Curr Colorectal Cancer Rep DOI 10.1007/s11888-015-0264-7

PERSONALIZED MEDICINE IN COLORECTAL CANCER (CMS ROCHA-LIMA, SECTION EDITOR)

Role of Cytoreduction Surgery With HIPEC in the Management of Peritoneal Carcinomatosis From Colorectal Cancer and Pseudomyxoma Peritonei Raphael L. C. Araújo & Gilberto Lopes & Marcelo Aisen

# Springer Science+Business Media New York 2015

Abstract For most cancers, peritoneal carcinomatosis (PC) usually is considered a systemic disease and portends a very poor prognosis. However, in colorectal cancer, especially the mucinous colorectal adenocarcinoma (MCA) subtype and epithelial appendiceal neoplasms—particularly pseudomyxoma peritonei (PMP)—the pattern of PC represents local celomic extension of disease rather than systemic metastasis. Among the treatment options for isolated PC, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the de facto standard of care in many institutions, based on prospective single-center and multicenter studies and randomized clinical data. However, the use of HIPEC seems to benefit only patients who have undergone complete CRS and present with favorable histology (MCA and PMP). Determining the feasibility of complete CRS is the key to adequate patient selection, because peritoneal tumor burden, both before and after CRS, is the main prognostic factor. If complete CRS is achieved, HIPEC may be offered in the effort to improve long-term outcomes.

This article is part of the Topical Collection on Personalized Medicine in Colorectal Cancer R. L. C. Araújo Liver Surgery Unit, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil G. Lopes : M. Aisen Centro Paulista de Oncologia, São Paulo, SP, Brazil G. Lopes (*) Centro Paulista de Oncologia and HCor Onco Cancer Centre, Rua Desembargador Eliseu Guilherme, 12° andar, 04004-030 São Paulo, SP, Brazil e-mail: [email protected]

Keywords Hyperthermic intraperitoneal chemotherapy . HIPEC . Peritonectomy . Cytoreductive surgery . Colorectal cancer . Pseudomyxoma peritonei . Surgery . Chemotherapy . Mucin . Carcinomatosis

Introduction Colorectal cancer (CRC) is the third most common malignancy in the USA [1]. Peritoneal metastasis may be present in 17 % of patients with CRC, and isolated carcinomatosis is seen in 2 % [2]. The mucinous colorectal adenocarcinoma (MCA) subtype accounts for 10 to 20 % of all CRCs and has a pattern of peritoneal spread representing local celomic extension of disease rather than systemic metastasis [3, 4]. Epithelial appendiceal neoplasms are rare malignancies with an annual incidence of 9 per 1 million people as reported by national pathology database of the Netherlands [5]. They usually are discovered during appendectomy; occasionally, some patients also present with peritoneal mucinous dissemination. Pseudomyxoma peritonei (PMP) is a clinical condition characterized by mucinous ascites and mucinous implants diffusely involving the peritoneal surfaces. It also may contain epithelial cells, but usually very few. Thus, tumors associated with mucinous adenomas of the appendix and MCA both are included under the term PMP. Peritoneal carcinomatosis (PC) generally was considered a lethal cancer, but research into cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in the 1990s resulted in this approach becoming of potential benefit for isolated PC [6, 7]. The aim of this review is to examine the prognostic factors and the role of current therapy for PMP and MCA in patients with disease confined to the peritoneum.

