Date Published: April 6, 2017
Publisher: Public Library of Science
Author(s): Mathieu Orré, Igor Latorzeff, Aude Fléchon, Guilhem Roubaud, Véronique Brouste, Richard Gaston, Thierry Piéchaud, Pierre Richaud, Olivier Chapet, Paul Sargos, Peter C. Black.
Radical cystectomy (RC) and pelvic lymph-node dissection (LND) is standard treatment for non-metastatic muscle-invasive urothelial bladder cancer (MIBC). However, loco-regional recurrence (LRR) is a common early event associated with poor prognosis. We evaluate 3-year LRR-free (LRRFS), metastasis-free (MFS) and overall survivals (OS) after adjuvant radiotherapy (RT) for pathological high-risk MIBC.
We retrospectively reviewed data from patients in 3 institutions. Inclusion criteria were MIBC, histologically-proven urothelial carcinoma treated by RC and adjuvant RT. Patients with conservative surgery were excluded. Outcomes were evaluated by Kaplan-Meier method. Acute toxicities were recorded according to CTCAE V4.0 scale.
Between 2000 and 2013, 57 patients [median age 66.3 years (45–84)] were included. Post-operative pathological staging was ≤pT2, pT3 and pT4 in 16%, 44%, and 39%, respectively. PLND revealed 28% pN0, 26% pN1 and 42% pN2. Median number of lymph-nodes retrieved was 10 (2–33). Forty-eight patients (84%) received platin-based chemotherapy. For RT, clinical target volume 1 (CTV 1) encompassed pelvic lymph nodes for all patients. CTV 1 also included cystectomy bed for 37 patients (65%). CTV 1 median dose was 45 Gy (4–50). A boost of 16 Gy (5–22), corresponding to CTV 2, was administered for 30 patients, depending on pathological features. One third of patients received intensity-modulated RT. With median follow-up of 40.4 months, 8 patients (14%) had LRR. Three-year LRRFS, MFS and OS were 45% (95%CI 30–60), 37% (95%CI 24–51) and 49% (95%CI 33–63), respectively. Five (9%) patients had acute grade ≥3 toxicities (gastro-intestinal, genito-urinary and biological parameters). One patient died with intestinal fistula in a septic context.
Because of poor prognosis, an effective post-operative standard of care is needed for pathological high-risk MIBC. Adjuvant RT is feasible and may have oncological benefits. Prospective trials evaluating this approach with current RT techniques should be undertaken.
Muscle-invasive urothelial bladder cancer (MIBC) (cT2-T4) is an aggressive disease with poor 5-year overall survival (OS) of 50% [1, 2]. Current optimal management is based on radical cystectomy (RC) and pelvic lymph node dissection (LND), generally associated with pre-operative cisplatin-based chemotherapy. Despite the enthusiasm for chemotherapy, loco-regional recurrence (LRR) remains an early event that appears in 4 to 25% of cases [2, 3]. Prognosis after LRR appears poor with a possible impact on metastasis-free survival (MFS)  and OS .
Results from our study, with a medium-term follow-up in order to evaluate LRR, show that adjuvant RT for pathological high-risk MIBC is feasible and may have oncological benefits, especially since there is no other standard of care. We observed acceptable results in terms of acute toxicities. Indeed, less than 10% of patients presented grade > 3 toxicities although only 19 (33.3%) patients were irradiated with IMRT techniques. Some of them received dose escalation with boost that could impact acute toxicities. Moreover, our study included patients with neobladder and to our knowledge, there is no data regarding neobladder tolerance to RT. This study shows that orthotopic ileal neobladders can tolerate moderate doses of radiotherapy without significant induced morbidity but more data are required to provide important reassurance regarding the feasibility of including patients with orthotopic neobladders in studies examining the integration of surgery and post-operative radiotherapy. Regarding oncological outcomes, LRR was observed in 14% of cases with a median follow-up of 40.4 months. In our population, this rate may be considered as low, regarding the high-proportion of patients (26.3%) with positive surgical margins considered as the strongest independent predictive factor for LRR [1, 2, 13]. According to the risk stratification developed by the Philadelphia team , the expected rates of LRR were about 8%, 22% and 50% for low, intermediate and high risk groups, respectively. In our cohort, rates of LRR by subgroup were 9%, 27% and 7% respectively, clearly lower than expected for high risk patients and only for this subgroup. Even if we cannot show any correlation between LRR rates and RT in our study, this rate is in agreement with Zaghloul et al.’s results [6, 14] regarding the potential benefit of adjuvant RT, potentially reducing LRR rates by 50%.
In this retrospective contemporary cohort including only standard urothelial bladder cancers treated by RC, adjuvant RT showed good loco-regional control. Tolerance was acceptable (less than 10% of grade ≥ 3 toxicities). With postoperative nomograms correlating tumor pathological characteristics (pT, pN, number of lymph nodes retrieved, margin status) with LRR incidence and preferential sites, it could be possible to target more accurately the “at-risk” areas for well selected patients with adjuvant RT. Moreover, technical considerations such as use of IMRT and IGRT in this indication may allow lower toxicities by better sparing of adjacent organs-at-risk. For patients with pathological-risk MIBC, no postoperative standard of care is established despite the poor prognosis. Several groups such as the National Cancer Institute in Egypt, groups in North America (NRG Oncology), France (GETUG-AFU), United Kingdom (NCRI) and India (Tata Memorial Hospital) have already opened or are in the process of developing phase II trials to re-evaluate the feasibility of adjuvant RT for MIBC.