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Surgical Management of Peritoneal Metastases from Colorectal Cancer

Oncology
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1. Introduction

The peritoneal cavity is the third most common metastatic site for colorectal cancer (CRC) after the liver and lungs. Approximately 8-13% of CRC patients have synchronous or metachronous peritoneal metastases, with up to 2/3 occurring at the moment of diagnosis.[1] The cumulative risk of developing metachronous peritoneal lesions is estimated to be 3.5-6.0% in patients after curative treatment and varies between stages at diagnosis, ranging from 1.5% in stage I to 11% in stage III.[1-4]
Median time from curative treatment to diagnosis of metachronous peritoneal disease is 18 months (16 months for colon and 21 months for rectal cancer patients).[2] Risk factors for peritoneal spread include pT4 tumor, positive lymph nodes, pN1c disease, mucinous or signet ring cell pathology, and presence of tumor perforation or obstruction at diagnosis.[1, 4-6] The right colon is the most common primary site leading to peritoneal metastases, followed by the left colon, rectosigmoid junction, and rectum.[3, 6, 7]
Despite significant recent advances in the systemic treatment of CRC, its prognosis with peritoneal disease remains extremely poor, with 3-year survival not exceeding 5-8%.[3] Peritoneal metastases alone convey genuine risk and provide 1.5-2 times worse survival compared to CRC patients with visceral metastases.[8, 9] Therefore, many physicians still consider CRC with peritoneal spread a terminal disease, which can benefit only from palliative systemic chemotherapy.
Current data show that a substantial proportion of CRC patients (up to 35%) have isolated synchronous or metachronous peritoneal lesions with no extraperitoneal metastatic sites.[2, 10-12] In these cases, CRC behavior may resemble appendiceal and ovarian cancer biology and indicate the local spread of tumor in the peritoneal cavity. This aspect advocates for use of aggressive locoregional methods, such as cytoreductive surgery (CRS).[13]
During the last 30 years, high-volume expert centers in the United States, Europe, and Australia have collected vital evidence and made substantial progress in the surgical treatment of CRC patients with isolated peritoneal metastases.[14-24]
This chapter will review advances and controversies of the locoregional treatment for CRC patients with the peritoneal disease.

2. Symptoms

The character and severity of symptoms typically correlate with intraabdominal tumor burden and the precise location of CRC peritoneal lesions. Increasing tumor volume eventually leads to the development of multi-level chronic bowel obstruction presenting with nausea, vomiting, cramping abdominal pain, and constipation.[25]
Patients with extensive pelvic lesions may present with signs of distal bowel obstruction, characterized by profound spastic pain in the lower parts of the abdomen, distended abdomen, and, occasionally, vomiting.[26] Patients with prolonged episodes of vomiting eventually develop hypochloremic hypokalemic metabolic alkalosis, which can lead to electrolyte abnormities and related symptoms, including arrhythmia, muscle spasms, and worsened obstipation.[27]
Ascites accompanies peritoneal spread of CRC in up to 70-80% of cases and can have additional signs, such as increased abdominal girth, early satiety, sense of fullness, bloating, abdominal and lower extremity swelling, and weight gain.[28]
Another group of signs is non-specific and develops mainly as a result of cancer progression. It includes cachexia and muscle wasting, weight loss, and fatigue.
Symptoms related to the primary tumor will occur in patients with synchronous peritoneal metastases. Iron-deficiency anemia from prolonged occult intraluminal bleeding can accompany CRC.[29] During laboratory workup, it should be distinguished from anemia of chronic disease, which is common among patients with advanced cancer including peritoneal dissemination. Other patients will suffer from obstruction due to annular and encircling tumor growth that narrows the lumen.[29]
Hematochezia can also be present, but patients commonly dismiss it. Since peritoneal metastases commonly develop in CRC with high-risk features, primary tumor complications can also occur. They include tumor perforation with abscess or peritonitis and sepsis, severe bleeding with significant blood loss, and acute large bowel obstruction, which can lead to a fast, fatal outcome if left unattended.[30]
Finally, patients with peritoneal metastases from CRC can experience no symptoms at all, in which case peritoneal disease is an incidental finding during imaging, laparoscopy, or laparotomy for another reason.

