I just returned from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). This year, 30,000 participants gathered at the McCormick Convention Center in Chicago to consider more than 11,000 scientific contributions. As in all fields, one of the important aspects of a convention is to provide a place for meeting and greeting old friends. There was collegiality in abundance at the 2008 ASCO. But what was conspicuously lacking was any real sense of progress in the war on cancer, especially in the treatment of the most common forms of advanced disease.

The study that garnered the most attention was the much-anticipated FLEX study, a phase III clinical trial which was designed to assess the effect of adding the targeted drug Erbitux (cetuximab) to standard chemotherapy for advanced non-small cell lung cancer (NSCLC). There are 215,000 cases of lung cancer each year in the US, 80 percent of which are classified as NSCLC, so the stakes are obviously high.

ASCO's public relations department put out a press release stating that in the FLEX study the addition of Erbitux "improved survival" in patients with advanced NSCLC, a group for which few options now exist. While technically true - Erbitux did improve survival - the improvement amounted to just five extra weeks. The survival time for patients who were given Erbitux in addition to chemotherapy averaged 11.3 months as opposed to 10.1 months for the patients who received chemotherapy alone.

I didn't meet anyone who wasn't disappointed with these findings, although leaders of the field naturally tried to put a brave face on the situation.

"These findings are likely to have a significant impact on the care of patients with these kinds of cancer," said Howard Sandler, MD, of the University of Michigan. In other words, it's probable that more doctors will start to prescribe Erbitux to their patients. This would be a shot in the arm for ImClone, a company still recovering from the Martha Stewart scandal. (Its founder, Sam Wachsal, is still in prison for insider trading.)

"It's not a home run, it's just a single," said Dr. Roy Herbst of the M. D. Anderson Cancer Center, who was not involved in the study but has been a consultant to ImClone.

Currently, the cost of Erbitux is $10,000 per patient per month. But because of the FLEX trial announcement at ASCO it is expected that increased demand for Erbitux will add more than $700 million in annual US sales. This will boost shares of ImClone by 35 percent, according to analyst Eric Schmidt of Cowen & Co. (Bloomberg 2008)

The Problem with Clinical Trials

But let us look at the bigger picture. Targeted therapies such as Erbitux are intriguing drugs. There are innovative oncologists who are using them in interesting ways. So I for one am happy these drugs exist and are available to practitioners. Nonetheless, when used alone in high doses, or when added to standard chemotherapy, as in the present study, they do not do much for most cases of advanced cancer. With a few notable exceptions, they have not lived up to their billing.

I also think we need to question whether the results of the FLEX study can be generalized to a wider population. In the FLEX study, potential participants were pretested for over-expression of a particular gene called EGFR, and only those who over-expressed EGFR were included. (EGFR over-expression strongly increases the likelihood of benefit from Erbitux.) Will the drug work as well when it is also given to patients who do not over-express EGFR, as it bound to happen in the wider population? Probably not.

In addition, the clinical trial employed several exclusion criteria - i.e., people with certain specific characteristics were not accepted for the trial, again in order to improve the likelihood of good results. For example, patients were excluded if they had had:

• Previous exposure to monoclonal antibodies, signal transduction inhibitors or EGFR-targeting therapy
• Previous chemotherapy for NSCLC
• Documented or symptomatic brain metastasis
• Superior vena cava syndrome contra-indicating hydration
• Previous malignancy in the last 5 years except basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix

In addition, patients who had brain metastases were deliberately excluded from the clinical trial, yet according to a 2008 study from the Fox Chase Cancer Center, Philadelphia, 35 percent of patients with stage IV NSCLC have brain metastases at the time of diagnosis (Paralkar 2008).

Thus, many "real world" patients were excluded from the study in order to increase the chance of a positive result. In the wider community setting, by contrast, such selectivity will very likely not be possible. Such "run of the mill" patients are often sicker and their disease may have progressed despite previous treatments. Will they also get five weeks extra survival from Erbitux? This is not known but seems unlikely.

Lack of Blindness

I want to raise another issue that is little discussed, but may influence clinical trial results. Once upon a time, most clinical trials were what is called ‘double-blinded' and placebo-controlled - i.e., neither the patients nor their physicians knew who was getting the drug under evaluation. But, for various reasons, double blinding has become less frequent in clinical trials of oncologic drugs. The National Institutes of Health's clinicaltrials.gov Web site presently lists over 16,000 cancer treatment clinical trials. Yet only 1,165 of these are also placebo-controlled and double-blind. The FLEX study was not one of these.

In the FLEX study, one group of patients was randomly assigned to receive chemotherapy with a combination of two standard anticancer drugs, cisplatin and vinorelbine, while the other group was given cisplatin and vinorelbine plus the additional drug, Erbitux. This random assignment created two very different psychological pathways. One group of patients knew they were getting the added, and potentially more promising, agent. The other group consisted of patients who were only given the standard chemo treatment. This divergence may be reflected in the somewhat better results seen in the treatment group.

At the same time, the oncologists monitoring the trial also knew who was getting the experimental treatment and who was not. For a variety of reasons, not least the simple hope of being able to provide something more effective, oncologists have an interest in seeing the experimental group do better than those in the standard treatment group. In addition, the sponsoring company has a strong vested interest in seeing a positive outcome. And of course a positive finding and a high-profile publication will advance everyone's careers. Finally, while I am not suggesting any ethical impropriety or deliberate attempt to control the outcome, there are certainly ways in which doctors and nurses can unconsciously enhance the care of the patients in one group over those in another, thereby influencing the course of the disease.

So, in order to believe in the relevance of the FLEX results to the general population, you must accept the proposition that changes in doctors' and patients' consciousness has no significant bearing on the outcome of the trial. If you accept the basic idea that psychological factors can influence survival, you then have to pose the question: To what degree do mood, attitude, intention, etc. influence survival? Could it result in one week of extra life? Two weeks? Or even five weeks?

Some work has been done on this question. Dr. Hermann Faller and colleagues, in Würzburg, Germany, showed that "active coping and hope were associated with longer survival" while emotional distress, depression and depressive coping were associated with shorter survival (Faller 1997). These researchers looked particularly at patients with lung cancer. "Both coping and emotional distress had a statistically independent effect on survival among patients with lung cancer," they wrote (Faller 1999). In a 10-year review of results with lung cancer, they again found that "a depressive coping style…was linked with shorter survival" (Faller 2002). The relative risk was 1.91, which means that depressed patients' risk of dying was nearly double that of non-depressed patients.

Dr. Kirk W. Brown and colleagues, of the University of Rochester, NY, drew similar conclusions. In a study of more than 200 cancer patients, they showed that "depressive symptomology was the most consistent psychological predictor of shortened survival time" (Brown 2003). So depression influences survival - a proposition that is both common sense and good science.

I would love to see a study of the effect that either inclusion or, conversely, exclusion from the more promising arm of a clinical trial has on patients' survival. It is probable that being excluded from the active treatment arm does indeed predispose to depression in some individuals, and that this in turn may influence their survival. Such a study might throw an interesting light on the reasons for increased survival in some non-blinded clinical trials, especially when difference between the two arms is small, as it was in the FLEX trial recently reported at ASCO.

THE WAR ON CANCER by GUY FAGUET, MD

Two years ago in this newsletter I reviewed an important book, The War On Cancer: An Anatomy of Failure; A Blueprint for the Future, by Guy Faguet, MD.

To read my review please click or go to:
http://www.cancerdecisions.com/040206.html

The paperback edition of the book has just been published and is now available at www.Amazon.com. You can access it by clicking here.

--Ralph W. Moss, Ph.D.