University of Toronto scientist Robert Kerbel has discovered a novel way to cure cancer in mice. His findings, published this month in the Journal of Clinical Investigation, rank among the most exciting work on cancer in the past decade, according to some researchers.
But some physicians who treat cancer are skeptical. Though the research holds promise, they say, it's been oversold to doctors, and hyped on the front pages of newspapers at the end of February and again this past weekend. The result is that cancer clinics throughout Toronto have been hearing from desperate people wanting the new treatment, only there is no new treatment that's been tested and proven beneficial. Unless you're a mouse.
Dr. Kerbel's work is based on the idea that if you shut down the blood supply of a cancer, you stop it from growing and spreading. Pioneered by Judah Folkman of Harvard, the idea is relatively new. Many doctors first heard about it two years ago when an experimental drug that starves mouse tumours by choking off their blood vessels was billed as a possible cure for cancer in a front-page article in the Sunday New York Times. Since then, Dr. Folkman's idea has spawned one of the fastest growing areas in cancer research.
Dr. Kerbel's advance involves combining one of these experimental tumour-starving drugs with very low doses of standard chemotherapy. Giannoulla Klement, a pediatrician working in Prof. Kerbel's lab, led the painstaking effort to give this cocktail of new and old drugs to mice suffering from a cancer called neuroblastoma. In the mice treated with the combination cocktail, the cancer disappeared. By contrast, in mice receiving just the experimental drug, or just the chemotherapy, the cancer shrunk but eventually came back, probably because it became resistant to treatment.
Resistance to chemotherapy is one of the major stumbling blocks that has kept doctors from curing cancer. The combination of drugs Dr. Kerbel used may have prevented the mouse cancers from becoming resistant. A study using a similar combination published last week by Dr. Folkman's group at Harvard produced equally dramatic results.
"This is probably the most exciting thing I've heard in Sunnybrook research in the 10 years I've been associated with the place," says Mark Henkelman, former head of research at Toronto's Sunnybrook Hospital, where Dr. Kerbel has his lab. "It's a new way of treating cancers," says Robert Phillips of the National Cancer Institute of Canada. But Dr. Phillips adds, "The caveat is, it works well in simple systems, but is it going to work well in patients?"
For cancer doctors, that is the overriding question. Carol Sawka, head of the Toronto-Sunnybrook Regional Cancer Centre, notes, "We've had all kinds of important work in mice that hasn't turned into effective treatment."
These sorts of skeptical comments don't surprise Dr. Kerbel. In fact, he's said similar things himself. "One of the most serious obstacles facing investigators involved in . . . new anticancer drugs is the failure of . . . rodent-tumour models to predict in a reliable way whether a given drug will have antitumour activity and acceptable toxicity in humans," he wrote in 1998, in an article for the journal Cancer Metastasis Reviews.
He speaks differently about this new discovery, however, even though it's based on a rodent model. And he's not alone. Judah Folkman, the father of this field, has been described as "effusive" about the findings in Dr. Kerbel's lab.
But where Dr. Kerbel stepped over the line, some of his colleagues say, was in advising people about how to translate his laboratory results into an untested human therapy. Via e-mail, he and Dr. Klement sent out a sort of position paper implying that the strategy that succeeded in their lab could be used on human patients, though all they'd done was an experiment in mice.
It all started when Jerome Goldenberg, the director of cancer programs at the University of Toronto, invited Dr. Kerbel to give a seminar on his research at citywide oncology rounds -- a meeting of all the cancer specialists affiliated with the university.
Dr. Kerbel had already been in touch with a few doctors who were testing his theories on individual cancer patients. These doctors came to the meeting. Around that time, Dr. Kerbel also agreed to be profiled by The Toronto Star, and he invited the Star's reporters to the meeting. It took place on Friday, Feb. 25, at Women's College Hospital.
At the rounds, the doctors who were testing his ideas described their patients' progress. They told their colleagues that the patients had not responded to conventional treatments. Then, they detailed what drugs they were using and in what doses in an attempt to reproduce Dr. Kerbel's lab results. As Dr. Kerbel explained, "What was said was that in some cases responses were seen that were miraculous." Only Dr. Kerbel knew that reporters were listening in.
