Treatment of Metastatic Upper Tract Urothelial Cancers

141 Treatment of Metastatic Upper Tract Urothelial Cancers

Jose Pacheco, Saleha Sajid, and Teresa Gray Hayes

FIRST-LINE CHEMOTHERAPY OPTIONS

Urothelial carcinoma (UC) of the upper tract is a rare, aggressive urologic cancer with a tendency to metastasize early. Level 1 evidence from a prospective randomized controlled trial (RCT) is not available given its rarity, and treatment strategies are adapted from metastatic UC of the bladder (Chapter 26). The two first-line chemotherapy options in patients with good organ function and performance status (Eastern Cooperative Oncology Groups Performance Status 0 to 1) are gemcitabine plus cisplatin (GC) and dose-dense methotrexate + vinblastine + adriamycin + cisplatin (ddMVAC) (Table 21.1). However, a direct comparison between GC and ddMVAC has not been done in a randomized trial. The phase 3 multicenter RCT that suggested similar survival and a more tolerable side effect profile for GC (significantly less grade 3/4 neutropenia, neutropenic fever, neutropenic sepsis, mucositis, and alopecia) was comparing it to standard MVAC (sMVAC) (1). The reasons why ddMVAC is preferred in clinical practice over sMVAC are 3-fold based on the results of an RCT in metastatic UC of the bladder:

i. ddMVAC demonstrated an improved overall response rate (ORR) compared to sMVAC (64% vs. 50%) and improved progression free survival (PFS) (9.5 months vs. 8.1 months)

ii. While there was no significant difference in median overall survival (OS), the 5-year OS was significantly better for ddMVAC at 21.8% versus 13.5% with sMVAC

iii. ddMVAC was better tolerated than sMVAC with less grade 3 to 4 leukopenia, neutropenic fever, and mucositis (2)

142Table 21.1 First-Line Regimens for Advanced Urothelial Carcinoma

Cisplatin eligible

Cisplatin ineligible^a^b

If Her2 positive

a. ddMVAC

b. GC

a. Carboplatin-based regimens

b. Taxol-based regimens

c. Single agent chemotherapy regimens

d. Clinical trial

e. Can consider atezolizumab, nivolumab, or another immune checkpoint inhibitor*

a. Can consider clinical trials of Her2 targeting agent alone or in combination with chemotherapy

ddMVAC, dose-dense methotrexate + vinblastine + adriamycin + cisplatin; GC, gemcitabine + cisplatin.

^aIneligibility criteria for cisplatin include: creatinine clearance less than 60 mL/min by the Cockcroft Gault formula, ECOG PS ≥ 2, grade ≥ 2 hearing loss, and grade ≥ 2 peripheral neuropathy.

^bFor select patients with creatinine clearance between 45 and 59 mL/min by the Cockcroft Gault formula, one can consider split dose cisplatin-based regimens.

^*Immune checkpoint inhibitors have not been approved at the time of this publication for first-line therapy in cisplatin ineligible patients with metastatic urothelial cancer. However, several of them are undergoing Federal Drug Administration review for this indication and are likely to be approved soon.

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