Gemcitabine maintenance versus observation after first-line chemotherapy in patients with metastatic urothelial carcinoma: a retrospective study.

BACKGROUND: Gemcitabine with platinum is one of the most important first-line treatments for metastatic urothelial cancer (mUC). However, continuation of platinum agents results in cumulative toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity, which lead to discontinuation of chemotherapy after 4-6 cycles despite a favorable response in the patients. The strategy of maintenance treatment can give clinical benefit to patients, but there is no consensus about maintenance treatment. The aim of this study was to investigate the clinical impact of the gemcitabine maintenance (GEM-m) in mUC patients who achieve disease control from first-line gemcitabine with platinum agents.
METHODS: A total of 117 patients who showed response to 4-6 cycles of gemcitabine plus cisplatin or carboplatin as the first-line palliative chemotherapy were reviewed between 2014 to 2018. Patients who were treated with GEM-m received a 1,000 mg/m2 dose of gemcitabine on day 1 and 8 for 3 weeks until disease progression or development of unacceptable toxicity. The patients who are not treated with GEM-m were followed up with regular radiologic evaluation. Statistical analyses were performed using the log-rank test and Cox proportional hazards method.
RESULTS: Fifty-eight patients (49.6%) received GEM-m. The median cycle of GEM-m was 4 (range, 1-12). Six patients (10.3%) in the GEM-m group showed an objective response. A median overall survival (OS) of 11.8 months and 9.6 months was observed for the GEM-m and non-GEM-m groups, respectively [HR 0.621; 95% CI, 0.39-0.97; P=0.026]. Additionally, median progression-free survival (PFS) was 4.6 months and 3.3 months in the GEM-m and non-GEM-m groups, respectively [HR 0.612; 95% CI, 0.41-0.91; P=0.009]. Grade 3 or higher neutropenia occurred in 17.2% of patients in the GEM-m and 1.7% in the non-GEM-m group.
CONCLUSIONS: Our results suggest that GEM-m can be considered in patients who respond to gemcitabine with platinum. Large-scale prospective study should be warranted. 2020 Translational Andrology and Urology. All rights reserved.

Introduction

Bladder cancer is the 9th most common cancer worldwide and the 7th most common among men (1). About 430,000 new cases were reported with 165,000 deaths in the year 2012 (2). Urothelial carcinoma is the most common histologic subtype and accounts for 90–95% cases of bladder cancer (3). Main treatment for patients with inoperable locally advanced or metastatic urothelial cancer (mUC) comprises of systemic chemotherapy, and gemcitabine plus cisplatin (GP) is the most widely used in first-line setting in these patients (4). Compared to MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), which was previous standard 1st line chemotherapy for mUC, GP showed similar survival, better safety profile, and tolerability (5-7). In patients who are unfit for cisplatin, gemcitabine with carboplatin is most widely used, which provides about 40% response rate with comparable survival outcomes (8,9). Long-term treatment with platinum results in decreased performance status and several toxicities, such as nephrotoxicity, peripheral neuropathy, and irreversible hearing loss, and hence results in its discontinuation (10,11). Moreover, the incidence of these side effects increase with the number and cumulative dose of chemotherapy cycles. Thus, treatment for mUC mostly consists of 4–6 cycles of platinum-based chemotherapy, and most patients experience disease-progression after discontinuing chemotherapy (12). Recently, the immune checkpoint inhibitors (ICIs), such as atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab, have showed clinical benefit in second or above settings (13). Despite the availability of these promising agents, platinum-based chemotherapy is still a mainstay of first-line treatment in mUC. Therefore, there is an unmet need to maximize the therapeutic effect of first-line chemotherapy. Previous studies suggested utility of maintenance approach after first-line treatment in patients who respond to first line treatment (14,15). However, due to the small number of patients (17 subjects) or regimen consisting of 5-FU based chemotherapy (14,15), further studies are needed for patients treated with Gemcitabine with platinum.

Gemcitabine, a difluorinated deoxycytidine analogue, enters the cancer cells and transforms into an active triphosphate metabolite (16). This active form interferes with DNA synthesis and DNA repair processes, and thus imparting its antitumor effects (16). Gemcitabine monotherapy provides a 25% overall response rate and presents with tolerable toxicity (12,17), such as the commonly occurring myelosuppression, in patients with mUC (16,18). These previous studies on gemcitabine monotherapy raise the expectation of gemcitabine maintenance (GEM-m) for mUC to avoid the cumulative toxicity caused by platinum and to maintain the therapeutic effect.

