AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).

METHODS: An electronic literature search was carried out to identify publications reporting oncological outcome data (overall survival and/or disease free survival and/or recurrence rates) following CRS and IPC for treatment of CPM. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if data were reported independently for colorectal cancer-associated cases; in addition studies reporting outcomes for peritoneal carcinomatosis of appendiceal origin were excluded.

RESULTS: Twenty seven studies, published between 1999 and 2013 with a combined population of 2838 patients met the predefined inclusion criteria. Included studies comprised 21 case series, 5 case-control studies and 1 randomised controlled trial. Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). In the majority of included studies (20/27) CRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC). In 3 studies HIPEC was used in combination with early post-operative intraperitoneal chemotherapy (EPIC), and 2 studies used EPIC only, following CRS. Two studies evaluated comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM. The delivery of IPC was performed using an “open” or “closed” abdomen approach in the included studies.

CONCLUSION: The available evidence presented in this review indicates that enhanced survival times can be achieved for CPM after combined treatment with CRS and IPC.

Colorectal cancer (CRC) is a major cause of cancer-associated mortality world-wide with over 1 million new cases diagnosed annually[1]. Disseminated disease represents the principal cause of mortality in CRC and a significant proportion of patients are found to have locally advanced or systemically disseminated disease at initial presentation. It is estimated that at the time of diagnosis 30%-40% have locally advanced disease (Stage II-III) and approximately 20% have distant metastases (Stage IV)[2,3]. Haematogenous spread to the liver is the most common route for distant-organ dissemination, followed by pulmonary metastases[4]. Historically, patients with stage IV disease have been offered supportive therapy only, with 5-year survival rarely exceeding 5%[5]. Over the past two decades the widespread use of newer chemotherapeutic agents such as irinotecan and oxaliplatin, as well as novel targeted therapies, have led to a significant improvement in progression-free and overall survival in stage IV CRC[6,7]. In parallel there has been sharp increase in the volume of surgical resections/ablative procedures being undertaken for stage IV disease, and curative intent hepatic and pulmonary metastasectomy are now routinely performed[8,9].

Synchronous peritoneal carcinomatosis is identified at primary surgery in approximately 5%-10% of patients undergoing CRC resection[10-12]. Additionally up to 20%-50% of patients undergoing curative intent colorectal cancer resection can go on to develop disease recurrence limited to the peritoneal cavity[10]. In theory, the development of colorectal peritoneal disease starts with primary tumour rupture or invasion through the serosa, followed by seeding of free intra-peritoneal tumour cells[13]. The precise mechanistic principles that govern distribution within the peritoneal cavity are multifactorial and have been well described and referred to as “redistribution phenomena”[14,15]. Briefly, these factors include gravitational pooling of cancer-cell containing fluid in the pelvis, clockwise directional flow of peritoneal fluid in the abdominal cavity leading to sub-phrenic implantation[16], and phagocytic activity of the greater and lesser omentum which leads to the formation of characteristic “omental cake” deposits[16-18].

The presence of peritoneal disease in the context of CRC confers a dismal prognosis, and traditional treatment involving systemic chemotherapy, with or without palliative surgery (typically reserved for acute complications such as intestinal obstruction) is associated with a median survival of 5-7 mo[10-12]. Since the 1990s however, several pioneering groups around the world have sought to employ more radical strategies for the treatment of peritoneal surface malignancy. Cytoreductive surgery (CRS), popularised by Sugarbaker initially for relatively non-invasive tumours such as Pseudomyxoma Peritonei[19,20], is now offered to selected patients at specialist units for what is best termed “Colorectal peritoneal metastases (CPM)”, analogous to the concept of resectable liver metastases[21]. The aim of CRS is to remove all macroscopic disease through peritonectomy and multi-visceral resections where required. The extensiveness of these approaches varies according to cancer volume and anatomical location; CPM involving visceral peritoneal surfaces requires organ resection at times[13,19], while treatment of disease confined to the parietal peritoneum involves more limited regional peritoneal stripping[20].