3. Principles of surgical approach

The presence of colorectal peritoneal metastases generally means that curation is unrealistic and these patients are candidates for systemic chemotherapy and/or symptomatic management. It is essential not to worsen patient prognosis with unnecessary procedures or delay the main treatment.[31]
Therefore, surgical management of these patients must be based on the following key principles:
  1. Removal of an asymptomatic primary tumor in the presence of peritoneal disease does not provide any survival benefit over systemic chemotherapy alone and leads to post-colectomy morbidity and mortality.[32-34]
    The risks of primary tumor complications, such as bleeding and obstruction/perforation are relatively low (3% and 7-14%, respectively) for the entire duration of systemic treatment, even with anti-VEGF agents.[35-37] Therefore, these patients must be referred to a medical oncologist. Primary tumor removal can be considered only in patients refusing chemotherapy, with low compliance, or without permanent access to medical oncology service.
  2. For symptomatic patients, management of the primary tumor is warranted since they can benefit from surgical palliation of obstruction, perforation, and bleeding.[38] A surgeon must be reasonably confident that symptoms will be palliated with a favorable quality of life for the patient and there will be minimal time in the hospital. Once managed, patients are referred to a medical oncologist.
  3. In an urgent setting, removal of any peritoneal lesions not causing symptoms does not achieve any therapeutic goal. Debulking attempts are not beneficial for patients, can lead to serious morbidity, and delay systemic chemotherapy.[31]
  4. Cytoreductive surgery (CRS) with complete removal of all peritoneal disease is an extremely aggressive approach with substantial surgical complexity and high morbidity. It is an evolving treatment for CRC peritoneal metastases and has limited prospective data.[39] CRS remains under investigation and is performed exclusively at specialized centers with demonstrated experience and ongoing research.[14, 40] However, we understand a growing interest in CRS among general surgeons and surgical oncologists and will devote a separate section to this topic (see part 5).

