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Over the past 2 decades, two major trends in the treatment of breast cancer-breast-conserving therapy and neoadjuvant (or preoperative) chemotherapy-have converged to stimulate interest in the use of neoadjuvant chemotherapy to facilitate breast conservation in women presenting with large tumors. After being established as the treatment of choice for locally advanced or inoperable breast cancer, theoretical considerations and the desire to extend breast-conserving therapy to more patients with large tumors have resulted in an increase in the use of neoadjuvant chemotherapy in operable patients. Drs. Green and Hortobagyi have provided us with a comprehensive review of the background and the current state of neoadjuvant chemotherapy for breast cancer.
Over the past 2 decades, two major trends in thetreatment of breast cancerbreast-conserving therapy and neoadjuvant (orpreoperative) chemotherapyhave converged to stimulate interest in the use ofneoadjuvant chemotherapy to facilitate breast conservation in women presentingwith large tumors. After being established as the treatment of choice forlocally advanced or inoperable breast cancer, theoretical considerations and thedesire to extend breast-conserving therapy to more patients with large tumorshave resulted in an increase in the use of neoadjuvant chemotherapy in operablepatients. Drs. Green and Hortobagyi have provided us with a comprehensive reviewof the background and the current state of neoadjuvant chemotherapy for breastcancer.
As the authors explain, several early nonrandomized and randomized trialswere interpreted as indicating a survival advantage for neoadjuvant chemotherapyover the standard adjuvant approach. Nonrandomized trials reaching thisconclusion have little weight, and even some of the randomized trials ofneoadjuvant therapy were seriously flawed, making this conclusion questionable.
For example, in two large European trials, a significant proportion ofpatients in the adjuvant group received no chemotherapy at all, whereas allpatients in the neoadjuvant group received systemic treatment.[1,2] By thecurrent standard of adjuvant treatment, patients with tumors > 3 cm indiameter would receive chemotherapy regardless of nodal status. Moreimportantly, this selective use of chemotherapy in the adjuvant arms of thesestudies results in unbalanced treatment, invalidating conclusions about thepreferred sequence of therapy. In addition, as Green and Hortobagyi pointed out,with longer follow-up, the survival advantage attributed to preoperativechemotherapy disappeared.[3,4]
The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-18demonstrated the equivalence of neoadjuvant chemotherapy in terms of survival,as well as an increase in the use of breast-conserving therapy.[5,6] Thus, thereare adequate data to support the use of this approach in women with largetumors, to make breast-conserving therapy feasible.
The difficulty in assessing the extent of residual tumor after chemotherapy,discussed briefly in this review, raises a number of issues relevant to thesurgical management of women whose tumors have been "shrunk" byneoadjuvant chemotherapy. As the authors point out, no single test orcombination of tests has been completely reliable in delineating whether andwhere viable tumor remains in the breast. This explains why attempts to omitsurgical excision of the primary tumor site, even in highly selected patientswith an apparent complete response, have often led to unacceptably high localrecurrence rates.[3,4,7,8] In NSABP trial B-18, in which surgical excision witha negative margin was required by protocol, early results indicated a higherrate of local recurrence among women who became candidates for breast-conservingtherapy as a result of preoperative chemotherapy.
This demonstrates that our notion of what happens to a tumor during the"shrinkage" process may be inaccurate. It may be that some tumorsreally do shrink down to a smaller size, but others become more vague andill-defined, leaving nests of viable tumor cells scattered at the perimeter ofthe original tumor dimensions. Whether positron-emission tomography, magneticresonance imaging, or another approach will solve this dilemma remains to beseen.[9-13] Furthermore, as shown by the results of B-18, the presence ofresidual tumor on pathologic examination of the breast tissue has prognosticimportance.
As pointed out in the review, nodal status after chemotherapy remains anotherpowerful predictor of outcome. It is unclear, however, whether the presence ofnodal tumor in this setting indicates a large tumor burden at diagnosis or thechemoresistance of the tumor (or both).[6,14-17] Conversely, it is also unclearwhether the absence of nodal metastases means that the nodes were initiallynegative or that chemotherapy has eliminated nodal disease.
Whatever the case may be, pathologic assessment of lymph nodes has importantprognostic significance. It may turn out that the relatively new sentinel lymphnode mapping technique can be applied after chemotherapy to avoid axillary lymphnode dissection in these patients, but this has not been clearly established.Several recent studies suggest that the accuracy of this technique afterchemotherapy is similar to that in the primary surgery setting.[18-21]
What has been clearly established in many of the studies on neoadjuvantchemotherapy is that tumor response is a powerful predictor of patient outcome.This, in fact, may provide the strongest rationale for the use of neoadjuvanttreatment, at least in the setting of a clinical trial. By using clinical orpathologic response (the latter being the strongest predictor of survival inmost series) as a "surrogate" for survival, we may be able to comparesystemic treatment regimens and new drugs more rapidly than can be done incurrent adjuvant trials.
Unfortunately, however, the rate of pathologic complete responses reported sofar has been quite lowmostly in the range of 10% to 15%, and sometimeslower.[5,15,22] Furthermore, it has not yet been demonstrated convincingly thata change in neoadjuvant treatment that increases response rates will alsoimprove survival. Based on the correlation between response and survival, theimplicit assumption is that this will be the case, but solid data on this issueare lacking. It could be that the link between response and survival simplyreflects the biology of the tumor.
