“Do I need radiotherapy every day?” the elderly woman mused plaintively in the breast cancer radiology waiting room, addressing no one in particular. “Other people here seem to be on another schedule, but my doctor didn’t discuss that with me?” Her concern is palpable.
I discuss new recommendations for short course radiotherapy in a previous blog; but an equally important question is: did this elderly patient need to be in that waiting room at all?
Recommendation for radiation therapy for low-risk breast cancers depends on age at diagnosis
Radiotherapy does not increase survival for women over 70 with early, estrogen positive breast cancer: this has been known and part of the NCCN guidelines since 2005:
“National Comprehensive Cancer Network guidelines were amended in 2005 with a footnote stating, “Breast irradiation may be omitted in those 70 years of age or older with estrogen receptor positive, clinically node-negative, T1 tumors who receive adjuvant hormonal therapy.”
A recent study in the Journal of the American Medical Association found that there is data to support omitting radiotherapy regardless of tumor stage. It is an important finding, the authors note, because “ older patients are more prone to adverse effects that can have a substantial impact on quality of life and the ability to perform functions of daily living.”
Yet articles written in the medical and lay press over the past 20 years repeat the same question:
“Radiotherapy in older women with low-risk breast cancer: why did practice not change?”
I will amend that to ask: why is practice not changing?
First, let’s review the reasons behind the NCCN recommendation not to radiate women over 70 with early breast cancer, summarized from this article:
- Adjuvant radiotherapy (RT) after breast-conserving surgery does not change survival;
- Older women have fewer local recurrences;
- Adjuvant therapy (like tamoxifen, aromatase inhibitors) after breast conservation decreases the risk of in-breast recurrence;
- Local recurrence after breast-conserving treatment without irradiation can be salvaged by repeat lumpectomy or lumpectomy with radiotherapy; once the breast has been irradiated, if there is local recurrence, one must have a total mastectomy;
- Shorter life expectancy in older women leaves less time for local recurrence;
- Time to distant metastasis was identical between those treated with radiotherapy plus tamoxifen vs. tamoxifen alone ( 5% in the Tam RT group and 5% with Tam alone at 10 years).
Yet despite the observed similarity in overall survival and reduction of risk of local recurrence (about 7%) between patients who receive or don’t receive radiotherapy, the majority of radiation oncologists, studies show, are still recommending radiotherapy.
One article found a less than 5% decrease in use of radiotherapy in clinical practice; a more recent 2016 study at Johns Hopkins showed about a 30% decrease in use at that institution. One author suggests that doctors are more likely to change a therapy dose or add a new therapy–but not stop a given therapy.
I would suggest three additional factors:
1/ Financial incentive to prescribe;
2/ Patient lack of knowledge;
3/ Failure of physicians to volunteer this guidance.
Financial incentives
Given the aging patient population and the significant investment by hospitals and medical practices in radiotherapy technologies, there is undoubtedly tremendous pressure on physicians to continue to prescribe this intervention to elderly women, as this NPR article and this article in US News and World Report suggest.
Patient lack of knowledge and concern about possible negative outcomes if they don’t pursue the therapy recommended to them
The recent experience of Josie, a 70 year old patient I advocated for, falls into this category.
“Would you walk out in front of a bus?” her radiation oncologist asked Josie, when she questioned whether or not she needed radiotherapy for her newly diagnosed early, estrogen positive breast cancer.
Her oncologist’s rather aggressive promotion of radiatiotherapy led Josie to seek my help in pulling together the latest research on this topic, as well as my help in identifying another radiation oncologist for a second opinion.
Josie wondered:
1/ Did the benefits of radiotherapy for her breast cancer outweigh the risks?
2/ Did radiation therapy prevent metastatic disease (spread of the cancer elsewhere in the body)?
3/ What would her prognosis be if she only took aromatase inhibitors, the oral medication recommended to her?
Josie scheduled an appointment for a second opinion with another radiation oncologist to discuss her concerns.
The new radiation oncologist initially said that she agreed with her colleague’s recommendations for therapy, and outlined a possible radiation therapy course, albeit an abbreviated regimen: one time a week for five weeks. She then discussed the side effects of radiotherapy.
But then the new doctor added: “Of course, if you take the aromatase inhibitors, you don’t need to do the radiation therapy.”
Lack of discussion of alternatives
For this patient’s type of breast cancer, her doctor’s recommendation not to receive radiation therapy aligns with the current literature, according to a review in UpToDate by Dr. Alphonse Taghian at the MGH:
“The option to omit RT in patients with estrogen receptor-positive, node-negative, small breast cancers is supported by a 2014 meta-analysis that included five trials of mostly postmenopausal women, most of whom received tamoxifen. Most women had T1, node-negative tumors and were older than 65 years; 39 percent were over 70 years old. At five years, leaving out the radiotherapy showed no difference in the absolute risk of a distant recurrence or death.”
The new radiation oncologist did kindly take the time to answer Josie’s questions and concerns.
1/ What were the benefits vs. risks of radiation therapy?