4. Clinical presentation

Presentation of CRC patients with intraperitoneal metastases can vary significantly and so will diagnostic and treatment algorithms. Frequently, peritoneal disease is an unexpected finding, especially in case of emergency, in which physicians can make non-optimal decisions. In this section, we will discuss common clinical scenarios of CRC with peritoneal lesions and provide key steps of patient management to facilitate decision-making outside specialized CRS institutions.
4.1 Non-urgent presentation
A. Patients with non-urgent and non-specific symptoms.
Long-lasting symptoms of nausea, abdominal discomfort, distension, and constipation often cause patients to seek medical attention. Patients and their relatives may also notice ascites, which is common in CRC with peritoneal dissemination. Weight loss, muscle wasting, and fatigue are rarely the first symptoms occurring due to CRC peritoneal metastases, but might also motivate patients to seek medical care. Typically, they go to their primary care physician or gastroenterologist, who perform diagnostic tests.
Generally, endoscopic evaluation is the first step in patients with these symptoms and complaints. Colonoscopy is the most accurate method for CRC detection (sensitivity: 94.7%).[41] It not only localizes a lesion, but also allows for biopsy and histopathologic verification.
A three-zone computed tomography (CT) of the chest, abdomen, and pelvis with oral and intravenous contrast is usually the next test. It is widely available, fast, relatively inexpensive, and can be interpreted by surgeons. When peritoneal metastases are suspected, CT is the first choice imaging method to establish their presence, location, and size, as well as diagnose extraperitoneal disease. The highest CT sensitivity for detecting peritoneal metastases was reported in the epigastrium region, pelvis, liver surface, and greater omentum. Low sensitivity was found on the splenic surface, small bowel wall, lesser omentum, and ligament of Treitz.[42, 43]
One study demonstrated CT sensitivity of 100% for peritoneal lesions >5 cm, 87% for lesions more than 5 cm, and only 43% for lesions less than 0.5 cm.[43] Significant discordance in CT findings and diagnostic accuracy can be present among different radiologists and the correctness tends to be higher in radiologists experienced in imaging of peritoneal metastases.[44-46]
Tumor markers (CEA, CA-19.9, and CA-125) may correlate with tumor burden andcan be used in addition to imaging for CRC diagnosis, response assessment, and prognosis estimation.[47-50] To use tumor markers for follow-up, baseline levels should be obtained prior to any definitive treatment.
Diagnostic laparoscopy (DL) with biopsy of peritoneal lesions is not always necessary, but might be helpful in some cases, such as when the origin of the peritoneal disease is not established. DL allows thorough abdominal examination with a recording of all visible lesions and histopathologic classification with biopsy.[51] However, sometimes it is impossible to identify all existing implants due to adhesions or patient anatomy.
In the presence of ascites, aspiration under ultrasound (US) or CT guidance and cytology is a useful method, especially in patients refusing or not suitable for DL or laparotomy, since almost all patients with peritoneal metastases have viable malignant cells in the ascitic fluid.[52] Once a diagnosis is made and verified, patients are referred to a medical oncologist.
B. Patients undergoing elective surgery for the primary colorectal tumor.
The diagnostic sequence for patients newly diagnosed with CRC is similar to the one described above in scenario A. Sometimes patients do not experience any symptoms related to small peritoneal metastases that are not seen on imaging. In these patients, the peritoneal disease is an incidental finding during elective colectomy for primary CRC. In this case, we recommend limiting the surgical procedure to abdominal examination with a recording and biopsy of visible peritoneal lesions and referring the patient to a medical oncologist. The finding of stage IV disease at surgery requires multidisciplinary discussion as it changes the entire outlook for the patient and treatment team.
