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There is an ongoing debate in the oncology community about a treatment technique that involves cutting all visible cancer out of the abdomen and then flooding the cavity with heated chemotherapy drugs. The procedure -- known as cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC), or a "hot chemotherapy bath" -- is used to treat peritoneal metastases resulting from several primary cancers, including colon cancer. Some oncologists and patients credit CRS followed by HIPEC with saving lives. Other oncology practitioners believe that more evidence -- in the form of a large, randomized, controlled study -- is needed before the double technique should be accepted as a standard of care for peritoneal carcinomatosis.
According to David P. Ryan, MD, clinical director of the Massachusetts General Hospital Cancer Center, such a study would end debate about whether the techniques increase survival or simply appear promising because doctors tend to use them on their youngest, strongest patients -- those with less advanced cancer who might fare just as well if treated with systemic chemotherapy.
"The [first] question is: Is there really long-term survival from this surgery? The second question is: Is it the cytoreductive surgery making a difference -- if there is one -- or [is it] a combination of cytoreductive surgery plus the HIPEC?" Ryan said.
Based on the results he's documented within his practice, Paul Sugarbaker, MD, a pioneer of the techniques and director of the Peritoneal Surface Malignancy Program at the Washington (DC) Cancer Institute at Washington Hospital Center, who's been performing the procedures since the early 1980s, feels confident he can answer those questions. While it is true that he prefers to use the techniques on patients with less advanced disease, because the measures do not lead to long-term survival if any cancer is left behind, CRS plus HIPEC are that population's best hope for a cure, according to Sugarbaker.
"If you can find for me, in the medical-surgical oncology literature, a patient who survived long-term with [only] systemic chemotherapy for peritoneal metastases, I'd like to know, but it's not out there," Sugarbaker said. "I can show you 30% of a whole group of colon cancer patients we've treated who are alive and well after 10 years."
How the Treatment Works
Even for believers, the procedures can be difficult. For doctors, performing the surgeries and unusual chemo delivery can mean remaining on their feet for up to 13 hours. And the aggressive operation can be a harsh experience for patients, who, according to Sugarbaker, spend 2 to 4 weeks recovering in the hospital and up to 6 months unable to work.
In Sugarbaker's operating room, the surgery begins with the removal of the zyphoid bone and "the biggest abdominal incision you can make without going into the chest." Sugarbaker then removes large portions of the lining of abdomen and pelvis, in addition to any affected organs, wherever there's a malignancy. The goal is to make the patient visibly disease-free in the abdomen and pelvis.
Next comes HIPEC, often referred to by doctors as a "shake and bake," and by the media as a "hot chemo bath." HIPEC involves the distribution of cytotoxic drugs, such as mitomycin C -- heated to a maximum of 107.6 F -- throughout the abdominal cavity, ideally killing any microscopic disease that remains. While Sugarbaker distributes the drugs internally with his hands, some doctors prefer to close the abdomen, pour the chemo in through tubes, and then manipulate the peritoneum from the outside to help distribute the cytotoxics (figure, top). Sugarbaker also includes some systemic chemotherapy during the procedure and for several days afterward.
The treatment regimen ends, Sugarbaker said, with any necessary reconstruction within the abdomen, such as small bowel anastomosis or visceral resections, along with sutures.
Retrospective data collected by Andrew Lowy, MD, who performs the procedures at the University of California, San Diego Medical Center, show a 1.5% mortality rate and a 1 in 3 complication rate for his CRS and HIPEC patients.
A Demand for Proof
Together, the 2 procedures are generally accepted as the standard of care in several rare cancers -- appendix cancers, pseudomyxoma peritonei and peritoneal mesothelioma, Sugarbaker and Lowy agree. Because those diseases affect small numbers of patients, the doctors said, it is unlikely there will ever be studies conducted to confirm that the methods work. But with colon cancer, which affects more patients and is the most common cause of peritoneal carcinomatosis, there is greater disagreement in the oncology community.
Five years ago, in a consensus statement, the Peritoneal Surface Malignancy Group, consisting of 72 surgical oncologists from 55 cancer centers in 18 countries, wrote that "systemic treatment alone is no longer appropriate for patients with limited peritoneal dissemination from primary or recurrent colon cancer. A clinical pathway for the management of these patients should include cytoreductive surgery and HIPEC as part of a multidisciplinary approach." Signers of the statement included the Walter Reed Army Medical Center in Washington, DC, the University of Medicine and Dentistry of New Jersey, and the National Cancer Institute in Bethesda, Maryland.
