Hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally advanced gastric cancer after D2 radical resection: a randomized controlled study

doi:10.21203/rs.3.rs-2490302/v1

Background: Currently, there is a lack of effective strategy for the prevention of peritoneal metastasis(PM) from locally advanced gastric cancer (AGC). This randomized controlled study aimed to evaluate the outcome of D2 radical resection with hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally AGC patients.

Methods: All patients enrolled were randomly assigned to receive HIPEC plus systemic chemotherapy (HIPEC group) or systemic chemotherapy alone (non-HIPEC group) after radical gastrectomy. HIPEC was performed intraperitoneally with cisplatin (40 mg/m²) within 72h after surgery, while systemic chemotherapy based on SOX regimen (S-1 combined with oxaliplatin) was administered 4-6 weeks after radical surgery. Patterns of recurrence, adverse events, 3-year disease-free survival (DFS) and overall survival (OS) were analyzed.

Results: A total of 134 patients were enrolled in the present study. The 3-year DFS rate was 73.8% in the HIPEC group, which was significantly higher than that in the non-HIPEC group (61.2%, P=0.031). The 3-year OS rate was 73.9% in the HIPEC group and 77.6% in the non-HIPEC group, with no significant difference (P = 0.737). PM was the most common distant metastasis in both groups. The occurrence rate of PM in the HIPEC group was statistically lower than that in the non-HIPEC group (20.9% vs. 40.3%, P=0.015). Grade 3 or 4 adverse events were occurred in 19 (14.2%) patients, and there was no statistic difference between the two groups.

Conclusion: Radical surgery followed by HIPEC combined with systemic chemotherapy is a safe and feasible strategy for locally AGC patients and could effectively improve the DFS and reduce the occurrence of PM. However, more prospective randomized studies with a large sample size are warranted.

Trial registration: This study was registered with www.medresman.org.cn as ChiCTR2200055966 on 30/01/2022.

Gastric cancer

Chemotherapy

hyperthermic intraperitoneal chemotherapy (HIPEC)

Peritoneal metastasis

Prognosis

Gastric cancer (GC) is one of the most common malignancy worldwide, ranking the fourth leading cause of cancer-related deaths with a poor 5-year survival rate, which is mainly caused by tumor progression and recurrences[1-3]. Peritoneum is the most common metastasis site in GC patients after curative resection, especially for the patients with serosal invasion or lymphatic metastasis, and exfoliation of free cancer cells in abdominal cavity is the main cause of peritoneal metastasis (PM)[4-6]. As reported by previous studies, more than 50% GC patients occurred PM after radical surgery, causing a gloomy prognosis of these patients with a median survival time less than 6 months[7, 8]. Hitherto, there is a lack of consensus on preventing PM and improving the prognosis of patients with locally advanced gastric cancer (AGC).

Hyperthermic intraperitoneal chemotherapy (HIPEC) provides direct delivery of concentrated, heated chemotherapeutic drugs into abdominal cavity, maintaining the thermo-thermal effect and increasing the exposure of cancer cells to chemotherapy to improve the anti-tumor efficacy[9, 10]. Combination of HIPEC and systemic chemotherapy is emerging as a potential regimen in prevention and treatment of PM in various malignancies[11-14]. The effect of HIPEC in preventing tumor recurrence and metastasis of AGC still remains controversial. Some studies reported that GC patients treated with HIPEC and systemic chemotherapy had a significantly higher recurrence-free survival than patients who did not[15, 16]. Whereas, other studies indicated that HIPEC failed to improve the OS and DFS of GC patients[17, 18]. Thus, the adoption and efficacy of HIPEC in GC patients need further study.

This prospective, randomized, controlled study was performed to find out the clinical benefit of the combination of HIPEC and systemic chemotherapy on locally AGC patients after radical resection and provide an effective treatment strategy for these patients.

Study design

This prospective, randomized, controlled study (registration: www.medresman.org.cn; #ChiCTR2200055966) was performed at Zhejiang Cancer Hospital from January 2017 to January 2021. The study was approved by the Institutional Ethics Review Board of Zhejiang Cancer Hospital (approval number: IRB-2016-157). Written informed consent was obtained from each patient enrolled. The primary endpoint was 3-year OS rate and the secondary endpoints were 3-year DFS rate and the safety.

Enrollment criteria were as follow: (1)first diagnosed AGC patients with T3~T4b confirmed by histologic evidence of resected specimens according to the 7^th edition of the TNM classification for gastric cancer[19]; (2) without distant metastasis; (3) age ranges from 18 to 75 years; (4) did not receive any preoperative treatment, such as preoperative chemotherapy or radiotherapy; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; (6) with white blood cells≥3.5×10⁹/L, neutrophil≥1.5×10⁹/L, platelet≥100×10⁹/L, serum total bilirubin≤1.5-fold of the upper limits of the normal ranges (ULNS), serum creatinine≤1.2-fold ULNS, serum aspartate transaminase (AST) and alanine transaminase (ALT) level≤1.5-fold ULNS. Patients with positive cytology were excluded from the study.

Treatment

All patients were randomly assigned to HIPEC group or non-HIPEC group after radical gastrectomy using a web response system. Patients in HIPEC group received HIPEC treatment and systemic chemotherapy, while patients in non-HIPEC group received only systemic chemotherapy. The treatment-schedule of this study was showed in Figure 1.

I. Surgical treatment

All patients received open or laparoscopic surgery and a distal or total gastrectomy were selected depending on the tumor location. Routine D2 lymph node dissections were performed according to the Japanese gastric cancer treatment guidelines (4^th edition)[20]. Different reconstruction methods including Billroth I gastroduodenostomy, Billroth II gastrojejunostomy, and Roux-en-Y esophagojejunostomy were selected based on the extent of gastrectomy. Resected specimens were evaluated by two experienced pathologists to confirm the exact pathological staging. A routine peritoneal cavity washing with at least 1-liter normal saline was performed in both groups after radical surgery.

II. HIPEC

For the patients allocated to HIPEC group, two inflow catheters were inserted in the upper abdomen and two outflow catheters in the pelvic cavity. HIPEC treatment was conducted twice within 72h after gastrectomy. Generally, the first HIPEC treatment was performed within 24h after surgery followed by the second HIPEC at an interval of 24-48h. Approximately 3 liters of heated normal saline containing cisplatin (40mg/m²) was infused into peritoneal cavity at a rate of 500 ml/min and circulated for 60 minutes using a custom-developed high-precision body cavity hyperthermic perfusion treatment system (BR-TRG-II, Bright Medical Technology Co., Ltd., Guangzhou, China). The temperature of the perfusate was maintaining at 43±0.3℃ during the process of intraperitoneal chemotherapy. And the perfusate was drained out after the completion of HIPEC.

III. Postoperative systemic chemotherapy

Postoperative systemic chemotherapy based on SOX regimen (6-8 cycles of S-1 combined with oxaliplatin) was administered for patients in both groups after 4-6 weeks of radical surgery. Oxaliplatin (130mg/m²) was administered intravenously on day 1 and S-1 (80, 100 and 120 mg/day for body surface area below 1.25 m², between 1.25 and 1.5 m² and above 1.5m², respectively) was administered orally, twice a day for two consecutive weeks followed by a one-week rest.

Evaluation and follow up

The postoperative complications were confirmed by investigators according to Clavien-Dindo grading[21] and chemotherapy related adverse events were evaluated according to common terminology criteria for adverse events (CTCAE)[22]. The OS time was calculated from the date of initial diagnosis to the time of death or the date of the last follow-up. The DFS time was defined as the time from surgery to tumor recurrence.

After postoperative systemic chemotherapy, patients were assessed by physical examination, computerized tomography scan or the serum tumor markers every 3 months for the first 2 years, then every 6 months for 3–5 years. The last follow-up was performed in June 2022.

Sample size

According to some previous studies[23, 24], the 3-year overall survival (OS) rate of AGC patients was 74.2%-83% (mean, 78%). After D2 radical resection with HIPEC and systemic chemotherapy, the 3-year OS rate of AGC patients is estimated to be 86%. Assuming a two-sided α of 0.05 and 90% statistical power, with an estimated dropout rate of 15%, the required sample size was estimated to be 130 patients.

