Peritoneal carcinomatosis (PC) represents the involvement of the peritoneal surface with neoplastic process. Mostly this results from intracavitary dissemination of tumor that may arise from variety of primary sites like gastrointestinal, gynecologic primary peritoneal, or mesothelioma. Historically this has been thought to have poor prognosis with the few treatment options1. Although the natural history of this disease is not well documented, the overall prognosis is believed to be extremely poor with survival <6 months2. Cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been utilized successfully for the treatment of this challenging condition and its role has been evolving. This paper reviews the rationale, evidence, and surgical technical updates in the current era of minimally invasive surgery.
2. Rationale for CS and HIPEC
In the past, PC was considered as advanced metastatic spread of the tumor. The only treatment options considered for patients were systemic chemotherapy, supportive care with the surgery reserved only for palliation. Although surgery could achieve gross reduction in tumor burden, there was still a need to address the micro-metastases as well as the invisible cells in the peritoneal cavity. Addition of intraperitoneal chemotherapy was thought to address this with the significantly higher concentration of selected agent in the local regional area. The effects of chemotherapy drugs are further enhanced by addition of hyperthermia (ideally to 42°C–43°C), which is understood to have synergistic effects3.
Professor Paul Sugarbaker pioneered the use of aggressive surgery to achieve complete cytoreduction and combined it with hyperthermic intraperitoneal chemotherapy for treatment of selected patients with the peritoneal spread4. Phase III randomized control trials by Verwaal et al5,6 showed improvement in long-term survival in selected group of patients with colorectal cancer. This led adoption of CS with HIPEC for other peritoneal malignancies including gastric, ovarian, mesothelioma, and pseudomyxoma7–10. Over the past 2 decades there has been a tremendous interest and increase of use of CS with HIPEC all over the world11,12.
3. Patient selection and quantification of disease
CS and HIPEC is a complex surgical procedure with the potential for high morbidity and mortality. A review of the ACS NSQIP database reporting on 695 patients showed the average operative time was 7.6 hours, with 15% of patients requiring intraoperative transfusions13. The average length of stay was 13 days, with a 30-day readmission rate of 11%. Postoperative bleeding (17%), septic shock (16%), pulmonary complications (15%), and organ-space infections (9%) were the most prevalent postoperative complications. Hence, patient selection is the key. Age, poor nutritional status (hypoalbuminemia), and Eastern Cooperative Oncology Group (ECOG) performance status are the preoperative factors having a strong association with perioperative morbidity and mortality14.
Regarding preoperative imaging, a consensus was reached at the Fifth International Workshop on Peritoneal Surface Malignancy, stating that contrast-enhanced multisliced computed tomography remains the fundamental imaging modality, whereas magnetic resonance imaging, positron emission tomography, laparoscopy, and serum tumor markers were helpful but nonessential15. Although combined imaging modalities can assess the extent of peritoneal disease, the exact quantification of the disease is best done at surgery. With recent advancements in the minimally invasive surgery, laparoscopy has been increasingly used to accomplish staging16.
Various measures are used to quantify the disease burden including the commonly used PC index score as well as the Dutch simplified peritoneal cancer index and the Gilly PC staging system17. More critical is the completeness of cytoreduction (CC) score that is used to quantify the residual disease left at completion of surgery with the aim to achieve CC of <1. Of all the perioperative factors, this CC score is the most important predictor of survival and recurrence18.
4. Choice of chemotherapeutic agent
Although over a dozen of drugs could be used, the heat-augmented drugs that are most effective are mitomycin C, Oxaliplatin, Cisplatin, and doxorubicin3. The agent of choice of chemotherapeutic drug depends upon various factors including the primary cancer to be treated and preference of the team. For example the majority of the surgical oncologists in North America favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-minute chemoperfusion for patients undergoing CS for PC of colorectal origin19.
5. Role of laparoscopy
Laparoscopy can logically have an inherent benefit in visualization of peritoneal disease including evaluation of small bowel and ability to perform biopsy3. Several studies have reported success in the use of laparoscopy for staging peritoneal metastasis in colorectal, mesothelioma, and appendiceal cancer20,21. A recent multicenter trial reported accuracy for laparoscopy of 80% for staging peritoneal metastasis from ovarian origin22.
In patients with disease limited to 1 part of the peritoneal cavity CS can be accomplished laparoscopically. Among them, in a select subgroup of patients, HIPEC can also be successfully administered by laparoscopic approach and has been found to be safe23. Several studies have been reported with the indications for laparoscopic HIPEC having ranged from neoadjuvant to adjuvant (most common) to palliative. When performed to treat refractory malignant ascites, the laparoscopic HIPEC was effective in 95% of cases23.
