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Evolution of surgery with hyperthermic intraperitoneal chemotherapy extends peritoneal cancer survival
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Pseudomyxoma peritonei — which usually develops in the appendix — and peritoneal mesothelioma, which starts in the lining of the abdomen known as the peritoneum, are rare indolent cancers that, unless treated aggressively, always have a terminal outcome.
In the past decade, the treatment of peritoneal metastases has gained interest from oncologic communities around the world because of cytoreductive surgeries and hyperthermic intraperitoneal chemotherapy (HIPEC), procedures popularized in the 1980s by Paul Sugarbaker, MD, medical director for the Center for Gastrointestinal Malignancies at MedStar Washington Hospital Center.
The surgery, which can take as long as 10 hours, involves removal of the lining of the abdomen and pelvis (peritonectomy), examination of all organs for traces of cancer, and meticulous surgical removal of all visible tumor cells. A heated chemotherapy solution is pumped into the abdomen and used to bathe the organs for up to 90 minutes before it is drained and the surgical incisions are closed.
Prior to HIPEC, patients with peritoneal metastases were treated with palliative support. Today, survival rates have increased to 5 years or longer in some patients.
HemOnc Today spoke with Sugarbaker about his approach, which is now performed more than 10,000 times a year in more than 100 medical centers across the United States and has become standard of care in Europe.
Question: How did you first get into medicine?
Answer: My father, Everett Dornbush Sugarbaker, MD, FACS, was a surgical oncologist in Missouri and one of the founding members of the James Ewing Society, and my mother, Geneva van Dyke Sugarbaker, was a nurse. I’m one of 10 children — five doctors, one nurse, one minister and three teachers. We grew up in Jefferson City and my older brother, Everett, and I harvested 5,000 bushels of apples a year for 7 or 8 years before I went to Wheaton College in Chicago and then Cornell Medical School in New York. I had a strong background in medicine; I would assist my father in the operating room in the summers when I was off from medical school. After a prolonged stay at Peter Bent Brigham Hospital in Boston, I worked as a senior investigator at the NIH for another decade. I was intrigued by liver metastases; a majority of oncologists thought liver resection for cancer was an exercise in futility. We felt liver metastases was a valid target for surgical resection. We had a lot of negative reaction from the NCI review boards, but we developed a successful program with excellent outcomes and even long-term survivors. This success morphed from liver metastases to peritoneal metastases.
Q: When were you first introduced to HIPEC and why did the procedure make sense to you?
A: It was in the late 1970s when I was at the National Institute of Health; I was there from 1976 to 1986. There was a branch chief named Robert L. Dedrick, PhD, in the biomedical branch who did some experiments. He had a PhD candidate by the name of Michael F. Flesner, MD, and they showed that you could deliver high dose of chemotherapy to the peritoneal space and spare the body some of that toxicity.
There were a number of protocols at the NIH that investigated the use of intraperitoneal chemotherapy in ovarian cancer, and I took over the investigation of the role of intraperitoneal chemotherapy in colorectal cancer. I did a randomized controlled study that was published in 1983 in Surgery that compared, in a poor-prognosis group of patients, intraperitoneal to intravenous chemotherapy, and although the survival of the two groups was the same, we felt we really could have an impact on the incidence of peritoneal recurrence in that group of patients. I think that was the first real positive study in colorectal cancer, and then there was this kind of accident. We recruited a large number of patients with pseudomyxoma peritonei. No one had any treatment for those patients anywhere, so whenever my colleague, Ernie de Moss, MD, would hear about one, he’d give me a call. We treated quite a number of these patients, and that was our first report on the treatment of the mucinous appendiceal cancers. That was reported at the American Society of Colon and Rectal Surgery meeting in 1987, and in an article in Diseases of the Colon and Rectum. That’s where it started, with these two manuscripts.
Q: Has the HIPEC procedure changed much since then?
A: The concept has not, but the surgical procedure has evolved tremendously and now involves peritonectomy procedures. When I was in surgical training, we were taught you should never violate the peritoneum, that if you took large amounts of peritoneum, the bowel would become snarled and hopelessly scarred and the patient would not recover. That is untrue. We now often remove the entire peritoneal lining and patients get along just fine. That mistaken surgical concept needed to be overcome. Gradually, over time, we realized that parietal peritoneum was not essential, that it regenerated itself. You could remove huge amounts of it with the peritoneal metastases and the patient would not suffer. There is a prolonged postoperative recovery period, of course, but in the long run, they all do just fine.
Q: Why is it that peritoneal cancers often go undiagnosed?
A: Peritoneal mesothelioma is a strange disease because it does not have any primary site. The primary site is a field defect of the peritoneal surface. Patients will gradually develop ascites or a general expansion of the abdomen, but unless they have a CT scan or a laparoscopy, the diagnosis is not made. It is often an indolent and progressive disease, and patients come in with advanced disease.
The same is true of pseudomyxoma peritonei. People gradually have an expanding abdomen, but other than that they have no symptoms. In other words, there is no stomach cancer to cause bleeding, obstruction or perforation of the stomach. There’s no colon cancer to cause bleeding, obstruction or perforation of the colon. The disease just grows along.
