Survival benefit of intravenous and intraperitoneal paclitaxel with S-1 in pancreatic ductal adenocarcinoma patients with peritoneal metastasis: a retrospective study in a single institution
2017; Wiley; Volume: 24; Issue: 5 Linguagem: Inglês
10.1002/jhbp.447
ISSN1868-6982
AutoresSohei Satoi, Hiroaki Yanagimoto, Tomohisa Yamamoto, Satoshi Hirooka, So Yamaki, Hisashi Kosaka, Kentaro Inoue, Yuki Hashimoto, Yoichi Matsui, Masanori Kon,
Tópico(s)Neuroendocrine Tumor Research Advances
ResumoJournal of Hepato-Biliary-Pancreatic SciencesVolume 24, Issue 5 p. 289-296 Original ArticleFree Access Survival benefit of intravenous and intraperitoneal paclitaxel with S-1 in pancreatic ductal adenocarcinoma patients with peritoneal metastasis: a retrospective study in a single institution Sohei Satoi, Corresponding Author Sohei Satoi satoi@hirakata.kmu.ac.jp Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 Japan Correspondence to: Sohei Satoi, Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Japan e-mail: satoi@hirakata.kmu.ac.jpSearch for more papers by this authorHiroaki Yanagimoto, Hiroaki Yanagimoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorTomohisa Yamamoto, Tomohisa Yamamoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorSatoshi Hirooka, Satoshi Hirooka Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorSo Yamaki, So Yamaki Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorHisashi Kosaka, Hisashi Kosaka Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorKentaro Inoue, Kentaro Inoue Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorYuki Hashimoto, Yuki Hashimoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorYoichi Matsui, Yoichi Matsui Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorMasanori Kon, Masanori Kon Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this author Sohei Satoi, Corresponding Author Sohei Satoi satoi@hirakata.kmu.ac.jp Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 Japan Correspondence to: Sohei Satoi, Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Japan e-mail: satoi@hirakata.kmu.ac.jpSearch for more papers by this authorHiroaki Yanagimoto, Hiroaki Yanagimoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorTomohisa Yamamoto, Tomohisa Yamamoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorSatoshi Hirooka, Satoshi Hirooka Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorSo Yamaki, So Yamaki Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorHisashi Kosaka, Hisashi Kosaka Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorKentaro Inoue, Kentaro Inoue Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorYuki Hashimoto, Yuki Hashimoto Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorYoichi Matsui, Yoichi Matsui Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this authorMasanori Kon, Masanori Kon Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010 JapanSearch for more papers by this author First published: 16 March 2017 https://doi.org/10.1002/jhbp.447Citations: 7AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Background We evaluated the clinical efficacy of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) combined with S-1 in patients with chemotherapy-naïve pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastasis. Methods Forty-nine patients were diagnosed with peritoneal metastasis during 2007–2014; 29 received gemcitabine or S-1-based chemo(radio)therapy from 2007 to 2011 (control group), and the remaining 20 received i.v. (50 mg/m2) and i.p. (20 mg/m2) PTX on days 1 and 8, and S-1 at 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest from 2012 to 2014 (study group). Results The median survival time in the study group was significantly longer than that in the control group (20 vs. 10 months, respectively; P = 0.004). At 1 year after initial treatment, a significant difference in ascites development on CT was found between the study (5/20 patients) and the control group (18/29 patients, P = 0.009). The frequency of objective response (9/20 patients) and conversion surgery (6/20 patients) in the study group was higher than those in the control group (8/29 and 2/29, respectively). Patients who underwent conversion surgery had improved survival in both groups. Conclusion Implementation of the S-1+i.v./i.p. PTX regimen was closely associated with improved overall survival in PDAC patients with peritoneal metastasis. Introduction Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and it continues to have a dismal