Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms

mesothelioma and serous carcinoma of the peritoneum. Secondary psm is by far the most frequent. Its origin is often cancers of the gastrointestinal tract, but it can frequently arise from ovarian cancer and breast cancer (mostly the lobular subtype). However, many cancers can metastasize to the peritoneum 1–7. Surgical treatment of psm is recent 8–10. Before 1989, cures were anecdotal, and median survival was 9 months. Now, long-term survival is possible in 25%–85% of patients 1,2,4–6,8,11,12, depending on patient and disease characteristics 8,13–20. Despite that success, a lack of agreement on many issues (drug, dose, duration) means that many questions remain, and few randomized controlled trials have provided comparative evidence. In selected cases, optimal treatment of psm consists of a combination of cytoreductive surgery (crs) and hyperthermic intraperitoneal chemotherapy (hipec). This complex procedure requires a dedicated multidisciplinary team. Unfortunately, worldwide, philosophic and fundamental differences exist about issues ranging from patient selection to treatment approaches. Consequently, no accepted standard of care for the provision of this treatment has been developed. A primary concern in the medical community regarding psm treatment by crs plus hipec is the paucity of phase iii studies to support this modern therapeutic approach. The lack of studies is, in part, a result of the strong personal biases found among surgeons providing psm care, the rapid increase in the number of centres offering this multimodal approach, and the relatively small number of patients at risk. Well-selected psm patients can clearly be treated with crs and hipec. However, in the absence of a large body of level 1 evidence, Canadian surgical and medical oncologists should offer psm patients a thoughtful, carefully integrated approach founded in surgical and biologic principles and supported by the available evidence. To that end, it is strongly recommended that all ABSTRACT


INTRODUCTION
A peritoneal surface malignancy (psm) is a cancer arising from or spreading to the peritoneal surfaces.It can be a primary disease arising from the peritoneum (such as malignant peritoneal mesothelioma) or a secondary disease (such as metastasis originating from a primary malignant neoplasm).Primary psm is rare; the most frequent forms are primary peritoneal patients with a psm from a colorectal or appendiceal neoplasm be considered for referral to one of the hipec centres listed in Table i.Referrals should occur as a first-line metastatic cancer treatment intervention.
To meet the needs of patients and assure the highest possible standard of care, leading Canadian experts in the treatment of psm, together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg, Appendix a).This initiative is supported by the Colorectal Cancer Association of Canada (http://www.colorectal-cancer.ca/en/)and sponsorship from pharmaceutical companies.

METHODS
Before these guidelines were written, the literature in PubMed was searched using the key words "peritoneal carcinomatosis," "PC," "intraperitoneal chemotherapy," "HIPEC," "colorectal neoplasms" (or cancers), "colonic neoplasms" (or cancers), "rectal neoplasms" (or cancers), "pseudomyxoma peritonei," "debulking," and "chemohyperthermia."Descriptive studies and clinical trials (phase ii and iii) published between 1990 and 2013 were retained.As additional sources of information, published guidelines from national and international organizations were obtained: • L'Association Française de Chirurgie and Direction de la lutte contre le cancer (France) Before the final revision, a census of the available Canadian resources (any combination of expertise, equipment, and time dedicated to hipec) was taken to align the guidelines with those resources.
Over the course of three full-day meetings and two teleconferences, surgical (PD, LS, CL, LM, EH, CG, AG, YM, WT, RY, JAM) and medical oncology (MKK, PM) experts in the treatment of psm addressed 40 questions (referenced in this paper as Q1, Q2, and so on, and detailed in Table ii).Each question was discussed by the chicg membership, and conclusions were based on the level of evidence and the level of consensus among the chicg members.The guidelines presented here focus on psm of colorectal and appendiceal origin.Questions about peritoneal mesothelioma (Q13, Q24, Q39, Q40) and other secondary sites (Q26) will be discussed in future editions of the guidelines.
The evidence was graded using the five levels set out by the American Society of Clinical Oncology.Level 1 evidence is based on meta-analyses or multiple randomized trials (phase iii).Level 2 evidence is based on 1-2 randomized trials.Level 3 evidence is based on nonrandomized trials (phase ii).Level 4 evidence is based on observational studies, and level 5 is based on case reports or expert opinion.
The level of consensus (loc) concerning each question was adopted from the approach described by Murphy et al. 21as used by the Program in Evidence-Based Medicine of Cancer Care Ontario.The loc a-d definitions were determined a priori by the chicg members, based on a combination of the already defined levels of evidence, applicability (based on discussion and available resources), and vote of the members (  The chicg has developed criteria based on the chicg loc system, as defined in this guideline, that provincial and national agencies can use to help to coordinate development, improve efficacy, and promote accessibility of hipec therapy to Canadian patients (loc a).
Accreditation will improve accessibility across Canada, because referring physicians will have to be convinced of the benefit of the proposed treatment before they will refer patients to chicg centres (Q3, loc a).

