|Year : 2014 | Volume
| Issue : 2 | Page : 279-283
Post-mastectomy radiation beyond chest wall in patients with N1 breast cancer: Is there a benefit?
Budhi Singh Yadav, SC Sharma, Philip George, Anushama Bansal
Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||14-Jul-2014|
Budhi Singh Yadav
Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Introduction: Nodal stage is the most important prognostic factor and one of the indicators for loco-regional radiation in patients with breast cancer. N1 (patients with 1-3 lymph node metastases in axilla) nodal stage is a controversial area as far as axillary and supraclavicular fossa (SCF) irradiation is concerned. We conducted a retrospective analysis at our institute to assess the impact of post-mastectomy radiotherapy (PMRT) beyond chest wall (CW) in N1- nodal stage breast cancer patients.
Materials and Methods: Since January 2004 to December 2007, 293 post-mastectomy patients with N1 nodal stage breast cancer were analyzed for patient-related characteristics such as age, menopausal status, pathological stage/tumour size, tumour location, histology, oestrogen/progesterone receptor status, histological grade, extra capsular extension, lymph vascular invasion and treatment-related factors, PMRT and systemic therapy. Outcome studied were locoregional recurrence rate (LRR), disease free survival (DFS) and overall survival (OS).
Results: At a median follow up of 55m, 260 patients received radiotherapy; 212 to CW+SCF, 48 to the CW only; and 33 patients did not receive radiotherapy. LRR was 5% in patients who received radiotherapy to CW+SCF and 8% in CW only (P = 0.34). There was no difference in the DFS between the two groups. OS at 5 year was 88% in CW+SCF group and 76% in CW only group respectively (P < 0.001).
Conclusion: In N1 nodal stage patients with breast cancer LRR was not significantly different after radiation to CW+SCF or to the CW only but OS was significantly better.
结果：平均随访55个月，260例病人接受了放疗：212例 CW + SCF（胸壁+锁骨上窝），48例只进行胸壁放疗。另外33例未接受放疗。局部复发率LRR ：胸壁+锁骨上窝组为5%，单纯胸壁组 8%（P = 0.34）。两组之间在DFS无显着差异。5年生存率为88%（胸壁+锁骨上窝组）和 76%（单纯胸壁组）（P＜0.001）。
Keywords: Breast cancer, chest wall, local recurrence, overall survival, post-mastectomy radiation
|How to cite this article:|
Yadav BS, Sharma S C, George P, Bansal A. Post-mastectomy radiation beyond chest wall in patients with N1 breast cancer: Is there a benefit?. J Can Res Ther 2014;10:279-83
|How to cite this URL:|
Yadav BS, Sharma S C, George P, Bansal A. Post-mastectomy radiation beyond chest wall in patients with N1 breast cancer: Is there a benefit?. J Can Res Ther [serial online] 2014 [cited 2020 Feb 22];10:279-83. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/279/136560
| > Introduction|| |
Nodal stage is the most important prognostic factor and one of the indicators for radiation of chest wall (CW), axilla and supraclavicular fossa (SCF) in patients with breast cancer. The role of post-mastectomy radiotherapy (PMRT) is the most controversial issue for adjuvant treatment of breast cancer especially in patients with N1 nodal stage.  This issue has been explored in the subgroup analysis of Denmark 82 B and C and British Columbia randomised trials, where it was shown that PMRT benefits equally in both N1 and N2 node group patients in terms of locoregional recurrence (LRR). ,, These trials also demonstrated a significant improvement in overall survival (OS) with PMRT in this group of patients. Studies from United States in which patients with N1 lymph nodes were treated with mastectomy and standard axillary level I-II lymph-node dissection without PMRT followed by systemic therapy reported 10-year LRR of <15%. ,,] Hence, decision for delivering PMRT according to the number of positive lymph node status is controversial due to discrepancies in reported baseline LRR risks and non standard local and systemic therapies administered in these trials. The National Cancer Institute of Canada Clinical Trials Group, MA25 study also tried to answer this issue of PMRT to N1 group of patients with breast cancer but it was closed because of lack of patient accrual. The debate does not end here itself; what should be the volume of PMRT? The another question is - whether in these patients radiation should be delivered to the CW only or axilla (AX) and SCF also needs to be irradiated have not been adequately addressed in any of the clinical trials. This question is of interest to the radiation oncologists who see these patients daily in the clinic. We did a retrospective analysis at our institute to determine the impact of radiotherapy to CW, AX and SCF and CW only in N1- nodal stage breast cancer patients following mastectomy in terms of LRR, distant metastasis (DM) rate, disease free survival (DFS) and OS.
