Colorectal peritoneal metastases of the (a) omentum and (b) rectovesical pouch
The incidence of resectable synchronous or metachronous peritoneal metastases without extra-abdominal spread is unknown and can only be estimated at approximately 3 % of all patients with CRC . This can be extrapolated to approximately 1,000 of the ~30,000 cases of CRC per year in England, though many patients are too unhealthy, or are unwilling, to undergo the complex strategy of CRS and HIPEC .
28.2 Pathophysiology and the “Redistribution Phenomenon”
The fundamental basis of metastatic peritoneal spread within the abdomen revolves around the pathophysiology of intraperitoneal fluid dynamics by a process called the “redistribution phenomenon” . A fundamental knowledge of this phenomenon is central not only to the understanding of the surgery required in managing peritoneal malignancy but also the sites to focus on during noninvasive abdominal imaging or laparoscopic assessment of any patient with suspected or actual peritoneal malignancy.
The redistribution of abdominal free-floating cells occurs via two main mechanisms – namely, gravity and a concentration of tumor at sites of peritoneal fluid absorption. The peritoneal cavity is a highly sophisticated, flexible container that allows the mobility of the motile contents, particularly the gastrointestinal tract. Physiologically it has a fluid interface between the parietal and visceral peritoneum, analogous to lubricating oil in a combustion engine. A mechanism to absorb and filter this physiological fluid, akin to an oil filter in an engine, incorporates the greater and lesser omentum and lacunae on the undersurface of the diaphragm, predominantly on the right side. Thus “redistribution” of peritoneal malignant cells occurs by gravitational forces, resulting in tumor accumulation in the pelvis, paracolic gutters, and subphrenic spaces and by a “filtration” and concentration effect in the omentum and undersurface of the diaphragm, predominantly on the right side.
Tumor biology is also pivotal, and the “invasive” potential of the cells determines whether peritoneal malignancy is confined to the peritoneum or invades vital abdominal viscera. The motility of the intra-abdominal organs, particularly the small bowel, is protected from involvement by relatively noninvasive tumor cells (classically pseudomyxoma peritonei [PMP]) and may similarly apply to some patients with CPMs.
Extensive prior surgery, with resulting inevitable adhesions, can interfere with bowel motility and can affect tumor spread. This may result in tumor concentration in and infiltration of the small bowel, potentially affecting resectability.
28.3 Evidence to Support CRS and HIPEC
The treatment strategy of CRS and HIPEC has evolved predominantly from the work of various researchers, initially in the field of PMP  and subsequently extrapolated to other peritoneal malignancies. Animal studies , a randomized controlled trial , numerous case series, and two meta-analyses [10, 11] support the benefits of CRS and HIPEC.
An elegant animal model of peritoneal carcinomatosis, randomizing to surgery alone (CRS) or CRS and HIPEC, demonstrated a reduction in peritoneal tumor volume and a prolonged survival in the group treated by a combination of CRS and HIPEC .
In humans, the landmark randomized controlled trial by Verwaal et al.  reported that CRS and HIPEC significantly improved survival compared with the best systemic chemotherapy, with acceptable toxicity. In an updated report of this study, which included 103 patients, at a median follow-up of 96 months there was an improvement in the median disease-free survival – from 12.6 to 22.2 months – favoring the group receiving CRS and HIPEC. To date, criticisms of this unique randomized controlled trial have been the relatively small number of patients; the inclusion of some cases with appendiceal carcinomatosis, which is known to have a more favorable outcome than CPMs; and the now outdated systemic chemotherapy. Nevertheless, the findings are valid and a credit to the Dutch investigators in such a complex field.
A number of publications on nonrandomized comparative case-control studies report improved survival in patients with CPMs who underwent CRS and HIPEC. Elias et al.  studied a series of 96 patients with CPM in a case-control study comparing CRS and HIPEC with systemic chemotherapy. They reported superior median survival (62.7 vs. 23.9 months), 2-year survival (81 % vs. 51 %), and 5-year survival (51 % vs. 13 %) in the CRS and HIPEC group.
Franko et al.  similarly reported on 105 patients and documented improved 1-, 3-, and 5-year survival of 90 %, 50 %, and 25 %, respectively, in the CRS and HIPEC group compared with the group receiving only systemic chemotherapy (55 %, 12 %, and 7 %, respectively)
Mahteme et al.  studied 36 patients and compared CRS and early postoperative intraperitoneal chemotherapy versus systemic chemotherapy alone. They found improved overall survival in the CRS + early postoperative intraperitoneal chemotherapy group (5-year survival: 28 % vs. 5 %).
A publication reporting on 107 patients who had CRS and intraperitoneal chemotherapy for CPM reported overall 5- and 10-year survival rates of 35 % and 15 %, respectively. In the subset who had complete cytoreduction and HIPEC, 16 % were regarded as cured, with a disease-free interval of at least 5 years .
