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  Peritoneal Carcinomatosis in colorectal and appendiceal malignancies: Role of CRS and HIPEC

Peritoneal metastasis by all standards is considered to be the last stage (stage IV disease). In the past, it was considered inoperable and patient was planned for palliative chemotherapy. However, this approach is associated with poor quality of life and is ineffective in improving survival. However, the pioneering work of Dr Paul Sugarbaker in the field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has given a glimmer of hope for a select group of patients with peritoneal metastasis. The rationale for this particular approach is the restriction of tumor dissemination to the peritoneal compartment justifying a radical surgical procedure followed by HIPEC.
Although there is enough literature now to suggest that CRS and HIPEC is superior to systemic chemotherapy, it has not made its way into the routine management of stage IV disease as most of the treating surgeons still consider this strategy to be experimental. Similar thinking was considered for liver metastasis in colorectal cancers. But now surgery is considered as the treatment of choice for resectable liver metastasis of colorectal origin. Management of peritoneal surface malignancies requires a dedicated multidisciplinary team comprising of proactive surgeon, medical oncologist, anaesthesiologist, radiologist and intensivist.  
Rationale behind CRS and HIPEC
Systemic chemotherapy is considered by most as the treatment of choice for patients with peritoneal metastasis. But, one of the main limiting factors governing dosimetry in systemic chemotherapy is hematological toxicity. In other words, the actual dose given intravenously  is not so much the dose one wants to give based on cytotoxicity studies, but rather the dose tolerated by the patient’s hematological reserve. But in CRS, all the visible disease is removed and chemotherapy given at higher temperature intraperitoneally. This gives us an opportunity to give maximal dose of chemotherapy to the tumor cells without significant effect on hematological reserves. The rationale of HIPEC is the synergistic cytotoxic effect of heat, ideally 42-43 degree Celsius, and the chemotherapeutic agent itself on tumor cells. Hyperthermia causes vasodilation with improvement in tumor oxygenation improving the effects of chemotherapeutic agents. 
Procedure of CRS and HIPEC
The cytoreductive surgery consists of a laparotomy from xyphoid to pubis. The presence of macroscopic tumor deposits is recorded in 12 abdominal regions according to PCI chart (Peritoneal Carcinomatosis Index). The procedure involves removal of peritoneum from all the five regions – Right and Left hemidiaphragm, Right and Left paracolic gutters and pelvic peritoneum. All the disease involving small bowel and its mesentery is also removed which may also involve resection and anastomosis of small bowel. In order to achieve complete cytoreduction, many times adjacent organs need to be resected like anterior resection for deposits on sigmoid and pouch of douglas, distal gastrectomy, colectomies. The objective of cytoreduction is to leave no macroscopic tumor behind (CC-0; complete cytoreduction); but, if that could not be achieved, attempts are made to leave no residual tumor exceeding 2.5 mm in thickness (CC-1). Various animal studies have shown the effect of heated chemotherapy for tumor thickness upto 2.5mm
At completion of cytoreduction, the abdominal cavity is inspected for residual tumor. If there is no remaining macroscopic tumor, this is stated as R-1. If the largest residual tumor is smaller than 2.5 mm, it is regarded as an R-2a resection. In cases of residual tumors thicker than 2.5 mm, cytoreductive surgery is scored as R-2b. Main benefits for HIPEC are for CC-0 and CC-1. However, people have shown some benefit of HIPEC for CC-2 also. The limiting factor for complete cytoreduction in most of the cases is extensive small bowel resection. Those with extensive small bowel involvement (with deposits on mesenteric side of small bowel) are difficult to treat as removing whole of the disease for a CC-0 or CC-1 would require multiple resection and anastomosis. 
The hyperthermic intraperitoneal chemotherapy is carried out according to the open colliseum technique or closed technique (which one is better has not been proved in any trials). Perfusion is started with a minimum of 2 litres of isotonic dialysis fluid, with an inflow temperature of 41–42oC. As soon as the temperature in the abdomen is stable above 40 oC, chemotherapeutic agents are added to the perfusate and circulated for 90 min. Drug used for intraperitoneal chemotherapy depends upon the primary disease. Position of the patient is changed to allow for complete mixing of drug in whole of the abdomen. In open technique, whole of the drug is mixed thoroughly so that it comes in contact of all the peritoneal surfaces. Patient is also given intravenous chemotherapy to increase the effect of intraperitoneal chemotherapy. 
Before closing the abdomen the drains are inserted in all the five peritonectomy regions for the purpose of early postoperative chemotherapy. 
Early postoperative intraperitoneal chemotherapy (EPIC)
EPIC is another form of intraperitoneal chemotherapy given to patients who have received HIPEC. It is commenced on post operative day 1 and is continued for 5 days. It includes administering chemotherapeutic agents intraperitonealy through one of the abdominal drains and kept inside for 23 hours with all drains clamped. Position of the patient is changed for effective mixing of drug in all the quadrants of the abdomen. Drug is drained for next one hour by declamping all the drains and then readministered. This chemotherapy is given for 5 days. 
