Sequencing of Therapy in Breast Cancer

Oncology & Hematology Review, 2014;10(1):33–6

Abstract:

Breast cancer represents a common malignancy in the developed world. The treatment of breast cancer is multimodal, and includes surgical management, chemotherapy, radiation, and hormonal modulation. The selection and sequencing of the different facets of treatment are based on patient and tumor variables, including prognostic scores and desire for breast conservation or reconstruction. The role of irradiation of the breast in breast-conserving surgery is well established. Radiation of the chest wall post mastectomy has also been associated with survival benefit in patients with node-positive disease. Unlike several cancers for which preoperative chemoradiation is the standard of care, radiation is generally reserved as a final step in the treatment of breast cancer, and can delay reconstruction, as the presence of an autologous flap or an implant may reduce the capacity to deliver effective chest wall radiation. The question arises therefore, if neoadjuvant radiotherapy delivered after tumor chemosensitization, but in advance of definitive surgery, might offer an advantage over adjuvant radiotherapy.

Keywords: Breast cancer, radiotherapy, immediate reconstruction, neoadjuvant, postmastectomy irradiation
Disclosure: The authors have no conflicts of interests to declare.
Received: November 05, 2013 Accepted March 04, 2014 Citation Oncology & Hematology Review, 2014;10(1):33–6
Correspondence: Terri P McVeigh, MB BAO BCh, MRCS, MSc (Clin Ed), Discipline of Surgery, Clinical Sciences Institute, National University of Ireland, Galway, Galway City, Ireland. E: terri.mcveigh@gmail.com

An erratum to this article can be found below.

Breast cancer is the most common female malignancy in Europe and North America, and represents a heterogeneous group of proliferative lesions, the prognosis of which depends on a host of interrelated factors including draining axillary lymph node status, tumor size, grade, mitotic index, and molecular profile. The treatment of breast cancer is multimodal, and can include surgical management, chemotherapy, radiation, and hormonal modulation. The selection and sequencing of the different facets of treatment are based on patient and tumor variables, including prognostic scores and axillary or distant metastases.

Indications for Radiotherapy in Breast Cancer
Radiation therapy in breast cancer is indicated in all patients undergoing breast conservation, and postmastectomy in patients with T3 or T4 tumors, or with four or more positive axillary nodes.1–4 The role of radiotherapy in breast cancer management has undergone overwhelming changes since its initial application. Its utility was highest in the pre-screening era when women often presented with advanced stage breast cancer or positive axillary disease. Technique-related cardiac complications precipitated a decline in its application, but technical improvements have facilitated its integration into standard management regimes. The aim of radiotherapy in breast cancer care is to reduce the risk for loco-regional recurrence, thereby conferring a survival advantage. Local recurrence is associated with higher rate of distant metastasis and death. Radiation of the chest wall post mastectomy has also been associated with survival benefit in patients with node-positive disease5,6 and has been shown to greatly reduce the risk for local recurrence or chest wall failure.5 A large review has shown that for every four local recurrences prevented, one death from breast cancer is avoided over the subsequent 15 years.5 Postmastectomy radiotherapy also has been shown to confer a survival benefit to nodepositive patients at lower risk for recurrence. The British Columbia trial showed greater relative reduction in patients with only one to three involved axillary nodes compared with those with more than four positive nodes. The role of irradiation of the breast in breast-conserving surgery is well established as it is associated with significant reduction in the rate of local recurrence as well as breast cancer deaths, by virtue of eradication of any residual microscopic disease at the surgical margins.7 Loco-regional and distant disease-free survival benefit has been noted in patients undergoing breast conservation followed by radiotherapy,8 and some groups therefore recommend the use of radiotherapy in the majority of patients with nodepositive disease, regardless of nodal burden.9 Postmastectomy irradiation has been shown to be particularly beneficial in patients with triple negative breast cancer, a cohort that has been previously identified as bearing an inflated risk for loco-regional recurrence irrespective of nodal status.10

In cases of breast cancer we tend to use chemotherapy in the neoadjuvant setting, unlike several cancers for which preoperative chemoradiation is the standard of care, ahead of definitive surgery, with radiation reserved as a final step in treatment. This paradigm has evolved as radiation oncologists have tried to stratify patients into those requiring radiotherapy post mastectomy, based on pathologic tumor characteristics, including tumor stage and nodal status.11 This historically applied to patients assigned to chemotherapy after mastectomy, where the pathology was easily interpretable. The equivalence of neoadjuvant chemotherapy compared with adjuvant chemotherapy in the setting of breast cancer is well established.12 Furthermore, pathologic tumor response to neoadjuvant chemotherapy can provide important prognostic and predictive information, and can facilitate planning of further required therapeutic interventions.13,14 The indications for neoadjuvant chemotherapy in invasive breast cancer were traditionally limited to large or locally aggressive tumors, but it is now being applied in smaller earlier stage cancer in an attempt to downsize the tumor and in some cases facilitate breast conservation.15–17 In some institutions, the assessment of axillary nodal status is performed in advance of neoadjuvant chemotherapy.18,19 No randomized control trials exist on investigating the role of postmastectomy irradiation in this subgroup of patients. Patients with histologic confirmation of axillary metastases prior to chemotherapy are therefore often assigned to radiotherapy irrespective of tumor or axillary response to chemotherapeutic agents. Debate remains as to how this selection process may be refined, but it remains current practice across a range of centers internationally.5

Role of Reconstruction in Breast Cancer Management
With improved diagnostic and therapeutic techniques, the number of breast cancer survivors is increasing, and the sequelae of treatment and their impact on quality of life are becoming a concern for patients and clinicians. Survivors of breast cancer who have undergone mastectomy can experience poor body image, low self-esteem, depression, and impaired quality of life. It is well recognized that breast reconstruction can improve psychologic health and body image in this cohort of patients. Breast reconstruction can immediately follow mastectomy, or it may be delayed, necessitating a second subsequent operation. Immediate reconstruction, as well as having superior psychologic benefits for the patient, also allows streamlining of the surgical process, requiring only one operation, thereby reducing hospital stay and cost overall.20–24 It also allows normal breast landmarks to be preserved, facilitating shaping of a natural-appearing breast mound. For decades, immediate postmastectomy breast reconstruction was not favored in the management of breast cancer because it was felt that it could lead to increased morbidity and impaired survival by delaying adjuvant therapy. The use of immediate breast reconstruction in the group of patients who require postmastectomy irradiation is contentious—as adjuvant radiotherapy may increase the risk for capsular complications, and can have a deleterious effect on cosmesis.20,25 While some units have used immediate breast reconstruction successfully in this subgroup of patients,26–29 other institutions do not favor immediate breast reconstruction in patients at risk for requiring postmastectomy irradiation.30 Delays in the administration of radiotherapy have been reported in patients undergoing immediate reconstruction.31 Research from patients undergoing breast conservation has illustrated a correlation between increasing intervals between surgery and radiation and the risk for local recurrence,32 and other studies have shown increased mortality risk if the interval between chemotherapy and radiation therapy exceeds 6 months.6 Furthermore, the presence of an autologous flap or an implant may reduce the capacity to deliver effective chest wall radiation.33,34

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Keywords: Breast cancer, radiotherapy, immediate reconstruction, neoadjuvant, postmastectomy irradiation