”There is no survival benefit,” she said. “There is a 1% risk of recurrence in the same breast at 10 years with radiotherapy, and a 10% risk of recurrence without radiotherapy. Put another way, the elderly woman I was advocating for had a 90% risk of no recurrence at 10 years if she didn’t do radiotherapy. At five years–the difference between the two risks was 1.4% and 4%.
Importantly, if Josie were treated with radiotherapy and the disease recurred–she could not get lumpectomy surgery–or radiotherapy. If the disease recurred, she would require mastectomy, due to the fibrosis from the radiation therapy.
2/ Prevention of metastatic disease: Would the radiation therapy prevent metastatic disease? The second radiation oncologist shared that radiation therapy ONLY prevents recurrence in the same breast–not in the other breast, and not metastatic disease. By preventing disease in the same breast that could progress to metastatic disease, it could, in a way, be of benefit.
3/ If Josie were only to take aromatase inhibitors–what would the risk of recurrence be?
“The value of hormonal therapy,” according to a Josie’s oncologist, “is multidimensional: it reduces risk of local recurrence by 7-8%; it reduces the risk of cancer in the other breast by 7-8% and it reduces the risk of distant metastatic disease (which can be lethal) by about 10%,“ she noted.
The reason the study of radiotherapy was undertaken was that doctors who undertook the study had observed, in their practice, that elderly women were getting a lot of radiotherapy–and suffering a lot of side effects from it; and they wondered if it was benefiting them. They found that those patients were, for the most part, dying of other things. So the radiotherapy was offering a lot of side effects–but little benefit.
Moreover, the recent JAMA study also showed that lymph node biopsy does not prolong life or decrease recurrence in this patient population either. The study authors state: “ These findings further support the possibility that both sentinel lymph node biopsy and radiotherapy can be omitted for all patients, regardless of tumor grade or comorbidity status.”
Conclusion
For patients with early, estrogen positive breast cancer asking your oncology team if radiotherapy adds benefit to your treatment regimen will allow you to better evaluate the risks and benefits in your particular case.
Medical disclaimer:
The suggestions given here are not intended as a substitute for the medical advice of your physician. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention. For additional questions, please call your healthcare provider for reliable, up-to-date information on testing and symptom management of all medical concerns.
All names are changed to protect patient confidentiality.
Photo credit: thank you to Josh Appel, from Unsplash, photos free to use and share.
References
1. Breast Cancer Over 70: How Much Treatment Is Enough?
https://www.usnews.com/news/health-news/articles/2021-04-20/breast-cancer-over-70-how-much-treatment-is-enough
2. Giordano S. Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Did Practice Not Change? Journal of Clinical Oncology 2012 30:14, 1577-1578
3. Pollock YG, Blackford AL, Jeter SC, et al. Adjuvant radiation use in older women with early-stage breast cancer at Johns Hopkins. Breast Cancer Res Treat. 2016;160(2):291-296.
4. Adjuvant radiation therapy concerns for older patients and/or those with a small tumor. JAMA Network Open. 2021;4(4):e216322.
Summary:
“Recent research studies have looked at the possibility of avoiding radiation therapy for women age 65 or older with an ER-positive, lymph node-negative, early-stage tumor (see Introduction), or for women with a small tumor. Importantly, these studies show that for women with small, less aggressive breast tumors that are removed with lumpectomy, the likelihood of cancer returning in the same breast is very low. Treatment with radiation therapy reduces the risk of breast cancer recurrence in the same breast even further compared with surgery alone. However, radiation therapy does not lengthen women’s lives.
Guidelines from the National Comprehensive Cancer Network (NCCN) continue to recommend radiation therapy as the standard option after lumpectomy. However, they note that women with special situations or a low-risk tumor could reasonably choose not to have radiation therapy and use only systemic therapy (see below) after lumpectomy. This includes women age 70 or older, as well as those with medical conditions that could limit life expectancy within 5 years. People who choose this option will have a modest increase in the risk of the cancer coming back in the breast. It is important for these women to discuss the pros and cons of omitting radiation therapy with their doctor.”
5. Carleton et al. Outcomes After Sentinel Lymph Node Biopsy and Radiotherapy in Older Women With Early-Stage, Estrogen Receptor–Positive Breast Cancer https://jamanetwork.com/searchresults?author=Osama+Shiraz+Shah&q=Osama+Shiraz+Shah
6. 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(19):2382-2387. doi:10.1200/JCO.2012.45.2615 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691356/
Summary:
CALGB 9343 was originally conceived based on several observations. First, adjuvant RT after breast-conserving surgery does not change survival. The Early Breast Cancer Trialists’ Collaborative Group 2005 meta-analysis11 reported a significant reduction in mortality at 15 years with RT, but it is clear that this only applied if the difference in IBTR was > 10%. Most trials reported here revealed a difference in IBTR of < 10%. The data continue to support no survival advantage with the addition of adjuvant RT in the cohorts represented by these trials.