Statistical analysis

All data were systematically collected to establish a comprehensive database. The data were analyzed by SPSS software for windows, version 26.0 (SPSS Inc., Chicago, IL, USA). The Chi-squire test was used to compare the differences in age, gender, pathologic stage, differentiation degree, tumor size, tumor location and the occurrence rate of metastases, etc. The survival curves were calculated and compared by Kaplan-Meier method and the log-rank test. A p-value<0.05 was considered as statistically significant. Patients without complete data will not be included in the final analysis.

Patient characteristics

A total of 143 patients were assessed for eligibility and finally 134 patients were included and randomly assigned to HIPEC group and non-HIPEC group in Zhejiang Cancer Hospital from January 2017 to January 2021.

For the all patients enrolled, including 104 males and 30 females with a median age of 61 year (22~75 years), there were 118 patients with poorly differentiated adenocarcinoma and 16 patients with moderately differentiated adenocarcinoma. According to the postoperative pathologic staging, 13 (9.7%) patients were stage II, while the other 121 (90.3%) patients were stage III. There was no statistically significant difference in gender, age, pathologic stage and histologic type of tumor between the two groups (Table 1).

Treatment results

For the both two groups, open and laparoscopic D2 radical resection were performed on 108 and 26 patients. All patients enrolled achieved R0 resection. Multivisceral resection due to the tumor invasion was performed in 4 patients, including 3 patients in the HIPEC group (one each of splenectomy, pancreatectomy, and splenectomy combined with left lobe partial hepatectomy) and 1 patient in the non-HIPEC group (diaphragmatic muscle resection). No operation-related mortality or intraoperative morbidity was occurred in both groups.

However, postoperative complications regarded as Clavien-Dindo grade II or above were observed in 11 patients, including 6 patients in HIPEC group and 5 patients in non-HIPEC group without a significant difference. The most common complication was pneumonia (5 cases), followed by intestinal obstruction (2 cases), anastomotic leakage (2 cases), intraperitoneal abscess (1 case) and abdominal hemorrhage (1 case). Re-surgery was required in the patient with abdominal hemorrhage for debridement and hemostasis. The other patients suffering from postoperative complications were treated with conserved strategies and the conditions were under well control.

In the HIPEC group, 42 (62.7%) patents completed twice HIPEC treatments as planned and the other 25 (37.3%) patients received only once of it. In both groups, postoperative chemotherapy with SOX regimen was performed on all patients. 44.8% patients in the HIPEC group completed at least 6 cycles of postoperative chemotherapy with an average cycle of 4.5 (2-8 cycles), while 46.3% patients in the non-HIPEC group completed at least 6 cycles of postoperative chemotherapy with an average cycle of 4.5 (2-8 cycles).

Treatment toxicity

No adverse event concerning HIPEC treatment was observed in the HIPEC group. Grade 3 or 4 adverse events concerning postoperative chemotherapy were found in 19 patients, including 11 (16.4%) patients in HIPEC group and 8 (11.9%) patients in non-HIPEC group, and there is no statistic difference between the two groups. Among the whole study cohort, leucopenia/neutropenia (7 patients, 5.2%) and thrombocytopenia (6 patients, 4.5%) were the most common hematological toxic effects, while the elevated serum AST levels (11 patients, 8.2%) was the most common non-hematological toxic effect (Table 2).

Survival and recurrence

The median follow-up was 44.0 months (3-65 months). The mean survival time (MST) of the 134 patients was 51.4 months (95% confidence interval [CI] 48.0-55.0 months).

The estimated 3-year OS rate was 73.9% and 77.6% for HIPEC group and non-HIPEC group respectively, and difference was not statistically significant (P=0.737, Figure 2). The 3-year DFS was 73.8% in HIPEC group and 61.2% in non-HIPEC group, a difference was statistically significant (P=0.031, Figure 3).

