Systematic Reviews Open Access
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World J Gastroenterol. Oct 14, 2014; 20(38): 14018-14032
Published online Oct 14, 2014. doi: 10.3748/wjg.v20.i38.14018
Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases
Reza Mirnezami, Section of Biosurgery and Surgical Technology, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Building, St Mary’s Hospital, London W2 1NY, United Kingdom
Brendan J Moran, Kate Harvey, Tom Cecil, Kandiah Chandrakumaran, Faheez Mohamed, National Pseudomyxoma Peritonei Centre, Hampshire Hospitals Foundation Trust, Basingstoke RG24 9NA, United Kingdom
Norman Carr, Alexander H Mirnezami, Somers Cancer Research Building, University of Southampton Cancer Sciences Division, Southampton University Hospital NHS Trust, Southampton SO166YD, United Kingdom
Author contributions: Mirnezami R, Moran BJ, Mohamed F and Mirnezami AH contributed to study conception, literature search and manuscript preparation; Harvey K prepared the manuscript; Cecil T, Chandrakumaran K and Carr N prepared and edited the manuscript.
Supported by Cancer Research United Kingdom; Wessex Medical Research
Correspondence to: Dr. Alexander H Mirnezami, Somers Cancer Research Building, University of Southampton Cancer Sciences Division, Southampton University Hospital NHS Trust, Tremona Road, Southampton SO166YD, United Kingdom. ahm@soton.ac.uk
Telephone: +44-2380-795170  Fax: +44-2380-794020
Received: September 29, 2013
Revised: December 16, 2013
Accepted: June 26, 2014
Published online: October 14, 2014

Abstract

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.

Key Words: Colorectal cancer, Peritoneal metastasis, Cytoreductive surgery, Intraperitoneal chemotherapy, Hyperthermic intraperitoneal chemotherapy

Core tip: Colorectal cancer peritoneal metastases (CPM) confer a dismal prognosis and traditional treatment involving systemic chemotherapy, with or without palliative surgery has poor outcomes. Cytoreductive surgery (CRS) combined with intraperitoneal chemotherapy (IPC) is now advocated for selected patients with CPM. The present study provides a comprehensive summary of the available evidence relating to CRS in combination with IPC in the setting of CPM, focusing on techniques, oncological outcomes, and complications.



INTRODUCTION

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.

MATERIALS AND METHODS
Identification of studies

An electronic literature search was carried out using the following medical subject heading (MeSH) terms: “colorectal cancer”; “peritoneal”; “carcinomatosis”; “cytoreductive surgery”; “chemotherapy”; “intra-operative”; “intra-peritoneal”. The “related articles” function was used to broaden search output. All potentially eligible publications were obtained in full text and assessed for suitability. Text references were manually searched for identification of additional eligible studies.

Study inclusion criteria and data extraction

Review methodology was conducted according to guidelines outlined in the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” framework[29]. Identified publications had to meet the following criteria to be included in the systematic review process: (1) English language; (2) ≥ 15 male/female adult patients (≥ 18 years); and (3) histologically verified diagnosis of CPM receiving multi-modality treatment with CRS and IPC. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if survival outcome data were reported independently for CRC-associated cases; in addition studies reporting outcomes in patients undergoing treatment for peritoneal disease of appendiceal origin were excluded, as there is significant variation in the natural history and prognosis of this sub-group of patients[28]; and (4) reporting oncological outcome data (survival and/or recurrence rates). Complication related data was also extracted where provided. Where multiple studies with potentially overlapping patient populations were identified, the most recent study was included. Figure 1 summarizes the review search strategy. Two reviewers (RM and AHM) derived the following data from eligible publications: author, location, year of publication and study timeframe, study type, population characteristics, primary or recurrent disease, stage of CPM [peritoneal cancer index (PCI)[30] or alternative scoring method for disease extent], chemotherapeutic regimen, details of previous treatment (chemotherapy/radiotherapy), length of follow-up, treatment associated morbidity and mortality, completeness of cytoreduction [completeness of cytoreduction (CCR) score[31] and/or R-classification where reported], oncological data (survival and/or recurrence rates). Studies that met inclusion criteria were evaluated based on methodological quality and validity using the Scottish Intercollegiate Guidelines Network (SIGN) framework[32].