Resources
To create viable Canadian guidelines, a census of the resources available across Canada was taken.All centres have access to computed tomography imaging and modern diagnostic equipment, but access to positron-emission tomography imaging is limited in some areas.Most teams have dedicated intraperitoneal perfusion equipment, but some use a modified extracorporeal circulation machine dedicated to cardiac surgery (an important difference, because perfusion temperature is limited to 41°C with the latter machine).Finally, drug access is not the same across Canada: The choice of chemotherapeutic and dose is limited by some authorities.Oxaliplatin is used for hipec at some sites in Canada; mitomycin C is currently available at all sites.

TEAMS
Multi-and interdisciplinary teams are needed for the treatment of psm patients 9,22,23 .Ideally, complex psm patients should be discussed at local tumour boards (loc a) 24 .

Team Composition
The core team is composed of surgical oncologists, anesthesiologists, perfusionists (optional), pharmacists, nurses, supportive care professionals (physiotherapists, psychologists, nutritionists, and so on), fellows and residents, pathologists, intensivists, and research personnel (nurses, research coordinator, data manager, and so on).These members should be on site and available when needed.The surgeon directs the team (loc a) 25 .Other team members (medical oncologists, gastroenterologists, and basic scientists) are ideally on site, but if they are not, they can be part of a network to ensure services and future development.
Surgeons must have surgical oncology training, including appropriate cytoreductive surgery and hipec training (Q4, loc a) and a surgical and research practice dedicated to psm patients.The rest of the team should have an interest in hipec, to support development and research (Q5, loc b).The minimum number of cases handled each year per surgeon has not yet been defined, but a team or centre should handle at least 20 cases a each year (loc b).
a This recommendation is based on recent recommendations from the Peritoneal Surface Oncology Group International.A new team should be handling at least 1 case each month, with the goal of treating 20 patients each year.Until a new team has the referral base to handle 1 case per month, consideration should be given to referring those patients to an existing centre.Activities performed by each team should be part of the chicg national research program-at a minimum with respect to quality assurance and contributing to the national prospective database.
One research coordinator and operating room nurse can be identified and dedicated to the development of hipec for each local team (Q6, loc a).The team should be recognized and supported by the institution (hospital and university) (loc a).

PATIENT SELECTION
Patient selection (Table iv) can be divided into patientrelated criteria and disease-related criteria.Essentially, a patient must be fit enough to undergo a high-risk procedure, and the disease must demonstrate biologic behaviour that is potentially curable by a combination of crs and hipec 7,26-34 .On occasion, palliative hipec for intractable ascites can be considered 35 .

Patient-Related Criteria
Patients should not have any major comorbidities (loc a), and their Eastern Cooperative Oncology Group performance status at the time of hipec should be 0 (loc a).In selected patients, especially in those whose performance status is reversible, a performance status of 1 can be acceptable 27,36 (loc a).
Physiologic age should be considered (Q7).When less than 65 years of age, all eligible patients are good candidates (loc a).When 65 years of age and older, only carefully selected patients without comorbidities and with a low peritoneal carcinomatosis index (pci) (Table v) and a low-grade tumour should be considered (loc a) 37,38 .Body mass index should also be considered (Q8).A body mass index above 35 is a relative contraindication 39,40 , and age, pci, and tumour biology should be taken into consideration (loc b).Patients must be motivated and must understand the extent, the risks, and the potential benefits of the procedure (loc a).Finally, patients should be encouraged to participate in clinical trials and to be included in the chicg database (Q9, loc a).

