Review
Treatment and prevention of peritoneal carcinomatosis from gastric cancer by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Overview and rationale

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Abstract

Peritoneal carcinomatosis (PC) from gastric cancer is a condition with a very bleak prognosis. Most authors consider it to be a terminal disease and recommend palliative therapy only. Multimodal therapeutic approaches to PC have emerged in the last decades, combining cytoreductive surgery (CRS) and peritonectomy procedures with perioperative intraperitoneal chemotherapy (IPEC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC).

We reviewed the pertinent literature concerning the HIPEC modality both for the treatment of established PC and the prevention of peritoneal recurrence after potentially curative gastric cancer (GC) surgery. Basically, the two procedures relate to different aspects of GC and they are not comparable, since the latter has been used as an adjuvant when PC is still not macroscopically evident and the former has been exclusively used in advanced gastric cancer stages with peritoneal dissemination. Data supporting beneficial effects once gastric PC is already manifest is scarce and limited to few centres with specific experience in this field. Conversely, with regards to the peritoneal perfusion for preventing PC in high risk gastric cancer patients, there are phase III trials and meta-analysis which support beneficial effects resulting from the HIPEC procedure. To offer a baseline guide, we summarized the actual status and general outcome obtained by this multimodal technique, in association or not with CRS as treatment of advanced GC.

Introduction

The peritoneum is a preferential site for gastric adenocarcinoma (gastric cancer, GC) dissemination. There is no established treatment for GC with peritoneal seeding. The lack of efficient systemic therapy1 with the fact that a substantial number of synchronous peritoneal carcinomatosis (PC) is confined to the peritoneal cavity and is a localized disease has been the impetus for many investigators to study intraperitoneal administration of cytotoxic agents (intraperitoneal chemotherapy IPEC) in both therapeutic and adjuvant settings. Diverse modalities of intraperitoneal delivery of the perfusate have been introduced over time, i.e. peri-operatively, such as normothermic intraperitoneal chemotherapy (NIPEC) and hyperthermic intraperitoneal chemotherapy (HIPEC), or post-operatively, such as early postoperative intraperitoneal chemotherapy (EPIC) and delayed postoperative intraperitoneal chemotherapy (DIPEC).2 The combination of HIPEC, first described in 1980 by Spratt et al.,3 with cytoreductive surgery (CRS) has undergone an especially important development during the last 30 years thanks to both its encouraging favourable oncologic results and its global superiority compared to alternative intraperitoneal modalities. The theoretical advantage of the HIPEC is to add the potentiating effect of hyperthermia on the cytostatic drug property to the high local concentration of the used agents, as well as the direct cytotoxic effects of heat.4, 5 The efficacy of HIPEC associated to surgery against PC of gastric origin appears globally worse than those obtainable for other malignancies.6 However, HIPEC has gained increasing support as adjuvant treatment for the prevention of peritoneal recurrence after radical surgery for primary gastric carcinoma. The issue is to show whether these procedures effectively improve the patients' prognosis with respect to conventional treatments. In the present review we summarized current knowledge on this subject.

Traditionally, the survival rate for gastric carcinoma patients with PC has been considered unsatisfactory, with mean survival ranging from 2.2 to 8.8 months and no survival at 5 years.6, 7, 8 Neither neo-adjuvant nor adjuvant treatment approaches have been shown to decrease the incidence of peritoneal carcinomatosis.9 Indeed, peritoneal dissemination is the most common reason for failure after intensive chemotherapy10 and systemic chemotherapy, as well as radiation, is largely ineffective when PC occurs.11 As opposed to ovarian cancer, in which CRS was established as an inherent part of the standard treatment regime,12 surgical treatments directed at removing the primary lesion of gastric PC have always resulted as being palliative with rapidly recurring tumour growth within the abdominal cavity.13

During cytoreduction manoeuvres, exfoliating tumour cells colonize injured peritoneal surfaces rapidly and massively.14 The simply irrigation at the time of surgery of the bed of the resected tumour with distilled water or saline solution has been shown to be ineffective in removing any neo-plastic cells and preventing local recurrences.15 However, historical studies reported the efficacy of high volume irrigation with saline solution in removing neo-plastic cells that may have contaminated the peritoneal cavity, becoming the impetus for successive investigations.16, 17 Brundell et al.18 reported significantly greater numbers of cells were removed by lavage, from the first to third lavage cycle. Intraperitoneal chemotherapy has the theoretic advantage of delivering a high local concentration of an anticancer drug with a direct cytotoxic property in addition to the mechanical washing effect obtained by abdominal lavage.4, 5, 6 Phase II–III studies demonstrated that patients receiving IPEC (with or without hyperthermia; mainly with mitomycin C, but also cisplatinum or fluorouracil) after curative resection for locally advanced GC revealed a beneficial effect in overall survival.19 In this context, particularly encouraging survival results have emerged by combining CRS with HIPEC as the best treatment options for carcinomatosis from GC, even though there are some significant limitations.4, 5