Figure 1
Figure 1 Modified preferred reporting items for systematic reviews and meta-analyses flow diagram outlining study selection strategy.
RESULTS
Literature search and description of studies

Initial literature searching identified 265 publications of potential relevance. From these 57 reviews and 118 irrelevant studies were excluded, leaving 90 articles retrieved in full text. Manual reference searches from these articles revealed an additional 3 potentially eligible publications, providing a total of 93 articles. Of these, 66 failed to meet inclusion criteria and were withdrawn after full text appraisal, leaving 27 studies (1999-2013) for systematic review (Figure 1). The combined number of patients with CPM in these studies was 2838 (range 18-523), of whom 2683 (95%) underwent combined modality treatment involving CRS and IPC. The remaining 155 patients (5%) received systemic chemotherapy alone. Studies included in the review comprised 21 case series[17,33-52] (evidence level 3), 5 case-control studies[53-57] (evidence level 2-) and 1 randomised controlled trial[26] (evidence level 1-). Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone[26,53-55]. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). Table 1 provides a summary of study design, treatment indications and treatment protocols for studies included in the systematic review process.

Table 1 Summary of study design, treatment indications and treatment protocols for studies included in systematic review process n (%).
Ref.Time framenStudy design (evidence level)IndicationExtent of CPMTreatment summaryTechniqueIntraperitoneal chemotherapeutic regimen
Portilla et al[33]1985-199618Case series (3)rCPM1PCI < 12, 10/18 (60)CRS + EPICClosed techniquePOD 1: MMC in 1 L 1.5% dextrose peritoneal dialysis solution (10-12.5 mg/m2)
PCI > 12, 8/18 (38)POD 2-6: 5-FU in 1 L 1.5% dextrose peritoneal dialysis solution + 50 mEq sodium bicarbonate
Witkamp et al[34]1995-199729Case series (3)CPM2-CRS + HIPECClosed techniqueMMC 35 mg/m2 in 3-4 L of isotonic dialysis fluid at a temperature of 40 °C-41 °C for 90 min
Pilati et al[35]1995-200134Case series (3)CPM2-CRS + HIPEC10/34 closed techniqueMMC (3.3 mg/m2 per liter) + cisplatin (25 mg/m2 per liter) for 90 min at temperature of 41 °C-42 °C
14/34 open technique
Verwaal et al[36]1995-2003106Case series (3)rCPM2-CRS + HIPECClosed abdomen techniqueMMC 35 mg/m2 in 3-4 L of isotonic dialysis fluid at a temperature of 40 °C-41 °C for 90 min
Glehen et al[37]1989-200253Multicentre case series (3)CPM2Stage2 I 13/53 (25)CRS + HIPECClosed abdomen techniqueMMC 40-60 mg in 4-6 L of perfusate at a temperature of 46 °C-48 °C for 90 min
Stage II 8/53 (15)
Stage III 7/53 (13)
Stage IV 25/53 (47)
Mahteme et al[53]1991-199936 (18 vs 18)Case-control (2-)CPM2-Treatment arm: CRS + EPIC (n = 18)Closed abdomen techniqueEPIC protocol: 5-FU 550 mg/m2 in 500 mL normal saline administered intraperitoneally from POD 1. IV infusion of leucovorin (60 mg/m2) commenced at 60 min after initiation of PIC. Regimen offered 1-8 courses as tolerated with 4-6 wk interval between cycles.
Control arm: Systemic CT onlySystemic CT protocol: Chemotherapeutic regimen not specified
Glehen et al[38]1987-2002506Multinational case series (3)CPM3Limited 171/506(n = 18)CRS + HIPEC and/or EPICOpen or closed techniqueHIPEC protocol: Various (MMC alone 274/506; MMC + cisplatin 48/506; oxaliplatin 32/506; other 29/506)
Extended 329/506EPIC protocol: Various (MMC alone 2/506; MMC + 5-FU 113/506; 5-FU alone 95/506; other 7/506)
Shen et al[39]1991-200277Case series (3)CPM3-CRS + HIPEC40 mg MMC introduced into dialysis fluid for 120 min at ≥ 38.5 °C
Cavaliere et al[40]1996-2005120Multicentre case series (3)CPM1-CRS + HIPECClosed abdomen technique Open 56.7%109/120: MMC (3.3 mg/m2 per liter) and cisplatin (25 mg/m2 per liter) at 41.5 °C-43 °C for 60-90 min
Closed 43.3%11/120: oxaliplatin (460 mg/m2) for 30 min after IV 5-FU and leucovorin
Kianmanesh et al[41]1996-200643Case series (3)CPM3Stage2 I/II 10/43 (23)CRS + HIPECOpen techniqueMMC 120 mg + cisplatin 200 mg/m2 at 41 °C-43 °C for 90 to 120 min
Stage III 6/43 (14)
Stage IV 27/43 (63)
Gusani et al[42]2002-200528Case series (3)CPM2-CRS + HIPECClosed techniqueMMC 30-40 mg in 3 L saline solution at temperature of 40 °C for 100 min
Verwaal et al[26]1998-2001105 (54 vs 51)Randomized trial (1-)CPM2-Treatment arm: CRS + HIPEC (n = 54)Open coliseum techniqueHIPEC protocol: MMC 17.5 mg/m2 at 40 °C for 90 min
