Breast cancer radiotherapy: controversies and prospectives
YU Jin-ming, WANG Yong-sheng
YU Jin-ming Breast Cancer Center, Shandong Cancer Hospital, Jinan, Shandong 250117, China; WANG Yong-sheng Breast Cancer Center, Shandong Cancer Hospital, Jinan, Shandong 250117, China
Correspondence to: YU Jin-ming Breast Cancer Center, Shandong Cancer Hospital, Jinan, Shandong 250117, China (Tel:86-531-87984777 Fax:86-531-87984079 Email:jn7984729@ public.jn.sd.cn )
No abstract available
Despite consensus on breast cancer radiotherapy, there are still some controversies over post-mastectomy radiotherapy (PMRT) in patients with 1–3 positive lymph nodes, accelerated partial breast irradiation (APBI), appropriate sequence of radiotherapy, chemotherapy and hormonal treatment, and radiotherapy after preoperative systemic therapy.
PMRT in patients with 1–3 positive axillary lymph nodes
Maximal control of locoregional tumor is required to achieve the highest ultimate survival rate of patients. The role of PMRT is not clearly defined in this group of patients. Theoretically, the long-term survival of these patients might be benefited after eradication of locoregional tumor because of the lower probability of metastasis beyond the regional lymph nodes.1 The cutoff point of 4 involved axillary nodes is challenged by a recent report of Overgaard et al,2 which demonstrates that the number of involved nodes should not be used as a threshold to prescribe PMRT. This adds to the growing evidence that PMRT should be given to all patients with involved axillary lymph nodes. In fact, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 2005 meta-analysis showed a similar effect of radiotherapy on local relapse free survival (LRF) and survival in favor of PMRT irrespective of the number of involved lymph nodes.3 Moreover, this result was even more pronounced and significant in the EBCTCG 2005-2006 worldwide overview presented at the 2006 SABCS.4 Therefore, sufficient evidence seems to be available for a new shift towards more aggressive locoregional treatment in breast cancer and adaptation of the treatment guidelines accordingly.5 PMRT to the chest wall and supraclavicular lymph nodes should be considered for these patients in the NCCN 2007 guidelines,6 and strongly considered in the NCCN 2008 guidelines.7
Further evidence will be obtained from several well-designed large prospective randomized clinical trials, like EORTC 22922/10925, NCIC CTG MA20 and SFRO CMI, which examined the thin line between advantages and side-effects of PMRT for early breast cancer patients. Until the results of these trials become available, patients with 1–3 involved axillary lymph nodes should be given PMRT at least to the chest wall and the supraclavicular lymph node area.5
Whole-breast irradiation (WBI) produces well-established results, good cosmesis and low toxicity. Conventional WBI takes 5–7 weeks, with attendant costs and inconveniences. This represents a significant hardship to certain subsets of patients and leads to disparity in breast cancer treatment. Obstacles such as inability to find an X-ray telescope (XRT) center close to home, difficulty in finding transportation to and from a center, lack of family support, and extreme age and/or physical handicap prevent some patients from electing to enter a 6-week course of WBI.
Results from the breast-conserving therapy (BCT) trials suggest that up to 86% of the risk for ipsilateral breast cancer recurrence resides in close proximity to the original tumor site. This leads investigators to consider the role of an accelerated and more tumor bed-focused course of radiotherapy. APBI involves the treatment of a limited volume of breast tissue with a dose of irradiation per fraction increased and the treatment time course decreased. The goal is to deliver a dose of irradiation to a limited volume in less time, that is equivalent to the clinical outcome of the conventional 6-week treatment.8
The importance of proper patient selection cannot be over-stressed when discussing the efficacy of APBI. This includes early stage breast cancer as determined by tumor size less than 2–3 cm, node-negative disease, age of patients more than 45–50 years, and tumor-free margins.9,10 Additional criteria under study include features such as lobular histology, presence of extensive intraductal component (EIC), lymphvascular invasion, tumor grade and limited node-positive disease. When the tumor histology demonstrates a higher risk for multicentric disease and thus a higher rate for non-tumor bed cancer recurrence, the patients should not be considered for APBI.8
During the last decade, there are some compelling clinical observations and preliminary results: acceptable 5-year local tumor control, good to excellent cosmesis, and low-grade toxicity, suggesting APBI may be a more appropriate and user-friendly mode for delivering radiotherapy than WBI.8 Issues to be contended with include proper selection, optimizing fractionation-dose schemes, quality assurance of treatment delivery, and minimal longer-term follow-up. More recently, newer techniques that are more patient and physician friendly have been developed, and the interest in APBI has, as a result, increased dramatically.
