Breast cancer therapy is developing towards individualized treatment, trying to maintain efficacy with the least aggressive treatment possible. After the introduction of breast-conserving surgery in the 1980s (1), data was updated in 2002 (2) and demonstrated the equivalence between mastectomy and breast conserving surgery (BCS) with radiotherapy. Since then, techniques have been evolving towards less intensive treatments such as accelerated partial breast irradiation (APBI) and intraoperative radiotherapy (IORT) for breast cancer. More than 40% of patients with breast cancer are diagnosed after 65 years of age (3). Conversely, as age increases, the probability of performing conservative treatment of breast cancer decreases at stages I and II, sentinel lymph node in N0, and radiotherapy, especially in patients over 80 years old decrease (4).
Breast cancer tends to present with less aggressive characteristics as age increases (5), including greater expression of estrogen receptors, lower proliferation rate, normal p53, and absence of expression of the epidermal growth receptor and c-erbB2. Older patients with small tumours and node-negative axilla have a life prognosis similar to the general population according to the Surveillance, Epidemiology, and End Results (SEER) data (5), so treatment is unlikely to have an impact on survival.
A recently published trial, the CALGB 9343 (6,7), suggests that radiotherapy can be omitted in low-risk patients aged 70 years or older undergoing adjuvant treatment with tamoxifen, based on the premise that five years of tamoxifen is better than a course of radiotherapy.
This article reviews these recommendations, as well as the possible benefit of radiotherapy, especially IORT in this group of patients.
Local recurrences after conservative treatment without adjuvant treatment
The percentage of local relapses when radiotherapy is omitted in low-risk patients is not negligible, reaching up to 20.7% in a study by the German Breast Cancer Study Group (GBSG) (8), with relapses extending beyond 5 years (Table 1).
Relapse risk factors have been identified for N0 patients, such as age, size, tumour type, hormone receptors and tumour grade (14). Both the GEC-ESTRO (15) and the ASTRO (16) have identified a subgroup of patients with low risk of local relapse suitable for partial breast irradiation (Table 2).
Holli et al. randomized 152 patients (10) comparing lumpectomy alone vs. lumpectomy plus radiotherapy without tamoxifen. In both groups, were included patients between 40 and 76 years with low-risk tumours less than 2 cm N0. In local recurrences, they were 7.1% vs. 18.1% favourable to radiotherapy, without differences in overall survival.
In the meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (14) that included 10,801 patients, of which 1,340 were older than 70 years, radiotherapy shows a benefit at 10 years in relapses of breast cancer in any location (local and distant), with 8.8% for the BCS + RT group vs. 17.7% for BCS without RT. This suggests that for every four relapses prevented, one life could be saved.
Randomized trials in older patients with low-risk tumours, comparing BCS with tamoxifen vs. BCS with radiotherapy and tamoxifen
Only two specific trials have been realized for patients over 65 years. In 2004 (6), the Cancer and Leukaemia Group B (CALGB) published randomized trial results in 636 patients aged 70 years or older, comparing low-risk patients treated with BCS with adjuvant tamoxifen vs. tamoxifen plus radiotherapy. At 5 years, recurrences were 1% for combined treatment and 4% for tamoxifen alone, P<0.001, without differences in survival or mastectomy, concluding that radiotherapy can be safely omitted in this group of patients. In 2013, this same group, CALGB 9343, published results at 10 years of follow-up (7), showing that local recurrences continue to appear beyond 5 years, reaching 10% for the tamoxifen group vs. 2% for the combined tamoxifen plus radiotherapy group. There was no difference in overall survival or in salvage mastectomies. It was noted that by omitting radiotherapy, local recurrences continue at a rate of 1% per year.
The PRIME trial II (9) includes 1,326 patients aged 65 years or older with tumours smaller than 3 cm treated with lumpectomy; the randomization was adjuvant treatment with tamoxifen vs. tamoxifen plus radiotherapy. Local recurrences at 5 years were 1.3% vs. 4.1% favourable to combined treatment. There were no differences in overall survival. These results are very similar to those observed in CALGB 9343 (6,7).
Non-randomized trials in patients older than 70 years BCS vs. BCS plus radiotherapy
Martelli et al. (11) performed a retrospective study of 627 T1-T2 patients, N0, treated with BCS or BCS plus radiotherapy. At 15 years of follow-up, found no differences in local recurrence, metastasis, cancer mortality or overall survival in patients with pT1. In patients with pT2, local recurrences were 14.6% for patients without radiation therapy vs. 0.8%, P=0.004, for patients with radiotherapy. There were no differences in overall survival or cancer mortality. Patients with positive estrogen receptors also received tamoxifen. The patients were treated with quadrantectomy, which perhaps explains the equality of results in patients with T1.
Randomised trials comparing BCS and radiotherapy vs. BCS and hormone therapy
Several randomized trials have been realized that set out to analyse the benefit of radiotherapy and hormone therapy in the conservative treatment of low-risk breast cancer (T1-T2 N0). Two trials include BCS as a control group without adjuvant treatment, the BASO II trial (12) and the GBSG trial (8); this control group is not included neither the NSABP 21 (17) nor in the Fyles et al. trials (13). None are designed specifically for elderly patients, although all do include patients older than 60 years, except the BASO II trial (12) in which all patients are under 70 years.
The BASO II trial (12) includes 1,171 patients; the benefit of radiotherapy is still observed in the presence of hormonal treatment, with local recurrence at 10 years of 22% for surgery alone, 8% for radiotherapy or hormone therapy and 2% when both are associated. Tamoxifen and radiotherapy have the same results in local recurrence, and with equal survival.
The study conducted by the German group GBSG (8) with 347 patients, 186 patients older than 60 years; local relapse was 20.7% for surgery alone, 9.5% for BCS plus radiotherapy, 7.5% for BCS plus tamoxifen and 5.3% for BCS + RT plus tamoxifen.
The NSABP 21 trial (17) studied 1,009 patients treated with lumpectomy with tumours less than 1 cm to compare tamoxifen alone, radiotherapy plus placebo or tamoxifen and radiotherapy. After 8 years of follow-up, local recurrences were 16.5%, 9.8% and 2.8% respectively. Survival was similar in the three groups. 80% were patients older than 50 years and 490 patients (49%) were older than 60 years.
Similar results were reported by Fyles et al. (13) when comparing tamoxifen alone vs. tamoxifen plus radiotherapy in 769 patients with T1-T2N0 conservative treatment older than 50 years, of whom 325 were older than 70 years, with local recurrences at 5.6 years of 0.6% vs. 7.7% favourable to combined treatment.
The main conclusions regarding local recurrences and survival are:
APBI has been shown to be effective in preventing recurrence in patients treated with BCS and low-risk tumours (16). Among these IORT get excellent results in local control.
There are few publications referring to elderly patients, but in none of the published studies have been excluded. There are two randomized trials with IORT, the ELIOT (Electron Intraoperative Radiotherapy) trial (18) and the TARGIT-A (targeted intraoperative radiotherapy) trial (19).
The trial carried out by the Milan-based group, ELIOT, randomized 1,305 patients to BCS plus external radiotherapy, 25 Gy, 2 Gy fraction and boost of 10 Gy vs. IORT 21 Gy with electrons, in patients with tumours less than or equal to 2.5 cm aged between 48 and 75 years, with 50% of the patients being older than 60 years and 10% older than 70 years. It included N0-1 patients and patients with any degree or status of hormone receptors. At 5 years, local recurrences were 0.4% for the external radiotherapy group vs. 4.4% for the IORT P<0.0001 group. There were no differences in survival (18). When selecting a group of patients with criteria recommended by ASTRO (16) for APBI, local recurrences were 1.5% and following the recommendations of the GEC-ESTRO (15,20) 1.9%. Of the 35 local relapses, only 4 were in the 62 patients older than 70 years.
The TARGIT-A trial (19) randomized 3,451 patients older than 45 years, N0-1 with any degree and status of hormone receptors: external radiotherapy 50 Gy, 2 Gy fraction vs. 20 Gy on the surface of the applicator with X-ray of 50 KV, with the dose at 1 cm being 5–7 Gy. One thousand and two hundred twenty-two patients had a minimum follow-up of 5 years. IORT was randomized into two groups, one administering IORT at the time of the lumpectomy and in the other group, in the weeks later the lumpectomy, with pathological result.
Recurrences at 5 years were 3.3% vs. 1.1% favourable to external radiotherapy. In the analysis by subgroup, local recurrences in the IORT group in the time of lumpectomy were 2.1%, with this 1% difference being not significant. The deferred IORT group presented 5.4% of local relapses. Results were also analysed according to hormonal receptor status, showing patients with progesterone receptors positives a local relapse of 0.18%. Another interesting issue of this study (19) is that patients with IORT had a lower overall mortality, 3.9% vs. 5.9%, P=0.09, with there were fewer deaths unrelated to breast cancer in the IORT group, 1.4% vs. 3.5%, P=0.008. In both trials, the toxicity was not greater than external radiotherapy.
This same group initiated a phase II trial aimed at patients aged 70 years or older, with tumours less than 3.5 cm, N0, TARGIT-E (21) with 3 years of follow-up included in 538 patients, with only 1 relapse (0.18%) being noted.
Based on the CALGB 9343 (6,7) and PRIME II (9) trials, the National Comprehensive Cancer Network (NCCN) (22) and the National Institute for Health and Care Excellence (NICE) (23) guidelines, among others, recommended that radiotherapy can be omitted in patients aged 70 years or older with low-risk breast cancer who receive hormonal therapy.
We must make several comments about these trials and recommendations. First, the survival benefit in patients younger than 70 years with low risk breast tumors, T1 N0, positive receptors, margins greater than 2 mm as demonstrated in the EBCTCG meta-analysis (14) and BASO II trial (12) is minimum. And secondly, the percentage of local recurrence even with tamoxifen is not negligible, 10% at 10 years, a percentage which is considered inadmissible in younger patients.
Meanwhile, the recommendation to administer tamoxifen and omit radiotherapy is very questionable. The BASO II trial (12) showed that the benefit of external radiotherapy and tamoxifen are similar in reducing local recurrence with equal survival. With these results, there is nothing to support that 5 years of treatment with tamoxifen in elderly patients, usually polymedicated, is better than a radiotherapy treatment of one month or less as is the case of hypofractionation. Radiotherapy in healthy elderly patients is well tolerated.
Hershman et al. (24) studied a group of 8,769 patients with early breast cancer and found that only 49% of patients received hormonal treatment for the all time of prescription, with those younger than 40 years and older than 75 years being the most likely to discontinue treatment. Moreover, this non-compliance (discontinuation and non-adherence) has effects on the result of the treatment, while reducing survival.
Another argument used to omit radiotherapy is financial. Sen et al. (25) studied the cost-effectiveness of external radiotherapy in 18,340 patients in a group of 8,769 patients over 70 years with early breast cancer and treated with BCS, all from SEER program, and concluded that despite the concern for the overtreatment of this group of patients, radiotherapy is cost-effective. Logically, this benefit decreases in patients with short life expectancies and as they get older. This cost-effectiveness increases in IORT (26), which is the preferable treatment in patients with early breast cancer together with hypofractionation.
There are few publications on patients older than 80 years and no randomized trials that study the benefit of adjuvant treatment with early tumours. The tendency is to omit radiotherapy in a greater percentage and recommend tamoxifen alone, although this may result in undertreatment that worsens its prognosis. Bouchardy et al. (27), in a retrospective study of patients over 80 years, concludes that more than 50% of patients receive suboptimal treatment compared to patients younger than 80 years (47% vs. 91%), with the best results being patients who are treated with BCS + RT, so undertreatment clearly decreased survival.
In recent years, new radiotherapy treatment techniques have been introduced which have the same results but considerably shorten treatment time (hypofractionation) and irradiation volume, such as APBI and IORT. The latter are especially interesting because in a single intraoperative session, the recurrences in low-risk group are equivalent to external radiotherapy, as demonstrated both in the ELIOT and TARGIT-A trials (18,19). This makes it especially attractive in this group of elderly patients.
Another important advance in the treatment of breast cancer in elderly patients has been the generalization of hypofractionated treatments following publication of the START-A and B trials (28,29), demonstrating equal effectiveness in a randomized trial between standard treatment (25 fractions of 2 Gy) and hypofractionation (15 fractions of 2.67 Gy, 13 sessions of 3.2 or 3 Gy). Other non-randomized trial (30) with more extreme hypofractionation with 5 fractions of 6.5 Gy one a week, have shown similar efficacy in patients older than 70 years.
With these advances and results published with APBI, particularly IORT and hypofractionation, it is difficult to argue that adjuvant tamoxifen alone is the treatment of choice in older patients with low-risk breast cancer treated with BSC.
There are few randomized trials that analyze optimal treatment in elderly patients with low-risk breast tumours. The behavior of these tumours does not seem very different from tumours of similar risk in younger patients, where neither does the treatment adjuvant to BCS seem to influence overall survival. Local recurrences after BCS without adjuvant treatment are unacceptable for all groups, so it is advisable to perform adjuvant treatment after BCS. Radiotherapy and tamoxifen seem to have a similar effect in preventing local recurrence and survival, so there is not rationale for recommending 5 years of tamoxifen instead of radiotherapy. Radiotherapy, in any of its modalities, especially IORT and hypofractionation, are cost-effective in this group of patients and it is well tolerated.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
- Fisher B, Bauer M, Margolese R, et al. Five years results of a randomized clinical trial comparing total mastectomy with segmental mastectomy with o without radiation in the treatment of breast cancer. N Engl J Med 1985;312:665-73. [Crossref] [PubMed]
- Fisher B, Anderson S, Bryant J, et al. Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer. N Engl J Med 2002;347:1233-41. [Crossref] [PubMed]
- Héry C, Ferlay J, Boniol M, et al. Changes in breast cancer incidence and mortality in middle-aged and elderly women in 28 countries with Caucasian majority populations. Ann Oncol 2008;19:1009-18. [Crossref] [PubMed]
- Joerger M, Thürlimann B, Savidan A, et al. Treatment of breast cancer in the elderly: A prospective, Population-based Swiss study. J Geriatr Oncol 2013;4:39-47. [Crossref] [PubMed]
- Diab SG, Elledge RM, Clark GM. Tumor Characteristics and Clinical Outcome of Elderly Women With Breast Cancer. J Natl Cancer Inst 2000;92:550-6. [Crossref] [PubMed]
- Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer. N Engl J Med 2004;351:971-7. [Crossref] [PubMed]
- Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol 2013;31:2382-7. [Crossref] [PubMed]
- Winzer KJ, Sauerbrei W, Braun M, et al. Radiation therapy and tamoxifen after breast-conserving surgery: Updated results of a 2 × 2 randomised clinical trial in patients with low risk of recurrence. Eur J Cancer 2010;46:95-101. [Crossref] [PubMed]
- Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015;16:266-73. [Crossref] [PubMed]
- Holli K, Saaristo R, Isola J, et al. Lumpectomy with or without postoperative radiotherapy for breast cancer with favourable prognostic features: Results of a randomized study. Br J Cancer 2001;84:164-9. [Crossref] [PubMed]
- Martelli G, Boracchi P, Guzzetti E, et al. Omission of radiotherapy in elderly patients with early breast cancer: 15-year results of a prospective non-randomised trial. Eur J Cancer 2015;51:1358-64. [Crossref] [PubMed]
- Blamey RW, Bates T, Chetty U, et al. Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. Eur J Cancer 2013;49:2294-302. [Crossref] [PubMed]
- Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer. N Engl J Med 2004;351:963-70. [Crossref] [PubMed]
- Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death : meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet 2011;378:1707-16. [Crossref] [PubMed]
- Polgár C, Limbergen EV, Pötter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: Recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group ba. Radiother Oncol 2010;94:264-73. [Crossref] [PubMed]
- Correa C, Harris EE, Leonardi MC, et al. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol 2017;7:73-9. [Crossref] [PubMed]
- Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, Radiation Therapy, or Both for Prevention of Ipsilateral Breast Tumor Recurrence After Lumpectomy in Women With Invasive Breast Cancers of One Centimeter or Less. J Clin Oncol 2002;20:4141-9. [Crossref] [PubMed]
- Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol 2013;14:1269-77. [Crossref] [PubMed]
- Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer:5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014;383:603-13. [Crossref] [PubMed]
- Leonardi MC, Maisonneuve P, Mastropasqua MG, et al. Accelerated partial breast irradiation with intraoperative electrons: Using GEC-ESTRO recommendations as guidance for patient selection. Radiother Oncol 2013;106:21-7. [Crossref] [PubMed]
- Neumaier C, Elena S, Grit W, et al. TARGIT-E(lderly)-Prospective phase II study of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer. BMC Cancer 2012;12:171-7. [Crossref] [PubMed]
- Gradishar WJ, Abraham J, Aft R, et al. NCCN Guidelines Version 1.2019 Breast Cancer NCCN Guidelines. Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
- National Institute for Health and Care Excellence. Early and locally advanced breast cancer: diagnosis and management: evidence reviews for breast radiotherapy. Available online: https://www.nice.org.uk/guidance/ng101
- Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 2011;126:529-37. [Crossref] [PubMed]
- Sen S, Wang SY, Soulos PR, et al. Examining the cost-effectiveness of radiation therapy among older women with favorable-risk breast cancer. J Natl Cancer Inst 2014;106:dju008. [Crossref] [PubMed]
- Patel R, Ivanov O, Voigt J. Lifetime cost-effectiveness analysis of intraoperative radiation therapy versus external beam radiation therapy for early stage breast cancer. Cost Eff Resour Alloc 2017;15:22-12. [Crossref] [PubMed]
- Bouchardy C, Rapiti E, Fioretta G, et al. Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 2003;21:3580-7. [Crossref] [PubMed]
- Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008;9:331-41. [Crossref] [PubMed]
- Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371:1098-107. [Crossref] [PubMed]
- Ortholan C, Hannoun-Lévi JM, Ferrero JM, et al. Long-term results of adjuvant hypofractionated radiotherapy for breast cancer in elderly patients. Int J Radiat Oncol Biol Phys 2005;61:154-62. [Crossref] [PubMed]