The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: Combined meta-analysis of efficacy and safety profile

Clinics and Research in Hepatology and Gastroenterology (2015) 39, 254—260

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ScienceDirect www.sciencedirect.com

ORIGINAL ARTICLE

The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: Combined meta-analysis of efficacy and safety profile Yang Liu , Qing-ke Huang , Wan-dong Hong , Jin-ming Wu , Xue-cheng Sun ∗ Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China Available online 7 October 2014

Summary Purpose: To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC). Methods: Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities. Results: Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR = 0.83, 95%CI = 0.72—0.96, P = 0.01), PFS (HR = 0.64, 95%CI = 0.56—0.74, P < 0.0001), and overall response rate (ORR; RR = 2.36, 95%CI = 1.73—3.22, P < 0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non-hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment. Conclusions: This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia. © 2014 Elsevier Masson SAS. All rights reserved.

∗

Abbreviations: CI, Confidence interval; RR, Relative risk; HR, Hazard ratio. Corresponding author. Tel.: +86 577 55579185; fax: +86 577 55579185. E-mail address: [email protected] (X.-c. Sun).

http://dx.doi.org/10.1016/j.clinre.2014.08.012 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.

Addition of S-1 to GEM-based chemotherapy for APC

255

Introduction

Study selection

Pancreatic cancer (PC) still remained a rather incurable disease for its aggressive tumor biology and late presentation with inoperable disease. Palliative chemotherapy was the only treatment option for most PC patients diagnosed at an advanced stage. At present, gemcitabine (GemzarTM ; GEM) was recommended as a first-line systemic chemotherapeutic agent for advanced pancreatic cancer (APC). However, it did not improve the dismal prognosis much. The median overall survival (OS) was reported of less than 6 months while 1-year OS rate of less than 20% [1]. To improve the effectiveness of GEM chemotherapy, many efforts had been made. 5-FU or platinum in combination with GEM indicated mild benefits on survival and response rate compared with GEM alone, while no risk reduction was observed in the trials combining GEM with camptothecin [2,3]. The addition of nab-paclitaxel to GEM provided modest benefits with increased toxic effects [4]. Molecular targeted agents (MTAs) in combination with GEM were also investigated in phase III randomized controlled trials (RCTs; e.g., pemetrexed, marimastat, tipifarnib, bevacizumab, cetuximab, erlotinib, axitinib). However, most of these trials failed to demonstrated further benefits [5], although evidence showed that anti-EGFR therapy may improve OS [6]. The fourth generation of fluoropyrimidine derivative, S1, had been applied in clinical practice for APC patients since 2006. It contained tegafur/gimeracil/oteracil potassium at a molar ratio of 1:0.4:1, to make prolonging of thymidylate synthetase inhibition, thus improving antitumor activity of fluoropyrimidine. With the advantage of convenient oral formulations, promising efficacy, and tolerable toxicity, S-1 offered an alternative to traditional intravenous 5-FU. It was shown to be effective in various types of solid tumors, particularly gastric cancer [7]. For S-1 and GEM combination, both of them were nucleoside analogs that inhibited different targets, showing a synergistic cytotoxic activity in vitro [8]. However, it remained to be determined whether this combination was better than GEM alone in first-line treatment for APC patients. In clinical trials comparing of the two treatments, some slightly favored GEM/S-1 on OS [9], while others reported equivalent results [10,11]. Meanwhile, no consensuses on toxicity profiles were reached. To evaluate whether GEM/S-1 was superior to GEM for APC patients with respect to survival, response and safety, we performed this meta-analysis.

Trials that met the following criteria were chosen for analysis:

Materials and methods Study identification PubMed, Cochrane Library, ISI Web of Knowledge and China Biology Medicine database were searched for randomized controlled trials (RCTs) related to the use of chemotherapy in APC, using the terms ‘‘chemotherapy’’, ‘‘S-1’’, ‘‘tegafur’’, ‘‘UFT’’, ‘‘gemcitabine’’ and ‘‘pancreatic cancer’’ (no limitation for language). The reference lists of pertinent articles were also inspected. The latest search was done on January 31st, 2014.