Control arm: Systemic CT only (n = 51)Systemic CT protocol: 5-FU (400 mg/m2) + leucovorin (80 mg/m2) weekly for 26 wk
Yan et al[62]1997-200750Case series (3)CPM3PCI < 10 20/50CRS + HIPECOpen coliseum techniqueMMC 10-12.5 mg/m2 in 3 L of 1.5% dextrose peritoneal dialysis solution for 90 min at 42 °C
PCI 10-20 23/50
PCI > 20 7/50
Elias et al[54]1998-200396 (48 vs 48)Case-control (2-)CPM3Treatment arm: Limited 27/48 Extended 21/48Treatment arm: CRS + HIPEC (n = 48)-HIPEC protocol: Oxaliplatin 460 mg/m2 in 2 L/m2 at 43 °C for 30 min. Before HIPEC (during CRS) patients received IV 5-FU 400 mg/m2 + leucovorin 20 mg/m2
Control arm:Control arm:Systemic CT protocol:
Limited 26/48 Extended 17/48Not recorded 5/48Systemic CT only (n = 48)Various regimens (5-FU based 46/48; Capecitabine based 1/48; Camptothecin 1/48)
Varban et al[43]1991-2007142Case series (3)CPM3-CRS + HIPECClosed techniqueMMC 40 mg at 40.5 °C-42.5 °C for 120 min
Vaira et al[44]1997-200840Case series (3)CPM2PCI > 16 11/40CRS + HIPECClosed techniqueCisplatin (100 mg/m2) + MMC (16 mg/m2) at 41.5 °C for 30 min
PCI < 16 29/40OR
Oxaliplatin (460 mg/m2) + IV 5-FU at 42 °C for 30 min
OR
MMC (35 mg/m2) at 40.5 °C for 60 min
Glehen et al[45]1989-2007523Multi-centre case series (3)CPM3-CRS + HIPEC and/or EPICVarious techniquesHIPEC protocol: MMC (30-50 mg/m2) with or without cisplatin (50-100 mg/m2) delivered over 60-120 min at 41 °C-42.5 °C
OR
Oxaliplatin (360-460 mg/m2) +/- irinotecan (100-200 mg/m2) +/- IV 5-FU and leucovorin delivered over 30 min at 43 °C
EPIC protocol: Abdominal cavity filled at the end of surgery with 1 L/m2 Ringer lactate. EPIC lasted 5 d (POD 1-5); POD 1: MMC (10 mg/m2); POD 2-5: 5FU (600 mg/m2)
Franko et al[55]2001-2007105 (67 vs 38)Case-control (2-)CPM2-Treatment arm: CRS+ HIPEC (n = 67)Closed abdomen techniqueHIPEC protocol: MMC 40 mg for 100 min
Control arm: Systemic CT only (n = 38)Systemic CT protocol: Chemotherapeutic regimen(s) not clearly described
Quenet et al[46]1998-2007146Case series (3)CPM3PCI < 10 69/146CRS + HIPECClosed techniqueIV 5-FU (400 mg/m2) + leucovorin (20 mg/m2) followed by: ip oxaliplatin (460 mg/m2) in 2 L/m2 dextrose
PCI 11-19 57/146OR
PCI >20 20/146ip oxaliplatin (300 mg/m2) + ip irinotecan (200 mg/m2) in 2 L/m2 dextrose
Cashin et al[57]1993-200832 (16 vs 16)Case-control (2-)CPM2HIPEC group: Mean PCI 14.4CRS + HIPEC (n = 16)HIPEC:Open coliseum techniqueEPIC: Closed techniqueHIPEC protocol: Oxaliplatin 460 mg/m2 for 30 min at 41 °C-42 °C combined with IV 5-FU (450-500 mg/m2) + leucovorin (25-30 mg/m2)
EPIC group: Mean PCI 13.2CRS + EPIC (n = 16)EPIC protocol: 5-FU (500-600 mg/m2) + IV leucovorin (20-30 mg/m2) once daily for 86-d cycles
Passot et al[47]1991-2010120Case series (3)CPM3Stage2 I-II 41/120CRS + HIPECClosed techniqueMMC + irinotecan or oxaliplatin
Stage III-IV 79/120Exact dosing protocol not described
Mean PCI 8.2
Hompes et al[48]2004-200848Case series (3)CPM2Median PCI 11 (1-22)CRS + HIPECOpen coliseum techniqueIV folinic acid (20 mg/m2) + 5-FU (400 mg/m2) followed by ip oxaliplatin (460 mg/m2) in 2 L/m2 5% glucose solution at 41 °C-42 °C for 30 min
Cashin et al[56]1996-2010151 (69 vs 57)Case control (2-)CPM3PCI 1-10 49/151CRS+ HIPEC (n = 69)HIPEC: Open coliseum techniqueHIPEC protocol: MMC ip (30 mg/m2) for 90 min at 41 °C-42 °C OR oxaliplatin (460 mg/m2) ip for 30 min at 41 °C-42 °C + IV 5-FU (400 mg/m2) and calcium folinate (60 mg/m2) OR oxaliplatin (360 mg/m2) ip + irinotecan (360 mg/m2) for 30 min at 41 °C-42 °C + IV 5-FU (450-500 mg/m2) and calcium folinate (60 mg/m2)
PCI 11-20 45/151CRS + EPIC (n = 57)EPIC: Closed techniqueEPIC protocol: 5-FU (500-600 mg/m2) ip + IV leucovorin (60 mg/m2) once daily for 8 6-d cycles
PCI 21-39 56/151
Klaver et al[49]1996-201024Case series (3)CPM14-CRS+ HIPEC (12/24)Open coliseum techniqueHIPEC protocol: ip chemotherapy (MMC or oxaliplatin; dosing not stated) at 42 °C for 90 min
CRS + EPIC (6/24)EPIC protocol: 5-FU (650-800 mg/m2 per day) in 1 L 1.5% dextrose for 23 h on POD 1-5
CRS + HIPEC + EPIC (6/24)
Turrini et al[50]2004-201026Case series (3)CPM1-CRS + HIPECOpen coliseum techniqueOxaliplatin ip (460 mg/m2) in 2 L/m2 dextrose solution at 43 °C for 30 min after 1 h infusion of IV 5-FU (400 mg/m2) + leucovorin (20 mg/m2)
Haslinger et al[51]2003-201138Case series (3)CPM2-CRS+ HIPECClosed techniqueMMC 40 mg at temperature of 41 °C for 60-120 min
Yonemura et al[52]2004-2012142Case series (3)CPM3-CRS + HIPEC-MMC 20 mg/m2 + cisplatin 100 mg/m2 in $L saline at 42 °C-43 °C for 60 min
Patient selection

