In Memoriam
I note with sadness the passing of two significant figures in the world of complementary and alternative medicine. Wolfgang Woeppel, MD, founding director of the Hufeland Klinik (hospital) in Bad Mergentheim, Germany, passed away on July 10, 2006. In addition, Alexander (Alex) S. Sun, PhD, 67, founder of the Connecticut Institute for Aging and Cancer and of the Sun Farm Soup Co., Milford, Connecticut, also passed away this summer. According to his son, Linus Sun, PhD, the cause was a sudden and fatal ventricular heart arrhythmia while exercising.

Both these men were personal friends as well as long-term colleagues. They were good people who fought hard for the benefit of cancer patients everywhere. I have requested details about their lives from the respective families (both of which, at this writing, intend to continue their founders' operations). When these details are forthcoming, I intend to write full obituaries for each of them. They will be greatly missed.

Company Kills Negative Clinical Trial
In late June 2006, the pharmaceutical company Genentech, Inc. abruptly halted a large phase III clinical trial of its drug, Avastin. This trial was designed to test whether Avastin (bevacizumab) could prolong the lives of patients with pancreatic cancer. The trial was halted at the recommendation of an independent data monitoring board because the addition of Avastin to an approved drug, Gemzar (gemcitabine), failed to improve overall survival. Significant improvement in Avastin's performance was deemed unlikely, given the results that had already been seen.

Avastin is a so-called "targeted" form of chemotherapy. It is a synthetic antibody designed to foil a specific cell surface protein called vascular endothelial growth factor (VEGF). VEGF is a signaling protein crucial to the ability of tumors to generate and maintain new blood vessels, a process called angiogenesis, which is essential for tumor growth.

Paradoxically, the premature halting of the clinical trial is likely to work in Genentech's – and Avastin's – favor. Genentech's losses have effectively been cut before worse damage could be inflicted by all the negative publicity that would follow publication of such mediocre results. The possibility that patients who received Avastin plus Gemzar might actually have fared worse than those receiving Gemzar alone will now not be allowed to occur. Genentech simply stated that significant differences in overall survival were "highly unlikely" between the two treatment arms. Since they were so unlikely, why not let the trial play out? The purpose of a clinical trial is supposed to be the generation of new knowledge, even when that knowledge is detrimental to the financial interests of the sponsor. The company promises that the results will eventually be published in a medical journal, but this will probably receive next to no publicity when and if it finally happens.

Early closure of the trial also precluded any new revelations about Avastin's adverse effects. The company has asserted that the trial was not halted for safety reasons and that no new safety concerns related to this product were observed in the trial. However, a complete and thorough peer-reviewed report might have also added new knowledge about the drug's potential toxicity.

Despite this setback, Avastin remains a huge profit center for Genentech and its majority stockholder, the Swiss pharmaceutical giant, Roche. US sales of Avastin in the first quarter of 2006 jumped 96% to $398 million, from the $203 million mark for the corresponding period a year earlier. For Roche, Avastin contributed $1.67 billion to its $27.27 billion 2005 revenue from prescription drugs. This is not bad for a drug that, so far, has had only a minimal effect on advanced cancers of any type, including its original approved indication, colorectal cancer.

The US Food and Drug Administration (FDA) had previously approved Avastin in combination with intravenous 5-FU-based chemotherapy as a first-line treatment of patients with metastatic colorectal cancer. In June 2006, the drug was also approved as a second-line treatment of colorectal cancer (i.e., for use in patients whose cancer has progressed despite having already received one course of chemotherapy). The company has also requested licenses from the FDA for Avastin for advanced non-small cell lung cancer and for the treatment of women with advanced breast cancer.

In colorectal cancer trials, the drug has been shown to extend the lives of patients by around 3.3 months (Kabbinavar 2005). In lung, breast, and now pancreatic cancer, however, there is not yet any proof of life extension from rigorous trials. Perhaps the most startling thing about Avastin is its price – around $100,000 per year for some indications.

Genentech has staked much on the success of this billion-dollar earner. The South San Francisco-based company is currently funding 130 clinical trials in 25 different types of cancer. For Roche-Genentech, the termination of this trial is only a minor setback, according to Hernani de Faria, analyst at Zuercher Kantonalbank. "The Avastin program is huge and broadly based, as they're investigating more than 20 types of cancer," he said (RTT 2006). Wall Street analysts still estimate that the drug could eventually reap revenues of up to $10 billion from these expanded indications.

It seems extraordinary that a drug with such a weak general performance record could earn so much money and garner such positive publicity. The two phenomena are related, as patients and their doctors opt for specific treatments largely because of favorable media coverage. Meanwhile, this abruptly halted clinical trial, with its unequivocally negative results, has received little publicity and certainly nothing like the intensely positive attention that surrounded the drug's approval last year. This kind of selective reporting helps to foster the illusion that targeted drugs such as Avastin are steadily improving the treatment and outcome of cancer. The truth, as revealed by the curtailed Genentech study, is very much less rosy. With a few notable exceptions, so-called "targeted" drugs are still not targeted enough to make much of a difference on the most common forms of cancer.

