(UroToday.com) The 2022 ASTRO annual meeting featured a session on managing challenging bladder cancer cases, including a presentation by Dr. Leslie Ballas discussing node-positive and oligometastatic disease. Dr. Ballas started her presentation with a clinical scenario of an 80 year old man with a 1-2 year history of gross hematuria who presented to the emergency department with clot retention. His CT of the abdomen and pelvis showed a lobulated bladder mass with no mention of lymphadenopathy. A subsequent TURBT demonstrated high-grade invasive papillary urothelial carcinoma with invasion into the lamina propria and muscularis propria. A CT of the chest was negative for metastasis and he was referred for trimodality therapy. In work-up for SWOG/NRG 1806, restaging imaging with CT of the abdomen and pelvis showed a 1.5 cm left pelvic lymph node:
The AJCC 8th Edition Staging System for bladder cancer has re-classified node positive disease [N+ (N1-N3)] as stage III disease (previously it was stage IV disease). This change was made given that node positive bladder cancer patients tend to behave differently than those with metastatic disease. Dr. Ballas notes that a prospective observational study for patients treated with radical cystectomy showed 5-year recurrence free survival to be 81% for node negative versus 25-35% for node positive bladder cancer patients. With regards to surgery in patients with lymph node positive disease, in the absence of visceral metastases and despite chemotherapy, 5-year OS rates are <20 %. Data from the NCDB looking at chemotherapy +/- radical cystectomy in clinical lymph node positive disease showed that 5-year OS rates were as follows :
- Neoadjuvant chemotherapy and radical cystectomy: 31%
- Radical cystectomy and adjuvant chemotherapy: 26%
- Radical cystectomy alone: 19%
Additionally, other studies have suggested that the rate of pathologic complete response in N1-N3 patients following neoadjuvant chemotherapy is 14.5%, compared to ~35-45% in patients who received neoadjuvant chemotherapy without N1-N3 disease. Better OS outcomes are associated with pN0 (which is a more important predictor than initial local tumor stage; 5 times higher cancer-specific survival in pN0 than pN+), >= 15 lymph nodes removed, negative surgical margins, and Cis residual disease after neoadjuvant chemotherapy. Additionally, the benefit of post-chemotherapy cystectomy for regionally metastatic urothelial carcinoma is associated with a 5-year OS of 41% versus 8% without surgery.
A key clinical trial in this disease space is the ECOG-ACRIN 8185 INSPIRE trial, which is the first prospective study for clinical lymph node positive bladder cancer patients, a population that has historically been underrepresented in advanced bladder cancer trials and has been ineligible for bladder sparing trials. The trial schema for INSPIRE is as follows:
The primary endpoint is clinical complete response, defined as no radiologically measurable disease in the lymph nodes and negative cystoscopy + bladder biopsy 8-10 weeks post-chemoradiation.
Dr. Ballas then discussed a second clinical scenario of a 76 year old male that presented with an elevated PSA of 6.6 ng/mL and hematuria. His prostate biopsy showed high grade PIN, and cystoscopy showed a bladder mass. A CT urogram showed no evidence of lymphadenopathy and subsequent TURBT demonstrated high grade urothelial carcinoma with invasion into the muscularis propria. The patient asked to undergo bladder preservation, and in the workup for eligibility on SWOG/NRG 1806, a CT chest showed a 1.5 cm right upper lung cavitary nodule:
CT guided biopsy of this lung lesion demonstrated metastatic urothelial carcinoma. The patient was subsequently offered first-line systemic therapy.
Dr. Ballas then discussed oligometastatic bladder cancer. With regards to assessing the impact of metastasectomy, a phase 2 trial from 1995-1999 enrolled 70 patients (52 men, 18 women) refractory to MVAC chemotherapy. Of note, 73% of patients had <= 2 sites of disease, and the median age was 64 years of age. The median survival was 7 months (1 year survival rate: 30%), and prognosis was independent of metastasis site. There was no benefit from surgery, however symptomatic cancer benefited from surgery in terms of tumor-related symptoms and performance score. Asymptomatic patients felt a reduced sense of well-being post-operatively. There have also been 11 retrospective studies ranging in size from 15-114 patients that have assessed the impact of metastasectomy. Findings have been inconsistent, with some patients deriving an OS benefit and others with no benefit. It appears that patients with lung lesions < 3 cm may have the opportunity to derive the greatest benefit. Additionally, absence of multiple visceral metastases, small volume disease, and use of perioperative chemotherapy seem to be associated with better response.
Some data may for stereotactic body radiotherapy may be abstracted from multi-disease site clinical trials. The SABR-COMET trial  was a randomized, open-label phase II study of patients with oligometastatic disease (up to five sites) between February 2012 and August 2016. This trial included patients with prostate, lung, breast, colorectal, and “other” cancer patients. The 5-year OS rate was 17.7% (95% CI 6-34%) in the standard of care arm versus 42.3% (95% CI 28-56%) in the stereotactic body radiotherapy arm (stratified log-rank p = 0.006):
The 5-year PFS rate was not reached (3.2% 95% CI 0-14% at 4 years) in the standard of care arm and 17.3% (95% CI 8-30%) in the stereotactic body radiotherapy arm (p = 0.001):
A recent combined analysis of the STOMP and ORIOLE trials  found that over a median follow-up for the whole group of 52.5 months, the median PFS was prolonged using metastasis-directed therapy compared with observation (pooled HR 0.44, 95% CI 0.29 to 0.66):
With regards to the impact of metastasis-directed therapy with radiotherapy, a Stanford retrospective analysis assessed 22 patients with metastatic urothelial carcinoma who received consolidative radiotherapy after partial response to chemotherapy. Patients were treated with 25-56 Gy of IMRT, with multiple nodes having a 18x greater odds for disease relapse after radiotherapy compared with single-node metastasis. Ultimately, 36% of patients were rendered disease-free at 6 years and the median PFS of19 months was better than surgical data but are also more modern. As follows are the stereotactic body radiotherapy trials in urothelial carcinoma patients:
Dr. Ballas concluded her presentation discussing node-positive and oligometastatic disease bladder cancer cases with the following take home messages:
- The data for the use of radiotherapy in node positive bladder cancer will come from ECOG-ACRIN 8185 INSPRE
- Stereotactic body radiotherapy in oligometastatic bladder cancer has only been evaluated in small retrospective series, so more data is needed
- Radiotherapy to the bladder in the setting of metastatic disease needs more clinical data, but may hold promise
Presented by: Leslie K. Ballas, MD, Cedars Sinai Medical Center, Los Angeles, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.
- Galsky MD, Stensland K, Sfakianos JP, et al. Comparative effectiveness of treatment strategies for bladder cancer with clinical evidence of regional lymph node involvement. J Clin Oncol. 2016;34(22):2627-2635.
- Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020 Sep 1;38(25):2830-2838.
- Deek MP, Van der Eecken K, Sutera P, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: Analysis of STOMP and ORIOLE trials. J Clin Oncol. 2022;40(29):3377-3382.