Audrey's Hepburn sad story of Pseudomyxoma Peritonei

The Fairest of All

Audrey Hepburn died of appendix cancer at 63, leaving behind a legacy of style and good works

By Jocelyn Selim

"..... It wasn’t easy work, and on the way back from a sobering trip to Somalia at the end of September 1992, Hepburn began to have crippling abdominal pain. She’d been suffering from gas since the cesarean birth of her second son, Luca, in 1970, but this time she believed something was really wrong.
After a round of routine tests at Cedars Sinai Hospital in Los Angeles revealed no cause for her pain, Hepburn’s physicians recommended laparoscopy—a procedure in which doctors insert a camera through a tiny incision in the abdomen. The exam found a tissue-paper-thin tumor encasing the last segment of her small intestine and the beginning of her large intestine; the medical team determined that the cancer had metastasized from her appendix.

A Diagnosis of Appendix Cancer
The appendix is a tiny, elongated sac about the width of a pencil that sits at the junction of the small and large intestines in the lower right abdomen. It has no confirmed function. Recent studies have suggested that it aids digestion, but biologists often accept it as the remnant of a much larger sac that allowed pre-human ancestors to digest the cell walls of plants.

Cancer of the appendix is extremely rare. “It’s sort of the poor orphan cousin of colon cancer,” says Edward Levine, a surgical oncologist at Wake Forest University School of Medicine in Winston-Salem, N.C. While colorectal cancer is diagnosed in roughly 150,000 people a year, cancers that start in the appendix are much less frequently diagnosed, with estimates ranging from a few hundred to 2,500 cases each year. Of those cases, one half or so are mostly harmless carcinoid tumors—cancers of the neuroendocrine, or hormone-producing, cells—that are found by chance when pathologists look at appendixes removed during routine appendectomies or other surgeries.

More serious are the minority of appendix cancers—roughly 30 percent, according to the American Society of Clinical Oncology—that are classified as adenocarcinomas. These start in cells that typically line the inside of organs, where they produce mucus and other fluids. Although scarce among appendix cancers, adenocarcinomas make up the vast majority, or about 95 percent, of colorectal cancers. Surprisingly, while they arise from the same type of cell as colon adenocarcinomas, appendix adenocarcinomas often behave dramatically differently from colon adenocarcinomas, for reasons oncologists still don’t understand.

Hepburn’s cancer was an adenocarcinoma. The tumor was strangling her intestines, creating an obstruction that was causing the intense pain she felt. There is no official staging system to describe the spread of most appendix cancers, but because the tumor had invaded Hepburn’s abdomen and peritoneum—the thin covering that lines the organs and separates the abdominal cavity from the rest of the body—her cancer would have been considered very advanced by any standard.

Adenocarcinomas that start in the appendix are much more likely than typical colon cancers to have what doctors call a “mucinous histology”—meaning that when the cells lining the intestine turn cancerous, they make excess amounts of the jellylike secretions they normally produce, says Jesus Esquivel, a surgical oncologist at St. Agnes Hospital in Baltimore. “A doctor will maybe see one of these cases over the entire course of his career,” he says. “I hear about cases where doctors open up a patient, take one look and think, ‘I really don’t know what this is,’ and then close the patient back up.”

Hepburn called the disease “abominable”—rather than “abdominal”—cancer, recalls Ferrer. On Nov. 1, 1992, just days after entering the hospital, his mother underwent surgery. The doctors removed about a foot of her intestine. A week later, she was started on intravenous fluorouracil (5-FU) and leucovorin, a drug combination that is still widely used to treat colon cancer today.

“The impact of the rarity of these cancers can’t be underestimated,” says Paul F. Mansfield, a surgical oncologist at M. D. Anderson Cancer Center in Houston. “Because there are so few cases, it’s much more difficult to extrapolate meaningful statistics about survival. And [looking back] over a long period of time, it becomes even more difficult, because in the past many of these have been lumped into the studies with colorectal cancers. So not only are there not neat official data on survival and treatment by stage—the way there are for more common cancers—there aren’t really any clinical studies, and there is very little funding for research.”

Appendix cancer’s rarity means that those who are diagnosed with it are often left with little of the support that other cancer patients rely on. Carolyn Langlie-Lesnik, a nurse who started an advocacy group and website for appendix cancer, tells how frightening her own diagnosis was eight years ago. “They basically said, ‘We don’t really know what this is or where to refer you, but the prognosis is really bad,’ and sent me home to die,” she says. After finding one of the dozen or so doctors experienced in these cancers, Langlie-Lesnik is alive today and helping others in similar situations find information, support and appropriate medical care. “Cancer is frightening enough without it being a kind of cancer no one seems to know anything about,” she says.

