Despite the high prevalence of breast cancer worldwide, it is important to recognize that > 40% of all cases occur in women aged 65 years or older in both the United States and the United Kingdom.1,2 Breast cancers in older patients are more often associated with indolent features and with overall better outcomes than those in younger patients. Thus, use of breast-conservation therapy may be preferable as the surgical treatment pathway to that of mastectomy, particularly for low-risk elderly patients with comorbidities, given the shorter recovery time and lower perioperative morbidity risk with more-limited surgery.
The standard approach for breast-conservation therapy has traditionally added whole-breast radiation therapy after a limited breast-conserving approach to remove the primary tumor, based on a large body of level I data with long-term follow-up. Furthermore, meta-analysis of the trials providing these data suggest that whole-breast radiation therapy not only provides a significant benefit in decreasing local relapse (relative benefit reduction of approximately two-thirds), but also adds a modest—but statistically significant—long-term improvement in breast cancer–specific survival (absolute benefit of approximately 3% at 15 years in N0 patients).3 While these data are routinely extrapolated across all subgroups of patients, the more indolent natural history of low-risk elderly patients and limited representation of these patients in the original breast-conservation therapy trials (with many of the protocols excluding patients ≥ 70 years of age) bring to question the practice of routine delivery of radiation therapy in low-risk elderly patients undergoing breast-conservation therapy.
Practice-Changing Studies
Thus, trials such as the PRIME II trial—recently reported by Kunkler and colleagues4 and reviewed in this issue of The ASCO Post—are major, practice-changing studies regarding low-risk elderly patients treated with breast-conservation therapy. This trial, along with the Cancer and Leukemia Group B (CALGB) 9343 trial,5 should be changing the paradigm of routine use of whole-breast radiation therapy in low-risk elderly patients.
In the PRIME II trial, patients ≥ 65 years with tumors < 3 cm in size with primarily grade I/II disease, all estrogen receptor (ER)-positive and pathologically node-negative, were randomly assigned to whole-breast radiation therapy plus hormone therapy vs hormone therapy alone. The findings parallel those of CALGB 9343, which included an even lower-risk cohort of patients (≥ 70 years with tumors ≤ 2 cm, clinically node-negative, ER-positive). Both studies have similarly reported local relapse rates for cohorts treated with or without whole-breast radiation therapy that were acceptable (PRIME II 5-year rate of 4.1% with no whole-breast radiation therapy vs 1.3% with whole-breast radiation therapy,
P = .0002; CALGB 9343 10-year rate of 10% with no whole-breast radiation therapy vs 2% with whole-breast radiation therapy, P < .001).
Though these differences in local relapse between the arms of each study were statistically significant, the addition of whole-breast radiation therapy did not result in differences in axillary recurrence, distant metastasis, or breast cancer–specific survival. In fact, the majority of deaths in both the PRIME II and CALGB trials were non–breast cancer–related events.5
Similar Findings
In addition to these two studies, others have similarly reported findings that suggest whole-breast radiation therapy may be omitted in subsets of patients at low risk for local relapse. For example, the 2×2 designed randomized BASO II trial included 1,135 women aged < 70 years.6 With a median age of only 57 years (range, 33–69 years), the study reported 10-year local relapse-free survival of 93% for the whole-breast radiation therapy–alone arm and 93% for the tamoxifen-alone arm (P = .90). For patients on the whole-breast radiation therapy/tamoxifen arm, local control was 100% and dropped significantly to 83% for the arm receiving no tamoxifen and no whole-breast radiation therapy.6
It is important to keep in mind that many patients in the trials cited herein received tamoxifen, whereas current practice standards recommend aromatase inhibitors in postmenopausal women. Due to the added (albeit small) further decrease in local relapse associated with aromatase inhibitors, it is highly likely that failure rates in low-risk elderly patients receiving hormone therapy alone will be slightly lower than those reported in these trials. Furthermore, the improved toxicity profile, better tolerability, and array of aromatase inhibitor choices relative to tamoxifen make compliance less of an issue in clinical practice.
