Favorable Response of Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma with Only Small Lesions to not be Considered Measurable by RECIST Yoshifumi Kadono1*, Shohei Kawaguchi1, Takahiro Nohara1, Kazuyoshi Shigehara1, Kouji Izumi1, Taiki Kamijima2, Chikashi Seto2, Akinobu Takano3, Satoshi Yotsuyanagi3, Ryunosuke Nakagawa4, Tohru Miyagi4, Shuhei Aoyama5, Hideki Asahi6, Rie Fukuda7, Atsushi Mizokami1 Purpose: Pembrolizumab is currently considered the standard second-line treatment for advanced urothelial car- cinoma (UC). This study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced UC in real-world data, which is not well-reported. Materials and Methods: The study included 97 patients with advanced UC whose lesions were classified ac- cording to the Response Evaluation Criteria in Solid Tumors (RECIST). The median age was 73 years. Nineteen patients (20%) with performance status (PS) 2–4 were included. The percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. The efficacy, safety, and risk factors for prognosis were evaluated for patients with and without measurable lesions. Results: The best response was complete response in nine patients (9%) and partial response in 16 patients (17%). The median progression-free survival and overall survival were 3.7 months (95% confidence interval [CI]: 2.8– 4.7) and 11.8 months (95% CI: 6.7–17.0), respectively. Twenty-one (22%) patients had no measurable lesions per RECIST. In univariate and multivariate analysis, PS 2–4 and lesions by RECIST were identified as factors associ- ated with short overall survival (OS). The median OS of 18.3 months in patients without lesions by RECIST was significantly longer than the median OS of 6.7 months in patients with lesions by RECIST (p = .012). Conclusion: We demonstrated that good PS 0–1 and no measurable lesions, especially small lesions, by RECIST were favorable prognostic factors in patients with advanced UC treated by pembrolizumab. Keywords: urothelial carcinoma; pembrolizumab; performance status; small lesions; RECIST INTRODUCTION Methotrexate, vinblastine, doxorubicin, and cispla-tin (M-VAC) chemotherapy,(1) and gemcitabine and cisplatin chemotherapy for advanced urothelial carcinoma (UC) are established treatments.(2) Plati- num-based chemotherapies as first-line treatment for advanced UC are effective, but few cases have achieved complete remission. Historically, there has been no ef- fective second-line treatment after failure of first-line chemotherapy for advanced UC. In a randomized, phase 3 study (KEYNOTE-045) for patients with ad- vanced UC after failure of platinum-based chemother- apy, treatment with pembrolizumab, a highly selective, humanoid monoclonal antibody against programmed death 1 (PD-1), resulted in longer overall survival (OS) than existing second-line chemotherapy (10.3 months vs 7.4 months) and achieved a 27% reduction in death risk.(3) In addition, the incidence of treatment-related adverse events (AEs) was lower with pembrolizumab, 1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. 2Department of Urology, Toyama Prefectural Central Hospital,Toyama, Japan. 3Department of Urology, Kouseiren Takaoka Hospital, Takaoka, Toyama, Japan. 4Department of Urology, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan. 5Department of Urology, Noto General Hospital, Nanao, Ishikawa, Japan. 6Department of Urology, Kaga Medical Center, Kaga, Ishikawa, Japan. 7Department of Urology, Fukui-ken Saiseikai Hospital, Fukui, Japan. *Correspondence: Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. Tel: +81-76-265-2393. E-mail: yskadono@yahoo.co.jp. Received January 2021 & Accepted August 2021 including fewer high-grade (grade 3–5) AEs that re- sulted in treatment discontinuation.(3) However, in the cited clinical trial, the inclusion of participants was lim- ited by cancer and patient status, such as measurable lesions evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) and the Eastern Coopera- tive Oncology Group performance status (ECOG-PS). (3) Therefore, real-world clinical practice data on pem- brolizumab for advanced UC is needed. In this study, we retrospectively investigated the efficacy and safe- ty of pembrolizumab in patients with advanced UC in real-world data from Kanazawa University and related hospitals. PATIENTS AND METHODS This study was approved by the ethics review board of our institution and related hospitals (No. 2018-082, 2847), and we