OPPOSITION TO THE ALTERNATIVE HYPOTHESIS

Before concluding their editorial on the intertwining of the Halstedian and Fisher hypotheses, Rabinovitch and Kavanagh abruptly deviate from their circuitous path by stating the following:

“In 1995… [Dr. Samuel] Hellman and Weichselbaum advanced the concept of oligometastases in JCO [the Journal of Clinical Oncology], describing an intermediate phase of cancer progression falling somewhere between the hypotheses of Halsted and Fisher. They [Hellman and Weichselbaum] hypothesized that there exists an opportunity for local therapy—targeting limited and measurable sites of metastatic disease—to meaningfully affect disease-free and overall survival. This concept has already been evaluated in prospective clinical trials, with provocatively encouraging results to date.”

The extensive criticism of our alternative hypothesis by Hellman is likely to have influenced the beliefs of Rabinovitch and Kavanagh, as well as those of other radiation oncologists. In fact, the Rabinovitch and Kavanagh editorial is an abbreviated version of a prior article by Punglia et al and is the forerunner of a recent report by Winkfield and Harris.

Because Hellman’s views continue to attract disciples, both in this country and elsewhere, his conception of our alternative hypothesis requires comment. To familiarize the reader with the alternative hypothesis, a brief summary of the origins and tenets of the alternative hypothesis is presented.

As a consequence of findings obtained by one of us (B.F.) from laboratory investigations in the biology of tumor metastasis conducted during the 1950s and 1960s, we formulated a new hypothesis that has relevance to breast cancer. Each principle of our thesis pertained to a different aspect of tumor biology, and none was the result of either conjecture, impression, or reinterpretation of findings reported by others. Because the tenets of our thesis were contrary to those of Halsted, it was designated the “alternative hypothesis.” (In 1994, our thesis began to be referred to by Hellman as the “systemic” hypothesis, a title that is inappropriate because that term relates to only one of the multiple precepts of our thesis.) A comparison of the tenets comprising the Halsted and alternative hypotheses is presented in Table 2. The comparison in Table 2 clearly demonstrates the dissimilarity of the tenets of the two hypotheses.

Table 2. Comparison of the Tenets Comprising the Halsted and Alternative Hypotheses

Because we recognized the importance of the admonition by French physiologist Claude Bernard, who focused attention on deductive scientific research, and who stated that, “A hypothesis… is the obligatory starting point of all experimental reasoning,” and is only of value if it can be tested, we proceeded to conduct randomized clinical trials to provide information that could lead to either rejection, modification, or support of our hypothesis. The first trial that we implemented in 1971 (NSABP B-04) compared the outcome of patients with clinically node-negative breast cancer who were treated with a Halsted radical mastectomy with the outcome of similar women who underwent either a total (simple) mastectomy followed by locoregional irradiation but no axillary dissection or total mastectomy with no irradiation and removal of axillary nodes only if they became clinically positive. Despite this therapeutic nonconformity, no significant differences in overall treatment failure, distant metastases, or survival were noted among the three groups during 25 years of follow-up. The findings from that trial supported the credibility of our alternative hypothesis, thus providing, for the first time, a biologic basis for breast cancer treatment. Moreover, they eliminated biologic considerations that might have contraindicated evaluating breast-conserving operations.

In October 1973, we began the planning of another study (NSABP B-06), which was implemented in 1976. Its intent was to re-evaluate the alternative hypothesis by appraising the worth of breast-conserving surgery. The findings from that trial, through 20 years of follow-up, revealed no significant difference in distant disease-free survival or survival among patients treated with total mastectomy, lumpectomy alone, or lumpectomy followed by breast irradiation. Those results further supported the merit of our hypothesis and demonstrated that there was neither a biologic nor a clinical rationale for opposing the treatment of stages I and II breast cancer patients by breast-conserving surgery followed by breast irradiation. Thus there resulted a new paradigm for the surgical treatment of breast cancer, one based on biologic principles formulated in the laboratory and confirmed in the clinical setting via randomized clinical trials.

During the past two decades, as a consequence of our previously noted efforts, there has been widespread acceptance of lumpectomy followed by radiation therapy and appropriate systemic therapy for the treatment of breast cancer. Over that time, however, Hellman has expressed criticism of the Fisher alternative hypothesis by challenging its credibility. His criticisms have not been based on information obtained via laboratory or clinical investigation. The subsequent eight bulleted statements by him are followed by our comments.

  * “That [the alternative] hypothesis suggests that breast cancer is a systemic disease and implies that small tumors are just an early manifestation of such systemic disease, which, if it is to metastasize, has already metastasized.”

This remark minimizes the alternative hypothesis by “suggesting” that breast cancer is a systemic disease. Actually, the hypothesis states that, based on extensive experimental findings, breast cancer “is” a systemic disease. Moreover, in neither the alternative hypothesis (Table 2), nor in any of our publications, has it been stated or intimated that a tumor of any size, “... if it is to metastasize, has already done so.” That assertion implies that “predeterminism” has dictated our concept of breast cancer biology, an assumption that is incorrect.

  * “The systemic hypothesis is binary: metastases either do or do not exist. If present, even if microscopic, they are extensive and widespread.”

This statement is antithetical to our understanding of breast cancer biology and, to our knowledge, has never been made by us.

  * “Local control, according to this theory [the alternative hypothesis], is unimportant to survival,” and that “The systemic disease hypothesis suggests that these [distant metastases] occur before clinical detection and argues that [according to Fisher] local eradication of disease makes little or no difference.”