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Pathologic Features PMP arises from primary appendiceal tumors and usually presents as mucinous ascites instead of intracellular mucin accumulation. These tumors have a high propensity to spread to peritoneal surfaces, but lymphatic or hematogenous metastases are rare. Tumor cells from the ruptured appendiceal neoplasm spread throughout the peritoneal cavity via fluid current and gravity. This passive movement might be explained by the absence of adhesive characteristics on the cell surface [4]. Implanted tumor cells may produce mucin, leading to the accumulation of progressive mucinous ascites, usually without peritoneal surface invasion. Pathologic subtypes have been described based on grade and clinical behavior [8–10]. The most widely used classification, proposed by Ronnett et al. [10], comprises three pathologic subtypes with different pathologic characteristics and different prognoses, as summarized in Table 1. Disseminated peritoneal adenomucinosis (DPAM), a low-grade lesion marked by abundant extracellular mucin and a lack of cytologic atypia or mitotic activity, usually derived from mucinous neoplasms of the appendix, has a good prognosis. Peritoneal mucinous adenocarcinoma (PMCA), a high-grade metastatic adenocarcinoma, usually derived from the appendix and colon, is characterized by abundant mucinous epithelium with architectural and cytologic features of carcinoma and a poorer prognosis. The intermediate subtype (PMCA-I) includes cases in which the peritoneal lesions predominantly demonstrate features of DPAM but also contain focal areas of PMCA; it has a prognosis between that of DPAM and PMCA. These differences in subtypes clearly affect long-term outcomes. Ronnett et al. [11] also demonstrated that patients with DPAM had 5- and 10-year survival rates of 75 and 68 %, respectively, and those with PMCA and PMCA-I had a significantly worse prognosis, with 5- and 10-year survival rates, respectively, of 50 and 21 % for PMCA-I and 14 and 3 % for PMCA. Table 1 [10, 11]

MCA is defined as a tumor with greater than 50 % of its volume composed of extracellular mucin [12]. Tumors with a mucinous component greater than 10 % but less than 50 % usually are termed adenocarcinoma with mucinous features or mucinous differentiation. MCA typically shows large glandular structures with pools of extracellular mucin [13]. A variable number of individual tumor cells, including signet ring cells, may be seen. Compared with the more common nonmucinous variety, mucinous tumors metastasize to lymph nodes with greater frequency and are more prone to PC [14]. Additionally, it appears that the fluid produced by MCAs is taken up by lymphatics, which may help promote tumor spread into regional lymph nodes [15]. MCA may be associated with hereditary nonpolyposis CRC (or Lynch syndrome), thus involving high-level microsatellite instability (MSI-H) and low-grade tumors [16]. Kakar et al. [17] analyzed data from 248 patients with MCA and found that long-term outcomes for MSI-H are better than those of microsatellite-stable mucinous carcinoma; however, MSI status was not an independent predictor of survival. In general, patients with microsatellite-stable tumors tend to have more aggressive disease.

Treatment Surgery The rationale for offering CRS and HIPEC to treat PMP and MCA is to attempt local control by focusing on locally advanced rather than systemic disease. Certainly, surgery cannot eliminate microscopic disease on the peritoneal surface; thus, the goal of improving local control with HIPEC is supported by that approach. CRS followed by HIPEC might provide complete lysis of adhesions and complete resection of macroscopic carcinomatosis, allowing optimal exposure to

Pathologic features and prognosis of mucinous colorectal adenocarcinoma and epithelial appendiceal neoplasm according to Ronnett et al.

Types

Pathologic features

Lesion Extracellular Cytologic atypia grade mucin Disseminated peritoneal adenomucinosis (DPAM) Peritoneal mucinous adenocarcinoma (PMCA)

Abundant

Primary tumor site

5-year 10-year

Lack of cytologic atypia or mitotic activity Usually from mucinous 75 neoplasms of the appendix High Present Abundant mucinous epithelium with Usually from adenocarcinoma 14 architectural and cytologic features of the appendix and colon of carcinoma Intermediate subtype (PMCA-I) Cases which the peritoneal lesions predominantly demonstrate features of DPAM but also contain 50 focal areas of PMCA a

Low

Overall survival (%)a

68 3

21

All patients were treated in the same fashion by the same surgeon. They underwent a series of peritonectomy procedures and organ resections to maximally debulk (cytoreduce) the tumor. In the early postoperative period (postoperative days 1–6), chemotherapeutic agents (mitomycin C and 5fluorouracil) were instilled into the peritoneal cavity

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intraperitoneal drugs. Many groups consider residual macroscopic disease a contraindication for HIPEC because it would prevent drug penetration [18, 19].