• only full-text RCTs were eligible for inclusion; • GEM plus S-1 and GEM single agent regimen were compared in first-line setting for APC patients; • if the same trial appeared on multiple publications, the data from the most recent or comprehensive one was included; • if a trial included concomitant interventions such as adjuvant surgery or radiotherapy treatment, the trial was excluded.

Data extraction and synthesis Trial selection was performed independently by two of the authors (Y. Liu and Q.K. Huang). The following information was extracted: first author, year of publication, country, study design, number of patients, intervention, and clinical outcome (OS, PFS, response rate and toxicity). An open assessment of the trials was performed according to Jadad scale [12]. The strength of the associations between treatments and outcomes were estimated by hazard ratio (HR) or risk ratio (RR) and 95% confidence interval (CI). New HRs for OS and PFS were calculated from Kaplan-Meier curves using the method reported by Tierney et al. [13]. P-value of >0.10 for the Q-test indicated a lack of heterogeneity across the studies, then HRs/RRs of each study were calculated by fixed effects model. Otherwise, random effects model was used. Meta-analyses were performed using Review Manager V. 5.2 (Nordic Cochran Centre, Copenhagen). Publication bias was evaluated by Begg’s and Egger’s tests, using STATA V. 11.0 (Stata Corporation, Texas).

Results Characteristics of studies Five trials were included in the final analysis, of which three were phase II trials and two were phase III trials (1 Chinese and 4 Japanese RCTs) [9—11,14,15]. A total of 917 patients received chemotherapy, of which 459 patients were with GEM alone and 458 patients were with GEM/S-1 combination. Table 1 described the main details of the selected studies.

OS, PFS and response The main results of the meta-analysis were shown in Table 2. Four trials provided data regarding OS. The pooled HR for OS was 0.83 (95%CI: 0.72—0.96; P = 0.01; Fig. 1). Four trials provided data regarding PFS. The pooled HR for PFS was 0.64 (95%CI: 0.56—0.74; P < 0.00001; Fig. 2). Significant differences in the two treatments were found in the proportion of patients who achieved partial response (PR; RR = 2.28, 95%CI: 1.66—3.13; P < 0.00001), progressive disease (PD; RR = 0.45, 95%CI: 0.35—0.60; P < 0.00001), overall response rate (ORR; RR = 2.36, 95%CI: 1.73—3.22; P < 0.00001) and

256 Table 1 Study Nakai et al. [10]

Y. Liu et al. Basic characteristics of trials included in the study. Year 2012

Country

Study design

Japan

Randomized phase II trial

n 53

53 Ozaka et al. [9]

2013

Japan

Randomized phase II trial

58

59 Ueno et al. [11]

2013

Japan

Randomized phase III trial

275

277 Liu et al. [14]

2013

China

Randomized phase II trial

21

20 Sudo et al. [15]

2014

Japan

Randomized phase III trial

51

50

Treatment regimen

OS (month)

PFS (month)

ORR (%)

Jadad

Gem 1000 mg/m2 d1, 15 + S-1 2 × 40/50/60 mg d1-14, q4w Gem 1000 mg/m2 d1, 8, 15, q4w Gem 1000 mg/m2 d1, 8 + S-1 2 × 40 mg/m2 d1-14, q3w Gem 1000 mg/m2 d1, 8, 15, q4w Gem 1000 mg/m2 d1, 8 + S-1 2 × 30/40/50 mg d1-14, q3w Gem 1000 mg/m2 d1, 8, 15, q4w Gem 1000 mg/m2 d1, 15 + S-1 2 × 40 mg/m2 d1-14, q4w Gem 1000 mg/m2 d1, 8, 15, q4w Gem 1000 mg/m2 d8, 15 + S-1 2 × 30 mg/m2 d1-15, q3w Gem 1000 mg/m2 d1, 8, 15, q4w

13.5

5.4

18.9

3

8.8

3.6

9.4

13.7

6.15

28.3

8.0

3.78

6.8

10.1

5.7

29.3

8.8

4.1

13.3

NA

NA

28.6

NA

NA

20.0

8.6

5.3

21.6

8.6

3.8

6

3

2

2

3

ORR: overall response rate; OS: overall survival; PFS: progression-free survival.

