Omitting radiotherapy in elderly breast cancer patients: Valid strategy or illusory hope?

Abstract

Breast cancer treatment strategies have evolved significantly over the years, and decisions regarding the use of radiotherapy have become increasingly complex. This paper explores the considerations and limitations associated with omitting radiotherapy as part of breast cancer treatment. While omitting radiotherapy may be a viable option for select patient groups, it is not without its challenges. The decision to omit radiotherapy in breast cancer treatment should be highly individualized and made after a comprehensive evaluation of the patient's specific circumstances.

Breast cancer ranks as the most prevalent cancer among women in Morocco, with an estimated 12,000 new cases diagnosed annually [1].

Adjuvant radiotherapy is a crucial component of breast cancer treatment. Several studies have consistently demonstrated that postoperative radiotherapy offers a significant reduction in the risk of local recurrence when compared to breast-conserving surgery (BCS) alone [2].

For older women diagnosed with early-stage breast cancer, the current standard treatment following breast-conserving surgery includes adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. However, there is an ongoing debate about whether it is safe to omit radiotherapy in women with low-risk breast cancer.

The PRIME II study is a phase III randomized clinical trial designed to address this question. It specifically investigates the potential omission of radiotherapy as a treatment approach for breast cancer in older patients. The study aims to provide valuable insights into the safety and effectiveness of omitting radiotherapy in this particular patient population, which could influence future treatment guidelines and decision-making for older women with low-risk breast cancer [3].

The trial enrolled a total of 1326 women who were aged 65 years or older and had hormone receptor-positive, node-negative T1 or T2 tumors (with a size of 3 cm or smaller in the largest dimension). These patients had previously undergone breast-conserving surgery with clear excision margins and were concurrently receiving adjuvant endocrine therapy as part of their treatment plan. Subsequently, they were randomly assigned to two distinct groups: one group received whole-breast radiotherapy typically administered at a radiation dose within the range of 40–50 Gy, while the other group did not receive radiotherapy as part of their treatment.

The primary goal of the study was to evaluate the rate of local breast cancer recurrence. Additionally, the study assessed several secondary endpoints, including regional recurrence, breast cancer-specific survival, distant recurrence, and overall survival (OS).

The 10-year follow-up data of the PRIME II study, one of the first long-term clinical trials in older breast cancer patients, suggests that for patients aged 65 years or older with low-risk, hormone receptor-positive early breast cancer, omitting radiotherapy resulted in a higher occurrence of local recurrence. However, this omission did not have a negative impact on distant recurrence or overall survival. This result aligns with the findings of the earlier CALGB 9343 study, which included patients aged 70 years or older with T1, node-negative, hormone receptor-positive tumors [4].

Neverthless, the study results should not diminish the recognized benefits of radiotherapy in improving local control of breast cancer, which remains an important outcome. It's worth noting that in this study, the recommended irradiation dose ranged from 40 to 50 Gy (Gy),delivered in fractions of 2-2,66 Gy each. This fractionated approach involved 20 to 25 treatment sessions over a period of 3–5 weeks with an additional dose of 10–15 Gy to the tumor bed. However, in light of the excellent results of FAST and FAST-Forward, two large randomized controlled trials testing ultra-hypofractionated whole-breast radiotherapy in 5 fractions offering a more convenient option for patients without compromising treatment effectiveness [5], [6]. Morever, advances in radiotherapy technology, including Simultaneous Integrated Boost (SIB), Intensity-Modulated Radiation Therapy (IMRT), and Deep Inspiration Breath-Hold (DIBH) radiotherapy, have transformed the landscape of breast cancer treatment over the past few decades [7].These innovations have significantly improved patient outcomes by allowing for precise targeting of tumors while sparing healthy tissues, ultimately resulting in higher rates of tumor control and reduced side effects.

It's worth highlighting that radiation therapy is primarily a local cancer treatment and the primary aim of adding adjuvant radiotherapy in the treatment of breast cancer is typically to reduce the risk of local recurrence, rather than improving metastasis-free survival, which is usually falls within the realm of systemic treatments such as chemotherapy or endocrine therapy. The trial demonstrates that even in older patients with tumors of favorable prognosis, radiotherapy ensure better local disease control. Specifically, within a 10-year period, the cumulative incidence of local breast cancer recurrence was 9.5 % (with a 95 % confidence interval of 6.8–12.3) in the group that did not receive radiotherapy, while it was significantly lower at 0.9 % (with a 95 % confidence interval of 0.1–1.7) in the group that received radiotherapy.

