cancer after RC, balanced with acceptable late GI toxicity. Their results suggest a role for adjuvant therapies to address both local & distant disease.

Limitations / Discussion Points:
  1. This is a post-hoc analysis, so it wasn’t powered from the outset to answer this question. In fact, they ended up with a greater proportion of urothelial histology than expected.
  2. Patients underwent a standard, rather than extended, lymph node dissection
  3. Dr. Lerner asked again about the role in patients with margin-positive disease – which this study cannot answer, as these patients were excluded.

Presented by: Brian C. Baumann, MD, Assistant Professor of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

  1. Zaghloul MS, Christodouleas JP, Smith A, Abdallah A, William H, Khaled HM, Hwang WT, Baumann BC. Adjuvant Sandwich Chemotherapy Plus Radiotherapy vs Adjuvant Chemotherapy Alone for Locally Advanced Bladder Cancer After Radical Cystectomy: A Randomized Phase 2 Trial. JAMA Surg. 2018 Jan 17;153(1):e174591. doi: 10.1001/jamasurg.2017.4591. Epub 2018 Jan 17.