National Cancer Institute in Trouble
The game around the National Cancer Institute (NCI) these days is to guess how long it will take the acting director, John Niederhuber, MD, to remove some of the embarrassing statements of his predecessor, Andrew von Eschenbach, MD, from the Institute's web site. For the past three years, Dr. von Eschenbach touted what he called his "challenge goal" of eliminating all suffering and death due to cancer by the year 2015. Nobody in the cancer field really believed that Quixotic goal was attainable. How, just to give one example, could the federal government hope to eliminate lung cancer within a dozen years when the American Lung Association's "report card" gives the government three Fs and a D in the area of tobacco control? A few intrepid scientists have spoken out publicly against this ludicrous goal, most notably Sir Paul Nurse, President of Rockefeller University, New York. "This cannot be justified even as a statement of aspiration, because when we fail to deliver, as we surely will with such a claim, we will lose the confidence and trust of both the politicians and the public," Nurse said. But most cancer scientists felt it wiser to remain silent because funding for cancer research comes largely from the NCI.

Even the National Cancer Advisory Board (NCAB), which is supposed to oversee the operations of the NCI's war on cancer, remained subservient. The members knew that in his dealings with critics, von Eschenbach could be vindictive, as when he cancelled NCI's group subscription to the well-respected Cancer Letter after that publication criticized his 2015 goal as unrealistic. The NCI publicly began referring to Dr. von Eschenbach's goal as a "Vision," as if it had come to him as a divine revelation and was not simply the flawed and overreaching projection of an imperious government bureaucrat.

Another of von Eschenbach's dubious decisions was his appointment of Anna D. Barker, PhD, as his deputy director. Not only does Dr. Barker have insufficient scientific background to hold such an important post (just a dozen scientific articles, all dating from the 1970s), but she has publicly expressed opposition to the rigorous testing of new medicines, undercutting the work of independent investigators. However, the acting NCI head, John Niederhuber, MD, has also defended this appointment and expressed the desire to continue her tenure. "Of course, Anna Barker has scars all over her body," Dr. Niederhuber said, "because she's ‘the terrible witch of Bethesda' that created all these huge, big projects, and we know that these big projects have sapped the strength of NCI.... Anna and I have defended this on a numerous occasions, and I think all of you know the importance of NCI continuing to lead biomedical research."

In fact, much of NCI's money has been poured into exactly the sort of huge favored projects that Niederhuber criticizes. Big laboratories doing genomics, proteomics, informatics, and nanotechnology have received massive funding, leaving other critical areas – and young researchers – woefully underfunded.

"The success rate of awards compared with applications has slipped from close to one in three in the late 1990s to nearly one in five," said Sir Paul Nurse. "When many applications are of a high quality, low success rates increase to an undesirable level the influence of chance in decision making. This is bad for the overall research enterprise and is demotivating for the investigators making applications" (Nurse 2006).

Adding insult to injury, in September 2005, President Bush appointed von Eschenbach to head the Food and Drug Administration (FDA) after then-commissioner Lewis Crawford, DVM, abruptly resigned. For a while, Von Eschenbach ran the NCI and the FDA simultaneously. He finally resigned from NCI on June 8, 2006, to concentrate on his job as acting commissioner of the FDA and to prepare for confirmation hearings to become full commissioner of that massive agency. He left the NCI in disarray, after misusing the agency's resources in pursuit of his Quixotic goals. So far, this seems to have escaped Congressional attention.

There are indeed signs that the 2015 "Vision" is tottering. At the June 14, 2006 meeting of the National Cancer Advisory Board (NCAB), there was zero mention of the 2015 goal. Acting NCI Director Niederhuber informed the NCAB that last year (2005), cancer center directors around the country had actually plotted a palace revolt against von Eschenbach's unattainable plan and were drafting a report of their own seeking to provide an "honest" alternative to his goal. At the same NCAB meeting, according to the Cancer Letter, Dr. Niederhuber went through verbal gymnastics simply to avoid mentioning the embarrassing 2015 deadline.

In the fall of 2005, Niederhuber said, the rebellious center directors "felt that they wanted to have greater input into some of the strategic goals and priorities that they felt would be necessary to advance towards our goals and to make a difference in the burden of cancer in this country." Whew – it isn't easy to criticize your predecessor without appearing to be criticizing anything! Yet as the Cancer Letter's veteran reporter Kirsten Boyd Goldberg commented: "The de-2015-ization at the Institute isn't complete. The NCI web site is yet to be cleansed of now-antiquated agitprop" (June 15, 2006).

Von Eschenbach's presence still haunts the NCI. At this writing, the NCI web site still carries a dozen or so articles elaborating on the "realistic goal" (as NCI calls it) of eliminating all cancer suffering and death in less than a decade. "We believe that the Vision is within our grasp," the erstwhile Director states. In fact, the Vision was more like a will-o'-the-wisp, which has led essentially nowhere over the past four years.

References
American Lung Association's State of Tobacco Control report card is available at: http://lungaction.org/reports/national05.html.

Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005 Jun 1;23(16):3706-12.

Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005 Nov 1;23(31):8033-40.

RTTNews. Genentech stops avastin pancreatic cancer trial as results fail to meet endpoint – update. June 27, 2006. Available at: http://www.tradingmarkets.com/.site/news/TOP%20STORY/290927/

Sir Paul Nurses's comments on NCI's challenge goal. Available at: http://www.cell.com/content/article/fulltext?uid=PIIS0092867405014613

Ralph W. Moss, PhD
www.cancerdecisions.com