From the Townsend Letter for Doctors & Patients
The War on Cancer
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Everything about the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO) in May was huge. There were 26,000 attendees, many of whom came from Europe, Latin America and Asia. For nearly a week they converged on Orlando's convention center, to hear thousands of lectures, seminars and presentations. The Exhibition Hall was a multistoried bazaar of new therapies. Even the press room was gargantuan.
Yet, after four days, I came away with a hollow feeling. There were advances, to be sure. A study compared Gleevec (STI-571) to the standard therapy for chronic myeloid leukemia (CML). Gleevec resulted in significantly greater reductions in the number of cancer cells in the bone marrow, which led to the complete disappearance of cancer cells in 40% of the patients. Only six patients treated with Gleevec were in the dangerous "blast crisis” six months after therapy compared to 26% of those receiving standard therapy. Six months after treatment, leukemia continued to worsen in 8 patients taking Gleevec compared to 57 taking the interferon-based therapy.
"[T]he long-term results of STI-571 remain unknown,” said its discoverer, Brian Drucker, MD, of the Oregon Health and Science University, Portland. However, he believes "it should now be considered as standard therapy for newly diagnosed CML.” Gleevec was approved last year for the treatment of patients who no longer respond to interferon-based therapy or who are in the "blast crisis.” This report will add to the drug's luster. Overall, however, I was disappointed by the lack of breakthroughs in the treatment of cancer.
Carefully targeted drugs like Erbitux are central to the oncology profession's latest strategy for conquering cancer. As the director of the National Cancer Institute, Andrew von Eschenbach, MD, said in another lecture, these newer drugs mark a transition from the "seek and destroy" strategy of 20th century chemotherapy to the "target and control" strategy of the 21st, from "weapons of destruction" to "interventions for control and prevention." In principle, advocates of complementary and alternative medicine (CAM) support such a development, since it represents a departure from the slash-burn-and-poison school of conventional cancer treatment. There are side effects of Erbitux, but they are relatively mild, and consist mainly of an acne-like rash. Who in their right mind wouldn't want these new drugs to succeed?
Dr. Mendelsohn was a pioneer in using monoclonal antibodies, or "guided missiles," to block the growth of cancer cells. The primary outcome of his work was the development of Erbitux, which targets epidermal growth factor (EGF) receptors. EGF is present in all cells that line our organs and skin, and high levels of EGF have been found to correlate with a poorer prognosis for cancer patients.
Preliminary research looked highly promising. At last year's ASCO meeting, the manufacturer of Erbitux, ImClone Systems, claimed a 22.5% response rate in patients with advanced cancer treated with a combination of Erbitux and chemotherapy. The jubilation at ASCO culminated in a Doobie Brothers concert that ImClone sponsored for the doctors attending the conference.
In his lecture this year, Dr. Mendelsohn naturally emphasized the positive aspects of Erbitux. But the world's first phase III clinical trial of Erbitux was reported a few days after Dr. Mendelsohn's inspiring speech. In it, the standard drug cisplatin was compared to combination therapy using cisplatin and Erbitux in the treatment of head and neck cancer. The results were less than stellar. Just one patient out of 44 (2.3%) achieved a complete response and five (11.4%) had a partial response. The median disease-free survival for the group as a whole was 6.7 months and the median overall survival was just 7.2 months.
It turned out that the response rate, poor as it was, enclosed an even more sobering reality: the response rate among so-called "real world" patients (patients who received their treatment outside the rarefied atmosphere of clinical trials) was just 5.7 percent. And that was a measurement of tumor shrinkages, not survival. For the Erbitux-added patients, the median time until the tumors worsened was just 4.10 months, compared to 3.37 months for the control patients. This difference of three weeks was not statistically significant.
So, while on Saturday oncologists were applauding Dr. Mendelsohn for his brilliant insights, on Monday they were hearing that a treatment based on these insights simply did not work. If it were true that EGF "plays a critical role in the process that regulates tumor cell growth and survival," as ImClone still claims on its website, then one would expect a treatment that targets EGF to yield significant clinical results. It doesn't.
Because of the weak performance of Erbitux, the Food and Drug Administration (FDA) has refused to approve it. The company's stock, which traded at $75 per share at the end of last year, now hovers around $10. In the wake of the ASCO meeting, the president and CEO, Samuel Wachsal, resigned all his posts. According to ASCO, some of those involved in the current clinical trial of Erbitux received honoraria and funding from its co-marketer, Bristol Myers-Squibb, and own stock or serve on the board of ImClone. The search for a magic bullet for cancer detracts from the study of approaches that actually extend the lives of cancer patients while maintaining or improving their quality of life. It also detracts attention away from cancer prevention strategies using natural and nutritional substances. These less toxic (and less expensive) approaches represent for me, the real promise of cancer research.
ASCO's CAM Symposium
David Rosenthal, MD, director of Harvard University's Health Services, introduced the speakers: Eric Winer, MD, of Dana-Farber Cancer Institute; Eric Small, MD, of the University of California, San Francisco; Maurie Markman, MD, of the Cleveland Clinic Foundation; Norman Farnsworth, PhD, of the University of Illinois; Jimmie Holland, MD, of Memorial Sloan-Kettering Cancer Center; and Michael Hawkins, MD, of the Washington Hospital Center.
