Hyperthermic intraperitoneal chemotherapy plus SOX chemotherapy versus SOX chemotherapy alone in patients with gastric cancer and peritoneal metastasis: a phase II randomized clinical trial.

In 2020, gastric cancer (GC) ranked fifth in incidence and fourth in mortality globally ( 1 ). Later in 2022, GC ranked third in both incidence and mortality in China ( 2 ). Peritoneal metastasis (PM) appears to be the most common pattern of metastasis or recurrence in patients with GC and is discovered in 10–30% of patients with GC ( 3 ). Furthermore, more than 50% of patients with GC develop PM after radical resection ( 4 ). The prognosis of GC with PM (GCPM) is exceedingly poor, with a median survival of just 3–9 months ( 4 , 5 ). GCPM still lacks an internationally recognized standard treatment program that provides a significant curative effect, and systemic chemotherapy remains the recommended program in guidelines and consensus documents. Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery (CRS) has shown promising outcomes in GCPM, but several studies have reported that satisfactory CRS is a highly challenging surgery with problematic perioperative mortality and morbidity, limiting its use in the treatment of GCPM ( 6 - 8 ). HIPEC combined with chemotherapy has been reported to confer a statistically significant survival benefit for patients with GCPM ( 3 ), and S-1 and oxaliplatin (SOX) is recommended as one of the standard regimens for advanced GC according to the relevant guidelines ( 9 , 10 ). Therefore, we conducted a randomized trial to investigate the efficacy and safety of HIPEC with paclitaxel plus SOX in the treatment of GCPM. We present this article in accordance with the CONSORT reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-807/rc ).

This single-center, randomized controlled trial was conducted at Guangdong Provincial Hospital of Chinese Medicine (GPHCM) in China. The study protocol was approved by the ethical committee of GPHCM (No. Z2017-077-01). The study purpose and procedures were explained to all participants in detail on an information sheet, and written informed consent was obtained from each participant. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Eligibility criteria included pathologically proven primary gastric adenocarcinoma, clinically proven PM according to laparoscopy, an age 18–80 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an American Society of Anesthesiologists (ASA) score of I–III. Meanwhile, the exclusion criteria included pregnant or breast-feeding women; severe mental illness; preoperative imaging or intraoperative exploration revealing distant blood, liver, lung, or brain metastases; history of other malignancies within 5 year; history of unstable angina or myocardial infarction within 6 months; history of cerebral infarction or cerebral hemorrhage within 6 months; history of sustained systemic corticosteroid treatment within 1 month; emergency operation due to complications (bleeding, perforation, or obstruction) caused by the primary tumor; predicted forced expiratory volume in the first second (FEV1) <50% in pulmonary function testing; and a peritoneal nodule pathologically proven to not be metastasis. Patients with advanced GC underwent a laparoscopic exploration. If PM was found without other distant metastasis, then the patient was assigned a random number. The patients allocated to the HIPEC group were implanted with four catheters in the abdominal cavity (two inflow tubes were placed in the upper abdomen, and two outflow tubes were placed in the lower abdomen), while those allocated to the SOX group did not undergo catheterization. In the SOX group, patients were treated with systemic chemotherapy (oxaliplatin 100 mg/m 2 intravenously on day 1 and S-1 40–60 mg twice a day orally on days 1–14 in a 3-week cycle) the day after the laparoscopic exploration. In the HIPEC group, HIPEC was carried out for 60 minutes with paclitaxel (75 mg/m 2 intraperitoneally on day 1 and 50 mg/m 2 on days 2–3) in 1 L of physiologic saline maintained at 43 ℃ and was conducted on days 1, 3, and 5, respectively. Systemic chemotherapy was then administered within 1 month after the laparoscopic exploration, with those in the SOX group receiving the chemotherapy regimen. After three courses of SOX chemotherapy were completed, the curative effect was evaluated. Those who reached the standard of conversion surgery were treated with R0 resection, and subsequently, SOX chemotherapy was continued for a total of 6–8 cycles. Patients without progression after chemotherapy were administered S-1 single-agent maintenance