2 or 3 histology, no lymph node metastases, and complete CRS; 66 % for the group who had any histology, lymph node metastases, and complete CRS; and only 20 % for patients in whom complete CRS was not achieved [24].

Patient Selection Selecting Bgood responders^ to HIPEC starts with histologic examination of the primary tumor to predict its invasiveness and preoperative imaging (CT) of the chest, abdomen, and pelvis. However, the principal approach to patient selection is exploratory laparoscopy and/or laparotomy to inspect these cavities. Sugarbaker et al. [20] developed the peritoneal cancer index (PCI), an objective method to assess the presence and size of macroscopic tumor in 13 different abdominal regions before and after CRS. The PCI score represents an integration of the size and location of peritoneal implants, and it should be used in the decision-making process during laparotomy [21]. A lesion size score of 0 (LS-0) denotes no visible disease; a score of LS-1 represents tumor nodules <0.5 cm, LS-2 tumor nodules between 0.5 and 5 cm, and LS-3 tumor nodules >5 cm. The abdominopelvic distribution of lesions is evaluated according to these 13 regions [22]. Each region is counted separately for a maximum LS score of 39 (13×3). Sugarbaker [23] reported that an overall survival (OS) rate of 50 % may be achieved in patients who presented with colon cancer and underwent CRS and HIPEC with a PCI ≤10. However, patients with higher PCI are also candidates to HIPEC if complete cytoreduction can be achieved. If the primary tumor was not resected previously, it may be resected during CRS, which should be followed by tumor debulking according to disease distribution. In general, resection includes organs grossly affected by visceral peritoneal spread, as well as any parietal peritoneal surfaces involved (usually subdiaphragmatic spaces, paracolic recesses, and the anterior abdominal wall). After CRS, the efficacy of removal should determine whether the patient receives HIPEC. If surgical anastomoses are necessary after CRS, they should be done after HIPEC to prevent any tumor implant from seeding in the anastomosis area. The efficacy of CRS may be evaluated by the Jacquet/Sugarbaker system for classifying the completeness of cytoreduction (CCR): CCR-0 indicates no peritoneal seeding exposed or no residual macroscopic disease. CCR-1 signifies residual peritoneal deposits <2.5 mm, which is the size limit thought to be penetrable by chemotherapy; thus, it represents complete CRS. CCR-2 indicates residual deposits between 2.5 mm and 2.5 cm, and CCR3 represents residual deposits >2.5 cm or confluent tumors; both these scores signify incomplete CRS [20, 22]. In a series with 181 patients with MCA and PMP who underwent CRS and HIPEC, the 3-year OS rates varied according to grade, the presence of lymph node metastases, and CRS completeness: 99 % for the group with grade 1 histology, no lymph node metastases, and complete CRS; 65 % for the group with grade

