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. 2023 Mar 2;18(3):e0282360. doi: 10.1371/journal.pone.0282360

Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: A systematic review and meta-analysis of randomized controlled trials

Wei Tian 1, Lina Zhang 2, Xiao Liu 1, Xiao Ma 3, Rui Wang 1,*
Editor: Alberto Meyer4
PMCID: PMC9980826  PMID: 36862702

Abstract

Objectives

Fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine. We conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in such patients.

Methods

The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts were systematically searched. Randomized controlled trials (RCTs) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer were included. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. Statistical analyses were performed by using Review Manager 5.3. Egger’s test was performed to assess the statistical evidence of publication bias by using stata 12.0.

Results

A total of 1183 patients from six randomized controlled trials were included for this analysis. Fluoropyrimidine combination therapy increased ORR [RR 2.82 (1.83–4.33), p<0.00001] and PFS [HR 0.71 (0.62–0.82), p<0.00001], without significant heterogeneity. Fluoropyrimidine combination therapy improved OS [HR 0.82 (0.71–0.94), p = 0.006], with significant heterogeneity (I2 = 76%, p = 0.0009). The significant heterogeneity might have been caused by the different administration regimens and baseline characteristics. Peripheral neuropathy and diarrhea were more common in the regimens containing oxaliplatin and irinotecan, respectively. No publication bias was detected by Egger’s tests.

Conclusions

Compared with fluoropyrimidine monotherapy, fluoropyrimidine combination therapy had a higher response rate and longer PFS in patients with gemcitabine-refractory advanced pancreatic cancer. Fluoropyrimidine combination therapy could be recommended in the second line setting. However, due to concerns about toxicities, the dose intensities of chemotherapy drugs should be carefully considered in patients with weakness.

Introduction

Pancreatic cancer is associated with a poor prognosis and the seventh leading cause of cancer-related death worldwide, with 432,242 deaths reported in 2018 [1].

Gemcitabine-based chemotherapy has been the standard treatment for locally advanced and metastatic pancreatic cancer since 1997, based on modest improvement on survival when compared with fluorouracil [2]. More recently, FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil and folinic acid) and gemcitabine plus nab-paclitaxel have showed superiority over gemcitabine alone in appropriately selected patients with advanced disease in phase III trials [3,4]. These two regimens have emerged as new first-line treatment options.

However, pancreatic cancer often presents with a substantial deterioration in quality of life and performance status. And FOLFIRINOX was accompanied by a substantial increase in toxicity. As such, it is demonstrated that many patients with advanced pancreatic cancer will not be eligible for this regimen and will likely receive first-line gemcitabine-based therapy.

Progression after first line therapy is inevitable in advanced pancreatic cancer, leaving clinicians with few options. In order to improve the prognosis of such patients, there is an urgent need to establish an effective second line therapy with low toxicity and high efficacy. Over the past several years, fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients who failed in gemcitabine alone or gemcitabine-based treatment, but with diverse results. Therefore, we have undertaken this systematic review and meta-analysis to evaluate the available evidence from the relevant randomized controlled trials (RCTs).

Materials and methods

Search strategy

We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts up to January 2022 to identify the eligible studies. Our search strategy was detailed in Table 1. We used Cochrane highly sensitive search strategy to identify randomized controlled trials in MEDLINE (Ovid format). And the strategy was adapted in other databases.

Table 1. Search strategy for MEDLINE (Ovid format) used in this meta-analysis.

1. randomized controlled trial.pt. 19. (pancreas adj5 neoplasm$).mp.
2. controlled clinical trial.pt. 20. (pancreatic adj5 carcinoma$).mp.
3. randomized.ab. 21. (pancreas adj5 tumor$).mp.
4. placebo.ab. 22. (pancreas adj5 tumour$).mp.
5. drug therapy.fs. 23. or/12-22
6. randomly.ab. 24. exp drug therapy/
7. trial.ab. 25. chemothera$.tw.
8. groups.ab. 26. drug therap$.tw.
9. or/1-8 27. antineoplastic$.tw.
10. humans.sh. 28. or/24-27
11. 9 and 10 29. gemcitabine
12. exp pancreatic neoplasms/ 30. GEM
13. (pancreatic adj5 cancer$).mp. 31. Gemzar
14. (pancreatic adj5 neoplasm$).mp. 32. or/29-31
15. (pancreatic adj5 carcinoma$).mp. 33. 23 and 28
16. (pancreatic adj5 tumor$).mp. 34. 32 and 33
17. (pancreatic adj5 tumour$).mp. 35. 11 and 34
18. (pancreas adj5 cancer$).mp.
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Demonstration for characters used in the search strategy. pt: Publication type. ab: Abstract. fs: Floating subheading. sh: Subheading. adj: Adjacent. mp: Indicates a search of title, original title, abstract, name of substance word and subheading word. tw: Text word. $: Truncation operator.

All the randomized controlled trials on drug therapy or chemotherapy for patients with advanced pancreatic cancer who had experienced progression during first-line gemcitabine-based chemotherapy were collected and identified.

Inclusion criteria

We collected all phase II–III and prospective randomized controlled trials. The criteria for inclusion were as follows: (1) Type of participants: adults with locally advanced or metastatic pancreatic cancer who developed progression after previous gemcitabine-based therapy in a neoadjuvant or adjuvant setting. (2) Type of study: studies had to be RCTs comparing fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory pancreatic cancer. Gemcitabine-refractory was defined as follows: (1) Participants confirmed advanced or metastatic pancreatic cancer who had experienced progression during or after the first-line chemotherapy including gemcitabine. (2) Participants with pancreatic cancer who relapsed within 6 months after completing gemcitabine-based chemotherapy as adjuvant or neoadjuvant.