C. Asymptomatic patients.
Patients not experiencing any symptoms due to primary CRC or its peritoneal metastases are typically diagnosed accidentally during laparoscopy or laparotomy for another reason (e.g. cholecystectomy, hernia repair, etc.). In this scenario, we recommend evaluating the abdomen, documenting and biopsying peritoneal tumor, and performing the planned surgical procedure. The biopsy is mandatory, as its results will guide the order of further diagnostic steps. Intraoperative detection of the primary is not always possible, but it can significantly help with diagnostic workup. Once discharged, a medical oncologist must see the patient.
4.2 Urgent presentation
A. Bowel obstruction.
This urgent clinical problem can be due to obstructing primary tumor and/or peritoneal metastases compressing the intestine. Therefore, CT of the abdomen and pelvis with oral and intravenous contrast is the preferred diagnostic modality required to identify the source of obstruction.[53, 54]
When CT is not available or patient condition does not allow it, plain abdominal radiography is a fast and reasonable alternative, though it is significantly less sensitive and specific.[55, 56] The addition of small bowel follow-through and gastrografin enema can aid in identifying the level of obstruction, but should not be utilized when the patient is unstable.
Identifying the source of bowel obstruction preoperatively is important because in urgent patients with CRC and peritoneal disease, surgery must aim only to resolve it. When the obstruction is caused by the primary tumor, surgical treatment depends on patient condition as well as available resources and includes (in descending order of preference):
  • Colectomy with primary anastomosis
  • Colectomy with end colostomy
  • Bypass anastomosis
  • Diverting end colostomy (should be avoided in patients with ascites if possible)
Regardless of the chosen method, the laparoscopic (vs open) approach is preferred due to lower risks of postoperative complications, but only if it does not compromise the patient state.[57] Evaluation of the abdomen and peritoneal lesions biopsy are recommended.
When a patient cannot tolerate an intraabdominal procedure or refuses surgery, palliative options consist of:
  • Endoscopic placement of a self-expanding metal stent. This approach provides faster recovery time and shorter hospital stay than a palliative surgery and permits earlier administration of systemic chemotherapy.[58, 59]
  • Laser ablation of a primary tumor is effective in restoring luminal patency in up to 97% of patients with a partially obstructing tumor.[60] However, most patients will require multiple procedures due to the short duration of the palliative effect and the risk of perforation during the procedure increases with the number of procedures performed.
Bowel obstruction due to peritoneal metastases is managed by resection, bypass, or ostomy. We also highly recommend examining the abdomen and biopsying peritoneal lesions. However, extensive debulking significantly increases the length of the procedure and surgical trauma and is not recommended. Patients with extensive peritoneal disease and/or high small bowel or multilevel obstruction have a poor prognosis and should be managed in a palliative manner using bypass anastomoses, intraluminal stenting, enteric tubes for decompression and nutrition, and pharmacologic agents (octreotide, dexamethasone, haloperidol, metoclopramide, olanzapine, and scopolamine).[61, 62]
B. Bowel perforation and tumor bleeding are possible clinical presentations of CRC patients with peritoneal metastases; however, they are not related to the peritoneal lesions per se so the management is similar to urgent general surgery. In patients requiring laparoscopy or laparotomy, abdominal evaluation and biopsy of visualized lesions are also performed. A chronic obscured intraluminal bleeding from the tumor should be treated by the start of systemic chemotherapy and correction of iron deficiency, not palliative surgery.[35]
Patients presenting with an emergency will require certain time to recover, after which they should be referred to a medical oncologist for systemic chemotherapy and/or symptomatic management.  

