Abstract
Background
Second‐line (2 L) chemotherapy is important for improved survival. However, the efficacy of S‐1 after nab‐paclitaxel plus gemcitabine (AG) for advanced pancreatic cancer (APC) remains unclear.
Aim
We retrospectively investigated the clinical impact of S‐1 after AG.
Methods and results
From January 2015 to July 2018, 37 patients with APC underwent AG as first‐line chemotherapy at our institute. Of these patients, 14 (38%) underwent S‐1 as 2 L chemotherapy after AG (S‐1 group), five (14%) received another agent after AG, and 18 (49%) underwent no 2 L chemotherapy (best supportive care [BSC] group). The clinical features were retrospectively compared between the S‐1 and BSC groups. Prognostic factors for residual survival (RS) were analyzed using a Cox proportional hazards model. The induction rate of 2 L chemotherapy was 51%, and most patients received S‐1 monotherapy (74%). The disease control rate and progression‐free survival duration were 57.1% and 2.8 months, respectively. The median RS duration in the S‐1 and BSC groups was 5.2 and 2.4 months, respectively; this difference was statistically significant (hazard ratio, 0.33; P = .005). The median overall survival duration in the S‐1 and BSC groups was 12.3 and 5.0 months, respectively; this difference was also statistically significant (hazard ratio, 0.26; P = .001). The efficacy of S‐1 in 2L chemotherapy for RS was identified in the multivariate analysis, as was age (<65 vs ≥65 y) and the presence of liver metastasis.
Conclusion
The antitumor activity of S‐1 was retained after AG, and the induction of S‐1 after AG might improve the prognosis of patients with APC.
Keywords: chemotherapy, gemcitabine, nab‐paclitaxel, pancreatic cancer, S‐1
1. INTRODUCTION
In Japan, pancreatic cancer (PC) is the fourth leading cause of cancer‐related mortality, and 34 224 people in this country died of PC in 2017.1 Gemcitabine (GEM) became the standard treatment for advanced PC (APC), showing an improved clinical response and overall survival (OS) compared with fluorouracil (23.8% vs 4.8% and 5.65 vs 4.41 mo, respectively).2 Since then, GEM‐based combination regimens have been developed. Erlotinib added to GEM showed a survival benefit over GEM alone (6.24 vs. 5.91 mo, respectively),3 and nab‐paclitaxel plus GEM (AG) has recently demonstrated a survival benefit over GEM alone for patients with metastatic PC in North America, Europe, and Australia (8.5 vs. 6.7 mo, respectively) (MPACT trial).4 In Japan, a phase I/II study of AG showed significantly better survival (13.5 mo).5 In contrast, fluorouracil/leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX) has shown a survival benefit over GEM (11.1 vs 6.8 mo, respectively).6 In retrospective studies, the AG group had a higher 1‐year survival rate (46.6% vs 16.6%),7 and the median OS was significantly better than that in the FOLFIRINOX group (11.8 vs 8.9 mo and 11.4 vs 9.6 mo, respectively7, 8).
Second‐line (2L) chemotherapy is another option to improve survival and has been developed for GEM‐refractory PC.9, 10, 11 In the MPACT trial, patients who received fluoropyrimidine (5‐fluorouracil or capecitabine)‐containing treatment or fluoropyrimidine monotherapy after AG had better survival than patients who received no 2 L chemotherapy (13.5 or 11.9 vs 6.3 mo, respectively).12 In studies in Japan, S‐1, an oral fluoropyrimidine, was reportedly active against GEM‐refractory PC.13, 14 However, the efficacy of S‐1 in 2L chemotherapy after AG for APC remained unclear because S‐1 was not administered in the West.12 Moreover, capecitabine was not covered, and the administration of oxaliplatin or irinotecan was restricted to combination therapy in the FOLFIRINOX regimen for APC by the national medical insurance in Japan.
Most studies of 2L chemotherapy investigate only patients who can receive 2L chemotherapy. In reality, the induction rate of 2L chemotherapy after AG does not seem to be high because of rapid disease progression of PC or adverse events; however, little is known about the actual induction rate. Therefore, in the present study, we retrospectively investigated the induction rate and clinical impact of S‐1 as 2L chemotherapy after AG.
2. PATIENTS AND METHODS
2.1. Patients
From January 2015 to July 2018, 37 patients with APC underwent AG as first‐line (1L) chemotherapy at Higashiosaka City Medical Center. Of these, 14 patients (38%) received S‐1 as 2L chemotherapy after AG (S‐1 group), five (14%) received another agent after AG, and 18 (49%) received no 2L chemotherapy (best supportive care [BSC] group). The patients' demographic information and clinical features were retrospectively compared between the S‐1 and BSC groups.
