Current Status and Future Directions of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Abstract: Introduction: The appropriate sequence and timing of currently available therapies for patients with peritoneal carcinomatosis of gastrointestinal origin continue to be debated among medical and surgical oncologists. Material and Methods: We conducted a review of the literature that included medical and surgical management of patients with colon cancer with peritoneal dissemination as well as studies evaluating the role of hyperthermic intraperitoneal chemotherapy (HIPEC). Results: HIPEC data are scarce and mostly come from nonrandomized, single-institution studies. Carcinomatosis patients are underrepresented in randomized studies with modern systemic therapies. Recently, there appears to be support for collaboration between medical and surgical oncologists through the American Society of Peritoneal Surface Malignancies in order to better select patients for cytoreductive surgery and HIPEC and to determine the timing and duration of systemic therapy. Conclusion: The current status of the management of patients with peritoneal carcinomatosis demonstrates that there is a high level of interest and willingness regarding evaluation and standardization of  therapies among health care providers, but many important questions remain unanswered. Future studies directed at maximizing the efficacy of each of these therapies will need to follow.

Key words: cytoreductive surgery, heated intraperitoneal chemotherapy, HIPEC

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Peritoneal carcinomatosis (PC) represents a widespread metastatic dissemination throughout the abdomen and pelvis of many organ-based malignancies, particularly carcinomas of the gastrointestinal tract and ovaries. The mode of presentation, the radiologic findings, and the clinical outcome will be directly related to the site of origin and the burden of disease. The most common malignancies that can develop peritoneal carcinomatosis include (1) mucinous appendiceal neoplasms and appendix cancer, (2) colorectal cancer, (3) ovarian cancer and primary peritoneal carcinomas, (4) peritoneal mesothelioma, (5) gastric cancer, (6) small bowel cancer, (7) pancreatic cancer, and (8) sarcomas. 

In the past, treatment for patients with peritoneal carcinomatosis was an exploratory laparotomy. After the procedure, patients were sent for palliative care and very frequently they were referred to hospice from the recovery room.

It has been 35 years since Dr. John Spratt from the University of Louisville reported in Cancer Research the first combination of cytoreductive surgery (CRS) and a heated perfusion with intraperitoneal chemotherapy very similar to what we call HIPEC (hyperthermic intraperitoneal chemotherapy) today in a patient with pseudomyxoma peritonei.¹ Since then, the treatment of patients with peritoneal surface malignancies has undergone significant transformation with meaningful clinical advances.  

The popularity of this combined modality increased significantly over the 2 decades following the Spratt publication as the surgical approach changed from a debulking procedure to a more comprehensive surgery that involved stripping the peritoneal surfaces in addition to some visceral resections, and HIPEC was used after the complete surgical eradication of the metastatic disease to the abdomen and pelvis to eradicate microscopic residual disease.² The results with this new technique were so superior to the standard approach that the combination of CRS and HIPEC became the new standard of care for patients with a widespread intra-abdominal dissemination from the benign mucinous appendiceal neoplasm pseudomyxoma peritonei.  

As surgeons became more familiar with this surgical procedure, this therapeutic intervention was offered to patients with other gastrointestinal and gynecologic malignancies with carcinomatosis. Our knowledge about selection criteria improved as did our understanding of the role of HIPEC. The aim of HIPEC is to obtain higher local concentrations of the used cytostatic agents, combined with hyperthermia, to eradicate any microscopic residual disease.³

While the surgical technique is becoming fairly standard around the world as more evidence demonstrates the need of a complete CRS, there exists tremendous variation when it comes to application of HIPEC. Hyperthermic intraperitoneal chemotherapy is characterized by seven parameters: (1) method of delivery, (2) drugs, (3) drugs dosage, (4) timing of drug administration, (5) volumen of perfusate, (6) temperature of infusate and, (7) duration of perfusion. Different cytostatic agents such as mitomycin C (MMC), doxorubicin, cisplatin, oxaliplatin, or irinotecan are used depending on the tumor histology and the individual experience and preference of the peritoneal carcinomatosis treatment center. The chemoperfusion can be performed in an open or closed abdominal technique, or even via the laparoscopic route using a roller pump and a heat exchanger.⁴ The duration of perfusion ranges from 30 minutes to 120 minutes depending on the individual protocol, and the degree of hyperthermia ranges from 40 degrees Celsius to 43 degrees Celsius. A review of the literature also shows a wide range of HIPEC delivery, with many methodological variations including the technique, drug selection and the time of perfusion (Table 1).⁵ 