prognosis, with a 5-year survival rate of <5%, even in the modern era 1, 2. The median survival time (MST) of patients with distant organ metastasis, including peritoneal metastasis 3, 4, is extremely poor, at less than 12 months. Most patients with peritoneal metastasis are diagnosed in the presence of massive ascites followed by cytological examination or multiple nodules with a large diameter on contrast-enhanced computed tomography (CT) or magnetic resonance imaging. The MST of patients with peritoneal metastasis has been reported to be 6–7 weeks 3, 4. The MST of patients with peritoneal metastasis diagnosed only by staging laparoscopy for radiographically defined unresectable locally advanced PDAC ranged from 7 to 10 months 5, 6. The presence of peritoneal metastasis can lead to intestinal obstruction, massive ascites, and malnutrition, resulting in poor performance status 4, which in turn deprives patients of the opportunity to receive chemotherapy 5. Compared to systemic chemotherapy, intraperitoneal (i.p.) chemotherapy appears to be advantageous for the treatment of peritoneal metastasis due to the high drug concentration in the peritoneal cavity that can directly contact the tumor nodules 7-11. Previously, it was shown that i.p. paclitaxel (PTX) provided favorable clinical benefits in patients with peritoneal metastasis in clinical trials of ovarian cancer 7, 8, gastric cancer 9, 10, and even PDAC 11. Most notably, our multicenter phase II study revealed a response rate of 36%, a conversion surgery rate of 24%, and an MST of 16.3 months in 33 chemotherapy-naïve PDAC patients with peritoneal metastasis 12. Since there is no comparative study of intravenous (i.v.) and i.p. PTX combined with S-1 therapy, we conducted a retrospective study in a single institution to evaluate the clinical efficacy of i.v. and i.p. PTX combined with S-1 in comparison with S-1 or gemcitabine-based chemo(radio)therapy in chemo-naïve PDAC patients with peritoneal metastasis but without other distant organ metastases. Patients and methods Patient selection Peritoneal metastasis was defined as peritoneal dissemination and/or positive peritoneal washing cytology during staging laparoscopy or open laparotomy in this study. From January 2007 to June 2014, 49 chemotherapy-naïve patients PDAC with only peritoneal metastasis and without other distant organ metastases were enrolled in this study. Twenty-nine patients received gemcitabine or S-1-based chemotherapy from 2007 to 2011 (control group), and the remaining 20 patients received the S-1+i.v./i.p. PTX regimen from 2012 to June 2014 (study group). The eligibility criteria were as follows: histologically proven PDAC, presence of cancer cells on peritoneal cytology performed using staging laparoscopy in patients with radiographically defined unresectable locally advanced PDAC, or peritoneal dissemination in all types of PDAC on staging laparoscopy or open laparotomy, chemotherapy-naïve, Eastern Cooperative Oncology Group performance status 0–1, and adequate bone marrow, liver and renal function. Patients were excluded for any of the following: presence of metastasis in other distant organs, such as the liver, lungs, bone or others; positive peritoneal washing cytology in patients with resectable or borderline resectable PDAC; other active concomitant malignancies; or other severe medical conditions. Written informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the institutional review board (H160516). Treatment Study group Upon diagnosis of peritoneal dissemination or identification of positive peritoneal cytology during staging laparoscopy or open laparotomy, a peritoneal access port was implanted in the lower abdomen, with a catheter placed in the pelvic cavity. S-1 was administered orally twice daily at a dose of 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest. PTX was administered i.v. at a dose of 50 mg/m2 and i.p. at 20 mg/m2 on days 1 and 8. PTX was diluted in 1 liter of normal saline and administered through the implanted peritoneal access port over 1 h concurrently with i.v. infusion after standard premedication. The treatment course was repeated every 3 weeks until observation of unacceptable toxicity, disease progression or planned surgical resection. The surgical indications for conversion surgery were tumor remission on CT, disappearance of peritoneal dissemination on staging laparoscopy or open laparotomy, decreased levels of tumor markers, and maintenance of performance status. Control