informed all patients that they could opt out at any time. We retrospectively evaluated advanced UROLOGICAL ONCOLOGY Urology Journal/Vol 19 No. 3/ May-June 2022/ pp. 202-208. [DOI:10.22037/uj.v18i.6652] Table 1. Demographics of the study population Variable Median (range) or n (%) Total number of patients 97 Age, years 73 (48 to 85) Male/Female 69 (71) / 28 (29) Current or former smoker/non-smoker 60 (62) / 37 (38) Primary tumor site, upper urinary tract 42 (43) / 55 (57) Pure UC in histologic testing 86 (89) / 11 (11) Radical surgery of the primary lesion 48 (50) / 49 (50) ECOG PS, 0-1/2-4 78 (80) / 19 (20) Number of prior regimens, 1/2/3 67 (69) / 27 (28) /3 (3) Number of prier platinum agent courses 4 (1 to 30) Metastatic sites, liver/lung/bone/lymph node* 17(18) / 26(27) / 18(19) / 74(76) Lesions by RECIST evaluation, Yes/No 76 (78) / 21(22) Number of metastatic organs, 1/2/3/4/5* 22(23) / 43(44) / 21(22) / 7(7) / 4(4) Time from previous chemotherapy, <3 / >3 months 78 (80) / 19 (20) UC, Urinary carcinoma; ECOG PS, Eastern Cooperative Oncology Group Perfromance status; RECIST, Response Evaluation Criteria in Solid Tumor. * The lesions were evluated and reported by doctors in charge. Urological Oncology 114 Pembrolizumab for UC with small lesions-Kadono et al. Vol 19 No 3 May-June 2022 203 Figure1: Kaplan–Meier curves of progression-free survival (PFS) (A), overall survival (OS) (B) and duration of response (DOR) in patients with deter- mined objective response (C). A B C Pembrolizumab for UC with small lesions-Kadono et al. Table 2. Univariate and multivariate analyses of prognostic factors for overall survival with pembrolizumab therapy Univariate Multivariate Reference category* HR (95% CI) p-Value HR (95% CI) p-Value Age, years 0.971 (0.938-1.005) 0.091 0.967 (0.933-1.002) 0.067 Continuous Gender 0.737 (0.413-1.318) 0.304 Male/Female ECOG PS 7.474 (3.955-14.124) < 0.001 8.189 (4.178-16.051) < 0.001 PS2-4/PS0-1 Smoking status 1.122 (0.639-1.970) 0.687 Current+Former/Never Primary tumor site 1.710 (0.999-2.926) 0.05 1.679 (0.968-2.914) 0.065 Upper tract UC/BT Histologic testing 1.930 (0.907-4.105) 0.088 1.409 (0.649-3.058) 0.385 With others/Pure UC Radical surgery of the primary lesion 0.775 (0.453-1.325) 0.351 Yes/No Lesions evaluated by RECIST 2.445 (1.187-5.037) 0.015 2.333 (1.096-4.968) 0.028 Yes/No Time from previous chemotherapy 1.321 (0.643-2.713) 0.448 <3 months/>3months HR, Hazard ratio, ECOG PS, Eastern Cooperative Oncology Group Performance status; RECIST, Response Evaluation Criteria in Solid Tumor. *In a categorical values, the right side is the reference. Urological Oncology 204 Figure2: Kaplan–Meier curves of progression-free survival (PFS) (A), and overall survival (OS) (B) in each patient with or without lesions evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria A B and recurrent UC patients who were treated with pem- brolizumab after progression of platinum-based chemo- therapy at our and related hospitals from January 2018 to October 2019. The recurrence of UC and the timing of pembrolizumab administration were determined by the doctors in charge. Pembrolizumab was administered at a dose of 200 mg every three weeks until discontinuation due to disease progression or unacceptable AEs. We obtained medical records, and clinical features were recorded, including age, sex, smoking status, primary tumor site, histology, metastatic organs, duration since previous chemother- apy, and ECOG-PS. Treatment efficacy was assessed according to RECIST version 1.1,(4) wherein non-meas- urable lesions, such as small lesions or bone metastasis, with a 20% (and over 5 mm) increase in total diameter size or a new lesion were defined as progressive disease (PD); lesions with a 30% decrease in total diameter size were defined as partial response (PR); and the disap- pearance of all measurable lesions indicated complete response (CR). The objective response rate (ORR) was defined as the proportion of PR and CR, and disease control rate (DCR) was defined as the proportion of PR, CR, and stable disease (SD). Progression-free sur- vival (PFS) was calculated from the commencement of pembrolizumab to radiographic or clinical disease pro- gression or death. The durable response rate (DRR) and duration of response (DOR) from the commencement of pembrolizumab to radiographic or clinical disease progression or death of CR and PR patients were also calculated. OS was calculated from the commencement of pembrolizumab to death or the time of last follow-up. Pseudoprogression (PP) was defined as a response to treatment after an initial increase in the volume of cancer lesions or with the appearance of new lesions subsequently followed by disease stabilization or a dis- ease response before confirming the progression with a second assessment using imaging evaluation.