Colon Cancer With Peritoneal Carcinomatosis

In the last decade, tremendous progress has been made in the medical management of metastatic colorectal cancer. The addition of oxaliplatin and irinotecan to previously existing 5-flurouracil (5-FU) and leucovorin-based therapies has improved the overall median survival that previously rarely exceeded 12 months. Coupled with the addition of biological targeted therapies including bevacizumab and cetuximab, the overall median survival is frequently 20 months or greater.⁶ With the recent comprehensive molecular characterization of human colon and rectal cancer by The Cancer Genome Atlas Network, numerous mutations have been found in other genes besides those already known (K-ras, APC, PIK3CA).⁷ These genes represent new targets for additional biologic agents. The FDA approved aflibercept after Van Cutsem et al demonstrated that adding aflibercept to FOLFIRI significantly improved survival relative to placebo plus FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin.⁸ Overall survival for the aflibercept group was 13.5 months vs 12.06 months for those receiving placebo, a highly statistically significant difference, (P=.0032), but a clinical benefit of only 44 days.

The current staging system for colorectal cancer from the American Joint Committee on Cancer is problematic with respect to PC. The 2012 version divided Stage IV into IVA and IVB. Patients with IVA are those with M1a disease, meaning metastatic disease confined to one organ (e.g., liver, lung, ovary, nonregional nodes) and IVB are patients with M1b disease with metastases in more than one organ or site or in the peritoneum. This staging system puts a patient with 3 small peritoneal implants underneath the right hemidiaphragm in the same staging category as a patient with multiple liver and lung metastases.

It is estimated that about 40% of patients with colorectal cancer will develop peritoneal metastases at some point in time after initial diagnosis. The majority of patients with colorectal cancer who develop PC will also have other sites of hematogenous dissemination, will be classified as Stage IVB, will be categorized as patients with unresectable metastatic disease, and will appropriately receive a palliative combination of cytotoxic chemotherapy and a biologic agent. Those that have measurable disease in other sites than the peritoneum and have a good performance status might be entered into a clinical trial. Less than 1% of patients with peritoneal metastases will be referred for CRS and HIPEC. This is the current status for about 15,000 patients per year in the United States and many more patients around the world.

Recently, Franko et al reported the outcome of patients with CRCPC from a pooled analysis of two large phase III trials from the North Central Cancer Treatment Group (NCCTG) that included 2,101 patients treated with systemic chemotherapy.⁹ Of these 2,101 patients, the majority participated in the N9741 trial of first-line chemotherapy for metastatic CRC (n=1,646), and the remaining participated in the N9841 trial of second-line chemotherapy (n=455). The vast majority of patients (>80%), had metastatic disease via the hematogenous route with only 17% of the total group having PC in addition to liver and/or lung metastases and only 2.1% (44 patients) having metastatic disease only confined to the peritoneal surfaces. Patients with PC had higher risk of death owing to all causes than patients without PC (median OS 12.7 vs 17.6 months, HR=1.32, 95% CI, 1.15 -1.50; P<.001). The unfavorable prognostic influence of PC in patients with metastatic CRC remained after adjusting for age, performance status, liver metastases, and other factors (OS: HR=1.3; P<.001).

Klaver et al reported the results of two similar studies by the Dutch Colorectal Cancer Group (DCCG) and came to the same conclusion as the North American group.¹⁰ In her report, data were obtained from patients with metastatic CRC enrolled in 2 phase III studies. In the CAIRO study, 820 patients were randomized between sequential treatment (first-line: capecitabine, second-line: irinotecan, and third-line: oxaliplatin plus capecitabine, arm A) and combination treatment (first-line: irinotecan plus capecitabine, second-line: oxaliplatin plus capecitabine, arm B).¹¹ In the CAIRO2 study, 755 patients were randomized between capecitabine, oxaliplatin, and bevacizumab (CB regimen), and the same regimen plus weekly cetuximab (CBC regimen). In these studies, the number of patients with metastatic CRC but no PC exceeded 90%. In the CAIRO study, only 34 patients (4%) had PC and of these 34 patients, only 4 had isolated PC. In the CAIRO2 study, only 47 patients (6%) had PC and 5 of them had isolated PC.