Exclusion criteria

We excluded quasi-randomized studies which possessed insufficient quality. Cross-over studies were also excluded in order to evaluate the overall effect on OS. Leucovorin or folinic acid was considered as chemotherapy sensitizer for fluoropyrimidine. So fluoropyrimidine plus leucovorin or folinic acid was seen as fluoropyrimidine monotherapy. Studies of fluoropyrimidine plus leucovorin or folinic acid compared with fluoropyrimidine were also excluded. Two reviewers (Wei Tian and Rui Wang) independently screened each record and each report retrieved. And two other reviewers (Lina Zhang and Xiao Liu) independently analyzed all the details of each article to confirm that they met the inclusion criteria.

Data extraction

Two reviewers (Wei Tian and Rui Wang) independently extracted the data from all eligible studies. When discrepancies arose, a third reviewer was needed to make the final decision. Conflicts were resolved through discussion. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. We analyzed hazard ratio (HR) of time-to-event data for OS and PFS, as provided by Jayne F Tierney et al [5]. In addition, we analyzed risk ratio (RR) of dichotomous data for ORR and toxicities. The HRs were extracted from the original studies or accounted from the reported events and the corresponding p-value of the log-rank statistics, or by reading off survival curves. We used Jadad score to assess the methodological quality of the included studies. Three items (description of randomization, double blindness and withdrawals) were directly related to the quality of studies. When randomization, double blindness and withdrawals were mentioned in the study, 1 score for each item was given. When appropriate methods of randomization or double blindness was described, another 1 score for each item was given. Each eligible study was evaluated and given a score from 0 to 5. Missing data would be obtained through contacting the authors or reading off the Kaplan-Meier curves.

Statistical analysis

Review Manager 5.3 software was used to perform the statistical analysis on the data. Time-to-event outcomes were compared using HR. Dichotomous data were compared using risk ratio (RR). 95% confidence intervals (CI) were calculated for each estimate. Statistical heterogeneity was assessed by the chi-square test, and expressed by the I2 index. The fixed-effect model weighted by the Mantel-Haenszel method was used. Further analysis (subgroup analysis, sensitivity analysis or random-effect model) was performed to identify the potential cause when considerable heterogeneity was found (p < 0.1, or I2 > 50%). Furthermore, we used Stata 12.0 to perform Egger’s test in order to assess the publication bias.

Results

Study identification

Our search screened 95 trials, and found 6 publications related to 6 randomized controlled trials (1183 patients) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory pancreatic cancer. Two phase II [6,7] and four phase III [8–11] trials were included. 3 of the trials compared fluoropyrimidine and oxaliplatin with fluoropyrimidine monotherapy [6,8,10]. 2 of the trials compared fluoropyrimidine and irinotecan with fluoropyrimidine monotherapy [7,9]. 1 of the trials compared fluoropyrimidine, oxaliplatin and irinotecan with fluoropyrimidine monotherapy [11]. A diagram representing the flow of the identification of the RCTs was shown in Fig 1.

Fig 1. Flow chart for identification and inclusion of trials for this meta-analysis.

Fig 1

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Characteristics of included studies

Characteristics of patients included in the studies were shown in Table 2. The distribution of baseline for patient characteristics was found to be a little inconsistent, mainly caused by Gill 2016 [8]. We found that Wang 2015 had 117 and 149 patients in the 2 arms, which indicated some imbalance in the randomization [9]. The study of Wang 2015 had 3 arms. The arm consisting of nanoliposomal irinotecan and fluorouracil was added after the protocol amendment. 30 patients were assigned to fluoropyrimidine monotherapy arm before all sites switched to the new protocol. Regimens and endpoints of included studies were shown in Table 3. Methodological details which might cause bias were shown in Table 4. All the 6 studies included in this meta-analysis were open-label, and included illustrations regarding randomization. 4 of the trials described the detailed methods used for randomization [6,9–11]. All the 6 trials reported detail information of withdrawals. PFS was defined as the time from randomization to the disease progression or death from any cause. OS was defined as the time from randomization to death from any cause. There were no differences in the definitions of PFS and OS between trials. However, 2 of the trials did not define PFS and OS [9,11]. The frequencies of imaging scans to review tumor responses were not uniform between trials. 3 of the trials performed imaging scans every 6 weeks [8,9,11]. 2 of the trials performed imaging scans every 4 weeks [6,7]. 1 of the trials performed imaging scans every 2 months [10]. Only 2 of the trials illustrated that imaging scans to assess tumor responses were reviewed by independent review committee [6,7].

Table 2. Patients characteristics of included studies.

References Description for GEM-refractory Patients
enrolled		 Male
(%)		 ECOG ≤1 or
KPS ≥70 (%)		 Median age
(years)
Ohkawa et
al. 2015 [6]		 progression during first-line GEM or relapsed within
24 weeks after adjuvant GEM		 136
135		 61.2
61.5		 100
100		 65
63.5
Ioka et al.
2017 [7]		 progression during first-line GEM or relapsed within
24 weeks after adjuvant GEM		 67
70		 58.3
67.2		 100
100		 62
65
Gill et al.
2016 [8]		 progression during or after first-line GEM 54
54		 57.4
55.6		 88.9
94.4		 65
67
Wang et al.
2015 [9]		 progression during or after first-line GEM or relapsed
within 6 months after adjuvant/neoadjuvant GEM		 117
149		 59
56		 97
99		 63
62
Oettle et al.
2014 [10]		 progression during first-line GEM 77
91		 52.6
57.1		 100
100		 62
61
Se-Il et al.
2021 [11]		 progression during or after first-line GEM or relapsed
within 6 months after adjuvant GEM		 41
41		 72
68		 100
100		 59
62
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GEM: Gemcitabine. ECOG: Eastern Cooperative Oncology Group. KPS: Karnofsky Performance Status.