Disease-Related Criteria
Disease classification is based on the primary tumour (origin), the tumour histology (and tumour biology), and the extent of disease 11,18,31,32 .Histology is documented by biopsy when feasible, because characteristics can change over time and might not match those of the primary tumour 19 .Extent of disease is evaluated during the preoperative work-up, at laparoscopy in some cases, and at laparotomy.
For psm of colorectal and classical appendiceal adenocarcinoma origin 41 , histology is based on differentiation.A well-differentiated classical adenocarcinoma is considered grade 1, an intermediate or moderate one is grade 2, and a poorly or undifferentiated tumour is grade 3.
For mucinous tumours of the appendix, the histologic classification is more complex and controversial, and thus multiple classifications are used.The presence of signet-ring cells in any group is a marker of a high-grade tumour (grade 3).The term pseudomyxoma peritonei is used more to describe the clinical presentation rather than the pathologic designation.Two main pathologic classifications have been described.In 1995, Ronnett et al. 42 divided these tumours into three main groups: namely, low-grade disseminated peritoneal adenomucinosis (dpam), highgrade peritoneal mucinous carcinomatosis (pmca), and intermediate-grade pmca (pmca-i).In 2003, Misdraji et al. 43 described another classification designating appendiceal tumours as either low-grade appendiceal mucinous neoplasms or high-grade mucinous adenocarcinomas.Knowing both of these classifications is important, because both are used in the literature.Both classifications essentially categorize appendiceal tumours into a low-grade or high-grade category.The categories are associated with different natural histories and thus different outcomes.
Extent of disease is reported using the pci 2,32,44 .A pci evaluation on preoperative work-up is suboptimal, but provides an indication of whether the pci exceeds 20, which is a contraindication in the case of grade 1 or 2 adenocarcinomas (Q37, Q38).In certain selected cases with favourable patient and disease factors, a pci exceeding 20 can be considered, depending on the type of resection required (loc a).In the case of dpam and pmca-i (Q36), a high pci is not a contraindication to proceed to hipec.It is important to emphasize that, currently, pci can be accurately evaluated only at laparotomy 45 .
Disease evaluation should be based on a recent work-up, which consists of • an appropriate history and physical examination; • appropriate blood tests (carcinoembryonic antigen in non-mucinous disease); • total colonoscopy; • computed tomography imaging of chest, abdomen, and pelvis 30,46,47 ; • positron-emission tomography-computed tomography imaging (if available in cases of nonmucinous disease) 47 ; • confirmation of disease (that is, pathology review, tissue biopsy, or progression on imaging); and • other appropriate examinations, including laparoscopy as judged necessary by the investigator 48 .

The Eligible Patient
Absolute contraindications as defined by the preoperative work-up (Q10) include • extra-abdominal disease proven by histology 18,b,c (Q29, Q32, Q35; loc a); • extraperitoneal disease, such as more than 3 liver metastases (Q28, Q31, Q34) 49 , and N3 (retroperitoneal) lymph nodes (Q27, Q30, Q33) d ; or • unknown primary tumour (Q18) e .b Appropriate selection of patients is key and must be based on histopathologic examination.All material related to the current episode must be reviewed, and appendiceal adenocarcinoma must be classified according to a recognized classification system (loc b).c For example, supraclavicular nodes or histology-proven lung metastasis.If histology is not possible, reassessment over a 2-to 3-month period of observation with or without chemotherapy is a good option (loc b).d If clearly not peritoneal carcinomatosis.e In the case of dpam or pmca-i, the patient is eligible for debulking plus hipec even if the primary is unknown, and chances of cure are good.In most patients, even women, the primary is the appendix.