(5) Hyper- progression (HP) was defined as rapid tumor progres- sion after the initiation of pembrolizumab.(6) Toxicity, including immune-related adverse events (irAE), was assessed according to the Common Terminology Crite- ria for Adverse Events version 4.0.(7) The categorical variables used for calculating the inci- dence and percentage of each factor as well as the con- tinuous variables were summarized as their median and range. When making comparisons, the chi-square test was used for categorial variables, while the Mann-Whit- ney U test was used for continuous variables. PFS and OS were estimated using Kaplan–Meier methods, and the differences were evaluated using the log-rank test. Cox proportional hazards models were used to identify the prognostic factors for OS. All data analyses were performed using SPSS for Windows (SPSS Inc., Chica- go, IL), taking p-value < 0.05 as statistically significant. RESULTS The study included 97 patients with advanced UC who were treated with pembrolizumab after platinum-based chemotherapy at Kanazawa University and seven re- lated hospitals. The characteristics of the patients are presented in Table 1. Twenty-one (22%) patients had no measurable lesions by RECIST (6 cases of small lymph node metastasis only; 8 cases of unmeasured primary and lymph node metastasis; and 7 cases of small viscer- al metastasis, including unmeasured bone metastasis). Nineteen (20%) patients were ECOG-PS 2–4. The median follow-up period after pembrolizum- ab commencement was 7.8 months (range 0.4–24.8 months). The number of deaths during follow-up were 55 (57%) patients. The causes of death were UC in 47 (85%) patients, AEs in four (7%) patients, acute mye- loid leukemia (AML) in two (4%) patients, suicide in one (2%) patient, and unknown cause in one (2%) pa- tient, respectively. The best response was CR in nine (9%) patients, PR in 16 (17%) patients, SD in 26 (27%) patients, and PD in 46 (47%) patients. Therefore, the ORR was 26% and DCR was 49%. The median PFS and OS were 3.7 months (95% confidence interval (CI): 2.8–4.7) and 11.8 months (95%CI: 6.7–17.0), respec- tively (Figure 1A, B). At 12 months after pembroli- zumab commencement, the DRR was 79%. At the time of last follow-up, 16 out of 25 (64%) patients with a response continued to show a response. The median DOR was not reached (Figure 1C). PP was observed in three (3%) patients and HP was observed in nine (9%) patients. The median OS of patients with HP was 28 days (range 10–43 days). We investigated variables that predict shorter OS. In univariate and multivariate analysis, PS 2–4 lesions by RECIST were identified as factors associated with short OS (Table 2). The PFS of patients without lesions by RECIST was longer than that of patients with lesions by RECIST; however, it was not statistically significant (p = .088) (Figure 2A). The median OS of 18.3 months in patients without lesions by RECIST was significantly longer than the median OS of 6.7 months in patients with lesions by RECIST (p = .012) (Figure 2B). The best response of patients with and without lesions by RECIST were CR 4 cases (5%), PR 13 cases (17%), SD 17 cases (22%), and PD 42 cases (56%) versus CR 5 cases (24%), PR 3 cases (14%), SD 9 cases (43%), and PD 42 cases (19%), respectively (p = .004). Severe AEs (including grade 3–5 AEs) were observed in 18 (19%) patients. Interstitial pneumonia was the most frequent grade 3–5 AE in this study. Other types of pneumonia included one pneumocystis pneumo- nia and one bronchial pneumonia. Five (5%) patients died after pembrolizumab treatment because of AEs. Two (2%) patients died of interstitial pneumonia, one (1%) of pneumocystis pneumonia, one (1%) of ulcer- ative colitis, and one (1%) of AML, respectively. Two (2%) patients with persistent bone marrow suppression caused by previous chemotherapy suffered with AML after two and four administrations of pembrolizumab, respectively. DISCUSSION We report the clinical outcome after pembrolizumab in Japanese patients with advanced UC. The most signif- icant