Table 3. Regimens and endpoints of included studies.

References Regimens
(per arm)		 Interventions Primary
endpoint
Ohkawa et
al. 2015 [6]		 S-1+OXA
S-1		 Arm A: OXA 100 mg/m2 iv d1, S-1 80/100/120 mg/d based on BSA, po
d1–14, q3w.
Arm B: S-1 80/100/120 mg/d based on BSA, po d1–28, q6w.		 PFS
Ioka et al.
2017 [7]		 S-1+IRI
S-1		 Arm A: IRI 100 mg/m2 iv d1 d15, S-1 80/100/120 mg/d based on BSA,
po d1–14, q4w.
Arm B: S-1 80/100/120 mg/d based on BSA, po d1–28, q6w.		 PFS
Gill et al.
2016 [8]		 FU/LV+OXA
FU/LV		 Arm A: OXA 85 mg/m2 iv d1, FU 400 mg/m2 iv d1, FU 2,400 mg/m2
continuous infusion 46 hours, LV 400 mg/m2 iv d1, q2w.
Arm B: FU 400 mg/m2 iv d1, FU 2,400 mg/m2 continuous infusion 46
hours, LV 400 mg/m2 iv d1, q2w.		 PFS
Wang et al.
2015 [9]		 FU/LV+Nal-IRI
FU/LV		 Arm A: Nal-IRI 80 mg/m2 iv d1, FU 2,400 mg/m2 continuous infusion
46 hours, LV 400 mg/m2 iv d1, q2w.
Arm B: FU 2,000 mg/m2 continuous infusion 24 hours, d1 d8 d15 d22,
LV 200 mg/m2 iv d1 d8 d15 d22, q6w.		 OS
Oettle et al.
2014 [10]		 FU/LV+OXA
FU/LV		 Arm A: OXA 85 mg/m2, iv d8 d22, FU 2,000 mg/m2 continuous infusion
24 hours, d1 d8 d15 d22, LV 200 mg/m2 iv d1 d8 d15 d22, q6w.
Arm B: FU 2,000 mg/m2 continuous infusion 24 hours, d1 d8 d15 d22,
LV 200 mg/m2 iv d1 d8 d15 d22, q6w.		 OS
Se-Il et al.
2021 [11]		 FU/LV+OXA+IRI
S-1		 Arm A: OXA 65 mg/m2, iv d1, IRI 135 mg/m2 iv d1, FU 1,000 mg/m2
continuous infusion 24 hours, d1 d2, LV 400 mg/m2 iv d1, q2w.
Arm B: S-1 80/100/120 mg/d based on BSA, po d1–28, q6w.		 OS
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S-1: An oral agent of fluoropyrimidine. BSA: Body surface area. FU: Fluorouracil. LV: Leucovorin. OXA: Oxaliplatin. IRI: Irinotecan. Nal-IRI: Nanoliposomal irinotecan. PFS: Progression free survival. OS: Overall survival.

Table 4. Methodological details which might cause bias of included studies.

References Phase Random Blind Randomization
description		 Withdraw
description		 ITT
analysis		 Multi-
center		 Jadad
score
Ohkawa et
al. 2015 [6]		 II Yes No Yes Yes Yes Yes 3
Ioka et al.
2017 [7]		 II Yes No NC Yes Yes Yes 2
Gill et al.
2016 [8]		 III Yes No NC Yes Yes Yes 2
Wang et al.
2015 [9]		 III Yes No Yes Yes Yes Yes 3
Oettle et al.
2014 [10]		 III Yes No Yes Yes Yes Yes 3
Se-Il et al.
2021 [11]		 III Yes No Yes Yes Yes Yes 3
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NC: No clear. ITT: Intend-to-treat.

Overall survival

The impact of fluoropyrimidine combination therapy on OS was extracted directly from published data of the 6 included trials. The analysis showed that, fluoropyrimidine combination therapy improved OS compared with fluoropyrimidine monotherapy in patients with gemcitabine-refractory pancreatic cancer [HR 0.82 (0.71–0.94), p = 0.006]. But significant heterogeneity was found among the studies (I2 = 76%, p = 0.0009) (Fig 2). When random-effect model was used, the final result of OS changed, which showed no statistical significance [HR 0.80 (0.59–1.09), p = 0.16]. Then we performed sensitivity analysis by excluding each study individually. The heterogeneity fluctuated between 62% and 80%.

Fig 2. Comparison of OS between fluoropyrimidine combination therapy and fluoropyrimidine monotherapy.

Fig 2

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SE: Standard error. CI: Confidence interval. IV: Inverse variance. Diamonds represented the 95% confidence interval of overall effect.

In the subgroup analysis, fluoropyrimidine combined with irinotecan improved OS compared with fluoropyrimidine monotherapy [HR 0.70 (0.55–0.89), p = 0.004], without significant heterogeneity among studies (I2 = 0%, p = 0.66). The HR for OS failed to show advantage in combining fluoropyrimidine with oxaliplatin [HR 1.03 (0.64–1.67), p = 0.90].

