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.