Phase III Trial Comparing Intraperitoneal and Intravenous Paclitaxel Plus S-1 Versus Cisplatin Plus S-1 in Patients With Gastric Cancer With Peritoneal Metastasis: PHOENIX-GC Trial
Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival.
This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (< 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m2 and intravenous paclitaxel 50 mg/m2 on days 1 and 8 plus S-1 80 mg/m2 per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m2 per day on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety.
We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated.
The prognosis of gastric cancer with peritoneal metastasis remains poor despite recent advances in systemic chemotherapy.1-5 Patients are generally treated with systemic chemotherapy in the same way as patients with other distant metastases, with a combination of platinum and fluoropyrimidines for first-line treatment and paclitaxel (PTX) plus ramucirumab for second-line treatment.6-8 However, given that only a small fraction of the systemically administered drug is delivered to the peritoneum, it seems reasonable to approach peritoneal metastasis directly, using intraperitoneal chemotherapy. A meta-analysis of adjuvant intraperitoneal chemotherapy demonstrated a survival benefit,9 but two randomized control trials yielded conflicting results.10,11 Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy has shown effectiveness in patients with limited peritoneal metastasis.12,13 Moreover, there are preliminary reports of the effectiveness of intraperitoneal PTX with systemic chemotherapy, originally developed for ovarian cancer and supported by convincing clinical trials,14,15 in gastric cancer with peritoneal metastasis.16,17
We designed a regimen combining weekly intraperitoneal PTX with S-1 (tegafur, gimeracil, oteracil potassium) plus intravenous PTX that showed activity in a phase II trial.18 The recommended dose of intraperitoneal PTX was determined to be 20 mg/m2,19 and the 1-year overall survival rates were 77% and 78% in two phase II trials.20,21 The median survival time (MST) of 100 patients treated with this regimen at the University of Tokyo Hospital was 20.6 months.22 In this trial, we aimed to assess the safety and efficacy of intraperitoneal and intravenous PTX plus S-1 (IP) compared with the Japanese standard regimen of S-1 plus cisplatin (SP) in patients with gastric cancer with peritoneal metastasis.
Eligibility criteria included pathologically proven primary gastric adenocarcinoma, peritoneal metastasis, no or short-term (< 2 months) previous chemotherapy without disease progression, age 20 to 74 years, Eastern Cooperative Oncology Group performance status of 0 or 1, adequate oral intake, and adequate organ function. Exclusion criteria included distant metastasis other than peritoneal or ovarian metastasis, previous palliative gastrectomy, and massive ascites requiring frequent drainage for palliation.
The institutional review board or independent ethics committee of each participating center approved this study. The Ministry of Health, Labour and Welfare of Japan acknowledged the IP regimen in the Advanced Medical Treatment System, which is a verification system for including new medical treatments in the public health insurance coverage. This trial followed the ethical principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research. All patients provided written informed consent.
Patients were randomly assigned at a two-to-one ratio to receive IP or SP by a minimization method, stratified by center, previous chemotherapy (present v absent), and extent of peritoneal metastasis (P1 v P2/P3). Peritoneal metastasis was categorized according to the Japanese Classification of Gastric Carcinoma (first English edition)23 as follows: P1, metastatic nodule(s) limited to the adjacent peritoneum; P2, several scattered metastatic nodules within the peritoneal cavity; and P3, numerous metastatic nodules throughout the peritoneal cavity. Because the distinction between P2 and P3 is ambiguous, these categories were expediently integrated into a P2/P3 category, which also included advanced peritoneal metastasis diagnosed only via imaging.
Patients with peritoneal metastasis confirmed by previous laparoscopy, laparotomy, or imaging were randomly assigned and then underwent laparoscopy and intraperitoneal port implantation if allocated to the IP arm. Implantation of a peritoneal catheter instead of a port and omission of laparoscopy were allowed for patients with obvious peritoneal metastasis on imaging and sufficient ascites for percutaneous puncture. Patients with suspected peritoneal metastasis on imaging underwent diagnostic laparoscopy and were randomly assigned if peritoneal metastasis was confirmed. Intraperitoneal ports were implanted in the patients allocated to the IP arm. The peritoneal cancer index24 was calculated if the whole peritoneal cavity was successfully evaluated laparoscopically.