All studies defined first-time treated or recurrent CPM as the primary indication for treatment. Patient selection characteristics with respect to consideration for CRS +/- IPC were stated as follows: Inclusion criteria: (1) CPM of colorectal origin[17,26,33-57]; (2) Adequate resection deemed technically feasible based on pre-operative imaging[34,55,57]; and (3) Normal marrow indices/renal function/liver function pre-operatively[26,34,36,43,47,50,56].

Exclusion criteria: (1) Evidence of extra-abdominal disease on pre-operative imaging[17,33-38,43-45,47,48,50-54,56,57]; (2) Evidence of liver metastases on pre-operative imaging[26,34-37,44,48,51,53,55,57]; (3) Advanced age (>71 years;[26,36] >70 years;[37,44,47] > 75 years[46,50,53]; > 80[17]; > 66[54]); and (4) Significant medical co-morbidity[34,43,44,46,47,51,52,55-57]. In the case of the latter criterion, 3 studies used the WHO performance score to determine suitability for aggressive treatment (≥ 2 excluded)[47,56,57] and 3 studies used the Eastern Cooperative Oncology Group (ECOG) Performance Status metric[58] (≥ 2 excluded)[46,51,52]. The remaining 4 studies did not use any formal method for functional assessment[34,43,44,55]. None of the identified studies performed formal assessment of functional capacity using cardiopulmonary exercise testing.