Criterion Definition
Peritoneal carcinomatosis index (pci) 32 The pci index describes the extent of carcinomatosis before surgery.The abdomen is divided into 13 sections.Each section is assigned a score from 0 to 3: 0 = No tumour 1 = Tumour < 5 mm 2 = Tumour 5 mm-5 cm 3 = Tumour > 5 cm The sum of the scores for the 13 sections yields a total score out of 39.
Score for completeness of cytoreduction (cc) Assessment of residual disease after cytoreductive surgery: cc0 = no visible macroscopic disease cc1 = residual disease < 0.25 cm cc2 = residual disease 0.25 cm-2.5 cm cc3 = residual disease > 2.5 cm At the time of hipec, patients should not have signs of bowel obstruction (loc a), must be responding to neoadjuvant chemotherapy (if used to downstage the disease), and for adenocarcinoma, should have a tumour grade of 1 or 2 (Q22, Q23).Grade 3 adenocarcinoma (including signet-ring cells and pmca) is a relative contraindication (Q22, Q23) 50,f .In the case of a short interval (Q17, Q18, Q19, Q21) 46,g between the primary adenocarcinoma and peritoneal carcinomatosis (synchronous or <6 months), patients should be carefully selected, and neoadjuvant chemotherapy is strongly recommended before crs plus hipec so as to select patients who will benefit the most from this aggressive approach (for example, no development of extra-abdominal or unresectable disease) 13 (loc b).Patients with up to 3 liver metastases responding to neoadjuvant chemotherapy could be eligible if all other patient and disease criteria favourable (loc a) 51,52 .

Pathology classification of appendiceal neoplasms
The presence of a frozen pelvis secondary to a rectal cancer recurrence is a relative contraindication to hipec (Q25, loc a).

SURGICAL CONSIDERATIONS
Cytoreductive surgery is divided into 3 phases: • Assessment Phase: It is imperative to rule out extraperitoneal disease (for example, >3 liver metastases 49,51 or N3 lymph nodes 6,7,15,17,18 ) and to evaluate if a resection is feasible.It is during this phase that the pci is measured (loc a).The decision to proceed-or not-is then made 53 .• Cytoreduction Phase: The goal is to proceed with the resection of all macroscopic disease 54 .
After resection, the completeness of cytoreduction (cc) 27,29,55 is evaluated using the cc score (Table v).• HIPEC Phase: Delivery of hipec is performed, followed by creation of diverting stomas (if required).The abdomen is then closed (loc a).
Reconstructions are performed either before or after hipec, per the surgeon's choice (loc a).

Intraoperative Assessment
The goal of the intraoperative assessment is to confirm the results of the preoperative work-up and to determine the potential completeness of resection (loc a).A laparotomy through a xyphopubic incision optimizes exposure, and a complete adhesiolysis is mandatory to allow for a meticulous visual inspection (loc a).The role of laparoscopic exploration is controversial, but it can be of use when extensive miliary peritoneal carcinomatosis is suspected in the presence of a normal preoperative workup 48 (loc b).Intraoperative ultrasonography is not recommended (Q11, loc b).After adhesiolysis, the pci score is calculated.
In the case of a high pci discovered at laparotomy, or when a cc0 resection is not achievable, three subsequent strategies are possible: • Close the abdomen and consider neoadjuvant systemic chemotherapy until the best tumour response has been achieved and then try again 56 (loc b).This approach is encouraged in the case of grade 1 or 2 classical adenocarcinoma, when a cc0 resection seems hard to achieve as demonstrated by the assessment or when a very-highrisk resection seems the only way to achieve cc0.• Proceed to a double cytoreduction with or without systemic chemotherapy between the procedures (loc c).This approach is used mainly in the case of dpam or pmca-i with a pci score exceeding 20.The goal of the first procedure is to remove all tumour from the upper or the lower abdomen; during the second procedure, the goal is to remove all remaining tumour and to proceed to the hipec phase.• Close the abdomen and consider best supportive care if neoadjuvant systemic chemotherapy is not an option (loc a).
If unexpected extraperitoneal disease is found during the exploration, the therapeutic plan must be revised (loc b).
In the case of classical adenocarcinoma, a cc0 resection is required to proceed with hipec 57 (loc a).In the case of dpam and pmca-i originating from the appendix 58 , a cc0 resection should be the goal, but a cc1 resection could be beneficial and might improve survival (loc a).
If, at any time, the situations that follow have to be considered to achieve cytoreduction, the treatment plan should be revisited by the team.A decision to go ahead with the procedure should be reserved for very motivated and highly selected patients (loc b).The relevant situations are • definitive end stoma with concomitant ileal bladder (pelvic exenteration), • Whipple procedure, • short-bowel syndrome, or • major hepatectomy 34,59 .