The IP regimen comprised intraperitoneal PTX 20 mg/m2 and intravenous PTX 50 mg/m2 on days 1 and 8 plus oral S-1 80 mg/m2 per day (40 to 60 mg twice per day, depending on body surface area, as follows: < 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and ≥ 1.5 m2, 60 mg) on days 1 to 14 of every 3-week cycle. PTX was diluted in 500 mL of normal saline and administered intraperitoneally via an intraperitoneal port or catheter over 1 hour, after intraperitoneal administration of 500 mL of normal saline. The SP regimen comprised intravenous cisplatin 60 mg/m2 on day 8 plus oral S-1 80 mg/m2 per day on days 1 to 21 of every 5-week cycle. Patients received protocol treatment until disease progression, unacceptable toxicity, investigator decision, or patient withdrawal. Intraperitoneal chemotherapy was prohibited after receiving protocol treatment in the SP arm.
The primary end point was overall survival in the full analysis set (FAS) after 2-year follow-up from the completion of patient enrollment. Secondary end points were response rate, 3-year overall survival rate after 3-year follow-up, and safety. The response rate, defined as the proportion of patients with a best overall response of complete or partial response, was assessed in patients with target lesions based on the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1).25 The study protocol was revised before the primary analysis as advised by the Ministry of Health, Labour and Welfare of Japan on the grounds that some patients were still receiving IP at that time. We were advised to extend the study period by 1 year and to include the 3-year overall survival rate as a secondary end point. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).
Additionally, we exploratorily assessed response to chemotherapy in terms of the amount of ascites and the peritoneal cytology findings, indicative of peritoneal metastatic activity. The amount of ascites was evaluated by computed tomography and categorized as none, small (within the pelvic cavity), or moderate (beyond the pelvic cavity) at enrollment. The effect of treatment on ascites was assessed in patients with a moderate amount of ascites based on radiologic changes during the treatment period. In the IP arm, peritoneal cytology was performed at initial laparoscopy and on the first day of every treatment cycle, using peritoneal lavage fluid obtained via the port. In the SP arm, peritoneal cytology was performed at initial laparoscopy as well as second-look laparoscopy, if performed.
This study was designed to verify the superiority of IP over SP in terms of overall survival. On the basis of the results of previous studies,1,20-22 we expected MSTs of 22 and 11 months in the IP and SP arms, respectively. A required sample size of 170 patients was calculated using the Lakatos method,26 assuming a log-rank test with a two-sided α of 0.05 and statistical power of 90%, and therefore, the target sample size was set at 180 patients. We used the log-rank test, stratified by previous chemotherapy (present v absent) and extent of peritoneal metastasis (P1 v P2/P3), to assess overall survival. Survival curves were estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using a stratified Cox regression model. The proportion of patients with an objective response was compared using Fisher’s exact test. Analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC). Two interim analyses were scheduled after enrollment of 90 and 160 patients, and therefore, the final analysis of the primary end point used a significance level of 4.976%, based on the O’Brien-Fleming method. The primary efficacy analyses were performed using the FAS, including all randomly assigned eligible patients who received the allocated treatment. Safety analyses were performed using the all-patients-treated set (APTS). Sensitivity analyses for overall survival were performed using the APTS and the per-protocol set (PPS), defined as patients without protocol violations. The follow-up period, treatment periods, and relative dose-intensities were analyzed using the APTS.
We performed post hoc subgroup Cox regression analyses of overall survival to assess the consistency of the effect across subgroups. The best response in the amount of ascites, classified as disappeared, decreased, no change, or increased by independent radiologists was compared between treatment groups using the Mantel test.
Between October 2011 and November 2013, we enrolled 183 patients from 20 centers in Japan. Figure 1 shows the trial profile at the primary analysis cutoff date. The results of the interim analyses did not meet the efficacy or futility early stopping criteria. Therefore, follow-up continued for 2 years and was extended for 1 additional year as described in Patients and Methods. The median follow-up period for censored patient cases was 30.1 months (interquartile range [IQR], 25.9 to 36.5 months). The median duration of treatment was 39 weeks (IQR, 27 to 81 weeks) in the IP arm and 15 weeks (IQR, 10 to 30 weeks) in the SP arm. The median relative dose-intensities of intraperitoneal PTX, intravenous PTX, and S-1 were 89.9% (IQR, 80.8% to 96.8%), 87.2% (IQR, 77.2% to 95.2%), and 84.6% (IQR, 73.3% to 93.5%), respectively, in the IP arm; those of cisplatin and S-1 were 94.6% (IQR, 82.5% to 100%) and 92.1% (IQR, 81.4% to 96.8%), respectively, in the SP arm. The median follow-up period was 41.7 months (IQR, 37.0 to 48.0 months) in the additional 1-year follow-up analysis.
