Could radiotherapy be omitted in elderly patients receiving breast conserving surgery?

Cancer management in elderly patients is a challenge, and treatment choice is often based upon literature data derived from clinical trials performed in patients of younger age. In the past, elderly patients, typically older than 65 years, were often excluded from clinical trials because of patient- or family-related factors, such as difficulty accessing care centres or lack of adequate information, and of physician-related factors, including perception that the patient would not be able to tolerate treatment due to comorbidities and advanced age.

Consequently, elderly patients could receive treatments that were only tested in a younger population, with potential increased risks of treatment-related toxicity. Moreover, in the absence of clear literature data, the generalization of evidenced-based medical practice may be tenuous, making decisions more susceptible to physician biases and market-based influences^1–3.

Over the last years, we have witnessed a growing interest in the treatment of elderly cancer patients, and various studies have shown that they can well tolerate multimodality treatments, including high dose radiotherapy with curative intent^1–5. An increasing number of studies showed that also stereotactic body radiotherapy, i.e. a highly sophisticated and high precision treatment modality can be safely delivered in fit elderly patients with lung cancer⁶. A previous study from our group, analysing gynecological cancer patients with a median age of 67.4 years (range = 29–86 years)⁷, reported that quality-of-life (QoL) of long-term survivors after surgery and post-operative radiotherapy for endometrial and cervical cancer correlates with the response to treatment and shows a quite favorable profile without any age-related difference in older and younger patients. An emblematic and widely debated issue remains the indication to adjuvant treatment in elderly breast cancer patients after breast-conserving surgery. Two randomized controlled trials included elderly patients with early stage breast cancer to assess the benefit of adjuvant radiation therapy: the CALGB 9343 and the PRIME II^8,9. The CALGB 9343 study demonstrated that women aged >70 years with a tumor size ≤2 cm with positive estrogen receptor status and negative lymph nodes may not benefit from adjuvant radiation therapy plus hormone therapy, with no difference in overall survival and local relapse rates when compared to those who received hormone therapy alone. The PRIME II phase III international, randomized, and controlled trial examined the same question, obtaining similar results. These two non-inferiority trials clearly demonstrated no overall survival benefit from irradiation in the elderly patient population with low-risk breast cancer.

Quite interestingly, a direct consequence of these results was a commentary by Hughes and Schnaper¹⁰ in Lancet Oncology that concluded “… it is time to stop radiating these older women”. This assumption was mainly based on recurrence and survival data, but should be considered in the context of the studies that analyzed highly selected low-risk patients. Moreover, both trials only marginally analyzed the aspects related to QoL and economic parameters.

A recent meta-analysis confirmed that adjuvant radiotherapy in addition to hormone therapy in older patients with low risk breast cancer has no impact on overall survival, but can improve local control, with a relevant reduction of the hazard of local recurrence¹¹. The authors conclude that individual counseling should be recommended in this patients’ population and, taking into account that modern radiotherapy can minimize potential side-effects, adjuvant radiotherapy should be advised in patients with long-life expectancy.

Quality-of-life is a crucial point in elderly patients: in fact, whereas a goal of anti-tumor therapy is prolonged survival, many elderly patients are not willing to accept compromised QoL to achieve potentially longer survival. Moreover, a few studies indicate that QoL can influence patients’ outcome in terms of life expectancy, perception of recovery, and reduced hospitalization^12–14.

The CALGB 9343 trial analyzed QoL differences between the two groups of patients with and without adjuvant irradiation, and found only a worsening in shoulder pain and stiffness in the irradiation group, although non-significant in the physician evaluation.

Of note, only a few studies on elderly patients analyzed QoL in combination with health utility weights, such as life-years and quality-adjusted-life-years (QALYs) gained.

In this regard, it is interesting to underline how women older than 65 years were found to represent 58% of all deaths due to breast cancer, while they accounted only for 28% of treatment cost as reported by Boncz et al.¹⁵. This finding indicates a shift in the distribution of treatment cost and of deaths due to breast cancer in favor of younger patients, and reveals a new aspect of the problem connected with cost-effectiveness of cancer treatment, which is related with age and risk of recurrence^15,16.

A relevant aspect to be considered in older breast cancer patients is the finding of favorable or unfavorable clinical and pathological prognostic factors, such as receptors status, tumor diameter, and regional node involvement. In this regard, the NCCN guidelines, after the results of the CALGB 9343 and the PRIME II multicentric trials, allowed for the use of conservative surgery with adequate negative margins without breast irradiation only in women older than 70 years with positive estrogen receptor status, T1 stage, and negative sentinel node¹⁷.

To overcome this stringent selection criteria, a nomogram was developed to predict the 10-year cancer specific survival in patients >70 years old who do not meet the CALGB criteria¹⁸. Based on that, it emerges that radiotherapy should not provide any survival benefit in patients with stage I and negative estrogen receptors or stage II/III, regardless of estrogen receptors status, being the predicted 10-year cancer specific survival rate higher than 90% after conservative surgery alone. On the other hand, there is a potential benefit from adjuvant radiotherapy in patients with predicted 10-year cancer specific survival rates lower than 80%¹⁸.