CRS
Cytoreduction should be planned according to the area at risk of incomplete resection 60 .The area of the abdomen at highest risk of incomplete resection should be addressed first, because it serves as an indicator-that is, the procedure should be stopped if the resection is not possible 28,61,62 (loc b).f In highly selected grade 3 cases, if other factors are favourable, hipec can be considered (loc b).g In the presence of dpam, pmca-i, or appendiceal adenocarcinoma grade 1 or 2, the primary tumour can be addressed at the same time as the peritoneal carcinomatosis (loc b).
Current OnCOlOgy-VOlume 22, number 2, April 2015 Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
In selected cases of a high pci score and dpam or pmca-i, performing the cytoreduction as two separate procedures is an option if complete cytoreduction is expected to last more than 10-15 hours, if blood loss is too high, or if surgical complications make proceeding with hipec a contraindication (Q15, loc c).In such a situation, the infra-mesocolic area is addressed during the first surgery; the second surgery focuses on the supra-mesocolic cytoreduction and hipec.A complete adhesiolysis of the infra-mesocolic abdomen should be performed during the second procedure before hipec.An adhesiolysis of the upper abdomen can be more complex 63,64 (thus the recommendation to perform cytoreduction of the upper abdomen as the second procedure).

6.2.1
Peritonectomy Selective peritonectomy is defined as disease-oriented peritonectomy.These procedures are selective when they are performed to remove macroscopic disease.They are indicated when a cc0 resection is performed for an adenocarcinoma of colorectal origin or when a cc1 resection is performed for a dpam or pmca (loc b).
Radical peritonectomy is defined as the resection of all parietal, diaphragmatic, and near total mesenteric peritoneum.It can be indicated when a cc0 resection is performed for a or pmca-i (Q12, loc c).

Reconstruction
Bowel continuity is restored before or after hipec, per the surgeon's preference (loc a).Stomas are performed after hipec (loc b).Anastomoses should be created according to the usual principles and surgeon's preference (loc a).Hand-sewn or stapled anastomoses are acceptable (loc a).
Definitive stomas should be created for the usual reasons, but diverting stomas should be considered (Q15) for high-risk anastomoses such as left-sided anastomoses and low anterior resections (loc a).
Total gastrectomy is occasionally necessary to achieve a cc0 resection or in the case of gastric devascularization.Although a standard reconstruction with a Roux-en-Y esophagojejunostomy is generally performed, the very high risk associated with that anastomosis has to be recognized, and early re-operation and drainage should be considered if a leak occurs (loc a).