Median OS was decreased for patients with PC compared to patients without PC in both studies. In the CAIRO study, this was 10.4 months vs 17.3 months, respectively (P<.001), and in CAIRO2, this was 15.2 months vs 20.7 months, respectively (^P<.001). The median number of treatment cycles did not differ between patients with or without PC in both studies. The occurrence of major toxicity was more frequent in patients with PC treated with sequential chemotherapy in the CAIRO study as compared to patients without PC. However, this was not reflected in reasons to discontinue treatment. In the CAIRO2 study, no difference in major toxicity was observed. The authors concluded that their data demonstrate decreased efficacy of current standard chemotherapy with or without biologic agents in patients with PC of colorectal origin and that the poor outcome compared to those patients without PC cannot be explained by undertreatment or increased susceptibility to toxicity, but rather by a relative resistance to treatment secondary to a different biologic behavior of tumors that spread to the peritoneal cavity.

Analysis of these 4 studies demonstrates that few patients with PC of colorectal origin are included in prospective randomized trials of patients with unresectable metastatic CRC and that the vast majority of the patients with PC that are included in these trials will also have other sites of hematogenous metastases. In addition, measuring the severity of the carcinomatosis in patients with isolated peritoneal disease in order to compare similar patients represents an unmet need.

Chua et al reviewed the therapeutic options of 2,492 patients with metastatic colon cancer from 19 studies between 1995 and 2009. He reported a global survival of 33 months (20-63) for patients with complete CRS and HIPEC and only 12.5 months (5-24) for patients having undergone palliative surgery and/or systemic chemotherapy.¹³ In summary, the vast majority of patients with PC from colorectal origin will be treated with systemic therapies even though there are no data to document their benefit in this particular group of patients.

Current Status of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

The combined-modality treatment of CRS to remove all visible metastatic disease and HIPEC to eradicate microscopic residual disease continues gaining acceptance as 5-year survival rates in completely resected patients with colorectal cancer and peritoneal carcinomatosis approaches rates of complete resection of colorectal cancer metastatic to the liver.^14-15 But even with multiple phase II studies demonstrating far superior results with the combined therapy, HIPEC has not been universally embraced by the medical community. There are several reasons that this multimodality approach has not been accepted by many health care providers, including a paucity of randomized data comparing it to modern systemic therapies, its being considered “experimental” by some insurance companies, concerns about the potential morbidity and mortatlity of the procedure, and the multiple variations in how HIPEC is delivered. 

Consequently, selection criteria for treatment type and sequence of therapeutic modalities at the time of diagnosis of PC of colorectal origin remain ill defined. This leaves important questions unanswered.

The American Society of Peritoneal Surface Malignancies

The American Society of Peritoneal Surface Malignancices (ASPSM) was created in an effort to encourage health care providers with a particular interest in the treatment of patients with peritoneal surface malignancies of gastrointestinal and gynecological origin to collaborate in a multidisciplinary approach, discuss the key issues that are needed in order to advance the science behind the care of this group of patients, and exchange ideas that could improve their outcome. The first goal established for the society was “Standardization of HIPEC Delivery in the United States.” During the next several years, the ASPSM developed a proposal for standardizing the delivery of HIPEC in various disease processes treated within the United States.  In May 2014, the society published the Consensus Guidelines on Standardization of HIPEC Delivery in Colorectal Cancer Patients in the United States (Table 2).¹⁶ This manuscript represents an important first step in enhancing research in this field. Once there is a uniform way of delivering HIPEC, then additional studies can be directed at maximizing the efficacy of each of the seven key elements.

While these additional studies will help our understanding of HIPEC, they will not answer a question that is frequently posed by the medical oncology community: What is the added value of HIPEC to a complete surgical resection of the metastatic disease to the abdomen and pelvis? Also, this question would have to be answered for each of the organ-based malignancies. Multiple prospective randomized trials would have to be performed in order to answer these questions. Over the past decade, several attempts at conducting this type of trial have taken place in the United States without success. Some of the main reasons include lack of cooperation between institutions, the fact that most patients do not want to be randomized, and also the fact that many cytoreductive surgeons believe that systemic therapy does not work in patients with PC. Unlike metastatic CRC via hematogenous dissemination, when it comes to PC of colorectal origin, there is a paucity of prospectively collected outcome data.  Most of these trials require measurable disease according to the RECIST criteria in order to enroll patients; a large number of patients with PC have nonmeasurable disease and identifying target lesions in current imaging modalities represents a radiologic challenge.  

