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EAU Annual Congress 2021

EAU 2021: Neoadjuvant Chemotherapy in Upper Urothelial Cancer

(UroToday.com) Dr. Mohammad Abufaraj from Jordan University Hospital discussed neoadjuvant chemotherapy for upper tract urothelial carcinoma at the joint session of the European Association of Urology (EAU) and the Arab Association of Urology. Dr. Abufaraj started by highlighting that urothelial carcinoma is the 5th most frequent cancer diagnosed in the United States, with upper tract urothelial carcinoma accounting for only 5-10% of cases. Approximately 60% of upper tract urothelial carcinoma patients present with muscle-invasive disease at the time of diagnosis and ~7% harbor distant metastasis. Radical nephroureterectomy with bladder cuff excision is the standard treatment of high-risk non-metastatic upper tract urothelial carcinoma, however, 1/3 of patients experience disease recurrence and over 80% succumb to their disease. Although it would seem reasonable to equate bladder and upper tract urothelial carcinoma, they are distinct diseases, with practical, anatomical, and molecular differences that warrant consideration in clinical decision-making:


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There are several challenges in the treatment of upper tract urothelial carcinoma, including (i) small/low grade/non-invasive tumors with limited capacity for progression being over-treated by radical surgery, and (ii) high-grade invasive tumors with a significant rate of occult metastasis being under-treated by radical surgery alone. There are several rationales for perioperative chemotherapy for patients with upper tract urothelial carcinoma:

  • The local and metastatic recurrence rate is ~40% at 2 years
  • Deaths are generally not local events, and patients typically die as a result of metastatic disease
  • Local interventions will not deal with micrometastases
  • Urothelial carcinoma is chemosensitive, with a chemotherapy benefit seen in some patients with metastatic urothelial carcinoma
  • Upper tract urothelial carcinoma shares similar biology with muscle-invasive bladder cancer, and chemotherapy is standard in the perioperative setting for muscle-invasive bladder cancer

One of the challenges with chemotherapy for patients with upper tract urothelial carcinoma is that prior to radical nephroureterectomy ~50% of patients have an eGFR <60 mL/min/1.732, whereas after radical nephroureterectomy ~75% of patients have an eGFR <60 mL/min/1.732. A decade ago, Matin and colleagues1 evaluated the incidence of pathologic downstaging and complete remission in patients with high-grade ureteral and renal pelvic urothelial carcinoma who received neoadjuvant chemotherapy followed by surgery. There were 107 patients in the control group that underwent initial surgery and 43 patients in the study group who received neoadjuvant chemotherapy. Overall, there was significant downstaging in study group patients compared with the historic control group (p = 0.004). The incidence of tumors classified as pathologic pT2 or as pT3 or higher was significantly lower in the study group (pT2, 65.4% vs 48.8%; p = 0.043; pT3 or higher, 47.7% vs 27.9%; p = 0.029), and 14% of patients who received neoadjuvant chemotherapy had a pathologic complete response:

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A follow-up study by the group at MD Anderson looked at survival rates of patients with upper tract urothelial carcinoma who received neoadjuvant chemotherapy before surgery with the rates among patients who did not.2 Among 112 patients in the study, there were 31 that received neoadjuvant chemotherapy and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved overall survival and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year overall survival rate of 80.2% versus DSS and overall survival rates of 57.6% for those who underwent initial surgery (p = 0.0204 and p = 0.0015, respectively).

Published last year, Margulis et al.3 performed a phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high-grade upper tract urothelial carcinoma (ECOG-ACRIN 8141). There were 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin, and cisplatin arm from 2015 to 2017, as well as six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Among 29 eligible patients in the MVAC arm, 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0, and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8) of patients. The ECOG-ACRIN 8141 trial demonstrated feasibility of a prospective multicenter trial of cisplatin-based neoadjuvant chemotherapy in upper tract urothelial carcinoma.

Dr. Abufaraj concluded his presentation with the following take-home messages:

  • The role of neoadjuvant chemotherapy in upper tract urothelial carcinoma is still unclear, as its use is being extrapolated from the bladder cancer literature
  • Data from the ECOG-ACRIN 8141 trial have shown that neoadjuvant chemotherapy can achieve pathological downstaging and pathological complete response
  • Patients may be offered neoadjuvant cisplatin-based chemotherapy for those planning radical nephroureterectomy for high-risk upper tract urothelial carcinoma
  • If patients do not receive neoadjuvant chemotherapy and have pT2-4 Nx/No or N+ disease, they should be offered adjuvant platinum based chemotherapy based on the POUT trial4

Presented by: Mohammad Abufaraj, MD, Jordan University Hospital, The University of Jordan, Amman, Jordan

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

  1. Matin SF, Margulis V, Kamat A, et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer. 2010 Jul 1;116(13):3127-3134.
  2. Porten S, Siefker-Radtke AO, Xiao L, et al. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer. 2014 Jun 15;120(12):1794-1799.
  3. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma. J Urol. 2020 Apr;203(4):690-698.
  4. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): A phase 3, open-label, randomized controlled trial. Lancet 2020 Apr 18;395(10232):1268-1277.