Response Rates and Survival
Several studies that have recently completed accrual and for whichpreliminary results have been reported may provide some answers, for example, asto whether the addition of a taxane to neoadjuvant treatment will increaseresponse rates and survival. Preliminary results from NSABP protocol B-27,reported at the 2001 San Antonio Breast Cancer Symposium, demonstrate that theaddition of preoperative docetaxel (Taxotere) sequentially after four cycles ofdoxorubicin and cyclophosphamide (Cytoxan, Neosar) nearly doubled the pathologiccomplete response rate, but no survival data were available. A small trial fromAberdeen, Scotland, reported at the same meeting also demonstrated that theaddition of docetaxel after anthracycline-based chemotherapy increasedpathologic response rates, as well as 3-year disease-free and overallsurvival.
If long-term follow-up of these studies provides convincing evidence that thechange in treatment, which precipitated an increase in local tumor response alsoimproves survival, then the potential of neoadjuvant chemotherapy to accelerateprogress in breast cancer treatment may well be realized. Eventually, with thedevelopment of sophisticated methods of measuring gene expression and thebioinformatic techniques to analyze these data, the use of neoadjuvant therapyto evaluate the biological and genetic markers that may predict response couldprove to be the most meaningful contribution of this approach and the key tofuture progress in cancer chemotherapy.
1. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy inconservative treatment of breast cancer patients with operable tumors largerthan 3 cm. Results of a randomized trial in a single centre. Ann Oncol2:347-354, 1991.
2. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvantchemotherapy in premenopausal patients with tumours considered too large forbreast conserving surgery: Preliminary results of a randomised trial: S6. Eur JCancer 30A:645-652, 1994.
3. Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy foroperable breast carcinoma larger than 3 cm: A unicentre randomized trial with a124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). AnnOncol 10:47-52, 1999.
4. Scholl SM, Pierga JY, Asselain B, et al: Breast tumour response to primarychemotherapy predicts local and distant control as well as survival. Eur JCancer 31A:1969-1975, 1995.
5. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapyon local-regional disease in women with operable breast cancer: Findings fromNational Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol15:2483-2493, 1997.
6. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapyon the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685,1998.
7. Perloff M, Lesnick GJ, Korzun A, et al: Combination chemotherapy withmastectomy or radiotherapy for stage III breast carcinoma: A Cancer and LeukemiaGroup B study. J Clin Oncol 6:261-269, 1988.
8. Baillet F, Rozec C, Ucla L, et al: Treatment of locally advanced breastcancer without mastectomy: 5- and 10-year results of 135 tumors larger than 5centimeters treated by external-beam therapy, brachytherapy, and neoadjuvantchemotherapy. Ann N Y Acad Sci 698:264-270, 1993.
9. Raylman RR, Fisher SJ, Brown RS, et al:Fluorine-18-fluorodeoxyglucose-guided breast cancer surgery with apositron-sensitive probe: Validation in preclinical studies. J Nucl Med36:1869-1874, 1995.
10. Smith IC, Welch AE, Hutcheon AW, et al: Positron-emission tomographyusing [18F]-fluorodeoxy-D-glucose to predict the pathologic response of breastcancer to primary chemotherapy. J Clin Oncol 18:1676-1688, 2000.
11. Schelling M, Avril N, Nährig J, et al: Positron-emission tomographyusing [18F]fluorodeoxyglucose for monitoring primary chemotherapy in breastcancer. J Clin Oncol 18:1689-1695, 2000.
12. Abraham DC, Jones RC, Jones SE, et al: Evaluation of neoadjuvantchemotherapeutic response of locally advanced breast cancer by magneticresonance imaging. Cancer 78:91-100, 1996.
13. Gligorov J, Chopier J, Benchimol Y, et al: Breast magnetic resonanceimaging (MRI): A useful tool for therapeutic decision in patients treated forlocally advanced breast cancer (LABC) by neoadjuvant chemotherapy (abstract206). Breast Cancer Res Treat 69:238, 2001.
14. McCready DR, Hortobagyi GN, Kau SW, et al: The prognostic significance oflymph node metastases after preoperative chemotherapy for locally advancedbreast cancer. Arch Surg 124:21-25, 1989.
15. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy inoperable breast cancer: Eight-year experience at the Milan Cancer Institute. JClin Oncol 16:93-100, 1998.
16. Machiavelli MR, Romero AO, Pérez JE, et al: Prognostic significance ofpathological response of primary tumor and metastatic axillary lymph nodes afterneoadjuvant chemotherapy for locally advanced breast carcinoma. Cancer J Sci Am4:125-131, 1998.
17. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancerpatients with complete pathologic primary tumor and axillary lymph node responseto doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999.
18. Breslin TM, Cohen L, Sahin A, et al: Sentinel lymph node biopsy isaccurate after neoadjuvant chemotherapy for breast cancer. J Clin Oncol18:3480-3486, 2000.
19. Mamounas E, Brown A, Smith R, et al: Sentinel node biopsy (SNB) followingneoadjuvant chemotherapy in breast cancer (BC): Results from NSABP B-27.Abstracts from the Society of Surgical Oncology 54th Annual Cancer Symposium,Washington, DC, 2001.
20. Tafra L, Verbanac KM, Lannin DR: Preoperative chemotherapy and sentinellymphadenectomy for breast cancer. Am J Surg 182:312-315, 2001.
21. Julian TB, Patel N, Dusi D, et al: Sentinel lymph node biopsy afterneoadjuvant chemotherapy for breast cancer. Am J Surg 182:407-410, 2001.
22. Powles TJ, Hickish TF, Makris A, et al: Randomized trial ofchemoendocrine therapy started before or after surgery for treatment of primarybreast cancer. J Clin Oncol 13:547-552, 1995.
23. Hutcheon AW, Heys SD, Miller ID, et al: Improvements in survival inpatients receiving primary chemotherapy with docetaxel for breast cancer: Arandomized controlled trial (abstract 506). Breast Cancer Res Treat 69:298,2001.