Jco 2009-rabinovitch-2422-3


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Jco 2009-rabinovitch-2422-3

  1. 1. VOLUME 27 NUMBER 15 MAY 20 2009 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L Double Helix of Breast Cancer Therapy: Intertwining the Halsted and Fisher Hypotheses Rachel Rabinovitch and Brian Kavanagh, Department of Radiation Oncology, University of Colorado Denver, Aurora, CO It takes 25,000 years for light from the Double Helix Nebula to NSABP B-04 study2 challenged Halstedian philosophy by comparing reach Earth. Astronomers gazing on its spiral arms know that the place radical mastectomy (the standard treatment of the day) with simple where it seems to be located is actually a place where it has already mastectomy and regional irradiation and with simple mastectomy been. Fortunately for patients with cancer, whose lives are measured in alone (ie, no treatment to the axillary lymph nodes). The lack of shorter segments of the space-time continuum, progress in oncology difference in disease-free and overall survival between the arms despite occurs at a pace much quicker than that of transgalactic signaling. differences in regional recurrence exposed a major chink in the Hals- Nevertheless, waiting for the light to come into view can still require tedian armor. As Dr Fisher himself stated, “the B-04 findings sup- patience and time, and it just might be that the place in which we now ported our alternative hypothesis and corroborated our previous find ourselves is a place we have seen before. contention that variations in the treatment of locoregional disease We were led to our most recent viewpoint by Dr Bernard Fisher, were unlikely to affect survival.”2 whose National Surgical Adjuvant Breast and Bowel Project (NSABP) The firm commitment of the NSABP to the model that local has performed landmark studies advancing treatment of breast cancer therapy and local disease control cannot affect survival outcomes for more than five decades. Dr Fisher can be credited for much of the (given the presumed presence of occult systemic disease) is evident in direction and clarity of this research effort; few organizations have the design of the subsequent B-06 trial,3 which established breast been fortunate enough to have a single visionary at the helm for so conservation as a standard approach to early-stage breast cancer. This long. Dr Fisher’s many accomplishments include the promotion of trial compared total mastectomy with segmental mastectomy with or the scientific process and the randomized clinical trial to obtain an- without breast irradiation. Interestingly, according to the guidelines of swers to questions directly affecting clinical care. Outcomes of the that protocol, disease recurrence in the breast after breast-conserving NSABP trials have been evaluated as puzzle pieces, filling in a picture surgery was treated with mastectomy and considered merely a “cos- and contributing to his understanding of cancer biology. He has metic failure;” recurrence in the breast was not even scored as an always been one of the first to advocate for redirection of scientific event affecting disease-free survival. Furthermore, for patients in inquiry on the basis of this changing picture. Like the old axiom he the B-06 study experiencing ipsilateral breast tumor recurrence once quoted—“that which is logical is apt not to be true, and that (IBTR), the protocol specified that other than salvage mastectomy, which is true often seems illogical”1— he has made it clear that scien- “no other therapy will be permitted without evidence of tumor tific reality is not always readily intuitive. elsewhere. This includes radiation therapy, systemic therapy such At the scientific core of Dr Fisher’s work is his self-described alternative hypothesis, known to most of us as the systemic or Fisher as chemotherapy, hormonal therapy, and castration.”3 Local re- hypothesis of breast cancer. In this model, breast cancer is considered currences were not considered potential sources of subsequent a systemic disease at time of diagnosis, a condition requiring treatment metastatic spread. of the entire patient rather than just the source organ. Ultimate man- There is now, however, a sizable body of evidence, much of it ifestation of systemic (metastatic) disease is the result of tumor and originating from within the NSABP itself, suggesting a need to re- patient heterogeneity and the complex interactions between them. evaluate the Fisher hypothesis and consider bringing Halsted back This theory diverges dramatically from the Halsted hypothesis, the into view. Data in this issue of Journal of Clinical Oncology reported established paradigm of the preceding 100 or so years, named for the by Anderson et al,4 taken together with numerous other analyses, surgeon who performed the first radical mastectomy in 1882. Halsted reveal a constellation of provocative observations. A sampling of and his disciples saw breast cancer as a disease spreading in an orderly these include: and typically contiguous manner: from breast to lymph nodes and ● Lumpectomy followed by breast irradiation, as compared only then to distant metastatic sites. This concept supported the use of with lumpectomy alone, was associated with a marginally extensive local surgery (ie, radical mastectomy) to remove all contig- significant decrease in deaths due to breast cancer (P .04),” uous regional disease; this was expected to yield the greatest cure rates. as reported in the 20-year follow-up of the NSABP B-06 trial.5 The Fisher hypothesis was formulated after the integration of ● The risk of distant disease for patients treated on the NSABP years of laboratory and clinical investigations. The degree to which this B-06 trial was 3.41 times greater in patients who developed paradigm shift was original and dramatic cannot be overstated. The IBTR than in patients who did not.6 2422 © 2009 by American Society of Clinical Oncology Journal of Clinical Oncology, Vol 27, No 15 (May 20), 2009: pp 2422-2423 Downloaded from jco.ascopubs.org on October 7, 2010. For personal use only. No other uses ahead of print at www.jco.org on April 6, 2009 DOI: 10.1200/JCO.2009.21.8453; published online without permission. Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
