Breastconserving Therapy After Preoperative Chemotherapy

Chemotherapy can also be administered in the preoperative setting (also known as neoadjuvant, primary or induction chemotherapy). There are several theoretical arguments for the use of preoperative chemotherapy. These include the ability to carry out in vivo assessment of tumor response, using the primary tumor to monitor and optimize treatment effects on micrometastases. Also, there is a theoretical advantage of decreasing drug resistance by early exposure to systemic therapy with the hope of improving disease-free and overall survival, as well as producing less favorable growth kinetics for micrometastases. Patients with a good response to neoadjuvant chemotherapy can become eligible for BCT even when their initial tumor was too large for this treatment.

In the NSABP-B27 study, 87% of patients had a clinical response and 26.1% had a pathological complete remission after a combination of AC and docetaxel neoadjuvant chemother-apy.121 In the meta-analysis of neoadjuvant versus postsurgery adjuvant therapy clinical trials, there was a significant reduction in the number of mastectomies after neoadjuvant chemotherapy (16.6% absolute reduction; 95% confidence internal, (CI) 15.1-18.1%).122 An as yet unanswered question is to what extent the choice for BCT in these patients that were treated after neoadjuvant chemotherapy has resulted in an increase in local recurrence rates. In four randomized controlled trials123-126 long-term follow-up showed no difference in survival between the two treatment regimens, nor any significant difference in local tumor control. In the NSABP-18 trial,125 for patients who underwent BCT, at 9 years an LR rate of 10.7% was found for the neoadjuvant chemotherapy group versus 7.6% in the adjuvant chemotherapy group. Because of the heterogeneity of the designs of these studies, firm conclusions cannot be drawn. In the meta-analysis122 there was a 22% increase in the risk of local regional recurrence after neoadjuvant chemotherapy (relative risk (RR) 1.22; CI 1.04-1.43).122 The risk of local recurrence was highest in studies where patients with a clinical complete remission,124 or even with macro-scopical remaining tumor, were treated with radiotherapy alone without surgery.123,127,128 The relative risk increase of local recurrence in these three studies was 1.53 (CI 1.17-2.00). In the other studies combined, there was no increase in the risk of local recurrence (RR 1.10; CI 0.87-1.38). These results suggest that even after a complete remission, surgery remains an important component of BCT.

On the basis of a study in 340 patients after neoadjuvant chemotherapy, who all underwent BCT, investigators at the MD Anderson Cancer Center have developed a prognostic index.129 Risk factors in this study were: clinical (c)N2 or cN3 nodal status; residual pathological tumor size >2 cm; lymphangio invasion; multifocal growth pattern of the remaining tumor. If two of these risk factors are present, the risk of local recurrence was considered too high for BCT (12% with two risk factors; 18% with three risk factors after 5 years).

This prognostic index based on three risk factors was validated in a dataset of 815 patients who underwent BCT after neoadjuvant chemotherapy.130 In this study, patients with no risk factors or only one risk factor had very low local recurrence rates after 10 years; when more risk factors were present, 10-year local recurrence rates were as high as 61%. These findings highlight that good patient selection for BCT after neoadjuvant chemotherapy is extremely important.

In summary, mastectomy instead of BCT after neoadjuvant chemotherapy should be advised when: there are diffuse malignant microcalcifications throughout the breast; when the resection is not radical with more than focally involved resection margins; if there are contraindications for radiation therapy; if it is not possible to localize the tumor area after a complete remission (for this reason, leaving markers in the breast at the position of the tumor should be considered prior to neoadjuvant chemotherapy). Mastectomy should also be considered if two or more of the risk factors found in the MD Anderson study are present: cN2 or cN3 nodal status (before or after chemotherapy); remaining tumor size >2 cm; multifocal tumor (which is often observed in invasive lobular carcinoma); if there is lym-phangio invasion.

If these guidelines are followed, neoadjuvant chemotherapy will help to enable selected patients with large tumors eligible for BCT. However, it should be kept in mind that the majority of patients are already eligible for BCT without neoadjuvant chemotherapy and only selected patients with large tumors will benefit in this way. Therefore, converting mastectomy to BCT is not a very important justification for the use of neoadjuvant chemotherapy.

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