During HIPEC, urine output should be monitored and should be more than 1ml/kg/hr. Care should be taken to avoid the spillage of chemotherapeutic drugs. During EPIC, these patients are prone to leucopenia. White cell counts should be daily monitored and if required Granulocyte-macrophage colony-stimulating factor (GM-CSF) should be administered. 
Peritoneal carcinomatosis (PC) is present in 10% of patients at the time of diagnosis. Survival following best palliative chemotherapy has been dismal to about 6 months although with introduction of targeted therapy the survival has significantly improved to about 22 months in few studies. However, best results were mainly found in patients with lung or liver metastasis. Patients with peritoneal disease continued to have poor survival compared to liver or lung metastasis. Surgical advances have improved survival in these patients. 
Recent data suggests that patients with PC may have an option of cytoreductive surgery (CRS) to treat visible disease and HIPEC (Hyperthermic IntraPEritoneal Chemotherapy) to treat non visible peritoneal disease with favourable results. A randomized trial comparing HIPEC and CRS vs systemic chemotherapy alone showed a significant improvement in survival following HIPEC. 
Dr Sugarbaker et al reviewed 2300 patients of pseudomyxoma peritonei of appendiceal origin and found that following CRS + HIPEC, median survival rate was astonishingly 16.3 years. The overall 3-, 5-, 10-, and 15-year survival rates were 80%, 74%, 63%, and 59%, respectively. 
Another option for patients with peritoneal disease is complete cytoreduction without HIPEC. Results of incomplete resection versus complete resection have shown favorable results for complete cytoreduction. Glehen in his “world series” had shown that patients with gross complete cytoreduction had a median overall survival of 35.4m compared to only 8.4m for patients with incomplete cytoreduction. Thus this procedure offers a ray of hope in patients who otherwise had dismal outcomes following best of chemotherapy to patients with peritoneal carcinomatosis. Although robust data is still not present, but preliminary results favour use of HIPEC along with complete CRS. Most important factor is that CRS should be complete as incomplete CRS with HIPEC showed poor results similar to those receiving systemic chemotherapy.  Randomized trial comparing this issue is still ongoing and the results are still awaited (Prodige 7)
A study published in 2009 compared patients of PC with those receiving CRS plus HIPEC to those with CRS with systemic chemotherapy. 5 year survival was 51% with CRS plus HIPEC group compared to 13% for non HIPEC group.
Selection criteria for CRS and HIPEC
  • Patients with colorectal malignancy with peritoneal disease
  • No evidence of extra abdominal disease.
  • Good performance status
  • PCI score less than 20
  • Patients with good response to neoadjuvant chemotherapy
Contraindications to CRS and HIPEC
  • Poor general status
  • Presence of extraperitoneal metastases
  • Huge and diffuse PC.
  • Presence of CRLMs (relative)
All studies have shown that patients who benefit most with HIPEC and CRS are those with less bulky peritoneal disease. However, detecting early PC is not possible with current clinical or radiological means. It is possible only with laparotomy. So a second look laparotomy may be performed with the aim of diagnosing PC at an early stage and treat it with CRS with HIPEC. But this is a major undertaking and a specific group of patients only should be considered for a prophylactic “Second Look Laparotomy”. Such at-risk population was defined by Sugarbaker et al-
(1) Visible evidence of peritoneal carcinomatosis
(2)  Ovarian cysts showing adenocarcinoma suggested to be of gastrointestinal origin
(3)  Positive cytology either before or after cancer resection
(4)  Adjacent organ involvement or cancer-induced fistula
(5)  Obstructed cancer
(6)  Perforated cancer
(7)  T3 mucinous cancer
(8)  T4 cancer or a positive “touch prep” of the primary cancer
(9)  Cancer mass ruptured with the resection
(10) Positive lateral margins of excision
A multicentric RCT (Prodige 15) has been started in 2011 that compares high risk group patients to either systemic chemotherapy or second look laparotomy. Main aim of this would be to see the rate of peritoneal recurrence after 3 years. 
Rajiv Gandhi Cancer Hospital is the first hospital in India to have a dedicated machine (Belmonte) to administer hyperthermic chemotherapy. Over the past one and a half years, we at RGCI have operated upon nearly 20 patients of PC. Primary disease was mainly from colon (12), appendix (6), small bowel (1) and peritoneal mesothelioma (1).  Till now all except one are surviving with good result and most of them are disease free.
Up to 15% of patients with metastatic colorectal cancer have isolated peritoneal carcinomatosis. Peritoneal carcinomatosis in colorectal cancer carries poor prognosis. Systemic chemotherapy can marginally improve survival. Cytoreductive surgery + HIPEC is the only hope to improve long term survival or may even cure selected patients with peritoneal carcinomatosis.
Fig 1: Figure shows patient of pseudomyxoma peritonei with extensive diaphragmatic deposits.
Fig 2: Figure shows same patient after complete peritonectomy. 
Fig 3: Figure showing pelvic peritonectomy of the same patient
Fig 3: Dedicated Belmonte Machine to administer hyperthermic chemotherapy


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