The original systematic review in 2006  concluded that available evidence in favor of CRS and HIPEC for the treatment of CPMs was weak. An updated analysis and systematic review in 2014 by Mirzenami et al.  concluded that “enhanced survival times can be achieved for CPM after combined treatment with CRS and intraperitoneal chemotherapy.”
While many criticize the concept of CRS and HIPEC, evidence to support its use may in fact exceed the well-accepted role of surgical resection of pulmonary and hepatic metastases from CRC, which have never been subjected to randomized controlled trials. Part of the problem has been terminology; “diffuse colorectal carcinomatosis” is an exclusion criterion, and the recent concept of “resectable CPM” helps to focus attention on suitable cases for this novel strategy .
There has also been an overview of published evidence by the United Kingdom’s National Institute of Health and Clinical Excellence, which concluded that the overall 5-year survival was 19 % and that CRS plus HIPEC was an appropriate strategy in select patients .
The associated morbidity and mortality need to be taken into account when performing CRS and HIPEC. In their systematic review, Mirzenami et al.  found that mortality ranged from 0 % to 12 % and morbidity from 21.8 % to 62 %. The most common complications encountered were wound related (3–12 %), fistulas (1–11 %), intra-abdominal abscess (1.8–14 %), reoperation rate (4–20.8 %), and chemotherapy-related hematological toxicity (2–52 %) . The importance of the “learning curve” is now well recognized in this complex procedure, and most centers have reported a decline in the overall complication rate as the number of cases performed increased . Moreover, improvements in anesthesia, operative technique, critical care, and both diagnostic and interventional radiology have all added to the early recognition and active treatment of complications . Recent large-scale studies are now reporting acceptable morbidity and mortality rates following CRS plus HIPEC [19, 20].
28.4 Technical Aspects of CRS and HIPEC
The concept of CRS and HIPEC was initially popularized by Sugarbaker  and was subsequently adopted globally (a “global learning curve”) . The techniques have been developed and refined in PMP. Patients with extensive PMP may require all five primary, and two secondary, peritonectomies together with organ resections. The fundamental basis for CRS is the distribution of an abdominal tumor via the “the redistribution phenomenon,” described earlier.
CRS involves a series of “peritonectomy procedures” in addition to the resection of involved nonvital organs such as the spleen, gallbladder, right colon, and rectosigmoid. Peritonectomy consists of resection of the parietal peritoneum lining the abdominal cavity in the relatively avascular subperitoneal plane.
The five primary peritonectomy procedures are (1) right parietal, (2) left parietal, (3) right diaphragmatic, (4) left diaphragmatic, and (5) pelvic. The liver and spleen are enveloped by the peritoneum, and peritonectomy of the right and left liver involves capsulectomy of the right and left liver to complete the total of seven peritonectomy procedures.
Peritonectomy, particularly liver capsulectomy, is facilitated by the use of high-powered electrosurgery using “rolly ball” diathermy with “cut” and “coag” at the highest settings. At these settings substantial smoke is produced, and a high-powered smoke extractor is mandatory to reduce smoke contamination.
Both peritonectomy and organ resectional procedures in CRS for PMP have applications in other peritoneal malignancies, including CPMs. However, it is pertinent to note that patients with CPM who benefit from CRS and HIPEC should have localized disease and will never require the same extent of surgery as patients with extensive PMP.
A radical greater omentectomy (inside the gastroepiploic vessels) is performed and the spleen is carefully assessed. If it is involved by disease, the splenic artery and vein are clamped, transfixed, and ligated, and a splenectomy is performed, taking great care to avoid damage to the tail of the pancreas. The lesser omentum is removed and dissection is carried upward in the aortocaval groove behind the caudal lobe of the liver. The gallbladder is removed and the portal structures identified, removing any peritoneal disease in this area.
Pelvic dissection is commenced by rectal mobilization in the total mesorectal excision plane posteriorly, with full mobilization of the rectum. The peritoneal mobilization is carried anteriorly toward the bladder, and the peritoneum is carefully dissected off its posterior surface. The rectum and sigmoid colon can usually be preserved, but prior pelvic surgery (especially major gynecological surgery such as hysterectomy and salpingo-oophorectomy) may mean that the tumor has infiltrated the anterior rectal wall, and an anterior resection may be needed.
In women, the ovaries are routinely removed; removal of the uterus may or may not be required.
In many patients with PMP, appendicectomy alone may suffice to resect the tumor, but a right hemicolectomy is required if there is extensive peritoneal involvement of the cecum and/or terminal ileum, or if there are suspected involved nodes on the ileocolic chain. If right and left colectomies are performed, then anastomoses are generally performed after completing HIPEC. If a low colorectal anastomosis is needed, consideration should be given to performing a proximal temporary defunctioning loop ileostomy, which is our usual practice.