However, despite this statement and patient testimonials, there is still a demand for proof that the double procedure brings better results than the current standard of care, conventional chemotherapy.
To Sugarbaker, the call for evidence seems ironic for 2 reasons. First, he said, with the exception of 3 small evaluations conducted by surgeons, there are "no studies that establish efficacy for the treatment of peritoneal metastases from colorectal cancer with modern systemic chemo." Second, Sugarbaker is satisfied with the evidence provided by a randomized study of CRS followed by HIPEC (J Clin Oncol. 2003;21:3737-3743), whose results were reported in 2003.
Ryan says the study showed only minimal survival benefit, was not properly controlled because it included patients with >1 cancer type, and failed to specify which cytotoxic agents were used. Sugarbaker disagrees, saying the study of 105 patients with colon and appendix cancers, run by Vic J. Verwaal, MD, of the Netherlands Cancer Institute, "randomized a little over 100 patients, and was very successful. It showed that patients lived twice as long if they got these procedures as compared to the standard of care: systemic chemo."
While no other randomized studies of the 2 techniques have been completed, Sugarbaker says there is abundant evidence that the procedures are effective.
Some of that support was generated in 2009 by Dominique Elias, MD, PhD, of the Institut Gustave Roussy in France, and his fellow researchers. Their study (J Clin Oncol. 2009;27:681-685) compared the outcomes of patients with colorectal adenocarcinoma, some treated with systemic chemotherapy and others with CRS followed by HIPEC. The conclusion: "Patients with isolated, resectable peritoneal carcinoma achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%."
A Final Answer?
In an attempt to find out once and for all if the procedures can prolong survival, doctors in France are enrolling patients in a randomized, controlled study, Sugarbaker said. All participants will undergo cytoreduction, but only some will have HIPEC, the doctor said.
Meanwhile, a 340-patient, phase III randomized, controlled, multicenter clinical trial (goo.gl/VfxoA) has been enrolling patients in the United States. The trial will analyze the results of systemic chemotherapy versus CRS with HIPEC followed by systemic therapy, in patients with limited periteoneal carcinomatosis that stems from colorectal cancer.
So far, accrual of patients has been slow. Lowy said enrollment may improve now that the trial is open to patients who have previously undergone a chemotherapy regimen for their disease. Also, patients who fail the systemic chemotherapy regimen will be allowed to switch to the surgical group.
But Sugarbaker said many will still avoid the trial for fear they won't be initially chosen to receive CRS with HIPEC."If I were a patient, I would not enter that study," he said.
A Lack of Standardization
Due in part to the paucity of clinical data, there is a lack of standardization in the availability, insurance coverage, and costs associated with CRS followed by HIPEC.
In all, about 120 treatment centers in the United States, 30 each in France and Germany, 5 in Holland, and many in Australia and Japan, offer the procedures, Sugarbaker said. That means that the majority, however, do not.
Additionally, many insurance companies refuse to cover the double procedure. A clinical policy bulletin on hyperthermia in cancer therapy from health insurer Aetna, last reviewed in June, says the company considers CRS combined with HIPEC medically necessary for the treatment of pseudomyxoma peritonei and peritoneal mesothelioma, but experimental when used to treat other causes of peritoneal carcinomatosis, including colon or ovarian cancers. Similarly, a September policy statement by Cigna said that the company covers HIPEC in combination with CRS only for pseudomyxoma peritonei.
With the lack of availability and insurance coverage, the costs associated with the procedure are highly inconsistent, according to Laurie Todd, a patient advocate who successfully underwent the procedures while battling Stage IV appendiceal cancer. Todd knows of 1 doctor who charges $383 for a consultation about whether CRS and HIPEC will make sense for a patient. Another doctor charges $25,000 for the same service. Where 1 doctor charges $2000 for HIPEC, another charges $20,000. Her own surgery, HIPEC, and hospital stay carried a price tag of $345,000.
Sugarbaker hopes these issues are resolved soon and that CRS followed by HIPEC becomes a standard treatment that is routinely considered by teams of doctors treating patients with peritoneal metastases.
"This has huge implications for patient management," he said. "It works best when integrated into the medical-surgical oncologic network. These procedures have to be part of the treatment package for people with these diseases to survive."
Sugarbaker expects discussion of the issue to evolve further next fall during the 8th International World Congress on Peritoneal Surface Malignancies, when the agenda will focus on CRS followed by HIPEC.