I have nothing against any of these fine people, but none of them is a CAM practitioner. In fact, Eric Winer, MD, who described himself as a "traditional” medical oncologist, opened his presentation by asking, "Why am I here?” and then set the tone for the symposium by telling the audience of nearly 200 oncologists, "I have not done research in complementary therapies.” Dr. Winer went on to speak about CAM use among women with breast cancer, although his derogatory attitude towards CAM was apparent when he stated, "We do a real disservice to our psychosocial colleagues to classify psychotherapy as a complementary therapy.” In other words, the CAM label is a stigma.
Eric Small, MD, of the University of California, San Francisco, presented information on dietary and herbal approaches to prostate cancer, and reviewed research on the herbal formula PC SPES, a project he described as "not for the faint of heart.” After showing that PC SPES was effective even in some hormone-refractory prostate cancer patients, Dr. Small had arranged a clinical trial to compare PC SPES to the drug DES in advanced prostate cancer. However, when he discovered a minute amount of DES in the herbal formula (3% of the dose used in the DES arm of the study), he and his colleagues cancelled the study. This was a decision I still could not understand, even after his attempt at an explanation.
Dr. Maurie Markman, a co-chair of the symposium, spoke on safety issues in CAM. He began by asserting, "My intent is not to indict CAM. The evidence overall is that [these treatments] are remarkably safe.” He then proceeded to run down almost every alternative treatment, reciting a litany of alleged horrors: toxic effects, harmful interactions with other medications, problems in methods of administration, reduced effectiveness of standard therapies, impairment in overall quality of life, and delays in obtaining known effective therapy. According to Dr. Markman, almost every alternative cancer treatment, such as laetrile, shark cartilage, hydrazine sulfate, macrobiotic diets, and antineoplastons, was toxic.
Horror piled on horror. He even claimed that green tea could cause "nausea, vomiting, insomnia, fatigue, diarrhea, abdominal pain and confusion,” a remark that caused some nervous laughter among the tea drinkers in the audience. Herbal medicines, Dr. Markman said, were bedeviled by contamination, crop variability, misidentified plant species, renal and hepatic toxicity, and outright fraud. Chiropractic could cause "cerebrovascular accidents,” while acupuncture could cause pneumothorax hemorrhaging, the transmission of infection, and injury from "forgotten needles.” Dr. Markman included in this Grand Guignol the damage caused by herbs that, by his own admission, are not even used in treating cancer.
The main problem with his presentation was a failure to contextualize. How frequently do such effects occur? Very rarely. It is likely that millions of cups of green tea are drunk for every case of nausea, vomiting and confusion. As Paracelsus said in 1564, "Everything is a poison. There is nothing without poison. Only the dose makes a thing not a poison.” The "toxicity” of CAM treatments needs to be compared to truly dangerous treatments, such as chemotherapy. This simply wasn't done.
Dr. Markman was followed by Norman Farnsworth, PhD, a distinguished professor at the University of Illinois and a voice of reason in the field of herbalism. His first comment: "I feel like sneaking out the back door after hearing the previous speaker.” Farnsworth then gave a subdued presentation on the attempt to isolate chemotherapeutic drugs from herbal sources, which he characterized as "looking for needles in a haystack.” He did not discuss any of the herbal remedies for cancer that are of greatest interest to patients.
Michael J. Hawkins, MD (who is chairman of the NIH panel on which I serve) gave a detailed presentation on antioxidants and chemotherapy. He excluded all in vitro and animal experimental data, something that is rarely done when considering new chemotherapeutic approaches. Instead, he focused on the clinical data for vitamins A, C, and E; glutathione; CoQ10; and the synthetic antioxidants dexrazoxane (also called ICRF-187) and amifostine. Dr. Hawkins mainly had positive things to say about the concurrent use of antioxidants and chemotherapy, and there was no doubt from his data that most antioxidants do not interfere with the efficacy of chemotherapy. In fact, most have been shown to decrease toxicity. Dr. Hawkins ended his presentation, certainly the most fair-minded of the symposium, with a call for large-scale randomized trials.
It was hard to ignore the infuriating lack of balance on the panel. Real experts on the use of CAM in cancer were not asked to speak. I myself sat between E. Dieter Hager, MD, PhD, director of the BioMed clinics of Germany, and Ann Fonfa, a breast cancer activist who directs the innovative Annie Appleseed Project. Neither of them was asked to participate. I saw a number of other CAM clinic directors in the audience. How ironic that the audience wound up listening to non-CAM practitioners while genuine experts, who administer these treatments every day, sat unacknowledged in their midst.
To be sure, this meeting was free of the cant of outright enemies of alternative medicine, such as characterized the 2000 ASCO symposium. In particular, Dr. Hawkins' carefully worded appraisal of antioxidants and chemotherapy was the most balanced presentation on the subject I have heard at ASCO. But when, I wonder, will ASCO allow its members to hear from those who have a profound knowledge of this subject, as physicians, patients and health advocates, instead of from those who have never personally used the therapies they talk about? When they do that, it will be a meeting that makes history.
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|March 25, 2003|