Progression free survival

The impact of fluoropyrimidine combination therapy on PFS was extracted directly from the 6 included trials. The analysis showed that, fluoropyrimidine combination therapy improved PFS compared with fluoropyrimidine monotherapy [HR 0.71 (0.62–0.82), p<0.00001], with moderate heterogeneity among studies (I2 = 55%, p = 0.05) (Fig 3). When random-effect model was used, the final result of PFS did not change [HR 0.70 (0.57–0.87), p = 0.001].

Fig 3. Comparison of PFS between fluoropyrimidine combination therapy and fluoropyrimidine monotherapy.

Fig 3

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SE: Standard error. CI: Confidence interval. IV: Inverse variance. Diamonds represented the 95% confidence interval of overall effect.

In the subgroup analysis, fluoropyrimidine combined with irinotecan improved PFS [HR 0.64 (0.50–0.80), p = 0.0001], without significant heterogeneity (I2 = 42%, p = 0.19). The HR for PFS also showed advantage in combining fluoropyrimidine with oxaliplatin [HR 0.81 (0.68–0.97), p = 0.02], without significant heterogeneity (I2 = 11%, p = 0.33).

Overall response rate

5 of the included trials described the impact of fluoropyrimidine combination therapy on ORR. The analysis revealed a significant difference between two arms. Fluoropyrimidine combination therapy improved ORR compared with fluoropyrimidine monotherapy [RR 2.82 (1.83–4.33), p<0.00001], without significant heterogeneity between studies (I2 = 46%, p = 0.11) (Fig 4).

Fig 4. Comparison of ORR between fluoropyrimidine combination therapy and fluoropyrimidine monotherapy.

Fig 4

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CI: Confidence interval. M-H: Mantel-Haenszel. Diamonds represented the 95% confidence interval of overall effect.

The subgroup analysis showed that, comparative analysis of RR for ORR showed advantage for the fluoropyrimidine combination therapy with oxaliplatin [RR 1.75 (1.05–2.95), p = 0.03]. The analysis for the regimen of fluoropyrimidine combined with irinotecan also showed advantage [RR 6.45 (2.54–16.39), p<0.0001].

Toxicities

The outcome of the toxicities with grade≥3 for fluoropyrimidine combination therapy was assessed. Only certain toxicities were consistently described in the 6 articles. We assessed the toxicities of peripheral neuropathy mainly caused by oxaliplatin, toxicity of diarrhea mainly caused by irinotecan, and other common toxicities occurred in the routine chemotherapy procedure, for example, the nausea, vomiting, neutropenia and anemia. The analysis showed that the grade≥3 toxicities increased by the combination therapy were peripheral neuropathy [RR 5.18 (1.15–23.28), p = 0.03] (I2 = 0%, p = 0.93), nausea [RR 2.31 (1.15–4.64), p = 0.02] (I2 = 0%, p = 1.00), vomiting [RR 3.64 (1.54–8.61), p = 0.003] (I2 = 0%, p = 0.97), and neutropenia [RR 3.74 (2.40–5.84), p<0.00001] (I2 = 85%, p<0.0001) (Fig 5). In the subgroup analysis, grade≥3 diarrhea was observed in the regimens containing irinotecan [RR 2.41 (1.07–5.42), p = 0.03] (I2 = 0%, p = 0.37).

Fig 5. Comparison of toxicities between fluoropyrimidine combination therapy and fluoropyrimidine monotherapy.

Fig 5

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CI: Confidence interval. Diamonds represented the 95% confidence interval of overall effect.

Publication bias

We used the highly sensitive search strategy to identify the relevant trials to minimize the potential of publication bias. And papers were collected strictly according to the inclusion criteria. Publication bias was detected by funnel plot. The statistical evidence of funnel plot symmetry was provided by Egger’s test. No apparent publication bias was found (Fig 6). Egger’s test did not suggest any evidence of publication bias for OS (p = 0.79) and PFS (p = 0.49). However, the small number of the included studies limited the accuracy of the analysis.

Fig 6. Funnel plot to assess for evidence of publication bias.

Fig 6

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Oblique line represented the pseudo 95% confidence interval. Circles represented the included studies.

Discussion

Patients with advanced pancreatic cancer always have poor prognoses as a result of the high lethality of the disease. Compared with gemcitabine alone, combination therapy has obtained significant survival benefits, which is mainly due to the introduction of new cytotoxic and targeted drugs in the past 20 years [12–14]. Patients with advanced pancreatic cancer are usually treated with first-line gemcitabine-based chemotherapy. There remains the problem of second-line setting in patients refractory to first-line gemcitabine-based treatment. Here, we conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy.

Our meta-analysis showed that fluoropyrimidine combination therapy increased ORR and PFS, in patients with gemcitabine-refractory pancreatic cancer. Fluoropyrimidine combination groups could prolong OS, but significant heterogeneity (I2 = 76%) in the analysis of OS was found. This phenomenon might have been caused by the different administration regimens and baseline characteristics. The combination arm in Oettle 2014 used the OFF regimen, in which oxaliplatin was administered at a lower dose intensity on days 8 and 22 every 42 days [10]. Patients allocated to the combination arm in Ohkawa 2015 received oxaliplatin on day 1 every 21 days [6]. The dose intensity of oxaliplatin in these two regimens was lower than the administration of every 14 days in Gill 2016 [8]. In Gill 2016, the tolerability of the fluoropyrimidine monotherapy arm was remarkably better than the combination arm. The incidence of grade 3/4 adverse events in the combination arm was six-fold higher than that in the monotherapy arm (63% v 11%). Thus, the reduction of oxaliplatin intensity might lead to better tolerance in the combination regimen. The randomized phase 2 trial conducted by Yoo et al compared modified version of FOLFOX (folinic acid, fluorouracil, and oxaliplatin) regimen for treatment of gemcitabine-refractory advanced pancreatic cancer, in which oxaliplatin was administered on day 1 every 14 days [15]. However, the median overall survival was only 3.5 months in this study. All these indicated the considerable importance of the second-line treatment tolerance in patients with advanced pancreatic cancer, which might influence the final results of overall survival. Due to concerns regarding toxicity in second-line treatment, it should be carefully considered to use administration of oxaliplatin every 14 days in frail patients with pancreatic cancer.