This clinical research was approved by the institutional review board (02‐0487). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
2.2. Treatment
Beginning in January 2015, AG was administered as 1L chemotherapy for APC until progressive disease (PD) or intolerance due to adverse events occurred. After AG, the indications for 2L chemotherapy were based on the patients' general condition and willingness to receive the treatment.
S‐1 was orally administered in 6‐week cycles at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14‐day rest period. According to the doctors' judgment considering the patients' general condition or opinion, 3‐week cycles at a reduced dose twice daily for 14 days followed by a 7‐day rest period were permitted.
2.3. Tumor response and safety
Tumor response was assessed by computed tomography using the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Evaluation was repeated every two courses or more frequently in patients with clinically suspected progression. The objective response rate (ORR) was defined at the proportion of patients with a complete response (CR) and partial response (PR) maintained for greater than or equal to 4 weeks. The disease control rate (DCR) was defined at the proportion of patients with a CR, PR, and stable disease (SD) maintained for greater than or equal to 4 weeks. PD was defined by the RECIST 1.1 criteria. Adverse events were evaluated at each cycle according to The Common Terminology Criteria for Adverse Events (CTCAE version 4.0).
2.4. Statistical analysis
Data are expressed as median (range). Statistical analyses were performed using JMP version 13.0 software (SAS Institute, Cary, NC, USA). Differences between the two groups were compared with chi‐square statistics, Fisher's exact test, and the Mann‐Whitney U test. OS, residual survival (RS), and progression‐free survival (PFS) were estimated using the Kaplan‐Meier method and compared using the log‐rank test. OS was calculated from treatment initiation to patient death or censored time. RS was calculated from the end of AG to patient death or censored time. PFS was calculated from treatment initiation to the first recognition of PD.
A multivariate Cox proportional hazards model was used to analyze prognostic factors for RS. Prognostic factors with P values of less than .05 in the univariate analysis or clinically important factors were entered into the multivariate analysis. All P values of less than.05 were considered significant.
3. RESULTS
3.1. Patient characteristics
All 32 patients had a performance status (PS) of 0 or 1 at the introduction of AG. The ORR and DCR of AG in 31 evaluable patients according to RECIST were 22.6% (95% confidence interval [CI], 11.4%‐39.8%) and 61.3% (95% CI, 43.8%‐76.3%), respectively. The PFS duration of AG was 3.9 months (95% CI, 1.9‐5.6 mo). The characteristics of all 32 patients at the end of AG are summarized in Table 1. With the exception of the PS at the end of AG and PFS of AG, the baseline characteristics did not differ significantly. A PS of 0 or 1 and long PFS duration of AG were more frequent in the S‐1 than BSC group.
Table 1.
Patient characteristics at the end of AG for advanced pancreatic cancer
| S‐1 (n = 14) | BSC (n = 18) | P value | |
|---|---|---|---|
| Male:Female | 5:9 | 7:11 | .85 |
| Age (years) | 73 (51‐79) | 68 (53‐77) | .36 |
| PS (0‐1:2‐4) | 12:2 | 3:15 | <.001a |
| Distant metastasis (yes:no) | 12:2 | 16:2 | .79 |
| Site of metastasis | |||
| Liver | 11 | 12 | .46 |
| Lung | 8 | 5 | .093 |
| Lymph node | 9 | 10 | .62 |
| Peritoneum | 7 | 9 | 1.00 |
| Bone | 1 | 0 | .25 |
| No. of metastatic sites (≧4:1‐3) | 5:9 | 3:15 | .22 |
| CA19‐9 (median, U/mL) | 4315 | 1021 | .36 |
| PFS of AG (≧3.9:<3.9 mo)b | 11:3 | 5:13 | .004a |
| NLR (≦5:>5) | 9:5 | 11:7 | .85 |
Abbreviations: AG, nab‐paclitaxel plus gemcitabine; CA19‐9, carbohydrate antigen 19‐9; NLR, neutrophil‐to‐lymphocyte ratio; PFS, progression‐free survival; PS, performance status.
Statistically significant.
The median PFS of AG was 3.9 months in this study.