group Gemcitabine-based chemotherapy consisted of gemcitabine alone in nine patients and gemcitabine+S-1 in nine patients, including one patient who concomitantly received radiation therapy. S-1-based chemotherapy consisted of S-1 alone in one patient, S-1 followed by gemcitabine in three patients, and S1+concomitant radiation therapy in three patients. Four patients who were scheduled to receive chemotherapy did not receive any chemotherapy due to patient wish. Primary and secondary endpoints The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), objective response rate (ORR), frequency of negative peritoneal washing cytology, ascites-onset rate within 1 year after initial treatment, resection rate, and frequency of adverse events. The ORR was evaluated every 2 to 3 months during the study, and classified based on the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines 13. To evaluate the antitumor effects of treatment on peritoneal metastases, peritoneal washing cytology through a peritoneal access port was examined with Papanicolaou and May-Giemsa staining every 2 months in the study group. Toxicity was monitored weekly and graded according to the National Cancer Institute – Common Terminology Criteria for Adverse Events, version 4.0. Statistical analysis Continuous variables were expressed as median and range. The MST was estimated with the Kaplan–Meier method. Survival rates were estimated with Kaplan–Meier survival curves and the log-rank test. Univariate and multivariate analyses were carried out to determine prognostic factors. Patients alive at the time of follow-up were censored. The last follow-up date was August 2016. All patients were followed-up for at least 26 months. Statistical analyses were performed with the JMP statistical discovery software (JMP version 11.0; SAS Institute, Cary, NC, USA). A P-value <0.05 was considered statistically significant. Results Clinical background As shown in Table 1, there were no significant differences between groups in age, gender, performance status, tumor size, and CA19-9 level. Body mass index and albumin level in the study group were significantly higher than those in the control group (P < 0.05). The study group had a higher tendency for peritoneal dissemination relative to the control group. Table 1. Patient characteristics, clinical course, and clinical response Patient characteristics Control (n = 29) S-1+PTX (n = 20) P-value Male:Female 17:12 8:12 0.199 Age, years 64 (41–85) 69 (42–81) 0.398 Body mass index, kg/m2 18.6 (13.3–24.2) 21.9 (14.4–25.5) 0.017 Performance status, 0 vs. 1 21:7:1 16:4:0 0.541 Tumor location, body/tail:head 16:13 16:4 0.073 Tumor diameter, mm 42 (21–91) 40 (25–105) 0.119 Peritoneal dissemination: positive peritoneal (washing) cytology 14:15 13:7 0.245 Total bilirubin, mg/dl 0.7 (0.4–2.8) 0.7 (0.5–1.6) 0.742 Albumin, g/l 3.8 (2.7–4.6) 4.2 (2.4–4.8) 0.012 CA19-9, IU/l 366 (1–18,977) 479 (1–8,083) 0.576 Clinical course and response Duration of first line CTx, months 6.0 (0–15) 9.0 (0.8–21.8) 0.039 Radiation, yes: no 5:24 0:20 0.018 Tumor response, CR/PR vs. SD/PD 8: 21 9:11 0.296 Decreased CA19-9, % 17.1 (0–97.8) 51.8 (0–99.6) 0.019 Normalization of CA19-9, n (%) 3 (10%) 8 (40%) 0.033 Peritoneal cytology became negative, n (%) NE 18 (90%) Ascites development within 1 year after initial treatment, n (%) 18 (62%) 5 (25%) 0.009 Conversion surgery, n (%) 2 (7%) 6 (30%) 0.032 The data are expressed as median (range), except where noted otherwise CA19-9 carbohydrate antigen 19-9, CR complete response, CTx chemotherapy, PD progressive disease, PR partial response, SD stable disease Clinical courses and responses As shown in Table 1, the median (range) duration of first-line chemotherapy in the study group, 9.0 (0.8–21.8) months, was significantly greater than that in the control group, 6.0 (0–15) months (P = 0.039). The ORR in the study group (9/20) tended to be higher than that in the control group (8/29, P = 0.296). At 1 year after initial treatment, ascites development on CT was found in 5/20 patients in the study group and 18/29 patients in the control group (P = 0.009). Positive peritoneal washing cytology became negative in 18/20 patients in the study group during chemotherapy. Although the CA19-9 level at baseline did not differ between groups, rates of CA19-9 decrease and normalization in the study group were significantly higher than those in the control group (P < 0.05). Survival analysis As shown in Figure 1, 17 of 20 patients in the study group, and 