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Invited Commentary
Surgery
January 11, 2019

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Safety Is Only Half of the Story

Author Affiliations
  • 1Department of Surgery, University of Michigan, Ann Arbor
  • 2Center for Healthcare Outcomes and Policy, Ann Arbor, Michigan
JAMA Netw Open. 2019;2(1):e186839. doi:10.1001/jamanetworkopen.2018.6839

Peritoneal carcinomatosis is typically a diagnosis associated with poor survival. Historically, this diagnosis was viewed as a terminal stage of disease not amenable to surgical treatment. In the 1990s, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) emerged as a promising treatment for patients with peritoneal carcinomatosis from gastrointestinal and ovarian cancer without extraabdominal disease.1 More recent studies have continued to demonstrate improved overall survival with CRS/HIPEC compared with systemic chemotherapy alone. For example, a randomized clinical trial in 2003 reported that patients with colorectal peritoneal carcinomatosis treated with CRS/HIPEC had an overall survival of 22 months compared with 12.5 months in those receiving only systemic chemotherapy.2

Cytoreductive surgery with HIPEC is an aggressive locoregional treatment that begins with resecting disseminated intraabdominal disease, either completely or at least to minimal residual disease. Cytoreduction is followed by infusion of chemotherapy into the abdominal cavity. Local delivery of chemotherapy allows high concentrations to be used, and the addition of hyperthermia is thought to both improve penetration into the peritoneal surface as well as enhance tumoricidal effect.3,4 Early studies evaluating CRS/HIPEC reported high morbidity and mortality; however, more contemporary series have demonstrated significantly decreased morbidity and mortality rates.5,6 Although CRS/HIPEC has gained popularity, its use in the United States remains controversial, with ongoing uncertainty about appropriate patient selection.

Foster et al7 expand on single-institution case series to provide a national perspective on the safety of CRS/HIPEC by benchmarking it against other widely accepted complex oncologic procedures: hepatectomy, pancreaticoduodenectomy (Whipple), and esophagectomy. From their retrospective analysis of the National Surgical Quality Improvement Program (NSQIP) database, the authors report that CRS/HIPEC had a lower superficial infection rate (5.4%) than Whipple (9.7%) and esophagectomy (7.2%), and a lower deep space infection rate (1.7%) than Whipple (2.7%). Additionally, CRS/HIPEC had a 30-day mortality rate of 1.1%, lower than the rates of 2.5% to 3.9% for the comparison operations. Based on these results, Foster et al7 suggest that CRS/HIPEC is a safe procedure, at least as safe as the comparison oncologic procedures, and concerns regarding the safety of this treatment should not deter referral of patients.

The authors should be commended for attempting to address a potential barrier to use of this locoregional therapy in appropriately selected patients. However, the study has several notable limitations that should be borne in mind. Cytoreductive surgery encompasses a wide range of procedures, from resection of 1 peritoneal nodule to multivisceral resection with peritoneal stripping, and, thus, reflects a wide range of possible morbidity. As noted in the article, 76% of patients had at least 1 non-HIPEC code reported, and 46% had at least 2 codes. Unfortunately, NSQIP does not allow a more thorough description of the CRS procedures involved. Similarly, details on HIPEC (eg, type of chemotherapy and duration) are lacking. The NSQIP database contains limited information on tumor characteristics, treatment history, or details of surgical procedures beyond Current Procedural Terminology (CPT) codes. While the authors report low morbidity and mortality following CRS/HIPEC, the lack of treatment detail in NSQIP limits our understanding of which patients and what procedures were associated with these outcomes.

Finally, comparison with disparate oncologic procedures is inherently limited. Risk adjustment in this analysis considered only American Society of Anesthesiologists physical status classification. More importantly, comparison with other procedures for different indications constructs a straw man. A patient with pancreatic cancer has no other curative option besides a Whipple procedure. A patient with peritoneal carcinomatosis, on the other hand, could be offered continued palliative systemic therapy or CRS without HIPEC. Thus, the authors show that in a selected cohort of patients undergoing a heterogeneous group of procedures at highly specialized centers, CRS/HIPEC can be performed with acceptable morbidity and mortality. However, oncologists must weigh the short-term outcomes of any procedure against its benefits and its alternatives.

Although concerns over morbidity and mortality may influence referrals for CRS/HIPEC as the authors suggest, a more salient concern may be its oncologic effectiveness. The results of this study need to be interpreted in the context of emerging evidence questioning previously held assumptions regarding HIPEC and its survival benefit. For example, recent data from the phase 3 randomized clinical trial PRODIGE 78 suggest that the addition of HIPEC following CRS for patients with colorectal peritoneal carcinomatosis adds morbidity but not a survival advantage over CRS alone. On the other hand, a recent phase 3 randomized trial evaluating CRS vs CRS/HIPEC for epithelial ovarian cancer concluded that the addition of HIPEC to CRS increased overall survival.9 However, others have cautioned against changing practice based on these results given concerns over small sample size, imbalances in effects seen across centers, and overall survival with CRS/HIPEC that was similar to other studies’ reported survival following interval debulking alone.10

Legitimate concerns regarding the efficacy of CRS/HIPEC exist, and appropriate patient selection for this aggressive treatment remains a challenge. Foster et al7 demonstrate acceptable morbidity and mortality rates for CRS/HIPEC in this highly selected patient cohort. However, until the benefit for individual patients is more thoroughly understood, clinician referral and treatment practices will remain difficult to transform.

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Article Information

Published: January 11, 2019. doi:10.1001/jamanetworkopen.2018.6839

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Smith ME et al. JAMA Network Open.

Corresponding Author: Margaret E. Smith, MD, MS, Center for Healthcare Outcomes and Policy, University of Michigan, 2800 Plymouth Rd, Bldg 16, Office 016-122W, Ann Arbor, MI 48105 (smargare@med.umich.edu).

Conflict of Interest Disclosures: Dr Smith reported funding from the National Institute of Health Obesity Surgery Scientist Training Grant. Dr Nathan reported grants from the Agency for Healthcare Research and Quality and National Institute on Aging.

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Foster  JM, Sleightholm  R, Patel  A,  et al.  Morbidity and mortality rates following cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy compared with other high-risk surgical oncology procedures.  JAMA Netw Open. 2019;2(1):e186847. doi:10.1001/jamanetworkopen.2018.6847Google Scholar
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Vergote  I, Chiva  L, du Bois  A.  Hyperthermic intraperitoneal chemotherapy in ovarian cancer [letter].  N Engl J Med. 2018;378(14):1362-1363. doi:10.1056/NEJMc1802033PubMedGoogle ScholarCrossref
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