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© 1999 American Society for Clinical Oncology
Neoadjuvant Chemotherapy, Locally Advanced Breast Cancer, and Quality of LifeUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY
University of Texas, M.D. Anderson Cancer Center, Houston, TX THE STUDY REPORTED by Kuerer et al in this issue of the Journal of Clinical Oncology provides evidence that preoperative (neoadjuvant) chemotherapy for locally advanced breast cancer identifies a group of patients with an excellent prognosis: those with a pathologic complete response. Patients whose tumors disappear completely with preoperative chemotherapy have a significantly improved survival rate (almost 90% at 5 years) compared with those who have an incomplete pathologic response (60% at 5 years). One drawback, however, is that it is not possible to determine which patients have had a complete pathologic response until the definitive breast cancer operation has been performed. This underscores the continued role for surgical resection of the primary tumor site, even in the face of a complete clinical response to chemotherapy. Because long-term survival is common among women with locally advanced breast cancer, quality-of-life issues become vitally important. Certainly there are many women who choose to undergo mastectomy and who express no interest in breast conservation or reconstruction. For most women, however, loss of a breast is an emotionally disturbing and difficult circumstance. Yet, breast conservation and immediate reconstruction are infrequently considered to be reasonable options for patients with larger tumors or locally advanced disease. We believe that it is time to reconsider the assumptions that have long limited the options for women with locally advanced breast cancer. Consider the following scenarios: Patient A is a 50-year-old woman who presents with a T3N1 breast cancer. Her surgeon recommends modified radical mastectomy, with postoperative chemotherapy and radiation therapy. The patient wishes to avoid mastectomy but is told that breast conservation is not possible because of the size of her tumor and the high risk of recurrence. She asks about breast reconstruction and is told that, because she has a locally advanced tumor, she should wait 2 years before undergoing breast reconstruction, to ensure that she is cancer-free. Patient B is a 50-year-old woman with a T3N1 rectal cancer, 5 cm from the anal verge. Because of the size and location of the tumor, abdominoperineal resection would be required to resect the tumor. Because the patient does not wish to have a permanent colostomy, she is treated with neoadjuvant chemoradiation therapy. Her tumor shrinks in response to treatment and a sphincter-preserving operation is performed. Physicians go to great lengths to allow patients with poor-prognosis rectal cancers to undergo sphincter-preserving operations rather than have a permanent colostomy. Why? The standard answer is "to preserve function." However, the real issues are avoiding unnecessary disfigurement, maintaining self-esteem and dignity, and social acceptance, in short, improving quality of life. These issues apply equally well to patients with breast cancer, but often physicians do not consider the importance of conserving or reconstructing the breasts of women with locally advanced breast cancer. Although the concept of using preoperative chemoradiation to downstage rectal cancer and allow sphincter preservation is widely accepted, the notion of reducing tumor size with preoperative chemotherapy to allow breast conservation or reconstruction is not pervasive. Why not? Certainly it is not because the prognosis for breast cancer patients is worse than it is for rectal cancer patients. In the examples given, the patient with rectal cancer has approximately a 15% risk of local recurrence and 60% chance of dying of her cancer within 5 years,1 whereas the patient with locally advanced breast cancer has 5-year local recurrence and mortality rates of approximately 10% and 40%, respectively.2-4 Cost is not a factor either; it does not cost appreciably more to perform breast conservation or breast reconstruction procedures than to perform sphincter-preserving operations for rectal cancer. In fact, the only good reasons not to recommend breast conservation or reconstruction for any given patient with locally advanced breast cancer are the same reasons not to perform sphincter-preserving operations for locally advanced rectal cancer, ie, the function- or appearance-preserving procedure (1) is not technically possible, (2) has a substantially increased risk of complications, (3) is not as likely to achieve local disease control as the alternative procedure, or (4) is not important, in the opinion of the patient, for her quality of life. Therefore, breast conservation or immediate breast reconstruction