A total of 53 (39.6%) patients developed distant metastases during follow-up, including 18 (26.9%) patients in HIPEC group and 35 (52.2%) patients in non-HIPEC group, with a statistically significant difference between the two groups (P=0.003). Peritoneal metastasis was found in 20.9% (14/67) patients in HIPEC group and 40.3% (27/67) patients in non-HIPEC group, with a significantly statistical difference (P=0.015). The other sites of metastases were liver (1.5% vs 4.5%), distant lymph node (1.5% vs 1.5%), lung (1.5% vs 3.0%), brain (0% vs 3.0%) and bone (1.5% vs 0%), and difference were statistically not significant (Table 3).

In the past decades, a significant improvement has achieved in the treatment of GC and the combination of surgery and postoperative chemotherapy is the standard strategy for locally AGC[24-26]. However, the high incidence of PM and the limited effect of systemic chemotherapy are the main reasons of treatment failures. There is a lack of effective management strategies to prevent PM in patients with locally AGC[27-29].

Previous studies indicated that HIPEC has an advantage in antitumor effects by directly increasing the exposure of free cancer cells to chemotherapy perfusate and enhancing the cytotoxicity with the thermo-thermal effect[12, 30, 31]. The combination of HIPEC and systemic chemotherapy could effectively improve the prognosis of gastric cancer patients with limited peritoneal metastasis[32-34]. However, the effect of prophylactic HIPEC in patients with locally AGC remain controversial.

The results of a randomized trial enrolled 113 GC patients with cT4N0-3M0 indicated that postoperative prophylactic HIPEC plus intravenous chemotherapy could dramatically reduce the possibility of peritoneal recurrence (18.2% vs 37.9%, P=0.020) and improve the DFS and OS rate compared with the patients who did not receive HIPEC treatment[35]. Our study showed that the 3-year DFS rate of HIPEC group was better than that of non-HIPEC group (73.8% vs. 61.2%, P=0.031), however, a significant difference in 3-year OS rate was not observed between the two groups (73.9% vs. 77.6%, P=0.737). The results from another meta-analysis, including 13 studies from the year of 1988 to 2021, showed that there was no significant difference in survival rates between HIPEC group and control group at 1-, 2- and 3-year follow-up, while a statistically significant overall survival effect was found at the 5-year follow-up[36]. Thus, whether prophylactic HIPEC could effectively improve the long-term survival of locally AGC patients still needs further study.

Peritoneal metastasis is the most common recurrence pattern of AGC after radical surgery. Whereas, as a regional treatment strategy, HIPEC could effectively eliminate micro-metastases and free cancer cells in the abdominal cavity through its thermo-thermal effect. The results from Beeharry et al. showed that the combination of surgery and HIPEC could significantly reduce the peritoneal recurrence rate when compared to surgery alone (23% vs 3%, P < 0.05)[37]. In the present study, the occurrence rate of PM in the HIPEC group was significantly lower than that of non-HIPEC group (20.9% vs. 40.3%, P=0.015). Thus, HIPEC was effective to prevent peritoneal metastasis in AGC patients after radical gastrectomy.

However, we found that the metastases to other sites, such as liver metastasis and distant lymph node metastasis, were similar between the two groups, suggesting limited role of HIPEC in preventing distant metastases other than peritoneal metastases. New strategies like development and use of new chemotherapeutic drugs, immune checkpoint inhibitors and targeted therapy may be necessary to prevent distant metastasis.

Some studies have reported that HIPEC may increase the side effects, such as anastomotic leak, bowel obstruction and abdominal sepsis[30, 38]. However, Zhang et al. indicated that obvious complication concerning HIPEC was not observed[39]. In present study there was no serious HIPEC-related adverse event and the postoperative complications were similar in the two groups. Therefore, it seems that combination of HIPEC and systemic chemotherapy is a safe and feasible strategy for locally AGC patients who have a high risk of PM.

Although a strict selection criterion was conducted in this prospective randomized study, there are also several limitations. First, this trial was performed in a single center with a relatively small sample size, which hindered a further comprehensive subgroup analysis. Besides, due to the relatively short duration of follow-up, a significant difference in overall survival was hard to observe. Despite these limitations, the results of this study might be enlightening for the future exploration in the postoperative adjuvant treatment of locally AGC.