The analyses of adverse events were slightly different between groups, indicating that both therapeutic regimens were well tolerated. Incidence of grade≥3 peripheral sensory neuropathy, the most critical toxicity of oxaliplatin, was low (4.1%, 3.9% and 0.8%) in the 3 trials included in this analysis. In the treatment of metastatic colorectal cancer, when the cumulative dose of oxaliplatin ranging from 765 mg/m2 to 1020 mg/m2, 30% of patients will experience grade≥3 neuropathy induced by oxaliplatin [16–18]. And the less cumulative dose of oxaliplatin led to less frequency of grade≥3 neuropathy in the second line setting in pancreatic cancer. In our analysis, grade≥3 diarrhea was observed in the regimen of fluoropyrimidine combined with irinotecan. In Wang 2015, the severe gastrointestinal events caused by nanoliposomal irinotecan monotherapy at a higher dose (120 mg/m2) every 3 weeks were much more common than that caused by nanoliposomal irinotecan combination therapy at a lower dose (80 mg/m2) every 2 weeks. The mFOLFIRINOX regimen in Se-Il 2021 [11] comprised intravenous oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), leucovorin (400 mg/m2), and continuous infusion of 5-FU (2000 mg/m2 for 2 days). We found the drug dosages in this study were more attenuated than those used in routine practice. But the frequencies of grade≥3 neutropenia were still high (28%). Furthermore, one-third of patients treated with the regimen of mFOLFIRINOX required dose reduction during treatment. But the attenuated dosages of drugs and timely adjustment might have prevented discontinuation of treatment, and brought clinical benefits to patients with advanced pancreatic cancer.

There were several limitations that should be taken into account in this analysis. First of all, although no apparent publication bias was found by funnel plots and Egger’s test, the small number of the included studies limited the power of the analysis. Second, heterogeneity was found among the included studies due to different treatment regimens and baseline characteristics. Third, the frequency of imaging examination between different studies was not consistent, which might affect the final results of ORR. Fourth, we found that the drug dosages might have important impact on the OS of patients, so the subgroup analysis such as age would be needed to make the conclusion stronger. 5 of the included studies performed subgroup analysis by age [6–9,11], but the dividing points of age were not uniform. Some studies used the age of 65 as the dividing point [6,7,9,11], while Gill 2016 used the age of 70 [8]. Finally, all the 6 trials included in this analysis were open label, which might have caused certain bias. These limitations indicated the urgent need to design clinical trials using standardized, unbiased methods and a larger sample size to confirm the efficacy and safety of fluoropyrimidine combination regimens.

Our study focused on the fluoropyrimidine-based therapy in second-line treatment of gemcitabine-refractory pancreatic cancer. We found that the dosage of chemotherapy drug added to fluoropyrimidine might be one of the important factors affecting the prognosis of patients. In conclusion, fluoropyrimidine combination therapy showed advantage compared with fluoropyrimidine monotherapy. The identification of reasonable dose intensity of chemotherapy drugs is warranted in future trials to bring better clinical benefits.

Supporting information

S1 Table. PRISMA checklist.

(DOCX)

Click here for additional data file. (33.3KB, docx)
S1 Appendix. PRISMA flow diagram.

(DOC)

Click here for additional data file. (63KB, doc)

Acknowledgments

We thank Daidi Fu for her helpful advice in paper writing.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Alberto Meyer

5 Dec 2022

PONE-D-22-27493Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: a meta-analysis of randomized controlled trialsPLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Alberto Meyer, MD, PhD

Academic Editor

PLOS ONE

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3. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and previous work in the Abstract, Methods and Discussion section. We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications. Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work. We will carefully review your manuscript upon resubmission and further consideration of the manuscript is dependent on the text overlap being addressed in full. Please ensure that your revision is thorough as failure to address the concerns to our satisfaction may result in your submission not being considered further.

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Additional Editor Comments:

Wang et al report a study-level meta-analysis of 6 RCTs, in second-line treatment of pancreas cancer, comparing fluoropyrimidine alone (either 5FU or S-1; note capecitabine was not included), with the same FP in addition to another chemotherapy agent (oxaliplatin (2 studies), irinotecan (2 studies), Nal-Iri – a modified formulation of irinotecan (one study) – or oxaliplatin plus irinotecan (one study)).

The MA design is reasonable and the search seems to have been done well, revealing only 6 eligible studies.

There is limited information in this paper on the characteristics of each of the 6 papers, and the patients therein. For example, there is not a description of how each study defined “gemcitabine refractory advanced pancreatic cancer” , whether some were limited to disease progression during gemcitabine treatment, whether a time limit after gem treatment was specified as part of a definition of gem-refractory disease.

Revise.

REgards,

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1、The last date of the article screen is January 2022, please update the most recent research.

2、Please specify in the article which guides Jadad score is based on.

3、The results of Egger’s test should be added in detail in the “Publication bias”.