  2. 2. Editorial ● In the NSABP adjuvant trials, the hazard rate for mortality In the end— or maybe in another beginning—after many years after IBTR was 4.49 in estrogen receptor–negative node- of searching the skies, we have arrived at a necessarily double-stranded negative patients and 2.33 in estrogen receptor–positive node- approach that involves both local and systemic considerations. As we negative patients, as reported by Anderson et al.4 continue to explore the universe for new breast cancer treatments, we ● In the NSABP adjuvant trials, the hazard rate for mortality should be open to illumination from new and old sources. To para- after IBTR was 2.58 in node-positive patients, as reported by phrase a passage from the late Douglas Adams, something of an Wapnir et al.7 authority on galactic travel, let’s keep hoping that even if we don’t go ● There was a highly significant reduction in the annual breast where we intend to go, we’ll end up where we need to be.12 cancer mortality rate for patients treated with radiotherapy after lumpectomy versus lumpectomy alone (breast cancer AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST death rate ratio, 0.83; 95% CI, 0.75 to 0.91; 2P .0002), as The author(s) indicated no potential conflicts of interest. reported in a meta-analysis by Early Breast Cancer Trialists’ AUTHOR CONTRIBUTIONS Collaborative Group.8 Conception and design: Rachel Rabinovitch ● In numerous trials and meta-analyses, improved regional Manuscript writing: Rachel Rabinovitch, Brian Kavanagh control with postmastectomy radiotherapy was associated Final approval of manuscript: Rachel Rabinovitch with improved survival.9 There is little room for doubt that patients who experience IBTR REFERENCES have a significantly increased risk of death. The benefit of breast 1. Fisher B: Laboratory and clinical research in breast cancer: A personal adventure—The David A. Karnofsky memorial lecture. Cancer Res 40:3863-3874, radiotherapy in maintaining a cancer-free breast is not only cosmetic. 1980 Furthermore, even after mastectomy, regional control is still necessary 2. Fisher B: From Halsted to prevention and beyond: Advances in the to optimize the chance for long-term survival. Breast cancer recur- management of breast cancer during the twentieth century. Euro J Cancer rence cannot merely be an indicator of aggressive disease, as ex- 35:1963-1973, 1999 3. Fisher B, Bauer M, Margolese R, et al: Five-year results of a randomized plained by the Fisher hypothesis, if local therapies affect ultimate clinical trial comparing total mastectomy with or without radiation in the treat- distant disease dissemination. ment of breast cancer. N Engl J Med 312:665-673, 1985 There have been several other visionaries over the years who have 4. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral proposed similarly rebellious theories of solid tumor dissemination. breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel In 1995, for example, Hellman and Weichselbaum10 advanced the Project protocols of node-negative breast cancer. J Clin Oncol 27:2466-2473, concept of oligometastases in JCO, describing an intermediate phase 2009 of cancer progression falling somewhere between the hypotheses of 5. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a random- Halsted and Fisher. They hypothesized that there exists an oppor- ized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233- tunity for local therapy—targeting limited and measurable sites of 1241, 2002 metastatic disease—to meaningfully affect disease-free and overall 6. Fisher B, Anderson S, Fisher ER, et al: Significance of ipsilateral breast survival. This concept has already been evaluated in prospective clin- tumour recurrence after lumpectomy. Lancet 338:327-331, 1991 ical trials, with provocatively encouraging results to date.11 7. Wapnir IL, Anderson SJ, Mamounas EP, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Ultimately, the demonstrated benefits of successful local therapy Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. to the primary site, and perhaps also to sites of oligometastatic disease, J Clin Oncol 24:2028-2037, 2006 would not be visible without effective systemic therapies and vice 8. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence versa. Shifting patterns of disease recurrence are the signs of newly and 15-year survival: An overview of the randomised trials. Lancet 366:2087- effective local or systemic therapies; improvements in disease control 2106, 2005 imparted by one therapy complement and magnify the importance of 9. Overgaard M, Nielsen HM, Overgaard J: Is the benefit of postmastectomy moving forward with another. In the earliest years of the NSABP, irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c when patients were generally diagnosed with higher rates and burdens randomized trials. Radiother Oncol 82:247-253, 2007 of occult systemic disease and treated with far fewer and less effective 10. Hellman S, Weichselbaum RR: Oligometastases. J Clin Oncol 13:8-10, systemic therapies, local disease management indeed had little impact 1995 on ultimate treatment outcome. Today, with downward stage migra- 11. Milano MT, Zhang H, Metcalfe SK, et al: Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer tion of newly diagnosed breast cancer, and much broader use of highly Res Treat [epub ahead of print on August 22, 2008] effective layered chemotherapy and endocrine therapy, the impact of 12. Adams D: The Hitchhiker’s Guide to the Galaxy. London, United Kingdom, local disease control is coming into telescopic focus. Pan Books, 1979 ■ ■ ■ www.jco.org © 2009 by American Society of Clinical Oncology 2423 Downloaded from jco.ascopubs.org on October 7, 2010. For personal use only. No other uses without permission. Copyright © 2009 American Society of Clinical Oncology. All rights reserved.