August 1, 2007 (Vol. 27, No. 14)
Ralph W. Moss Ph.D.
Overhyping Decline in Cancer Deaths Is Leaving Promising Treatments Unexamined
The number of cancer deaths in the U.S. declined by one-half of one percent between 2003 and 2004—and the world went wild. Soon after the announcement, on January 17, President Bush paid a rare visit to the NIH to bask in the reflected glory of this alleged turning point in the war on cancer.
“Progress is being made,” Bush intoned. He characterized this decline in cancer deaths as “the steepest drop ever recorded.” While technically true, this gave the misleading impression that the decrease in the number of deaths was both dramatic and precipitous. In fact, the number of cancer deaths had steadily risen for over 70 years after record keeping began—a point that is frequently overlooked. Furthermore, as the population steadily ages and the baby boom generation enters its years of peak cancer incidence, the annual death toll is likely to steadily increase.
Understand that the widely trumpeted decline in U.S. cancer deaths amounted to only a few thousand, a fraction of a percentage point of the toll that cancer takes every year. Yet scientists and politicians made a self-congratulatory mountain out of a statistical molehill. One can, of course, always select facts and figures to argue that progress is being made, but, in my opinion, despite billions of dollars in private and governmental investment, the war is, to say the least, not going well.
From an economic point of view, however, certain pharmaceutical companies are having great success marketing new products for cancer. Since 1949, when FDA approved poisonous Mustargen for the treatment of cancer, scores of new oncology drugs have been licensed.
After the war on cancer was formally launched in December 1971, the rate of innovation slowly began to accelerate. While there were few new FDA approvals for cancer drugs in the 1970s and early 1980s, there were seven new approvals in 1987, 16 in 1996, 21 in 1998, and 28 in 2006. Of course, the absolute number of approvals reveals nothing about the effectiveness of those drugs. Many of them were new indications for older formulations; some drugs have been approved half a dozen or more times on separate occasions for various uses.
As researcher Guy Faguet, Ph.D., pointed out in his book The War on Cancer last year, it is a fallacy to believe that traditional chemotherapy has succeeded in reducing the number of deaths from advanced cancers. But often, FDA, under pressure from industry and patient advocacy groups, has approved new anticancer drugs based not upon evidence that they prolong survival but upon changes in surrogate endpoints. In this way, temporary decreases in tumor size or fluctuations in the serum level of a particular marker have become convenient substitutes for objective demonstrations of survival benefit.
To show that a drug temporarily reduces the size of a tumor is relatively quick and straightforward. To prove that a drug safely and reliably prolongs life may require years of careful observation and follow-up if it can be done at all. This substitution has sometimes confused patients about the actual benefits of a proposed treatment.
To be fair, there have also been certain notable milestones during this protracted campaign. There was justifiable optimism when the FDA gave approval in May 2001 to Gleevec, among the first of a new generation of targeted drugs that selectively attack certain cancer cells.
I was at the meeting where the pending approval of Herceptin was announced. There was euphoria among the gathered oncologists. Here, at last, was a drug that could be used against advanced breast cancer, a mAb that would destroy only those cells that overexpress the human epidermal growth factor receptor, HER-2/neu.
To be sure, these were elegant drugs, a far cry from the crude mustard-gas derivatives and antimetabolites that ushered in the golden age of chemotherapy. Yet most of the targeted drugs that followed have, so far, failed to live up to expectations. For a start, these are no magic bullets. Targeted drugs are not particularly effective when given alone. Even when given alongside standard chemotherapy, their benefit is often only modest.
I recently spoke to a man with stage IV colorectal cancer whose oncologist was recommending the standard regimen of oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) followed by a targeted drug, Avastin. The oncologist conveyed his enormous enthusiasm for this new drug. I pointed out that the results of Eastern Cooperative Oncology Group study E3200, published weeks earlier in the Journal of Clinical Oncology, told a more sobering story.
In this study, patients with metastatic colorectal cancer were treated with FOLFOX4, Avastin, or a combination of the two. For patients treated with Avastin alone, overall survival was 10.2 months; with FOLFOX4 alone, 10.8 months; and, when FOLFOX4 and Avastin were given in combination, survival was extended by an average of just eight weeks.
Furthermore, these two extra months were hardly trouble free: the new drug was associated with increased hypertension, bleeding, and vomiting. Avastin has also been associated with intestinal perforations—an unanticipated side effect that can be fatal.
Meanwhile, as colorectal cancer specialist Leonard Saltz, M.D., of Memorial Sloan-Kettering Cancer Center, has pointed out, the cost of treating advanced colorectal cancer has skyrocketed from $500 per patient in 1999 to $250,000 today, largely due to the addition of these targeted drugs. “There is not enough money in the till to treat everyone,” Dr. Saltz has duly warned.
Changing Cancer Drug Development
In oncology today, new drugs are usually announced amid a carefully orchestrated media blitz involving scientists, company representatives, and politicians. There follows a surge of near-euphoria as the latest potential cure is rolled out for public consumption. But, as we have seen time and again, these drugs quickly turn out to have minimal efficacy in clinical practice.
This public excitement serves the interest of the drug companies, which reap billions of dollars in sales from each new agent. Doctors also profit in various ways, not least from the generous rebates paid by drug companies to physicians who purchase or prescribe certain drugs, as revealed recently in the New York Times.
The media also benefit: feel-good news improves ratings and thereby boosts advertising revenue. Various government bureaucrats and patient advocates benefit because the hope generated by the arrival of each of these new drugs makes their own tenure more secure. The people who profit least from this repetitive cycle are the patients, whose hopes may be inordinately raised—and then dashed—by exaggerated claims. They also, directly and indirectly, foot the bill.
The domination of the cancer field by big pharmaceutical firms has also meant the cultivation of economically safe treatments and avoidance of “the romantic flights of the imagination, the leaps of faith and plummets into the unknown, which alone are likely to open up new worlds,” to quote economist William J. Baumol.
In particular, the current reliance on watertight product patents to recoup the high cost of R&D has discouraged the full investigation of other, nonpatentable agents. This lack could possibly be remedied by FDA’s woefully under-funded Orphan Drug program or by support from philanthropic organizations. At the moment, some promising agents are withering on the vine because of lack of interest by big pharma.
At best, we will continue to face a stalemate for the foreseeable future. Our greatest hope of victory lies in a fundamental reform of the way in which we presently fund and conduct the fight against this dreaded disease.
Ralph W. Moss, Ph.D., directs The Moss Reports,
a continually updated library of evidence-based, diagnosis-specific reports on cancer treatment. The author of many books and articles on cancer, he edits a weekly online newsletter and podcast at www.cancerdecisions.com. E-mail: firstname.lastname@example.org.