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Indications for Neoadjuvant Therapy in Breast Cancer
Indications for Neoadjuvant Therapy in Breast Cancer Suparna Bonthala Wedam, MD, and Sandra M. Swain, MD Neoadjuvant therapy has become prevalent for many tumor types including breast cancer, especially for locally advanced disease. Although a survival advantage has not been shown, such an approach offers the oppurtunity to monitor treatment response and possibly perform more conservative surgical therapy. Given similar survival outcomes to adjuvant therapy and the potential for breast conservation, neoadjuvant therapy is being used more commonly for operable breast tumors. Semin Breast Dis 7:58 – 60 © 2004 Elsevier Inc. All rights reserved.
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hemotherapy has become an integral component in the management of breast cancer since the systemic nature of this disease was accepted. Before systemic therapy, treatment with local therapy alone resulted in poor outcomes. With results from the Early Breast Cancer Trialists’ Groups meta-analysis showing a survival advantage, adjuvant systemic therapy has become a standard of care.1,2 Neoadjuvant treatment, also known as preoperative or primary systemic therapy, refers to the administration of chemotherapy before locoregional therapy with surgery and/or radiation therapy. Such an approach has become common for many solid tumor types including breast cancer and acknowledges the possible presence of micrometastatic disease remote from the primary tumor at diagnosis. Preoperative chemotherapy was first introduced for breast cancer in the 1970s for tumors considered to be inoperable. Haagenson and Stout described breast cancers with certain features that could not be cured by even the most radical surgery.3 Characteristics of such tumors included pregnancy, distant metastases, peau d’ orange greater than one third of the breast, satellite nodules in skin, intercostal or parasternal nodules, arm edema, supraclavicular node involvement, and inflammatory breast cancer. Neoadjuvant therapy has been employed in such tumors in the hope of improving outcome and survival. There are many potential advantages to primary chemotherapy. Theoretically, earlier treatment of a tumor with systemic chemotherapy may decrease the likelihood of sponta-
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD. Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, CCR NCI, Building 8, Room 5101, MSC 1903, 8901 Wisconsin Ave., Bethesda, MD 20889.
58
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.003
neous emergence of resistant tumor clones. Animal models have shown that accelerated metastatic growth can occur after resection of the primary tumor.4 Goldie and Coldman also showed that as the number of tumor cells increase, the likelihood of chemoresistant clones may also increase.5 Early systemic therapy may minimize the development of these chemoresistant clones. Certain tumors may release antiangiogenic factors such as angiostatin.6 Removal of the primary tumor and loss of such antiangiogenic factors may cause the progression of micrometastases. Preoperative chemotherapy also allows for the administration of treatment via intact vasculature before it has been disrupted by surgery. Clinically, preoperative chemotherapy reduces the size of the primary tumor and nodal metastases, allowing for breastconserving surgery in patients who might not otherwise qualify.7-12 The presence of a palpable tumor permits a direct in vivo assessment of sensitivity to the chemotherapeutic regimen. Early detection of drug resistance enables the regimen to be altered to avoid unnecessary toxicity and a potentially more effective regimen to be instituted. Finally, having a tumor in place allows for serial evaluation of biomarkers to predict response to chemotherapy that may be useful in the future. From a research perspective, monitoring a tumor’s response to neoadjuvant chemotherapy allows for the design of smaller trials compared to adjuvant chemotherapy, which requires a much larger number of patients. There are a few theoretical disadvantages to neoadjuvant chemotherapy. First, there may be complications associated with surgery and radiation following chemotherapy.13 Second, preoperative chemotherapy may obscure the true pathologic stage of the cancer by altering tumor size and margins, confounding the interpretation of results. Third, with a dramatic clinical response, an inappropriately conservative surgical procedure may be performed and put the pa-