4、The content of the article needs to be examined carefully to avoid some grammatical mistakes.

Reviewer #2: In this study “Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine”, the authors conducted a meta-analysis study of RCTs to compare fluropyrimidine based therapy. While studies have been accumulating with such evidence, similar review of meta-analysis have been reported by Yang et al 2015 that included demographic data, treatment response, objective response rate (ORR), progression-free and overall survival (PFS and OS, respectively), and toxicities.

While it is interesting, this meta-analysis provides just another addition to the study pool but derived from just a handful of 6 study trials. As such comparative meta-analysis study from larger study trials with multiple locations, demographic group, age etc will make the conclusion stronger. Although, the written text is alright I find the result difficult to compare with the poor-quality figures presented with no legends and explanation.

I encourage the authors to include all abbreviations, legends, labels and explanation of the figures and here’s my comments-

Table1: Please explain the abbreviation used for search strategy. Readers find it difficult in understating what is meant by “$” or “mp” etc. While this may be familiar for clinical researchers, simply putting a table of keyword used for the search lacks clarity.

Please provide high resolution figure and all the figure legends

Fig 6- Label axes properly and explain the funnel plot in legend, what the circles meant etc

Table2- What is S-1?

Reviewer #3: PONE -D- 22-27493 – Wang et al - MA of FP alone vs FP-combination

Wang et al report a study-level meta-analysis of 6 RCTs, in second-line treatment of pancreas cancer, comparing fluoropyrimidine alone (either 5FU or S-1; note capecitabine was not included), with the same FP in addition to another chemotherapy agent (oxaliplatin (2 studies), irinotecan (2 studies), Nal-Iri – a modified formulation of irinotecan (one study) – or oxaliplatin plus irinotecan (one study)).

Overall Comments:

The subject of this MA is relevant, as recurrent pancreas cancer after first line chemotherapy is a serious issue, now with several possible treatments. The MA design is reasonable and the search seems to have been done well, revealing only 6 eligible studies.

The first author does not seem to have provided an ORCID.

There are multiple minor grammatical errors throughout, such as Line 126: are shown, and Line 143 uses the incorrect tense.

More information about how data was analysed would be valuable. For example, were medians compared? How were confidence intervals managed or data ranges managed?

There are already 4 papers titled meta-analysis in the 2L treatment of pancreatic cancer (Lu W, J Int Med Res, 2022; Wainberg Z BMC Cancer 2020; Sonbol MB, Cancer 2017; Zhong S, Medicine (Baltimore) 2017.) What will this paper add to the literature?

Major Comments:

There is limited information in this paper on the characteristics of each of the 6 papers, and the patients therein. For example, there is not a description of how each study defined “gemcitabine refractory advanced pancreatic cancer” , whether some were limited to disease progression during gemcitabine treatment, whether a time limit after gem treatment was specified as part of a definition of gem-refractory disease.

The description of patient characteristics is not as extensive as, for example, in the tables of the Ohkawa paper.

The primary and secondary outcomes, and how each study defined them, are not explained in detail. How were PFS and ORR defined? (were there differences in definition between papers?). ORR requires an assessment of response, usually with CT scans, but the frequency and veracity of scans (independent expert reporting, or a potentially biased investigator) can affect the ORR.

Since this is a retrospective study-level meta-analysis, it is possible that data elements are recorded differently in each paper, and that some data elements are missing. There is no consideration in Methods about how missing or “difficult to determine” data was dealt with. How did the 2 data collectors work together? How were inconsistencies, missing data and differences in interpretation dealt with?

Is there missing data in any of the studies (there is some data inconsistencies in the paper of Ohkawa)?

What is the duration of followup (median and range) in each paper and is it important?

There is not data about dose-intensity for each study – the doses referred to are intended; there is no consideration of doses actually received, or to duration of treatment in each study. This may be important as oxaliplatin neuropathy is a function of total dose over time.

I note Wang-Gillam et al has 117 and 149 patients in the 2 arms of their study; this suggests that there was some imbalance in the randomisation. This is not discussed.

Two studies are called phase II and 4 are called phase III – What is the difference here?

Table 3 has a column called “allocation concealment” (4 yes, 2 not clear) – what does this mean? I note that all studies are said in the text to be “open label” – this usually means there is no blinding of treatment so no allocation concealment.

Minor Comments:

Abstract:

the second sentence in Conclusion is not based on any data in the rest of the abstract. The abstract needs revision after the paper itself is revised, to ensure consistency and so the Abstract can stand alone but still be a fair summary of the paper.

Figures:

The Forest plots need more annotation and the terms which appear need to be all defined, including IV and M-H. What does the size and length of the diamonds represent. Why is the number at risk or observed/expected not reports in the figures?

The direction of the figure (favours monotherapy vs favours combination) is switched between fig 3 and 4. These should be consistent.

Fig 4 has a typographical error (momotherapy).

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2023 Mar 2;18(3):e0282360. doi: 10.1371/journal.pone.0282360.r002

Author response to Decision Letter 0

16 Jan 2023

January16, 2023

Reply for manuscript “Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: a meta-analysis of randomized controlled trials”

Reply to editor:

Dear editor:

Thank you for providing us with opportunity to submit the revised manuscript. We would like to express our sincere gratitude to all the reviewers for their constructive comments. According to the helpful comments, we have extensively revised the manuscript by correcting mistakes and supplementing the required materials to make our manuscript better. At the same time, we ensure that the manuscript meets PLOS ONE's style requirements.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

Answer: We carefully checked the manuscript to make it meet the requirements.