therapy for 1 year. If patients progressed during the treatment, a new treatment plan was formulated after multidisciplinary team discussion according to the patient’s condition, and follow-up continued until the endpoint event occurred. The primary endpoint was progression-free survival (PFS), which was defined as the time from the laparoscopic exploration surgery to disease progression or the last follow-up. Progressive disease was assessed according to the Response Evaluation Criteria in Solid Tumors ( 8 ). The secondary endpoints were 1-year survival rate, overall survival (OS), and safety. The last follow-up date for the study was October 1, 2022. Adverse events were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study was designed to evaluate the efficacy of HIPEC in terms of PFS. On the basis of the results of previous studies ( 11 , 12 ), we expected a median PFS of 6.2 and 4.0 months in the HIPEC group and SOX group, respectively. Assuming a two-sided P value of 0.05 and a statistical power of 80%, a target sample size of 60 patients was calculated. Sixty random numbers were generated with an online random number generator and maintained by a third party. The generated random numbers were arranged from 1 to 60 in the order in which they appeared. The patients assigned even numbers were allocated to the HIPEC group, and those with odd numbers were allocated to the SOX group. The assessor and statistician were blinded to the treatment allocation throughout data collection and analysis. Quantitative data with a normal distribution and a homogeneity are expressed as the mean and standard deviation and were compared with the t -test. Quantitative data with a nonnormal distribution of measurement are expressed as the median and interquartile range (IQR) and were analyzed with the Wilcoxon rank-sum test. Differences in categorical data between groups were determined with the Chi-squared test or the Fisher exact test. Survival curves were estimated using the Kaplan-Meier method. The efficacy analyses were performed using the full analysis set (FAS) and included all randomly assigned eligible patients who received the allocated treatment. Post-hoc subgroup analyses of PFS and OS were also performed in terms of the amount of ascites and the peritoneal cancer index (PCI) to assess the consistency of the effect across subgroups. Safety analyses were performed using the safety set (SS), defined as patients without protocol violations and containing actual data with safety indicators. Data management and statistical analyses were conducted with SPSS software version 24.0 (IBM, Armonk, NY, USA). A P value <0.05 was considered to be significant.

Between August 2017 and September 2020, we enrolled 60 patients in the GPHCM. Among these, one patient was excluded due to the presence of endometriosis as opposed to PM. Two patients (one in each group) were lost to follow-up, and no valid data were available, so they were excluded from the analysis. Consequently, the FAS for the primary efficacy analysis comprised 57 patients. One patient in each group lacked essential safety data, and four patients in the SOX group did not receive SOX chemotherapy, so the SS comprised 53 patients. Figure 1 shows the trial profile at the analysis cutoff date (October 1, 2022). The median follow-up period for censored patient cases was 26 months (IQR, 23.5–48.5 months). A comparison of characteristics between the two groups of patients is provided in Table 1 . There was no difference between the two groups regarding the typical risk factors for survival, including age, male sex, body mass index, ECOG performance status, clinical T and N stages, or PCI, confirming that the groups were well matched. Trial profile at the primary analysis cutoff date. Data are presented as n (%), median (IQR) or mean ± SD. HIPEC, hyperthermic intraperitoneal chemotherapy; SOX, S-1 plus oxaliplatin; BMI, body mass index; PCI, peritoneal cancer index; IQR, interquartile range; SD, standard deviation. Survival analysis revealed that patients in the SOX group had a significantly higher median PFS than did those in the HIPEC group (SOX: median 8.5 months, IQR, 3.8−21.8 months; HIPEC: median 6.1 months, IQR, 3.3−10.8 months; P=0.004). Furthermore, the median OS in the SOX group was significantly higher than that in the HIPEC group (SOX: median 13.0 months, IQR, 6.3−16.6 months; HIPEC: median 10.0 months, IQR, 5.2−24.0 months; P=0.02) ( Figure 2 ). Primary analysis of the progression-free survival (A) and the overall survival (B). HR, hazard ratio; CI, confidence interval; HIPEC, hyperthermic intraperitoneal