CUOS 2019: High-grade Upper Tract Urothelial Carcinoma – Neoadjuvant Chemotherapy

Toronto, Ontario ( Dr. Kala S. Sridhar participated in a debate and supported the use of neoadjuvant chemotherapy instead of adjuvant chemotherapy for high-grade upper tract urothelial carcinoma (UTUC).

UTUC is a rare disease involving the renal pelvis and ureter. High-grade disease is usually treated with radical nephroureterectomy, with a 5-year cancer-specific survival of less than 50% for pT3 disease, 5-10% for pT4 disease, and less than 35% for the pN+ disease. Perioperative chemotherapy plays an important role in the treatment of this high-grade disease.

Dr. Sridhar continued and described the top reasons to give neoadjuvant chemotherapy:

  1. UTUC and bladder cancer are very similar. There is level 1 evidence demonstrating the benefit of neoadjuvant chemotherapy in bladder cancer, and this could also be extrapolated to UTUC. Pathologic complete response and tumor downstaging are linked to improved overall survival. Retrospective studies have reported cancer-specific survival benefits with neoadjuvant chemotherapy in UTUC.
  2. The biggest risk in UTUC is that of distant metastases. Neoadjuvant chemotherapy targets micrometastatic disease early. All courses of neoadjuvant chemotherapy are usually completed by the time there is an operating date. When going through the alternative route of adjuvant chemotherapy instead of neoadjuvant chemotherapy, there is often a significant delay of over three months.
  3. Upstaging remains a major issue in this disease so treating with neoadjuvant chemotherapy may mitigate that.
  4. Patient tolerance and compliance are usually much better before surgery than after surgery. The performance status of the patient is usually better preoperatively, and patients are not dealing with postoperative complications. With neoadjuvant chemotherapy, patients usually tolerate the entire dose and the complete planned treatment with no issues.
  5. Renal function deteriorates significantly postoperatively, with reduced cisplatin eligibility
  6. In-vivo demonstration of chemotherapeutic efficacy guides therapy. It may prevent futile treatment if disease progression is demonstrated, and it may help facilitate drug development, biomarkers, and imaging modalities.
The POUT trial1 was a randomized controlled trial randomizing patients with invasive UTUC within 90 days following radical nephroureterectomy to either surveillance or platinum-based chemotherapy, typed by glomerular filtration rate. This trial compared adjuvant chemotherapy to surveillance but not to neoadjuvant chemotherapy. Dr. Sridhar raises the question of whether it might have been better to compare adjuvant chemotherapy to neoadjuvant chemotherapy, instead of surveillance.

When analyzing the results of the POUT trial, it seems that only 62% of the patients received Gemcitabine and cisplatin, and only 68% of them completed four full cycles. Adverse events of grade 3 or above were present in 62% of patients. The benefit in disease-specific survival was seen in patients who received gemcitabine and cisplatin, who also had better kidney function. However, the most favorable kidney function in these patients is always seen preoperatively, making the possibility of neoadjuvant chemotherapy the better alternative.

In summary, UTUC is an aggressive disease with poor outcomes. The biggest risk is the presence of micrometastatic disease. These patients require an effective treatment that can be given early. POUT is an important trial confirming a role for chemotherapy in UTUC. The question of neoadjuvant chemotherapy vs. adjuvant chemotherapy in this disease remains largely unanswered, but it is being addressed by the URANUS clinical trial. This is a phase 2 randomized clinical trial comparing neoadjuvant vs. adjuvant chemotherapy, with an expected study completion date in 2023. Lastly, treatment in the neoadjuvant chemotherapy setting opens the door for future research, combining immunotherapy, and targeted therapies.

Presented by: Srikala (Kala) Sridhar, MD, MSc, FRCPC, Medical Advisory and Research Board, Princess Margaret Hospital, Toronto, Ontario, Canada

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada

1. Birtle A. 2018 GU-ASCO

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High-grade Upper Tract Urothelial Carcinoma – Adjuvant Chemotherapy