28 of 29 patients in control group died, with a follow-up period of at least 26 months. In comparison with the control group, a significantly higher OS was observed in the study group (Fig. 1a, P = 0.004). The MST in the study and control groups was 20 and 10 months, respectively. The 1- and 2-year survival rate was 65% and 34% in the study group, and 45% and 3.5% in the control group, respectively. With regard to PFS, although a significant difference was observed between groups (Fig. 1b, P = 0.048, median; 13.5 months in the study group and 6.8 months in the control group), most patients in both groups had disease progression at 2 years after initial treatment. In a sub-group analysis, a survival difference between patients with peritoneal dissemination (Fig. 2a, MST; 12 months in the study group and 7 months in control group) or positive peritoneal washing cytology (Fig. 2b, MST; 22 months in the study group and 13 months in control group) was observed between groups (P = 0.014 and P = 0.049, respectively). Figure 1Open in figure viewerPowerPoint Overall survival (a) and progression-free survival (PFS) (b) in the study (solid line) and the control groups (dotted line). (a) The MST in the study and control groups was 20 and 10 months, respectively. The 1- and 2-year survival rates were 65% and 34%, respectively, in the study group, and 45% and 3.5%, respectively, in the control group. (b) A significant difference in PFS was observed between groups (median PFS; 13.5 months in the study group and 6.8 months in the control group, P = 0.048) Figure 2Open in figure viewerPowerPoint Comparison of overall survival curves in the study group (solid line) and the control group (dotted line) according to peritoneal metastasis (a) and positive peritoneal washing cytology (b). (a) There was a significant survival difference for patients with peritoneal dissemination between the study group (median survival time (MST); 12 months) and the control group (7 months, P = 0.014). (b) A significant difference in the overall survival of patients with positive peritoneal washing cytology in the study group and (MST; 22 months) and the control group (13 months) was observed between groups (P = 0.049). Overall survival curves of patients who did (solid line) and who did not (dotted line) undergo conversion surgery in the study group (c) and the control group (d). The MST in patients who underwent conversion surgery was significantly longer than that in patients who did not undergo conversion surgery in the study group (27.8 months vs. 14.2 months, respectively) as well as in the control group (not reached vs. 9 months; P < 0.05) Conversion surgery Conversion surgery was performed for six patients (four with peritoneal dissemination and two with positive cytology; five R0 and one R1 resections) in the study group, which was significantly higher than two patients with positive cytology who underwent margin-negative resections in the control group (P = 0.032). No in-hospital deaths occurred in this study. As shown in Figure 2c,d, the MST in patients who underwent conversion surgery was significantly longer in the study group (27.8 months vs. 14.2 months, respectively) as well as in the control group (not reached vs. 9 months) compared with the MST in patients who did not undergo conversion surgery (P < 0.05). Table S1 summarizes the details of patients who underwent conversion surgery. Postoperatively, disease relapse was found in the liver in one patient, in a local region in two patients, and in the peritoneum in two patients at 8–9 months after surgical resection in the study group. Only one patient is still surviving without disease relapse for 29 months after pancreatectomy and for 41 months after initial treatment. Univariate and multivariate analyses for OS As shown in Table 2, four factors, which were implementation of i.v./i.p. PTX with S-1, conversion surgery, presence of ascites on the initial presentation, and normalization of CA19-9, were identified as significant for OS in a univariate analysis. Multivariate analysis revealed that implementation of i.v./i.p. PTX with S-1 and conversion surgery were significantly independent prognostic factors in this study (P < 0.05, hazard ratio; 0.703 and 0.455, respectively). Table 2. Univariate and multivariate analyses Parameters Univariate analysis Multivariate analysis HR (95% CI) P-value HR (95% CI) P-value Gender, Male: Female 1.01 (0.75–1.36) 0.931 Age, < 66: ≥ 66 years 0.99 (0.73–1.32) 0.883 Group, Control: Study 0.64 (0.46–0.88) 0.006 0.703 (0.493–0.985) 0.041 Location, Ph: Pbt 0.96 (0.71–1.32) 0.784 Primary tumor diameter, < 41: ≥ 41 mm 0.78 (0.57–1.06) 0.107 Peritoneal dissemination, none: present 0.80 (0.59–1.07) 0.137 Presence of ascites at initial presentation, none: present 0.71 (0.51–0.97) 0.030 0.888 (0.607–1.271) 0.524 CA19-9, < 376: ≥ 376 U/ml 1.10 (0.82–1.49) 0.510 Normalization of CA19-9, none: achieved 0.65 (0.46–0.89) 0.007 0.832 (0.560–1.220) 0.350 Conversion surgery, none: done 0.40 (0.23–0.63) 0.001 0.455 (0.254–0.746) 0.001 Underline indicates the responsible parameters for analysis CA19-9 carbohydrate antigen 19-9, CI confidential interval, HR hazard ratio, Pbt pancreatic body and tail, Ph pancreatic head Profile of adverse events As shown in Table 3, hematologic adverse events included neutropenia (60%), leukopenia (30%), febrile neutropenia (10%), and thrombocytopenia (10%), and non-hematologic adverse events included appetite loss in 15% and vomiting and diarrhea in 10% in the study group. These adverse events were highly developed in the study group, relative to the control group. A total of three of 20 patients in the study group discontinued treatment within 1 month, and four of 29 patients in the control group did not start chemotherapy. One of these patients died of superior mesenteric arterial thrombosis after the first infusion of this regimen in the study group. Complications related to the peritoneal access device presented as infection of the i.p. catheter in one patient and dislocation of the device in one patient. Table 3. Profile of G3 and G4 adverse events by CTCAE v4.0 Grade 3 and 4 adverse events, n (%) Study group (n = 20) Control group (n = 29) P-value Leucocytopenia 6 (30) 3 (10) 0.083 Neutropenia 12 (60) 7 (24) 0.011 Febrile neutropenia 2 (10) 0 0.054 Anemia 1 (5) 2 (7) 0.783 Thrombocytopenia 2 (10) 1 (3 0.351 General fatigue 0 0 – Appetite loss 3 (15) 1 (3) 0.147 Vomiting 2 (10) 1 (3) 0.302 Diarrhea 2 (10) 0 0.054 Mucositis oral (stomatitis) 0 0 – Discussion Recent progress in chemotherapy has provided an improved MST in patients with unresectable PDAC from 6–8 months to 8.5–11.5 months 14-16. A few authors have reported that the prognosis of PDAC patients with peritoneal metastasis remains extremely poor (MST, 6–7 weeks) 3, 4. However, the natural history of patients with peritoneal metastasis still remains unknown. We have reported that most PDAC patients with peritoneal metastasis suffered from massive ascites, showed poor performance status, and received less opportunity for chemotherapy 5. Staging laparoscopy can provide important information on the presence of minute distant organ metastasis in patients with unresectable locally advanced PDAC 6, 17, 18. Clark et al. 17 have reported that staging laparoscopy upstaged 58 of 202 patients (29%) to stage IV, 20% (n = 41) of patients had positive peritoneal lavage cytology, 13% (n = 26) had hepatic metastases, and just 3% (n = 5) had peritoneal metastases. Ferrone et al. 6 also reported that distant metastatic disease was identified in 150 patients (32%) of the 462 PDAC patients who underwent staging laparoscopy and peritoneal cytology. They reported an MST of 7 months in patients with PDAC with peritoneal dissemination, and 6 months in patients with locally advanced disease who had positive peritoneal washing cytology during staging laparoscopy. Our previous report also revealed an MST of 8 months in PDAC patients with peritoneal dissemination and 13 months in patients with locally advanced disease who had positive peritoneal washing cytology diagnosed by staging laparoscopy for radiographically defined locally advanced PDAC 5. Moreover, we also reported that pancreas body-tail tumors and tumor size >42 mm in 110 patients with radiographically-defined locally advanced PDAC were significantly risk factors for peritoneal metastasis 19. In this study, 65.4% of patients with pancreas body-tail tumors >42 mm had peritoneal metastasis. Peritoneal metastasis was defined as the presence of positive peritoneal washing cytology in patients with unresectable locally advanced PDAC and peritoneal dissemination in any category of resectability status. This is clearly a very select group of patients with only peritoneal metastasis and no other distant organ metastases. Very recently, results of a multi-center phase II study to investigate the clinical efficacy of this regimen revealed a response rate of 36% (12/33), a conversion rate of 24% (8/33), an MST of 