Techniques used for IPC

In the majority of included studies (20/27) CRS was combined with HIPEC[17,26,34-37,39-44,46-48,50-52,54,55]. In 3 studies HIPEC was used in combination with EPIC[37,45,49], and 2 studies used EPIC only following cytoreduction[33,53]. Two studies were specifically designed to assess comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM[56,57].

The delivery of IPC was performed using an “open” or “closed” abdomen approach in the included studies. The open approach was generally performed using the Coliseum technique, as proposed by Sugarbaker (Figure 2A)[59]. Briefly, this involves placement of a Tenckhoff catheter and four closed suction drains through the abdominal wall before the skin edges are suspended with a running suture to a Thompson self-retaining retractor, creating an open cavity for IPC delivery. Typically, IPC is pumped into the open abdomen via the Tenckhoff catheter for between 30-90 min at a temperature of 41 °C-43 °C. This fluid is then circulated back out of the abdomen via the four suction drains. The main advantage with this technique is that IPC is distributed evenly throughout the abdomen, though heat dissipation makes it more time consuming to reach the required temperature. With the closed technique catheters are introduced before the laparotomy wound is sutured and perfusion is carried out via a closed circuit, with the abdominal wall manually agitated to facilitate even distribution of IPC and temperature (Figure 2B). After adequate perfusion, the abdominal wound is opened in order to evacuate the IPC before re-closure. An advantage with this method is the ability to rapidly achieve the required temperature, as heat dissipation is minimized.

Figure 2
Figure 2 Open (A) and closed (B) methods of intraperitoneal chemotherapy.
Oncological outcomes

Oncological outcome data from the 27 studies included in this review are summarised in Table 2. Median survival ranged from 3.7 to 62.7 mo and showed strong correlation with completeness of cytoreduction (as determined by CCS score or R-classification). To date there has been only one RCT carried out to compare outcomes with CRS + HIPEC and conventional systemic chemotherapy alone for treatment of CPM[26]. This study included 105 patients randomly assigned to receive either IV 5-FU or experimental treatment which consisted of an aggressive multimodality approach incorporating CRS combined with HIPEC using mitomycin C. After a median follow up time of 96 mo the authors reported median survival of 22.2 mo in the CRS + HIPEC group compared with 12.6 mo in patients receiving chemotherapy alone[26]. Three case-control studies provided non-randomized comparative data evaluating the impact of aggressive treatment on survival for patients with CPM. Mahteme et al[53] reported outcomes in 18 patients undergoing CRS + EPIC compared with 18 age and gender matched patients receiving chemotherapy only. This study reported overall 2- and 5-year survival of 60% and 28% in the CRS + EPIC group compared with 10% and 5% respectively in the chemotherapy group. Median survival for patients undergoing complete cytoreduction (CC0) was 32 mo compared with 14 mo in the control group. A 2009 study by Elias et al[54] reported similarly improved survival with aggressive multi-modality treatment; here the authors compared survival data from 48 patients undergoing CRS + HIPEC with 48 receiving chemotherapy alone. Median survival, 2- and 5-year survival were all superior in the CRS + HIPEC treatment group (62.7 mo, 81% and 51%) compared with the chemotherapy group (23.9 mo, 65% and 13%). Franko et al[55] reported outcomes of a case-control study of 105 patients with CPM in which 67 underwent CRS + HIPEC and 38 received systemic chemotherapy only. The authors reported 1-, 3- and 5- year survival of 90%, 50% and 25% in the CRS + HIPEC group compared with 55%, 12% and 7% in the control group.