At the end of CRS, the completeness of cytoreduction (CC) is measured using the CC score. This ranges from CC-0 (no visible tumor), CC-1 (tumor nodules <2.5 mm), CC-2 (tumor nodule between 2.5 and 2.5 cm), and CC-3 (tumor nodule >2.5 cm) (Table 28.1). CC-0 and CC-1 are classed as “complete cytoreduction,” since intraperitoneal chemotherapy penetrates to a depth of 3 mm. Patients with PMP after CC-0 and CC-1 cytoreduction have shown similar long-term, disease-free outcomes.
Completeness of cytoreduction
No visible residual tumour
Largest residual tumor <2.5 mm in size
Largest residual tumor 2.5–2.5 cm in size
Largest residual tumor >2.5 cm in size
28.5 Hyperthermic Intraperitoneal Chemotherapy
After completion of CRS, a closed or open (coliseum) technique is used to administer HIPEC for 60–90 min at 42° C. The intraoperative chemotherapeutic agents commonly used for PMP or CPM are mitomycin-C (10 mg/m2) or oxaliplatin (460 mg/m2). The concept of HIPEC is that cytotoxic drugs penetrate to a depth of approximately 3 mm . Hyperthermia enhances this penetration, and the drug’s effectiveness and the hyperthermia induce tumor cell destruction as a result of the formation of heat shock proteins . An additional benefit of hyperthermia is that the heat corrects the patient’s physiology. A prolonged laparotomy usually results in hypothermia; HIPEC reverses this hypothermia, avoiding adverse effects and facilitating hemostasis. In our experience, HIPEC reduces secondary hemorrhage requiring reintervention, probably by restoring hemostasis and providing a long interval in which to detect bleeding points.
Once HIPEC is completed, the abdominal cavity is washed out with copious volumes of water or saline and low-suction abdominal drains are inserted into the four quadrants of the abdomen.
28.6 Patient Selection
With increasing awareness among oncologists of CRS and HIPEC as a treatment option for selected patients with CPM, there has been an increase in referrals to peritoneal malignancy treatment centers. The challenge still remains in selecting those patients who would benefit from CRS and HIPEC in terms of longer survival and improved quality of life. The best results occur in patients with limited disease (usually confined to one or two quadrants of the abdomen and with a minimum of ~200 cm of uninvolved small bowel), where complete tumor removal is achieved, ideally at the time of primary colorectal tumor resection in patients with synchronous disease .
The Peritoneal Carcinomatosis Index (PCI) is the most widely accepted quantitative prognostic indicator in selecting and treating CPMs . The PCI is an intraoperative assessment that quantifies the extent of peritoneal disease distribution in combination with the size of tumor nodules (Table 28.2).
Regions and scoring used for calculating the Peritoneal Carcinomatosis Index
Regions of the abdomen
No tumor seen
Tumor ≤0.5 cm
Tumor ≤5.0 cm
Tumor >5.0 cm or confluence
Total number of regions
Maximum PCI score
The numeric score ranges from 0 to 39, with a higher score indicating a greater tumor load. The abdomen and pelvis are divided into nine regions and the small bowel into four. If the lesion size is >5 cm in a region, the region is given a score of 3. If the lesion size is up to 5 cm, the region is given score of 2, and if it is up to 0.5 cm, it is given a score of 1. If no tumor is seen in a particular region ,it is scored as 0. The maximum PCI score that can be calculated is 39. In a French multi-centre study including 523 patients with CPM, Elias et al.  found that survival at 4 years in patients with a PCI score <6 was 44 %; for a score between 7 and 12 4-year survival was 22 %, and with a score >19 it was 7 %. It has since been recommended that CRS and HIPEC should be avoided in patients with CPM with a PCI score >20. A more recent study of 180 patients by Goere et al.  suggested that this threshold may be lowered further to a PCI score >17. Ideally, a preoperative PCI score would help select patients for surgery; work is ongoing in this field using a combination of cross-sectional imaging (predominantly computed tomography [CT]) and selective use of laparoscopy. The problem is that imaging tends to underestimate the extent of low-volume peritoneal disease, and neither CT, magnetic resonance imaging, nor positron emission tomography (PET)/CT is sufficiently accurate in determining disease extent.
In the event that imaging predicts a high PCI and possible incomplete resection, optimal maximal palliative tumor debulking may be beneficial, particularly in patients with less aggressive tumours .
Nomograms to assess the suitability of patients for CRS and HIPEC are complex and not widely used. They serve more as guidelines as opposed to absolute recommendations.
The Peritoneal Surface Disease Severity Score is calculated on the basis of clinical symptoms, the extent of peritoneal metastases, and tumor histology . Esquivel et al. , in a study of 1,013 patients, concluded that the Peritoneal Surface Disease Severity Score can be used as a useful adjunct in decision making when considering patients with CPM for CRS and HIPEC, and for stratification within clinical trials.
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