| > Materials and methods|| |
Since January, 2004 to December 2007, 293 post-mastectomy patients with N1 nodal stage breast cancer, who underwent radiotherapy, were analysed retrospectively. Detailed analysis was done for patient-related characteristics such as age, menopausal status, pathological stage/tumour size, histology, grade, extra capsular extension (ECE), lymphovascular invasion, oestrogen/progesterone, human epidermal growth factor receptor 2 (HER-2) status, and treatment-related factors such as radiotherapy, chemotherapy and hormonal therapy [Table 1]. All parameters were entered into a computerised database. A total of 260 patients received radiotherapy; 212 to CW, AX and SCF and 48 to the CW only. Patients who did not receive any radiotherapy (33) were excluded from the analysis. Patients and treatment related characteristics were well matched in the two groups except for multicentric lesions that were not seen in CW group as compared to 7% patients in CW+SCF group. Estrogen receptor positive patients were more in CW+SCF group as compared to CW (46% vs 37.5%). HER-2 positive patients were more in the CW group (21%) as compared to 5% in CW+SCF radiotherapy group. In the systemic treatment, chemotherapy use was more in CW group (94% vs 84%) and hormonal therapy use was more in the CW+SCF group (84% vs 67), respectively.
Two tangential opposed fields were used to irradiate CW. The borders for CW radiation fields were; anterior midline (medial), the mid-axillary line (laterally), bottom of the head of the clavicle (superior) and the inframammary fold (inferior). Hypofractionated radiotherapy, 35 Gy was delivered in 15 fractions over 3 weeks to CW. Dose was prescribed at the mid-point of the central axis. The supraclavicular, infraclavicular and high axillary lymph nodes were treated with an anterior photon field; the inferior portion of this field was matched to the superior edge of the tangent fields. The head of the humerus was also shielded from the radiation beam in patients with adequate axillary dissection. Dose delivered was 40 Gy/15#/3 weeks calculated at a point 3 cm beneath the skin surface. Radiation therapy was delivered using 60 Co-units or 4MV linear accelerator. It was departmental protocol to give radiation to CW+SCF to all patients irrespective of axillary lymphnode involvement till December 2006. Since January 2007, CW radiation was given to all patients postmastectomy but SCF was irradiated in patients with ≥4 lymph nodes metastases in axilla. Patients with only CW irradiation on follow up were coming with more recurrences, so this analysis was done. At present again it is a routine to give radiation to CW+SCF in all mastectomy patients.
Two chemotherapy regimens used were FAC (5-FU: 600 mg/m 2 , adriamycin: 50 mg/m 2 and cyclophosphamide: 600 mg/m 2 ) and taxanes or combination of both. Only 15% patients received CMF (cyclophosphamide: 600 mg/m 2 , methotrexate: 40 mg/m 2 and 5-FU: 600 mg/m 2 ) based chemotherapy in the CF+SCF arm. Tamoxifen was given to ER/PR positive premenopausal patients and letrozole to postmenopausal patients for 5 years. Patients were followed at regular intervals; every 3 m till 1 year, 4 m till 3 years, 6 m till 5 years and yearly thereafter. Further tests were done only if they had symptoms or evidence of recurrent or metastatic disease.
LRR and survival curves were generated by the Kaplan-Meier method. LRR was defined as any recurrence in the skin or soft tissue over CW or a recurrence in the regional lymphatic sites (axilla, internal mammary nodes, infraclavicular and supraclavicular). Univariate analysis was done using the log-rank test. Multivariate analysis was done using the Cox proportional hazards model for age, menopausal status, tumour stage, histological grade, deep resection plane, ECE, multicentricity, lymph vascular invasion (LVI), ductal carcinoma in situ (DCIS), ER/PR and HER-2status, radiotherapy, chemotherapy and hormones. The outcomes studied were LRR, distant failure, loco regional recurrence-free survival (LRRFS), DFS and OS using univariate and multivariate analyses. All statistical tests were two-tailed and differences were considered to be statistically significant if P < 0.05. Statistical analysis was performed using SPSS software version 18.0(Statistical Package of Social Science, Chicago, IL).