Neoadjuvant indications in breast cancer tient at higher risk of recurrence. Finally, rarely patients will progress while receiving neoadjuvant therapy; thus, these patients’ local treatment will be delayed or may no longer be possible. Preoperative therapy is now part of the multimodality approach for inoperable locally advanced breast tumors. In most cases, these patients represent a group with an unfavorable prognosis (stage III or T3-4 disease), including classic inflammatory breast cancer or involvement of ipsilateral supra- or infraclavicular lymph nodes (N3). Even though there has been no survival advantage compared with adjuvant therapy, neoadjuvant chemotherapy has resulted in more residual negative axillary lymph nodes and breast-conserving surgery. The largest randomized trial comparing neoadjuvant to adjuvant chemotherapy, The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18, established that neoadjuvant treatment of operable early stage breast cancer with 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) every 3 weeks had equivalent survival results compared with the same regimen in the adjuvant setting.14 NSABP B-18 was based on the theory by Fisher et al that removal of the primary tumor may cause accelerated metastatic growth.4 Disease-free survival and overall survival were similar in both groups, but breast-conserving surgery was performed more frequently in those patients who received neoadjuvant chemotherapy. The clinical response rate for patients receiving neoadjuvant AC was 79%, with 36% having a clinical complete response (CR). Thirteen percent of patients with a clinical CR had a pathologic CR (pCR). At 9 years’ follow-up, patients with a pCR had higher disease-free survival and overall survival rates than patients with residual invasive disease noted at the time of surgery.15 All large randomized clinical trials of neoadjuvant versus adjuvant therapy indicate that these therapies offer similar survival advantages.15-20 Therefore, neoadjuvant chemotherapy has now become an acceptable alternative to adjuvant chemotherapy for small operable tumors (stage I-II) in patients who desire potentially more conservative surgical treatment. Among patients receiving neoadjuvant chemotherapy versus adjuvant therapy for operable breast cancer (stages I-III), there has been a 5% to 36% increase in breast-conserving surgery.14,18,20,21 Preoperative therapy also can be considered for patients who have medical contraindications to surgery or who simply wish to delay surgery, for example, pregnant patients diagnosed with breast cancer in which surgery and radiation therapy can be performed after delivery. Even though there have been substantial clinical response rates with neoadjuvant therapy, pCR has remained low. As shown in NSABP B-18, pCR may act as a surrogate marker of prognosis.14,22,23 Improving the pCR may be the way to improve on neoadjuvant therapy for breast cancer. However, how this should be accomplished remains to be determined. Many questions regarding the best application of preoperative chemotherapy still remain, including the best combination of treatment, the optimal length of neoadjuvant therapy, and the proper role for adjuvant chemotherapy following surgery and radiation. Neoadjuvant chemotherapy offers the unique advantage of being able to observe a tumor’s response
59 to therapy. By clinically and biologically monitoring response, doctors can tailor therapy to each individual patient. Such an approach also provides a way to rapidly screen new compounds and identify important surrogate markers to response.
References 1. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352:930-942, 1998 2. Early Breast Cancer Trialists’ Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988 3. Haagensen CD, Stout AP: Carcinoma of the breast. II. Criteria of operability. Ann Surg 118:859-863, 1943 4. Fisher B, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43:1488-1492, 1983 5. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979 6. O’Reilly MS, Holmgren L, Shing Y, et al: Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 59:471-482, 1994 7. 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 8. Jacquillat C, Weil M, Baillet F, et al: Results of neoadjuvant chemotherapy and radiation therapy in the breast-conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer 66:119-129, 1990 9. Anderson ED, Forrest AP, Hawkins RA, et al: Primary systemic therapy for operable breast cancer. Br J Cancer 63:561-566, 1991 10. Smith IE, Walsh G, Jones A, et al: High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. J Clin Oncol 13:424-429, 1995 11. Chollet P, Charrier S, Brain E, et al: Clinical and pathological response to primary chemotherapy in operable breast cancer. Eur J Cancer 33: 862-866, 1997 12. 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 13. Graham MV, Perez CA, Kuske RR, et al: Locally advanced (noninflammatory) carcinoma of the breast: results and comparison of various treatment modalities. Int J Radiat Oncol Biol Phys 21:311-318, 1991 14. 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 15. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96-102, 2001 16. Semiglazov VF, Topuzov EE, Bavli JL, et al: Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol 5:591-595, 1994 17. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol 2:347-354, 1991 18. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus 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 19. 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 20. van der Hage JA, van de Velde CJ, Julien JP, et al: Preoperative chemo-
