In 1962, Bloom and colleagues described the natural history of locally advanced breast cancer. (For the purposes of this manuscript, we will define locally advamced breast cancer as tumors that measure more than 5 cm, tumors that extend to the chest wall or skin, and tumors with fixed ipsilateral nodes or ipsilateral internal mammary nodes. These characteristics therefore correspond to operable disease stage IIIA (T3, N1 or any N2) and to initially inoperable stage IIIB (any N3 or any T4) disease.) Bloom et al retrospectively analyzed data from 250 untreated patients with locally advanced breast cancer (97.6% of whom had T3 or T4 disease) who were hospitalized in the Middlesex Hospital in London between 1805 and 1933. The patients, who were in the hospital for at least 6 months, died in the hospital and were autopsied. Mean survival time was 2.7 years (range, 3 months to 18 years).
Today, with the use of a consistent multimodality approach including surgical excision followed by appropriate systemic adjuvant therapy and radiotherapy, 3-year survival rates for women with locally advanced breast cancer range from 50% to 80%. However, 10-year survival rates are between 30% and 40%.
Surgical therapy has traditionally involved modified radical mastectomy, but by downstaging the primary tumor with induction chemotherapy, breast-conserving surgery becomes an option for some patients. The extent and dose of radiotherapy depends on the size of the cancer, adequacy of axillary dissection, number of axillary nodes involved, and type of primary surgery performed. The major obstacle to long-term survival for patients with locally advanced breast cancer is the development of distant metastases. Therefore, the development of more effective systemic therapies is required.
Systemic therapy has traditionally involved chemotherapy followed by hormonal agents. Recently developed cytotoxic agents (the taxanes in particular) are starting to be incorporated in clinical studies targeted to patients with locally advanced breast cancer. High-dose chemotherapy requiring stem-cell rescue is also being studied as is the use of monoclonal antibodies against breast cancer-related antigens (either individually or as vehicles to deliver chemotherapy, radioisotopes, or natural toxins). Determination of the ultimate impact of these newer agents on overall and long-term disease-free survival, local control, and quality of life will require further investigation.
In this article, we will discuss several issues relating to the optimal management of patients with locally advanced breast cancer, including the roles of combined-modality therapy; new chemotherapy agents, such as the taxanes; and high-dose chemotherapy with stem-cell transplantation. We also will describe the tools currently available to assess response to induction chemotherapy, as well as biologic correlates to predict response to treatment.
The surgical options for patients with locally advanced breast cancer include radical mastectomy, modified radical mastectomy, and breast-conserving surgery. Studies have demonstrated that radical or modified radical mastectomy as a single treatment modality leads to local relapse rates ranging from 20% to 50%, with a 5-year overall survival of only 30% to 40% and a 10-year overall survival of approximately 20% to 30%.[3-5]
Locoregional control has traditionally been achieved using mastectomy and postoperative radiotherapy. Historically, breast conservation has not been a treatment option for women with stage III disease. Recently, however, the use of induction chemotherapy has allowed increasing numbers of patients to undergo breast-conserving surgery.
Breast Conserving SurgeryNumerous investigators, including Winchester and Cox, have discussed the standards for breast-conserving surgery. The absolute and relative contraindications to breast-conserving surgery are:
- First- or second-trimester pregnancy;
- More than one malignancy in separate quadrants of the breast or diffuse malignant or indeterminate microcalcifications;
- History of prior therapeutic radiation to the involved breast;
- Large tumor in a breast in which adequate resection would cause significant cosmetic deformity; and
- Subareolar location, which may result in suboptimal cosmesis due to the removal of the nipple-areolar complex.
Clinically suspicious mobile axillary lymph nodes or microscopically involved axillary nodes are not considered contraindications to breast-conserving surgery. Beside the usual radiotherapeutic contraindications, additional surgical concerns must be considered when a patient is evaluated for breast-conserving surgery.