| > Results|| |
Patient characteristics were as shown in [Table 1]. Median age was 50 years and 48 years for CW+SCF and CW groups, respectively. Median follow up was 56 m in the CW+SCF group as compared to 54m in the CW irradiation group. Median numbers of lymph nodes examined were 10 and 12 in CW+SCF group and CW group, respectively. LRR was not significantly different between the two groups, 5% in patients who received radiotherapy to CW+SCF and 8% in CW only [Table 2]. Distant metastases rate was 16.5% and 29% in CW+SCF and CW only irradiation group respectively [Table 2]. Recurrence rate in the chest wall was comparable in both the groups (4% vs 5%). However regional relapse in the two groups was different. Recurrence in the AX and SCF was seen in the CW group only (2%) compared to none (0%) in CW+SCF group, respectively [Table 3]. LRRFS at 5 years was 90% in CW+SCF group as compared to 86% in CW group and was not significant [Figure 1]. DFS at 5 years was 62% in CW+SCF group and 54% CW only irradiation group. It was not significant (P = 0.15). However, OS at 5 year was 88% in CW+SCF group and 76% in CW only group [Figure 2], and it was statistically significant (P < 0.001). Median DFS was 41 vs 40 mo and OS was 56 vs 54 mo in CW+SCF and CW irradiation group, respectively.
Univariate analysis revealed that, multicentricity (P = 0.045), PR receptor (P = 0.04) and HER-2 receptor positivity (P <0.001) were the factors which affected DFS. On multivariate analysis HER-2 receptor positivity was an independent significant poor prognostic factor to affect DFS (P <0.001).
Factors affecting OS on univariate analysis were PR receptor (P = 0.042), HER-2 receptor positivity (P <0.001) and radiotherapy (P < 0.001). On multivariate analysis HER-2 receptor (P <0.001) and radiotherapy (P < 0.001) were prognostic factors to affect OS.
Arm edema was seen in 1 (2%) patients with CW only irradiation and 7 (3.5%) in CW+SCF irradiation group; it was not statistically significant. Clinically, there was no cardiac, lung toxicity, rib fracture and axillary neuropathy evident in any of the irradiation groups.
| > Discussion|| |
The exact target volume for PMRT in patients with N1 nodal disease is not known. It is also unknown whether full locoregional radiation gives additional benefit as compared to CW radiation alone. Our results showed that LRR was not significantly different with PMRT to CW+SCF or CW alone in patients with N1 nodal disease. It may be because firstly, these patients had adequate axillary dissection; median number of lymph nodes examined in CW+SCF group was 10 compared to 12 in the CW group, respectively. Secondly, 85% of patients were given anthracyclin and taxane based modern era chemotherapy. But it was not a significant prognostic factor either on univariate or multivariate analysis. OS was significantly better in patients who were given CW+SCF radiation as compared to CW only. Absolute OS benefit was 12% in favour of CW+SCF irradiation group. Previous randomised studies have also demonstrated absolute benefit ranging from 7-11% with PMRT in N1disease. ,,, Head to head comparison with these trials cannot be done because of several reasons related to local and systemic therapy.
Poor OS in CW irradiation group may be because more ER negative and higher HER-2 expression in these patients. HER-2 receptor expression was also a significant poor prognostic factor in these patients both for DFS and OS on multivariate analysis. Herceptin was given to only 3 out of 10 patients because of the cost constraint. But full locoregional radiation has also demonstrated significant OS benefit and it is an affordable short treatment completed within 3 weeks.
In a previous analysis from our institute in patients with T1T2 tumours the effect of radiotherapy was equally pronounced for N1 and N2 nodal disease; but these patients did not had adequate axillary dissection and most of the patients had received CMF chemotherapy. In the present study only 15% of patients were given CMF based chemotherapy and all were from CW+SCF group. Another limitation in that study was HER-2 expression was not routinely done during that time so it could not be correlated with DFS and OS.  . Kyndi et al., have analyzed the molecular features of tumours in a subgroup analysis of the Danish Breast Cancer Cooperative Group 82 B and C trials. They concluded that hormone receptor-negative and HER-2 positive tumours did not seem to have OS benefit from PMRT, whereas the patients with more favourable biologic features had both a lower LRR and a greater improvement in OS with PMRT. Patients in the Danish studies were not treated with anthracyclines, taxanes, or HER-2 inhibitors, so one should be cautious to extrapolate this data to current practice.