for locally advanced breast cancer should receive the same risk/benefit considerations as sphincter-preserving operations for rectal cancer. There seems to be no difference in survival of women with locally advanced breast cancer whether chemotherapy is given before or after surgery. National Surgical Adjuvant Breast and Bowel Project Trial B-18, which compared preoperative with postoperative chemotherapy in 1,523 women, reported no differences in disease-free survival, distant disease-free survival, or overall survival between the two groups.5 However, as pointed out by Kuerer et al, there is certainly no survival disadvantage for preoperative therapy. Even though preoperative chemotherapy is not superior to postoperative treatment in terms of survival, there are several reasons to recommend preoperative chemotherapy, most of which involve quality of life. Preoperative chemotherapy allows (1) direct assessment of the response of the tumor to chemotherapy, with the chance to cross over to alternate regimens if first-line treatment is ineffective, (2) the possibility for breast conservation, and (3) the opportunity for immediate breast reconstruction in patients who require mastectomy. As demonstrated by Kuerer et al and others, the patient's response to preoperative chemotherapy is a powerful prognostic factor in predicting disease-free and overall survival from locally advanced breast cancer.6-11 By assessing the response to preoperative chemotherapy, it is possible to select out a better-prognosis group of patients who will have improved long-term survival and a low rate of local recurrence. Although it is not possible to determine which patients are in the best-prognosis group (those with a pathologic complete response) before surgery, patients with a clinical response (50% or more reduction in the size of the tumor determined by physical examination, mammogram, and/or ultrasound) also have an improved prognosis compared with those with no response.2-11 Therefore, patients who respond to preoperative chemotherapy are often the best candidates for breast conservation or immediate breast reconstruction, allowing for less disfigurement with preservation of function and self. Locally advanced breast cancer is usually defined as stage III disease. If preoperative chemotherapy is used to reduce tumors to allow the opportunity for breast conservation, there is no reason to exclude patients with T2N0-1 or T3N0 breast cancer who seem to be poor candidates for breast conservation because of tumor size. Tumor response to chemotherapy is inversely related to tumor size3; therefore, women with smaller lesions are more likely to have sufficient tumor shrinkage to allow breast conservation. Furthermore, many physicians are hesitant to perform immediate reconstruction for patients with stage IIB disease (T2N1 or T3N0) because of the concern about the high risk of recurrence and the potential need for radiation therapy. Since most of these patients will receive chemotherapy, preoperative chemotherapy should be considered if a good response would allow the opportunity for breast conservation or immediate reconstruction. Radiation therapy is used to reduce the likelihood of local-regional recurrence after segmental mastectomy (breast conservation) and to lessen the risk of chest-wall recurrence after mastectomy in patients with large primary tumors or locally advanced breast cancer. Radiation therapy has also been used by several institutions as the primary treatment for local disease control after preoperative chemotherapy, with surgery reserved for treatment failures. This approach clearly results in higher rates of local recurrence compared with surgery as the primary local treatment.9,11,12 It is possible to use radiotherapy before surgery to downsize tumors and allow breast conservation or immediate reconstruction in patients who do not respond to preoperative chemotherapy.4,11,12 However, patients whose tumors do not respond to preoperative chemotherapy have a poor prognosis in terms of both local and distant disease-free survival.2-11 For this reason, we do not recommend breast conservation or immediate reconstruction when patients have no response or less than a partial response to preoperative chemotherapy. Several studies have documented the feasibility and safety of breast conservation for locally advanced breast cancer after preoperative chemotherapy. Breast conservation is possible in 27% to 90% of patients after preoperative chemotherapy.3-5,12-17 Local recurrence rates after breast conservation are low (5% to 10%) in patients who respond to preoperative chemotherapy.3,4,12-14 Because some patients will have a complete response (disappearance of the tumor), it is important to assess response carefully by ultrasound examination or by mammography after the first and second cycles of chemotherapy. If a