Introduction
In the United States, approximately 20% of patients with colorectal cancer present with distant metastasis at diagnosis. In 25% of cases, the peritoneal cavity is the only site of metastatic disease, which is not indicative of a generalized systemic disease, as is the case with lung or liver metastases.[1] Peritoneal carcinomatosis arising from colorectal cancer has generally been considered terminal, with a median life expectancy of 5.2 to 7 months after initiation of fluorouracil (5-FU)–based chemotherapy, but newer management approaches have improved patient outcomes.[2] At the Icahn School of Medicine at Mount Sinai, we have utilized cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) over the past decade as a therapeutic option for this complex and difficult-to-treat condition. In highly selected groups of patients with no macroscopic disease after CRS and HIPEC, the median disease-free survival and overall survival (OS) times in our patients with colorectal cancer were 14.3 months and 43.8 months, respectively.[3]
Patient Selection
The peritoneal carcinomatosis index (PCI) is used to quantify the extent of peritoneal carcinomatosis found during surgical exploration. This scoring system, proposed by Jacquet and Sugarbaker, was elected as the best staging system by an expert panel.[2,4-7] The PCI is derived from the peritoneal implant size and the distribution of the tumor nodules on the peritoneal surface in 13 areas of the abdominal and pelvic cavity (range for total PCI score, 0 to 39).[6,7] Median survival time with a PCI score less than 10 is between 31 and 48 months, with a 5-year OS rate between 22% and 50%. When there is increasing involvement of peritoneal carcinomatosis, patient survival decreases. We maintain that a PCI score over 20 should be considered a relative contraindication for CRS and HIPEC.[2,5,6]
Imaging and Diagnostic Laparoscopy
Pretreatment and preoperative assessment of peritoneal carcinomatosis of colorectal cancer can be very challenging despite imaging availability at our institution. We readily utilize multidetector computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted sequences, and positron emission tomography (PET) in combination with either CT or MRI. The size and location of peritoneal implants, lymph node involvement, and the presence of ascites are all essential to provide the surgeon with a detailed preoperative assessment of peritoneal disease, as well as the calculation of the radiologic PCI. Prognosis correlates with a lower PCI, and we have found it useful in selecting patients who will benefit from CRS plus HIPEC vs those who would be better suited to receive systemic chemotherapy.[2,6,7]
There remains wide variability in the overall sensitivity and specificity of multimodal imaging in identifying peritoneal disease, which is likely multifactorial. The size and radiodensity of tumor, patient body habitus, and postsurgical changes, as well as interpretation and diagnostic criteria limited to radiologist expertise, all affect the preoperative staging of peritoneal disease.[8,9] In carcinomatosis of colorectal origin, PET with the tracer fluorodeoxyglucose has an increasingly important role in the diagnosis, staging, and surveillance of malignant disease. Dual-modality PET/CT further improves staging accuracy.[2,9] However, evaluation of the patient’s peritoneal carcinomatosis by direct visualization at the time of CRS and HIPEC remains our gold standard. We are also examining the accuracy of PET/MRI in peritoneal surface malignancies through an ongoing clinical trial at our institution that is accruing patients.
Laparoscopy is being used at our center for staging and diagnosis in patients with carcinomatosis, because it allows for direct assessment of the peritoneal cavity, with minimal morbidity and mortality.[10] We will often perform diagnostic laparoscopy to confirm the extent of peritoneal disease when imaging techniques are equivocal, as well as to obtain a histopathologic diagnosis. Performing laparoscopy prior to CRS plus HIPEC enables accurate evaluation of the intra-abdominal peritoneal deposits. It allows the surgeon to predict optimal cytoreduction and assess the response to neoadjuvant and adjuvant chemotherapy. We also find that the information gathered during diagnostic laparoscopy involves patients in the discussion of their ongoing treatment; this is of particular value to patients who are electing to undergo CRS plus HIPEC that may require resections of the bowel (with or without ileostomy) and other viscera, such as pelvic organs. Furthermore, we are prospectively evaluating the role of interval diagnostic laparoscopy as a surveillance tool for patients who have previously undergone CRS plus HIPEC and are at high risk for recurrence.