Table 2

Clinical efficacy of response between GEM/S-1 and GEM regimen.

Outcome

No. of study

RR (95%CI)

CR PR SD PD ORR (CR + PR) DCR (CR + PR + SD)

5 5 5 4 5 5

2.96 2.28 0.96 0.45 2.36 1.23

(0.71, (1.66, (0.82, (0.35, (1.73, (1.11,

12.24) 3.13) 1.11) 0.60) 3.22) 1.37)

P

Pheterogeneity

0.13 <0.00001 0.56 <0.00001 <0.00001 0.0002

0.98 0.50 0.27 0.72 0.69 0.61

CR: complete response; PR: partial response; PD: progressive disease; SD: stable disease; ORR: overall response rate; DCR: disease control rate.

Figure 1

Comparison of OS between GEM/S-1 and GEM.

Addition of S-1 to GEM-based chemotherapy for APC

Figure 2

Comparison of PFS between GEM/S-1 and GEM.

disease control rate (DCR; RR = 1.23, 95%CI: 1.11—1.37; P = 0.0002) according to the combined analysis. No significant differences in the two arms were found in the proportion of patients who achieved complete response (CR) or stable disease (SD).

Toxicity Grade 3/4 toxic effects according to National Cancer Institute Common Toxicity Criteria were summarized in Table 3. As expected, adverse events were more frequently appeared in the combination treatment group. With regard to hematological toxicity, severe neutropenia (RR = 1.60, 95%CI: 1.14—2.25, P = 0.007) and thrombocytopenia (RR = 1.73, 95%CI: 1.21—2.49, P = 0.003) were found in GEM/S-1 group. With regard to non-hematological toxicity, diarrhea (RR = 2.84, 95%CI: 1.13—7.13, P = 0.03), nausea/vomit (RR = 2.55, 95%CI: 1.38—4.71, P = 0.003), rush (RR = 6.17, 95%CI: 2.01—18.94, P = 0.001) and stomatitis/mucositis (RR = 7.02, 95%CI: 1.61—30.62, P = 0.01) were significantly higher with the GEM/S-1 arm treatment. No significant differences were found for other side effects between the two treatments.

Publication bias Begg’s funnel plot and Egger’s test were performed to assess the publication bias. The shape of the funnel plots did not reveal any evidence of asymmetry (P = 1.00 for ORR; Fig. 3). Egger’s test also did not suggest any evidence of publication bias (P = 0.72 for ORR).

Figure 3

257

Begg’s funnel plot of publication bias test.

Discussion For decades, the chemotherapy containing GEM was the cornerstone of palliative treatment for APC. However, previous studies on GEM combination regimens showed minimal or no significant change on survival compared with GEM alone. Since the development of S-1, the controversies arose on the additional benefits for survival or response when it combined with GEM. However, no definite conclusions were drawn about the efficacy and safety of the two treatments with limited number of individuals assessed. In this meta-analysis, we confirmed that GEM/S-1 therapy significantly prolonged survival in APC patients compared with GEM treatment. With respect to primary efficacy end points, GEM/S-1 showed significantly improved OS and PFS. We could see OS for GEM/S-1 was mainly around 8.6 to 13.5 months while OS for GEM ranged from 8.0 to 8.8 months from the trials included. The pooled HR for OS performed by our analysis was 0.83, representing a 17% reduction in the risk of death in patients treated with GEM/S-1 doublet regimen. However, it should be noticed that four trials performed in Japan reported a proportion of patients in GEM arm switched to S-1 as second-line chemotherapy; this crossover might obscure the OS of GEM/S-1 over GEM alone. In contrast, PFS offered a direct measurement of activity and was not obscured by subsequent interventions. We could see PFS for GEM/S-1 was mainly around 5.3 to 6.2 months while PFS for GEM ranged from 3.6 to 4.1 months in the trials. HR for PFS performed was 0.64, representing a 36% reduction in the risk of disease progression in patients treated with GEM/S1. With respect to secondary efficacy end points, ORR for all patients treated was 24.7% in GEM/S-1 arm and 10.5% in GEM arm respectively, indicating that GEM/S-1 had an almost 200% higher ORR than GEM alone. A similar tendency could also be found in DCR. Although the regimens and doses of drugs were not consistent in the meta-analysis, no heterogeneity was detected in survival and response rate, which strengthened the robustness of our conclusion. Grade 3/4 toxicities related to chemotherapeutic treatment had also been assessed. We found there was statistical difference between the two regimens. Severe neutropenia (53.55%) and thrombocytopenia (15.50%) were significantly greater in GEM/S-1 group, which were not surprising in the realm of cancer chemotherapy. The incidence of nonhematological grade 3/4 toxicities was low in both arms, although diarrheas (3.66%), nausea/vomit (7.42%), rush (4.58%) and stomatitis/mucositis (2.75%) were more likely occurred in GEM/S-1 group. Despite high levels of hematological toxicity, rare toxic deaths occurred. Only JCCRO PC-01 study reported one treatment-related death in each

