Cytoreductive surgery and Hyperthermic intra-operative peritoneal chemotherapy with Cisplatin for gastric peritoneal Carcinomatosis Monocentric phase-2 nonrandomized prospective clinical trial

Gastric cancer is a major health problem worldwide, with more than 950,000 new patients diagnosed every year and an estimated 720,000 deaths in 2012. Despite declining incidence and mortality for several decades, and despite substantial advances in understanding its epidemiology, pathogenesis, and therapeutic strategies, gastric cancer is still the fourth most common cancer and the second leading cause of cancer deaths worldwide [1].

Today, adequate surgical resection is the only chance for patients to be cured from gastric cancer, often in combination with peri-operative chemotherapy, or with postoperative chemo-radiotherapy [2‐4]. However, only patients with localized disease are potential candidates for surgical management with curative intent. Most patients with gastric cancer present in an advanced stage with metastases in the peritoneal cavity and/or in the liver, and have an extremely poor prognosis. Peritoneal metastases, also called peritoneal carcinomatosis (PC), develop in up to 60% of gastric cancers and are a major cause of death [5]. Systemic combination chemotherapy is the standard of care for patients with metastasis, resulting in a median survival of about 8 months and almost no survivors at 3 years [6‐8].

As the effect of systemic chemotherapy on gastric PC is unclear and is believed to be minimal, other treatment strategies have been studied aiming to improve survival of these patients. For about two decades, cytoreductive surgery (CRS) combined with hyperthermic intra-peritoneal chemotherapy (HIPC) has been used to treat PC from colorectal, ovarian, or mucinous appendiceal cancer, offering patients improved survival [9‐11]. CRS + HIPC is now considered an important option in well-selected patients. Although CRS + HIPC has also been used in gastric PC, its beneficial effect on survival is still unclear and controversial. A recently published phase 3 randomized clinical trial on gastric PC showed improved survival after CRS + HIPC as compared with CRS alone, i.e. 11 vs 6.5 months (p = 0.046) [12]. The latest systematic reviews have demonstrated insufficient data to recommend CRS + HIPC as standard of care in gastric PC due to the lack of survival benefit and the heterogeneity among the published studies in terms of HIPC technique, duration, and cytotoxic agents used. Although a clear recommendation cannot yet be provided, evidence based on the literature suggests a potential role for CRS + HIPC in gastric PC [13, 14].

We conducted a monocentric phase-2 non-randomized clinical trial to evaluate long-term survival after CRS + HIPC with cisplatin in patients with gastric PC and to define selection criteria for this treatment modality.

Our study demonstrates that CRS + HIPC with cisplatin can improve survival of selected patients with PC from gastric cancer, with acceptable morbidity and no mortality. We found 3 variables that determine survival and define the best candidates for CRS + HIPC. In patients having PCI scores of 12 or less without PC on any small bowel region with 4 or more non-small bowel regions, CRS + HIPC resulted in a median OS time of 24.7 months and a 1-year OS rate of 90%. These patients also had significantly better DFS and peritoneal-DFS outcomes as compared to other patients treated with CRS + HIPC. Patients having PCI scores of 13 or more and the presence of PC on any small bowel region with 4 or more non-small bowel regions died within 18 months after CRS + HIPC. In the only phase 3 randomized clinical trial published so far, the median OS time after CRS + HIPC for gastric PC was 10.2 months in the low PCI group (PCI < 20; n = 20), and 13.5 months in the high PCI group (PCI > 20; n = 14). The authors also found the completeness of cytoreduction to determine survival. CRS + HIPC plus CCR-0-1 (n = 20) was associated with median OS time of 12.0 months [12]. These figures seem to be inferior to the median OS of 16 months in our study, which might be explained by tumour biology, the fact we obtained a CCR-0 status in all our patients, and on histopathological examination an R0 resection was obtained in all patients. The peri-operative mortality rate in our patient population was zero, just like it was in the study of Yang et al. [12].