The surgeon should not cut the surgical specimen before the pathologist has examined it and should orient the specimen for the pathologist. Both the pathologist and surgeon should examine the specimen for adequate margins. Despite the widespread use of breast-conserving surgery for patients with breast cancer, the optimal resection margin is still not well defined. Moreover, examination of breast specimens is far from uniform.
Pathologists need to reach a better consensus about the definition of a positive margin, since positive or unknown margins of excision are associated with a significantly greater incidence of residual tumor on reexcision[8-10] and a higher risk of local recurrence after radiation therapy.
Despite the precautions taken at initial biopsy, reexcision of a previous biopsy site may be necessary to ensure negative margins. Proper orientation of the original biopsy specimen will help avoid reexcision of already clear margins, and thus the unnecessary removal of normal breast tissue. When the site of the positive margin is unknown, a rim of tissue around the entire biopsy cavity will need to be removed. Placing clips to outline the breast cavity may aid in marking the tumor bed and in planning radiation therapy.
Axillary DissectionThe prognosis of patients with locally advanced breast cancer is related to nodal status, size of the primary lesion, and estrogen/progesterone receptor status. Axillary node status, the single most important prognostic indicator, still requires axillary dissection with histologic examination for definitive diagnosis. With breast-conserving surgery, axillary dissection is generally done through a separate axillary incision for better cosmesis.
The extent of the axillary dissection depends on the extent of disease. A level I and II dissection is appropriate for most invasive tumors, with a minimum of six lymph nodes required to adequately sample the axilla. Levels I, II, and III lymph nodes that contain obvious disease are removed. The long thoracic, thoracodorsal, and medial pectoral nerves are preserved routinely.
Axillary dissection has the potential morbidity of arm edema (reported incidence, 2% to 22%), upper extremity cellulitis (which often aggravates arm edema), and sensory disturbance in the distribution of the intercostal brachial nerve.
The length of hospitalization necessary following these surgical proceduresie, mastectomy, breast-conserving surgery, and axillary dissectionhas decreased significantly over the last few years, with outpatient surgery being technically possible for an increasing number of patients.[13,14]
Surgery Following Induction ChemotherapyThe role of surgery following induction chemotherapy has been debated recently.[15-17] Investigators from British Columbia evaluated the impact of mastectomy in patients with locally advanced breast cancer who received induction chemotherapy (three cycles of doxorubicin [Adriamycin] and cyclophosphamide [Cytoxan] on day 1 and methotrexate and 5-fluorouracil [5-FU] on day 14) followed by radiotherapy between 1979 and 1983.[Joseph Ragaz, md, personal communication, December, 1996] If patients were deemed to have operable disease, the physician could recommend mastectomy or continued observation.
Ten-year results document a statistically significant improvement in overall survival for the mastectomy group compared with the observation group. However, when a subset of patients who achieved either a complete or partial response to induction chemotherapy was analyzed, no statistical difference in overall survival emerged.
The role of breast-conserving surgery (lumpectomy) for patients who have undergone induction chemotherapy for locally advanced breast cancer has also been evaluated recently.[18-20] Touboul and co-workers examined three different locoregional approaches based on response to induction chemotherapy. Patients who had residual tumors > 3 cm or multifocal tumors underwent a mastectomy; patients deemed to have no residual disease received radiation therapy alone; and patients who had small tumors (defined as
£ 3 cm) after induction chemotherapy underwent wide excision and radiation therapy. Between 1982 and 1990, 97 patients were enrolled.
At a median follow-up of about 8 years, the 5-year locoregional relapse rate was 16% in patients treated with radiation alone, 16% in those given radiation plus wide excision, and 5.4% in those who had mastectomy (P = .04 for mastectomy vs radiation alone or with wide excision). However, the 5-year breast-conservation rate was 52%, and the 5-year overall and disease-free survival rates were identical for all three arms with 5- and 10-year overall survival rates of 80% and 69%, respectively. (Five-year and 10-year survival rates after conservative local treatment were 85.5% and 67.8%, respectively, vs 75.7% and 71.9% after nonconservative treatment, P = .9). The study concluded that local treatment does not influence 5- and 10-year overall survival and that preoperative chemotherapy and radiation therapy do allow conservative surgery to be used more often.