Based on these considerations, we investigated the clinical implication of GEM-m in patients who achieve disease control after first-line gemcitabine with platinum chemotherapy, retrospectively. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tau-20-772).

Methods

Study population

All the patients who were included in this study had locally advanced and unresectable or metastatic urothelial carcinoma. Additionally, this study included patients who were treated with gemcitabine plus platinum (cisplatin or carboplatin) as 1st line chemotherapy and 0–2 of ECOG performance status. The medical records of 117 patients, who presented with radiological response [complete response (CR), partial response (PR), and stable disease (SD) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] following 4–6 cycles of first-line gemcitabine with, were reviewed ().

Figure 1

Study design.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and the Harmonized Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonization. This retrospective study was approved by the Institutional Review Board of the Seoul St. Mary’s Hospital of the Catholic University of Korea (KC20RISI0160). Further, informed consent was not required as we only reviewed their routine medical records.

Treatment and response evaluation

Patients were treated with 4–6 cycles of gemcitabine plus cisplatin or carboplatin as a first-line palliative chemotherapy between the years 2012 and 2018. This included intravenous administration of 1,000 mg/m2 gemcitabine on days 1 and 8, while 70 mg/m2 cisplatin or 5/AUC carboplatin on day 1, every 3 weeks. Among the responders (CR, PR and SD) to gemcitabine with platinum, GEM-m or observation without GEM-m (non-GEM-m) were performed to these patients. GEM-m or non-GEM-m was determined in consideration of the clinical factors of patients and clinician’s decision (intolerability to chemotherapy, patient’s denial of GEM-m, and so on) The GEM-m group received 1,000 mg/m2 gemcitabine, on days 1 and 8 every 3 weeks, until disease progression or unacceptable toxicity. Non-GEM-m was continued until disease progression. Baseline imaging with computed tomography (CT) imaging of the chest, abdomen, and pelvis was acquired within 4 weeks after completion of the first-line chemotherapy. Both GEM-m and non-GEM-m group received regular radiographic evaluation with CT scan every 6±2 weeks. Radiological changes were evaluated using the RECIST version 1.1. Hematologic toxicities were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0.

Statistical analysis

Overall survival (OS) and progression-free survival (PFS) were defined as the time from baseline imaging date till death from any cause and disease progression or death, respectively. The baseline characteristics were compared using chi-squared or Fisher’s exact test for category. Survival curves were obtained using the Kaplan-Meier method, and compared using the log-rank test. The Cox proportional hazards method was used to perform multivariate analysis to evaluate the significance of the prognostic variables for PFS and OS. All statistical analyses were performed using SPSS software (version 24; IBM Corp., Armonk, NY, USA), and a two-sided P value <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 117 patients were included in this study; 58 patients (49.6%) received GEM-m. Distribution of clinical factors including response to first-line chemotherapy were not different between GEM-m and non-GEM-m. The baseline characteristics of both the patient groups have been summarized in . The risk factors included Hemoglobin <10 g/dL, ECOG performance status score of 1 or above and presence of liver metastases (19).

Table 1

Baseline characteristics

Characteristics	BSC (N=59)	Gemcitabine (N=58)	P
Age	67.5±10.1	67.5±9.6	0.996
<65	23 (39.0%)	21 (36.2%)	0.905
≥65	36 (61.0%)	37 (63.8%)
Sex			0.357
F	13 (22.0%)	8 (13.8%)
M	46 (78.0%)	50 (86.2%)
ECOG			0.875
0	22 (37.3%)	24 (41.4%)
1	24 (40.7%)	23 (39.7%)
2	13 (22.0%)	11 (19.0%)
Primary site			0.874
Renal pelvis	9 (15.3%)	8 (13.8%)
Ureter	13 (22.0%)	11 (19.0%)
Bladder	37 (62.7%)	39 (67.2%)
Disease status			0.762
Locoregional	6 (10.2%)	4 (6.9%)
Metastatic	53 (89.8%)	54 (93.1%)
Number of risk factors			0.877
0	17 (28.8%)	19 (32.8%)
1	23 (39.0%)	19 (32.8%)
2	17 (28.8%)	17 (29.3%)
3	2 (3.4%)	3 (5.2%)
Number of metastatic organs			0.311
<2	24 (40.7%)	30 (51.7%)
≥2	35 (59.3%)	28 (48.3%)
Previous chemotherapy			0.148
Gemcitabine/cisplatin	27 (45.8%)	18 (31.0%)
Gemcitabine/carboplatin	32 (54.2%)	40 (69.0%)
Chemotherapy response to previous chemotherapy			0.834
CR	9 (15.3%)	7 (12.1%)
PR	32 (54.2%)	31 (53.4%)
SD	18 (30.5%)	20 (34.5%)

Risk factors: hemoglobin <10 g/dL, ECOG performance status score of 1 or above, presence of liver metastases. BSC, best supportive care; CR, complete response; ECOG, eastern cooperative oncology group; PR, partial response; SD, stable disease.