More interesting is the proactive use of HIPEC along with “second look” surgery in patients with advanced local disease with or without tumor perforation24. An interesting trial comparing simple follow-up to exploratory laparotomy plus “in Principle” HIPEC in Colorectal Patients (“PROPHYLOCHIP” study) is underway.
6. Interdisciplinary concept
As with all cancer care, CS with HIPEC is best offered to patients by a dedicated multidisciplinary team. Here a group of individuals including surgeons, radiologist, anesthesiologists, nurses, HIPEC technicians, and oncologists can be involved in setting up the program and delivering it starting from patient selection to perioperative care and long-term follow-up25.
7. Literature overview for CS and HIPEC in various cancers
7.1. Colorectal cancer
A phase III randomized controlled trial by Verwaal et al5,6, initially reported in 2003 and recently updated with an 8-year follow-up, showed the median disease-specific survival of 22.2 months in the HIPEC arm compared with 12.6 months in the control arm (P=0.028). Additional multi-institutional studies have confirmed the benefit of HIPEC with median survival from 29.4 to 62.7 months especially when complete CS is achieved8,9.
Recently the focus has been to make CS with HIPEC when available to be the standard of care for PC from colorectal cancer in addition to systemic chemotherapy26. Also the roles of second look surgery and adjuvant HIPEC following a curative resection of a locally advanced or intra-abdominally perforated colon cancer in preventing the development of PC in addition to the standard adjuvant systemic treatment is being investigated (NCT02231086).
7.2. Gastric cancer
Evidence is not as robust for improved survival in patients with gastric cancer especially since the outcomes for adjuvant treatments for gastric cancer remain poor7,27. However, a recently reported first randomized controlled trial for CS with HIPEC showed improvement in survival to 11.2 months compared with 5.6 months28. A recent novel approach has been the use of bidirectional (intraperitoneal and systemic) chemotherapy where in a Japanese center with 194 patients, median survival was 15.8 months29.
7.3. Ovarian cancer
Advanced stage ovarian, primary peritoneal, and fallopian tube cancers are very challenging to treat as demonstrated by a 70%–80% recurrence rate. A recent Cochrane review showed women were less likely to die if they received an intraperitoneal component to chemotherapy (8 studies, 2026 women). Intraperitoneal component chemotherapy prolonged the disease-free interval (5 studies, 1311 women; hazard ratio=0.78; 95% confidence interval, 0.70–0.86)30.
8. Pseudomyxoma peritonii (PMP)
PMP results from rupture of mucinous neoplasms commonly from appendix or ovary and sometimes primary peritoneal origin. This has traditionally had a poor prognosis with median survival of 3 years. CS with HIPEC has been extensively applied at the significant improvement in overall survival 70% at 20 years31. A retrospective multi-institutional registry looking at 2298 patients from 16 specialized centers who underwent CRS with HIPEC for PMP, showed a median survival rate of 196 months (16.3 y) and a median progression-free survival rate of 98 months (8.2 y), with a 10- and 15-year survival rates of 63% and 59%, respectively32.
CS and HIPEC have now evolved to being a promising treatment for patients with PC. This complex procedure is associated with significant mortality and morbidity and patient selection remains the key. Minimally invasive approaches have been successfully used in delivery of CS and HIPEC and their future role in treatment and prevention of peritoneal metastasis continues to evolve.
Conflict of interest statement
The author declares that there is no financial conflict of interest with regard to the content of this report.
1. Pilati P, Rossi CR, Mocellin S, et al. Multimodal treatment of peritoneal carcinomatosis
and sarcomatosis. Eur J Surg Oncol 2001;27:125–134.
2. Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis
in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 1989;63:364–367.
3. Sugarbaker PH, Van Der Speeten K. Surgical technology and pharmacology of hyperthermic perioperative chemotherapy. J Gastrointest Oncol 2016;7:29–44.
4. Sugarbaker PH, Graves T, DeBruijn EA, et al. Early postoperative intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal carcinomatosis
from gastrointestinal cancer: pharmacologic studies. Cancer Res 1990;50:5790–5794.
5. Verwaal VJ, Van Ruth S, Witkamp A, et al. Long-term survival of peritoneal carcinomatosis
of colorectal origin. Ann Surg Oncol 2005;12:65–71.