HIPEC Procedure Chemotherapy to treat the microscopic disease may be delivered intraoperatively and in the early postoperative phase. However, experiments with blue dye showed that intraperitoneal fluid distribution in the early postoperative phase is not optimal, probably because of early postoperative adhesions and the development of preferential intraperitoneal pathways for perfusion fluid once the abdomen is closed [25]. Thus, intraoperative perfusion appears to be more adequate, and peritoneal expansion via an open approach is applied in most centers to provide optimal delivery to the surface of intraabdominal organs and the parietal peritoneum. In the coliseum technique, abdominal skin is attached to a retractor ring and the abdominal cavity is covered with a plastic sheet, which has a small opening in the center to allow entry of the surgeon’s hand, promoting exposure of the peritoneal surfaces and a more uniform distribution of drug and heat [26]. To deliver the chemotherapy solution, a Tenckhoff catheter and two suction drains are placed in the abdominal cavity, and roller pumps infuse and remove the fluid from the abdominal cavity. This circulation of chemotherapy is based on drug concentration and hyperthermia during the infusion, which generally takes 90 min. The main advantage of this approach is that it creates a controlled distribution of fluid, heat, and cytotoxic drugs, and generally, the fluid used is not reperfused. The main disadvantages of the coliseum technique are that heat is lost through the open laparotomy and the peritoneal expander may prevent small areas of the parietal peritoneum from being fully exposed. Another risk of this technique is leakage of drugs or aerosol chemotherapy, exposing operating room personnel to toxins. An option is to use a closed system (the abdominal wall is closed with the drains inside), ensuring staff safety and avoiding late adhesions in the early postoperative phase. The clinical use of hyperthermia comes from its synergistic effects. Hyperthermia, usually ≥41 °C, generally is more toxic to tumor than to normal cells because of its direct cytotoxic effects due to impaired DNA repair; denaturation of proteins; induction of heat-shock proteins, which may serve as receptors for natural killer cells; induction of apoptosis; and inhibition of angiogenesis [27, 28]. Synergism between hyperthermia and chemotherapy already has been observed with mitomycin C, cisplatin, melphalan, mitoxantrone, bleomycin, and doxorubicin [29]. Moreover, cell membrane permeability is increased at higher temperatures, improving drug uptake by tumor tissue [30]. After the infusion phase of HIPEC, the

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abdominal cavity is dried and the abdominal wall reopened before anastomosis is performed safely.

Chemotherapy The goal of combination treatment with CRS and HIPEC is for CRS to remove the macroscopic peritoneal disease and for intraoperative chemotherapy to eradicate residual tumor cells. This approach has been suggested as standard of care for peritoneal dissemination from MCA and PMP. Verwaal et al. [31] in 2003 reported the first results of a randomized controlled trial (RCT) with 105 patients receiving Bstandard treatment^ consisting of fluorouracil (5-FU) and leucovorin (LV) with or without palliative surgery, or the same chemotherapy with aggressive CRS and HIPEC with mitomycin C. Their long-term outcomes were updated (after a median follow-up of 8 years) and showed a median disease-free survival (DFS) and progression-free survival (PFS) of 12.6 and 7.7 months, respectively, in the standard chemotherapy arm and 22.2 and 12.6 months, respectively, in the CRS-plusHIPEC group (P=.028 for each) [32]. They reported a mortality rate of 8 % and 5-year survival of 20 % (50 % for those who achieved complete CRS). A criticism of this study is that it used 5-FU-based chemotherapy rather than the more active oxaliplatin- or irinotecan-based regimens, but this regimen was chosen because it was state of the art at the time of the trial [33]. Elias et al. [32] reported a two-center RCT comparing early postoperative intraperitoneal chemotherapy (EPIC) plus systemic chemotherapy with systemic chemotherapy alone, both after complete CRS of PC from CRC. Systemic chemotherapy was established as 5-FU and LV bimonthly for 6 months (some patients received oxaliplatin or irinotecan) starting within 1 month after EPIC; EPIC was based on mitomycin C on postoperative day 1 and 5-FU on postoperative days 2 to 5, given in a 2-L solution over 23 h/24. Among the 35 patients in both groups who underwent complete CRS of PC, the 2year survival rate was 60 %. However, the study failed to accrue the 90 patients needed within 4 years so was terminated prematurely. Remarkably, the authors reported that the main barrier to accrual was patients’ dissatisfaction with their inability to choose their treatment. These patients considered the trial unethical and detrimental because they were fully aware of the futility of the control arm of the study [32]. In a phase II trial with 48 patients with PC from CRC who underwent complete CRS and HIPEC with oxaliplatin [34••] and a median follow-up of 22.7 months, OS was 88.7 % at 2 years and DFS was 45.5 % (95 % confidence interval (CI), 34.3–55.9) at 2 years. The median time to recurrence was 19.8 months, and differences in OS were found only between patients with low and those with high PCI scores [34••]. In a systematic review of patients with PC from CRC, Yan et al. [35] looked at two RCTs (Verwaal et al. [31] and Elias