In our personal experience with CRS plus HIPEC, we have previously evaluated 211 patients with diagnostic laparoscopy, 31.3% of whom were excluded from cytoreduction by laparoscopy. Of those 68 patients initially excluded, 7 subsequently underwent CRS plus HIPEC after receiving systemic chemotherapy. Our intraoperative morbidity and mortality rates were 0.4% and 0%, respectively.[10]
Multidisciplinary Conference
All patients at Icahn School of Medicine at Mount Sinai who present with peritoneal surface malignancies are discussed in a multidisciplinary conference, which includes specialists from medical oncology, radiation oncology, interventional radiology, gastroenterology, and surgical oncology. If the patient presents with low-grade peritoneal carcinomatosis (indicated by a low PCI), the general consensus is to proceed with CRS plus HIPEC if the preoperative imaging indicates that a complete cytoreduction can be achieved. If, on preoperative imaging, the disease burden is determined to be high by radiologic PCI or there is undocumented carcinomatosis, it is our standard approach to proceed with diagnostic laparoscopy in a separate setting, to further examine the abdominal cavity and obtain new biopsies. Patients who present with high-grade peritoneal surface malignances will typically proceed with neoadjuvant chemotherapy followed by restaging CT or PET/CT to reassess for tumor response in 3 to 4 months. If there is a notable decrease in peritoneal disease in response to systemic chemotherapy, CRS plus HIPEC will be arranged as the next step based on both the interval imaging and consensus at the multidisciplinary conference. Progression while on chemotherapy suggests the presence of resistant tumor that would be unlikely to respond to adjunctive CRS plus HIPEC, as well as the associated higher morbidity and mortality.[11,12]
CRS
CRS is aimed at removing all visible peritoneal tumor implants. The goal of intraperitoneal chemotherapy is to eliminate remnant microscopic tumor cells. Intraperitoneal chemotherapy can be administered under hyperthermic conditions in the operating room following CRS (HIPEC) or under normothermic conditions several days after CRS (early postoperative intraperitoneal chemotherapy [EPIC]).[2,5,6] We routinely employ HIPEC at the time of CRS for colorectal carcinomatosis.
As previously mentioned, we perform a diagnostic laparoscopy to assess the abdominal cavity. All four quadrants are examined, with special attention to both the right and left hemidiaphragm, the peritoneal surface, small bowel, and mesenteric involvement, as well as pelvic structures.
If the patient has extensive small bowel involvement that may warrant resection, has hepatoduodenal ligament and lesser sac involvement, or requires a total gastrectomy, then the associated operative morbidity and potential of an optimal CRS are re-evaluated in the operating room. If the surgeon makes the decision to proceed, a generous midline laparotomy is made from the xiphoid process to the pubis, and the abdomen is again examined to accurately determine the patient’s PCI following complete lysis of adhesions.
Diaphragm involvement with deeply infiltrating tumor deposits increases the risk of exposing the pleural cavity to the neoplastic process, as well as inadvertent entry into the chest. The right and left lobes of the liver are fully mobilized depending on the side of involvement, and we systematically perform a diaphragm stripping. A diaphragm resection is rarely required; however, the defect is primarily closed shortly after entry to minimize contiguous spread and avoid the need for pleural drainage. Subsequently, all peritoneal surfaces involved are stripped and an omentectomy is performed.
When there is small bowel and mesenteric involvement, care is taken to preserve as much bowel as possible. Nodules more than 2.5 mm in diameter are resected with primary repair. If the small bowel segment is densely involved, a segmental resection is performed. The mesenteric border, if involved, can be managed with repair or resection, in combination with ablation techniques using electrocautery or argon ablation. The primary goal is to remove all visible tumor and preserve as much involved viscera as possible. We have found from our personal experience that extreme multivisceral resection as part of CRS plus HIPEC is associated with higher major morbidity and inferior oncologic outcomes.[3]
In female patients, if the uterus or ovaries are involved with tumor, total abdominal hysterectomy and bilateral salpingo-oophorectomy are performed. This should be discussed with patients preoperatively, and should include appropriate counseling if the patient is of childbearing age.
Peritoneal stripping is usually sufficient for bladder involvement. If tumor involvement is full thickness, a partial bladder resection is undertaken. If the ureters are also involved, ureterolysis is performed with careful attention to the ureteral blood supply. Otherwise, a segmental resection and primary repair can be performed over a stent.
If the rectum is directly involved, a partial or full-thickness resection and primary repair can be done. The presence of extensive tumor involving the rectum or its mesentery necessitates a low anterior resection with or without a diverting loop ileostomy. All anastomoses are routinely done after HIPEC is completed, and the skin is approximated with staples.
Key Points
- Cytoreductive surgery (CRS) is aimed at removing all visible peritoneal tumor implants. The goal of hyperthermic intraperitoneal chemotherapy (HIPEC) is to eliminate remnant microscopic tumor cells.
- The peritoneal carcinomatosis index (PCI) is used to quantify the extent of peritoneal carcinomatosis found during surgical exploration. With increasing involvement of peritoneal carcinomatosis, patient survival decreases.
- Multimodal imaging and diagnostic laparoscopy are essential to provide the surgeon with a detailed preoperative assessment of peritoneal disease, as well as the calculation of the radiologic PCI.
- CRS plus HIPEC should be preferentially offered to patients with minimal intraperitoneal tumor burden and the possibility of complete surgical resection of gross peritoneal disease.
The standard of care for liver metastases from colorectal cancer is adjuvant or neoadjuvant chemotherapy combined with liver resection. Patients with peritoneal carcinomatosis require intraperitoneal chemotherapy to be administered at the time of resection in an attempt to treat any microscopic residual disease.[13] Multi-institutional retrospective studies have suggested that select patients may benefit from combined surgery for peritoneal carcinomatosis and distant metastasectomy.[14] Varban et al showed that liver resection combined with CRS plus HIPEC resulted in patient survival that was similar to that achieved with CRS plus HIPEC alone. The median OS for patients with liver metastases was 23 months.[15] We do not routinely perform liver resection in the setting of peritoneal disease, except in select cases of favorable tumor response with neoadjuvant chemotherapy.