difference in patient background between this re- al-world study and KEYNOTE045 arises from the fact that patients with poor PS and no measurable lesions, as defined by RECIST, cannot be included in clinical trials. There have been some reports of poor prognosis in patients with poor PS;(1,8) however, to the best of our knowledge, we could not find a report that examined the prognosis of patients without lesions by RECIST treated by immune checkpoint inhibitors. Non-measur- able lesions defined by RECIST are small lesions (long- est diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-meas- Urological Oncology 116 Pembrolizumab for UC with small lesions-Kadono et al. Vol 19 No 3 May-June 2022 205 urable lesions.(4) Lesions considered truly non-measur- able included: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdom- inal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.(4) In this study, all the cases, which had only non-measurable lesions defined by RECIST, had only small lesions. The median PFS and OS were 3.7 months and 11.8 months, respectively, and the ORR was 26%. These outcomes were slightly better than the KEYNOTE-045 trial.(3) This might be because of the patients’ backgrounds. Poor prognostic factors after systemic treatment for advanced UC are poor PS and visceral metastases,(9-12) especially liver metastases.(13) In the KEYNOTE-045 trial, the proportion of PS 0–1, PS 2, and PS 3–4 participants were 97.1%, 2.9%, and 0%, respectively.(3) In our study, the proportion of pa- tients with PS 2–4 was 20%. The evaluation of risk fac- tors for OS revealed poor PS and badly affected OS. The median OS of patients with PS 0–1 and PS 2–4 was 17.7 months and 1.4 months, respectively (data not shown). The inclusion criteria for KEYNOTE-045 trial for cancer status determined at least one measurable le- sion evaluated by RECIST version 1.1.(3) In our study, 21 cases (22%) did not have lesions per RECIST. The visceral metastases and liver metastases, which were reported as poor prognostic factors,(9-13) were 62% and 18% in our study, compared to 89% and 34% in KEY- NOTE-045.(3) In our study, patients with good PS 0–1 and without measurable lesions by RECIST, which were good prognostic factors for OS (Table 2), would contribute to the improved outcomes of our study. In clinical practice, we often determine that the lesion has metastasized due to its growth over time. In particular, with regard to the evaluation of lymph node metastasis, RECIST does not result in the evaluation of metastasis until the lymph nodes are more than 15 mm in short diameter. In actual clinical practice, we rarely wait to treat lymph node metastases until they grow to that size. In fact, in this study, most of the patients without RECIST-evaluated lesions had small lymph node and visceral metastases. In the present study, treatment was initiated before the size of the lesion was assessed as metastatic by RECIST, and the period of earlier inter- vention can be considered as the time until the lesion grew to a measurable size by RECIST, which may be counted as a prolonged prognosis. However, since the median difference was about 12 months (Figure 2B), it is conceivable that early intervention may have had a greater therapeutic effect. Basic research reported that PD-1-positive CD8-positive T-cell infiltration was higher in early-stage tumors with smaller size, and the efficacy of anti-PD-1 antibody was higher, suggesting the usefulness of early therapeutic intervention with immunotherapeutic agents.(14) In fact, in this study, ORR was better in the group of patients without RE- CIST-evaluated lesions. Although this study showed a high short-term efficacy for small lesions, the results of Kaplan–Meier analysis showed that treatment efficacy and survival approached the long-term (Figure 2A, B). The durable effect of long-term treatment may depend more on the immunity of the individual than on the size of the lesion. The long-term effects of the treatment need to be examined with an extended observation pe- riod. After treatment with immune checkpoint inhibitors, atypical patterns of response, such as PP and HP, were reported. The PP is characterized by a transient increase followed by a decrease in tumor size.(5) The histopatho- logical findings of the lesion biopsies revealed the pres- ence of inflammatory infiltration or necrosis; therefore, PP is possibly associated with the infiltration of active T cells and other immune cells at the lesion.