chemotherapy; SOX, S-1 and oxaliplatin. Subgroup analysis revealed that among patients with GCPM and PCI ≤6 or ascites 6 or ascites ≥1,000 mL, the median PFS and OS in HIPEC group were slightly higher, but not significantly so ( Table 2 ). Data are presented as median (IQR). HIPEC, hyperthermic intraperitoneal chemotherapy; SOX, S-1 plus oxaliplatin; PCI, peritoneal cancer index; IQR, interquartile range. The 1-year survival rate was 37.9% in HIPEC group and 50.0% in the SOX group, but this did not represent a statistically significant difference (P>0.05). However, in the subgroup analysis, HIPEC demonstrated promising outcomes in patients with GCPM and PCI >6, with a higher rate of 1-year survival (42.1% vs. 33.3%), but this difference was not statistically significant (P>0.05). After being treated either by systemic chemotherapy combined with HIPEC or systemic chemotherapy alone, 15 patients (6 in the HIPEC group and 9 in SOX group) were successfully converted to R0 resection. The median PFS of patients converted to surgery was significantly longer (median 16 months; IQR, 12.8–43.0 months) than that of patients without surgery (median 5.8 months; IQR, 3.0–8.8 months) (P<0.001) and the median OS was also significantly longer in patients with surgery (median 23 months; IQR, 16.6–44.5 months) than in those without (median 8.7 months; IQR, 3.3–14.0 months) (P6 in the SOX group were successfully converted to surgical treatment; meanwhile, 3 patients with PCI >6 in the HIPEC group were successfully converted to surgical treatment. The most common adverse events in both groups were leukopenia, anemia, hyponatremia, anorexia and fatigue, and there were no significant differences between the groups ( Table 3 ). No serious adverse events related to the protocol treatment occurred in any patients. Adverse events were graded based on the Common Terminology Criteria for Adverse Events version 5.0. Data are presented as n (%). AST, aspartate aminotransferase; ALT, alanine transaminase; HIPEC, hyperthermic intraperitoneal chemotherapy; SOX, S-1 plus oxaliplatin.

This randomized controlled trial investigated the efficacy and safety of HIPEC with paclitaxel plus SOX in the treatment of GCPM. The results found that the median PFS and OS in SOX group were significantly higher than those in HIPEC group. However, subgroup analysis revealed that HIPEC may confer benefit for patients with GCPM and a PCI >6 or ascites ≥1,000 mL. No serious adverse events related to the protocol treatment occurred in any patients. The median survival of patients with GCPM has been reported to be 3−9 months, even when the disease is treated by standard systemic chemotherapy ( 4 , 13 - 15 ). Therefore, PM is often considered incurable in patients with GC, and thus prognosis of the disease is poor. The current therapies for GCPM include palliative chemotherapy and supportive care, but these have limited efficacy ( 3 , 16 ). Given that only a small fraction of the systemically administered drug is delivered to the peritoneum, intraperitoneal chemotherapy appears to be reasonable to approach for treating PM directly and by extension, for treating GCPM. First, under this approach, high concentration of chemotherapeutic drugs in the abdominal cavity is in full contact with scattered tumor tissues and free tumor cells. Second, intraperitoneal infusion chemotherapy provides a long duration of drug action. Third, intraperitoneal chemotherapy drugs mainly enter the liver through the portal vein system and are metabolized by the liver, and so the chemotherapy drugs maintain a higher concentration in the abdominal cavity, portal vein, and liver, while the concentration of chemotherapy drugs in the systemic circulation is limited, which can reduce the systemic adverse reactions of chemotherapy drugs. Indeed, studies have confirmed that intraperitoneal chemotherapy provides survival benefits for patients with GCPM ( 17 - 19 ). Finally, in HIPEC, normal tissue cells can continuously tolerate temperature of 47 ℃ for up to 1 hour, while malignant tumor cells can only tolerate a temperature of 43 ℃ for 1 hour ( 20 ). The expected median PFS of 6.2 months in the HIPEC group was not reached, with the actual median PFS being 6.1 months, which is not in line with the results of previous studies ( 3 , 21 , 22 ) in which HIPEC was found to improve survival for GCPM. A retrospective propensity score-matched multicenter cohort study performed by Lei et al. aimed to evaluate the safety and efficacy of HIPEC in patients with GCPM. The results indicated that patients receiving HIPEC combined chemotherapy had a