HIPEC
Delivery of hipec can be performed using an open or a closed technique 65 .Both techniques are performed across the country and are considered safe.The highest risk for chemotherapy exposure is during clean-up, which is the same for both procedures.Whichever technique is chosen, the dose, the duration, and the temperature of perfusion should not be modified (loc b).
Oxaliplatin and mitomycin C are currently the most commonly used drugs.Doxorubicin, irinotecan, cisplatin, and others can be used for special indications 57,66 .The recommended dose of oxaliplatin is 460 mg/m 2 perfused for 30 minutes at 43°C 44,[67][68][69][70][71] (loc b).Systemic 5-fluorouracil and leucovorin can be administered by the anesthetist to potentiate oxaliplatin efficacy and should be considered for classical adenocarcinoma of colorectal origin (loc b).The dose of 5-fluorouracil is 400-450 mg/m 2 administered over 30 minutes by the intravenous route, 30-60 minutes before hipec (loc b).Leucovorin (20 mg/ m 2 ) is given before the 5-fluorouracil, intravenously over 10 minutes.When mitomycin C is used 14,72 , the U.S. guidelines suggest 40 mg as a fixed dose to be delivered in 2 syringes 73,74 (loc b).Taking local habits, equipment, and funding into consideration, the ranges accepted in Canada are listed in Table vi.
No concomitant systemic chemotherapy is given when mitomycin C is used for hipec (loc a).
Good prognostic factors include appendiceal origin, dpam and low-grade tumours, a low pci score, and a patient who is asymptomatic and has no comorbidities 11 .
Evaluation of outcomes is needed for the future development and funding of hipec programs 81 .To assess outcomes, all Canadian patients should be included in a prospective database, ideally with matched tissues (normal and cancerous).

RESEARCH
The priority of the chicg research program is to maintain a national prospective database and matchedtissue tumour bank.All Canadian psm patients should be included in a database, either locally or nationally, and have tumour, normal tissue, and blood stored in a local tumour bank, if available.

Statistics
As published by the Canadian Cancer Society 89  30%-35% would be estimated to be eligible for hipec (approximately 800 patients).The incidence of pseudomyxoma peritonei (dpam and pmca-i) is 1 case annually per million population.In Canada, this incidence represents between 30 and 40 new cases annually, with most patients being eligible for crs plus hipec.

Accessibility
After the chicg census, it was estimated that the existing Canadian teams can treat 200-250 new patients annually-a number that doesn't come close to matching the number of predicted new cases.Ideally, a national coordinating centre should be created to improve accessibility (Q16).

SUMMARY
Given the increasing evidence that selected patients with psm can benefit from an aggressive surgical approach combined with hipec, the guidelines presented here are intended to provide the physicians who treat these patients with the necessary tools to do so.The key messages to take from these guidelines are the importance of a multidisciplinary team approach, the need for strict patient selection, early referral to a centre with expertise in the surgical management of psm, and close collaboration between and surgical oncologists to devise a treatment plan.will be important to standardize the approach to these patients so that the benefits of crs and hipec can be realized across the country and so that all eligible patients have the opportunity to receive treatment.

ACKNOWLEDGMENTS
The authors are indebted to Mr. Barry D. Stein and Ms. Filomena Servidio-Italiano of the Colorectal Cancer Association of Canada, who spearheaded the formation of the chicg and the writing of these guidelines.Financial support for meetings was provided by the Colorectal Cancer Association of Canada with sponsorship from Sanofi-Aventis, Amgen, Pfizer, and Belmont Instruments.

table i
Centres currently providing a hyperthermic intraperitoneal chemotherapy program in Canada a Director of program and contact.Currently, 8 centres in Canada have hipec programs (Tablei).All are part of an academic university centre, and all are dedicated to the development of hipec therapy in Canada.Centres involved in hipec in Canada should be

table iii
Level of consensus system chicg = Canadian HIPEC Collaborative Group

table iv
Absolute and relative criteria for patient eligibility Generally, a relative contraindication, but can be considered depending on other patient and disease factors.Referral to a peritoneal surface malignancy treatment centre is advised.ecog = Eastern Cooperative Oncology Group; dpam = disseminated peritoneal adenomucinosis; lamn = low-grade appendiceal mucinous neoplasm; pmca[-i] = peritoneal mucinous carcinomatosis[-intermediate].
a Up to 3 resectable liver metastases can be considered.b Classical signifies adenocarcinoma grades i-iii.c

OnCOlOgy-VOlume 22, number 2, April 2015
Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e108 Current OnCOlOgy-VOlume 22, number 2, April 2015
, 23,900 new colorectal cancer cases were expected in 2013, and up to 10% (n = 2390) would be expected to have peritoneal carcinomatosis.Of the latter group, Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table vi
Administration of hyperthermic intraperitoneal chemotherapy