complete response is anticipated, metallic markers can be placed within the breast to mark the center of the tumor. In cases of complete response, it is often difficult to identify the area of the primary tumor when lumpectomy is performed if a marker has not been placed. Although not every patient responds to chemotherapy sufficiently to allow breast conservation, this is an option worth considering for women with larger tumors. Conventional wisdom holds that women with locally advanced breast cancer should not undergo immediate breast reconstruction. Often, a 2-year waiting period is imposed after mastectomy, and reconstruction is considered if no metastatic disease or local recurrence develops during that interval. The rationale for the 2-year waiting period is based on several assumptions that do not hold up under careful scrutiny: Immediate reconstruction is associated with a greater risk of complications, especially among patients who receive preoperative chemotherapy. There is no evidence that the complication rate for breast reconstruction is higher among patients who undergo preoperative chemotherapy. The complication rates in such patients are similar to those in patients with early (stages I and II) breast cancer and are not prohibitive.19 Immediate reconstruction requires a longer recovery time and may delay postoperative chemotherapy and radiation therapy. Patients who undergo breast reconstruction after preoperative chemotherapy do not have a significant delay in proceeding to the next scheduled cycle of chemotherapy. There is evidence, however, that smokers have more complications and possibly a delay in therapy.20 Reconstruction impairs detection of local recurrence. Studies have not substantiated the fear that breast reconstruction impairs the ability to detect local recurrence.21 The rate of local recurrence among patients with locally advanced breast cancer (including inflammatory carcinoma) treated with preoperative chemotherapy is 15% (identical to rectal cancer).1,7 In one series, the rate of local recurrence was 5.5% in patients who demonstrated a clinical or mammographic complete response to preoperative chemotherapy, and there were no local recurrences among patients with stage IIIa disease treated with preoperative chemotherapy.7 It is therefore possible to identify subgroups with better prognoses on the basis of tumor stage and response to treatment. Radiation therapy of the reconstructed breast will cause undesirable consequences. Postoperative radiation therapy may lead to undesired consequences after breast reconstruction with implants. However, available data indicate that breasts reconstructed using free or pedicled autologous tissue flap reconstructions can be irradiated safely without compromising the cosmetic outcome.22 Irradiation of a well-vascularized flap seems to be tolerated as well as irradiation of the native breast, when proper techniques are used.19,22 Radiation therapy is routinely administered after autologous tissue transfer in other locations (eg, head and neck), so why is this not the case for breast reconstruction? Certainly, there are some specialized issues related to delivery of radiotherapy to the chest wall with a reconstructed breast mound, especially when high doses are used for inflammatory cancer or other high-risk situations. Radiation therapy given in the preoperative period may be preferable in some cases.12,19 Furthermore, the need for routine radiotherapy after mastectomy in patients who respond to preoperative chemotherapy has been questioned because the local recurrence rates may be lower among patients with a good response.10 The decision to perform immediate reconstruction should be made jointly among patient, surgeon, plastic surgeon, medical oncologist, and radiation oncologist. Future clinical studies should better define the subsets of patients who respond to preoperative chemotherapy who truly benefit from adjuvant radiotherapy. These issues do not, however, preclude immediate reconstruction for patients with locally advanced breast cancer. Why perform an expensive breast reconstruction operation if the patient is going to die of breast cancer anyway? This is implied but never stated. If the goal is to never perform reconstruction for women who will develop local recurrence or eventually die of their cancer, then immediate reconstruction should never be performed for locally advanced breast cancer. If the goal is to improve the quality of life of patients with locally advanced breast cancer, then immediate reconstruction should be offered to all patients who are reasonable candidates for this procedure. In summary, immediate reconstruction for locally advanced breast cancer can be performed with low morbidity, low rates of local recurrence, and acceptable cosmetic results for locally advanced breast cancer.19-22 Women with a good response