Randomized Studies Evaluating HIPEC vs No HIPEC

 A review of the literature demonstrates only one publication on this subject. Yang and colleagues conducted a prospective randomized phase III trial in 68 patients with peritoneal carcinomatosis arising from gastric cancer and compared cytoreductive surgery and HIPEC vs cytoreductive surgery alone.  Median survival for the HIPEC group was 11 months while the median survival in the no-HIPEC group was 6.5 months (P<.05). Median survival increased to 13.5 months in those patients having a complete cytoreductive surgery.¹⁷  

Prodige 7 is a prospective randomized multicenter phase III trial by the French group where patients with colorectal cancer and limited peritoneal dissemination were taken to the operating room. If a complete cytoreductive surgery was achieved, the patients were randomized in the operating room to receive HIPEC or not. This study finished accrual at the end of 2013 and we are anxiously awaiting the results.  In this study, HIPEC was delivered with oxaliplatin (460mg/m²) in 2L/m² of dextrose 5% over 30 minutes at a minimal temperature of 42° C. One hour before the HIPEC, 20 mg/m² of leucovorin and 400 mg/m² of 5-fluorouracil were given intravenously. This study will answer the question of the added value (or not) of this particular HIPEC regimen to a complete cytoreductive surgery. 

Future HIPEC Directions

The lack of a standardized technique and reporting of HIPEC procedures has led to multiple barriers concerning patient care and insurance providers in the United States. The adoption of the proposed HIPEC delivery by the ASPSM, combined with the results from randomized trials from Europe and Asia, will hopefully assist in advancing the science behind the combined treatment of cytoreductive surgery and HIPEC and will help introduce this therapy as another tool in the armamentarium of health care providers to fight PC, maximizing benefits and minimizing morbidity to this complex group of patients.

Editor’s Note: Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports consultancy to Eight Medical, Inc.

Address for correspondence: Jesus Esquivel, MD, Cancer Treatment Centers of America, Surgical Oncology, 1331 East Wyoming Avenue, Philadelphia, PA 19124. Email: jesusesquivel@yahoo.com

Suggested citation: Esquivel J. Current status and future directions of hyperthermic intraperitoneal chemotherapy (HIPEC). Intervent Oncol 360. 2014;2(6):E45-E52.

References

1. Spratt J, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res.1980;40(2):256-260. 
2. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221(1):29-42.
3. 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(20):3737-3743.
4. Esquivel J, Averbach A. Combined laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a patient with peritoneal mesothelioma. J Laparoendosc Adv Surg Tech A. 2009;19(4):505-507.
5. Esquivel J. Technology of hyperthermic intraperitoneal chemotherapy in the United States, Europe, China, Japan and Korea. Cancer J. 2009;15(3):249-254.
6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
7. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-337.
8. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regime. J Clin Oncol. 2012;30(28):3499-3506.
9. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal cacinomatosis with systemic chemotherapy: A pool analysis of North Central Cancer Treatment Group phase III trials N9741 and N9841. J Clin Oncol. 2012;30(3):263-267.
10. Klaver YL, Simkens LH, Lemmens VE, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis  treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol. 2012;38(7):617-623.
11. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomized control trial. Lancet. 2007;370(9582):135-142.
12. Tol J, Koopman M, Rodenburg CJ, et al. A randomised phase III study on capecitabine, Oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO 2 study of the Dutch Colorectal Cancer Group. An interim analysis of toxicity. Ann Oncol. 2008;19(4):734-738.
13. Chua TC, Morris DL, Esquivel J. Impact of the peritoneal surface disease severity score on survival in patients with colorectal cancer peritoneal carcinomatosis undergoing complete cytoreduction and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2010;17(5):1330-1336.
14. 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 multi-institutional study. J Clin Oncol. 2004;22(16):3284-3292. 
15. 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(5):681-685.
16. 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(5):1501-1505.
17. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patient’s with Peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18(6):1575-1581.