Sometimes a Great Notion—An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer

JNCI: Journal of the National Cancer Institute, Feb 2005

Davidson, Nancy E., Morrow, Monica

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Sometimes a Great Notion—An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer

Journal of the National Cancer Institute Sometimes a Great Notion-An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer Nancy E. Davidson 0 1 Monica Morrow 0 1 0 DOI: 10.1093/jnci/dji049 Journal of the National Cancer Institute , Vol. 97, No. 3, © Oxford University Press 2005, all rights reserved 1 Affiliations of authors: Johns Hopkins Kimmel Cancer Center , Baltimore , MD (NED); Fox Chase Cancer Center , Philadelphia, PA (MM). Center, 1650 Orleans St., Rm. 409, Baltimore, MD 21231 , USA - Sometimes I live in the country, Sometimes I live in the town, Sometimes I get a great notion… From the song “Good Night, Irene” By Huddie Ledbetter and John Lomax as adapted by Ken Kesey The use of neoadjuvant (aka, preoperative or primary) systemic therapy for the management of operable breast cancer has been widely heralded as the future of breast cancer treatment. The underlying rationale consists of several important observations including the success of this strategy for locally advanced breast cancer, the utility of the approach to permit organ preservation in other tumor types, and a compelling preclinical literature suggesting that preoperative administration of chemotherapy is associated with improved survival in a rodent breast cancer model. Enthusiasm has also been engendered by the belief that preoperative therapy would improve clinical outcomes, enhance the likelihood of breast conservation, and facilitate prediction of treatment response, thereby leading to individualization of therapy ( 1,2 ). A meta-analysis of neoadjuvant versus adjuvant systemic therapy for early-stage breast cancer in this issue of the Journal provides an opportunity for reflection about this approach ( 3 ). This meta-analysis appears to be carefully performed and methodologically sound. Its assumptions and limitations are meticulously delineated. In brief, a search of the medical literature yielded 12 potentially eligible trials of neoadjuvant versus adjuvant chemotherapy or endocrine therapy; three were excluded because the results have not yet been published in the peer-reviewed literature. Participants in the nine trials total a surprisingly meager 3946 patients; more than half are derived from the NSABP B18 ( 4 ) and EORTC 10902 ( 5 ) trials. The meta-analysis did not show any statistically or clinically significant difference between the adjuvant and neoadjuvant arms for death, disease progression, or distant recurrence. Paradoxically, neoadjuvant therapy was associated with a statistically significantly increased risk of locoregional recurrence; this increased risk was largely attributed to trials where radiotherapy without surgery was used for patients who had a complete clinical response after neoadjuvant therapy. The rate of breast conservation was increased by neoadjuvant therapy in only six of the studies, and the rates of clinical and pathologic complete response were highly variable. The authors conclude that these results are not likely to change even with the inclusion of data from two studies of 1315 patients as yet unreported, a contention that is likely to be correct. What can we conclude? First, this meta-analysis confirms that surgery remains an essential part of early breast cancer management, even when systemic therapy appears to have eradicated all grossly evident disease. The absence of any tumor (invasive or intraductal) on pathologic examination after neoadjuvant therapy was demonstrated in less than 10% of women in the larger studies in this overview ( 4–6 ). Although we might anticipate that radiation alone would give favorable local control rates in these women, the identification of patients with a pathologic complete response before surgery has proved to be a difficult task. Use of mammography, physical examination, or magnetic resonance imaging cannot reliably assess degree of response in this setting ( 7,8 ). Newer approaches using functional MRI show promise but they remain to be validated in large studies (9). Until complete pathologic responses to neoadjuvant therapy can be reliably identified and until clinical trials demonstrate that local control rates equivalent to those seen with surgery and radiation are obtained with radiotherapy alone, surgery must be considered a routine part of management. Second, not only was the local failure rate increased by 22% in neoadjuvant recipients, but also the rate of conversion to breast conservation was not uniformly improved in these trials. This is in part because a large number of women were already candidates for breast conservation—66% and 24% of patients randomly assigned to neoadjuvant therapy on the NSABP B18 EDITORIALS and EORTC trials, respectively ( 4,5 ). Also, higher rates of local recurrence are seen in those women who require chemotherapy to undergo breast preservation. For example, local recurrence rates were 15% in patients requiring chemotherapy to undergo breast conservation compared with 7% for those who we (...truncated)


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Davidson, Nancy E., Morrow, Monica. Sometimes a Great Notion—An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer, JNCI: Journal of the National Cancer Institute, 2005, pp. 159-161, Volume 97, Issue 3, DOI: 10.1093/jnci/dji049