Peritoneal mesothelioma now has a median survival of almost 6 years, which is very long. Without the cytoreductive surgery and HIPEC, the median survival is about 1 year, and systemic chemotherapy does not help. It will cause the disease to regress, but it doesn’t prolong the survival.
Q: What is the most challenging part of the procedure?
A: I operate in the peritoneal space in a clockwise direction, going from the right side over to the left side, on around to the pelvis and do all of the peritonectomies first. The visceral resections follow. I think the most challenging aspect of it is to do it all perfectly. Even though it is 10 hours of work, it is about maintaining a high level of skill and not trying to do anything too fast. Everything is hard before it gets easy. After you have done a lot of these procedures, there is nothing especially hard about them, it is just that they are long.
Q: How long has the Sugarbaker technique been a standard of care in Europe, and how is it viewed in the United States?
A: It’s been a standard of care in Europe for colorectal cancer and peritoneal metastases for about 3 years now. It still is not a standard of care in the United States, and I think the major reason for that is a lack of randomized controlled studies. It is hard to do randomized controlled studies in surgery. There is a much closer collaboration of the medical and the surgical oncologist in Europe and they have done a large number of randomized controlled studies showing the superiority of cytoreductive surgery with HIPEC over systemic chemotherapy alone. They keep asking for more trials in the United States. In France, two of the most prominent surgeons, Dominique Elias, MD, PhD, chief of surgery at the Gustave Roussy in Paris, and Francois Gilly, MD, PhD, chief of surgery at University of Lyon, got together and said this really seems to be working well. They put out a monograph through the association of French surgeons and it became the standard of care throughout France.
Q: What are the next steps to making your procedure more available and perhaps more affordable?
A: Compared with the cost of oxaliplatin, bevacizumab (Avastin, Genentech), irinotecan and cetuximab (Erbitux, Lilly) — modern drugs which aren’t really so modern at all anymore — cytoreductive surgery and some more routine chemotherapy agents for HIPEC is really very inexpensive for a full cytoreduction and a 2-week hospital stay compared with systemic treatments.
Q: What are some of the side effects of the surgery and ways to counteract them?
A: The side effects of the surgery are straightforward. You can get a heart attack, stroke or pulmonary embolism or suffer a major complication like aspiration. The patient may have to go back in the operating room for infection or bleeding. But there is a 10% or less serious complication rate from the surgery. There also are some adverse events from the chemotherapy administered with the surgery. You can give too much, and patients will get neutropenia. The major side effect is just a slow return of bowel function. You’ve operated on the bowel and caused ileus as a result of that trauma to the bowel, and then you’ve soaked it in chemotherapy. It is going to have 5 or 7 days, maybe more, of ileus, and so patients are going to need to be treated with parenteral feeding for one or two weeks, sometimes longer, up to 3 or 4 weeks. It’s hard to say. Young people get out of the hospital fast, and older people get out more slowly.
Q: Are there any key messages you think oncologists should know about peritoneal metastases?
A: Number one is that peritoneal metastases can be cured and, in certain instances, we are convinced they can be prevented. There are patients with appendiceal malignancy, peritoneal mesothelioma, colon cancer, gastric cancer, and now we’re working with pancreas cancer, and there needs to be discussion for treatment or prevention at multidisciplinary team meeting. You don’t just have to accept peritoneal metastases as a part of the disease. They can either be prevented or they can be treated if indeed they are diagnosed. For the most part, people just undergo systemic chemotherapy, which is a palliative treatment. Assuming there is a surgical team with the sufficient skill to take the patient to the operating room safely, can do the cytoreductive surgery and administer the chemotherapy and get the patient out of the hospital in a reasonable period of time without a big complication, there may be a curative approach.
Q: What is the best form of prevention?
A: Prevention is using the HIPEC in primary gastric cancers that have invaded through the wall of the stomach. Those gastric cancers are going to have a very high risk for local recurrence and peritoneal metastases when they recur. So, you can significantly prevent peritoneal metastases and improve survival in gastric cancers by chemotherapy washing. Also, with a simple washing of the abdominal space with gemcitabine, we are convinced we can, if not completely eliminate local regional progression of pancreas cancer, greatly reduce it. In the absence of HIPEC, more than half the patients, when they recur, will have peritoneal metastases right where the surgeon was working. In other words, the surgery spread the disease around. The cancer cells that cause peritoneal metastases do not get there by chance. They get there because there is spillage, a transmission of the disease from the primary site to the peritoneal surfaces. In pancreas cancer and gastric cancer, it happens, for the most part, with the surgery. It’s not surprising. You are removing the pancreas with a one or two millimeter margin, and those tissues at the margin of resection are traumatized and leak a few cancer cells, maybe just a few hundred, into the peritoneal space. Then, 1 year later you’ve got a recurrence right in the bed of the pancreas. We think that happens frequently with gastric cancer, pancreas cancer and rectal cancer. – by Chuck Gormley
References:
Sugarbaker PH and Lampert MH. Surgery. 1983;93:462-466.
Sugarbaker PH, et al. Dis Colon Rectum. 1993;36:323-329.
For more information:
Paul Sugarbaker , MD, can be reached at paul.sugarbaker@medstar.net.
Disclosure: Sugarbaker reports no relevant financial disclosures.