A review of 60 consecutive patients with peritoneal carcinomatosis who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC)—sometimes called “hot chemotherapy”—found 0% mortality and 33% morbidity, with “a significant reduction of grade III/IV morbidity, perioperative transfusion, and reintervention rate after 20 procedures.” Reporting their results in the Archives of Surgery,¹ physicians at the Institut Paoli-Calmettes and Université de la Méditerranée in Marseille, France, noted that the “introduction of the HIPEC program was successful because of the surgical team’s prior experience in cytoreductive and cancer operations.”

Learning Curve

In an accompanying editorial, Nita Ahuja, MD, agreed: “The message that we can heed here is that experience matters.” In a follow-up interview with The ASCO Post, Dr. Ahuja said that there are cytoreduction-with-HIPEC programs with experienced physicians at several centers in the United States (see sidebar). These centers include Johns Hopkins Medicine, where Dr. Ahuja is Director of the Peritoneal Surface Malignancies Program, Chief of the Section of Gastrointestinal Oncology, Breast, Melanoma, Sarcoma, and Endocrine Cancers, and Associate Professor of Surgery and Oncology. The Johns Hopkins Medicine program started in 2008 and has treated approximately 60 patients.

The number of centers introducing such programs is “exploding,” Dr. Ahuja added. The complexity of the procedure means that these newer centers will have a learning curve as they gain experience. As Dr. Ahuja stated in her editorial, “This study again shows that complex surgery is best performed at high-volume, experienced centers, similar to what has been shown for pancreas or esophageal resections. Programs initiating HIPEC would do well to heed this advice.”

Perioperative Factors Compared

Among the 60 patients treated in the French study, peritoneal carcinomatosis “originated from colorectal cancer in 26 patients (43%), ovarian cancer in 12 (20%), appendix cancer in 10 (17%), pseudomyxoma/mesothelioma in 10 (17%), pancreatic cancer in 1 (2%), and small-bowel cancer in 1 (2%).” The mean peritoneal cancer index (PCI) was 9.6. (Dr. Ahuja explained that the PCI is a scale to measure the extent of disease within the peritoneum, based on the distribution of tumor throughout 13 abdominopelvic regions and lesion size. The highest score possible is 39; a lower score means less disease.) Systemic chemotherapy was received by 53 patients (88%) before cytoreduction and HIPEC and by 37 patients (62%) afterwards.

Perioperative factors were studied and compared for the first, second, and third groups of 20 successive patients. “Perioperative red cell transfusion (P < .01), grade III/IV morbidity (P = .02), and reintervention rate (P =. 04) significantly decreased during the three periods. No difference was observed between the three periods with regard to mean PCI, operative duration, blood loss, mortality, overall morbidity, length of hospital stay, and readmission,” the authors stated.

The authors noted that even before the HIPEC program was started at their institution in 2004, surgeons had been using aggressive cytoreduction and perioperative systemic chemotherapy to treat patients with peritoneal carcinomatosis. “Because of our experience with cytoreduction, the only learning curve that we experienced was with the introduction of HIPEC itself,” they wrote.

Safety Considerations

“The heat may have potentially more side effects,” Dr. Ahuja said, but for surgeons who do not have the extensive experience of those conducting the French study, the cytoreduction may be more technically challenging. The concept of “hot chemotherapy” creates interest among patients because it is something different, she noted, but “it is not going to accomplish any wonders if you didn’t achieve a complete cytoreduction for diseases such as colorectal cancer. So if you are leaving visible disease behind and just delivering chemotherapy for 30 or 90 minutes, it will not have much efficacy.”

Dr. Ahuja pointed out that while the French series used oxaliplatin, most U.S. centers performing cytoreduction with HIPEC use mitomycin because the “toxicity profile seems a little bit safer.” Safety is also the reason for using a closed circuit technique for the heated chemotherapy vs the open technique used in the French series. “Open means you leave the abdomen open when you circulate the chemotherapy, whereas closed means you close the abdomen temporarily. The Europeans are doing it open. Most of the Americans are doing it closed. There is no difference in survival,” Dr. Ahuja explained. At Johns Hopkins, “we tend to do it closed,” she said, “because it is presumed safer for our staff.”

“The data are unclear” about incremental benefit of HIPEC, Dr. Ahuja said. “A lot of preclinical basic science data suggest that if you heat chemo, it penetrates better. You get better delivery of the drug.” She said that there are also good lab data with mice. “Then you go to the clinical scenario and it is harder to tease out the benefit. Is it just good surgery, that a good surgeon takes out all visible disease? Or is the chemo adding much more benefit? Because the chemo does add toxicity. The hematologic toxicity they see on the study is related to the chemo, especially oxaliplatin, and the higher risk of fistula is likely related to the chemotherapy. So it clearly has a risk profile associated with it, oxaliplatin more than mitomycin.”