The combination of these surgical approaches with peri-operative intra-peritoneal chemotherapy (IPC) has been advocated in order to eradicate residual cancer cells after macroscopic cytoreduction[22]. The peritoneal route of chemotherapy is based on the peritoneal-plasma partition concept whereby a high concentration of the chemotherapy is in direct contact with cancerous cells with minimal systemic absorption and side effects. A variety of strategies have been proposed and investigated including hyperthermic intraperitoneal chemotherapy (HIPEC)[23,24] and early post-operative intraperitoneal chemotherapy (EPIC)[25]. The rationale for this combination in favour of systemic therapy alone stems from the understanding that reducing tumour burden represents a critical factor in achieving tumour response to chemotherapy[13]. This notion is supported by the findings of a Dutch randomized-controlled trial (RCT) which reported significantly improved survival outcomes with CRS and HIPEC compared with systemic chemotherapy alone for patients with CPM[26]. Despite these encouraging reports, the otherwise lack of level-1 evidence and concerns with respect to peri-operative morbidity, mortality, quality of life, and healthcare related costs, have polarised opinions regarding these aggressive multi-modality approaches, and the management of CPM remains controversial[21].

To date there has been only one systematic review and meta-analysis of data regarding the utility of CRS and IPC in the context of CPM[27,28].

The present study therefore aims to provide an up-to-date systematic review of the available literature regarding the use of CRS in combination with intra-peritoneal chemotherapy for treatment of CPM specifically. In particular, we focus on the current techniques, oncological outcomes, and associated complications.

Peritoneal metastasis from colorectal cancer (CPM), either at initial presentation, or at subsequent recurrence, presents significant challenges. The majority of patients have extensive disease (correctly labelled colorectal carcinomatosis; Figure 3A), and are not amenable to curative surgical intervention. A proportion, best categorized as Colorectal Peritoneal Metastasis (CPM) (Figure 3B and C) can be treated with curative intent by a combination of CRS and IPC. Without treatment, practically all patients with cancer spread to the peritoneum have poor outcomes, exceptionally impaired quality of life, and abbreviated survival. Conventional surgical resection alone has not been demonstrated to be effective for treatment of CPM, and is associated with a median survival of less than 6 mo[60]. Similarly, orthodox systemic chemotherapy treatment for CPM has only limited efficacy, at least in part owing to the plasma-peritoneal barrier which results in decreased intra-peritoneal drug penetration.

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Figure 3 Widespread colorectal peritoneal carcinomatosis (A) compared to colorectal peritoneal metastasis on the parietal peritoneal surface (B, arrows) or on the peritoneum of the small bowel mesentry (C).

For all these reasons, aggressive multidisciplinary treatment incorporating cytoreductive surgical (CRS) techniques and intra-peritoneal chemotherapy has been proposed and pursued as a logical treatment strategy to improve long-term survival, and may represent an appealing and natural evolution of the management of complex and advanced CRC.

Historically, this form of radical approach has been rarely applied owing to concerns regarding high morbidity and mortality. In more recent times however, advances in radiological staging and surgical and anaesthetic practice, improved experience in chemotherapeutic methods, and better management of associated toxicity, have helped expand the treatment options for patients with peritoneal disease, allowing enhanced prognosis and survivorship through increased application of CRS and IPC. However, despite a recent consensus statement published on the role of CRS in combination with HIPEC in the management of CPM[24], there is on-going disagreement and controversy regarding the precise role of this multimodality approach in treatment algorithms, and firm evidence to support widespread implementation has been questioned.

The purpose of the present review was to systematically and critically analyse the available literature. Twenty seven studies with a combined population of 2838 patients met the predefined inclusion criteria and were included in the review process. Only publications in the last 15 years were included to eliminate any time-dependant bias from subtle alterations to treatment approaches and drugs. The available literature consists mainly of low-grade evidence with small case series or comparative studies, with the exception of one relatively recent randomised trial. Furthermore, there is substantial between-study heterogeneity, non-standardised definitions, and inconsistent reporting of data. In spite of these limitations, this body of data clearly indicates that the greatest survival times from CPM are achieved after treatment in specialist institutions by CRS and IPC, with a predictable high, but perhaps acceptable, frequency of complications. The exact nature and location of re-recurrence was reported in few studies, with disease recurring in the peritoneal compartment (ranging from 28%-59%); in distant organs alone (12%-17%); or in both peritoneal and distant organs (18%-28%; Table 2).