5. Cytoreductive surgery

5.1. Goals
Cytoreductive surgery (CRS) is an evolving approach in surgical oncology and its role in the management of CRC patients with peritoneal metastases is yet to be established. It was introduced several decades ago as an alternative to recommended life-long systemic chemotherapy with two principal goals:
  1. To extend overall survival (OS)
  2. To provide treatment-free survival
5.2. Evidence for cytoreduction 
The data on the efficacy of CRS for treating CRC peritoneal metastases come predominantly from observational studies and is biased. However, to date, there are several randomized controlled trials (RCT) warranting continued investigation of this aggressive locoregional approach.
  • In an early RCT published in 2003, 105 patients were randomized into CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin-C followed by systemic chemotherapy with 5-FU and leucovorin (n=54) or systemic chemotherapy with 5-FU and leucovorin alone (n=51).[63] Median OS was almost two times higher in the CRS+HIPEC group (22.3 vs 12.6 months, p=0.035). However, the use of modern oxaliplatin or irinotecan-based chemotherapy combined with biologic agents provides median survival longer than either studied group.
  • Another trial from 2016 featured 48 patients (24 per arm) with CRC peritoneal metastases randomized into CRS with intraperitoneal 5-FU or systemic chemotherapy with oxaliplatin and 5-FU.[64] Median OS, as well as 2- and 5-year OS rates, were significantly higher in the CRS + intraperitoneal 5-FU group while progression-free survival was similar. The results of this study are promising; however, considering the sample size, it is hard to make any conclusions.
  • The most recent PRODIGE 7 trial on this topic was published in 2021 and included 265 patients, who were randomly assigned to CRS with (n=133) or without (n=132) oxaliplatin-based HIPEC.[65] After a median follow-up of 63.8 months, the median OS was similar between the groups: 41.7 months in CRS+HIPEC vs 41.2 in CRS alone (p=0.99). According to the subgroup analysis, the only patients who benefited from CRS+HIPEC were those with peritoneal cancer index (PCI) of 11-15 (HR 0.44, 95% confidence interval [CI]: 0.21-0.90). It is important to note that in this trial, 30-minute perfusion with oxaliplatin was chosen for HIPEC; therefore, other chemoagents and regimens are yet to be studied.
Existing evidence demonstrates that complete removal of the tumor (complete cytoreduction) is highly important and should be a cornerstone of locoregional management when feasible. The role of intraperitoneal chemotherapy in CRC patients with peritoneal metastases currently remains uncertain and requires further investigation.
5.3. Essential components of the CRS center
CRS is a demanding and complex procedure associated with significant postoperative morbidity, which varies even among high-volume expert centers from 6.7% to 45%.[14] Therefore, we highly discourage providing this treatment outside specialized CRS institutions. The 2020 Chicago Consensus on peritoneal surface malignancies has established standards for centers performing CRS+HIPEC and, in this paragraph, we will highlight key settings and elements required for meeting these criteria and building a successful and safe CRS program.[40]
  • A. Multidisciplinary tumor board including surgical, medical, and radiation oncologists, as well as pathologists, radiologists, genetic counselors, and specialists in palliative medicine creates continuity of care and improves patient selection and outcomes.[66, 67]
  • B. Trained surgical, anesthesia, and intensive care unit (ICU) teams are essential. A surgical oncology fellowship is mandatory, but it usually lacks separate CRS/HIPEC training, so most cytoreductive surgeons are taught by their more experienced colleagues with an extensive learning curve (130-220 independent procedures to improve completeness of tumor removal and morbidity rates).[17, 68, 69] The structure and work of the CRS center can be gleaned during clerkships and workshops in the CRS centers or from special programs conducted by experts in the field.[70, 71]
  • C. Permanent 24-hour access to CT, interventional radiology, and interventional gastroenterology allows the earliest detection and management of postoperative complications.[14] Specialists in nutrition and occupational therapy are also required for a full recovery and return to preoperative quality of life (QoL).[72]
  • D. CRS center data collection and its routine evaluation provide important information about previous and current results, facilitate patient selection, promote diligent follow-up, and allow the application of evidence-based modifications to improve outcomes.[14] Cytoreductive surgery in CRC remains an area of research and so the expert center, whether academic or not, must also be involved in research.
5.4. Additional workup and selection of patients to refer to the CRS center
Diagnostic workup aims to identify surgical candidates among patients with CRC peritoneal metastases, who will benefit the most from this approach. Meticulous patient selection is essential because unsuccessful surgical attempts (aborted procedures) in those with unresectable disease do not provide any survival benefit and can lead to serious morbidity and delay systemic treatment.[31]