Continuum of Expanding Options

Cytoreduction with HIPEC “was first espoused by Paul Sugarbaker, MD, for pseudomyxoma peritonei,” Dr. Ahuja said. (For more information on Dr. Sugarbaker and his experience with this procedure, see the October 2011 issue of The ASCO Post.²) For pseudomyxoma peritonei, “you can take patients with a very high PCI and it is completely appropriate to be super-aggressive with this therapy because there is nothing else to offer. No one is debating that. Where we debate is for colorectal cancer,” Dr. Ahuja said.

Cytoreduction with HIPEC can be viewed as part of the continuum of expanding options for patients with advanced colorectal cancer. “As colon cancer treatments have become better—median survival for someone who has no surgical options is now over 27 months with chemotherapy—we have started operating on cases of metastatic disease that would not have been considered for surgery in the past,” Dr. Ahuja explained. Five-year survival rates are now about 40% for patients who undergo resection of a solitary liver metastasis and 35% for resection of a solitary lung metastasis, Dr. Ahuja reported.

“If you think of the peritoneum as an organ and you consider that cancer has only spread to that area and hasn’t spread anywhere else, you could apply the same idea of aggressive surgery with cytoreduction and HIPEC,” Dr. Ahuja said. “And you see somewhat similar results—35% to 40% 5-year survival in very carefully selected patients.”

In the French study, all patients were under 70 years old, had no symptomatic disease, and had good clinical status. Dr. Ahuja generally agrees with those criteria, while noting that the Johns Hopkins program may soon allow patients as old as 75 years.

A subject of debate, according to Dr. Ahuja, is whether to include patients with synchronous metastases of the liver. Some think cytoreduction plus HIPEC should be limited to peritoneal disease, which spreads locally through a perforated or ruptured tumor, rather than liver metastases, which would have come through the blood or lymph nodes.

“I don’t think there is a good answer to that,” Dr. Ahuja said. “When I started, I said absolutely no liver metastases, but now we are doing it on a case-by-case basis. It should not be an absolute contraindication; it’s a relative contraindication. Extra-abdominal metastases should be an absolute contraindication.”

Not a Last-ditch Effort

The option of using cytoreduction with HIPEC “should be brought up early in the treatment course rather than as a last-ditch effort. You are not going to see any benefit if the disease is everywhere,” Dr. Ahuja stated. For patients with colorectal cancer, “we say you should never operate on someone whose PCI is greater than 20,” she added. Patients may have received previous chemotherapy, and Dr. Ahuja said, “I tend to give patients three cycles upfront, generally with FOLFOX [leucovorin, fluorouracil (5-FU), oxaliplatin] or FOLFIRI [leucovorin, 5-FU, irinotecan].

Follow-up chemotherapy is generally determined by Dr. Ahuja and her group on a case-by-case basis, “if I am able to complete the cytoreduction and give the HIPEC and have cleared all visible disease,” she said. “This is where the multidisciplinary part comes in, in that we all discuss it at our colorectal conference,” she added. Most patients in whom complete cytoreduction is possible are managed with expectant observation and chemotherapy in the case of a recurrence.

Cytoreduction’s reputation as the “Mother of All Surgeries” is “a little outdated,” Dr. Ahuja said, coming from the era when cytoreduction was a last resort. Now that patients are coming to cytoreduction earlier and with lower PCI scores, recovery is similar to that for other colorectal surgery.

“I tell them they’ll need a 2-week in-hospital stay, and younger people go home in 7 days,” Dr. Ahuja said. “We’ve prepared them psychologically. There is a little bit longer recovery for most people—6 to 8 weeks—but they are at home. They are living their life, and they are recovering.”

Ideal Treatment?

The French study report begins by asserting, “peritoneal carcinomatosis originating from digestive or ovarian malignant tumors is ideally treated by cytoreduction and HIPEC.” According to Dr. Ahuja, that would be true only in cases of pseudomyxoma peritonei but should “absolutely not” be the only therapy offered to patients with peritoneal carcinomatosis originating from colorectal cancer. “You cannot deny people systemic therapy, when we have 15 years of data saying that systemic chemotherapy works.”

Morbidity and the occasional need for reintervention may also make cytoreduction plus HIPEC less than ideal. The morbidity rates in the French study and at Johns Hopkins, as reported by Dr. Ahuja, are about 30%. Morbidity could range up to 40% internationally, Dr. Ahuja noted, but it is hard to compare the data internationally because of the different drugs used (oxaliplatin vs mitomycin) and different patient selection criteria.

“There are real morbidities that require reintervention, like fistulas,” Dr.Ahuja said. Some patients could also require a second surgery due to a massive bleed or a perforation, which could affect long-term recovery and possibly survival. ■

Disclosure: Dr. Ahuja reported no potential conflicts of interest.

References

1. Turrini O, Lambaudie E, Faucher M, et al: Initial experience with hyperthermic intraperitoneal chemotherapy. Arch Surg. June 18, 2012 (early release online).

2. Bath C: ‘Hot chemotherapy’ generates heated debate about its use with cytoreductive surgery to manage peritoneal metastases. The ASCO Post. October 15, 2011.