Our survival data seem to be better than those reported with any other treatment modality for PC from gastric cancer, and may have several explanations. A recent systematic review that focused on survival, mortality, and morbidity of CRS + HIPC for PC from gastric cancer showed significant heterogeneity in the studies, which might bias final conclusions (441 patients from 3 retrospective and 7 prospective studies published between 2000 and 2010) [13]. Although contrasting data were presented about survival rates, all findings pointed to the necessity of complete cytoreduction (CCR-0) to improve survival. With a relatively high postoperative mortality rate of about 5%, the published median 1-y OS rate was 43% (range 22 – 68%). Given these results, major controversy had arisen about the role of CRS + HIPC, as current systemic chemotherapy without surgery offers patients with metastatic gastric cancer 1-y OS rates of up to 52% [17].

Peritoneal carcinomatosis is present in about one third of patients presenting with metastatic gastric cancer, and is associated with a median survival time of about 8 months, 1-year survival rate of around 50%, and almost no survivors at 3 year despite systemic chemotherapy [7, 8]. Indeed, to date, systemic chemotherapy is the standard of care for patients suffering from gastric PC. In some cases, peritoneal carcinomatosis may be the only site of dissemination, and CRS + HIPC may be a therapeutic option. In colon or appendiceal cancer with isolated PC, a benefit is suggested for CRS + HIPC, whereas its role in gastric cancer is less clear. In the absence of randomized controlled trials, several cohort studies addressed the use of CRS + HIPC for peritoneal carcinomatosis from gastric cancer. In our study, the 1-y OS rate was 90% for patients having favourable prognostic factors, and seems better than the reference of 52%. Completeness of cytoreduction (CCR-0) and R0-resection may contribute to this favourable outcome. Other factors with a positive effect on survival may be the absence of postoperative mortality, appropriate selection of patients, and high rates of systemic chemotherapy in neo-adjuvant and adjuvant settings. As our study is a phase-2 nonrandomized prospective clinical trial, its promising survival warrants further study in future phase-3 randomized controlled trials to investigate whether the survival advantage is due to tumour biology or to CRS + HIPC. Furthermore, it should be taken into account that quality of surgery and its clinical outcome depend on the skills of the surgical team and might therefore not be replicated in routine clinical practice, but would need to be limited to experienced centres. The extent of PC appears to have a negative effect on survival. We found PCI scores greater than 12 and the presence of PC on small bowel combined with PC on more than 3 non-small bowel regions as criteria not eligible for CRS + HIPC. Studies on PC from other cancer types in some series support a good outcome for patients with a maximum PCI of 16 [18].

The potential role of CRS + HIPC in patients without overt peritoneal metastases is also under debate. Although patients with localized gastric cancer are treated with curative intent by means of radical surgery with either neo-adjuvant or adjuvant systemic chemotherapy, many of them will finally develop PC resulting in fatal outcome. In the absence of macroscopic peritoneal metastases, staging laparoscopy with peritoneal lavage showing positive cytology results in poor survival and is defined as metastatic disease [19]. Therefore, the addition of CRS + HIPC in the therapeutic armamentarium of surgical oncologists to treat advanced gastric cancer without clinically overt metastases is worth studying in future randomized controlled trials.

The morbidity rate and the severity of complications in our study were in accordance with those of other studies, but there was no mortality. Despite adequate hydration in the perioperative stage, transient cisplatin-associated nephrotoxicity was observed in 16% of patients. At the time our study was started, cisplatin was the standard of care as systemic chemotherapy both in neo-adjuvant as in adjuvant setting in potentially curable patients with operable gastric cancer, and in palliative setting for metastatic disease. Today, the administration of oxaliplatin in HIPC, as often used in PC from colorectal cancer, might be an alternative since systemic oxaliplatin is less nephrotoxic and as effective as systemic cisplatin in advanced esophagogastric cancer [20]. However, whether oxaliplatin could provide similar survival outcomes as cisplatin used in CRS + HIPC for gastric PC, needs to be evaluated in future studies.

In patients with limited PC from gastric cancer, CRS + HIPC with cisplatin results in favourable survival, provided a complete cytoreduction (CCR-0) and histopathological R0 resection are obtained. It should be restricted to patients having PCI scores of 12 or less. Patients having PC on any small bowel region with PC on 4 or more non-small bowel regions should be refused for CRS + HIPC.