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Cytoreductive Surgery/HIPEC: Safer for Peritoneal Metastases? (CME/CE)

Action Points

  • Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for patients with peritoneal metastasis was found to have a lower 30-day mortality rate, and either similar or lower infection rates compared with other high-risk surgeries in a retrospective cohort study.
  • Understand that CRS/HIPEC may be safer when compared with other high-risk surgeries for peritoneal metastases, and safer than the same procedure performed in the 1980s and 1990s, but superior efficacy has not been proven to date.

CME Author: Vicki Brower

Study Authors: Jason M. Foster, Richard Sleightholm, et al.

Target Audience and Goal Statement:

Medical and surgical oncologists, gastrointestinal oncologists, gynecological oncologists

The goal was to determine the morbidity and mortality of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) compared with four other major oncologic surgical procedures in patients with peritoneal metastases.

Questions Addressed:

  • How does the safety of CRS/HIPEC compare with four other high-risk surgical procedures: right lobe hepatectomy (RLH), trisegmental hepatectomy (TSH), pancreatectomy/duodenectomy (Whipple), and esophagectomy? Safety parameters included superficial incisional infection in Whipple and esophagectomy, deep incisional infection in Whipple, organ space infection in RLH and TSH, and return to the operating room for esophagectomy.
  • How does median length of hospital stay and overall 30-day mortality compare among the other procedures compared with CRS/HIPEC?

Study Synopsis and Perspective:

Each year, doctors will diagnose approximately 60,000 new cases of peritoneal metastasis in the U.S., most commonly stemming from mesothelioma and cancers of the colon, ovaries, and appendix. Yet in 2015, less than 1,000 patients received a CRS/HIPEC procedure. In the current new study, researchers cited safety concerns, partly owing to a lack of available modern data, as playing a part in the lack of referrals for this procedure, among other factors.

The researchers compared CRS/HIPEC with other high-risk procedures in cancer in a retrospective database study to obtain up-to-date data on the safety of CRS/HIPEC for patients with peritoneal metastasis. They found that CRS/HIPEC was associated with lower 30-day mortality rates, and either similar or lower infection rates, versus other high-risk procedures, according to Jason M. Foster, MD, of the University of Nebraska Medical Center in Omaha, and colleagues in JAMA Network Open.

Foster and colleagues reviewed records of 34,114 patients from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database who underwent CRS/HIPEC (n=1,822), TSH (n=2,449), RLH (n=5,109), esophagectomy (n=7,941), or Whipple (n=16,793) from 2005 to 2015.

They found that the 30-day mortality rate was 1.1% for patients undergoing CRS/HIPEC, compared with rates ranging from 2.5% to 3.9% for Whipple, esophagectomy, and RLH or TSH.

“Cytoreductive surgery/HIPEC is not only safe when compared with procedures of similar risk, but is often associated with less morbidity,” the authors wrote. “Cytoreductive surgery/HIPEC had the lowest mortality risk, almost 50% to 75% lower than other advanced oncology surgical procedures.”

Compared with Whipple, lower infection rates with CRS/HIPEC were seen for both superficial (5.4% with HIPEC vs 9.7%, P<0.001) and deep incisional infections (1.7% with HIPEC vs 2.7%, P<0.01). Compared with esophagectomy, fewer HIPEC patients needed to return to surgery (6.8% with HIPEC vs 14.4%, P<0.001) and there were lower rates of superficial incisional infection (5.4% with HIPEC vs 7.2%, P<0.001).

Time in hospital was also shorter in the HIPEC group, at 8 days compared with 10 days each for both esophagectomy and Whipple (P<0.001).

For organ space infections, rates with CRS/HIPEC (7.2%) were significantly lower than those seen with Whipple (12.9%, P<0.001), and TSH (12.4%, P<0.001) or RLH (9.0%, P=0.02).

Patients undergoing CRS/HIPEC were younger (median age 57 vs median age 63 for other procedures).

