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Taxane Evidence Inconclusive in Adjuvant Setting

Judith Randal

The taxane drug paclitaxel (Taxol) prolongs the lives of many women whose breast cancers have metastasized. So it seems hardly far-fetched that it might also be good as adjuvant—i.e., postsurgical—therapy for women with early stage breast cancers. Indeed, the U.S. Food and Drug Administration approved Taxol for this purpose in 1999. (The agency has also approved Taxotere, a close chemical cousin of Taxol, but only for advanced disease.)

All of which is why early breast cancer patient Anna G. (at her request not her real name) decided to go to the Consensus Conference on Adjuvant Therapy for Breast Cancer at the National Institutes of Health in Bethesda, Md., in November. The 36-year-old teacher was nearing the end of 3 months of initial adjuvant chemotherapy with doxorubicin and cyclophosphamide and was planning on 3 months of Taxol or Taxotere next. As she settled in at the meeting to listen to the presentation on taxanes and the discussions of them that followed, she expected to learn that she had made the right choice.

Instead what she heard made her doubt her decision. And when the consensus panel’s report bluntly said that "available data is currently insufficient to justify the routine use of taxanes . . . in adjuvant therapy of breast cancer," she doubted it still more. After mulling it over further, she told her oncologist that she would prefer not to take either drug and was relieved when the physician did not object.

The reality, however, is that the consensus panel’s report on taxanes as adjuvant therapy may fall differently on different ears. At the Mayo Clinic in Jacksonville, Fla., for instance, Edith Perez, M.D., comes to the issue having been a participating physician in the multicenter Cancer and Leukemia Group B (CALGB) trial of adjuvant paclitaxel, one of the two studies that were presented to the panel and, though unpublished, were available for its review.



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Dr. Edith Perez

 
The panel’s report termed the results of these studies "inconclusive," an assessment that Perez agrees with and that she believes is good reason to give adjuvant paclitaxel the benefit of the doubt. Her practice, therefore, she said, is to offer this drug to virtually all patients with early breast cancer —providing they are node-positive—and to encourage them to accept it.

"Clearly Worthwhile"

Like Perez, Daniel Hayes, M.D., of Georgetown University in Washington, D.C., also participated in the multicenter CALGB trial. While perhaps not quite the adjuvant taxane enthusiast Perez is, his take on the matter is that "Taxol is clearly worthwhile in selected [primary breast cancer] patients."



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Dr. Daniel Hayes

 
Most important, in his view, is that patients in the CALGB study treated with paclitaxel had about a 20% lower risk of disease recurrence within 30 months of follow-up than did their counterparts who served as controls, and also had fewer early deaths. Therefore, he now tells patients that "if your estimated prognosis after [initial adjuvant] chemotherapy with Adriamycin and cyclophosphamide is sufficiently poor, then you should get Taxol."

There are more nuanced pro-taxane views as well. Carolyn Hendricks, M.D., a Bethesda medical oncologist in private practice who was on the consensus panel, noted, for example, that the panel had to wrestle with factors that some would construe as extraneous to its deliberations on taxanes but actually were not.

Among these, she said, is that initial adjuvant chemotherapy for breast cancer is far from uniform in the United States. Thus, while a drug in the anthracycline class—e.g., Adriamycin—in combination with cyclophosphamide is the standard formula on the east coast, 5-fluorouracil is often added to it in some parts of the country, and the standard regimen in still other parts is yet another variation. Though it is possible that the variation has little or no impact on subsequent taxane therapy, Hendricks explained that this is unknown.

Nor is it known, she continued, whether the benefits of adjuvant taxanes—assuming they are real—are due specifically to these drugs or merely to their prolonging the total time primary breast cancer patients undergo chemotherapy. Meanwhile, she noted, taxanes tend to make patients fatigue easily and the drugs’ other side effects—which are mainly neuromuscular—can be miserable. Among her adjuvant paclitaxel patients, for example, is a professional violinist who is finding it hard and sometimes impossible to play her instrument.

Conflicting Data

But perhaps the key issue the consensus panel tackled—though not specifically mentioned in its report—is that the same data that caused the FDA to approve adjuvant paclitaxel caused the European Community’s Drug Regulatory Authority to withhold approval of the drug except for advanced disease.

Sir Richard Peto, of the University of Oxford in England—an invited speaker at the consensus meeting and a world-renowned breast cancer trialist—did not mention either agency’s position. Nonetheless, a point he is famous for making and that he made again on this occasion was clearly taken seriously by the panel: To draw conclusions from clinical trials of oncology drugs too quickly—i.e., before there has been enough time for the results to play out—can be to get an overly rosy picture of how well they work.

Patricia Ganz, M.D., of the University of California at Los Angeles, believes that the FDA’s approval of adjuvant paclitaxel on the basis of preliminary data from the CALGB trial alone (at the time, the only data available for the agency to go on) may have been just such a rush to judgment.



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Dr. Patricia Ganz

 
"The trouble is," she said, "that early reporting of results in this disease may not give us the final answer. That seems likely in this case because the gap between the overall survival of patients who were given adjuvant paclitaxel and those who were not has narrowed since the approval and in the 52-month update that was presented at the consensus conference is no longer statistically significant.

"Besides," she added, "a second multicenter randomized trial (a collaboration of the National Surgical Adjuvant Breast and Bowel Project that began later than the CALGB trial) has thus far, at least, failed to show that adjuvant paclitaxel is beneficial. Although that might be because its patient mix is somewhat different, the fact remains that of the adjuvant Taxol studies for which there now are data one has had negative results and the positive results of the other have diminished over time."

Study Ongoing

On the brighter side for adjuvant paclitaxel, meanwhile, is that the CALGB data continue to show that it delays disease recurrence. However, two caveats apply. One is that the available evidence suggests that this is not true for the large patient subgroup that is hormone-receptor–positive, a point confirmed in the NSABP trial that was designed from the outset, unlike the CALGB trial, to tease out the risk of recurrence in such women. The other is that the decrease in the risk of recurrence in the CALGB trial, while still statistically significant, has declined from the 22% previously reported to 13% with longer follow-up.

So will there be patients who value an enhanced likelihood of disease-free time, however brief, so highly that they will opt for adjuvant paclitaxel almost no matter what? "Perhaps," said Ganz, "and that is surely their prerogative." On the other hand, her policy is "to discuss all the available evidence there is with a woman about this or other interventions to give her an optimum opportunity to weigh their pros and cons."

More broadly, Ganz’s concern is "whether you want to expose all node-positive patients to this (adjuvant paclitaxel) when it well could be that only those of them who are hormone receptor-negative stand to benefit.

"This is not to say," she insisted, "that initial adjuvant chemotherapy is not worthwhile; it has clearly helped to reduce breast cancer mortality. Rather, the question is whether adding 3 months of adjuvant paclitaxel to 3 to 6 months of initial adjuvant chemotherapy (the duration varies with the regimen) will extend women’s lives by at least that much.

"Given paclitaxel’s toxicity—which can be quite disabling—and the attendant physical and emotional burden of all those extra treatment sessions, the choice would be tough even if we had the answer," she said. "Since we don’t—at least, not yet—it is that much harder a judgment call for both patients and their oncologists."



             
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