presented the following case to facilitate the debate between Drs. Kassouf and Grivas titled: "In a patient who is pure UC, T2 disease; good GFR, should I go straight to radical cystectomy without neoadjuvant chemotherapy?" The patient case was as follows: 74 year-old-man, with a long-standing smoking history (otherwise healthy), normal renal function, who developed gross hematuria. He subsequently had a cystoscopy which demonstrated a 4-cm exophytic tumor on the left bladder wall and cytology positive for high-grade urothelial carcinoma. Upper tract imaging was negative and he was taken for a TURBT, which demonstrated T2 urothelial carcinoma, high-grade.
Dr. Wassim Kassouf started off his defense of immediate radical cystectomy without neoadjuvant chemotherapy by noting that the benefit, in his opinion, is modest, with an absolute improved overall survival benefit of 5% at 5 years, based on 2/11 positive randomized controlled trials (RCTs) being positive.
Based off of this data, Dr. Kassouf wonders if we can apply this data safely to a 74-year-old patient. Dr. Kassouf notes that the majority of the large RCTs did not include a large number of elderly patients. For example, in the phase III international BA06 30894 trial, there were only 15% of patients that were septuagenarians1. Similarly, in the SWOG-8710 study randomizing patients to immediate radical cystectomy or neoadjuvant chemotherapy followed by radical cystectomy, only ~20% of patients were T2 disease and ≥65 years of age; amongst these patients, 33% has Grade 4 toxicity2. As such, Dr. Kassouf suggests that we must extrapolate the neoadjuvant chemotherapy findings from previous RCTs with caution, considering that many of the patients in these trials were younger.
Second, Dr. Kassouf questions whether low-risk patients can benefit from neoadjuvant chemotherapy (cT2, no hydronephrosis, no variant histology/lymphovascular invasion, complete TUR)? Looking at the SWOG-8710 study once again, he notes that when assessing efficacy by stage, this certainly favors T3-T4a disease much more than T2 disease:
In Dr. Kassouf’s opinion, it is about selecting the right patient for neoadjuvant chemotherapy. In a combined analysis of patients from USC and MD Anderson Cancer Center assessing patients that underwent radical cystectomy without neoadjuvant chemotherapy, patients were considered high-risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection3. This study had 98 high-risk and 199 low-risk patients eligible for analysis. High-risk patients exhibited decreased 5-year OS (47.0% vs 64.8%) and decreased disease-specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival compared to low risk patients (p <0.001). In the Mayo clinic institutional study, 1,025 low and 906 high-risk patients were followed for a median 6.3 years (IQR 2.6-12), during which time 1,321 (68%) patients died, 753 (39%) from bladder cancer. High-risk patients had significantly lower 5-year CSS than low-risk patients (50% vs. 68%, p = 0.001). Neoadjuvant chemotherapy in low-risk patients was associated with greater odds of pT0 (OR 3.05; p < 0.001) and < pT2 (OR 2.53; p < 0.001) disease, but was not significantly associated with CSS (p = 0.31)4. In a study of 5,517 patients in the Netherlands Cancer Registry, Hermanns et al.5 compared complete pathological downstaging (pCD, ≤(y)pT1N0) and OS in patients with cT2 versus cT3-4aN0M0 urothelial carcinoma undergoing radical cystectomy with or without neoadjuvant chemotherapy or radiotherapy. In patients with cT3-4a disease, there was a significant OS benefit (HR 0.67, 95%CI 0.51-0.89), whereas no such benefit was found among patients with cT2 disease (HR 0.91, 95%Ci 0.72-1.15). Highlighting the SWOG-8710 data again, Dr. Kassouf notes that the best case scenario for neoadjuvant chemotherapy is a 5-year OS of 85% among patients who were pT02. This is the goal, to find the patients with the best likelihood of pT0 disease after radical cystectomy.
Dr. Kassouf concluded his argument for immediate cystectomy in T2 patients, by noting several take-home messages:
- The majority of patients recruited to the neoadjuvant chemotherapy trials were <65 years of age and as such the benefits of neoadjuvant chemotherapy in low-risk septuagenarians is unknown
- The risk/benefit ratio for neoadjuvant chemotherapy is in the high-risk tumors, considering that patients with cT2, complete TUR, and no hydronephrosis have excellent survival with immediate cystectomy, despite the risk of upstaging
- Outside of clinical trials, 30% of septuagenarians may not complete neoadjuvant chemotherapy
Presented by: Professor Marek Babjuk, CSc, Motol Hospital, and Charles University, Prague, Czech Republic
Wassim Kassouf, Professor, Department of Surgery in Urology, McGill University, Montreal Canada
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia Twitter: @zklaassen_md at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona Spain, March 15-19, 2019.
- International Collaboration of Trialists, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011 Jun 1;29(16):2171-2177.
- Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
- Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014 Jan;191(1):40-47.
- Lyon TD, Frank I, Sharma V, et al. A risk-stratified approach to neoadjuvant chemotherapy in muscle-invasive bladder cancer: Implications for patients classified with low-risk disease. World J Urol. 2018 Nov 3 [Epub ahead of print].
- Hermans TJN, Voskuilen CS, Deelen M, et al. Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer. Int J Cancer 2019 Mar 15;144(6):1453-1459.
Read the Opposing Argument - Neoadjuvant Chemotherapy: In a Patient Who is Pure Urothelial Carcinoma T2 Disease with Good GFR