3.2. Induction of 2L chemotherapy
Of the 37 patients who received AG as 1L chemotherapy, 19 patients (51%) underwent 2L chemotherapy: 14 (74%) received S‐1 (S‐1 group), three received modified FOLFIRINOX, one continued GEM, and one received GEM combined with carbon ion beam therapy. S‐1 was chosen more frequently than modified FOLFIRINOX because of its acceptable toxicity (especially for patients of advanced age or patients with a poor PS or renal dysfunction) and its convenience of oral administration without the need to prepare a central venous access port for intravenous administration. Eighteen patients (49%) received no 2L chemotherapy (BSC group). The reasons for the lack of 2L chemotherapy were a poor PS because of disease progression in 10 patients (56%), severe adverse events associated with AG in four patients (22%) (febrile neutropenia, n = 2; liver dysfunction, n = 1; interstitial pneumonia, n = 1), and patient refusal because of severe fatigue caused by AG in four patients (22%).
3.3. S‐1 as 2L chemotherapy after AG
S‐1 was administered to 14 patients as 2L chemotherapy. Their median age was 73 years (range, 51‐79 y). Five patients (36%) were male, and nine patients (64%) were female. Two patients (14%) had locally APC and 12 patients (86%) had metastatic PC at the end of AG. The metastatic sites were the liver (79%), lung (57%), peritoneum (50%), lymph node (64%), and bone (7%). The median carbohydrate antigen 19‐9 concentration was 4315 U/mL. No patients who received S‐1 as 2L chemotherapy were confirmed to have CR or PR according to the RECIST 1.1 criteria. The DCR was 57.1% (95% CI, 32.6%‐78.6%). The PFS duration was 2.8 mo (95% CI, 1.4‐3.7 mo). Seven patients (50%) had dose reductions of S‐1, and the median relative dose intensity (the proportion of the administered cumulative dose relative to the planned cumulative dose) was 91.5%. Twelve patients continued S‐1 until PD, and two patients discontinued S‐1 because of non‐hematological adverse effects. The adverse events are shown in Table 2. The hematological adverse events were anemia in seven patients (50%) and thrombocytopenia in two (14%). The non‐hematological adverse events were malaise in nine patients (64%), nausea in three (21%), vomiting in one (7%), constipation in one (7%), diarrhea in one (7%), and stomatitis in one (7%). Grade ≥ 3 adverse events were anemia in three patients (21%), thrombocytopenia in two (14%), and stomatitis in one (7%). Third‐line chemotherapy was administered after PD with S‐1 in three patients: combination therapy with S‐1 and GEM in one patient, reinduction of AG in one patient, and modified FOLFIRINOX in one patient.
Table 2.
Adverse events of S‐1 as second‐line chemotherapy after nab‐paclitaxel plus gemcitabine for advanced pancreatic cancer
| All Grades | Grade 3/4 | |
|---|---|---|
| No. of patients (%) | No. of patients (%) | |
| Hematological | ||
| Neutropenia | 0 | 0 |
| Anemia | 7 (50%) | 3 (21%) |
| Thrombocytopenia | 2 (14%) | 2 (14%) |
| Non‐hematological | ||
| Malaise | 9 (64%) | 0 |
| Nausea | 3 (21%) | 0 |
| Vomiting | 1 (7%) | 0 |
| Constipation | 1 (7%) | 0 |
| Diarrhea | 1 (7%) | 0 |
| Stomatitis | 1 (7%) | 1 (7%) |
3.4. RS and OS
Figures 1 and 2 show the RS and OS durations in the S‐1 and BSC groups. The survival curves revealed that the median RS duration in the S‐1 group was 5.2 months (95% CI, 3.8‐5.9 mo), whereas that in the BSC group was 2.4 mo (95% CI, 0.9‐3.3 mo); this difference was statistically significant (hazard ratio, 0.33; 95% CI, 0.14‐0.74; P = .005). The median OS duration in the S‐1 group was 12.3 mo (95% CI, 6.2‐15.0 mo), whereas that in the BSC group was 5.0 months (95% CI, 3.4‐6.8 mo); this difference was also statistically significant (hazard ratio, 0.26; 95% CI, 0.10‐0.60; P = .001).
Figure 1.
Kaplan‐Meier curves for residual survival in S‐1 group and BSC group. BSC, best supportive care; CI, confidence interval; HR, hazard ratio
Figure 2.
Kaplan‐Meier curves for overall survival in S‐1 group and BSC group. BSC, best supportive care; CI, confidence interval; HR, hazard ratio
3.5. Univariate and multivariate analyses of RS
Univariate and multivariate analyses were performed to analyze the prognostic factors of RS in patients who underwent AG as 1L chemotherapy for APC (Table 3). When the univariate analysis was performed by the variables at post‐1L chemotherapy, the significant prognostic factors were the PS (0, 1 vs ≥2), distant metastasis, liver metastasis, PFS of AG (<3.9 vs ≥3.9 mo), and S‐1 as 2L chemotherapy. The multivariate analysis revealed that age (≥65 vs <65 y), liver metastasis, and S‐1 as 2L chemotherapy were independent prognostic factors of RS for APC.