Physicians typically consider rounds to be a private forum. "You never know who's at rounds, you just always assume it's your colleagues," explains Dr. Phillips. And University of Toronto breast-cancer specialist, Michael Crump, points out, "Nobody went to that meeting thinking they were then going to read about it in the media." For his part, Dr. Kerbel says he made a major mistake by failing to let the people in the room know that there were journalists there.
In medicine, a few cases show that something's worth studying. They don't prove it works. Proof requires a clinical trial, a study that tracks patients who receive the treatment. But Dr. Kerbel's findings in mice are dramatic, his talk at the citywide rounds was enthusiastic, the case reports of patients were tantalizing. And this is cancer after all, where signs of victory, no matter how big or small, have a high currency value.
The day after the meeting at Women's College, the headline in The Toronto Star read: "New drug regimen buoys cancer doctors." The Star article was careful to note that Dr. Kerbel's experiment only involved mice. But it described patients who seemed to be responding miraculously. And the placement of the article, on the front page, above the fold, in the Saturday paper, left readers with the impression that a cure was at hand.
By Monday, Feb. 28, the phone lines to Toronto's cancer clinics were jammed. Cancer patients appeared at the clinic doors clutching their copy of the Star. Dr. Crump says some breast-cancer patients asked for specific drugs in specific doses, telling him, "Dr. Kerbel says this is the best way to treat cancer."
Dr. Kerbel was deluged with requests from patients and family members for more details. In response to the flood of calls, he and Dr. Klement wrote a paper titled Anti-Angiogenic Chemotherapy that they sent out over the Internet to patients and their family members. The paper was explicit. For example, the experimental drug Dr. Klement gave the mice couldn't be used, since it's not available for humans. So the paper spelled out other drugs that could be prescribed to block cancer's blood supply, such as the anti-arthritis medication, Celebrex, and even mentioned an actual dose of Celebrex.
Cancer physicians who saw the paper -- and several received it from their patients -- were taken aback that Dr. Kerbel would use mouse findings to suggest actual cancer treatments.
They phoned him, and other doctors, to express their concerns.
Sunnybrook's Dr. Sawka read through the paper that was being e-mailed to patients and requested that he stop sending it. "We aren't in a position to recommend a specific 'treatment' protocol at this point and he was bordering on this," she said. Within a week of having written the paper, Dr. Kerbel stopped sending it out.
That was where things stood in early March. Then Dr. Kerbel learned that the report he and Dr. Klement had written on the mouse experiment would be published in April. His hospital was interested in scheduling a press conference to announce the publication. And Dr. Kerbel also wanted a press conference, to "set the record straight," he said.
The press conference took place last Friday in a research building on the Sunnybrook campus. At one point, a reporter asked Dr. Kerbel what his results could mean for human cancer patients. The professor referred the question to cancer doctor Sylvain Baruchel of the Hospital for Sick Children in Toronto, a co-author on the Klement-Kerbel paper.
"These are very interesting results, but they are only in mice." Dr. Baruchel said, emphasizing that he will not test Dr. Kerbel's ideas at Sick Kids until a clinical trial is in place.
Clinical trials at hospitals throughout Canada could begin soon. Physicians have been poring over the data gathered in the Kerbel and Folkman labs, trying to design human studies.
Meanwhile, after the press conference on Friday, Dr. Baruchel predicted that his hospital would field multiple phone calls this week from parents wanting their cancer-stricken children to be put on the supposed new protocol. He was right. Despite Dr. Kerbel's efforts to keep his enthusiasm in check, the headline in Saturday's National Post read, "Discovery could win war on cancer," and ran in capital letters across the entire width of the front page. On Monday, cancer patients and their families trudged to the clinics, carrying their copies of the Post. This is war, after all, on many different levels. E-mail Dr. Shuchman at: shuchman@acsu.buffalo.edu