By all accounts, websites like Langlie-Lesnik’s have been a major development in getting appendix cancer patients the help they need. But when Hepburn was diagnosed 17 years ago, the internet was a slow prototype version of today’s information superhighway. “I would spend all night making calls to doctors and reading texts, anything I could find trying to learn about this, and then wake up and look bright for visiting hours,” says Ferrer. “It was desperate. I looked at everything from shark cartilage, to alternative therapies in Mexico, to drastic surgeries suggested by a doctor in Sweden.”

To further complicate matters, appendix adenocarcinomas can vary greatly from patient to patient. “They present with different degrees of aggressiveness and in a variety of different forms,” says Levine. “Some patients will have tumors with a few cells and a lot of mucin production, so the abdomen is full of this Jell-O-like material, while others will have more solid-appearing tumors that behave more like typical colon cancers. Some you can scrape off like rubber cement; others you have to [remove] the colon to get out.”

And the tumor’s aggressiveness can affect survival. “Some of the tumors are very slow-growing, so that the patient can survive for years with minimal treatment,” says Martin Goodman, a surgical oncologist at Tufts Medical Center in Boston, “while others have faster growing [cancers] and may only live a few months after diagnosis.”

Unlike colon cancers, appendix cancers very rarely spread through the blood or lymph system, he says. “We’re not sure why this happens at a molecular level, but we do know that because the appendix is so narrow it tends to rupture very early on, often without the patient knowing,”Goodman says. “So cancer cells disseminate inside the abdomen instead of through the blood or lymph.”

In a way, that’s good news: Because the cancer cells don’t travel through the blood, they very rarely metastasize to distant sites like the lungs or liver. And this means that if doctors can remove all of the tumor cells from the abdominal cavity via surgery and chemotherapy, a patient can conceivably become cancer-free, with very little risk of recurrence, says Esquivel. But it also means that traditional chemotherapy is much less likely to be effective, because the drugs, which are typically injected into the bloodstream, don’t always reach cancer cells that are isolated in the abdominal cavity.

Last Days
Less than a week after Hepburn finished her first treatment, another bout of severe abdominal pain caused her doctors to schedule another surgery. “They weren’t in there very long,” says Ferrer. “They came out and said that it had grown exponentially.”

Today, in cases like Hepburn’s, in which the cancer has spread through the abdomen, the No. 1 predictor of long-term survival is whether the surgeons can remove all the tumor cells. “It’s often a very invasive surgery,” says Levine. “We open up the abdomen and remove all the tumor we can see. If we can do that, then the next step is something we call HIPEC, or hyperthermic intraperitoneal chemotherapy wash: We bathe the abdominal cavity directly with chemotherapy drugs to get any of the cells we can’t see.” For this “hot wash” to be successful, the surgeons must not have left any pieces of tumor more than a few millimeters deep, because the drugs can’t penetrate them. If the patient survives the surgery, which can last up to 14 hours, and the therapy is successful, the procedure offers real hope of long-term survival, says Levine.

But very few medical centers offer HIPEC today, and while Hepburn’s doctors considered intraperitoneal chemotherapy—a procedure similar to HIPEC, but without heat—they ultimately decided that her cancer was too aggressive and widespread to justify the procedure. “The doctors described it as ‘sprinkled everywhere,’ ” recalls Ferrer. “The whole thing happened so quickly; it was just a few weeks. I was looking at these desperate alternatives, and then an opportunity came up to fly home, so we did that.” After returning to Hepburn’s 18th century farmhouse in a quiet corner of Switzerland, Hepburn, her longtime partner Robert Wolders, and her two sons spent a final Christmas. Ferrer describes the experience in his biography, Audrey Hepburn: An elegant spirit: “Since she couldn’t leave the house to go shopping, she had chosen things she owned to give to each one of us: a scarf, a sweater, a candle. This made it so touching and all the more valuable.”

Over the next few weeks, Hepburn slept more and more as the disease progressed. On Jan. 19, 1993, her doctor prescribed morphine for her pain, and she was barely awake for more than a few minutes at a time. On Jan. 20, she died quietly in her sleep at age 63.

Although Hepburn will always be remembered as one of the most beloved film actresses of classic Hollywood, she was more concerned about leaving a legacy that would inspire people to help others who are less fortunate than themselves. “I don’t know if she realized how long-lived her image would be,” says Ferrer. “I just read a news report, maybe a week ago, quoting Angelina Jolie as saying she wanted to follow in my mother’s footsteps.”

Hepburn, no doubt, would have been pleased that Jolie, and so many modern celebrities, followed her example by committing to humanitarian work. Hepburn “was among the first big names to do that sort of thing,” says Ferrer, who along with his brother and Wolders started the Audrey Hepburn Children’s Fund in 1994 to continue his mother’s efforts to raise money and awareness for needy children worldwide. “It was something we felt she would have wanted us to do,” he says. “I think she was more proud of the work she did as an ambassador for UNICEF than anything else.”


http://www.crmagazine.org/archive/Fall2009/Pages/AudreyHepburnAppendixCancer.aspx?Page=1