Therefore, a multidimensional diagnostic approach with qualitative and quantitative assessment of peritoneal lesions is required. Its objectives include:
  • Ruling out extraperitoneal metastases
  • Confirming tumor resectability
  • Assessing the probability of complete removal of the disease
  • Planning the surgical procedure
The qualitative step includes defining the location of peritoneal metastases and involvement of important anatomical structures. Quantitative evaluation implies the estimation of tumor burden using the peritoneal cancer index (PCI).[73] It provides a numerical measurement of intraabdominal tumor volume (from 0 to 39) considering lesion size and number of abdominal regions affected by them (Figure 1) and correlates with the probability of complete tumor removal and overall prognosis.[14, 74]
Figure 1. Scheme for calculation of peritoneal cancer index (PCI)
CT of the chest, abdomen, and pelvis with oral and intravenous contrast enhancement is key imaging for preoperative workup of CRC with peritoneal spread. However, its limitations listed above (see part 4) do not allow using it as a single method for diagnosing peritoneal disease, estimating resectability, or selecting surgical candidates.
Magnetic resonance imaging (MRI) can supplement CT in assessing peritoneal metastases from CRC, especially in patients with mucinous pathology (MRI provides high resolution of tumors with significant fluid content) and when there is a suspicion for tumor involvement of the ureter, vaginal cuff, or other important structure.
Positron emission tomography and CT (PET-CT) with 18F-fluorodeoxyglucose (18F-FDG) can provide additional information to CT and MRI in identifying occult extraperitoneal disease and navigating a precise biopsy of peritoneal metastases with the highest metabolic activity in selected cases.[75-79] PET should not be used without CT due to its low resolution.[80]
Diagnostic laparoscopy (DL) is gaining popularity among surgeons for selecting CRS candidates. Studies showed that DL can exclude up to 50% of patients from unnecessary surgery.[81-85] However, the rate of falsely excluded patients is unknown and currently there are no standard selection criteria for decision-making. DL is also limited in patients with multiple intraabdominal adhesions.
Despite all diagnostic modalities described above, in some patients, exploratory laparotomy is the only definitive way to predict complete removal of the tumor. However, sometimes it takes several hours for surgeons to establish that it is impossible.[31] Surgical exploration should include a quadrant-by-quadrant evaluation with PCI recording and assessment of complete CRS feasibility.
Ultimately, the decision to proceed with CRS is based on the following factors:
  • Overall tumor burden represented by PCI, which can be measured only after complete adhesiolysis.
  • Involvement of areas difficult or impossible for complete tumor removal, such as the porta hepatis and bile ducts, total involvement of stomach or pancreas, multiple lesions of the small bowel wall and mesentery and insufficient length of remaining small bowel, involvement of mesentery root, extensive invasion of the diaphragm, and ureters with ureter-bladder junction.[86]
  • Technical skills of the surgical team and availability of resources necessary for postoperative management.[14]
  • Patient comorbidities and overall functional and nutritional status (CRS is contraindicated in patients with ECOG status ≥3 due to a high risk of morbidity).[87-89]
  • Predicted postoperative QoL after all required resections.[72, 90]
There is no single diagnostic modality providing a sufficient preoperative assessment and selection of CRS candidates. Therefore, a combination of imaging methods and diagnostic laparoscopy or exploratory laparotomy is commonly required.
5.5. Cytoreductive procedure
The aim of CRS is complete resection of all visible tumor (complete cytoreduction) with maximum possible preservation of viscera. CRS quality is evaluated and recorded at the end of the procedure using the completeness of cytoreduction (CC) score, which was introduced by Sugarbaker and is based on the size of residual peritoneal lesions (Figure 2).[73]
Figure 2. Scheme for calculation of the completeness of cytoreduction (CC) score
Anesthesia support in CRS is challenging due to surgical trauma-related fluid shifts. A goal-directed approach in perioperative fluid management through stroke volume assessment is preferable since it decreases morbidity and length of stay compared to liberal fluid therapy protocol.[91-93] Standard monitoring including neuromuscular transmission, intraesophageal temperature, central venous pressure, and urine output is recommended throughout the procedure.[94]
Routine preoperative nasogastric tube (NGT) placement is not recommended as it showed delayed return of bowel function and no difference in anastomotic leak rates in a meta-analysis of 33 RCTs with 5,240 patients undergoing abdominal surgeries.[95] However, it can be beneficial for patients with a high risk of postoperative delayed gastric emptying after lesser omentectomy, porta hepatis dissection, or distal gastrectomy.[94] Ureteral stenting is also not used in all CRC patients, though it should be considered in cases of extensive pelvic disease or suspected urinary tract involvement to facilitate its visualization. Stenting is performed in the operating room before the procedure.