On-site monitoring identified five of 169 treated patients deemed ineligible by the data and safety monitoring board after having received protocol treatment, and consequently, the FAS for the primary efficacy analysis comprised 164 patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had more ascites (P = .015; Table 1). Another six patients in the SP arm were found to have received intraperitoneal chemotherapy against the protocol; these six patients were excluded from the PPS for the sensitivity analysis.
The MST was 17.7 months (95% CI, 14.7 to 21.5 months) in the IP arm and 15.2 months (95% CI, 12.8 to 21.8 months) in the SP arm (HR, 0.72; 95% CI, 0.49 to 1.04; P = .080; Fig 2A). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm (Fig 2B). The response rate was 53% (nine of 17; 95% CI, 31% to 74%) in the IP arm and 60% (three of five; 95% CI, 12% to 77%) in the SP arm (P = 1.0).
According to the sensitivity analysis in the APTS, the MST was 17.7 months (95% CI, 14.3 to 21.3 months) in the IP arm and 14.8 months (95% CI, 12.3 to 21.8 months) in the SP arm (HR, 0.71; 95% CI, 0.50 to 1.03; P = .067). In the PPS excluding the patients with postprotocol treatment violations, the MST was 17.7 months (95% CI, 14.7 to 21.5 months) in the IP arm and 14.3 months (95% CI, 12.1 to 17.7 months) in the SP arm (HR, 0.64; 95% CI, 0.43 to 0.94; P = .022). In an additional post hoc sensitivity analysis adjusted for baseline ascites using the FAS, overall survival was longer in the IP arm than in the SP arm (adjusted HR, 0.59; 95% CI, 0.39 to 0.87; P = .008).
In the subgroup analysis of overall survival, we detected significant interaction between treatment effect and amount of ascites (P = .001; Fig 3). The analysis of the amount of ascites showed that patients in the IP arm had more favorable responses (P = .001; Table 2). Peritoneal cytology was positive at enrollment in 93 (82%) of all 114 eligible patients in the IP arm and in 31 (78%) of 40 assessed patients in the SP arm. Of those with positive cytology who were reassessed at least once during the treatment period, peritoneal cytology reverted to negative in 69 (76%) of 91 patients in the IP arm and in three (33%) of nine patients in the SP arm.
The most common grade 3 or 4 adverse events were leukopenia, neutropenia, anemia, and anorexia in both arms (Table 3). Grade 3 or 4 leukopenia (25% v 9%; P = .023) and neutropenia (50% v 30%; P = .028) were more frequent in the IP arm. Nonhematologic toxicities were tolerable, with no differences between the arms. Eight adverse events related to intraperitoneal ports were observed in seven (6%) of 116 patients: intraperitoneal port infection (n = 3), catheter obstruction (n = 3), subcutaneous hematoma (n = 1), and fistula between the catheter and small intestine (n = 1). All patients recovered after either removal of the intraperitoneal port (n = 5) or conservative treatment (n = 2). None developed infectious peritonitis or other severe complications. There were neither unexpected serious adverse events nor deaths related to the protocol treatment.
The effect of anticancer drugs generally depends on the concentration and duration of tumor exposure to the drugs. Intraperitoneal chemotherapy enables intraperitoneal tumors to be exposed to high concentrations of drugs, without increasing the blood concentration to toxic levels. The effective duration after intraperitoneal administration is determined by the molecular characteristics of the drugs: small molecular hydrophilic drugs such as cisplatin and mitomycin C are rapidly absorbed, whereas large molecular lipophilic drugs such as PTX and docetaxel are slowly absorbed.14 In addition to this pharmacokinetic advantage, intraperitoneal PTX rarely causes adhesions in the peritoneal cavity, which enables long-term repeated administration. However, PTX infiltrates only the surface of the peritoneal tumor; it is not delivered to areas with adhesions in the peritoneal cavity. To obtain the maximum effect against these limitations, intraperitoneal PTX should be repeated frequently with systemic chemotherapy. Drug selection, frequency, duration of administration, and combination with systemic chemotherapy are key in intraperitoneal chemotherapy. On the basis of these concepts, we developed a regimen combining weekly intraperitoneal PTX with S-1 plus intravenous PTX.19-21 The serum and intraperitoneal concentrations of PTX remained above the effective dose for > 48 and 72 hours, respectively.19 In phase II trials, the 1-year overall survival rates were 77% and 78%.20,21 These promising results encouraged us to proceed with this phase III trial.