Together, these data suggest that in highly selected subsets of low-risk patients such as those older than 65 or 70 years with hormone receptor–positive disease and/or other favorable factors, breast cancer–specific survival is not affected by the omission of whole-breast radiation therapy. Yet, the uptake of these data into our clinical practices has been slow.
Recently, a study using the National Cancer Institute–Surveillance, Epidemiology, and End Results (SEER) database to compare use of radiation in a low-risk elderly population ≥ 70 years old from 2000 to 2004 (pre-CALGB 9343) vs 2005 to 2009 (post-CALGB) demonstrated that use of radiation therapy declined by < 7% (from 68.6% pre-CALGB to 61.7% post-CALGB, P < .001). Though the use of external-beam radiotherapy specifically went down from 66% to 54% (P < .001), an unexpected and fascinating finding was a simultaneous increase in implant-based radiotherapy from 1.4% to 6.2%, which diminished the overall effect of omitting radiation in these low-risk elderly patients.7
Reasons for Slow Adoption
Why are these level I data so slow to be adopted into clinical practice, particularly relative to other breast cancer practices such as the use of implant-based radiotherapy (accelerated partial-breast irradiation) for which similar published level I data with adequate follow-up remain limited? One can only postulate that despite the availability of data, we as a medical community may respond differently to implementing data supporting the withholding of established treatments compared with data that support the implementation of new therapies into clinical practice.
Furthermore, despite the lack of its benefits in survival endpoints, some physicians argue that there is an immeasurable psychological detriment when patients sustain local relapse, eliciting significant distress and anxiety for the patients and their families irrespective of the fact that the relapse does not ultimately affect breast cancer survival, and that this trauma is mostly avoidable given the excellent tolerability of whole-breast radiation therapy. Patients, in turn, also report more distress in clinical follow-up when choosing to omit radiation.8
In light of all of the above, and particularly in countries such as the United States, where physicians/institutions must face the direct consequences of omission of any treatment with regard to fee-for-service reimbursements and the monitoring of “relative value units” on individual physicians’ “productivity,” the slow acceptance and integration of omission of radiation into clinical practice for low-risk elderly patients are not surprising.
Time for Change
Nevertheless, the time has come. We now have a growing body of level I data supporting routine treatment of low-risk elderly patients undergoing breast conservation with surgery and hormone therapy alone. Along with the emergence of additional data supporting omission of radiation in selected subsets of low-risk patients, we have started to see the more routine use of biomarkers, gene assays, and other innovative methods for assessing an individual’s risk for local relapse; a shift in guideline recommendations from national organizations such as the National Comprehensive Cancer Network (NCCN) incorporating new standards for breast-conservation therapy (without radiation) in selected subsets of patients9; more clinical awareness and monitoring of physicians’ choices as part of national initiatives such as the Choosing Wisely campaign10; and national health-care reform evolving to reward physicians for quality over quantity of care. Given all these factors, we should anticipate a more drastic increase in omission of radiation therapy for low-risk elderly patients undergoing breast conservation in our country. ■
Disclosure: Dr. Moran reported no potential conflicts of interest.
References
1. Cancer Research UK: Breast cancer incidence statistics. Available at www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/. Accessed April 9, 2015.
2. American Cancer Society: Breast Cancer Facts & Figures, 2011-2012. Available at www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-030975.pdf. Accessed April 9, 2015.
3. Early Breast Cancer Trialists’ Collaborative Group: 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 378:1707-1716, 2011.
4. Kunkler IH, Williams LJ, Jack WJL, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II). Lancet Oncol 16:266-273, 2015.
5. 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 31:2382-2387, 2013.
6. 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 49:2294-2302, 2013.
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8. Prescott R, Kunkler I, Williams L, et al: A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population: The PRIME trial. Health Technol Assess 11:1-149, 2007.
9. National Comprehensive Cancer Network: Breast cancer (version 2.2015). Available at www.nccn.org/professionals/physician_gls/recently_updated.asp. Accessed April 9, 2015.
10. American Society for Radiation Oncology: Choosing Wisely: [10 Things] Physicians and Patients Should Question. Available at www.choosingwisely.org/wp-content/uploads/2013/09/ASTRO-5things-List_092013.pdf. Accessed April 9, 2015.