Response rate and Survival outcome in mUC patients treated with GEM-m

GEM-m was administered with a median of 4 cycles (range, 1–12 cycles) until disease progression or unacceptable toxicity. Disease progression was the most common cause for GEM-m discontinuation (55%). An objective response was observed in 6 patients (10.3%), while two patients showed CR (). Median OS were 11.8 and 9.6 months in patients treated with GEM-m and non-GEM-m, respectively [hazard ratio (HR), 0.621; 95% confidence interval (CI), 0.39–0.97; P=0.026]. Moreover, the median PFS were 4.6 vs. 3.3 months in the GEM-m and non-GEM-m, respectively (HR 0.612; 95% CI, 0.41–0.91; P=0.009) (). The Multivariate analysis using Cox regression suggested significant association of GEM-m and the 2 or higher risk factors with OS and PFS (). Further, after disease progression, second-line treatment was administered to 35 (60.3%) and 15 patients (25.4%) in the GEM-m and non-GEM-m, respectively.

Table 2

Treatment response

Variables	CR	PR	SD	PD	Total
BSC	0 (0.0%)	0 (0.0%)	39 (66.1%)	20 (33.9%)	59 (100%)
Gemcitabine	2 (3.4%)	4 (6.9%)	35 (60.3%)	17 (29.3%)	58 (100%)
Total	2 (1.7%)	4 (3.4%)	74 (63.2%)	37 (31.7%)	117 (100%)

BSC, best supportive care; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease.

Figure 2

Survival curves by using the Kaplan-Meier method. BSC, best supportive care; Gem, gemcitabine maintenance; OS, overall survival; PFS, progression free survival.

Figure 3

Multivariate analysis with cox regression for survival. Risk factor: Hemoglobin <10 g/dL, ECOG performance status score of 1 or above, presence of liver metastasis. OS, overall survival; PFS, progression free survival. ** means that there are statistically significant.

Safety associated with hematologic toxicities

Neutropenia was the most common hematologic toxicity, and 10 (17.2%), 8 (13.8%), 9 (15.5%), and 1 (1.7%) patient in the GEM-m presented with grade 1, 2, 3, and 4 neutropenia, respectively. Febrile neutropenia was observed in 2 patients during GEM-m, while the other hematologic toxicities were similar in the GEM-m and non-GEM-m. Although the risk of neutropenia was significantly higher in GEM-m, GEM-m was tolerable as a maintenance treatment after first-line gemcitabine with platinum chemotherapy ().

Table 3

Hematologic toxicities

Toxicity (grade)	BSC (N=59)	Gemcitabine (N=58)	P
Neutropenia			0.013
0	45 (76.3%)	30 (51.7%)
1	10 (16.9%)	10 (17.2%)
2	3 (5.1%)	8 (13.8%)
3	1 (1.7%)	9 (15.5%)
4	0 (0.0%)	1 (1.7%)
Anemia			0.167
0	47 (79.7%)	39 (67.2%)
1	10 (16.9%)	11 (19.0%)
2	2 (3.4%)	5 (8.6%)
3	0 (0.0%)	3 (5.2%)
Thrombocytopenia			0.325
0	55 (93.2%)	48 (82.8%)
1	3 (5.1%)	6 (10.3%)
2	1 (1.7%)	3 (5.2%)
3	0 (0.0%)	1 (1.7%)
Febrile neutropenia			0.988
No	58 (98.3%)	56 (96.6%)
Yes	1 (1.7%)	2 (3.4%)

Discussion

There is a strong correlation between PFS and OS in solid cancers, although it may not be always consistent (20,21). Therefore, efforts are being taken to prolong the duration of treatment response in the first-line chemotherapy responders. This is especially important for the mUC patients that show short PFS of 6–7 months upon GP chemotherapy (5,7,12), and maintenance treatment could be one of such efforts. The rationale behind the treatment is to increase exposure to effective therapies, decrease resistance to chemotherapy, and maximize the antitumor efficacy (21). We ultimately expect that chemotherapy maintenance can preserve the chances of subsequent therapy opportunities arising from prevention of abrupt deterioration, as well as enable long-term disease control.