Second, older women have fewer local recurrences. The Milan III trial12 suggested that with quadrantectomy and axillary dissection alone, the rate of IBTR decreased with advancing age. Women age < 45 years had a 17.5% rate of IBTR, whereas those age > 55 years had a 3.8% rate of IBTR. The trials listed in Appendix Table A2 (online only) reinforce this finding, demonstrating a trend toward higher IBTR in younger women with or without RT.
Third, adjuvant Tam after breast conservation decreases the risk of in-breast recurrence.13 Older women tend to have estrogen-sensitive tumors,14 and tamoxifen efficacy increases directly with levels of estrogen receptor expression.15 Tumor estrogen and progesterone receptor levels increase over time with maximum expression in women age > 75 years.16 Moreover, when compared with Tam, aromatase inhibitors (AIs) seem to show an even further decrease in risk of IBTR.17 In a meta-analysis of randomized trials comparing 5 years of either adjuvant Tam or an AI, patients receiving an AI had an HR of 0.70 for isolated local recurrence as a first event (two-sided P = .03).
Fourth, local recurrence after breast-conserving treatment without irradiation can be salvaged by repeat lumpectomy or lumpectomy with RT. Preservation of the breast, even after IBTR, has been demonstrated by Liligren et al,18 Clark et al,19 and Veronesi et al.12 In our study, there was no significant difference in ultimate rate of breast preservation.
We note that the definition of negative margins has changed since this study began. CALGB 9343 accepted the NSABP standard of no ink on tumor, essentially a one-cell minimum margin. Today, the trend is toward greater negative margins, usually 1 to 2 mm,20,21 and the low rate of IBTR without RT in this study might further decrease with wider excision, suggesting that any benefit of RT over antiestrogen treatment alone in local recurrence may be of even less significance today.
In our study, treatment of the axilla was left to the discretion of the physician. Among women who did not have an axillary dissection upfront, none in the TamRT arm experienced recurrence in the axilla; however, six (3%) in the Tam arm did. In the absence of RT or sentinel node biopsy, we might expect a 3% increase in local control compared with RT or sentinel node biopsy. If the results of a sentinel node biopsy are not likely to change the choice of systemic treatment, it is questionable whether this 3% decrement warrants the use of sentinel node biopsy in this population.
Fifth, shorter life expectancy in older women leaves less time for local recurrence. We anticipated that many women would die as a result of competing causes in a relatively short period of time and thus not live long enough to be at risk for IBTR. This was not correct, because the median survival was 12 years, and yet the rate of IBTR remained low. We would suggest that in this older population, comorbid conditions, not specific breast cancer treatments, dictate survival, and the biology of the tumor dictates the rate of IBTR, not the length of life.
Time to distant metastasis did not differ between the two treatment groups and continues to be low. The 10-year incidence of distant disease was only 5% in the Tam RT group and 5% with Tam alone.
The women in this study were significantly healthier and lived considerably longer than the general population of that set of ages. This suggests that the results of this study apply to healthy women in this age group, not just to those with comorbidities.
The durability of the results of this study is encouraging. When first presented, there was concern that with longer follow-up, the number of recurrences would increase. However, the number of events for both groups remains low. With median follow-up of 12.6 years, 334 of 636 women have died, but only 21 (6%) of these have died as a result of breast cancer. In comparison with our previous report of these results at median follow-up of 5 years,6 as expected, the all-cause mortality proportion has increased, but it is still similar between the two arms. The 10-year incidence of breast cancer survival is low in both arms.
The toxicity of tamoxifen is not trivial, particularly in this elderly population. Well-known adverse effects include hot flashes, thrombotic events, and a small risk of endometrial cancer.22 However, despite the possibility that all patients were not able to complete the prescribed course of treatment, local control, distant disease-free survival, and cancer-specific survival remained excellent in this population with generally favorable disease characteristics.
Despite the observed similarity in OS and absolute risk reduction by breast irradiation in locoregional recurrence of only 7%, this study has not had a notable impact on clinical practice. The recent article by Soulos et al7 found that RT use decreased < 5% after publication and dissemination of the data. The decision to use RT may depend more on concerns about our initial short-term 5-year follow-up, patient perception of substandard treatment, choosing the length of time for RT versus tamoxifen, financial considerations, and physician equipoise. The editorial by Giordano23 accompanying that article suggested that given the same level of significance, physicians are more likely to adopt a change in practice that adds or enhances a treatment, rather than a change in which a treatment is withdrawn.
CALGB 9343 was conceived based on the hypothesis that there was a subset of patients in NSABP B06 who did not benefit from breast irradiation after lumpectomy. We observed the indolent behavior of breast cancer in older women in everyday clinical practice and used that as the basis for our study design. Our goal was to offer this cohort of women another treatment option that might decrease morbidity, allow for adaption to social issues, and not complicate other medical problems. Our study offers evidence that such women should have the option of breast-conserving therapy even without RT.
Long-term follow-up of CALGB 9343 confirms and extends the earlier report that in women age ≥ 70 years with clinical stage I, ER-positive breast cancer treated with lumpectomy followed by tamoxifen, irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation, even though it provides a small decrease in IBTR.
