Clinical Research in Practice: The Journal of Clinical Research in Practice: The Journal of Team Hippocrates Team Hippocrates Radiation therapy for older women with early breast cancer: An Radiation therapy for older women with early breast cancer: An unnecessary hardship unnecessary hardship

A clinical decision report using: Kunkler IH, WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial [published correction appears in Lancet Oncol. 2015 Mar;16(3):e105]. Lancet Oncol. 2015;16(3):266-273. https://doi.org/10.1016/S1470-2045(14)71221-5 1 for an older patient seeking treatment for Stage 1 Ductal Breast Carcinoma.

Ms. Johnson's hesitancy to complete radiation therapy stemmed from her dependence on her daughter for transportation to appointments and her recollection of her friend's experience with radiation therapy. Her hesitancy led the team to truly question if ART was necessary in her case or if local reoccurrence could be prevented with AET alone. A review of UpToDate was performed to evaluate the current treatment recommendations for women with invasive ductal breast carcinoma.

Clinical Question
Does post-lumpectomy radiation decrease local reoccurrence in older women with early-stage breast cancer receiving adjuvant endocrine therapy?

Research Article
Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial [published correction appears in Lancet Oncol.

Description of Related Literature
Guidelines based on staging recommend that women with stage 1 breast cancer should be offered partial lumpectomy with sentinel lymph node biopsy followed by ART and AET. 4 However, UpToDate cited that women 65 years of age and older with small, less than 3-centimeter, ER+ invasive ductal carcinoma, may not need to complete ART in addition to AET. 5 Conflicting recommendations from "evidence based" guidelines requires an understanding not only of how the guidelines are constructed, but also the patient to whom the recommendation will be applied.
The literature review began with a search of PubMed using the terms "breast cancer" and "older women" which returned 2082 results. Adding "irradiation" to the search terms yielded 37 results. Further specifying the term "irradiation" as "irradiation" OR "radiation," identified 274 results. Between 2011 and 2021, there were 160 publications including 6 clinical trials and 4 randomized control trials (RCT). Three of these clinical trials and RCTs explored outcomes related to adjuvant therapy. Khan et al. was an observational study of 1,449 patients over 70 years old with early-stage breast cancer enrolled in the American Society of Breast Surgeons registry trial. 6 This study compared ART to AET and found similar levels of reoccurrence after 5 years. 6 The standard of care for older women with stage 1 breast cancer following lumpectomy is ART and AET. This study was excluded because the control group was only offered ART and not the standard-of-care, AET and ART. Meattini et al. is a proof-of-concept paper for the RCT, the EUROPA study, which also compared AET to ART. 7 Meattini et al. discusses the background and methods for the proposed study. Because this study was a proof-of-concept paper and did not include any outcomes, this publication was excluded. The remaining publications in the literature search did not include outcomes related to the reoccurrence of disease and therefore were excluded. [8][9][10] On PubMed, through identification of related articles to Kunkler et al., discussed below, Hughes et al. was additionally considered. Hughes et al. conducted a RCT comparing AET with or without ART. 1,11 This study included 636 women 70 years or older with breast cancer smaller than 2 centimeters. However, the AET used in this trial was tamoxifen, a selective estrogen receptor modulator (SERM), instead of aromatase inhibitors, the standard of care AET for postmenopausal women. 11 The team recommended an aromatase inhibitor for AET to Ms. Johnson. Therefore, this study was excluded because this made comparison difficult.
Kunkler et al. conducted a RCT comparing AET with or without ART in older women with early breast cancer following lumpectomy. 1 This trial included 1326 women 65 years or older with breast cancer that was smaller than 3 cm in greatest dimension. This study allowed the care team to choose the AET, SERMs or aromatase inhibitors, based on their evaluation of the patient and their disease. This study found that although only AET had a statistically significant increase in disease reoccurrence, mortality rates from breast cancer at 5 years between the two groups were similar. This study was relevant to Ms. Johnson because she was a woman older than 65 years old and was diagnosed with early-stage breast cancer. Kunkler  Johnson because it was the only paper that included women receiving adjuvant aromatase inhibitor therapy. 11 Additionally, compared to Hughes et al. the study was more recent and included more participants. 1,11 Based on the SORT criteria, the evidence for ART in older women with early stage breast cancer has a Strength of Recommendation level B based on the limited quality and quantity of clinical trials. 12