“Cytoreductive surgery/HIPEC was performed with a high level of safety, providing evidence to dispel misperceptions rooted in the historic data,” Foster’s group wrote. “Safety concerns should no longer be a deterrent to routine referral to high-volume centers.”

Source Reference: JAMA Network Open, Jan. 11, 2019; 2(1):e186847

Study Highlights: Explanation of Findings

Study authors set out to update data from the 1980s and 1990s, which showed that CRS/HIPEC carried serious safety concerns. “The perception of high morbidity, high mortality, and poor surgical outcomes remains a barrier to CRS/HIPEC patient referral as well as clinical trial development in the United States, despite the published non-comparative data establishing comparative safety,” they wrote.

More recent data showed better safety, but those studies were criticized for being mostly single-center and/or non-comparative experiences. They stated that their study, with its comparative design which includes outcomes in “similar risk procedures” and encompasses 600 U.S. and 60 Canadian medical centers, addresses those concerns implicitly.

Their study indicated that the CRS/HIPEC procedure is safe, and may be safer than other surgeries performed for similar medical reasons.

However, the authors noted study limitations, including the younger age in the HIPEC group, the higher American Society of Anesthesiologists classification in the esophagectomy group, and higher comorbidity rates in the esophagectomy and Whipple groups. In addition, they observed that CRS/HIPEC is only performed at high-volume centers, while the other procedures examined in the study included those performed at both high- and low-volume centers.

In an invited commentary, Margaret E. Smith, MD, and Hari Nathan, MD, PhD, both of the University of Michigan in Ann Arbor, wrote that the study authors “should be commended for attempting to address a potential barrier to use of this locoregional therapy in appropriately selected patients,” and for examining outcome nationally, rather than in one center. But they had a number of serious reservations about the study design, namely, comparing HIPEC with other high-risk surgeries for cancer. This, they wrote, constructs a “straw man.”

“A patient with pancreatic cancer has no other curative option besides a Whipple procedure,” they explained. “A patient with peritoneal carcinomatosis, on the other hand, could be offered continued palliative systemic therapy or cytoreductive surgery without HIPEC.”

Information in the study regarding tumor characteristics and treatments, such as which chemotherapies had been used, was lacking, Smith and Nathan added. The absence of treatment details in the database “limits our understanding of which patients and what procedures were associated with these outcomes,” they noted. It is important to understand that the heterogeneous group of procedures and conditions compared to CRS/HIPEC make comparison difficult, and that “oncologists must weigh the short-term outcomes of any procedure against its benefits and its alternatives,” they wrote.

Moreover, they asserted that a more “salient concern” with CRS/HIPEC in patients with peritoneal carcinomatosis may be its 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,” wrote Smith and Nathan. They pointed to recent results from PRODIGE 7, a phase III randomized trial in 265 patients with peritoneal carcinomatosis associated with colorectal cancer that showed adding HIPEC after CRS added morbidity but did not increase overall survival (OS) over CRS alone.

PRODIGE 7 showed a median OS of 41.7 months for CRS/HIPEC patients, and 41.2 months for those treated with surgery alone, with 1-year survival rates of 86.9% and 88.3%, respectively. The rate of 30-day mortality was roughly 1.5% in each arm of the trial. However, a different phase III randomized study testing CRS versus CRS/HIPEC in epithelial ovarian cancer showed that adding HIPEC to CRS increased OS.

Smith and Nathan also pointed out that not all cytoreductive surgeries are created equally, as some may call for removal of a single peritoneal nodule while more complex operations might require multivisceral resection with peritoneal stripping, but this level of information is not captured by the NSQIP database.

They concluded by noting that “legitimate concerns regarding the efficacy of CRS/HIPEC exist, and appropriate patient selection for this aggressive treatment remains a challenge.” While Foster and colleagues demonstrated “acceptable morbidity and mortality rates for CRS/HIPEC in this highly selected patient cohort … until the benefit for individual patients is more thoroughly understood, clinician referral and treatment practices will remain difficult to transform.”

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