16.3 (11.47–22.57) months, and a 1-year survival rate of 62% 12. The current study focused on the clinical efficacy and feasibility of i.v./i.p. PTX+S-1 therapy in comparison with S-1- or gemcitabine-based chemotherapy in chemotherapy-naïve patients with peritoneal metastasis without metastasis in other distant sites. The MST, and 1- and 2-year OS were 20 months, 65% and 34%, respectively, in the study group, and 10 months, 45% and 3.5%, respectively, in the control group, when all patients were followed up for at least 26 months. Considering that the patients with peritoneal metastasis generally have a particularly poor prognosis, favorable performance of the i.v./i.p. PTX + S-1 combination was revealed. In the current study, patients in the study group had a longer administration of first-line chemotherapy, 9.0 (0.8–21.8) vs. 6.0 (0–15) months, a higher response rate (45% vs. 28%), and a lower frequency of ascites development within 1 year after initial treatment relative to the control group (25% vs. 62%, respectively). Moreover, peritoneal washing cytology became negative in 90% of patients in the study group. These favorable clinical responses allowed surgeons to perform conversion surgery in selected patients. Generally, only a small fraction of patients with PDAC is eligible for conversion surgery, and in our experience, only 13 of 130 patients (10%) with initially unresectable locally advanced PDAC underwent surgical resection after a favorable response to chemo(radio)therapy 20. The MST after conversion surgery for patients with PDAC has previously been reported to reach 30–52 months 20-23. Surprisingly, the rate of conversion surgery was 30% (6/20) in the study group, which was significantly higher than the rate of 7% (2/29) in the control group (P = 0.032). Tumor remission was pathologically observed in all patients who underwent conversion surgery. The MST in patients who underwent conversion surgery was 27.8 months in the study group, which was significantly higher than 14.2 months in patients who did not undergo conversion surgery. This finding was also observed in the control group. Ishigami et al. suggested that i.p. administration of anticancer drugs enabled an extremely high concentration of drugs to directly contact the target cancer lesions in the peritoneal cavity due to their large molecular weight and fat solubility 9. Thus, the i.v./i.p. PTX + S-1 combination has shown remarkable performance, both in terms of the high conversion rate and the improved outcomes of patients who underwent conversion surgery. Although PFS was more favorable in the study group than in the control group (P = 0.048), the PFS rate at 2 years after initial treatment was 5.0% in the study group, and 3.5% in the control group. This finding may indicate that this regimen is not a curative option in patients with peritoneal metastasis, even in the study group. Exploration of a better way to prolong PFS is warranted. The clinical effect of i.p. PTX combined with FOLFIRINOX or Gemcitabine+nab-PTX should be investigated in clinical trials. The limitations of this study are as follows: retrospective and non-randomized nature, small sample size, different systemic chemotherapy regimen in the control group. The comparison between different chronological data, may affect survival. Sustainable efforts are warranted to conduct well-designed, randomized clinical trials to confirm the efficacy of this combination in the subset of PDAC patients with a high risk for death due to peritoneal disease. In conclusion, implementation of the S-1+i.v./i.p. PTX regimen was closely associated with the prevention of ascites and higher resectability, resulting in the improvement of OS in chemotherapy-naïve patients with PDAC with peritoneal metastasis. Conflict of interest None declared. Author contributions Study design: Sohei Satoi and Hiroaki Yanagimoto. Acquisition of data: Sohei Satoi, Tomohisa Yamamoto, Satoshi Hirooka, So Yamaki, Hisashi Kosaka, and Yuki Hashimoto. Analysis and interpretation: Sohei Satoi, Hiroaki Yanagimoto, Tomohisa Yamamoto Kentaro Inoue, and Masanori Kon. Manuscript drafted by: Sohei Satoi. Revision: all authors. Statistical advice: Yoichi Matsui and Masanori Kon. All authors approved the final draft of the article. Supporting Information Filename Description jhbp447-sup-0001-TableS1.docxWord document, 24.7 KB Table S1. Clinical characteristics of patients who underwent conversion surgery. 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