CRS starts with a midline incision and a thorough exploration of the abdominal cavity. PCI is calculated followed by peritonectomies and organ resections. Resections may include diaphragmatic, flank, and abdominal wall peritonectomy, diaphragmatic resection with repair, liver capsule and parenchyma resection, porta hepatis dissection, gastrectomy, pancreatectomy, omentectomy, splenectomy, small bowel resections, colectomy, total abdominal hysterectomy with oophorectomy, and cystectomy. These procedures are done as needed to achieve a complete cytoreduction or if organ sparing is impossible. CRS surgeons must have solid experience performing each procedure. At least 200 cm (≥80 in) of small bowel should be preserved to avoid short bowel syndrome, a devastating complication of CRS. Once procedures are done, the CC score is carefully assessed and recorded.
If HIPEC is planned, it is performed after CRS, but before all anastomoses except esophagojejunal. The purpose is to expose bowel section lines to the chemoperfusion agent and decrease the risk of anastomotic or staple line recurrence.[96] This approach is associated with a low rate of anastomotic leak (less than 6%).[14, 97, 98]
Abdominal closure is standard. Early extubation in the operating room following CRS is recommended when there are no contraindications. It is associated with fewer respiratory complications, reduced stay in the ICU and the hospital, quicker return of bowel function, and earlier ambulation.[99] After the procedure, we recommend transferring patients to the ICU for close monitoring and then to the inpatient surgical floor once clinically stable.
CRS is associated with significant rates of postoperative complications.[14] Therefore, centers performing this procedure must have an experienced surgical ICU, 24-hour access to CT, interventional radiology, and interventional gastroenterology to detect and manage any complications early and efficiently. Specialists in nutrition and occupational therapy are also required for a full recovery and return to preoperative QoL.[72]
5.6. Intraperitoneal chemotherapy
Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed in the operating room immediately following CRS and before all anastomoses except esophagojejunal. It can be done in two ways: open (“Coliseum technique”) or closed.[96]
Neither method is superior to the other in terms of efficacy and safety; however, a closed technique provides more stable intraabdominal temperature and fewer hemodynamic alterations.[100, 101] HIPEC is performed using the heating and perfusion machine with 2 inflow and 2 outflow catheters, solution temperature of 41-43ºC, and an inflow rate of 1,000-1,500 mL/minute.
Currently, there are several drugs and regimens used most frequently for HIPEC in CRC with peritoneal metastases:
  • Mitomycin-C 40 mg in 3 L of 1.5% dextrose peritoneal dialysis solution: 30 mg for 60 minute perfusion followed by another 10 mg for 30 minutes (total perfusion: 90 minutes).[20, 39, 102-104]
  • Mitomycin-C 35 mg/m2 in 3 L of 1.5% dextrose peritoneal dialysis solution: 17.5 mg/m2 at 0 minutes followed by 8.8 mg/m2 at 30 minutes and 8.8 mg/m2 at 60 minutes (total perfusion: 90 minutes).[105]
  • Melphalan 50 mg/m2 2 L of 1.5 % dextrose peritoneal dialysis solution for a 90-minute perfusion.[103, 106]
There are some retrospective studies comparing survival outcomes of HIPEC with mitomycin-C versus melphalan; however, the results are controversial.[107] Therefore, the decision on what HIPEC agent and technique to use is generally based on available data, center experience and resources, previous systemic regimens, and possible chemoresistance.
Prophylactic HIPEC was studied in 2 RCTs including CRC patients with a high risk of developing peritoneal metastases after primary tumor resection.
  • In the COLOPEC trial (2019), 204 patients with advanced (T4N0-2M0) or perforated colon cancer were assigned to colectomy + HIPEC with oxaliplatin + adjuvant chemotherapy (x6 months) or colectomy + adjuvant chemotherapy (x6 months).[108]
    There was no difference in peritoneal-free survival at 18 months: 80.9% in the experimental vs 76.2% in the control group (p=0.28). However, major postoperative morbidity was higher in the HIPEC group: 10% vs 3%.
  • The recent PROPHYLOCHIP-PRODIGE 15 trial (2020) included 150 CRC patients, who had a perforated tumor or a few synchronous localized peritoneal metastases or ovarian metastases removed during primary tumor resection.[109]
    All patients received 6 months of adjuvant chemotherapy and then were randomly assigned to surveillance or a second-look surgery (with complete removal of peritoneal disease if possible) + HIPEC with oxaliplatin. Second-look surgery + HIPEC did not improve 3-year disease-free survival compared to surveillance alone (44% vs 53%, p=0.82), but led to grade 3-4 morbidity in 41% of patients.
Despite risk factors of peritoneal disease development, adjuvant systemic chemotherapy with subsequent follow-up in these patients seems to be an adequate strategy in terms of survival. If recurrence with peritoneal lesions occurs, patients can be referred to an expert CRS institution.