et al. [32]), one comparative study, one multi-institutional registry study, and the ten most recent case series at the time that were considered eligible studies after quality evaluation. They found that patients who underwent complete CRS received the most benefit, with median survival varying from 28 to 60 months and 5-year survival ranging from 22 to 49 %. The overall morbidity rate varied from 23 to 44 %, and the mortality rate ranged from 0 to 12 % [35]. Regarding the use of Bnew-era^ drugs, Quenet et al. [36••] reported the results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after CRS for PC from CRC. However, it was a negative study showing no advantage from intensification of HIPEC by adding irinotecan to oxaliplatin-based HIPEC; therefore, the latter remains the preferred regimen for PC. Another phase II multicenter trial corroborated the use of oxaliplatin as the preferred drug for PC from CRC. This study evaluated 48 consecutive patients who underwent CRS (R0/1) with oxaliplatin HIPEC and had a median PCI score of 11 (range 1–22) [34••]. These patients achieved an OS of 97.9 % at 1 year and 88.7 % at 2 years and a DFS of 65.8 % at 1 year and 45.5 % at 2 years; the median time to recurrence was 19.8 months. However, these valuable data are limited by the low median PCI and short median follow-up (22.7 months) [34••]. Pushing the limits of CRS and HIPEC, some investigators have added other associated procedures to this approach. De Cuba et al. [37•] performed a systematic review and metaanalysis (including only observational studies) including a combination of colorectal liver metastasis treatment and PC treated by CRS and HIPEC. The authors showed a trend toward poorer OS in patients who underwent curative resection and HIPEC compared with those with isolated PC who underwent CRS and HIPEC (pooled HR, 1.24; CI 0.96– 1.60) [37•]. However, the authors also suggested that patients with metastatic CRC show a tendency toward increased median OS after CRS and HIPEC combined with resection of liver metastases compared with those receiving treatment with modern systemic chemotherapy. Currently, the major limitation is the lack of randomized data and the strong selection bias inherent in the design of retrospective studies, providing a lower level of evidence. However, COMBATAC, a multicenter trial open and accruing patients, is a single-stage phase II study investigating perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC in patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous PC [38••]. The primary end point is PFS; the secondary end points include OS, perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life, and histopathologic regression after preoperative chemotherapy [38••]. Moreover, another interesting trial has opened, investigating the benefits of routine second-look surgery with CRS and HIPEC versus

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observation in patients who previously underwent CRS and HIPEC for CRC [39]. Patients who have no evidence of disease based on imaging, physical examination, and tumor markers for 12 months after the primary CRS and HIPEC will be eligible to participate.

selected based on favorable histology—that is, mucinous disease, especially MCA and PMP—peritoneal disease extension, and the feasibility of complete CRS, because only patients who achieve it will potentially benefit from HIPEC, improving long-term outcomes. Compliance with Ethics Guidelines