In 1988, Fujimoto et al. were the first to report the application of HIPEC on 15 patients with PC secondary to advanced GC, with a low post-operative morbidity rate (13%) and a mean survival rate of 7.2 ± 4.6 months.20 This new treatment gradually gained acceptance in many countries and a number of groups have reported their experience (Table 1).2, 13, 21, 22, 23, 24, 25, 26, 27 In one of the largest series of 107 patients undergoing cytoreduction and HIPEC with MMC, etoposide, and cisplatin, Yonemura and colleagues reported 5-year survival rates of 6.7%, with patients who underwent complete resection surviving significantly longer than those with residual disease (13% vs 2%).25 After surgery, the completeness of cytoreduction (CCR) as described by Jacquet and Sugarbaker28, 29 (Table 2) has been clearly proven to be an independent prognostic indicator.30, 31 More recently, the largest experience published so far on the treatment of PC of gastric origin has been summarized in a multi-institutional retrospective French study collecting data from 159 patients undergoing CRS plus IPEC, principally with hyperthermia (HIPEC).2 The authors confirmed that this approach may achieve long-term survival rates in a selected group of patients, i.e. those with limited and resectable PC, in which a complete macroscopic resection (CCR-0) was achieved, with a resulting 5-year survival rate of 23%, that was significantly greater than the overall 5-year median survival rate of 13%.

However, less encouraging results have also been reported by other authors6, 32 and few studies specifically investigated the real additional impact of HIPEC to the cytoreduction phase.32 In an attempt to clarify this matter Yang et al., in a prospective randomized phase III study, recently compared gastric PC patients with both similar peritoneal tumour spread (PC index) and CCR score.27 Sixty-eight patients were randomly assigned to CRS alone (n = 34) or CRS + HIPEC. They demonstrated that CRS + HIPEC significantly improved the survival for gastric PC, and compared with CRS alone, CRS + HIPEC extended the overall survival rate by nearly 70% (6.5 vs 11.0 months). Studies with greater sample size are required to clarify this issue. However, this study confirmed the importance of complete cytoreduction for long term survival, both for patients who underwent CRS alone or CRS + HIPEC.

Intraperitoneal chemotherapy has limited drug penetration through the subperitoneal layer and consequently produces no anti-tumour effect on the deeply invasive microfoci.33, 34 This should explain why the effect on survival of CRS + HIPEC is dismal in patients with bulky mass or extensive PC not amenable to downstaging to CCR-0. Indeed, PCI should be converted to 0 by cytoreduction to make HIPEC in GC patients advantageous. If CCR-0 resection is achieved, the treatment strategy with HIPEC effectively acts as a powerful therapy,19 conversely when CRS does not allow sufficient downstaging, the survival benefit of HIPEC is inconsistent, and median survival rate does not exceed 6–8 months.19 It is for this reason, coupled with the risk of high postoperative complications, that HIPEC should not be performed in patients with CCR-1 or CCR-2/3 resection. A very recently published systematic review summed up and exactly confirmed these conclusions.35

Although the patients affected by advanced gastric carcinoma are submitted to apparently complete resection, their 5-year survival rate still remains dismal, ranging from 30 to 60%, which has been disappointing.36 Peritoneal metastasis is the most common type of recurrence and cause of death after surgery in patients with GC.37 Peritoneal recurrence develops in nearly 20–50% of patients submitted to a curative gastrectomy, rising to 80% for those with positive peritoneal cytology.6, 38, 39 Tumour -positive cytology has been clearly correlated with intraperitoneal recurrence and is significantly associated with decreased disease-free and overall survival rates.40, 41 Intravenous chemotherapy and radiotherapy did not show significant survival advantage as adjuvant treatment for patients with high risk of gastric PC.6, 9 On the other hand, intraperitoneal instillation of chemotherapy has been shown to prevent the development of PC after implantation of neo-plastic cells in animal models.42, 43, 44 The addition of hyperthermia acts synergistically with selected chemotherapeutic agents and also increases the depth of penetration of chemotherapeutic drugs into tumour tissue.45, 46, 47

At present, several studies,24, 30, 38, 48, 49, 50, 51, 52, 53, 54 principally conducted by Asian authors (from China, Japan, Korea), including a number of randomized clinical trials (RCTs) (Table 3), have been performed to investigate the usefulness of HIPEC in a prophylactic setting or as adjuvant treatment after potentially curative gastric-cancer resection.

Koga et al.51 were the first to evaluate, in a small pilot RCT, the efficacy of HIPEC as adjuvant treatment for the prevention of peritoneal recurrence after surgery for serosa-invasive GC. They reported a considerably higher 3-year survival-rate of patients in the HIPEC plus surgery group (83.0%) compared to the control group (67.3%), although not statistically significant (Table 3). In 1994, Hamazoe et al.52 published the final results of their prospective RCT on the prophylactic effects of HIPEC with high doses of mitomycin C for the prevention of peritoneal GC recurrence. They showed a lower incidence of peritoneal recurrence and a higher 5-year survival rate of patients in the HIPEC group with respect to the control group (64.2% vs 52.5%), although the survival benefit did not achieve a statistically significant difference.

