Abstract
Background/Aim: This study aimed to assess the efficacy and toxicity of second-line chemotherapy, especially combination chemotherapy, for advanced or metastatic urothelial cancer. Patients and Methods: This retrospective analysis included patients who received second-line chemotherapy after disease progression during first-line chemotherapy between January 2009 to May 2018. Progression-free survival (PFS), overall survival (OS) and toxicity associated with second-line chemotherapy were assessed. Results: In total 25 patients received second-line chemotherapy; 21 patients had combination chemotherapy and 4 had single-agent chemotherapy. Median PFS and OS were 3.6 months (range=0.2-23.5) and 11.9 months (range=0.5-29.0), respectively. Twenty patients (80%) exhibited grade 3 or more severe toxicities. Conclusion: PFS and OS benefits of second-line combination chemotherapy corresponded to those of the phase 3 study of pembrolizumab, but adverse events were more severe. Pembrolizumab is potentially a better second-line treatment than combination chemotherapy.
Bladder cancer is the ninth most common cancer in Japan (1). Radical cystectomy is the standard treatment for nonmetastatic muscle-infiltrating bladder cancer (2), whereas cisplatin-based systemic chemotherapy is the established treatment for metastatic or locally advanced urothelial cancer (UC) (3). The median survival of advanced or metastatic UC patients treated with methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) was found to be approximately 12 months, and the 6-year progression-free survival (PFS) rate was 3.7% (4). Grade 3 or higher adverse events occurred in 72-82% of patients (3), following insufficient therapeutic effects. Gemcitabine/cisplatin (GC) was developed as an alternative first-line treatment owing to its similar clinical efficacy and less severe adverse events (AEs) compared to the established standard treatment MVAC (5). Responsiveness to this cisplatin-based systemic chemotherapy was approximately 65% (6), but most cases became unmanageable with these chemotherapies; hence, the development of an effective second-line therapy has been intended for a long time. Although there is no established standard second-line chemotherapy for advanced or metastatic UC patients when cisplatin-based first-line chemotherapy fails, several second-line chemotherapies with limited evidence including both combination and single-agent regimens have been developed and used in real clinical situations (7-9). Recently, the programmed death-1 (PD-1) inhibitor pembrolizumab (approved in Japan) and the monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2) ramucirumab (not approved in Japan) have been proven to be second-line treatments for UC through randomized controlled trials (RCT) (10, 11). Since cisplatin-based systemic chemotherapy with advanced or metastatic UC has not been adequately evaluated in Japanese patients, this study retrospectively assessed and compared the efficacy and toxicity of conventional second-line chemotherapies to that of pembrolizumab in real clinical situations.
Patients and Methods
In this study, 25 patients with histologically confirmed metastatic or advanced UC who received second-line chemotherapy between January 2009 and May 2018 after disease progression during first-line chemotherapy were included. The patients had undergone surgical treatment, biopsy of the primary lesions was performed and clinical stage was determined by enhanced computed tomography. Adjuvant and neoadjuvant chemotherapies were not counted as first-line chemotherapy. Overall survival (OS) and PFS were analyzed using the clinical records. OS and PFS were calculated as the time from the first day of second-line chemotherapy administration to death or the last follow-up and appearance of local or distant metastasis, respectively. The histological type was determined in accordance with the 2004 World Health Organization definition. Clinicopathological variables included patient age, gender, primary tumor lesion, tumor (T) stage, lymph node status, metastatic site, and cancer stage. Survival curves were measured using the Kaplan–Meier method, and data were statistically analyzed using Prism7 (GraphPad, San Diego, CA, USA). This study was approved by the institutional review board of Kanazawa University Hospital.
Results
Patient characteristics. A total of 25 metastatic or advanced UC patients received second-line intravenous chemotherapy. Table I summarizes the patient demographics and baseline characteristics. At the start of the second-line chemotherapy, the median age was 70 years (range=56-84 years). Ten patients (40%) had primary tumor lesions in the renal pelvis, 9 (36%) in the bladder, and 6 (24%) in the ureter. Pathological diagnosis showed that 24 patients had pure UC and only 1 had UC with squamous differentiation. Regarding the metastatic site, 17 patients (68%) had lymph node metastasis, 10 (40%) had lung metastasis, 3 (12%) had bone metastasis, 2 (8%) had liver metastasis, 2 (8%) had brain metastasis, 2 (8%) had peritoneal dissemination, 1 (4%) had adrenal gland metastasis, 1 (4%) had penile metastasis, and 1 (4%) had local recurrence (with overlapping cases noted). As for the first-line chemotherapy, 9 patients (36%) received gemcitabine and carboplatin (GCarbo), 7 (28%) received GC, 5 (20%) received MVAC, 3 (12%) received dose- and schedule-modified GC, and 1 (4%) received other therapies (a clinical trial regimen). Of the 25 patients included in this study, 2 (8%) were in T1, 8 (32%) in T2, 9 (36%) in T3, and 6 (24%) in T4. Regarding second-line chemotherapy, 21 patients (84%) received combination therapy and 4 patients (16%) received single-agent chemotherapy. Of 21 combination therapy-received patients, 8 patients (32%) received paclitaxel plus carboplatin (TC) as the most frequent treatment. Six patients (24%) were given a third-line treatment and 1 (4%) received a fourth-line treatment.
