Laurie Barclay, MD

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS/HIPEC) appears to be safe and effective for select patients with advanced abdominal cancers, according to a retrospective analysis published in the June issue of Cancer Medicine.

“There has been much discussion as to whether there is a benefit with this procedure, and historically it has been associated with a lot of risk,” senior author Joseph J. Skitzki, MD, a surgical oncologist at Roswell Park Cancer Institute in Buffalo, New York, said in a news release. “However, reviewing our data in patients treated with CS/HIPEC over the last decade showed a statistically significant benefit in terms of survival, with low morbidity and low mortality.”

It is thought that candidates for CS/HIPEC are patients with appendiceal, colorectal, or mesothelioma tumors that are refractory to standard chemotherapy and/or previous surgery. With this approach, all visible metastases to the peritoneum are removed surgically and then high doses of heated chemotherapeutic agents are perfused throughout the abdomen to eradicate any remaining cancer cells. To limit systemic toxicity, the chemotherapy is administered only to the targeted area and is washed out after 90 minutes. The entire procedure takes 8 to 18 hours.

“HIPEC is an extremely invasive procedure that an increasing number of cancer centers across the United States offer,” Dr. Skitzki said. “Our research shows that when it’s used for appropriate candidates as part of a multidisciplinary treatment approach in an experienced setting, outcomes will be favorable, compared with standard combination therapy, with the added benefit of shorter-term side effects.”

Because most reports of CS/HIPEC use in the United States come from a very few high-volume centers, “the applicability of CS/HIPEC among a broader spectrum of providers has been questioned,” said Jan Franko, MD, PhD, from Mercy Medical Center in Des Moines, Iowa. He was asked by Medscape Medical News to comment on the analysis.

The study “provides increasing support of the technical safety of CS/HIPEC in proper settings,” Dr. Franko noted in an email. “The data demonstrate that CS/HIPEC can be safely implemented outside of traditional high-volume centers.”

History of Peritoneal Carcinomatosis Treatment

The average life expectancy for a patient with peritoneal carcinomatosis (PC) from nongynecologic adenocarcinomas has historically been 6 months. Surgical cytoreduction to remove all visible tumor was first reported in the 1930s for ovarian cancer, and was eventually accepted for nongynecologic PC, with proven survival benefit. CS/HIPEC was introduced several decades later, with accumulating evidence supporting clinical efficacy, Dr. Skitzki and colleagues explain.

They note that in 11 phase 2 studies of colorectal PC treated with CS/HIPEC, the 5-year overall survival rate ranged from 25% to 47% (J Clin Oncol. 2003;21:3737-3743). They also cite a phase 3 randomized controlled trial in this population that showed that overall survival was significantly better with CS/HIPEC than with standard therapy alone (21.6 vs 12.6 months), as was the 6-year survival rate (20% vs 5%). For patients in that study who achieved complete cytoreduction, 5-year survival was 45%; for those with incomplete cytoreduction, median survival was less than 1 year (Cancer J. 2009;15:212-215).

Caveats include potential selection bias and high morbidity. In many studies, perioperative complication rates range from 27% to 56% and mortality rates range from 8% to 11%.

Study Design and Findings

Dr. Skitzki and colleagues retrospectively reviewed 112 patients undergoing CS/HIPEC from 2003 to 2011. The mean age was 53 years, and half of the patients had received systemic chemotherapy.

 Morbidity associated with CS/HIPEC was similar to that associated with other major surgical oncology procedures. None of the patients died during surgery or within 30 days; the 60-day mortality rate was 2.7%, the researchers report.

That 60-day mortality rate “is extremely low,” Dr. Franko noted. “It is similar to other high-volume centers and directly comparable to the 60-day mortality of current cytotoxic chemotherapy for metastatic colorectal cancer.” This study validated the association between CS-HIPEC and low mortality and acceptable morbidity in proper settings, and “is best viewed as an important confirmatory and validating report,” he explained.

 Dr. Skitzki and colleagues note that an increasing number of bowel resections is associated with an increased incidence of abscess, enterocutaneous fistula, deep surgical-site infection, and the need for repeat surgery. Reoperation is linked to lower overall and progression-free survival.

“Akin to other reports of worsened overall and disease-free survival among those with surgical complications, this study demonstrated inferior overall survival and progression-free survival among those suffering from complications,” Dr. Franko said.

 Site of tumor origin and histology predicted 5-year overall survival rates, which were 91.3% for disseminated peritoneal adenomucinosis, 80.8% for mesothelioma, 38.7% for appendiceal adenocarcinoma, and 38.2% for colorectal adenocarcinoma.

In other words, more than 1 of 3 patients with stage IV colon cancer treated with CS/HIPEC survived for at least 5 years, and some never had a recurrence. In contrast, historic survival rates for peritoneal colorectal carcinoma have typically been measured in months, with 5-year overall survival rates approaching zero, Dr. Skitzki and colleagues point out.

 “With an acceptable morbidity and mortality rate, CS/HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases,” they write.


Study Limitations and Implications

Study limitations include the retrospective design of the analysis (leading to possible selection bias), the lack of inclusion of patients receiving only systemic chemotherapy, the relatively small sample size, the limited generalizability of the results, and the inclusion of a variety of tumor types.

 “It is difficult to analyze the survival data provided by the authors, because a great variety of histology was included. Clearly, survival analysis was not the primary objective,” Dr. Franko said.

In addition, the Peritoneal Cancer Index (PCI), a marker of the extent and location of disease in the abdominal cavity, was not scored intraoperatively. In many patients, pretreatment with systemic chemotherapy prevents the calculation of the true PCI score, he pointed out.

 Dr. Franko suggested that future research should focus on specific histologies and analyze subgroups of colorectal carcinomatosis and peritoneal mesothelioma separately, and should identify the best sequencing and combination of intraperitoneal and systemic chemotherapy.

The National Cancer Institute funded this study in part. The study authors and Dr. Franko have disclosed no relevant financial relationships. Cancer Med. 2013;2: 334-342.

Benefit From CS/HIPEC in Advanced Abdominal Cancers – Medscape – Jun 14, 2013.