During the past decade, better surgical expertise in the axilla and widespread use of adjuvant anthracyclines, taxanes, trastuzumab, and hormonal therapy had substantial impact in reductions in LRR. Radiation oncologists often confront patients with 1-3 positive lymph nodes following MRM in their routine clinical practice and which factors should be considered as risk factors when deciding whether a patient should receive RT to CW with or without locoregional lymphatic, is a hard decision to make. Nodal ratios which have been shown to have prognostic value might be a more relevant parameter to determine LRR.  There is evidence, however, that prognostic indicators such as nodal parameters may not be predictive of the survival effects derived from adjuvant radiotherapy. Unfortunately, the answer will have to wait to be clarified by randomized trials in the coming years. In Selective Use of Post Mastectomy Radiotherapy (SUPREMO), trial has recruited patients from four continents and aims to provide data applicable to the global breast cancer population. It may give us better information on the role of PMRT in this patient group. 
Studies by other authors, such as van de Steene et al., , have also demonstrated that improvement in locoregional controls leads to improvement in OS of the patients. There is accumulating evidence that biologic factors, including genetic alterations and gene expression profiles in the tumour, will be able to predict the response to both adjuvant radiotherapy and chemotherapy. Similar to the concept is the EORTC BIG 3-04 trial, known as the Micro-Array In Node-Negative Disease may Avoid Chemotherapy trial,  which uses molecular genetic analysis of the tumour to select patients who could avoid adjuvant chemotherapy (recently extended to include N1 disease), it is important to identify molecular markers which can guide treatment strategy for adjuvant radiotherapy. One of the most important aspects of the SUPREMO study is the translational research of the TRANS-SUPREMO sub study.
Recent data suggests that patients with HER-2 positive, ER/PR negative and basal tumors have a higher risk for LRR as compared with luminal A type tumours.  These observations suggest that breast cancer is very heterogenous and tumour biology is more complex than previously appreciated. So the molecular features of a tumour may provide better discriminators of which patients are likely to benefit from PMRT. In the modern era, gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence. This biological feature has been studied in breast-conserving therapy and can also be used for patients with mastectomy to individualise the treatment in these patients.  During Danish and British Columbia trials such tools were not available so it would be critical to evaluate such biologic features with contemporary local and systemic therapy trials to derive in particular prognostic and predictive assays for LRR and radiosensitivity, respectively. Present day need is to evaluate individual patient for these molecular features to tailor the treatment rather than following the contemporary guidelines. Further, since the survival benefits in postmenopausal women appear to accrue 5 or more years after PMRT, the patient's life expectancy must be considered as well.
Limitation of our study is the small sample size, single institutional and its retrospective nature. It is a routine practice to give radiation to CW+SCF to most of the patients at our institute, so a bias could not be avoided as PMRT decision is at the discrepancy of the radiation oncologist. Hormonal and HER-2 receptor status was not known in 1/4 th of the patients which may have an implication in the outcome of the patients, though hormonal therapy was given to 3/4 th of the patients.
Toxicity with PMRT is minimal with modern treatment planning and radiation delivery techniques. It is possible to avoid dose to the heart and minimize lung volume within the radiation fields. ,,,, Arm oedema is relatively uncommon when the radiation fields are designed to limit exposure of the dissected axillary tissues. Arm oedema was acceptable in both the groups with no significant difference whether radiation was delivered to CW or beyond CW. However; proper patient selection, planning and accurate execution of treatment are the factors needed to be considered so as to assure best outcome and minimal toxicity.