2. Please identify your study as "systematic review and meta-analysis" in the title.

Answer: We added the “systematic review” in the title and abstract in the manuscript. Line 2, 4, 38.

3. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and previous work in the Abstract, Methods and Discussion section. We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications. Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work. We will carefully review your manuscript upon resubmission and further consideration of the manuscript is dependent on the text overlap being addressed in full. Please ensure that your revision is thorough as failure to address the concerns to our satisfaction may result in your submission not being considered further.

Answer: We revised the parts of text overlap in the manuscript.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Answer: We revised the Data Availability Statement in the cover letter. All relevant data are within the paper and its Supporting Information files.

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Answer: We added the captions of Supporting Information Files at the end of the manuscript. Line 396-398

Additional Editor Comments:

Wang et al report a study-level meta-analysis of 6 RCTs, in second-line treatment of pancreas cancer, comparing fluoropyrimidine alone (either 5FU or S-1; note capecitabine was not included), with the same FP in addition to another chemotherapy agent (oxaliplatin (2 studies), irinotecan (2 studies), Nal-Iri – a modified formulation of irinotecan (one study) – or oxaliplatin plus irinotecan (one study)).

Answer: There was no eligible study about capecitabine.

The MA design is reasonable and the search seems to have been done well, revealing only 6 eligible studies.

There is limited information in this paper on the characteristics of each of the 6 papers, and the patients therein. For example, there is not a description of how each study defined “gemcitabine refractory advanced pancreatic cancer” , whether some were limited to disease progression during gemcitabine treatment, whether a time limit after gem treatment was specified as part of a definition of gem-refractory disease.

Answer: We added the median age of patients and the descriptions of “gemcitabine refractory” in Table 2.

Reply to reviewers:

Dear reviewer:

We are really grateful to you for your time spending on our manuscript and making helpful comments. Those comments are all valuable and helpful to make our manuscript better. We discussed each of the comments individually along with our responses and marked the line number in the Revised Manuscript with Track Changes. We hope you will find the revised version more satisfactory. We are more than happy to make any further revision that will improve the manuscript.

Reply to reviewer 1:

Reviewer #1: 1、The last date of the article screen is January 2022, please update the most recent research.

Answer: We searched the databases and found no latest eligible research.

2、Please specify in the article which guides Jadad score is based on.

Answer: We added the definition of Jadad score used in our analysis in the manuscript. Line 134-140.

3、The results of Egger’s test should be added in detail in the “Publication bias”.

Answer: We performed Egger’s test using stata and added the results in the manuscript. Line 49-50, Line 249-251.

4、The content of the article needs to be examined carefully to avoid some grammatical mistakes.

Answer: We examined the manuscript carefully and revised the mistakes.

Reviewer #2: In this study “Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine”, the authors conducted a meta-analysis study of RCTs to compare fluropyrimidine based therapy. While studies have been accumulating with such evidence, similar review of meta-analysis have been reported by Yang et al 2015 that included demographic data, treatment response, objective response rate (ORR), progression-free and overall survival (PFS and OS, respectively), and toxicities.

While it is interesting, this meta-analysis provides just another addition to the study pool but derived from just a handful of 6 study trials. As such comparative meta-analysis study from larger study trials with multiple locations, demographic group, age etc will make the conclusion stronger. Although, the written text is alright I find the result difficult to compare with the poor-quality figures presented with no legends and explanation.

I encourage the authors to include all abbreviations, legends, labels and explanation of the figures and here’s my comments.

Reply to Reviewer 2:

Table1: Please explain the abbreviation used for search strategy. Readers find it difficult in understating what is meant by “$” or “mp” etc. While this may be familiar for clinical researchers, simply putting a table of keyword used for the search lacks clarity.

Answer: We added the explanation of the abbreviations used in the search strategy in the legend of Table 1.

Please provide high resolution figure and all the figure legends.

Answer: We added all the abbreviations in the figure legends.

Fig 6- Label axes properly and explain the funnel plot in legend, what the circles meant etc

Answer: We added the explanations of oblique line and circles in the legend of Fig 6.

Table2- What is S-1?

Answer: We added the explanation of S-1 in the legend of Table 2.

Reviewer #3: PONE -D- 22-27493 – Wang et al - MA of FP alone vs FP-combination

Wang et al report a study-level meta-analysis of 6 RCTs, in second-line treatment of pancreas cancer, comparing fluoropyrimidine alone (either 5FU or S-1; note capecitabine was not included), with the same FP in addition to another chemotherapy agent (oxaliplatin (2 studies), irinotecan (2 studies), Nal-Iri – a modified formulation of irinotecan (one study) – or oxaliplatin plus irinotecan (one study)).

Overall Comments:

The subject of this MA is relevant, as recurrent pancreas cancer after first line chemotherapy is a serious issue, now with several possible treatments. The MA design is reasonable and the search seems to have been done well, revealing only 6 eligible studies.

Reply to Reviewer 3:

The first author does not seem to have provided an ORCID.

Answer: The ORCID of the first author was “https://orcid.org/0000-0002-8214-5347”.

There are multiple minor grammatical errors throughout, such as Line 126: are shown, and Line 143 uses the incorrect tense.

Answer: We examined the manuscript carefully and revised the mistakes.

More information about how data was analysed would be valuable. For example, were medians compared? How were confidence intervals managed or data ranges managed?

Answer: The hazard ratio (HR) of time-to-event data for OS and PFS, and the risk ratio (RR) of dichotomous data for ORR and toxicities with 95% confidence interval were extracted directly from published data of the 6 included trials.