Furthermore,The five-year outcomes of the SOUND trial [8], a prospective non-inferiority phase 3 randomized clinical trial, offer compelling evidence supporting the safety and effectiveness of omitting Sentinel Lymph Node Dissection (SLND) in patients of any age with breast cancer (BC) tumors up to 2 cm in size and a negative preoperative axillary ultrasonography result. One of the key takeaway from this study is that the omission of Sentinel Lymph Node Dissection (SLND) should be mandatory accompanied by the administration of adjuvant radiotherapy. This approach ensures that adjuvant radiotherapy maintains its effectiveness while minimizing the invasiveness and potential complications associated with surgical staging procedures.

Additionally, the criteria for determining which patients can safely omit radiotherapy are currently unclear. Advances in biological and genetic profiling of tumors may provide more precise ways to identify patients with low-risk breast cancer who can avoid radiotherapy. Moving beyond traditional histopathological features to consider tumor biology, genetic information, and molecular characteristics can lead to more tailored treatment decisions [9].

The data shows that without radiotherapy, there is a higher risk of local breast cancer recurrence over the long term even if it may not necessarily impact patient's overall survival or metastasis free survival. However, living with the concern of cancer relapse can be emotionally challenging. Ultimately, the decision regarding radiotherapy should be made jointly, taking into account patient's preferences, values, and individual circumstances.

Another recent prospective study, The LUMINA Study, which was published in the New England Journal of Medicine in August 2023 [10], has concluded that it is safe to omit radiotherapy following breast-conserving surgery for women who are at least 55 years old and have T1N0 luminal A breast cancer. Nevertheless, the relatively short follow-up duration is notably insufficient for assessing the long-term outcomes in breast cancer, especially when studies supporting radiotherapy in conjunction with breast-conserving surgery demonstrate survival benefits up to 15 years post-treatment [2]. Furthermore, the authors used a Ki67 cutoff of 13.25 % to define Luminal A breast cancer what's it is lower than what is recommended in current guidelines.

While the study suggests that radiotherapy is inconvenient, costly, and associated with side effects, it lacks an assessment of the side effects and cost of endocrine therapy and its impact on the quality of life of the patients.

In addition, the Lumina trial reported an adherence rate of over 82.7 % to endocrine therapy. This high adherence rate could be attributed to the controlled and supportive environment of a clinical trial, where participants may receive more frequent monitoring and support, potentially leading to better compliance with treatment regimens. In contrast, the results of a recent systematic review showed a mean adherence rate of 66.2 % at five years with a decrease in adherence from the first to the fifth year by 25 %, reflect the complexities and real-life challenges faced by breast cancer patients [11]. These challenges stem from various factors, including the long duration of treatment, side effects, and patient-related issues. Moreover, the financial aspect of endocrine therapy should not be underestimated. The costs associated with these medications can be substantial, particularly in the context of prolonged treatment.

In this context, the omission of endocrine therapy in women receiving adjuvant radiation therapy for breast cancer is an area that merits more attention in clinical research. It's crucial to strike a balance between the potential benefits of endocrine therapy and the individual circumstances of the patient, taking into consideration factors such as age, comorbidities, and the patient's ability to tolerate treatment.

One relevant study, the NSABP B21 trial, enrolled 1009 women with node-negative tumors up to 1 cm following breast-conserving surgery to explore various treatment approaches, including radiotherapy (RT) plus tamoxifen, tamoxifen monotherapy, or RT monotherapy after breast-conserving surgery [12]. The results showed that at 8 years, breast tumor recurrence was highest among women who received tamoxifen alone (16.5 %), compared to patients treated with RT alone (9.3 %) or combination therapy (2.8 %). However, there was no significant difference in overall survival or distant failures.

These findings suggest that there may be a subset of women who can safely be treated with adjuvant RT monotherapy without compromising distant recurrence and survival. Building on this evidence, the ongoing EUROPA trial (Exclusive Endocrine Therapy or Partial Breast Irradiation for Women 70 and Older with Luminal A-like Early-Stage Breast Cancer) is designed to compare treatment with endocrine therapy (ET) or radiation therapy (RT) monotherapy in older women with early-stage, favorable breast cancers [13]. This trial aims to provide valuable insights into the optimal treatment approach for this specific patient population, further emphasizing the importance of tailoring breast cancer treatment to individual patient characteristics and needs.

In light of these limitations, it's essential to recognize that the decision to omit radiotherapy in breast cancer treatment is highly individualized and should be made after a thorough evaluation of the patient's specific circumstances. This decision should be based on the best available evidence and guidelines and take into account the patient's preferences and values. In older patients, a comprehensive geriatric assessment can help healthcare providers assess overall health, functional status, and potential vulnerabilities. This assessment can guide treatment decisions and supportive care measures.

Funding source

This research received no external funding.

Ethical approval

Ethical approval was not required.

Declaration of competing interest

The authors declare no conflict of interest.