6. Verwaal VJ, Van Ruth S, De Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis
of colorectal cancer
. J Clin Oncol 2003;21:3737–3743.
7. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis
from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000;88:358–363.
8. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery
plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis
of colorectal origin. J Clin Oncol 2009;27:681–685.
9. Levine EA, Stewart JH IV, Shen P, et al. Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1000 patients. J Am Coll Surg 2014;218:573–585.
10. Glehen O, Schreiber V, Cotte E, et al. Treatment of peritoneal carcinomatosis
arising from gastric cancer by cytoreductive surgery
and intraperitoneal chemohyperthermia. Arch Surg 2004;139:20–26.
11. Teo M, Foo KF, Koo WH, et al. Lessons learned from initial experience with peritonectomy and intra-peritoneal chemotherapy infusion. World J Surg 2006;30:2132–2135.
12. Li Y, Zhou YF, Liang H, et al. Chinese expert consensus on cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies. World J Gastroenterol 2016;22:6906–6916.
13. Bartlett EK, Meise C, Roses RE, et al. Morbidity and mortality of cytoreduction with intraperitoneal chemotherapy: outcomes from the ACS NSQIP database. Ann Surg Oncol 2014;21:1494–1500.
14. Newton AD, Bartlett EK, Karakousis GC. Cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality. J Gastrointest Oncol 2016;7:99–111.
15. Yan TD, Morris DL, Shigeki K, et al. Preoperative investigations in the management of peritoneal surface malignancy with cytoreductive surgery
and perioperative intraperitoneal chemotherapy: expert consensus statement. J Surg Oncol 2008;98:224–227.
16. Seshadri RA, Hemanth Raj E. Diagnostic laparoscopy in the pre-operative assessment of patients undergoing cytoreductive surgery
and HIPEC for peritoneal surface malignancies. Indian J Surg Oncol 2016;7:230–235.
17. Neuwirth MG, Alexander HR, Karakousis GC. Then and now: cytoreductive surgery
with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical perspective. J Gastrointest Oncol 2016;7:18–28.
18. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery
combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis
from colorectal cancer
: a multiinstitutional study. J Clin Oncol 2004;22:3284–3292.
19. Turaga K, Levine E, Barone R, et al. Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer
patients in the United States. Ann Surg Oncol 2014;21:1501–1505.
20. Garofalo A, Valle M. Laparoscopy in the management of peritoneal carcinomatosis
. Cancer J 2009;15:190–195.
21. Pomel C, Appleyard TL, Gouy S, et al. The role of laparoscopy to evaluate candidates for complete cytoreduction of peritoneal carcinomatosis
and hyperthermic intraperitoneal chemotherapy. Eur J Surg Oncol 2005;31:540–543.
22. Fagotti A, Vizzielli G, De Iaco P, et al. A multicentric trial (Olympia-MITO 13) on the accuracy of laparoscopy to assess peritoneal spread in ovarian cancer. Am J Obstet Gynecol 2013;209:462.e1–462.e11.
23. Facchiano E, Risio D, Kianmanesh R, et al. Laparoscopic
hyperthermic intraperitoneal chemotherapy: indications, aims, and results: a systematic review of the literature. Ann Surg Oncol 2012;19:2946–2950.
24. Elias D, Goéré D, Di Pietrantonio D, et al. Results of systematic second-look surgery in patients at high risk of developing colorectal peritoneal carcinomatosis
. Ann Surg 2008;247:445–450.
25. Königsrainer I, Beckert S. Cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy: where are we? World J Gastroenterol 2012;18:5317–5320.
26. Sugarbaker PH. Cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy in the management of gastrointestinal cancers with peritoneal metastases: Progress toward a new standard of care. Cancer Treat Rev 2016;48:42–49.
27. Pyrhönen S, Kuitunen T, Nyandoto P, et al. Randomized comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995;71:587–591.
28. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis
from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol 2011;18:1575–1581.
29. Canbay E, Mizumoto A, Ichinose M, et al. Outcome data of patients with peritoneal carcinomatosis
from gastric origin treated by a strategy of bidirectional chemotherapy prior to cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy in a single specialized center in Japan. Ann Surg Oncol 2014;21:1147–1152.
30. Jaaback K, Johnson N, Lawrie TA. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2016;1:CD005340. doi: 10.1002/14651858.CD005340.pub4.
31. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasm and pseudomyxoma peritonei syndrome? Lancet Oncol 2006;7:69–76.
32. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012;30:2449–2456.