1. Bloom HJ, Richardson WW, Harris EJ: The natural history of untreated breast cancer. Br Med J 2:213-221, 1962.
2. Beahrs OH, Henson DE, Hutter RV, et al: Handbook for Staging of Cancer, 4th ed, pp 161-168. Philadelphia, JB Lippincott, 1993.
3. Heys SD, Eremin JM, Sarkar TK, et al: Role of multimodality therapy in the management of locally advanced carcinoma of the breast. J Am Coll Surg 179:493-504, 1994.
4. Yeatman TJ: The natural history of locally advanced primary breast carcinoma and metastatic disease. Surg Oncol Clin North Am 4:569-589, 1995.
5. Shen ZZ, Zhang YW, Pan TX, et al: Multidisciplinary approach to the treatment of unresectable breast cancer. World J Surg 19:843-846, 1995.
6. Winchester DP, Cox JD: Standards for breast-conservation treatment. CA Cancer J Clin 42:134-162, 1992.
7. Gould EW, Robinson PG: The pathologist's examination of the "lumpectomy"The pathologists' view of surgical margins. Semin Surg Oncol 8:129-135, 1992.
8. Vicini FA, Eberlein TJ, Connolly JL, et al: The optimal extent of resection for patients with stages I or II breast cancer treated with conservative surgery and radiotherapy. Ann Surg 214:200-204, 204-205 (discussion), 1991.
9. Gwin JL, Eisenberg BL, Hoffman JP, et al: Incidence of gross and microscopic carcinoma in specimens from patients with breast cancer after reexcision lumpectomy. Ann Surg 218:729-734, 1993.
10. Kearney TJ, Morrow M: Effect of reexcision on the success of breast-conserving surgery. Ann Surg Oncol 2:303-307, 1995.
11. Schnitt SJ, Abner A, Gelman R, et al: The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 74:1746-1751, 1994.
12. Bedwinek J: Breast conserving surgery and irradiation: The importance of demarcating the excision cavity with surgical clips. Int J Radiat Oncol Biol Phys 26:675-679, 1993.
13. Goodman AA, Mendez AL: Definitive surgery for breast cancer performed on an outpatient basis. Arch Surg 128:1149-1152, 1993.
14. Weltz CR, Greengrass RA, Lyerly HK: Ambulatory surgical management of breast carcinoma. Ann Surg 222:19-26, 1995.
15. Kent AL, Eaton M, Marshall N, et al: Locally advanced breast cancer: Is surgery warranted following chemotherapy? Aust N Z J Surg 65:229-232, 1995.
16. Touboul E, Lefranc JP, Blondon J, et al: Multidisciplinary treatment approach to locally advanced non-inflammatory breast cancer using chemotherapy and radiotherapy with or without surgery. Radiother Oncol 25:167-175, 1992.
17. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362-369, 1994.
18. 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.
19. 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.
20. Touboul E, Buffat L, Lefranc JP, et al: Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer. Int J Radiat Oncol Biol Phys 34:1019-1028, 1996.
21. Arriagada R, Mouriesse H, Sarrazin D, et al: Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys 11:1751-1757, 1985.
22. Chu AM, Cope O, Doucette J, et al: Non-metastatic locally advanced cancer of the breast treated with radiation. Int J Radiat Oncol Biol Phys 10:2299-2304, 1984.
23. Puthawala AA, Syed AM, Sheikh KM, et al: Combined external and interstitial irradiation in the treatment of stage III breast cancer. Radiology 153:813-816, 1984.
24. Balawajder I, Antich PP, Boland J: An analysis of the role of radiotherapy alone and in combination with chemotherapy and surgery in the management of advanced breast carcinoma. Cancer 51:574-580, 1983.