There are already 4 papers titled meta-analysis in the 2L treatment of pancreatic cancer (Lu W, J Int Med Res, 2022; Wainberg Z BMC Cancer 2020; Sonbol MB, Cancer 2017; Zhong S, Medicine (Baltimore) 2017.) What will this paper add to the literature?

Answer: Our study focused on the fluoropyrimidine-based therapy in second-line treatment of gemcitabine-refractory pancreatic cancer. We found that the dosage of chemotherapy drug added to fluoropyrimidine might be one of the important factors affecting the prognosis of patients. We added this part in the discussion. Line 329-331.

Major Comments:

There is limited information in this paper on the characteristics of each of the 6 papers, and the patients therein. For example, there is not a description of how each study defined “gemcitabine refractory advanced pancreatic cancer” , whether some were limited to disease progression during gemcitabine treatment, whether a time limit after gem treatment was specified as part of a definition of gem-refractory disease.

Answer: We added the descriptions of “gemcitabine refractory” in Table 2. This is part of the characteristics of patients.

The description of patient characteristics is not as extensive as, for example, in the tables of the Ohkawa paper.

Answer: We added the median age of patients and the descriptions of “gemcitabine refractory” in Table 2.

The primary and secondary outcomes, and how each study defined them, are not explained in detail. How were PFS and ORR defined? (were there differences in definition between papers?). ORR requires an assessment of response, usually with CT scans, but the frequency and veracity of scans (independent expert reporting, or a potentially biased investigator) can affect the ORR.

Answer: We added the definitions of OS and PFS in the part of “Characteristics of included studies”. The frequencies of imaging scans in the included studies were also added. The frequency of imaging examination between different studies was not consistent. And we discussed it in the “limitation part” of the manuscript. Line 171-178. Line 318-319.

Since this is a retrospective study-level meta-analysis, it is possible that data elements are recorded differently in each paper, and that some data elements are missing. There is no consideration in Methods about how missing or “difficult to determine” data was dealt with. How did the 2 data collectors work together? How were inconsistencies, missing data and differences in interpretation dealt with?

Answer: We added the descriptions of how to obtain missing data and how to deal with the discrepancies. Line 123-125. Line 139-140.

Is there missing data in any of the studies (there is some data inconsistencies in the paper of Ohkawa)?

Answer: We checked the data in the studies and found no missing data.

What is the duration of followup (median and range) in each paper and is it important?

Answer: All the included trials set the minimum number of events that were required for the analysis of detecting the assumed differences. As a result, duration of follow up was not mentioned in the trials.

There is not data about dose-intensity for each study – the doses referred to are intended; there is no consideration of doses actually received, or to duration of treatment in each study. This may be important as oxaliplatin neuropathy is a function of total dose over time.

Answer: We added the dosages and dose-intensities of drugs for each study in Table 3.

I note Wang-Gillam et al has 117 and 149 patients in the 2 arms of their study; this suggests that there was some imbalance in the randomisation. This is not discussed.

Answer: We added the reason why the number of patients was imbalance in the trial. Line 164-167.

Two studies are called phase II and 4 are called phase III – What is the difference here?

Answer: All the included studies did not mention the definitions of “phase”, so we did not know the exactly difference between them.

Table 3 has a column called “allocation concealment” (4 yes, 2 not clear) – what does this mean? I note that all studies are said in the text to be “open label” – this usually means there is no blinding of treatment so no allocation concealment.

Answer: We revised “allocation concealment” to “Randomization description” in the table. Table 4.

Minor Comments:

Abstract:

the second sentence in Conclusion is not based on any data in the rest of the abstract. The abstract needs revision after the paper itself is revised, to ensure consistency and so the Abstract can stand alone but still be a fair summary of the paper.

Answer: We revised the part of “conclusion” in the abstract. Line 58-64.

Figures:

The Forest plots need more annotation and the terms which appear need to be all defined, including IV and M-H. What does the size and length of the diamonds represent. Why is the number at risk or observed/expected not reports in the figures?

Answer: We added the annotations of “CI, IV, M-H and diamonds” in the legend of figures. The number at risk was reported in Kaplan-Meier curves in the clinical trials. But the forest plot in meta-analysis did not have this element.

The direction of the figure (favours monotherapy vs favours combination) is switched between fig 3 and 4. These should be consistent.

Answer: The Risk Ratio for ORR was greater than 1.0，so it located in the right side of the forest plot. But the HR for OS and PFS was less than 1.0, so it located in the left side of the forest plot. This was the reason why the direction of the figure (favours monotherapy vs favours combination) was switched between fig 3 and 4.

Fig 4 has a typographical error (momotherapy).

Answer: We revised it to “monotherapy”. Fig 4.

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Decision Letter 1

Alberto Meyer

14 Feb 2023

Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: a systematic review and meta-analysis of randomized controlled trials

PONE-D-22-27493R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Alberto Meyer, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

Thank you for accepting our recommendations for revision and incorporating the relevant changes.

I am satisfied with your response and thus happy to recommend in favour of publication of your study.

Kind regards

Reviewers' comments:

Acceptance letter

Alberto Meyer

21 Feb 2023

PONE-D-22-27493R1

Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: a systematic review and meta-analysis of randomized controlled trials

Dear Dr. Wang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Alberto Meyer

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. PRISMA checklist.

    (DOCX)

    Click here for additional data file. (33.3KB, docx)
    S1 Appendix. PRISMA flow diagram.

    (DOC)

    Click here for additional data file. (63KB, doc)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (28.2KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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