significantly higher median OS and 3-year OS rate than did those receiving chemotherapy alone (median OS: 15.9 vs. 10.8 months; 3-year OS rate: 18.4% vs. 10.1%) ( 3 ). Moreover, the results revealed that performing palliative gastrectomy with HIPEC and chemotherapy was associated with the highest survival (median OS: 20.8 months; 3-year OS rate: 27.0%). Rihuete Caro et al. also found that CRS combined with HIPEC provided improved survival in patients with GCPM, reporting a median OS of 16 months and a 3-year OS rate of 21.3% ( 21 ). Moreover, the median OS for patients with PCI ≤6 was 19 months, while that in patients with PCI >6 was 12 months. In a study performed by Rau et al. , CRS and HIPEC was found to improve survival in select patients with GCPM, with a median OS of 13 months and a 5-year survival rate of 6%. They additionally reported that in patients with a PCI of 0–6, 7–15, or 16–39, the median OS differed significantly (18 vs. 12 vs. 5 months, respectively) ( 22 ). There are three possible explanations that may account for the inconsistency in the data. First, GC is a systemic disease, and PM is the local manifestation of GC. Systemic chemotherapy is still the standard treatment for GCPM, but in our study, patients in HIPEC group received systemic chemotherapy about 1 month later than did those in the SOX group. Second, the earliest form of intraperitoneal chemotherapy for GC is HIPEC after CRS. Although the Clinical Practice Guidelines state that CRS combined with HIPEC has the application value for GCPM ( 23 ), Brandl et al. found that long-term survival and cure were possible only in those with complete cytoreduction and a low PCI ( 24 ). However, as reported in the CYTO-CHIP (Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Metastases) study, among others, satisfactory CRS is a highly challenging surgery and has unclear perioperative mortality and morbidity outcomes, which limits its use in the treatment of those with GCPM ( 6 - 8 , 25 ). In our study, the patients did not undergo CRS before HIPEC treatment. Finally, HIPEC kills tumor cells through hyperthermia, chemotherapy, a synergistic effect of hyperthermia and chemotherapy, and continuous mechanical flushing. The main effect of HIPEC may be accomplished via the mechanical flushing of free cancer cells in the abdominal cavity and the PMs. Therefore, when ascites were minimal or PCI was low, the effect of HIPEC was highly apparent. The biology of PM from GC is relatively aggressive, with a median recurrence-free survival of 6.5–7.4 months ( 25 - 27 ). Peritoneal dissemination is usually considered oncologically unresectable. An earlier study found that sufficient tumor reduction could enable a subsequent radical gastrectomy in one-third of patients with initially unresectable GC ( 28 ). A study conducted by Bismuth et al. also showed that the resection of previously unresectable metastases became possible in up to 16% of patients after chemotherapy, and this new approach could significantly prolong survival for patients ( 29 ). Moreover, cases of long-term survival for after conversion surgery for stage IV have been reported ( 30 ). These results indicate that the most effective means to improving the long-term survival of those with advanced GC remains surgery based on R0 resection. Therefore, improving the rate of conversion to surgery for with advanced patients in GC may be a critical goal for surgical oncologists. In our study, the median PFS and OS of patients that were converted to surgery were significantly longer than those in patients without surgery. However, patients with a PCI >6 successfully received conversion surgery only when they were treated by systemic chemotherapy combined with HIPEC, which indicates that these patients may benefit from HIPEC. Our study had several limitations which should be addressed. First, we employed a single-center design with a small sample size. Second, we conducted a randomized controlled trial, patients in the HIPEC group had more severe ascites and a higher PCI; however, these were not significantly different. Finally, double blinding in the study was not possible. However, data collection was performed by an individual who was blinded to the randomization, and the primary endpoint was PFS, and thus the risk of bias in our study was likely low.

In conclusion, our study failed to show the statistical superiority of HIPEC combined with systemic chemotherapy. However, HIPEC with paclitaxel plus SOX may have a benefit for select patients with GCPM, and thus further research is warranted.

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