At present, WBI remains the standard of care after lumpectomy. Patients with invasive or noninvasive breast cancer undergoing BCT or APBI should be aware of the data exploring this treatment approach and provide the opinion of participating in the ongoing phase III trials, as part of an institutional review board-approved clinical registry. Four important trials that attract our attention are the randomized NSABP B-39/RTOG0413 phase III study comparing conventional WBI with APBI for stage 0, I, or II disease, the European TARGIT and EIO trials for IORT, and the American Society of Breast Surgeons-sponsored MammoSite Breast Brachytherapy Registry Trial.
Sequence of radiotherapy and adjuvant systemic treatment
Radiotherapy and adjuvant systemic treatment contribute to an increased overall survival rate.3,11 However, the sequencing of both treatment modalities remains a matter of debate, with differing treatment policies in various countries and various centers. The best results for all clinical endpoints (local and regional control, quality of life, cosmetic results, survival) should be obtained by an optimal combination of surgery, systemic treatment and radiotherapy. This might be considered as a plea for dedicated breast clinics.
Postponement of radiotherapy might lead to an increased incidence of locoregional recurrence and a decreased survival after BCT. A comprehensive review dealing with prospective and retrospective studies in BCT showed that early radiotherapy might benefit patients with positive, close or unknown microscopic margins, whereas those with wider tumor free margins were not benefited.12
Only one small randomized trial in BCT was published where radiotherapy followed by chemotherapy was compared to chemotherapy followed by radiotherapy. Initially CTRT led to more local recurrences, whereas RTCT led to more distant metastases; but at a longer follow-up, this difference disappeared completely.13 Moreover, this trial never showed any survival benefit for either sequences. In an editorial accompanying a report of a retrospective study on the timing of radiotherapy in the prospective CALGB 9344 trial, Bellon and Harris14 concluded that with the available evidence radiotherapy should be given after completion of chemotherapy. However, they confirmed, based on their previous experience, that one should be cautious in the subset of patients with close surgical margins. They suggest that the risk of locoregional relapses, with or without radiotherapy, need to be re-examined as systemic therapy becomes more effective.
As the effectiveness of radiotherapy and chemotherapy for eradicating all clonogenic cancer cells diminishes with an increasing tumor burden, ideally both treatment modalities should start as soon as possible. Theoretically, the best way to achieve this goal is to administer adjuvant radiotherapy and chemotherapy concurrently. There are a lot of concerns opposing this approach, including more acute toxicity, decreased cosmetic outcome, and more (late) cardiac toxicity.5,12
Combined chemotherapy and radiotherapy lead to a higher risk of especially late toxicity: the sequential administration is therefore preferred. The question of which modality should be given first remains unanswered. Several attempts to address this in a properly designed randomized clinical trial failed. With the evidence that is available up to now, adjuvant hormonal treatment should start after completion of chemotherapy whereas no firm recommendations on its sequence with radiotherapy can be given.5
Patients undergoing preoperative systemic therapy
Apart from the routine use of such treatment for large tumors, a majority of the St. Gallen 2007 Expert Panel supported preoperative systemic therapy to improve resectability and thus cosmesis, while a minority also considered that the assessment of responsiveness constituted a reason to employ this treatment approach. A clear majority supported the inclusion of trastuzumab in the preoperative treatment program for patients with HER2-positive disease.15
There is insufficient evidence to make recommendations or suggestions on whether all patients initially treated with preoperative systemic therapy should be given PMRT after surgery as indicated in the ASCO guidelines.16 Buchholz et al17 reported the risk for LRF after neoadjuvant chemotherapy and mastectomy in 19% of patients with LRF of pathological complete remission (pCR) vs 28% of patients with residual cancer, suggesting that selection of patients for PMRT cannot be based on response alone. With the addition of PMRT, the LRF in patients with stage III disease declined from 20% to 9%, but did not significantly decrease in patients with stage II disease (which declined from 9% to 5%).18 Among the patients treated with mastectomy in NSABP B-18, none received PMRT. The recurrence rate was 0% in patients with pCR but 10.5% in patients with residual cancer not metastasized to the lymph nodes and 20.3% in those with residual cancer metastasized to the nodes. However, most of these patients had T1 and T2 tumors,19 suggesting that initial stage, degree, and location of residual disease should be used in determining the need for PMRT after neoadjuvant chemotherapy.
The patients who are not candidates for breast conservation on the basis of a large tumor in a small breast should be considered for preoperative chemotherapy to reduce the tumor size. The patients who are most likely to benefit from this approach are those with unicentric, high-grade, ER-negative cancers.
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