60 therapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19:4224-4237, 2001 21. Gianni L, Baselga J, Eiermann W, et al: First report of the European Cooperative Trial in Operable Breast Cancer (ECTO): effects of primary systemic therapy (PST) on local-regional disease. Proc Am Soc Clin Oncol 132a, 2002
S.B. Wedam and S.M. Swain 22. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999 23. Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002
C
hemotherapy has become an integral component in the management of breast cancer since the systemic nature of this disease was accepted. Before systemic therapy, treatment with local therapy alone resulted in poor outcomes. With results from the Early Breast Cancer Trialists’ Groups meta-analysis showing a survival advantage, adjuvant systemic therapy has become a standard of care.1,2 Neoadjuvant treatment, also known as preoperative or primary systemic therapy, refers to the administration of chemotherapy before locoregional therapy with surgery and/or radiation therapy. Such an approach has become common for many solid tumor types including breast cancer and acknowledges the possible presence of micrometastatic disease remote from the primary tumor at diagnosis. Preoperative chemotherapy was first introduced for breast cancer in the 1970s for tumors considered to be inoperable. Haagenson and Stout described breast cancers with certain features that could not be cured by even the most radical surgery.3 Characteristics of such tumors included pregnancy, distant metastases, peau d’ orange greater than one third of the breast, satellite nodules in skin, intercostal or parasternal nodules, arm edema, supraclavicular node involvement, and inflammatory breast cancer. Neoadjuvant therapy has been employed in such tumors in the hope of improving outcome and survival. There are many potential advantages to primary chemotherapy. Theoretically, earlier treatment of a tumor with systemic chemotherapy may decrease the likelihood of sponta-
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD. Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, CCR NCI, Building 8, Room 5101, MSC 1903, 8901 Wisconsin Ave., Bethesda, MD 20889.
58
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.003
neous emergence of resistant tumor clones. Animal models have shown that accelerated metastatic growth can occur after resection of the primary tumor.4 Goldie and Coldman also showed that as the number of tumor cells increase, the likelihood of chemoresistant clones may also increase.5 Early systemic therapy may minimize the development of these chemoresistant clones. Certain tumors may release antiangiogenic factors such as angiostatin.6 Removal of the primary tumor and loss of such antiangiogenic factors may cause the progression of micrometastases. Preoperative chemotherapy also allows for the administration of treatment via intact vasculature before it has been disrupted by surgery. Clinically, preoperative chemotherapy reduces the size of the primary tumor and nodal metastases, allowing for breastconserving surgery in patients who might not otherwise qualify.7-12 The presence of a palpable tumor permits a direct in vivo assessment of sensitivity to the chemotherapeutic regimen. Early detection of drug resistance enables the regimen to be altered to avoid unnecessary toxicity and a potentially more effective regimen to be instituted. Finally, having a tumor in place allows for serial evaluation of biomarkers to predict response to chemotherapy that may be useful in the future. From a research perspective, monitoring a tumor’s response to neoadjuvant chemotherapy allows for the design of smaller trials compared to adjuvant chemotherapy, which requires a much larger number of patients. There are a few theoretical disadvantages to neoadjuvant chemotherapy. First, there may be complications associated with surgery and radiation following chemotherapy.13 Second, preoperative chemotherapy may obscure the true pathologic stage of the cancer by altering tumor size and margins, confounding the interpretation of results. Third, with a dramatic clinical response, an inappropriately conservative surgical procedure may be performed and put the pa-
Neoadjuvant indications in breast cancer tient at higher risk of recurrence. Finally, rarely patients will progress while receiving neoadjuvant therapy; thus, these patients’ local treatment will be delayed or may no longer be possible. Preoperative therapy is now part of the multimodality approach for inoperable locally advanced breast tumors. In most cases, these patients represent a group with an unfavorable prognosis (stage III or T3-4 disease), including classic inflammatory breast cancer or involvement of ipsilateral supra- or infraclavicular lymph nodes (N3). Even though there has been no survival advantage compared with adjuvant therapy, neoadjuvant chemotherapy has resulted in more residual negative axillary lymph nodes and breast-conserving surgery. The largest randomized trial comparing neoadjuvant to adjuvant chemotherapy, The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18, established that neoadjuvant treatment of operable