(15) Rosen- berg et al reported that PP was observed in 20 (6%) out of 310 patients with advanced UC who were treated with atezolizumab after progression of platinum-based chemotherapy.(16) Sharma et al reported that PP was ob- served in 24 (9%) out of 265 patients with advanced UC who were treated with nivolumab after progression of platinum-based chemotherapy.(17) In our study, we ob- served PP in three (3%) patients. HP was defined as a rapid increase in tumor growth rate.(18) There were few reports of HP of UC. Hwang et al reported that HP in pa- tients with UC treated with PD-1/PD-L1 inhibitors was observed in 12 (11.9%) out of 101 patients.(19) Higher CRP, neutrophil count, and volume of target lesions were reported to be associated with increased risks of HP.(20) In our study, 9 patients progressed rapidly after pembrolizumab treatment, and these patients were de- fined as HP. All patients had multiple lesions with poor ECOG PS. Eight patients were PS 2-4, and the other, who was PS 1, had liver, brain, peritoneal, and lymph node metastases without removal of the primary lesion. The median OS of these 9 patients was 29 days (range 11–43 days). All patients died before the first scheduled imaging evaluation; therefore, there were no imaging data to evaluate the actual progressions of the cancer, and it was difficult to distinguish these cases as HP or natural course. In our study, 51 (53%) patients experienced AEs, in- cluding 18 (19%) patients with severe AEs (grade 3 or more), and 5 (5%) with death (grade 5). The frequency of AEs in our study was higher than that in the KEY- NOTE-045 trial.(3) The median age in our study was higher than the median age of patients in the KEY- NOTE-045 trial (73 vs 67 years, respectively),3 which might affect the proportion of AEs.(21) Interstitial pneu- monia was observed in 10 patients (10%) in all grade and 8 patients (8%) in grade 3–5. In our study, 5 pa- tients died after pembrolizumab treatment. One of the deaths was due to Pneumocystis jirovecii pneumonia. Cases with Pneumocystis jirovecii pneumonia caused by immunosuppression for immune checkpoint-related toxicity have been reported.(22) Therapy-related myelod- ysplastic syndrome or AML with chemotherapy for sol- id cancer is well known;(23) however, a report of AML after an immune checkpoint inhibitor was not found. The two cases of AML after pembrolizumab treatment each received 26 and 27 courses of platinum-based chemotherapy before pembrolizumab commencement and suffered chronic bone marrow suppression at the commencement of pembrolizumab; therefore, it was unclear whether the onsets of AML were the natural course after long-term chemotherapy or irAE. The limitations of our study are its retrospective design, small cohort, and short follow-up period. Our study revealed the features of pembrolizumab treatment for advanced UC current clinical practice in Japan. We could discuss the difference between clinical trial and real clinical practice; therefore, we also investigated the cohort whose background was incompatible with a clin- Pembrolizumab for UC with small lesions-Kadono et al. Urological Oncology 206 Vol 19 No 3 May-June 2022 207 ical trial, such as patients with poor PS and low volume or unmeasurable cancer status as evaluated by RECIST. CONCLUSIONS In conclusion, we demonstrated that good PS 0–1 and no measurable lesions, especially small lesions, by RE- CIST were favorable prognostic factors in patients with advanced UC treated by pembrolizumab. A favorable response to immunotherapeutic agents was observed when the lesions were small. HP was observed mostly in poor PS patients with high volume lesions. Atypi- cal AEs, such as, Pneumocystis pneumonia and AML, were observed in our cohort. This was a small size pilot study; therefore, a larger study population and long- term follow-up data are needed to clarify our outcomes. ACKNOWLEDGEMENTS The authors would like to thank the following indi- viduals and institutions that participated in this study for their invaluable help with data collection: Hiroaki Iwamoto, Hiroshi Yaegashi, and Masashi Iijima of the Department of Integrative Cancer Therapy and Urology in Kanazawa University Graduate School of Medical Science Kanazawa, Kanazawa, Japan; Yuuta Takeza- wa and Kazuaki Machioka of the Department of Urol- ogy, Toyama Prefectural Central Hospital, Toyama, Japan; Jirou Sakamoto of the