Table 2 Oncological outcome data n (%).
Ref.Median FU (mth)Pre-op CTPost-op CTExtent of cytoreduction/disease CCRS21-yr survival2-yr survival3-yr survival4-yr survival5-yr survivalMedian survival (mo)Local/distant recurrence
Portilla et al[33]36.2122% (regimen not stated)100% (regimen not stated)CC0-CC1 (14/18; 64)CC0-CC1 (91%)CC0-CC1 (64%)---Overall-
CC2-CC3 (4/18; 36)CC2-CC3 (43%)CC2-CC3 (14%)20
PCI < 12 (10/18; 56)PC1 < 12 (N/A)PCI < 12 (64%)
PCI > 12 (8/18; 44)PCI > 12 (N/A)PCI > 12 (14%)
Witkamp et al[34]38 (26-52)-72% (5-FU+ leucovorin)-82%45%23%---LR 28%
DR 17%
LR + DR 28%
Pilati et al[35]14.5 (6-34)0%-CC0-1 34/3468%31%---18LR 59%
DR 12%
LR + DR 18%
Verwaal et al[36]47.5 (1.3-88.3)-15% (leucovorin)R1 (54/106; 51)-----R1 11.1Unspecified recurrence 65%
R2a (37/106; 35)R2a 5.9
R2b (15/106; 14)R2b 3.7
Glehen et al[37]59.5-68% (5-FU + irinotecan leucovorin)CC0 (23/53; 43)CC0 85%CC0 54%--CC0 22%CC0 32.9Unspecified recurrence 19%
CC1 (11/53; 21)CC1 46%CC1 36%CC1 9%CC1 12.5
CC2 (19/53; 36)CC2 24%CC2 0%CC2 8.1
Mahteme et al[53]---CC0 (11/18; 61)-CRS + EPIC 60%--CRS + EPIC 28%CRS + EPIC overall 32; CC0 34.5 CC1-2 10-
CC1-2 (7/18; 39)Control arm 10%Control arm 5%Control arm: 14
Glehen et al[38]5354%40%CC0 (271/506; 54)CC0 87%-CC0 47%-CC0 31%MalesUnspecified recurrence 73%
CC1 (106/506; 21)CC1 79%CC1 29%CC1 15%16.8
CC2 (129/506; 25)CC2 38%CC2 6%CC2 0%Females
21.6
Shen et al[39]15 (3-85)75%-R0 (13/77; 17)--R0 69%-R0 55%R0 N/RUnspecified recurrence 68%
R1 (24/77; 31)R1 19%R1 19%R1 17.8
R2a (11/77; 14)R2a 28%R2a 14%R2a 12.7
R2b (9/77; 12)R2b 0%R2b 0%R2b 4.1
R2c (20/77; 26)R2c 6%R2c 0%R2c 5.0
Cavaliere et al[40]1672%-CC0 (102/120; 85)--Overall--19-
CC1 (9/120; 7)25.8%
CC2-3 (9/120; 7)CC0
33.5%
Kianmanesh et al[41]-70%75%--72%-44%38.4-
Gusani et al[42]35.9 (19-57.7)---78%37%37%--15.2-
Verwaal et al[26]96 (72-115)--R1 (22/54; 41)R1 95%R1 80%R1 58%R1 52%R1 45%CRS + HIPEC-
R2a (23/54; 43)R2a 65%R2a 20%R2a 10%R2a 10%R2a 10%22.2
R2b (9/54; 17)R2b 22%R2b 12%R2b 0%R2c 0%R2c 0%Systemic CT
12.6
Yan[17]14 (1-56)--CC0 (41/50; 82)CC0 85%-CC0 62%--CC0 37Unspecified recurrence 34%
CC1-3 (9/50; 8)CC1-3 51%CC1-3 0%CC1-3 14
Elias et al[54]95.7----CRS + HIPEC--CRS + HIPECCRS + HIPEC-
81%51%62.7
Systemic CTSystemic CTSystemic CT
65%13%23.9
Varban et al[43]14.6----HM 43.3%-HM 14.4%-HM 23-
No HM 36.8%No HM 17.4%No HM 15.8
Vaira et al[44]-55%-CC0 (29/40; 73)CC0 88%----Overall: 43-
CC2 (11/40; 27)CC2 42%CC0: 24
CC2: 9.7
Glehen et al[45]----81%58%39%34%28%--
Franko et al[55]-100--CRS + HIPECCRS + HIPECCRS + HIPECCRS + HIPECCRS + HIPECCRS + HIPEC-
90%65%50%42%25%34.7
Systemic CTSystemic CTSystemic CTSystemic CTSystemic CTSystemic CT
55%35%12%10%7%16.8
Quenet et al[46]48.5100%-CC0 (132/146; 90)OverallOverallOverallOverall-OverallUnspecified recurrence 70%
CC1 (12/146; 8)92%72%55%50%41
CC2 (2/146; 2)
Cashin et al[56]HIPECHIPECHIPEC-HIPECHIPEC groupHIPEC groupHIPEC group-HIPEC group-
3881%38%100%78%60%48%36.5
EPICEPICEPICEPICEPIC groupEPIC groupEPIC groupEPIC group
6644%38%80%48%25%17%23.9
Passot et al[47]58.5 (1-183)75%64.30%CC0 (93/120; 78)OverallOverall--OverallOverall-
CC1 (11/120; 9)77%51%33%36.2
CC2 (16/120; 13)
Hompes et al[48]22.7 (3.2-55.7)-62.50%CC0 (48/48; 100)OS 98%OS 89%-----
DFS 66%DFS 46%
Cashin et al[57]49 (0.5-100)31%18%CC0 (97/151; 64)HIPECHIPECHIPECHIPEC-HIPEC-
CC1-3 (54/151; 36)80%50%27%18%34
EPICEPICEPICEPICEPIC
5%---25
Klaver et al[49]10.5 (1-52)--CC0 (22/24; 92)Overall----OverallUnspecified recurrence 54%
CC1 (2/24; 8)83%35
Turrini et al[50]----100%-51%-37%--
Haslinger et al[51]--------OS 38%--
PFS15%
Yonemura et al[52]-77%-CC0 (108/142; 76)----OverallOverall-
CC1 34/142 (24)23.4%24.4
CC0 20%CC0 25.9
CC1 9.9%CC1 8
Complications

