It is also alleged in the Rabinovitch and Kavanagh editorial that, “... according to the guidelines of that protocol [B-06], disease recurrence in the breast after breast-conserving surgery was treated with mastectomy and considered merely a ‘cosmetic failure’... ” and that “recurrence in the breast was not even scored as an event affecting disease-free survival.” The authors’ use of the qualifying words “merely” and “not even” to suggest that we opted to treat disease recurrence after breast conservation in a cavalier fashion has no basis in fact. They have either misinterpreted, or are not familiar with, the specific aims and guidelines of the B-06 protocol with regard to the local control of breast cancer. They state further that, in patients in B-06 who experienced an IBTR, “... no other therapy [other than a salvage mastectomy] will be permitted without evidence of tumor elsewhere. This includes radiation therapy, systemic therapy such as chemotherapy, hormonal therapy, and castration.” Their inference seems to be that our treatment of the women in the B-06 trial was inadequate and that, as a consequence, we were putting our patients’ safety at risk. In the reference list that accompanies the Rabinovitch and Kavanagh editorial, the authors list one of our articles that was purported to contain the above statement about the use of other therapy. Such a statement never appeared, either in our first, or in any subsequent reports, of the findings from that study, but was, instead, part of a 54-page document that was distributed to participating NSABP physicians and that described in detail the Background, Specific Aims, Plan of Investigation, and Conduct of the B-06 trial (National Surgical Adjuvant Breast Project Protocol B-06. A protocol to compare segmental mastectomy and axillary dissection with and without radiation of the breast, and total mastectomy and axillary dissection [unpublished report]). The document also clearly defined the meaning of treatment failure, survival, and cosmetic failure and specifically indicated that, “No additional therapy will be permitted without evidence of tumor elsewhere.” (National Surgical Adjuvant Breast Project Protocol B-06. A protocol to compare segmental mastectomy and axillary dissection with and without radiation of the breast, and total mastectomy and axillary dissection [unpublished report, p 4]). It seems, however, that Rabinovitch and Kavanagh overlooked a subsequent paragraph included in that document, in which the following statement appears:
“When this [an IBTR] occurs in patients with histologically positive nodes who are receiving chemotherapy, those patients will be managed with total mastectomy. If necessary, chemotherapy [which all node-positive patients received] may be interrupted to permit operation and recovery. Effort should be made to re-establish treatment, ie, [every] 6 weeks cycle as soon as possible and no later than six (6) weeks after operation.” (National Surgical Adjuvant Breast Project Protocol B-06. A protocol to compare segmental mastectomy and axillary dissection with and without radiation of the breast, and total mastectomy and axillary dissection [unpublished report, p 5]).
Because Rabinovitch and Kavanagh have taken our statement about the use of additional therapy out of context, the question may be raised regarding whether they are cognizant of the complexities of clinical trial design, for example, the need for proper control groups, as well as the need for eliminating circumstances that could interfere with appropriate biostatistical analyses and conclusions. One wonders whether they are aware that the aim of the appropriately conducted clinical trial is to obtain information in such a way as to obviate empirical thinking. Another example of their misrepresentation of our data involves a statement that has appeared in more than 20 of our articles that were published between 1980 and 2008. In all of those publications, we stated that, “Variations in local-regional therapy are unlikely to substantially affect survival.” It seems strange that Rabinovitch and Kavanagh cite that article in which the word “substantially” was inadvertently omitted from a sentence quoted from the original source. (The importance of the omission of that word will become evident when the benefit in survival outcome after the use of postoperative radiation therapy is discussed later in this commentary.)
Most inappropriate was the assertion in the Rabinovitch and Kavanagh editorial that, before the design of the B-06 trial, the NSABP was firmly committed “... to the model that local therapy and local disease control cannot affect survival outcomes (given the presumed presence of occult systemic disease). ... ” It must be noted that no one associated with the NSABP had, a priori, any “commitment” to implement a study based on such a collective or personal bias. When the B-06 trial was designed and conducted to test the worth of the Fisher hypothesis and, consequently, the credibility of treating breast cancer with lumpectomy, the NSABP was an organization of hundreds of doctors, statisticians, nurses, and other professionals who were committed to the performance of clinical trials. Because the design, implementation, and initial reporting of the study were carried out by the principal investigator (B.F.), in collaboration with NSABP biostatisticians and selected radiation oncologists, and with the approval of officials of the National Cancer Institute and their intramural and extramural committees, any suggestion of bias in the design of the B-06 study is a challenge to the probity of all who were involved.
PUTATIVE NEED TO RE-EVALUATE THE ALTERNATIVE HYPOTHESIS?
Another example of the way in which Rabinovitch and Kavanagh have misinterpreted our findings is evidenced by their statement that, “There is now, however, a sizable body of evidence, much of it originating from within the NSABP itself,... together with numerous other analyses [that] reveal a constellation of provocative observations” that support the notion that the Fisher hypothesis requires re-evaluation and that Halsted should, perhaps, be brought “back into view.” This so-called evidence is portrayed in the Rabinovitch and Kavanagh editorial in six bulleted (•) statements, each one of which putatively supports the authors’ claim. Three of these statements relate to the effect of an IBTR on distant disease and mortality, whereas the others support the value of radiation therapy after lumpectomy for improving survival.
The following snippets of data from three NSABP publications about lumpectomy-treated women who subsequently developed an IBTR are presented without either explanation or discussion:
- “The risk of distant disease… was 3.41 times greater in patients who developed IBTR than in patients who did not.”
- “In the NSABP adjuvant trials, the hazard rate for mortality after IBTR was 4.49 in estrogen receptor–negative node-negative patients and 2.33 in estrogen receptor–positive node-negative patients, as reported by Anderson et al.”
- “In the NSABP adjuvant trials, the hazard rate for mortality after IBTR was 2.58 in node-positive patients, as reported by Wapnir et al.”
Although the statements are correct as presented, Rabinovitch and Kavanagh fail to indicate how these assertions support their claim that the NSABP has provided evidence to re-evaluate the Fisher hypothesis. Only by using the findings from the B-06 trial, in which randomized comparisons were made among patients treated with lumpectomy, lumpectomy and radiation therapy, or total mastectomy, can the relationship between the incidence of IBTR and patient survival be appropriately assessed. The results from the NSABP B-06 trial provide no support for consideration of a return to Halsted.
Rabinovitch and Kavanagh have also elected to present information from their “constellation of provocative observations” to bolster their claim that the use of postlumpectomy radiation has not only reduced the rate of IBTR but also resulted in increased survival. They state the following: