Role of radiotherapy in women over the age of 65 after breast conserving surgery for breast cancer: A 5-year retrospective study

Abstract

BACKGROUND/OBJECTIVE:

This study aimed to analyse the local recurrence (LR) and breast cancer related mortality (BCRM) in older women who underwent breast-conserving surgery (BCS) with and without adjuvant radiotherapy (XRT).

METHODS:

This retrospective study included a total of 299 women who underwent BCS for early breast carcinoma, between the years of 2007 and 2011. Predictive risk factors, local recurrence (LR) and breast cancer related mortality (BCRM) were assessed with a mean follow-up period of 84 months.

RESULTS:

Women over the age of 65 in the XRT and No-XRT groups showed similar incidence of LR (5.8% vs 5%, p = 0.838). Women over 65 years old with XRT had a higher rate of BCRM (5.8% vs 0%, p = 0.05). Resection margins >5 mm had a lower rate of BCRM (HR 0.395, p = 0.05). Women under the age of 65, invasive ductal carcinoma, grade-3 tumours, HER-2 positive, triple negative, lympho-vascular invasion, axillary lymph node positivity, high breast density on mammography were associated with increased risk of LR and BCRM.

CONCLUSIONS:

XRT in women over the age of 65 did not decrease the risk of LR. Adjuvant XRT in older women should be offered to selective patients with high risk patient and tumour factors.

1. Introduction

Breast cancer is the most common cancer in women worldwide. Screening, early diagnosis and multidisciplinary management has significantly improved the prognosis in patients with breast cancer. The current standard of care for early breast cancer is breast-conserving surgery (BCS) and whole breast radiotherapy. BCS with radiotherapy is a safe alternative to mastectomy [1–4]. Several randomised trials and meta-analyses have reported that radiotherapy provides a lower rate of loco-regional recurrence (LR) and also improves long-term cancer-specific survival.  Radiotherapy after BCS is associated with a survival advantage both node positive and negative breast cancer [1,5,6].

For most older women with early breast cancer, the current standard treatment is BCS with adjuvant radiotherapy and hormone therapy [7]. However some studies have reported that there was no significant benefit from radiotherapy in the more indolent low-risk cancer in older women [8,9]. CALGB study found that in women over the age of 75, the use of radiation decreased the risk of locoregional recurrence [8]. PRIME-2 randomised controlled trial reported a modest reduction in local recurrence. The benefit was low enough for omission of radiotherapy in selected older women [9]. These trials have had significant impact on our clinical practice. The NCCN guideline recommended that in women aged 70 and above with early breast cancer radiotherapy can be safely omitted [10]. The question whether radiotherapy can be safely omitted in older women with low risk early breast cancer is still debatable.

The aim of this single centre study was to analyse the loco-regional recurrence and breast cancer related mortality in older women who underwent BCS with and without adjuvant radiotherapy. The predictive risk factors for LR and mortality were also analysed.

2. Methods

A total of 299 women who underwent BCS for biopsy proven early unifocal breast carcinoma between the years of 2007 and 2011 were included. Women who had previous ipsilateral breast cancer, pure DCIS only, neoadjuvant chemotherapy and patients who underwent completion mastectomy were excluded from the study.

All patients were pre-operatively staged and managed based on a multidisciplinary approach. Pre-operative localisation for non-palpable tumours were performed using activated charcoal 120 mg in 3 ml injections (Charcotrace, Phebra Pty Ltd, Australia).

BCS was performed using the sector resection technique. This technique has been shown to offer excellent oncological and cosmetic outcome in early unifocal breast cancer [11–15]. Intra-operative specimen radiography was performed to ensure clear radiological margins. A sentinel lymph node biopsy was performed in clinically and radiologically node negative axilla for staging. Patients with positive lymph node on pre-operative workup or macrometastasis in their sentinel lymph node biopsy underwent axillary lymph node dissection (ALND).

Adjuvant chemotherapy and radiotherapy were given to selected patients based on their tumour biology. Patients who received whole breast radiotherapy received 25 fractions to the chest wall with a total dose of 50 Gy. Most patients underwent radiotherapy boost to the chest wall and/or supraclavicular fossa. In most of the low risk and older patients over the age of 65, adjuvant radiotherapy was omitted. Patients with positive oestrogen/progesterone receptors received adjuvant endocrine therapy. Patients with HER-2 positive tumours received standard Transtuzumab therapy.

After surgery patients were followed-up after 1 and 3 months, then every 6 months for clinical review for the first 2 years and every year subsequently. Surveillance included clinical examination and yearly mammography. The patients were divided into two groups namely BCS with radiotherapy (XRT) and BCS without radiotherapy (No-XRT). All patients were followed up for a minimum period of 5 years with a mean period of follow-up of 84 months. There was no loss to follow-up.

Statistical analysis was performed using SPSS version-24 (SPSS Inc., Chicago, IL, USA). Parametric variables were analysed using one-way ANOVA test while non-parametric variables were investigated using Mann-Whitney U-test. Chi-square test was used to assess proportions of nominal/ordinal variables in different groups. The overall 5-year survival rate was calculated using the Kaplan-Meier survival analysis. The univariate difference between the curves was assessed by the log rank test and multivariate analyses were performed using proportional hazard Cox regression model. A p-value of less than or equal to 0.05 was accepted as statistically significant.

3. Results

Amongst the 299 patients, 178 were under the age of 65 and 121 were over the age of 65. 238 received adjuvant radiotherapy (XRT group) and 61 did not receive adjuvant radiotherapy (No-XRT group). The patients in the XRT group were much younger than the No-XRT group with a median age of 59 and 76 respectively. Except one patient who refused radiotherapy, all the other women under the age of 65 received adjuvant radiotherapy.

The mean follow-up duration was 84 months (range – 60 to 108 months). The majority of carcinoma in both the groups was invasive ductal carcinoma (81.51% in the XRT and 67.21% in the No-XRT group). When compared to the No-XRT group, tumours in the XRT group showed a higher incidence of HER-2 positivity, triple negative and lymphovascular invasion. The rate of sentinel lymph node positivity and axillary lymph node dissections were higher in XRT group. 47% of women in the XRT group received adjuvant chemotherapy when compared to 6.5% in the No-XRT group. A higher proportion of patients required re-excision in the XRT group (5.46% vs 3.27%) (Table 1).

The rate of LR was lower in the XRT group (3.36% vs 4.91%, p = 0.9). The rate of distant metastasis was higher in the XRT group (7.56% vs 3.27%, p = 0.82). Breast cancer related mortality was 7.56% in the XRT group and there was no breast cancer related mortality in the No-XRT group (Table 1).

The Kaplan–Meier analysis demonstrated the probability of loco-regional recurrence and breast cancer related mortality between the XRT and No-XRT groups. Log-rank test for equality of survivor functions for local recurrence was Log-rank p = 0.190. Log-rank test for equality of survivor functions for mortality was Log-rank p = 0.022 (Graphs-1 & 2).

3.1. Margin status

The rate of local recurrence was lower in women who had margins >5 mm (HR 0.417, p = 0.14). Women with resection margin between 2–5 mm showed a higher incidence of LR (HR 3.868, p = 0.026). Women with resection margins >5 mm had a lower rate of breast cancer related mortality (HR 0.395, p = 0.05).

3.2. Age

Women under the age of 65 had a higher rate of grade-3 carcinoma (p = 0.004), triple negative carcinoma (p = 0.08), lymphovascular invasion (p = <0.001), sentinel lymph node positivity and axillary lymph node dissection. Most of women under the age of 65 received XRT. Rate of LR was lower in women under the age of 65 (2.8% versus 4.9%, p = 0.34). The rates of distant metastasis and breast cancer related mortality were higher in women under the age of 65 (p = 0.14 & 0.03 respectively) (Table 4).

3.3. Age and XRT

Women under the age of 65 in the XRT group had a higher rate of LR (2.67% vs 0%, p = 0.868) and mortality (8% vs 0%, p = 0.76). The annualised incidence of LR was 0.38% in the XRT group and 0% in the No-XRT group, p = 0.86. The XRT group had a significantly higher rate of annualised incidence of breast cancer related mortality (1.14% vs 0% respectively, p = 0.76) (Tables 5 & 6).

Women over the age of 65 in the XRT and No-XRT groups showed similar incidence of LR (5.8% vs 5%, p = 0.838). The older in the XRT group had a higher rate of mortality (5.8% vs 0%, p = 0.05). The XRT group showed a higher annualised incidence of LR (0.84% vs 0.71%, p = 0.83) and mortality (0.84% vs 0%, p = 0.05) (Tables 5 & 6).

3.4. Predictive risk factors for LR

Older women over the age of 65, invasive ductal carcinoma associated with DCIS, grade-3 tumours, HER-2 positivity, triple negative tumours, lympho-vascular invasion and high breast density on mammography were associated with increased risk of LR (Table 2).

3.5. Predictive risk factors for breast cancer related mortality

Women under the age of 65, invasive ductal carcinoma, grade-3 tumours, HER-2 positive, triple negative, lympho-vascular invasion, sentinel lymph node positivity, axillary lymph node dissection and positivity, re-excision, distant metastasis, high breast density on mammography were associated with increased risk of mortality (Table 3).

4. Discussion

Several studies have reported that the addition of XRT after BCS decreases the ipsilateral loco-regional recurrence and breast cancer related mortality when compared to BCS alone. EBCTCG meta-analysis reported from XRT in all types of breast cancers [16], however Lui et al found that high-risk tumours have the highest benefit from XRT [17]. Several attempts have been made to define and identify a low-risk group of older patients in whom XRT can be safely omitted. Meta-analysis has showed that high-risk tumours (HER2 positive, basal-like or triple negative) have the greatest benefit from [1]. The Prime-II randomised controlled trial reported only a modest benefit in women over the age of 65 who received XRT. The benefit was low enough for omission of XRT in women over the age of 65 [9]. Although CALBG trial reported a benefit in the rate of LR with XRT, there was no impact on overall survival, distant metastasis or the rate of breast conservation [8].

This study found similar results. The overall rate of local recurrence is lower in the XRT group. The carcinoma in the younger women showed more aggressive biology with tumours characteristic showing a higher rate of invasive ductal carcinoma, grade-3, triple negative tumours, HER-2 positivity and node positive disease. XRT in women over the age of 65 did not decrease the risk of LR but was associated with increased mortality. The findings of this retrospective study should be interpreted carefully as the sample size were small. The increased mortality is also correlated with the high-risk factors and tumour biology and therefore multifactorial.

This study also found the overall predictive risk factors for LR and breast cancer related mortality similar to the published studies in the literature [1,4,6,17,18]. The clinico-pathologic variables such as invasive ductal carcinoma, grade-3 tumours, HER-2 positivity, triple negative tumours, lympho-vascular invasion, axillary lymph node positivity, and high breast density on mammography were associated with increased rate of local recurrence and mortality. Contrary to the published studies, the resection margins >5 mm showed a non-statistically significant benefit with a reduced rate of LR and mortality.

In conclusion, the role of adjuvant XRT in older women is still controversial and debatable. This study did not find any benefit from adjuvant radiotherapy in women over the age of 65, however these findings were not statistically significant. Adjuvant radiotherapy in older women should be decided on both high-risk patient and tumour factors. The non-statistically significant findings in this study are likely due to the smaller sample size and unbalanced sample size between the groups.

More recently new radiotherapy techniques such as intraoperative radiation therapy (IORT) is being trialled [21,22]. ELIOT trial reported a significantly greater ipsilateral breast cancer recurrence rate with the IORT and recommended improved patient selection [21]. An analysis of TARGIT and ELIOT trials reported that the short-term data is not adequate and long-term results are needed for the use of IORT [23]. Patient selection using the ASTRO and ESTRO guidelines have shown early promising results [24]. However longer follow-up and additional randomised controlled trials with large sample size are necessary to validate those early findings. Until then, it will be prudent to consider not only the age of the patient, but also the other patient and tumour related factors when offering older women adjuvant radiotherapy. The life expectancy in women is consistently rising in the developed countries. With the increasing life expectancy in older women, it is important to discuss and counsel individual patients about the risks and benefits of adjuvant radiotherapy. Careful patient selection, patient participation and patient-centered multidisciplinary management are vital in the decision-making process [18–24].