Objectives
The primary objective of this study is to confirm the superiority of S1-PTX compared with GnP in patients with PDAC with peritoneal metastasis.
Study design
Multicenter, two-arm, open-label, randomized Phase Ⅲ trial
Endpoints
The primary endpoint is OS in all randomized patients. OS is calculated from the day of randomization to the day of death from any cause and censored at the last day that the patient is alive. The secondary endpoints are ORR, progression-free survival (PFS), proportion of patients with negative peritoneal washing cytology, alleviated cancer symptoms (intestinal ileus, ascites, hydronephrosis, etc.), decreased tumor marker levels, proportion of patients eligible for conversion surgery, % planned dose of chemotherapy, and safety (adverse event profile, etc.). PFS is defined as survival from the day of randomization to disease progression or death from any cause and is censored at the last day the patient is alive without any evidence of progression. Conversion surgery is planned for patients who are expected to have margin-negative resection with negative peritoneal washing cytology and disappearance of peritoneal dissemination during chemotherapy.
Inclusion criteria
・PDAC by histological or cytological diagnosis
・Presence of microscopic peritoneal metastasis during staging laparoscopy in patients with radiographically defined unresectable locally advanced PDAC or presence of macroscopic peritoneal dissemination on staging laparoscopy or open laparotomy in all types of PDAC
・Chemo(radio)therapy-naive or within 3 months from initiation of chemo(radio)therapy and no progressive disease during the 3 months
・Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
・Spared organ function satisfying the following laboratory data:
white blood cell count ≥3500/mm3 and <12000/mm3,
neutrophils ≥2000/mm3,
hemoglobin ≥8.0 g/dl,
platelet count ≥100000/mm3,
serum total bilirubin ≤2.0 mg/dl (or ≤3.0 mg/dl in patients with biliary drainage),
aspartate aminotransferase (AST) ≤150 IU/l,
alanine aminotransferase (ALT) ≤150 IU/l,
creatinine ≤1.2 mg/dl,
creatinine clearance ≥50 ml/min,
・Adequate oral intake
・Age 20-79 years
・Provision of written, informed consent
Exclusion criteria
・Presence of metastasis in other distant organs, such as the liver, lungs, bone or others, excluding the ovaries
・Presence of microscopic peritoneal metastasis in patients with resectable or borderline resectable PDAC without macroscopic peritoneal dissemination
・Allergy to chemotherapeutic agents (S-1, PTX, gemcitabine, nab-PTX)
・Unstable angina pectoris or myocardial infarction
・Serious co-existing illness (ileus, pulmonary fibrosis, interstitial pneumonia, unstable diabetes mellitus, renal failure, liver cirrhosis, etc.)
・Massive ascites extending continuously from the pelvic cavity to the upper abdominal cavity
・Bleeding in the alimentary tract with repetitive blood transfusion
・Severe diarrhea
・Psychiatric disease
・Synchronous malignancy except for carcinoma in situ or intramucosal tumor after adequate curative treatment
・Pregnancy, breast-feeding or desire of a woman to preserve fertility
・Regular use of fructosin, phenytoin or warfarin
・Cancer invasion to gastric or intestinal mucosa in the alimentary tract
Randomization
After confirmation of eligibility, including written informed consent, eligible patients are registered centrally and assigned randomly to treatment. Central randomization and registration are carried out with an electronic data capture (EDC) system. After being assessed for eligibility at registration, patients are randomized centrally to either the S1-PTX arm or the GnP arm (Fig.1). Randomization is performed by minimization methods to which the investigators are masked. Patients are stratified according to institution, peritoneal dissemination, and resectability status of the primary tumor defined according to the NCCN guideline 14).
Treatment
In the S1-PTX arm, PTX is administered i.v. at a dose of 50 mg/m2 and i.p. at 20 mg/m2 on days 1 and 8, and S-1 is administered orally at a dose according to body surface area (BSA), as follows: BSA<1.25 m2, 40 mg; BSA 1.25-1.50 m2, 50 mg; BSA>1.50 m2, 60 mg, twice daily on days 1-14 of a 21-day cycle. PTX is diluted in 500 ml of normal saline and administered after administration of 500 ml of normal saline through the implanted peritoneal access port over 1 hour concurrently with i.v. infusion after standard premedication.