This is the first randomized clinical trial to our knowledge to compare combined intraperitoneal and systemic chemotherapy with systemic chemotherapy in gastric cancer with peritoneal metastasis. The primary analysis in the FAS failed to show statistical superiority of the IP regimen despite a prolongation of the MST by 2.5 months and an HR of 0.72. However, the following exploratory analyses suggested clinical benefits of the IP regimen: the sensitivity analysis adjusted for baseline ascites, the sensitivity analysis in the PPS excluding patients with postprotocol treatment violations, the follow-up analysis with the 3-year overall survival rate, and the comparison of treatment response in the amount of ascites. Considering the results of these analyses, the efficacy of the IP regimen seems underestimated by the primary analysis as a result of the unexpected imbalance in the amount of ascites and the crossover from SP to IP.
The results of the primary analysis were most seriously affected by the baseline imbalance between the arms. The extent of peritoneal metastasis should be included as a stratification factor because of its potential relationship to prognosis. We adopted the Japanese Classification of Gastric Carcinoma (P1 v P2/P3), the most common and intensively investigated classification in Japan, for stratification, assuming the proportion of P1 to be 10% to 20% from our clinical experience. However, only six (4%) of 164 patients had P1 metastasis; therefore, this stratification was ineffective in ensuring equal allocation. Furthermore, there was a crucial imbalance in the amount of ascites that may have favored the SP arm. The difference in the peritoneal cancer index also suggested an imbalance in the extent of peritoneal metastasis, although the values were not comparable between the arms because of missing data. Given these circumstances, the results of the exploratory analysis adjusting for the imbalance, which showed an adjusted HR of 0.59 (95% CI, 0.39 to 0.87), should be considered in evaluating efficacy.
The results of the primary analysis were also affected by the crossover between arms. Although intraperitoneal chemotherapy was prohibited as postprotocol treatment in the SP arm, six patients received intraperitoneal chemotherapy after having received SP. The sensitivity analysis excluding these patients yielded inconclusive results, but the data, with a P value of .022 and an HR of 0.64 (95% CI, 0.43 to 0.94), suggest the efficacy of the IP regimen. This violation and the pretreatment withdrawal of another six patients allocated to the SP arm occurred inevitably, because many patients visited our trial centers hoping to receive intraperitoneal chemotherapy. It is ethically unacceptable to refuse patients’ withdrawal, even if it will affect the results of the trial.
We previously reported the usefulness of evaluating the amount of ascites by computed tomography27 and peritoneal cytology using an intraperitoneal port28 in patients treated with the IP regimen. In this trial, the IP arm showed better response in the amount of ascites. Moreover, the IP arm showed a high negative conversion rate (78%) on peritoneal cytology. These results further support the clinical benefits of the IP regimen.
Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy has been applied in gastric cancer with peritoneal metastasis.12,13 In a large retrospective study, the MST was 9.2 months and the mortality rate was 6.5%. The authors concluded that long-term survival could only be achieved in patients with limited peritoneal metastasis at experienced institutions.12 Even with cytoreductive surgery and hyperthermia, bolus intraperitoneal chemotherapy for 30 to 60 minutes with mitomycin C or oxaliplatin may not be sufficiently effective. Although a direct comparison is difficult, our strategy of long-term intraperitoneal PTX could be more convenient, safer, and probably more effective, especially in patients with advanced peritoneal metastasis.
Hematologic and nonhematologic toxicities were acceptable in both arms, with the incidence and severity within the range of those of common chemotherapy regimens.1-3 Intraperitoneal port-related adverse events were less frequent than in our initial experience29 and in a phase III trial of ovarian cancer,30 probably by virtue of the manual that had been completed based on the initial experience before starting this trial.
In conclusion, this trial failed to show statistical superiority of intraperitoneal PTX plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal PTX for gastric cancer. The IP regimen is now being tested in another single-arm trial, having enrolled 111 patients under the newly established Patient-Requested Medical Treatment System in Japan. In addition, several clinical trials of intraperitoneal chemotherapy with other systemic chemotherapy were recently completed or are ongoing or planned. The results of these trials are awaited to confirm the efficacy of intraperitoneal chemotherapy for gastric cancer.