6. Controversies

One of the existing controversies is whether or not it is necessary to resect a primary tumor in a CRC patient with peritoneal metastases. The surgeon’s intention and eagerness to remove it is understandable, especially when the peritoneal disease is detected unexpectedly or is localized. However, the fact remains that a colectomy for an asymptomatic primary in the presence of metastatic disease does not provide any survival benefit over systemic chemotherapy alone, but leads to postoperative morbidity and mortality.[32-34]
The risks that primary tumor symptoms will occur during the systemic treatment are low and stay so during the entire course of chemotherapy.[35-37] Prolonged obscured intraluminal bleeding from the tumor should be managed with an early initiation of systemic chemotherapy, not palliative surgery.[35]
Another important question in the locoregional management of CRC with peritoneal metastases is if there is a preoperative PCI cut-off when selecting candidates for CRS. Existing data demonstrate significantly worse survival in patients with high PCI (>15, 19, or 20) after CRS+HIPEC and many centers use different PCI cut-offs for selecting surgical candidates among CRC patients.[110-114]
However, there are no studies showing that CRS has no benefit in patients with high PCI or above a defined PCI cut-off. Tumor burden is an important factor that indicates how extensive the surgery will be. Therefore, we believe a pre-defined, data-driven PCI cut-off can be useful when estimating the risk-benefit ratio since the balance of surgical risks and postoperative patient QoL is a mainstay for the decision to proceed with CRS.[72, 90, 115]
One more major controversy already mentioned above is the impact of HIPEC on patient outcomes. Existing retrospective evidence supports its use after CRS, despite limited tissue penetration (1-3 mm). This is also supported by an RCT from 2003 that demonstrated the superiority of CRS+HIPEC (mitomycin-C) and systemic chemotherapy over systemic chemotherapy alone (median OS: 22.3 vs 12.6 months, p=0.035).[18-20, 63, 116, 117]
The PRODIGE 7 trial showed a significant survival in both groups undergoing CRS, but proved a 30-minute HIPEC with oxaliplatin has no effect on median OS (41.7 vs 41.2 months, p=0.99).[65] Thus, CRS performed in expert centers seems to be a justified treatment in select CRC patients that can provide a decent survival, but the role of HIPEC with various drugs and regimens requires further studying.

Summary

  • With an incidence of 8-13%, the peritoneal cavity is the third most common metastatic site for CRC after the liver and lungs. Up to 35% of these patients have isolated peritoneal lesions with no extraperitoneal metastases.
  • Patients with peritoneal metastases from CRC can be completely asymptomatic, but more commonly present with abdominal discomfort, nausea, constipation, and ascites, as well as symptoms related to the primary tumor.
  • Diagnostic workup directly depends on the clinical presentation and therapeutic goal and consists of several modalities including imaging, endoscopic, surgical, and histopathologic assessment.
  • Most patients with CRC peritoneal metastases receive palliative systemic chemotherapy as a standard of care.
  • Removal of an asymptomatic primary tumor in CRC patients with peritoneal disease does not provide any survival benefit over systemic chemotherapy alone, but can lead to post-colectomy morbidity.
  • Primary tumor removal or palliation should be considered in symptomatic and emergency cases, as well as patients refusing chemotherapy, non-compliant with treatment, and without access to medical oncology.
  • In an urgent setting, the removal of peritoneal lesions not causing symptoms does not achieve any therapeutic goals.
  • CRS is an evolving surgical management that remains under investigation and, hence, is performed only in specialized centers with substantial experience.
  • In select patients, complete removal of peritoneal disease might be an alternative to life-long systemic treatment with significant survival (median OS: 41.2 months).
  • The role of HIPEC in patients with CRC peritoneal metastases is yet to be established.
  • Prophylactic 30-minute HIPEC with oxaliplatin and a scheduled second-look surgery with HIPEC (oxaliplatin for 30 minutes) if the tumor is found are not beneficial and lead to postoperative morbidity in patients at high risk for peritoneal disease development after primary tumor resection.

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