In the past decades, studies on adjuvant SCT for the treatment of resectable gastric cancer have shown conflicting results (8
). Adjuvant SCT has not become the standard of care for gastric cancer except with S1 in Japan following the publication of the results of the ACTS-GC trial (6
). In addition, there is limited good quality evidence to determine the role of adjuvant IPCT in gastric cancer (17
). The optimal adjuvant chemotherapy approach for gastric cancer such as SCT, IPCT alone or in combination has not yet been well-defined and there is no widely accepted chemotherapeutic regimen. Based on the recurrence patterns following curative resection, the rationale and advantage for combined SCT and IPCT in an adjuvant setting for gastric cancer is evident. In addition, the efficacy and feasibility of combined SCT and IPCT have been well-established in other intra-abdominal malignancies including colon (18
) and ovarian cancer (14
), particularly in the latter, for which convincing clinical trials have confirmed the improvement in survival.
Despite the attractive rationale for the combination of adjuvant SCT and IPCT, clinical experience with this treatment modality in gastric cancer is limited. To our knowledge, there were only a few earlier studies available exploring the use of ACSIP in gastric cancer. The earliest was by Atiq et al
), published in 1993. This group assessed postoperative adjuvant intraperitoneal CDDP and 5-FU and systemic 5-FU chemotherapy in patients with resected gastric cancer. In that study, 16 out of 35 patients experienced recurrence, and 18 remained alive free of disease with a 3-year survival rate of 50.0%. The treatments were also associated with altered metastatic patterns (decreased incidence of peritoneal spread and liver metastases). In another study by Zuo et al
), a statistically significant improvement in 3-year survival was reported for the adjuvant intraperitoneal hyperthermic chemoperfusion combined with intravenous chemotherapy group; the 3-year survival rate was 83.0% in the combined group compared with 61.0% in the adjuvant intravenous chemotherapy alone group (P<0.05). Recently, a retrospective study by Shi et al
) revealed that the 5-year OS rate in the adjuvant systemic chemotherapy combined with intraperitoneal perfusion chemotherapy (IP+) group was significantly better than that in the systemic chemotherapy only (IP-) group (60.4 vs. 42.9%; P= 0.001). In addition, the average progression-free survival in the IP+ group was significantly longer than that in the IP- group (60.5 vs. 46.2 months; P=0.001). Although the different patient selection criteria and chemotherapy regimens tested make the comparison between these studies and the present study difficult, the results of these studies and ours are both encouraging, as the 3-year DFS rate was 66.1% and the 3-year OS rate was 74.2% in the present study. However, the benefit of this promising combined adjuvant treatment modality should be confirmed in prospective randomized controlled trials.
The incidences of hepatic and peritoneal failure were relatively low in this study. An initial intraperitoneal and hepatic relapse was noted in 6 (24.0%) and 3 (12.0%) out of 25 patients with recurrence in this study, respectively, thus the incidences are lower than those revealed in the study of Wu et al
), which addressed recurrence patterns following intended curative surgery in 611 patients with gastric cancer. In that study, 38.2 and 17.9% patients experienced peritoneal and hepatic recurrence, respectively. The low incidence of hepatic and peritoneal failure in this study is possibly related to the additive effects of systemic, intravenous and intraperitoneal drug administration. However, in the present study, 91.3% of patients succumbed to their condition within 1 year of the diagnosis of recurrence being made, and the median time from recurrence to mortality was only 4 months. These results are poorer than those of D’Angelica et al
). They reported that 70.0% of patients succumbed to their condition within 1 year of the diagnosis of recurrence and the median time from recurrence to mortality was 6 months. In multivariate analysis, they demonstrated that shortened median time until mortality was significantly correlated with a higher T stage (4 vs. 7 months, P=0.007) and involved lymph nodes (5 vs. 9 months, P=0.01). In the present study, 83.9% of patients had serosa-infiltrating cancer and 87.1% of them were lymph node-positive, which may be the main causes of the short time to death following recurrence.
Patient tolerance of ACSIP was excellent in this study. On the whole, toxicities were mild to moderate. Neutropenia, gastrointestinal side effects and peripheral neuropathy were the most common grade 3–4 toxicities; however, they were all infrequent and manageable. There were no treatment-related mortalities. Chemical peritonitis had been reported in patients with intra-abdominal cancer receiving intraperitoneal high doses of 5-FU and CDDP for long periods (23
); however, this did not occur in the present study as 5-FU and CDDP were administered for a shorter period of time. Several studies have suggested that there was an increase in morbidity and mortality with adjuvant perioperative intraperitoneal chemotherapy in gastric cancer. Yu et al
) reported that the overall morbidity and mortality rates in patients receiving early postoperative IPCT starting on postoperative day 1 (the study group) were both higher than in those who underwent surgery only (the control group), although the difference was not significant (28 vs. 20.3%, P=0.121; 5.6 vs. 0.8%, P= 0.299, respectively). By contrast, intra-abdominal sepsis without anastomotic leakage (P=0.008) and bleeding (P=0.002) occurred significantly more often in the study group compared with the control group. In a study by Rosen et al
), significantly higher postoperative complication and mortality rates were also observed in patients receiving intraperitoneal mitomycin bound to activated carbon particles compared with the surgical control group (35 vs. 16.0%; 11 vs. 2.0%, respectively), thus the protocol committee decided to stop further recruitment of patients into that particular study. However, the incidence of surgical complications was only 8.1% in the present study, which was much lower than that in the above-mentioned studies. The difference in incidence between these studies and ours may be related to the different cancer stage, type of surgery, timing of IPCT commencement and the chemotherapeutic agents intraperitoneally administered. This study indicates that adjuvant intraperitoneal 5-FU and CDDP delivered at 1–3 weeks postoperatively may not increase the rates of surgical complications and mortality in patients with gastric cancer. In addition, 55 patients (88.7%) completed more than 4 cycles of ACSIP and 48 patients (77.4%) completed 6 cycles in the present study. It is possible that the benefit of ACSIP may be greater if more patients successfully complete 6 cycles of treatment; however, the effect of the duration of treatment on clinical outcome has not been confirmed by any study.
A considerable amount of research into adjuvant chemotherapy in gastric cancer is still necessary. Further improvements will require the development of more effective treatment modalities and chemotherapeutic regimens. During the last decade, several new agents including paclitaxel, docetaxel, oxaliplatin, irinotecan, capecitabine and S1 have shown promising activity in gastric cancer. From a theoretical point of view, regimens with higher activity may have more efficacy as adjuvant therapies (26
). However, the selection, dosage, combination, schedule of chemotherapy agents and the route and timing of administration need extensive testing in confirmatory studies.
In conclusion, the results of this study indicate that ACSIP is effective and feasible in high risk patients with locally advanced gastric cancer following curative gastrectomy under D2 lymphadenectomy and has encouraging 3-year DFS and OS rates. Failure pattern data suggest possible decreased peritoneal and hepatic recurrences. The benefit of this promising combined adjuvant treatment modality for this challenging disease warrants further studies.