Dr. Fernando Maluf from Brazil started his defense of systemic therapy in this setting by noting that we have a long history of systemic therapy. But do we have the right scheme? More than two decades ago, the phase III Intergroup study randomized 255 patients with urothelial carcinoma to receive either single-agent cisplatin or combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Long-term follow-up from this study1 showed that M-VAC is associated with a high incidence of side-effects, including grade III and IV toxicities, and a treatment-related mortality rate of 4%. Furthermore, protocol adherence was a limitation in that only 25% of patients received treatment as planned without dose reduction or treatment discontinuation. Also, there were low rates of long-term survivors in that only 3.7% of patients were alive with no evidence of disease at 6 years follow-up.
Subsequently, a follow-up RCT randomized 263 patients with metastatic or advanced disease who had no prior chemotherapy to dense dose-MVAC (2-week cycles) or MVAC (4-week cycles)2. At a median follow-up of 38 months, on the dose-dense-MVAC arm there were 28 complete responses (CRs) (21%) and 55 partial responses (PRs) (41%), for an overall response rate of 62% (95% confidence interval [CI], 54% to 70%). On the MVAC arm, there were 12 CRs (9%) and 53 PRs (41%), for an overall response of 50%. There was no statistically significant difference in survival (p = 0.122) or time to progression (p =0.114). The 2-year progression-free survival rate was 24.7% for dose-dense-MVAC (95%CI, 17.1%-32.3%) versus 11.6% for MVAC (95%CI, 5.9%-17.4%).
New chemotherapy schemes were subsequently based on platinum combinations. In 2000, von der Maase et al.3 reported on 405 patients with metastatic urothelial carcinoma randomized 1:1 to receive GC or standard MVAC every 28 days for a maximum of six cycles. Overall survival was similar in both arms (HR 1.04, 95%CI 0.82-1.32), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments; toxic death rate was 1% in the GC arm and 3% in the MVAC arm.
This subsequently leads to another generation of chemotherapy in metastatic urothelial carcinoma that tested further platinum combinations by adding a third agent. Bellmunt et al.4 randomized 626 patients 1:1 to receive paclitaxel/cisplatin/gemcitabine vs gemcitabine/cisplatin. After a median follow-up of 4.6 years, the median OS was 15.8 months in paclitaxel/cisplatin/gemcitabine versus 12.7 months on GC (HR 0.85; p = 0.075). OS in the subgroup of all eligible patients was significantly longer on paclitaxel/cisplatin/gemcitabine (3.2 months; HR, 0.82; P = 0.03). PFS was not significantly longer in paclitaxel/cisplatin/gemcitabine (HR, 0.87; p = 0.11), whereas overall response rate was 55.5% in paclitaxel/cisplatin/gemcitabine and 43.6% in GC (p = 0.0031). Although the addition of paclitaxel to GC provided a higher response rate and a 3.1-month OS benefit, it did not reach statistical significance and has not become mainstream.
Often the issue with metastatic bladder cancer patients receiving chemotherapy are patients that are deemed “unfit” for cisplatin. De Santis et al.5 randomized 238 chemotherapy-naive patients with measurable disease and an impaired renal function (GFR < 60 but > 30 mL/min) and/or performance score of 2 to receive either gemcitabine/carboplatin or methotrexate/carboplatin/vinblastine (M-CAVI). Over a median follow-up of 4.5 years, the best ORRs were 41.2% (36.1% confirmed response) for patients receiving gemcitabine/carboplatin versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (p = 0.08). Median OS was 9.3 months in the gemcitabine/carboplatin arm and 8.1 months in the M-CAVI arm (p = 0.64). There was no difference in PFS (p = 0.78) between the two arms. More recently, the phase II KEYNOTE-052 study was also for patients ineligible for cisplatin, reporting that among 370 patients receiving at least one dose of pembrolizumab, 89 (24%, 95%CI 20-29) patients had a centrally assessed objective response, and 74 (83%) of 89 patients had ongoing responses over a median follow-up of 5 months (IQR 3.0-8.6)6. Additionally, a PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab: 42 (38%, 95%CI 29-48) of 110 patients had an objective response. Updated efficacy results demonstrate durable responses in this population.
Dr. Maluf concluded with several take-home messages advocating for chemotherapy in this first line setting of a 2-cm lung lesion:
- Cisplatin-based chemotherapy is the backbone treatment for unresectable or metastatic urothelial carcinoma
- For cisplatin-ineligible patients, PD-L1 negative patients are treated with carboplatin and gemcitabine, whereas PD-L1 positive patients should have individualized therapy with pembrolizumab or atezolizumab
- There are ongoing future trials evaluating the role of chemotherapy + IO, IO + IO, and targeted IO
- The integration of systemic and focal therapy should be done only in selected patients
- Biomarkers are urgently needed to define the optimal systemic therapy for each patient
Presented by: Professor James Catto MB ChB Ph.D. FRCS (Urol), Department of Oncology & Metabolism, The Medical School, Sheffield, United Kingdom and Fernando Cotait Maluf, Beneficencia Portuguesa, Sao Paulo, Brazil
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.
- Saxman SB, Propert KJ, Einhorn LH, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 1997 Jul;15(7):2564-2569.
- Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001 May 15;19(10):2638-2646.
- Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000 Sep;18(17):3068-3077.
- Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012 Apr 1;30(10):1107-1113.
- De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012 Jan 10;30(2):191-199.
- Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
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