Critical Appraisal
Kunkler et al. describes a prospective RCT comparing adjuvant therapies in older patients with early breast cancer. 1 This study enrolled women 65 years or older with ER+ T1-2, N0, M0 breast cancer following partial-mastectomy with clear margins (≥1mm) and negative lymph nodes. Patients with a history of another malignancy other than non-melanoma skin cancer were excluded from the trial. Patients were enrolled from 2003 to 2009 at 76 sites across four countries, the United Kingdom, Greece, Australia, and Serbia.
A total of 1326 women were randomized 1:1 into two groups of adjuvant therapy -radiation therapy (658 patients) and no radiation therapy (668 patients). Both groups received AET. Patients were followed for up to 10 years with a median follow-up of 5 years. No blinding occurred in this study. The primary outcome was ipsilateral breast tumor reoccurrence. Secondary outcomes were breast cancer-free survival rates, overall survival rates, contralateral breast cancer, and development of distant metastasis.
For the radiation therapy group, unilateral reoccurrence was 1.3% as compared to 4.1% in the non-radiation therapy group (p=0.0002). Therefore, Kunkler et al. calculated the hazard ratio to be 5.19 (p=0.0007). Interestingly, Kunkler et al. identified that there was no difference in survival benefit with ART with no statistical significance in overall 5-year survival (p=0.34). In the radiation therapy group, 40 women died, four from breast cancer. In the no radiation therapy group, 49 women died, eight from breast cancer. Therefore, this study argues that ART may not be necessary to improve survival even with a statistically significant increase in local reoccurrence.
Notable weaknesses of this study were related to AET. This study allowed patients to be placed on any AET at the discretion of their provider. Further, this study names Tamoxifen, a SERM, as the recommended AET. The current standard of care AET for ER+ breast cancer in postmenopausal women is aromatase inhibitors. 2 In postmenopausal women, aromatase inhibitors are more effective than SERMs at decreasing reoccurrence rates in ER+ breast cancer. 13 Because Kunkler et al. did not provide data on the AET each patient received, it is unclear whether this could have impacted outcomes.
Another limitation of this study is the lack of data on HER-2 receptor status. Recent research has shown that HER-2 positivity is significant for poor clinical response. 14 Because HER-2 receptor status was not analyzed, it is unclear if this could have affected the results.
This study was conducted in the United Kingdom, Australia, Greece, and Serbia and did not report race and ethnicity as patient characteristics. Additionally, this study had some attrition bias with overall attrition of 78.5% at 5 years. Kunkler et al. does not provide any rationale for the attrition. Given that this study includes an older participant group, the poor attrition may be due to morbidity related to breast cancer or other health problems leading to loss of follow-up.
This study was not blinded to patients or providers. Requiring patients to attend sham ART sessions would have been an unnecessary burden to patients. However, blinding providers and researchers could have strengthened this study. This study was conducted with an intention to treat analysis. This study was registered with ISRTCN without deviation from the treatment protocol and was funded by the Chief Scientist Office (of Scotland) and the Breast Cancer Institute. Kunkler et al. is a SORT Level 2 Evidence. 12

Clinical Application
Following National Comprehensive Cancer Network guidelines, Ms. Johnson was offered a treatment plan of a lumpectomy and axillary sentinel lymph node biopsy followed by AET and ART. 2  without ART. Ms. Johnson was presented with both plans, AET only or AET with ART, and she ultimately chose to complete AET only.
Ms. Johnson was hesitant about radiation therapy as she had watched her friend undergo an aggressive radiation regimen and suffer. She understood that the radiation schedule proposed to her would likely be less aggressive, but she continued to have concerns about the side effects. Ms. Johnson was informed that although there may be minimal benefits to radiation, risks of harm from radiation included fatigue, pain, and skin changes. AET only allowed Ms. Johnson more independence in her treatment, so she did not have to depend on her daughter to attend additional appointments. For Ms. Johnson, the possible harm of not completing ART increases her risk of local reoccurrence but does not increase her mortality risk. The patient was informed of this risk and believed that it was outweighed by the physiological and emotional stress of completing ART on herself and the weight on her daughter.

New Knowledge Related to Clinical Decision Science
Clinical Decision Science allows for individualized medicine. This clinical decision report is based on Ms. Josephine Johnson, an 81year-old female presenting with Stage 1 Ductal Carcinoma of the left breast following routine screening mammogram. This report highlights how the risks and benefits of completing treatments must evaluate social impact in addition to health outcomes.
This Clinical Decision Report highlights that the patient's familiarity with and experiences of recommended treatments plays an important role in clinical decisions. This is an important enough consideration that it might be wise to ask every patient what they know about and what their experience has been with recommended treatments. It is not only the experience of the clinician, but also the experience of the patient that were determinative for this clinical decision. In the absence of direct patient experience with treatments, patients often say, "You're the doctor, you decide." This Clinical Decision Report highlights the need to explore the individual patient's values and needs prior to making a doctor making such a clinical decision.
Again, this Clinical Decision Report highlights the fallibility of "evidence based" guidelines.
For older women with early-stage breast cancer, research shows a significant but small benefit of ART to prevent reoccurrence. However, without an impact on mortality, the toll on patients must be considered. Every patient is unique, and the burden of radiation therapy depends on the patient and their overall health, interest in therapy, and social situation. For some patients, their overall health prognosis due to other significant comorbidities may not project any benefit from aggressive treatment. Further, social situations may create boundaries including transportation, monetary costs, and time that may substantially impact a patients cost-benefit analysis of aggressive treatment.
Finally, the benefit of screening, diagnosing, and treating elderly women with early-stage breast cancer must be considered. Without substantial impact on quality of life and mortality, should we be screening elderly women for breast cancer? When overdiagnosing and overtreating disease does not benefit patients, we place a substantial burden on patients which can worsen health outcomes, and place significant psychosocial stress on patients and their families. As physicians, we must consider these consequences when initiating "harmless" screenings. Ms. Johnson's overall health and quality of life may not have been impacted if she was not screened, diagnosed, and treated for her new-onset breast cancer.