The RCT by Fujimoto and colleagues,38 conducted on 141 stage II and III gastric cancer patients, demonstrated a significantly improved peritoneal recurrence rate and long-term survival in the surgery plus HIPEC group compared to surgery alone after curative resection. In addition the peritoneal recurrence rate in the HIPEC group was significantly decreased (p < 0.0001) compared with that in the control group.

Two other large studies were conducted in the 1990s, by Fujimura et al.49 and Yonemura et al.,53 both from Kanazawa University in Japan, the first of which was a RCT. They showed a significantly higher rate of survival after adjuvant HIPEC combined with surgery as compared to surgery alone. The study conducted by Fujimura et al. also included in the control group (n = 36) a third arm of randomization, made up of a group of patients (n = 18) submitted to NIPEC after surgery (Table 3). This procedure was shown to be also effective for preventing peritoneal recurrence, with survival rates better than those of the group submitted to surgery alone, but nonetheless lower than those reached by HIPEC (Table 3). Despite the small number of cohort patient groups in this study, the results of Fujimura et al. highlight the independent and synergistic effect of hyperthermia, along with chemotherapeutic agents, against cancer cells, which seems to increase greatly at temperatures of 42.5 °C–43 °C. The amount of hyperthermia varies between studies, but most teams aim at a homogeneous intraperitoneal temperature of 42–43 °C,4, 30 as these intra-abdominal temperatures have been reported to be the optimal temperature obtaining effective synergism with the anti-neoplastic drugs used, whilst limiting regional toxicity to acceptable levels.55

The team of Yonemura et al.50 more recently confirmed similar results in a RCT including NIPEC procedures once again. One-hundred and thirty nine advanced GC patients without evidence of macroscopic peritoneal seeding were randomly allocated to 3 groups: HIPEC plus surgery, NIPEC plus surgery, and surgery alone. The 5-year survival rate of patients treated by the combination of HIPEC and surgery was significantly higher at 61% than those of the two other groups. In particular, NIPEC gave no survival benefit as compared with that of the surgery alone group.

Overall, the randomized clinical trials on adjuvant HIPEC-procedures demonstrate that the peritoneal recurrence rate is decreased and survival improved by this treatment in patients with advanced GC. The only investigators who have failed to demonstrate a survival benefit after adjuvant HIPEC in a randomized study are Ikaguchi et al.54

In recent years, two meta-analysis investigating the effectiveness and safety of adjuvant IPEC in treatment of advanced GC tried to clarify this issue too. Xu et al.36 comprehensively reviewed all the available randomized trials investigating IPEC in patients undergoing radical, potentially curative, resection for locally advanced GC and combined the results for meta-analysis. The authors found 11 RCTs, of which 7 comparing surgery + HIPEC with surgery alone. Based on their results, IPEC showed to benefit the patient after curative resection vs resection alone, and the combination of HIPEC or activated carbon particles was shown to be superior to other forms of IPEC due to the enhanced anti-tumour activity of drugs. Similarly, Yan et al.56 reviewed all clinical trials studying the adjuvant role of perioperative IPEC in resectable GC. They found 106 published peer-reviewed articles, of which 13 RCTs including patients with locally advanced GC (macroscopic serosal invasion but not distant metastases or PC), randomly assigned to receive surgery combined with IPEC vs surgery without IPEC. Of these 13 RCTs, 4 trials investigated the efficacy of HIPEC, 5 trials studied the efficacy of NIPEC, 2 trials evaluated the efficacy of EPIC, 2 trials reported the combined effect of HIPEC and EPIC, and 2 trials assessed the efficacy of DIPEC. Based on the meta-analysis of the pooled data from 1648 patients, a significant improvement in survival was noted with HIPEC alone or HIPEC combined with EPIC. A trend towards survival improvement with NIPEC was also shown, whereas there was no significant trend with either EPIC alone or DIPEC.

Section snippets

Discussion

The treatment of carcinomatosis from gastric cancer by peritonectomy and HIPEC has globally demonstrated worse long term results than for the treatment of PC from other causes.4, 6 Once gastric PC is manifest, CRS and peritonectomy procedures affect the reduction of tumour volume and the combination of HIPEC acts as an “intensification device”, but with poor survival benefit if a complete sterilization of the tumour peritoneal disease is not obtained. Whether to perform this combined procedure

Conclusions

In Eastern RCTs, HIPEC has shown potential survival benefit as adjuvant treatment for patients with a high risk of developing carcinomatosis after curative gastrectomy for advanced gastric carcinoma, in particular those of diffuse-mixed type, with serosal invasion or positive peritoneal cytology. Nevertheless, international protocol standardizing this procedure has not yet been validated and this statement has to be confirmed by western RCTs.

On the other hand, the benefit of HIPEC in overt PC

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