25. Ahern V, Barraclough B, Bosch C, et al: Locally advanced breast cancer: Defining an optimum treatment regimen. Int J Radiat Oncol Biol Phys 28:867-875, 1994.
26. DeLena M, Zucali R, Viganotti G, et al: Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol 1:53-59, 1978.
27. Bedwinek J, Rao DV, Perez C, et al: Stage III and localized stage IV breast cancer: Irradiation alone vs irradiation plus surgery. Int J Radiat Oncol Biol Phys 8:31-36, 1982.
28. Swain SM, Sorace RA, Bagley CS, et al: Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res 47:3889-3894, 1987.
29. Jacquillat C, Baillet F, Weil M, et al: Results of a conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy, and external and interstitial irradiation in 98 patients with locally advanced breast cancer (IIIA-IIIB). Cancer 61:1977-1982, 1988.
30. Perloff M, Lesnick GJ, Korzun A, et al: Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: A Cancer and Leukemia Group B study. J Clin Oncol 6:261-269, 1988.
31. Pierce LJ, Lippman M, Ben-Baruch N, et al: The effect of systemic therapy on local-regional control in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 23:949-960, 1992.
32. Inskip PD, Boice JD Jr: Radiotherapy-induced lung cancer among women who smoke. Cancer 73:1541-1543, 1994.
33. Neugut AI, Robinson E, Lee WC: Lung cancer after radiation therapy for breast cancer. Cancer 71:3054-3057, 1993.
34. Neugut AI, Murray T, Santos J, et al: Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer 73:1615-1620, 1994.
35. Harvey EB, Brinton LA: Second cancer following cancer of the breast in Connecticut, 1935-82. Natl Cancer Inst Monogr 68:99-112, 1985.
36. Cafiero F, Gipponi M, Peressini A, et al: Radiation-associated angiosarcoma: Diagnostic and therapeutic implicationsTwo case reports and a review of the literature. Cancer 77:2496-2502, 1996.
37. Shannon VR, Nesbitt JC, Libshitz HI: Malignant pleural mesothelioma after radiation therapy for breast cancer: A report of two additional patients. Cancer 76:437-441, 1995.
38. Hortobagyi G, Singletary S, McNeese M: Treatment of locally advanced and inflammatory breast cancer, in Harris J, Lippman M, Morrow M, (eds): Diseases of the Breast, pp 585-600. Philadelphia, Lippincott-Raven, 1996.
39. Borger JH, van Tienhoven G, Passchier DH, et al: Primary radiotherapy of breast cancer: Treatment results in locally advanced breast cancer and in operable patients selected by positive axillary apex biopsy. Radiother Oncol 25:1-11, 1992.
40. Klassen U, Wilke H, Seeber S: Paclitaxel combined with weekly high-dose 5-fluorouracil/folinic acid and cisplatin in the treatment of advanced breast cancer. Semin Oncol 23(suppl 11):1-5, 1996.
41. Schaake-Koning C, van der Linden EH, Hart G, et al: Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: A randomized clinical study. Int J Radiat Oncol Biol Phys 11:1759-1763, 1985.
42. Rubens RD, Bartelink H, Engelsman E, et al: Locally advanced breast cancer: The contribution of cytotoxic and endocrine treatment to radiotherapy: An EORTC Breast Cancer Cooperative Group Trial (10792). Eur J Cancer Clin Oncol 25:667-678, 1989.
43. Calais G, Berger C, Descamps P, et al: Conservative treatment feasibility with induction chemotherapy, surgery, and radiotherapy for patients with breast carcinoma larger than 3 cm. Cancer 74:1283-1288, 1994.
44. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant vs adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6. Eur J Cancer 30A:645-652, 1994.
45. Booser D, Frye D, Singletary S, et al: Response to induction chemotherapy for breast cancer: A prospective multimodality treatment program (abstract). Proc Am Soc Clin Oncol 11:82, 1992.
46. 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.