Supported by the Japan Agency for Medical Research and Development and by Nippon Kayaku and Sawai Pharmaceutical, which provided paclitaxel for intraperitoneal administration.
Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 3-7, 2016, and the European Society for Medical Oncology Congress, Copenhagen, Denmark, October 7-11, 2016.
Written on behalf of the Japan Intraperitoneal Chemotherapy Study Group.
Clinical trial information: UMIN000005930.
Conception and design: Hironori Ishigami, Ryoji Fukushima, Atsushi Nashimoto, Hiroshi Yabusaki, Motohiro Imano, Haruhiko Imamoto, Yasuhiro Kodera, Yoshikazu Uenosono, Hironori Yamaguchi, Takuhiro Yamaguchi, Joji Kitayama
Collection and assembly of data: Hironori Ishigami, Yoshiyuki Fujiwara, Ryoji Fukushima, Hiroshi Yabusaki, Motohiro Imano, Yasuhiro Kodera, Yoshikazu Uenosono, Kenji Amagai, Shigenori Kadowaki, Hiroto Miwa, Hironori Yamaguchi, Tempei Miyaji
Data analysis and interpretation: Hironori Ishigami, Takuhiro Yamaguchi, Joji Kitayama
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Honoraria: Taiho Pharmaceutical
Research Funding: Taiho Pharmaceutical (Inst), Chugai Pharma (Inst)
No relationship to disclose
Research Funding: Taiho Pharmaceutical (Inst), Eli Lilly (Inst), Ono Pharmaceutical (Inst)
No relationship to disclose
No relationship to disclose
No relationship to disclose
No relationship to disclose
Honoraria: Olympus, Chugai Pharma, Eli Lilly, Johnson & Johnson, Ajinomoto, Takeda Pharmaceuticals, Yakult Honsha, Taiho Pharmaceutical, Otsuka, Kaken Pharmaceutical, Ono Pharmaceutical, Asahi Kasei, Covidien/Medtronic, Merck Sharp & Dohme
Research Funding: Chugai Pharma (Inst), Daiichi Sankyo (Inst), Bristol-Myers Squibb Japan (Inst), Otsuka (Inst), Taiho Pharmaceutical (Inst), Takeda Pharmaceuticals (Inst), Abbott Japan (Inst), AbbVie (Inst), Sanofi (Inst), CSL Behring (Inst), Yakult (Inst), Eli Lilly Japan (Inst), Pfizer (Inst), Ono Pharmaceutical (Inst), Kaken Pharmaceutical (Inst), Tsumura (Inst), Merck (Inst), Covidien (Inst), Japan Blood Products Organization (Inst), Novartis (Inst), KCI Pharma (Inst), Maruho (Inst), EA Pharma (Inst)
No relationship to disclose
Research Funding: Taiho Pharmaceutical (Inst), Merck Sharp & Dohme (Inst)
Research Funding: Ono Pharmaceutical (Inst), Eli Lilly Japan (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst)
No relationship to disclose
No relationship to disclose
Consulting or Advisory Role: Ono Pharmaceutical, Kowa Pharmaceuticals, Japan Tobacco, Chugai Pharma, Tsumura, CAC Croit
Research Funding: AC Medical (Inst), A2 Healthcare (Inst), CAC Croit (Inst), Facet Biotech (Inst), Japan Tobacco (Inst), Japan Media (Inst), Luminary Medical (Inst), Medidata Solutions (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst)
Honoraria: Daiichi Sankyo
Research Funding: AC Medical (Inst), A2 Healthcare (Inst), CAC Croit (Inst), FMD K&L Japan (Inst), Japan Tobacco (Inst), Japan Media (Inst), Luminary Medical (Inst), Medidata Solutions (Inst), Ono Pharmaceutical (Inst)
Honoraria: Taiho Pharmaceutical
Research Funding: Eli Lilly Japan, Chugai Pharma, Merck Serono, Taiho Pharmaceutical
Travel, Accommodations, Expenses: Taiho Pharmaceutical
We thank all the patients and their families; investigators; support staff; members of the data and safety monitoring board (Takeshi Sano, Kei Muro, and Naoki Ishizuka); staff of the Clinical Research Support Center of the University of Tokyo Hospital; Yukari Uemura and Takuya Kawahara for statistical analyses; and Wei Peng Yong for review of this report.
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