258 Table 3

Y. Liu et al. Summary of grade 3/4 adverse events by treatment.

Adverse effect

No. of study

No. of patients

GEM/S-1 (No/%)

GEM (No/%)

RR (95%CI)

Hematological Anemia Leukopenia Neutropenia Thrombocytopenia

5 4 4 5

917 811 876 917

65/14.19 127/31.36 234/53.55 71/15.50

54/11.76 66/16.26 152/34.62 41/8.93

1.21 1.73 1.60 1.73

(0.86, (0.93, (1.14, (1.21,

Non-hematological Anorexia Asthenia Diarrhea Elevated ALT Elevated AST Elevated bilirubin Fever/infection GI hemorrhage Nausea/vomit Rush Stomatitis/mucositis

4 4 4 2 2 2 3 2 5 4 4

876 876 876 669 669 669 759 207 917 876 876

35/8.01 16/3.66 16/3.66 31/9.31 33/9.91 24/7.21 15/3.96 6/5.77 34/7.42 20/4.58 12/2.75

33/7.52 17/3.87 5/1.14 45/13.39 43/12.80 30/8.93 18/4.74 2/1.94 13/2.83 2/0.46 0/0.00

1.06 0.95 2.84 0.69 0.77 0.81 0.83 2.56 2.55 6.17 7.02

(0.67, (0.49, (1.13, (0.45, (0.51, (0.48, (0.44, (0.62, (1.38, (2.01, (1.61,

arm [9]. Other fluoropyrimidine-relating side effects, such as cardiac toxicity in the form of angina-like syndrome induced by S-1 had not appeared in the trials. Although more toxicity was found in combination group, the tolerability could be improved by rigorous dose adaption. Moreover, to date, granulocyte colony-stimulating factors and thrombopoietins could help controlling of corresponding hematologic toxicities, and prophylactic use of the 5-HT3 antagonist could reduce the severity of gastrointestinal side effects. Therefore, GEM/S-1 therapy might depend on careful monitoring and effective managements of toxicities. One important question that should be pointed out was whether reducing the dose of S-1 would cause less toxicity while retaining treatment efficacy, however, it remained to be determined in future practice. As to other fluoropyrimidine-containing therapies applied in clinical trials, traditional bolus or continuous intravenous 5-FU had not shown better therapeutic benefits [16,17]. Capecitabine (CAP), another oral fluoropyrimidine designed to generate 5-FU preferentially within tumors, showed a consistently improved survival when combined with GEM in previous phase III RCTs [18—20]. It was pointed that GEM/CAP could be an acceptable combination for APC patients with good performance status by National Comprehensive Cancer Network (NCCN) guidelines (category 2A). Compared with CAP-based therapy, S-1-based chemotherapy was associated with non-inferior antitumor efficacy and safety profile [21]. We could believe GEM/S-1 be as effective as GEM/CAP, however, further studies should be warranted to confirm this. FOLFIRINOX regimen (5-FU, leucovorin, irinotecan and oxaliplatin) were also recommended for the first-line treatment by NCCN guidelines (category 1) [22]. It showed an overwhelming superiority to GEM in previous phase III study. However, the survival benefits were only shown in a highly select population with good performance status and with no liver dysfunction [23]. Besides, FOLFIRINOX was associated with severe toxicities including febrile