One key consideration is the selection of patients for radical treatment strategies. The studies included in this review illustrate a wide variety of methods with no overall consensus or approach. While a number of studies stated medical co-morbidity as one exclusion criterion, this was generally poorly defined. Cardiopulmonary exercise testing is one of the most reliable methods of risk prediction in non-cardiopulmonary surgical procedures, outperforming alternative methods of risk stratification, and can readily aid in identification of patients at an increased risk of adverse perioperative events[61]. No studies included in the present review used formal pre-operative cardiopulmonary exercise testing as a risk stratification measure however. Similarly, while some authors would consider the presence of other solid organ metastases on pre-operative imaging to be a contraindication to CRS and PIC[26,34-37,42,44,48,51,53,55,57] this is not an absolute if other metastases are resectable[38]. Further stratification factors are the extent of disease, and the ability to achieve a complete cytoreduction. Both are major predictors of oncological outcome, however significant variability was noted in the assessment methods used for the evaluation of disease extent in the studies examined. In 10 of the included studies a marked reduction in long-term survival was reported following CC2-3, compared with CC0-1 resection[26,33,36-39,44,52,53,62]. In the largest study included in this review, analysis of outcomes in 506 patients treated with CRS and HIPEC found completeness of cytoreduction to be the strongest predictor of survival on multivariate analysis (P < 0.0001)[38]. The authors of this study also found extent of disease at time of surgery (PCI) to be a significant determinant of survival (P < 0.001)[38] This finding is supported by the results of Quenet et al[46] who reported 5-year survival of 65%, 26% and 18% respectively for patients with PCI < 10, PCI 11-19 and PCI > 20. Other factors such as tumour differentiation[17,35,38,52] the presence of bowel obstruction[39], malignant ascites[39], age[38] lymph node dissemination[38] and extent of small bowel involvement[52] have also been identified as negative prognostic indicators, and further investigation is required in order to better define the relative contributions of these factors to disease outcome.

The present systematic analysis is subject to a number of limitations. All but one of the studies were non-randomised, mainly with small sample sizes, and were heterogeneous with respect to extent of peritoneal disease and its manner of assessment; protocol and type of chemotherapy applied; and measured outcomes. Most were conducted in large tertiary referral cancer centres. Crucially, it is not possible to separate the incremental contribution of CRS and IPC from the available data, making it difficult to draw definitive conclusions regarding the individual contribution of each to the positive outcomes. Only one RCT has been undertaken to date comparing CRS and IPC with conventional systemic chemotherapy[26]. Verwaal et al[26] found improved survival with CRS + HIPEC compared with systemic chemotherapy alone, though these findings are limited somewhat by the single institution nature of the study, the relatively modest sample size, and the fact that patients in the control arm received 5-FU, rather than more contemporary oxaliplatin-based therapy. Clearly therefore, the findings presented here must be interpreted within these limitations. Nevertheless, in view of the limited evidence base in this field at the present time, synthesised evidence in the present form represents the most informative means of evaluation.

A number of questions still remain. Better methods of patient selection are clearly required, and the role of physiological testing preoperatively may well merit further study to more effectively gauge functional capacity and risk of adverse events. In addition, an important challenge in the future will be to identify methods to avoid over-treatment in patients with chemotherapy insensitive tumours, and to limit side-effects in those with chemo-sensitive disease. The exact type of chemotherapy and its method of administration remain unclear at the present time, as is the precise contribution of CRS and IPC to the favourable outcomes observed. A further key question will be whether different/more radical/dose escalated IPC regimes can counter unfavourable peritoneal disease extent scores. Robust molecular biomarkers of oncological outcome and disease response are clearly required and are presently lacking. Exciting developments in the molecular sciences and the multi-platform high-throughput methods increasingly applied to diverse tumour types are transforming established treatment approaches, and offer the opportunity for the development of more personalised strategies in the treatment of CPM. Although no targeted therapeutic agents are currently approved for use in the treatment of CPM, it is expected that emerging tumour-targeted molecular therapies will permit more cancer-specific cytotoxicity, potentially enhancing oncological outcome and minimising unwanted toxicity.

In conclusion, Peritoneal disease from colorectal cancer remains a significant clinical problem and presents unique challenges and opportunities. The concept of resectable CPM is useful in this complex field. The present review indicates that the evidence base for CRS and IPC is composed largely of prospective and retrospective series with only one RCT on the subject to date. Nevertheless these studies appear to demonstrate survival rates greater than any available alternative, justifying an aggressive approach. Similar to acceptance of surgery for liver, lung, and occasionally brain metastatic CRC, radical treatment for peritoneal disease from CRC now has an established place in selected patients, offering the only realistic chance of long-term survival. In the future, high-number, multi-institutional studies with limited heterogeneity in assessment and treatment protocols may better enable clarification of some of the controversies in the treatment of CPM.