Department of Urology, Kouseiren Takaoka Hospital, Takaoka, Toyama, Japan; Kazuhiko Shibata of the Department of Medical Oncol- ogy, Kouseiren Takaoka Hospital, Takaoka, Toyama, Japan; Satoko Urata, Mitsuo Ofude, and Takao Na- kashima of the Department of Urology, Ishikawa Pre- fectural Central Hospital, Kanazawa, Ishikawa, Japan; Hiderou Minami and Osamu Ueki of the Department of Urology, Noto General Hospital, Nanao, Ishikawa, Japan; Masaharu Nakai and Kazunori Kobashi of the Department of Urology, Kaga Medical Center, Kaga, Ishikawa, Japan; Masato Yagisawa, Masashi Takeda, and Hidekazu Yamamoto of the Department of Urolo- gy, Fukui-ken Saiseikai Hospital, Fukui, Japan; Atsuya Takimoto, Ryou Satou, Sotaro Miwa, and Kiyoshi Ko- shida of the National Hospital Organization Kanazawa Medical Center, Kanazawa, Japan. CONFLICT OF INTEREST The authors have stated that they have no conflicts of interest. REFERENCES 1. Tamura D, Jinnouchi N, Abe M, et al. Prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: Experience in real- world clinical practice. Int J Clin Oncol. 2020; 25: 899-905. 2. 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; 18: 3068-3077. 3. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. Pembrolizumab for UC with small lesions-Kadono et al. 2017; 376: 1015-1026. 4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 2009; 45: 228-247. 5. Chiou VL and Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol. 2015; 33(31): 3541-3543. 6. Kim JY, Lee KH, Kang J, et al. Hyperprogressive disease during anti-pd-1 (pdcd1) / pd-l1 (cd274) therapy: A systematic review and meta-analysis. Cancers (Basel). 2019; 11(11), doi: 10.3390/cancers11111699. 7. Institute NC. Common terminology criteria for adverse events (ctcae) version 4.0. Available via dialog. 2010. 8. Yasuoka S, Yuasa T, Nishimura N, et al. Initial experience of pembrolizumab therapy in japanese patients with metastatic urothelial cancer. Anticancer Res. 2019; 39: 3887-3892. 9. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional- cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999; 17: 3173-3181. 10. Stadler WM, Hayden A, von der Maase H, et al. Long-term survival in phase ii trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol. 2002; 7: 153-157. 11. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005; 23: 4602-4608. 12. Lin CC, Hsu CH, Huang CY, et al. Prognostic factors for metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens. Urology. 2007; 69(3): 479-484. 13. Bellmunt J, Choueiri TK, Fougeray R, et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol. 2010; 28: 1850-1855. 14. Umemoto K, Togashi Y, Arai Y, et al. The potential application of pd-1 blockade therapy for early-stage biliary tract cancer. Int Immunol. 2020; 32: 273-281. 15. Di Giacomo AM, Danielli R, Guidoboni M, et al. Therapeutic efficacy of ipilimumab, an anti-ctla-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: Clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 2009; 58: 1297-1306. 16. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet. 2016; 387: 1909-1920. 17. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (checkmate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017; 18: 312-322. 18. Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti- pd-1/pd-l1. Clin Cancer Res. 2017; 23: 1920- 1928. 19. Hwang I, Park I, Yoon SK and Lee JL: Hyperprogressive disease in patients with urothelial carcinoma or renal cell carcinoma treated with pd-1/pd-l1 inhibitors. Clin Genitourin Cancer. 2020; 18:e122-e133. 20. Sasaki A, Nakamura Y, Mishima S, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-pd1 treatment in patients with advanced gastric cancer. Gastric Cancer. 2019; 22: 793-802. 21. Baldini C, Martin Romano P, Voisin AL, et al. Impact of aging on immune-related adverse events generated by anti-programmed death (ligand)pd-(l)1 therapies. Eur J Cancer. 2020; 129: 71-79. 22. Schwarz M, Kocher F, Niedersuess-Beke D, et al. Immunosuppression for immune checkpoint-related toxicity can cause pneumocystis jirovecii pneumonia (pjp) in non-small-cell lung cancer (nsclc): A report of 2 cases. Clin Lung Cancer. 2019; 20: e247-e250. 23. Morton LM, Dores GM, Schonfeld SJ, et al. Association of chemotherapy for solid tumors with development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era. JAMA Oncol. 2019; 5: 318-325. Pembrolizumab for UC with small lesions-Kadono et al. Urological Oncology 208