P

Pheterogeneity

1.69) 3.21) 2.25) 2.49)

0.27 0.08 0.007 0.003

0.96 0.10 0.08 0.49

1.68) 1.84) 7.13) 1.07) 1.18) 1.35) 1.60) 10.69) 4.71) 18.94) 30.62)

0.79 0.88 0.03 0.10 0.23 0.41 0.59 0.20 0.003 0.001 0.01

0.56 0.60 0.47 0.70 0.72 0.27 0.70 0.59 0.61 0.97 0.92

neutropenia; it was more toxic than GEM-based therapy. In contrast, GEM/S-1 offered advantages of relatively safety, simplicity, and convenience. It would provide benefits in terms of OS, PFS, and ORR at the expense of increased but manageable toxicity. GEM plus nab-paclitaxel (GEM/NABP) was another first-line treatment recommended by NCCN guidelines (category 1). A phase III MPACT trial demonstrated an OS benefit in GEM/NAB-P group, although with more myelosupression and peripheral neuropathy [4]. Comparing the absolute survival data, GEM/NAB-P had a similar clinical outcome with 5.5 months in PFS, as well as 23% in response rate, but an inferior 8.5 months in OS compared to GEM/S-1. It should be noticed that most patients in MPACT trial were from North America, to further confirm its efficacy, more clinical researches should be performed on Asian races. PC still remained a treatment-refractory cancer. There was no standard second-line therapy after first-line chemotherapy failure. A recent phase I/II study showed that combination therapy of fixed dose rate infusion of GEM with S-1 (FGS) provided a promising antitumor activity and tolerable toxicity in GEM-refractory metastatic PC patients [24]. The median OS and PFS were 7.0 and 2.8 months respectively, seemed to be better than those treated with S-1 monotherapy [25,26]. GEM/S-1 could be potential salvage chemotherapy for GEM-refractory PC, but it was not fully determined whether this regimen could be applied to all GEM-refractory APC patients for lacking of large prospective researches and experiences. There would be a need to evaluate its efficacy for patients following GEM failure in further RCTs. Some limitations had to be mentioned regarding this meta-analysis. Firstly, the trials included were only performed on Asian races, especially Japanese. Reports from other parts of the world were not available yet. As more severe toxicity of S-1 occurred in Europe and US than in Asian patients [27,28], the results could not be simply extrapolated to Western patients and needed

Addition of S-1 to GEM-based chemotherapy for APC more confirmation. Secondly, planned dose intensity varied between the included studies (3- or 4-week regimen). Although these regimens were safely administered to APC patients, this difference might influence the efficacy of the two arms. Thirdly, only two of the five trials included were phase III trials [11,15]. Most trials had few patients per arm except GEST study [11]. This may lack statistical power and influence our findings to some extent. Besides, a lack of blinding might have resulted in an overestimate of the effects, although adequate randomization was reported in the trials included. Furthermore, quality of life could not be assessed in our study since not all studies analyzed this endpoint. Only Ueno et al. reported the quality of life parameters (Quality-adjusted life-years) favored GEM/S-1 arm [11]. Finally, this meta-analysis was based on published data rather than individual patient data, which might preclude us from conducting a more in-depth analysis. In conclusion, the addition of S-1 to GEM-based chemotherapy could lead to a statistically significant improvement in survival of APC patients, although with increased toxicity compared with GEM monotherapy. GEM/S1 could be used as first-line chemotherapy for APC, at least in Asia.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments The authors acknowledge all the colleagues in the Department of Gastroenterology and Hepatology.

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