Treatment-associated mortality ranged from 0% to 12% in the included studies and overall morbidity was high, ranging from 21.8%-62%. Five of the studies did not provide any morbidity data[26,33,36,54,55] and in two studies complications were not reported specifically for patients being treated for CPM[45,51]. Specific complications and their incidence are presented in Table 3. The most commonly encountered surgical complications were wound associated problems (infection/dehiscence, 3%-12%)[34,40-44,49] fistulae (intestinal/pancreatic/urinary, 1%-11%)[17,37,38,41-44,46-50] and intra-abdominal abscess formation (1.8%-14%)[17,38,41,42,44,46,48] The re-operation rate reported from all studies ranged from 4% to 20.8%. Haematological toxicity as a result of chemotherapy was reported with an incidence of 2% to 52%[34,35,38,39,43,44,48,50,53].

Table 3 Reported treatment-associated morbidity and mortality following multi-modality therapy for colorectal peritoneal metastase.
Ref.nMortality (%)Overall morbidity (%)No of bowel anastomosesIntra-abdominal complications (%)Extra-abdominal complications (%)
Portilla et al[33]180No treatment-associated morbidity data provided
Witkamp et al[34]293382 (0-5)Postoperative bleeding (3)Grade I-II leucopenia (21)
Bowel perforation (3)Grade III leucopenia (31)
Bladder perforation (3)Peripheral neuropathy (10)
Return to theatre (17)Subclavian vein thrombosis (3)
Hydronephrosis requiring nephrostomy (7)
Wound dehiscence (3)
Prolonged chyle leak (3)
Pilati et al[35]34035-Non-specified complications: Ozols’grade I (53), grade II (9), grade III (1), grade IV (1)Haematological toxicity (12)
Pneumonia (12)
Verwaal et al[36]106-No treatment-associated morbidity data provided
Glehen et al[37]534230.4 (0-4)Return to theatre (4)-
Gastrointestinal fistula (8)
Mahteme et al[53]18061-Severe nausea and vomiting (12)Transient neutropaenia (6)
Leak from drain (6)
Catheter-related problems (39)
Glehen et al[38]5064%22.9-Re-operation (10.7)Haematological toxicity (2.4)
Fistula (8.3)Systemic sepsis (2)
Intra-abdominal abscess (1.8)Cardiorespiratory complications (3.5)
Urinary fistula (1)
Shen et al[39]771230-Bowel perforation (3)Haematological toxicity (19)
Cavaliere et al[40]1203.322.5-Perforation (5)
Anastomotic leak (3.3)
Infection (3.3)
Kianmanesh et al[41]432.339-Deep abscess (14)Pleural effusion (12)
Intestinal fistula (9)Renal failure (7)
Delayed gastric emptying (9)Superficial wound infection (12)
Re-operation (4)
Gusani et al[42]28056.5-Re-operation (8)Systemic sepsis (4)
Anastomotic leak (8)
Intra-abdomoninal abscess (4)
Wound dehiscence (4)
Enterocutaneous fistula (2)
Verwaal et al[26]54-No treatment-associated morbidity data provided
Yan[17]50046-Small bowel obstruction (12)Pleural effusion (34)
Fistula (10)Pneumonia (4)
Intra-abdominal abscess (10)
Perforation (4)
Elias et al[54]48-No treatment-associated morbidity data provided
Varban et al[43]142CPM with HMCPM with HM-CPM with HMCPM with HM
7.1%57.1%Bowel leak (11)Pneumonia (7)
CPM with no HMCPM with no HMWound infection (11)Neutropaenia (7)
7.7%40.1%Pancreatic fistula (11)DVT (7)
Ileus (11)CPM with no HM
CPM with no HMPneumonia (6)
Bowel leak (5)Neutropaenia (8)
Wound infection (5)AF (3)
Ileus (5)Thrombocytopaenia (2)
Enterocutaneous fistula (1)
Vaira et al[44]402.5550 (17.5)Fistula (10)Haematological toxicity (12.5)
1(55)Abdominal abscess (7.5)Pleural effusion (22.5)
2 (27.5)Superficial wound infection (12.5)
Glehen et al[45]523-Not specifically provided for patients undergoing procedures for CPM
Franko et al[55]105-No treatment-associated morbidity data provided