Table 3.
Univariate and multivariate analyses for RS prognostic factors
| Factor | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Gender | ||||
| Female | 1 | 0.84 | ||
| Male | 1.09 (0.48‐2.33) | |||
| Age (y) | ||||
| < 65 | 1 | 0.35 | 1 | 0.011a |
| ≧65 | 1.52 (0.64‐4.16) | 4.22 (1.35‐17.32) | ||
| PS | ||||
| 0, 1 | 1 | 0.048a | 1 | 0.26 |
| ≧2 | 2.22 (1.01‐5.14) | 2.25 (0.56‐9.89) | ||
| Distant metastasis | ||||
| No | 1 | 0.043a | 1 | 0.82 |
| Metastasis | 3.69 (1.04‐23.71) | 1.30 (0.16‐14.03) | ||
| Site of primary tumor | ||||
| head | 1 | 0.67 | ||
| body and tail | 0.84 (0.38‐1.90) | |||
| Liver metastasis | ||||
| No | 1 | 0.026a | 1 | 0.002a |
| Yes | 2.92 (1.13‐9.15) | 7.32 (1.93‐36.98) | ||
| Lung metastasis | ||||
| No | 1 | 0.97 | ||
| Yes | 0.98 (0.44‐2.11) | |||
| Lymph nodes | ||||
| No | 1 | 0.29 | ||
| Yes | 1.54 (0.70‐3.58) | |||
| Peritoneum | ||||
| No | 1 | 0.22 | ||
| Yes | 1.62 (0.75‐3.54) | |||
| No. of metastatic sites | ||||
| 0‐3 | 1 | 0.27 | ||
| > 3 | 1.66 (0.66‐3.90) | |||
| CA19‐9 (U/mL) | ||||
| < 59 × ULN | 1 | 0.87 | ||
| ≧59 × ULN | 1.06 (0.50‐2.28) | |||
| PFSb, mo | ||||
| < 3.9 | 1 | 0.016a | 1 | 0.31 |
| ≧3.9 | 0.36 (0.15‐0.83) | 0.52 (0.15‐1.88) | ||
| NLR | ||||
| ≦5 | 1 | 0.97 | ||
| > 5 | 0.98 (0.45‐2.10) | |||
| S‐1 | ||||
| no | 1 | 0.007a | 1 | 0.009a |
| yes | 0.33 (0.14‐0.74) | 0.12 (0.02‐0.60) | ||
Abbreviations: CA19‐9, carbohydrate antigen 19‐9; CI, confidence interval; HR, hazard ratio; NLR, neutrophil‐to‐lymphocyte ratio; ; PFS, progression‐free survival; PS, performance status; RS, residual survival.
Statistically significant.
The median PFS duration of nab‐paclitaxel plus gemcitabine in this study was 3.9 months.
4. DISCUSSION
To reveal the efficacy of S‐1 as 2L chemotherapy after AG, we retrospectively studied the prognosis of the patients at our institute. The induction rate of 2L chemotherapy was 51%, and most of these patients received S‐1 monotherapy (74%). The RS and OS durations were prolonged at 2.8 and 7.3 months, respectively. The DCR, PFS, RS, and OS were 57.1%, 2.8 months, 5.2 months, and 12.3 months, respectively. Because S‐1 had acceptable toxicity with the convenience of oral administration, more patients preferred S‐1 over the modified FOLFIRINOX regimen. Because the S‐1 group included significantly more patients who had a PS of 0/1 at the end of AG, it was difficult to determine how much of the longer survival duration was due to the efficacy of S‐1 or inherent patient factors. Therefore, the real impact of S‐1 remains unclear though the efficacy of S‐1 in 2L chemotherapy for RS was identified, as was age (<65 vs ≥65 y) and the presence of liver metastasis in the multivariate analysis. A prospective study comparing an S‐1 group and BSC group with similar baseline characteristics may resolve this issue, but such a study might be clinically difficult to perform. Most studies of 2L chemotherapy investigate only patients with good condition who can receive 2L chemotherapy. Considering that patients who received fluoropyrimidine (5‐fluorouracil or capecitabine)‐containing treatment or fluoropyrimidine monotherapy after AG had a median RS of 5.7 or 4.7 months and OS of 13.5 or 11.9 months in the MPACT trial,12 the median RS of 5.2 months and OS of 12.3 months in the S‐1 group in the present study appears comparable, and induction of S‐1 after AG might improve the prognosis of patients with APC.