Outcomes. Figure 1 shows the PFS and OS of the patients. Median PFS and OS were 3.6 and 11.9 months, respectively (range=0.2-23.5 and 0.5-29.0 months). Regarding the combination chemotherapy, median PFS and OS were 3.7 and 11.4 months, respectively (range=0.2-23.5 and 1.7-29.0 months). The objective response rate of combination chemotherapy was 33%, and Table II shows that 7 patients obtained a partial response (PR). Moreover, Table III presents the AEs noted, with myelosuppression as the most common. Grade 3 or higher neutropenia was observed in 16 patients (76%) and febrile neutropenia in 4 patients (19%) and no severe infection was noted among the patients. Grade 3 or higher AEs such as vomiting, hyperkalemia and gastroenteritis were reported in 1 patient (5%) each and anorexia in 2 patients (10%). There were no treatment-related deaths, and only 3 patients had grade 3 or higher AEs.
Discussion
Several protocols have been reported as the second-line chemotherapy when cisplatin-based chemotherapy for advanced or metastatic UC fails (12-19); however, a standard second-line chemotherapy has not yet been established. Most treatments have been proposed in phase 2 trials, and none has been proven effective during phase 3 RCTs. In a phase 3 RCT, patients treated with vinflunine showed a better OS compared with the control arm in the eligible population, indicating that vinflunine may be a favorable second-line chemotherapy agent when cisplatin-based chemotherapy fails; however, it was not noted in the intent-to-treat population (20, 21). Recently, immune checkpoint inhibitors such as PD-1 or PD-L1 antibodies have been reported to be effective in several cancers (22-24). In bladder cancer, anti-PD-L1 antibody has been shown to have a favorable outcome in patients with metastatic bladder cancer and in those who had rare serious AEs with a 25% overall response rate (25). Pembrolizumab has been considered as a second-line standard treatment based on the results of the phase 3 RCT, Keynote-045 (10). Ramucirumab, a vascular endothelial growth factor receptor-2 antagonist, has been also recently established as a second-line standard treatment based on the results of the phase III RCT, RANGE (11). These trials compared single-agent chemotherapies, but no comparison with combination chemotherapies that are thought as more effective treatments than single-agent chemotherapies was performed.
In this study, the OS of patients who received second-line chemotherapy was 11.9 months, comparable to the OS of pembrolizumab in the Keynote-045 trial and similar to previous phase 2 and phase 3 RCT results (7-9). The response rate of the control arm in the Keynote-045 trial, which had a single-agent chemotherapy, was only 11.4% (CR 3.3% + PR 8.1%) (10), suggesting that the therapeutic effect of second-line combination chemotherapy determined in this study might be superior to that of single-agent chemotherapy. TC, as a second-line treatment, has been initially reported to have a high response rate of 30-70% (26), which was consistent with our data. Although several patients had grade 3 or higher AEs, there were no treatment-related deaths associated with second-line chemotherapy. The most common AE was grade 3 or higher neutropenia, and AEs were well controlled with supportive care including granulocyte-colony stimulating factor. In the Keynote-045 trial, the prevalence of grade 3 or higher AEs in the pembrolizumab group were only 15% (10). The incidence of AEs determined in this study was relatively high compared to that in previous reports of AEs of grade 3 or higher in second-line combination chemotherapy (27). Since this study used real-world data, the background of patients may be unfavorable compared to prospective trials. Hence, second-line combination chemotherapy may be manageable but more severe in the real-world cohort than pembrolizumab in advanced or metastatic UC patients.
Outcomes of combination chemotherapy were comparable with those of pembrolizumab in the Keynote-045 trial, and patients treated with combination chemotherapy finally progressed. Some patients treated with pembrolizumab showed durable response, suggesting that pembrolizumab induced less AEs and better responses than combination chemotherapy. However, a comparative study between anti-PD-L1 antibody and combination chemotherapy as second-line treatments is needed to determine the superiority.
The limitations of this study were its retrospective nature and the small sample size. Moreover, patients had received various regimens as a first-line chemotherapy prior to combination second-line chemotherapy; thus, it is unclear whether the specific first-line therapy affected the results or not.
Conclusion
The second-line combination chemotherapy showed similar treatment outcomes with pembrolizumab but revealed a higher incidence of AEs. Thus, this study suggests that pembrolizumab may be a better second-line treatment than combination chemotherapy in a Japanese cohort.
Footnotes
Authors' Contributions
R.N. and K.I. made substantial contributions to the conception and design of the study. R.N. collected the data. R.N. and K.I. drafted the manuscript and performed the statistical analysis. K.I., S.K., T.M., H.I., H.Y. and A.M. were involved in revising the manuscript critically for important intellectual content. K.S. and Y.K. participated in the acquisition and interpretation of the data. All Authors read and approved the final manuscript.
Conflicts of Interest
All Authors declare that there are no potential conflicts of interest relevant to this article.
- Received December 30, 2019.
- Revision received January 9, 2020.
- Accepted January 13, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved