Radiotherapy in the Neoadjuvant Setting
Radiation therapy delivered in advance of surgery would reduce delays between chemotherapy and radiotherapy, and similarly between surgery and radiation, and may therefore represent a favorable option. The question arises therefore, if neoadjuvant radiotherapy delivered after tumor chemosensitization, but in advance of definitive surgery, might offer an advantage over adjuvant radiotherapy. A number of large randomized phase III trials have confirmed the superiority of neoadjuvant radiotherapy over adjuvant radiotherapy in a number of other cancer sites, including rectal cancer35,36 and extremity soft tissue sarcoma.37,38 There are theoretical advantages in terms of timing, planning, and dosimetry. However, limited data exist on this therapeutic approach in the setting of breast cancer. Three recently completed prospective studies investigated the role of neoadjuvant radiation and taxane-based chemotherapy.39–41 In all studies, the regimen was found to be feasible and effective. A 20-year retrospective review of patients managed with neoadjuvant chemotherapy followed by neoadjuvant radiation in a single tertiary referral center in France found the approach to be oncologically safe and to facilitate immediate breast reconstruction while avoiding delays in mandatory radiation.42 A German study identified a survival advantage for neoadjuvant radiotherapy compared with adjuvant therapy in T2 tumors.43 A recent prospective study showed neoadjuvant chemotherapy and radiotherapy followed by mastectomy and immediate reconstruction to be equivalent to patients assigned to delayed reconstruction following completion of mastectomy and adjuvant chemoradiotherapy in terms of oncologic safety and cosmesis.44 These studies have been limited by small numbers and lack of standardization of chemotherapeutic regimes.
Neoadjuvant Radiotherapy Technique
One limitation in delivering chest wall irradiation in advance of surgical resection is the absence of pathologic prognostic information as regards nodal burden. Determination of exact number of nodes involved by metastatic disease, or indeed determining whether intra-thoracic nodal disease is present, is precluded by this approach. In light of this, we recommend a three-field approach to include delivery of radiotherapy to the whole breast and to the supraclavicular fossa. Computed tomography (CT) planning should be performed in advance of therapy to allow optimized targeting of therapy.
As outlined by Siewert et al.,45 there are numerous benefits to the delivery of radiotherapy and chemotherapy concomitantly, including organ preservation, radio-sensitization, and improved disease control. The treatment modalities exhibit ‘spatial co-operation,’ with radiotherapy acting to provide loco-regional control and chemotherapy against distant systemic micrometastases.46 Concomitant application of the modalities, however, may lead to increased toxicities.45 Sequential application of the treatments may facilitate the use of both at effective doses without increasing toxicity, and avoiding the need for dose reduction.
The most commonly applied drugs in neoadjuvant chemotherapeutic regimes include doxorubicin (Adriamycin®), paclitaxel (Taxol®), and cyclophosphamide. Doxorubicin has been used with efficacy in the radiosensitization of sarcoma; paclitaxel in non-small-cell lung cancer.45 It can be hypothesized therefore that these agents could also be applied as radio-sensitizing agents in breast malignancies. Commonly used radiosensitizing agents include cisplatin, which acts to interfere with doublestranded DNA (dsDNA) repair, and has been used with great efficacy in BRCA-1-associated triple negative breast cancer,47 a particularly challenging subtype. A certain subset of triple negative breast cancers can be deemed ‘basal-like’ by virtue of overexpression of epidermal growth factor receptor (EGFR), c-kit, and cytokeratin 5/6. These markers potentially represent targets for radio-sensitization. Sambade et al.48 investigated the use of lapatanib, a dual EGFR/Her2 kinase inhibitor, in combination with radiotherapy, in an in vivo murine model. Basal-like breast cancers exhibited complete resistance to lapatanib alone, but were shown to be highly growth impaired when radiation therapy was also applied. Similarly tumor control in Her-2 overexpressing subtypes was shown to be more pronounced when combination therapy was utilized compared with either modality in isolation. Tyrosine kinase inhibitors (TKIs), such as lapatinib, have also been shown to act in synergy with trastuzumab, and use of these agents together may further increase the efficacy of radiotherapy in Her2-positive subtypes.49
The luminal (hormone receptor-positive) subtypes of breast cancer have a more favorable prognosis than hormone receptor-insensitive tumors, which are associated with increased recurrence rates.50 In a series of patients undergoing breast conservation followed by adjuvant radiotherapy, Luminal A subtypes were shown to exhibit the lowest rates of loco-regional recurrence, followed by Luminal B subtypes.51 A Danish study also showed favorable response in hormone receptor-positive tumors to postmastectomy irradiation compared with hormone-negative subtypes.52 It has been hypothesized that estrogen-mediated acceleration between the G1 and S phases of the cell cycle impairs DNA damage repair mechanisms in tumor cells, enhancing radiation-mediated cell death. Hormone-sensitive tumors may therefore be particularly sensitive to radiotherapy.49,52
The role of radiotherapy in breast cancer is well validated, as is the use of neoadjuvant chemotherapy to render cancers operable or to facilitate breast conservation. We propose that neoadjuvant delivery of radiotherapy will have multiple benefits from oncologic and technical perspectives, as well as from a quality of life and patient satisfaction viewpoint, without increasing toxicity to an unacceptable level. Immediate breast reconstruction is the gold standard of care for patients requiring mastectomy. As disease-free and overall survival rates from breast cancer improve, quality of life and patient satisfaction become increasingly important. Delivery of adjuvant radiotherapy can disrupt the cosmesis of the reconstruction, negating the positive psychological effect of an immediate reconstruction. The presence of a prosthesis or an autologous flap may also make radiotherapy delivery technically challenging. Irradiation of the breast prior to surgery and reconstruction can improve delivery without compromising cosmetic results.
Sequencing of Therapy in Breast Cancer
Radiotherapy in the Neoadjuvant Setting
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