This study showed improvement in survival of patients, although with modest benefit. The modest 1.3 and 2.2 months’ improvement in PFS and OS, respectively, is rather difficult to interpret considering the quality of life (QOL) and cost effective. The chemotherapy-free interval following first-line regimen is the time taken to recover from toxicities of platinum agents and is usually a period of disease-related symptom control. Maintenance chemotherapy during this period would lead to about 30% of patients to continue and worsen general weakness and fatigue, and experience a decline in QOL (22). Whereas, it may also be possible to maintain or improve QOL while the disease is under control. This notion is supported by a pancreatic cancer study, which showed an improvement in QOL during the duration of the chemotherapy, and no worsening of QOL until one month before treatment failure (23,24). Further, continued disease control could slow the rate of deterioration of QOL (23,24). Thus, it is difficult to determine the balance between maintenance and rest of the chemotherapeutic regimen. Several preference studies have been published in this regard for NSCLC chemotherapy (25-27). First, the median OS benefit threshold, where the patients received chemotherapy despite the risks including a drop in QOL and side effects, was 4.5 months, and 70% of the patients chose best supportive care when they showed a three month survival benefit (21,27). The PFS benefits were worth treating if the patients had mild adverse events, though, many of the patients did not opt for intense chemotherapy (21,25). However, in a different survey, 43% of the patients assumed that they would receive chemotherapy with only one month survival benefit (26), which suggests that despite the smaller effects, certain patients willingly opt for the chemotherapy maintenance. In terms of cost of the treatment per patient, the treatment with gemcitabine does not require hydration, and can be administered in an outpatient clinic, which helps maintain QOL and also benefits in terms of cost savings.

The treatment with gemcitabine is actively followed for mUC (12), and similar outcomes and mild toxicity have been obtained in patients above and below 65 years of age (16,28). This observation suggests that gemcitabine may help in treating relatively elderly patients with mUC. The decreased renal function, together with mUC at origin of urinary tract, nephrectomy or old age, influence the consideration of repetitive chemotherapy. Moreover, gemcitabine is primarily metabolized in the liver, instead of kidney, and is therefore suitable for long-term dosing (18). Indeed, as reported by Kuş et al., treatment of patients with GEM-m after 6 cycles of gemcitabine with platinum (N=23) conferred a survival benefit, and showed grade 3 hematotoxicity in 30.4% cases (28). Further, gemcitabine monotherapy has shown favorable results in terms of benefits and side effects in other similar studies (17,18). Akaza et al. reported that second-line gemcitabine treatment in patients progressing after MVAC showed median PFS of 3.1 months, grade 3/4 bone marrow suppression in 47.7% cases, and grade 3/4 non-hematologic toxicities in 9.1% cases (17). Another study has compared the outcomes upon treatment with GEM-m following platinum based chemotherapy versus best supportive care (33 patients each), which suggested differences in time to progression (12 vs. 2 months) in both these groups, together with grad 3/4 hematologic and non-hematologic toxicities upon GEM-m as 27.3% and 3%, respectively (18). Moreover, our study showed a similar survival benefit and grade 3/4 hematologic toxicity in 27.5% cases. Taken together, these results suggest that treatment with GEM-m is beneficial with manageable toxicities in patients with mUC (17,18,28).

However, our study has few limitations. First, owing to the retrospective nature of the study, selection bias and issues with accuracy of data collected are inevitable. Second, although hematologic toxicities were assessed, we did not include data related to QOL, such as pain, fatigue, and other subjective factors, which affects the evaluation of comprehensive palliative effects (24). Moreover, survival benefits need to be interpreted with care due to smaller number of patients reviewed, which warrants identification of subgroups that could benefit from GEM given the low survival benefit obtained in our study. Furthermore, there are no prospective studies yet that have analyzed the effect of GEM-m on mUC. Additionally, similar to bladder cancer, other cancer types have not been studied with regard to the effectiveness of maintenance therapy, making them ineligible as a reference (21,29). Therefore, well-designed prospective studies enrolling large number of patients, with QOL and subgroup analysis, would be needed to support the results of this study.

Taken together, it is important to stratify appropriate patients because GEM may not benefit or apply to all patients treated with 6 cycles of gemcitabine with platinum. Additionally, factors expected to benefit from maintenance treatment include performance status, response to first-line therapy, and compliance to subsequent treatment related to disease-burden and socioeconomic status (21). We suggest that GEM-M can be considered for selected patients who achieve disease control from 1st line gemcitabine with platinum.

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