Malignant ascites often accompanies peritoneal carcinomatosis, and the most common clinical feature is a progressive increase of abdominal distension, resulting in pain, discomfort, anorexia, and dyspnea. Abdominal paracentesis and administration of diuretics are the most common treatment modalities, although the benefit from these approaches is often self-limited. One of the beneficial effects of using HIPEC for treatment of peritoneal malignancies is the improvement in malignant ascites.[16] In patients with refractory ascites who are not candidates for a complete cytoreduction, we have previously utilized laparoscopic HIPEC for palliation of the malignant ascites.
The goal of surgery is completeness of cytoreduction, which is defined as no macroscopic residual disease after the operative procedure. The completeness of cytoreduction is scored as follows: CC-0 is defined as no residual disease, CC-1 indicates less than 2.5 mm of residual tumor, CC-2 is defined as more than 2.5 mm but less than 2.5 cm of residual tumor, and CC-3 is defined as more than 2.5 cm of residual tumor.[2,4] The median survival of patients following complete CRS with no macroscopic tumor ranges from 24 months to 46 months. The 5-year OS rate varies between 29% and 55%. Incomplete CRS with peritoneal tumor remnants of more than 5 mm are associated with median survival times of 4.1 to 14.6 months and 3-year survival rates between 0% and 8.5%.[2,9] The penetration of cytotoxic drugs into tumor tissue is limited to a maximal depth of 1 to 2 mm. Thus, a 5-mm diameter for residual tumor remnants is the cutoff at which patients will benefit from HIPEC. Patients with inadequate CRS should be treated with systemic chemotherapy.[6]
HIPEC
Following complete CRS, patients are further treated with HIPEC. The major advantage of intraperitoneal therapy is regional dose intensity. After drug administration, the peritoneal cavity is exposed to higher concentrations than are the other parts of the body. The concentration differential occurs because drug movement from peritoneal cavity to plasma (peritoneal clearance) is slower relative to drug clearance from the body.[6,17] The most commonly used drug for colorectal carcinomatosis is mitomycin-C (at a dosage of 15 to 35 mg/m2), with a target intraperitoneal temperature of 39°C (102.2°F) to 42°C (107.6°F) infused for 60 to 120 minutes. Peritoneal surface malignancies exhibit altered thermoregulation, and have demonstrated cellular destruction with prolonged exposure to heat.[6,18] Monotherapy with mitomycin-C has been reported to yield a median survival time ranging from 32.9 to 42.9 months in patients who have undergone complete CRS with no macroscopically residual tumor implants remaining post surgery.[2,4] The use of an open vs closed method for the chemotherapeutic perfusion, and the use (or not) of EPIC with 5 days of 5-FU, is the surgeon’s preference. Lam et al showed that there was no difference in OS and recurrence-free survival between patients with colorectal carcinomatosis and high-grade appendiceal adenocarcinomatosis treated with CRS and HIPEC with EPIC vs HIPEC alone. However, patients who received HIPEC with EPIC experienced greater morbidity,[17] making HIPEC alone our institution’s preferred regimen.
Although potentially curative, CRS plus HIPEC is associated with substantial perioperative morbidity and mortality, as well as a short-term decline in quality of life.
Gusani et al, in a comparison of CRS plus HIPEC morbidity outcomes from 15 cancer centers, reported the incidence of major morbidity (grades 3 and 4 by National Cancer Institute criteria) as 29.8% and overall morbidity as 56.5%.[14] Other reports have described perioperative mortality rates of 0% to 12% associated with CRS plus HIPEC. It has also been demonstrated that quality of life returned to baseline at 1 year following CRS plus HIPEC. It is therefore important to identify patient characteristics affecting the outcome of this treatment. Our single-institution experience of CRS plus HIPEC procedures for peritoneal carcinomatosis demonstrates major 30-day morbidity rates between 17.4% and 34%. Comparing patients who required four or fewer organ resections or two or fewer bowel anastomosis procedures, our series shows disease-free survival and OS times of 14.3 months and 43.8 months, respectively.[3,4]
Conclusion
Since not every patient benefits from this aggressive approach, careful preoperative patient selection is mandatory. CRS plus HIPEC should be preferentially offered to patients with minimal intraperitoneal tumor burden and the possibility of complete surgical resection of gross peritoneal disease. Only then can it offer a chance for long-term survival in patients with peritoneal carcinomatosis of colorectal origin. We admit that limited prospective comparative data exist to guide decision making and treatment.
Continued clinical research into CRS and HIPEC is essential. The optimal approach to perioperative intraperitoneal chemotherapy has not been established, and currently there are no available data to support systemic chemotherapy as an alternative to CRS and HIPEC. At this time, the National Comprehensive Cancer Network considers CRS plus HIPEC to be investigational in the management of peritoneal carcinomatosis of colorectal origin. This procedure should only be performed in centers with demonstrated expertise, preferably in the context of a clinical trial and as an adjunctive treatment in conjunction with systemic chemotherapy.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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