Quenet et al[46]1464.147.2-GI fistula (4.8)-
Urinary fistula (1.4)
Abdominal abscess (2.7)
Reoperation (11.6)
Cashin et al[57]32HIPEC group;HIPEC group;-HIPEC group;HIPEC group;
6%37%Reoperation (12)CVA (6)
EPIC group;EPIC group;EPIC group;EPIC group;
6%19%Reoperation (6)-
Passot et al[47]1203.821.8-Reoperation (13.3)
Fistula (7.5)
Hompes et al[48]48052.11 (0-6)Prolonged ileus (23)Pulmonary (12.5)
Anastomotic leakage (10.4)Cardiac (2.1)
Bleeding (6.3)Urological (12.5)
Bowel perforation (2.1)Haematological (2.5)
Fistula (2.1)
Abscess (2.1)
Reoperation (20.8)
Cashin et al[56]151HIPEC group:HIPEC group:---
4%41%
EPIC group:EPIC group:
3%30%
Klaver et al[49]24062-Prolonged ileus (21)Superficial wound infection (4)
Intra-abdominal collection requiring drainage (21)Cardiorespiratory complications (38)
Fistula (4)Urological (4)
Splenic infarction (4)
Turrini et al[50]26033-Fistula (10)Haematological toxicity (10)
Delayed gastric emptying (10)
Haslinger et al[51]38-Not specifically provided for patients undergoing procedures for CPM
Yonemura et al[52]1420.742.9---
DISCUSSION

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.

Figure 3
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.

COMMENTS
Background

The finding of peritoneal surface malignancy in the context of colorectal cancer confers a dismal prognosis. Conventional treatment for this sub-group of patients involves systemic chemotherapy with or without palliative surgery. Multimodality treatment with cytoreductive surgery in combination with intraoperative chemotherapy is performed at specialist units around the world and can result in improved oncological outcome.

Research frontiers

The aim of cytoreductive surgery (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. The combination of CRS with intraperitoneal chemotherapy (IPC) has been advocated in order to eradicate residual cancer cells after macroscopic cytoreduction. In this study, the authors provide a Systematic Review of the available evidence regarding these multimodality treatment approaches.

Innovations and breakthroughs

Recent reports indicate that combined therapy involving CRS and IPC can result in improved oncological outcome and even long-term survival in patients with colorectal peritoneal metastases (CPM), compared to conventional treatment. This study provides a comprehensive and up-to-date review of the available literature in this field.

Applications

Although subject to inherent methodological limitations, the studies included in this review appear to support the use of an aggressive multimodality treatment approach in the management of CPM.

Terminology

CRS refers to the macroscopic removal of peritoneal surface cancer deposits through peritoneal stripping procedures and/or visceral resection, depending on extent and location of carcinomatosis. Intraperitoneal chemotherapy is administered in combination with CRS as a means of eradicating residual tumour.

Peer review

The authors present a systematic review of the literature of cytoreductive surgery combined with intraperitoneal chemotherapy in colorectal cancer peritoneal metastasis. The authors spent a lot of efforts on the summary of clinical data from 27 studies. It has been reported the effectiveness of intraperitoneal chemotherapy in the patients with peritoneal metastasis. However, this kind of review work has not been reported. Therefore, this work has very high originality to contribute to the further clinical works.

Footnotes

P- Reviewer: Garrido-Laguna I, Izuishi K S- Editor: Qi Y L- Editor: A E- Editor: Ma S

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