early stage breast cancer with 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) every 3 weeks had equivalent survival results compared with the same regimen in the adjuvant setting.14 NSABP B-18 was based on the theory by Fisher et al that removal of the primary tumor may cause accelerated metastatic growth.4 Disease-free survival and overall survival were similar in both groups, but breast-conserving surgery was performed more frequently in those patients who received neoadjuvant chemotherapy. The clinical response rate for patients receiving neoadjuvant AC was 79%, with 36% having a clinical complete response (CR). Thirteen percent of patients with a clinical CR had a pathologic CR (pCR). At 9 years’ follow-up, patients with a pCR had higher disease-free survival and overall survival rates than patients with residual invasive disease noted at the time of surgery.15 All large randomized clinical trials of neoadjuvant versus adjuvant therapy indicate that these therapies offer similar survival advantages.15-20 Therefore, neoadjuvant chemotherapy has now become an acceptable alternative to adjuvant chemotherapy for small operable tumors (stage I-II) in patients who desire potentially more conservative surgical treatment. Among patients receiving neoadjuvant chemotherapy versus adjuvant therapy for operable breast cancer (stages I-III), there has been a 5% to 36% increase in breast-conserving surgery.14,18,20,21 Preoperative therapy also can be considered for patients who have medical contraindications to surgery or who simply wish to delay surgery, for example, pregnant patients diagnosed with breast cancer in which surgery and radiation therapy can be performed after delivery. Even though there have been substantial clinical response rates with neoadjuvant therapy, pCR has remained low. As shown in NSABP B-18, pCR may act as a surrogate marker of prognosis.14,22,23 Improving the pCR may be the way to improve on neoadjuvant therapy for breast cancer. However, how this should be accomplished remains to be determined. Many questions regarding the best application of preoperative chemotherapy still remain, including the best combination of treatment, the optimal length of neoadjuvant therapy, and the proper role for adjuvant chemotherapy following surgery and radiation. Neoadjuvant chemotherapy offers the unique advantage of being able to observe a tumor’s response
59 to therapy. By clinically and biologically monitoring response, doctors can tailor therapy to each individual patient. Such an approach also provides a way to rapidly screen new compounds and identify important surrogate markers to response.
References 1. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352:930-942, 1998 2. Early Breast Cancer Trialists’ Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988 3. Haagensen CD, Stout AP: Carcinoma of the breast. II. Criteria of operability. Ann Surg 118:859-863, 1943 4. Fisher B, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43:1488-1492, 1983 5. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979 6. O’Reilly MS, Holmgren L, Shing Y, et al: Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 59:471-482, 1994 7. 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 8. Jacquillat C, Weil M, Baillet F, et al: Results of neoadjuvant chemotherapy and radiation therapy in the breast-conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer 66:119-129, 1990 9. Anderson ED, Forrest AP, Hawkins RA, et al: Primary systemic therapy for operable breast cancer. Br J Cancer 63:561-566, 1991 10. Smith IE, Walsh G, Jones A, et al: High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. J Clin Oncol 13:424-429, 1995 11. Chollet P, Charrier S, Brain E, et al: Clinical and pathological response to primary chemotherapy in operable breast cancer. Eur J Cancer 33: 862-866, 1997 12. 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 13. Graham MV, Perez CA, Kuske RR, et al: Locally advanced (noninflammatory) carcinoma of the breast: results and comparison of various treatment modalities. Int J Radiat Oncol Biol Phys 21:311-318, 1991 14. 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 15. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96-102, 2001 16. Semiglazov VF, Topuzov EE, Bavli JL, et al: Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol 5:591-595, 1994 17. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol 2:347-354, 1991 18. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus 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 19. 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 20. van der Hage JA, van de Velde CJ, Julien JP, et al: Preoperative chemo-
60 therapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19:4224-4237, 2001 21. Gianni L, Baselga J, Eiermann W, et al: First report of the European Cooperative Trial in Operable Breast Cancer (ECTO): effects of primary systemic therapy (PST) on local-regional disease. Proc Am Soc Clin Oncol 132a, 2002
S.B. Wedam and S.M. Swain 22. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999 23. Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002