Conclusion Although PC used to be considered a lethal condition in all cancers in general, this paradigm has changed for CRC in the past two decades. Although PC is a common presentation in CRC, it rarely is an isolated focus of secondary disease. With regard to advanced CRC, patients with PC from mucinous disease (MCA or PMP) and without evidence of systemic disease may be considered to have locally advanced rather than systemic disease. Therefore, as usually done in this situation, the oncologic approach to locally advanced disease might be to attempt to remove all macroscopic disease in these patients. The rationale of intraoperative hyperthermia and chemotherapy is to provide better penetration of the chemotherapy drug into all the peritoneal surfaces, treating microscopic tumor seeds to prevent local and distant recurrences. It appears CRS and HIPEC have become a therapeutic option for treating MCA and PMP since randomized data suggest a significant survival benefit from adding HIPEC to complete CRS. Surgical efforts might be made to remove all peritoneal macroscopic disease, or at least to keep the disease focus less than 2.5 mm. If multiorgan resections are required to achieve complete CRS, they should be performed for tumor lesions from peritoneal spread and not from hematogenic dissemination (e.g., liver metastasis). The PCI may be used, not only to predict long-term outcomes but also, to determine whether all peritoneal tissue is resectable and to evaluate inherent perioperative and postoperative implications on morbidity. Consequently, when complete CRS (CCR: 0 or 1) is achieved, HIPEC may be considered to optimize curative-intent treatment for locally advanced disease. A remarkable lack of standardization exists among techniques for delivering HIPEC, and this is considered an important drawback in analyzing studies. Whereas the use of mitomycin C is based largely on earlier studies, oxaliplatin tends to be used in newer trials and is supported by phase II data. The putative benefit of second-look surgery with CRS and HIPEC for patients who already have undergone this treatment and have no macroscopic recurrence is under evaluation in research protocols, and this approach should not be taken outside clinical trials. Improvements in patient selection are essential, perhaps with new molecular markers and more clinical trial data to clarify this process. Patients not eligible for complete CRS have a poorer prognosis and likely would not benefit from CRS and HIPEC. Therefore, patients should be

Conflict of Interest Raphael L.C. Araújo, Gilberto Lopes, and Marcelo Aisen declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2003;21(20):3737–43. 32. Elias D, Delperro JR, Sideris L, Benhamou E, Pocard M, Baton O, et al. Treatment of peritoneal carcinomatosis from colorectal cancer: impact of complete cytoreductive surgery and difficulties in conducting randomized trials. Ann Surg Oncol. 2004;11(5):518– 21. 33. Levine EA. The randomized trial of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion: what it does and does not tell us. Ann Surg Oncol. 2008;15(10):2633–5. 34.•• Hompes D, D’Hoore A, Van Cutsem E, Fieuws S, Ceelen W, Peeters M, et al. The treatment of peritoneal carcinomatosis of colorectal cancer with complete cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) with oxaliplatin: a Belgian multicentre prospective phase II clinical study. Ann Surg Oncol. 2012;19(7):2186–94. A phase II trial reports 48 patients with PC from CRC who underwent complete CRS and HIPEC with oxaliplatin. The OS was 88.7 % and DFS was 45.5 % (95 % CI, 34.3–55.9) both at 2 years. Differences in OS were found only between patients with low and those with high PCI scores as expected. 35. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol : Off J Am Soc Clin Oncol. 2006;24(24):4011–9. 36.•• Quenet F, Goere D, Mehta SS, Roca L, Dumont F, Hessissen M, et al. Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann Surg. 2011;254(2):294–301. This is a negative study showing no advantage from intensification of HIPEC by adding irinotecan to oxaliplatin-based HIPEC; therefore, the later remains the preferred regimen for PC. 37.• de Cuba EM, Kwakman R, Knol DL, Bonjer HJ, Meijer GA, Te Velde EA. Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: systematic review of all literature and meta-analysis of observational studies. Cancer Treat Rev. 2013;39(4):321–7. This is systematic review of literature and meta-analysis of observational studies from 1990 to April 2012. After full-text assessment of 39 papers, three articles provided enough statistical information for meta-analysis. The authors showed a trend toward poorer OS in patients who underwent curative liver resection and HIPEC compared with those with isolated PC who underwent CRS and HIPEC (pooled HR, 1.24; CI 0.96–1.60). 38.•• Glockzin G, Rochon J, Arnold D, Lang SA, Klebl F, Zeman F, et al. A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial. BMC Cancer. 2013;13:67. This multicenter trial is open and accruing patients to investigate perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC in patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous PC. The primary end point is PFS; secondary end points include OS, perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life, and histopathologic regression after preoperative chemotherapy. 39. Ripley RT, Davis JL, Kemp CD, Steinberg SM, Toomey MA, Avital I. Prospective randomized trial evaluating mandatory second look surgery with HIPEC and CRS vs. standard of care in patients at high risk of developing colorectal peritoneal metastases. Trials. 2010;11:62.