Breast cancer is second only to lung cancer in American women. The awareness of breast cancer, has grown significantly at the same time that screening has considerably improved. More patients than ever are diagnosed at an early stage, when tumors are still small and confined to a limited area. What is the best way to treat these very small tumors?
Patients with stage I breast tumors (less then two centimeters) in whom the underarm, or axillary, lymph
nodes are free of cancer, have an excellent prognosis with surgery alone. Approximately 90 percent of women in this group will live five or more years without a recurrence of their cancer. Women with even smaller tumors (less than one centimeter) probably have an even better prognosis.
A subset of this latter group, however, may benefit from post-surgical, or adjuvant, therapy, despite the additional risk associated with potential side effects (including serious infections and heart failure). Determining which patients may gain from adjuvant treatments, including chemotherapy and hormone therapy, is a problem facing researchers and clinicians.
In early 2001, a new look at five clinical trials conducted between 1976 and 1993 strongly suggested that adjuvant therapy be considered as an option for some women with very small breast tumors. The report by Bernard Fisher, M.D., of the National Surgical Breast and Bowel Project (NSABP) in Pittsburgh, Penn., appeared in the Jan. 17, 2001, issue of the Journal of the National Cancer Institute.
The report's main finding: post-surgical treatment with chemotherapy, hormonal therapy (tamoxifen), or both, reduced the risk of recurrence in women with tumors measuring one centimeter or less that had no associated sign of cancer in axillary lymph nodes.
In an editorial in the same issue, however, Marc E. Lippman, M.D., professor and chair of the Department of Internal Medicine at the University of Michigan, urged caution before shifting the current treatment paradigm to more liberal recommendations for adjuvant systemic therapy, especially for chemotherapy. So what should patients who fall into the report's profile make of these results?
An important point to keep in mind is that the data in Fisher's report came not from a new clinical trial, but from a "meta-analysis" of five small trials. A meta-analysis re-examines existing data in order to improve the strength of scientific findings by comparing information from similar patients whose numbers in each individual study may be small. The method is a way to combine the results of separate studies, and to synthesize summaries and conclusions.
Meta-analyses can be helpful in evaluating the effectiveness of therapies or in generating ideas about where researchers should go next for answers, but they do not often change medical paradigms or practice. That's because the separate studies in a meta-analysis have often been conducted over a period of 10 to 15 years, in which diagnostic and treatment methods may have changed. Also, different studies are not set up the same way, so data comparisons may be made between similar but not identical variables, or between different variables altogether.
In supporting his report's conclusion that at least some women with very small breast tumors may benefit from adjuvant therapy, Fisher said the meta-analysis for the first time showed with reasonable data that not all women with small tumors will be free from recurrence after surgery without adjuvant therapy.
"There are indeed benefits with this group of patients," Fisher said. "The big question is which patient should get the benefits of this," -- that is, be given the opportunity to get the drugs -- "and which ones shouldn't. This is a dilemma of all clinical trials. The question has to be considered very carefully and be based on the degree of benefit."
Better Prognostic Factors Needed
Part of the difficulty in deciding whether an early breast cancer patient would benefit from adjuvant therapy is that "in small tumors, prognosis changes millimeter by millimeter," Lippman wrote in the accompanying editorial. Where should the line be drawn?
In addition, if the women have no cancer in axillary lymph nodes, physicians can't use one of the strongest predictors of recurrence: the number of cancerous lymph nodes. Instead, physicians must rely on other indicators, such as hormone receptor status, age or menopausal status, all of which may be less reliable.
Another concern of Lippman's was that while the meta-analysis aimed to describe patients with tumors of one centimeter or less, many women in the pooled studies actually had larger tumors. That is, there might not be enough women of the right cancer profile in the pooled studies to support the call for a change in recommended treatment.
"This is a data- and evidence-based question," Lippman said. "The numbers in the study don't apply to most women with small tumors because most women in the study do not have tumors less than one centimeter, and it's not a randomized study."
In the end, wrote Lippman, "the small but real risks [associated with adjuvant therapy] of infection, hemorrhage, cardiomyopathy, deep-vein thrombosis, pulmonary emboli, uterine cancer, etc., may approach, if not exceed, therapy gains."
Jeff Abrams, M.D., coordinator of breast cancer treatment trials in the National Cancer Institute's Cancer Therapy Evaluation Program, said the meta-analysis' conclusion that adjuvant therapy may be beneficial to some early breast cancer patients appears consistent with recommendations from the National Institutes of Health's Consensus Development Conference in November 2000. But he agreed that questions remain.
There are potential pitfalls, he said, involved in combining data over many years. What's needed are additional studies to measure the interplay of factors such as patient's age, tumor size, grade and histological type, and the role of estrogen receptors, all of which must be factored into an assessment of the patient's overall health. Also, new research into genetic and molecular markers of breast cancer may help doctors better quantify the risk of recurrence on a person-by-person basis.
For the future, more studies will be needed to look at just this subgroup of patients. Doctors do not want to subject women who have such a low risk of recurrence to unnecessary therapy, nor do they want to neglect treating women for whom the risk of treatment may be worthy of the benefit.
"The only answer for these women with small tumors will actually come from clinical trials that directly test the question," Abrams said. A better understanding of molecular pathways might someday provide better answers, but those too, will need clinical testing to be sure they accurately predict the outcome for a given individual. "There is no shortcut around clinical trials," he added.