The present study is a new report revealing the efficacy of S‐1 after AG for APC. Phase II studies of S‐1 in patients with GEM‐resistant APC have demonstrated moderate activity (ORR, 9.5%‐15%; DCR, 52%‐58%; PFS, 2.0‐4.1 mo; median survival, 4.5‐6.3 mo) with acceptable toxicity.13, 15, 16 The DCR, PFS, and RS of S‐1 after AG for APC in the present study were comparable with those in previous studies of S‐1 after GEM. Moderate antitumor activity of S‐1 for APC was retained even after the administration of nab‐paclitaxel combination therapy with significantly strong antitumor activity.
Age (<65 vs ≥65 y) and the presence of liver metastasis were significant prognostic factors of total OS for patients with APC in the MPACT trial, but they were not reported as independent prognostic factors of RS.12, 17 Patients in the real clinical setting in Japan are older than patients in clinical trials overseas, and this might have led to the result of RS in the multivariate analysis of the present study. The presence of liver metastasis has also been reported as a prognostic factor of RS in patients with GEM‐refractory PC in Japan.14, 18 The Karnofsky PS at the end of AG and the PFS of AG were prognostic factors of RS in the MPACT trial.12 However, these factors were not independent prognostic factors in the present study. This might be because a PS of 0/1 at the end of AG and a long PFS of AG (≥3.9 mo) were significant predictive factors of induction of S‐1 in 2L chemotherapy.
In the MPACT trial, the induction rates of 2L chemotherapy between the AG group and GEM group were 40% and 44%, respectively.12 In two previous reports after 1L chemotherapy of GEM in Japan, the induction rates of 2L chemotherapy mainly using S‐1 were 46% and 47%, respectively.14, 19 Although S‐1 had acceptable toxicity with the convenience of oral administration, half of patients still could not receive 2L chemotherapy in the present study. Combination chemotherapy of nab‐paclitaxel with stronger antitumor activity did not seem to dramatically improve the induction rate of 2L chemotherapy. The main reason for the lack of 2L chemotherapy was a poor PS at the end of AG (53%) because of the rapid progression of PC. Patients who had long PFS after receiving AG were unlikely to lose the opportunity to move to 2L chemotherapy because better disease control brought enough time and opportunity to prepare for 2L chemotherapy. It was most important to gain disease control in 1L chemotherapy for patients with APC to move to 2L chemotherapy. However, if disease control was not achieved, considering that the efficacy of S‐1 was retained even after AG, early recognition of the ineffectiveness of AG in patients with a favorable clinical condition may increase the induction rate of S‐1 as 2L chemotherapy and may lead to prolonged RS and OS.
This study has several limitations. We were unable to eliminate potential selection bias because this was a small‐sample, single‐center retrospective study, and the statistical power was limited by the small sample size. The baseline characteristics significantly differed in terms of the PS at the end of AG and the PFS after receiving AG. A poor PS due to rapid disease progression and failure of disease control by AG may indicate aggressive malignancy, potentially resulting in a poor prognosis in the BSC group. The S‐1 group patients might have survived significantly longer if they had no treatment. Therefore, the real impact of S‐1 remains unclear. However, a prospective study comparing an S‐1 group and BSC group with similar baseline characteristics might be clinically difficult to perform, so we retrospectively investigated the efficacy of S‐1 after AG. Considering that patients who received S‐1 after AG had a median RS and OS of 5.2 and 12.3 months in the present study, induction of S‐1 after AG might be an important option.
In conclusion, the antitumor activity of S‐1 for APC was retained after the administration of nab‐paclitaxel combination therapy. Post‐AG induction of S‐1, which has acceptable toxicity and the convenience of oral administration, might improve the prognosis of patients with APC.
ETHICAL APPROVAL
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, K.I.; Methodology, K.I.; Investigation, K.I., Y.T., and S.N.; Formal Analysis, K.I. and T.Y.; Resources, K.I., R.K., M.U., Y.T., S.N., K.O., J.M., and M.I.; Writing ‐ Original Draft, K.I.; Writing ‐ Review & Editing, T.Y.; Visualization, K.I.; Supervision, T.Y. and S.T.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.
ACKNOWLEDGMENT
We thank Angela Morben, DVM, ELS, from Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript.
Iede K, Yamada T, Kato R, et al. Efficacy of S‐1 in second‐line chemotherapy after nab‐paclitaxel plus gemcitabine for patients with advanced pancreatic cancer. Cancer Reports. 2020;3:e1215. 10.1002/cnr2.1215
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.