The war on cancer

Townsend Letter for Doctors and Patients, August-Sept, 2002 by Ralph W. Moss

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.

Erbitux

One of the highlights of the meeting was the 2002 Karnofsky Lecture, "Targeting the EFG Receptor for Cancer Therapy," by John Mendelsohn, MD. Dr. Mendelsohn is the president of the M.D. Anderson Cancer Center in Houston and has had a distinguished medical career. Listening to him speak, I caught some of his excitement and could see why he was chosen to receive this high honor from his peers. Dr. Mendelsohn's speech, concerning the science behind a new drug called Erbitux (formerly known as IMC-C225), was enthusiastically received by an overflowing crowd.

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 cf 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.