The treatment of metastatic UTUC (mUTUC) is generally extrapolated from metastatic UBC (mUBC). Although we have entered the era of immune therapy, the anti-PD-1/PD-L1 immunotherapy has not established its role in the first-line treatment of metastatic urothelial carcinoma (mUC), while cisplatin-based chemotherapy remains the most common choice in the first-line setting. However, the benefit of chemotherapy in mUTUC remains uncertain because most of the clinical trials on chemotherapy in mUC enrolled a majority of patients with mUBC. Thus our study intended to investigate the clinical characteristics, chemosensitivity, and outcome of patients with mUTUC.
One of the features of our study is focusing on the metastatic patients with UTUC instead of the earlier stage or postoperative stage of disease, seeking to understand their characteristics so as guiding to resolve the clinical problems in the targeted population of patients. This study involved 250 UTUC cases over 12 years, which is also the largest clinical and prognostic study specialized in mUTUC by far.
The second highlight of this study is that we found the metastatic mode of UTUC was probably different from that of UBC. The most common metastatic sites of UTUC in this cohort were lung (39.6%), distant lymph nodes (39.2%), bone (19.6%), liver (18.0%), and adrenal gland (7.2%), respectively, while the local recurrence rate was only 10.4%. UTUC presented to be more prone to distantly metastasize than locally recur. Given that the proportion of stage IV disease of UTUC at initial diagnosis was high up to 22.4% and nearly 40 percent of the entire patients presented with more than or equal to 3 metastatic organs, these provided more evidence for the UTUC’s proneness of distant metastasis. Contrary to this, the UBC seemed to be prone to present local recurrence instead of distant metastases, according to the previous literature.
Thirdly, we also found that the mUTUC was probably less sensitive to chemotherapy. There were 222 patients in the entire cohort who received first-line chemotherapy, including nearly 70 percent of these patients received cisplatin-based standard chemotherapy. In results, the objective response rate (ORR) of the first-line chemotherapy was only 28.7% and the median progression-free survival (PFS) time was only 5.0 months. These data about the efficacy of chemotherapy in mUTUC were not comparable to those reported in mUBC from the previous clinical trials. In mUBC, the ORR after chemotherapy was up to 40-70% and the median PFS was around 7-9 months. However, whether the mUTUC was less chemosensitive than mUBC still needed to be verified in the controlled clinical trials.
Furthermore, Cox proportional hazard model indicated that the responders to the first-line chemotherapy would obtain more survival benefits than those non-responders. The better prognosis of survival was also found in patients received more cycles of chemotherapy (3-6 vs. 1-2 cycles), in patients not initially diagnosed as stage IV disease and in those had less than 3 metastatic organs. These implied that the response to chemotherapy besides the metastatic features of disease could also influence the prognosis of mUTUC.
These results helped us to understand more about the characteristics and prognosis of metastatic UTUC than before, and answered the question we raised up originally in some extent, that is, there probably exists a difference in the outcomes after chemotherapy between mUTUC and mUBC. The less chemosensitivity of mUTUC found in this study will have the potential of changing our views to consider the other treatments than chemotherapy in mUTUC. In fact, recent studies of UC molecular subtypes not only provided the evidence to the less chemosensitivity of UTUC but also guided the direction of choosing suitable treatment for mUTUC, since the obviously more FGFR mutations were found in UTUC other than UBC.
Written by: Siming Li, PhD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, P.R. China, and Xinan Sheng, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, P.R. China
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