Because of small number of patients in the CW group, and patient characteristics are not balanced for all prognostic risk factors, further sub grouping for comparison would not have given any conclusive results as patient number would further go down. Only in the radiotherapy subgroup had maximum number for comparison and findings are suggestive of survival benefit in the more RT arm. However concrete conclusion cannot be drawn because of limited sample size, single institutional and retrospective nature of the study. This was just an observation.
| > Conclusion|| |
PMRT in patients with N1 nodal disease patients is an ongoing debate. Our small data have shown OS benefit with PMRT in this group of patients when radiation is delivered to CW+SCF area as compared to CW only. Prospective randomised and retrospective reports have also demonstrated DFS and OS benefits in these patients. Since, patients are subjected to aggressive chemotherapy it would be a right decision to consider these patients for reasonable aggressive loco regional radiation.
| > References|| |
|1.||Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b and c randomized trials. Radiother Oncol 2007;82:247-53. |
|2.||Overgaard M, Hansen PS, Overgaard J, Rose C, Anderson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:949-55. |
|3.||Overgaard M, Christensen JJ, Johansen H, Nybo-Rasmussen A, Rose C, van der Kooy P, et al. Evaluation of radiotherapy in high-risk breast cancer patients: Report from the Danish Breast Cancer Cooperative Group (DBCG 82) Trial. Int J Radiat Oncol Biol Phys 1990;19:1121-4. |
|4.||Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005;97:116-26. |
|5.||Katz A, Strom EA, Buchholz TA, Thames HD, Smith CD, Jhingran A, et al. Locoregional recurrence patterns after mastectomy and doxorubicinbased chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817-27. |
|6.||Recht A, Gray R, Davidson NE, Fowble BL, Solin LJ, Cummings FJ, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen, without irradiation: Experience of the Eastern Cooperative Group. J Clin Oncol 1999;17:1689-700. |
|7.||Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, et al. Pattern of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or with tamoxifen and without radiotherapy: Results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22:4247-54. |
|8.||Yadav BS, Sharma SC, Patel FD, Bose SM, Ghosal S, Kapoor RK. Therapeutic benefit of radiotherapy after surgery in patients with T1-T2 breast tumour. Journal of Radiotherapy in Practice 2010;9:33-40. |
|9.||Kyndi M, Sørensen FB, Knudsen H, Overgaard M, Neilsen HM, Overgaard J, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1419-26. |
|10.||Woodward WA, Vinh-Hung V, Ueno NT, Cheng YC, Royce M, Tai P, et al. Prognostic value of nodal ratios in node-positive breast cancer. J Clin Oncol 2006;24:2910-6. |
|11.||National Health Service Scotland MRC Supremo Trial. Available from: http://www.supremo-trial.com [Last accessed on 21 Nov 2012]. |
|12.||Van de Steene J, Soete G, Storme G. Adjuvant radiotherapy for breast cancer significantly improves overall survival: The missing link. Radiother Oncol 2000;55:263-72. |
|13.||Van de Steene J, Vinh-Hung V, Cutuli B, Storme G. Adjuvant radiotherapy for breast cancer: Effects of longer follow-up. Radiother Oncol 2004;72:35-43. |
|14.||Cardoso F, Van′t VL, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: The MINDACT trial. J Clin Oncol 2008;26:729-35. |
|15.||Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26:2373-8. |
|16.||Nuyten DS, Kreike B, Hart AA, Chi JT, Sneddon JB, Wessels LF, et al. Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 2006;8:R62. |
|17.||Hardenbergh PH, Bentel GC, Prosnitz LR, Marks LB. Postmastectomy radiotherapy: Toxicities and techniques to reduce them. Semin Radiat Oncol 1999;9:259-68. |
|18.||Pierce LJ, Butler JB, Martel MK, Normolle DP, Koelling T, Marsh RB, et al. Postmastectomy radiotherapy of the chest wall: Dosimetric comparison of common techniques. Int J Radiat Oncol Biol Phys 2002;52:1220-30. |
|19.||Pedersen AN, Korreman S, Nystrom H, Specht L. Breathing adapted radiotherapy of breast cancer: Reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold. Radiother Oncol 2004;72:53-60. |
|20.||Chen MH, Cash EP, Danias PG, Kissinger KV, Bornstein BA, Rhodes LM, et al. Respiratory maneuvers decrease irradiated cardiac volume in patients with left-sided breast cancer. J Cardiovasc Magn Reson 2002;4:265-71. |
|21.||Krauss DJ, Kestin LL, Raff G, Yan D, Wong J, Gentry R, et al. MRI-based volumetric assessment of cardiac anatomy and dose reduction via active breathing control during irradiation for left-sided breast cancer. Int J Radiat Oncol Biol Phys 2005;61:1243-50. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]