to chemotherapy who are not candidates for breast conservation because of tumor size, multicentric disease, etc, should be considered for immediate breast reconstruction. Breast conservation and immediate reconstruction should be considered for women with locally advanced breast cancer, with the goal of improving quality of life. The use of preoperative chemotherapy provides the opportunity for breast conservation or immediate reconstruction for locally advanced breast cancer in much the same way as preoperative chemoradiation therapy provides the opportunity for sphincter preservation in locally advanced rectal cancer. Mastectomy (without reconstruction) is no less distressing to a breast cancer patient than colostomy is to a rectal cancer patient, and patients' lives can be improved by avoiding both whenever possible. Patients with locally advanced breast cancer should be encouraged to participate in clinical trials to further define the role of preoperative therapy as a means of facilitating breast conservation and immediate reconstruction. REFERENCES 1. Cohen AM, Minsky BD, Schilsky RL: Cancer of the rectum, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology (ed 5) Philadelphia, PA, Lippincott-Raven, 1997, pp 1197-1234 2. Perez CA, Graham ML, Taylor ME, et al: Management of locally advanced carcinoma of the breast: I. Noninflammatory. Cancer 74:453-465, 1994 (suppl 1)[Medline]
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Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 82:1539-1545, 1990 4. Schwartz GF, Birchansky CA, Komarnicky LY, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362-369, 1994[Medline] 5. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]
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Feldman LD, Hortobagyi GN, Buzdar AU, et al: Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578-2581, 1986 7. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1988[Medline] 8. Bonadonna G, Valagussa P, Brambilla C, et al: Preoperative chemotherapy in operable breast cancer. Lancet 341:1485, 1993 (letter) 9. Touboul E, Buffat L, Lefranc J, et al: Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced non-inflammatory breast cancer. Int J Radiat Oncol Biol Phys 34:1019-1028, 1996[Medline] 10. Schwartz GF, Cantor RI, Biermann WA: Neoadjuvant chemotherapy before definitive treatment for stage III carcinoma of the breast. Arch Surg 122:1430-1434, 1987[Abstract] 11. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast conserving surgery: Preliminary results of a randomised trial—S6. Eur J Cancer 30A:645-652, 1994 12. Calais G, Descamps P, Chapet S, et al: Primary chemotherapy and radiosurgical breast-conserving treatment for patients with locally advanced operable breast cancers. Int J Radiat Oncol Biol Phys 26:37-42, 1993[Medline] 13. Merajver SD, Weber BL, Cody R, et al: Breast conservation and prolonged chemotherapy for locally advanced breast cancer: The University of Michigan experience. J Clin Oncol 15:2873-2881, 1997[Abstract] 14. Veronesi U, Bonadonna G, Zurrida S, et al: Conservation surgery after primary chemotherapy in large carcinomas of the breast. Ann Surg 222:612-618, 1995[Medline] 15. Adenis A, Vanlemmens L, Fournier C, et al: Does induction chemotherapy with a mitoxantrone/vinorelbine regimen allow a breast-conservative treatment in patients with operable locoregional breast cancer? A French Northern Oncology Group trial in 105 patients. Breast Cancer Res Treat 40:161-169, 1996[Medline] 16. Singletary SE, McNeese MD, Hortobagyi GN: Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced breast carcinoma. Cancer 69:2849-2852, 1992[Medline] 17. Booser D, Frye D, Singletary S, et al: Response to induction chemotherapy for breast cancer: A prospective multimodality treatment program. Proc Am Soc Clin Oncol 11:82, 1992 (abstr A156)
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Powles TJ, Hickish TF, Makris A, et al: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13:547-552, 1995 19. Styblo TM, Lewis MM, Carlson GW, et al: Immediate breast reconstruction for stage III breast cancer using transverse rectus abdominis musculocutaneous (TRAM) flap. Ann Surg Oncol 3:375-380, 1996[Abstract] 20. Schusterman MA, Kroll SS, Miller MJ, et al: The free transverse rectus abdominis musculocutaneous flap for breast reconstruction: One center's experience with 211 consecutive cases. Ann Plast Surg 32:234-242, 1994[Medline] 21. Slavin SA, Love SM, Goldwyn RM: Recurrent breast cancer following immediate reconstruction with myocutaneous flaps. Plast Reconstr Surg 93:1191-1204, 1994[Medline] 22. Hunt KK, Baldwin BJ, Strom EA, et al: Feasibility of postmastectomy radiation therapy after TRAM flap breast reconstruction. Ann Surg Oncol 4:377-384, 1997[Abstract] This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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