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What Is "Dose-Dense" Chemotherapy?

There is a lot of excited talk these days about a new "dose-dense" way of giving chemotherapy. "Dose dense" means giving drugs in a shorter time period than usual. For example, drug doses that are normally given over a three-week period are now being administered in two weeks, with shorter intervals between treatments.

Most of the current interest in the dose-dense approach derives from a December 2002 presentation at the San Antonio Breast Cancer Symposium, a meeting that attracted 5,000 attendees from over 60 countries. A government-supported clinical trial group, headed by Dr. Marc Citron of Mt. Sinai Hospital, New York, presented data comparing several different schedules for giving drugs as an "adjuvant" treatment for breast cancer. (An "adjuvant" treatment is one given after the initial primary treatment, such as surgery, in order to reduce the risk of a recurrence.)

The 2,000 or so patients in this trial had, on average, three positive lymph nodes after their initial surgery. All received the same three familiar standbys of breast cancer chemotherapy (Adriamycin, Taxol, and Cytoxan), but according to differing regimens. The primary question asked in the trial was whether it would be more effective to give these drugs every two weeks rather than every three weeks. According to Dr. Citron and his colleagues, the answer was a definite "yes."

There are several ways to measure the success of cancer treatments. One parameter of success is "disease-free survival," which means that the disease has not yet recurred and the patient is still alive after a specified time period. In this study, the rate of disease-free survival after four years was 82 percent in the dose-dense group versus 75 percent in the group that received the same amount of drugs in the conventional way.

Another parameter of success is overall survival, which refers to the total number of patients who are alive at any particular point. For many reasons, I believe this is the most meaningful measurement of patient benefit. In this study, the overall survival at three years was 92 percent with dose-dense treatment versus 90 percent with conventional scheduling, a difference of two percent.

Intensive Publicity

This study was publicized in a widely read National Institutes of Health press release, which was picked up by hundreds of other news outlets. The story gathered steam as it progressed. For instance, the pro-chemotherapy Patient Advocate Foundation called this a "groundbreaking study" and a "breakthrough in breast cancer treatment." The Doctor's Guide website claimed that dose-dense chemotherapy "can significantly reduce recurrence and mortality without increasing toxicity." "Significantly" in this case translates to a two-percent difference in overall survival.

Breast cancer activist Barbara Brenner was in San Antonio when the Citron paper was delivered. "It was clear as I sat in the room listening to the presentation on dose-dense chemo and watching the audience's reactions," she wrote, "that the study would likely change clinical practice overnight." In commenting on the study, she made the important point that women who undergo dose-dense treatment must take the drug Neupogen (filgrastim) to support the bone marrow." Since Neupogen costs more than the chemotherapy drugs combined, this option may not be feasible for poor or uninsured women.

Although apologists for chemotherapy have made much of this research, we must not forget that this is a single study, albeit a well-conducted one. In its press release, the NIH acknowledged that "this is the first major controlled study to show a clear survival benefit for women with node-positive breast cancer" using the dose-dense schedule. Previous research in dose-dense chemotherapy, including a Greek study published in the Journal of Clinical Oncology in 2001, had not shown positive results, and even the "dose-dense" advocate Dr. Citron readily admitted that "statistical comparisons must be considere preliminary."

Although the study authors anticipate that the survival difference will increase over time, in fact, small differences in survival can also disappear when the data are analyzed five or more years after completion of treatment. At any rate, a two percent advantage is hardly a "clear survival benefit" in any commonsense definition of the term.

A Familiar Double Standard

In the excellent March/April 2003 issue of the Breast Cancer Action newsletter, Ms. Brennan observed that "to change practice based on one study is pretty common in the United States, so long as the study encompasses conventional treatments." On the other hand, as she rightly pointed out, "A positive study of an alternative therapy would be greeted with the cry 'It's only one study; we need confirming research.'" This is the now-familiar double standard in the evaluation of conventional versus alternative treatments. I believe that many complementary and alternative treatments could show a better than two percent advantage in overall survival. Unfortunately, non-conventional therapies are simply not given the chance to prove their merit in large, NIH-supported clinical trials such as this one.

It is easy to see why oncologists as well as the mainstream media have latched onto "dose-dense" chemotherapy. There are so few treatments in oncology that have been proven to have a real impact on survival that any glimmer of hope is a cause for celebration. Dr. Larry Norton of Memorial Sloan-Kettering Cancer Center, New York, whose research formed the basis for the concept of "dose density," sounded a typically jubilant note, saying, "If confirmed with additional research, this approach may change the standard of care in breast cancer treatment." He added that the improved treatment is based on a concept that migh also apply to other types of cancer.

However, as Ms. Brenner noted, moving too quickly to change practice based on a single study often requires backtracking later. "It would be far better for us to exercise some caution with dose-dense chemo," she concluded. I certainly worry about the possible health implications of making chemotherapy more intensive. What, for instance, will be the effects on the heart of more intensively administered Adriamycin? Since these chemotherapeutic agents are themselves carcinogenic, is there a chance that second cancers will emerge as time goes by? What about impairment in cognitive function (the so-called "chemo head")? All of these issues needs to be intensively studied to protect recipients of dose-dense chemotherapy from undue harm.

In the meantime, women who are facing treatment decisions for locally advanced breast cancer need to soberly study all the relevant documentary evidence, or get help in doing so. Breast Cancer Action is a group that might help make the right choices. In any case, do not let yourself be stampeded into making a quick decision for "dose-dense" chemo based on preliminary findings such as these.

Antisense Drug Fails Final Test

Affinitak, an experimental drug that was touted as a potential breakthrough in the treatment of the most common type of lung cancer, has failed its crucial phase III clinical trial. The 616-patient study found that patients with non-small-cell lung cancer who received Affinitak plus regular chemo survived on average 10 months compared with 9.7 months for those who got standard therapy. This survival difference of approximately one week wasn't statistically significant.

Affinitak, which was developed by Isis Pharmaceuticals in partnership with Eli Lilly and Company, was one of the first of the so-called "antisense" drugs to reach phase III testing. Many cancers are known to be linked to a malfunctioning portion of the patient's genetic code. Antisense drugs are synthetic polymers designed to "fit" this damaged portion of the patient's genome exactly, locking onto it and effectively disrupting its ability to function.

According to biotech commentator Matt Hougan, "Antisense has been the next big thing for, oh, about twenty years now." However, "despite twenty years of trying, only one tiny antisense drug has ever made it to market." With the disappointing findings from this recent trial, he wrote, "It's back to the drawing board for Isis and back to the drawing board for the entire antisense community."

It is said that about ninety percent of cancer drugs that make it to the last phase of human testing also fail to make it to market. This bleak fact of pharmaceutical economics must have hit home hard to Isis, whose shares, once valued at $18 apiece, fell to below $3 this week.

About the Moss Reports

I hope you enjoy receiving this newsletter, which we have produced for the past few years. Some readers have asked us how we are able to continue producing this newsletter free of charge month after month. While we accept no advertising, we do have a business, which is the independent study and analysis of current cancer treatments on behalf of patients. We produce an extensive series of detailed reports on specific cancers and the many treatments available, both conventional and alternative. We invite you to visit our website at www.cancerdecisions.com to learn more about these reports, which can be conveniently ordered online. Thank you.

--Ralph W. Moss, Ph.D.

References:

Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003;361:695-7.

Expanded patient rights. International Herald-Tribune, February 19, 2003.

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The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.