Chemotherapy is started when patients’ recovery status fulfills the following criteria on day 1 of each cycle of treatment: neutrophil count >1,500/mm3, platelet count >75,000 /mm3, creatinine <1.2 mg/dl, no febrile neutropenia, grade 1 or lower oral mucositis, diarrhea, and skin rash.
In the GnP arm, nab-PTX 125 mg/m2 is administered in combination with gemcitabine 1000 mg/m2 weekly for 3 weeks followed by one week of rest (4-week cycles).
Chemotherapy is started when patients’ recovery status fulfills the following criteria on day 1 of each cycle of treatment: neutrophil count >1,500/mm3, platelet count >75,000 /mm3, creatinine <1.2 mg/dl, no febrile neutropenia, grade 1 or lower oral mucositis, diarrhea, and peripheral sensory neuropathy.
Two levels of dose modifications are permitted according to the criteria. If toxicity requiring dose modification occurs following the second dose reduction of either study drug, further treatment should be discontinued.
In both arms, protocol treatment will be continued until disease progression, unacceptable toxicity, conversion surgery with exceptional response or patient refusal.
Discontinuation criteria
・Patient withdrawal of consent for participation.
・Adverse events directly attributable to the investigating treatment prohibiting resumption of treatment within 28 days.
・Disease progression confirmed by diagnostic imaging, etc.
・Requirement for and initiation of radiation therapy.
・Indication for and performance of surgery.
・Discontinuation of the entire study.
Follow-up
Enhanced abdominal CT and chest CT for assessing tumor response according to RECIST ver.1.1 15) and assessments of tumor markers (CA19-9, CA125 and CEA) are carried out every 8 to 9 weeks during protocol treatment in all randomized patients. In the S1-PTX arm, peritoneal (washing) cytology is evaluated every 8 to 9 weeks.
Physical examinations, complete blood counts (CBCs), and blood chemistry assessments are performed at each administration of i.v. chemotherapy in both groups. All adverse events are assessed according to the Common Terminology Criteria for Adverse Events, version 4.0. Quality of life is assessed with the EuroQOL-5 Dimension Questionnaire (EQ-5D) 16) and the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) 17) at baseline and every 8 to 9 weeks.
Data are collected via a case report form using an EDC system and paper and stored and managed securely by the data monitoring committee. To promote data quality, missing data will be pursued until received or confirmed as not available or until the trial reaches analysis.
Study design and statistical analysis
This randomized trial is designed to confirm the superiority of S1-PTX in patients with PDAC with peritoneal metastasis. We assumed that the MST of GnP was 9.0 months and that of S1-PTX was 14.0 months based on previous studies 4,13). According to these assumed values, the hazard ratio was calculated to be 0.643. Given the assumption of a power of 80% or higher and a two-sided significance level of 0.05, the required minimum sample size was 85 patients per group. The planned accrual period is 3 years and the follow-up period is 1.5 years for the primary analysis. Accordingly, the sample size was set as 90 patients or more per group with an assumption that a few patients would become ineligible for this trial.
The survival analysis is based on the intent-to-treat population, which includes all eligible patients enrolled in this trial, with survival estimates calculated using the Kaplan-Meier method and compared using the stratified log-rank test. Survival estimates are presented with 95% confidence intervals. Hazard ratios and 95% confidence intervals will be estimated by the Cox proportional hazard model. P <0.05 will be considered significant.
The data monitoring committee and study coordinator (Clinical Study Support Center, Wakayama Medical University School of Medicine) will conduct central monitoring and will issue a monitoring report every 6 months to evaluate study progress and improve data integrity and patient safety.
Ethics
This study is performed in accordance with the Declaration of Helsinki. This protocol was approved by the Wakayama Medical University Hospital Clinical Research Review Board on October 18, 2019. This study has been registered with the Japan Registry of Clinical Trials, and the registration number is jRCTs051180199 (https://jrct.niph.go.jp/).