In conclusion, this randomized trial demonstrated that, for locally AGC patients with the risk of PM, the adoption of HIPEC combined with systemic chemotherapy could effectively improve the DFS rate and reduce the occurrence of PM without causing serious side effect. However, prospective randomized clinical studies with a large sample size are warranted to validate the results of this study.

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Review Board of Zhejiang Cancer Hospital with approval number IRB-2016-157 and performed in line with the principles of the Declaration of Helsinki. A written informed consent was obtained from each study participant.

Authors’ contributions

Yian Du and Pengfei Yu designed the study. Xingmao Huang, Zeiyao Ye, Tengjiao Chai and Jingquan Fang analyzed the data. Xingmao Huang drafted the manuscript. Gaiguo Dai, and Qi Xu collected and registered the data. Yian Du, Pengfei Yu and Ling Huang interpreted the data, and revised the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated during and/or analysed during the current study are not publicly available due to ethics requirements but are available from the corresponding author on reasonable request.

Funding

None.

Acknowledgements

We thank all the study participants and research staff who participated in this work.

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Table 1. Clinical data of the HIPEC group and the non-HPIEC group

	HIPEC group (n=67)	non-HIPEC group (n=67)	P value
Age (years)			0.728
≤60	31(46.3%)	29(43.3%)
>60	36(53.7%)	38(56.7%)
Gender			0.407
Male	50(74.6%)	54(80.6%)
Female	17(25.4%)	13(19.4%)
Pathologic T stage			0.770
T3	7(10.4%)	6(9.0%)
T4a	48(71.6%)	57(85.1%)
T4b	12(17.9%)	4(6.0%)
Pathologic N stage			0.529
N0	9(13.4%)	4(6.0%)
N1	9(13.4%)	11(16.4%)
N2	18(26.9%)	19(28.4%)
N3	31(46.3%)	33(49.3%)
Differentiation degree			0.110
Poorly	62(92.5%)	56(83.6%)
Moderately	5(7.5%)	11(16.4%)
Nerve infiltration			1.000
No	19(28.4%)	19(28.4%)
Yes	48(71.6%)	48(71.6%)
Vascular tumor embolus			0.264
No	24(35.8%)	18(26.9%)
Yes	43(64.2%)	49(73.1%)
Tumor size（cm）			0.226
≤5	29(43.3%)	36(53.7%)
>5	38(56.7%)	31(46.3%)
Tumor location			0.511
Cardia	3(4.5%)	6(9.0%)
Body	17(25.4%)	14(20.9%)
Antrum	39(58.2%)	35(52.2%)
Total stomach	8(11.9%)	12(17.9%)
Operation ways			0.662
Open	55(82.1%)	53(79.1%)
laparoscopic	12(17.9%)	14(20.9%)
Surgical Procedures			0.481
Distal Gastrectomy	42(62.7%)	38(56.7%)
Total Gastrectomy	25(37.3%)	29(43.3%)

Table 2. Grade 3 or 4 toxic effects in the HIPEC group and the non-HPIEC group

Toxic effects	HIPEC group (n=67)	Non-HIPEC group (n=67)
Hematological
Leucopenia/neutropenia	4 (6.0%)	3 (4.5%)
Thrombocytopenia	2 (3.0%)	4 (6.0%)
Non-hematological
Transaminase elevation	7 (10.4%)	4 (6.0%)

Table3. Sites of Metastases in the HIPEC group and the non-HPIEC group

	HIPEC group (n=67)	Non-HIPEC group (n=67)	Total (n=134)
Overall	18(26.9%)	35(52.2%)	53(39.6%)
Peritoneum	14(20.9%)	27(40.3%)	41(30.6%)
Liver	1(1.5%)	3(4.5%)	4(3.0%)
Distant lymph node	1(1.5%)	1(1.5%)	2(1.5%)
Lung	1(1.5%)	2(3.0%)	3(2.2%)
Brain	0(0%)	2(3.0%)	2(1.5%)
Bone	1(1.5%)	0(0%)	1(0.7%)

No competing interests reported.

Hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally advanced gastric cancer after D2 radical resection: a randomized controlled study

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Abstract

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Background

Materials And Methods

Results

Discussion

Declarations

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Tables

Additional Declarations

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