The concept of health utility weight was recently introduced by Ali et al.¹, who estimated and compared the health utility of breast-conserving surgery followed by hormone therapy and associated or not with post-operative radiotherapy. The authors used an algorithm to determine the health utility weight by using health-related quality-of-life questionnaires. The analysis suggests that patients receiving radiotherapy have a higher utility weight compared with those who did not receive radiation. The authors underlined the need to also consider other factors such as comorbidities and life-expectancy in decision-making about adjuvant treatments, and concluded that the choice about adjuvant treatments in the elderly should consider both medical and economic factors to select patients upon a real cost-effectiveness analysis. This article is of relevant interest, despite potential weaknesses related to the retrospective study design and the use of the “Surveillance, Epidemiology and End Results (SEER)” database, that just collects data from clinical records, but without detailed information on patient characteristics and treatment modalities.

The cost-effectiveness of a treatment can be assessed in terms of economic aspects and quality-adjusted-life-years (QALYs) gained.

By critically analyzing the cost-effectiveness of radiotherapy in older women with favourable-risk breast cancer, Sen et al.¹⁹ designed an experimental model to simulate clinical outcome, to estimate QALYs gained, and to determine the incremental cost-effectiveness ratio of different radiation modalities such as three-dimensional (3D) external-beam radiation therapy (EBRT), intensity modulated radiotherapy (IMRT), and brachytherapy (BRT). According to this model, the total cost estimated for a 70-year old woman receiving EBRT with conformal 3D technique, during 10-years of follow-up, was ∼ $29,500, compared with $20,077 for no RT, resulting in an increment of ∼ $9,500, i.e. almost 50%. Interestingly, the cost-effectiveness for EBRT can vary by age and comorbidities: older women with more comorbidities or higher risk of local relapse have a decreased 10-year survival probability, which correspond to substantially less favorable cost-effectiveness for EBRT. This explains the increasing interest in identifying cancer characteristics and treatment factors that are predictive of recurrence. In fact, recurrent disease is associated with higher cost related to surgery, hospitalization, and general assistance. This model also allows for assessing cost-effectiveness of various radiation modalities such as IMRT and BRT in comparison with the conventional 3D-technique. These more sophisticated modalities should improve QALYs gained by at least 37% to be cost-effective, while there is no evidence that IMRT and BRT would be 37% more effective in reducing recurrence risk or improving survival or QoL^20,21.

The use of hypofractionated regimens may represent an advantage compared to conventional radiation treatment considering the favorable toxicity and QoL profile and the economic evaluations based on a shorter irradiation course and a smaller number of fractions^22–24. In this regard, Bekelman et al.²⁴ reported an increase of use of hypofractionation for breast cancer in the US from 10.6% in 2008 to 34.5% in 2014²⁴. The calculation of adjusted mean total healthcare expenditures in the first year after diagnosis was highly relevant, resulting as $28,747 for hypofractionation vs $31,641 for conventional breast irradiation (Δ$2,894; p < .001), representing a decrease of ∼10%, by reducing the number of fractions from 25–39 to 11–24.

In terms of irradiation modality, the multi-center international TARGIT-A trial²⁵ has recently shown that x-rays intra-operative radiotherapy (IORT) in single shot was less costly than EBRT and produced slightly more QALYs than conventional radiotherapy. The authors underline that “TARGIT had a positive incremental net monetary benefit that was borderline statistically” and “when TARGIT was used instead of conventional radiotherapy in suitable patients (age >45 years), it might potentially reduce costs to healthcare providers by £8–9.1 million each year”. Analog considerations could be made for intra-operative electron radiotherapy (IOERT) used in the ELIOT trial, as reported in an external cost-effectiveness analysis by Shah et al.²⁶.

From data nowadays available, we can deduce that irradiation after breast conservative surgery could be omitted only in an adequately selected group of low risk patients: early stage (I/II), estrogen receptor positive, no lymph vascular invasion, and lower proliferation index. In high risk patients, there is a higher risk of local relapse, and an increased potential risk in assistance costs.

Most importantly, we need an increasing representation of elderly patients in prospective clinical trials, with inclusion of geriatric assessment and multidisciplinary supportive care aiming at improving the outcome of these cancer patients. Patients’ preference is a relevant additional issue that should be carefully considered as well²⁷. Such studies should include not only local control and survival as end-points, but also cost-effectiveness and QoL assessment.

Marco Krengli, Carla Pisani Division of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy Department of Translational Medicine University of “Piemonte Orientale”, Novara, Italy [email protected]

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

The authors of this editorial have no financial/other relationships to disclose. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgement

The work of Carla Pisani was supported by “Fondazione Franca Capurro” (FFC 2015) and University Hospital “Maggiore della Caritá” of Novara (AOU 275 30-04-2015), Italy.