47. Trudeau ME. Docetaxel (Taxotere): An overview of first-line monotherapy. Semin Oncol 22:17-21, 1995.
48. Piccart M: Docetaxel: A new defense in the management of breast cancer. Anticancer Drugs 6:7-11, 1995.
49. Seidman AD, Hudis CA, Norton L: Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer: From advanced disease to adjuvant therapy. Semin Oncol 22:3-8, 1995.
50. Holmes FA: Update: The M.D. Anderson Cancer Center experience with paclitaxel in the management of breast carcinoma. Semin Oncol 22:9-15, 1995.
51. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
52. Gianni L, Capri G, Tarenzi E, et al: Efficacy and cardiac effects of 3-H paclitaxel (P) plus bolus doxorubicin (DOX) in women with untreated metastatic breast carcinoma (abstract). Proc Am Soc Clin Oncol 15:116, 1996.
53. Gianni L, Demicheli R, Moliterni A, et al: Pilot study of primary chemotherapy with doxorubicin-paclitaxel (AT) in women with T2-T3 locally advanced breast carcinoma (abstract). Proc Am Soc Clin Oncol 15:116, 1996.
54. deMagalhaes-Silverman M, Rybka WB, Lembersky B, et al: High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer. Am J Clin Oncol 19:169-173, 1996.
55. Mulder NH, Mulder PO, Sleijfer DT, et al: Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer. Eur J Cancer 29A:668-671, 1993.
56. Rutgers EJ, Richel DJ, Baars JW, et al: Preliminary analysis of a randomized phase II study of high-dose chemotherapy in high-risk breast cancer (abstract). Eur J Cancer 32A:34, 1996.
57. Colozza M, Gori S, Mosconi AM, et al: Induction chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (CAP) in a combined modality approach for locally advanced and inflammatory breast cancer: Long-term results. Am J Clin Oncol 19:10-17, 1996.
58. Forrest AP, Stewart HJ, Roberts MM, et al: Simple mastectomy and axillary node sampling (pectoral node biopsy) in the management of primary breast cancer. Ann Surg 196:371-378, 1982.
59. Schwartzberg L, Birch R, Weaver C, et al: Neoadjuvant chemotherapy with or without paclitaxel and high-dose chemotherapy with peripheral blood progenitor cell (PBSC) support for locally advanced breast cancer (LABC) (abstract). Proc Am Soc Clin Oncol 15:124, 1996.
60. Helvie MA, Joynt LK, Cody RL, et al: Locally advanced breast carcinoma: Accuracy of mammography vs clinical examination in the prediction of residual disease after chemotherapy. Radiology 198:327-332, 1996.
61. Pierce L, Adler D, Helvie M, et al: The use of mammography in breast preservation in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 34:571-577, 1996.
62. Abraham DC, Jones RC, Jones SE, et al: Evaluation of neoadjuvant chemotherapeutic response of locally advanced breast cancer by magnetic resonance imaging. Cancer 78:91-100, 1996.
63. Percivale P, Bertoglio S, Meszaros P, et al: Radioimmunoguided surgery after primary treatment of locally advanced breast cancer. J Clin Oncol 14:1599-1603, 1996.
64. Gardin G, Alama A, Rosso R, et al: Relationship of variations in tumor cell kinetics induced by primary chemotherapy to tumor regression and prognosis in locally advanced breast cancer. Breast Cancer Res Treat 32:311-318, 1994.
65. Masood S: Prediction of recurrence for advanced breast cancer. Traditional and contemporary pathologic and molecular markers. Surg Oncol Clin North Am 4:601-632, 1995.
66. Archer SG, Eliopoulos A, Spandidos D, et al: Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy. Br J Cancer 72:1259-1266, 1995.
67. Decker DA, Morris LW, Levine AJ, et al: Immunohistochemical analysis of P-glycoprotein expression in breast cancer: Clinical correlations. Ann Clin Lab Sci 25:52-59, 1995.
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