SBRT in Early Breast Cancer in Elderly Women

Study Overview
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Brief Summary
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Surgical treatment represents the standard of local therapy in patients with early breast cancer, however in women over75, the comorbidities related to aging reduce the possibility of candidates for surgical treatment. In the United Kingdom it is estimated that over 40% of elderly women do not receive surgery for their breast cancer, and that their primary treatment is hormonal only, the so-called primary endocrinotherapy. In Italy the recent AIOM guidelines of 2019 exclude, in patients with hormone-sensitive disease and age older than 70, the omission of surgery in favor of hormone therapy alone, thus underlining the importance of a treatment local. However, there are currently no local treatments that could in any way effectively control the primary tumor. In recent years, SRT has widely found space as a therapeutic alternative in patients not fit for surgery. Stereotactic Radiotherapy is a non-invasive treatment with ablative intent obtained with highly focused high intensity fields for a few fractions (generally 1-5). It is the standard treatment for surgically inoperable lung cancers, and is also used in the treatment of liver metastases, intermediate-risk prostate cancer and locally advanced pancreatic cancers. The applications of stereotactic treatment in breast cancer are limited to the neoadjuvant and adjuvant setting. Against this backgroung, in elderly patients with localized breast cancer candidates for hormonal therapy and non-fit for surgery due to age or comorbidity, a SBRT could more effectively control local disease, not excluding local treatment rather than in itself it is considered very important.

Detailed Description
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Breast cancer is the most common cancer diagnosis in females; with population ageing, this diagnosis may increase in 75 years old or older patients. According to AIRTUM data, 22% of new cases of breast cancer and 14% of death by breast cancer are expected in women over 70 years old. Surgery is the gold standard of treatment for breast cancer, but advanced age and age-related comorbidity could reduce the ability of a surgical approach. In the United Kingdom, it is estimated that over 40% of older women will not receive surgical treatment for breast tumor, while endocrine therapy alone is frequently offered. This treatment is known as primary endocrine therapy. In our country, AIOM guidelines favor endocrine therapy alone in women over 70 with ER-positive tumors instead of surgical resection, even emphasizing the importance of local treatment. Among nonsurgical methods to treat breast cancer, radiofrequency ablation and focused ultrasound have been investigated, but they are not widely available at present time. Radiation therapy has been used to treat patients with inoperable breast cancer, but most of these treatments were palliative. There are limited clinical data supporting the use of definitive conventionally fractionated radiotherapy and more specifically stereotactic ablative body radiotherapy in breast cancer. A collaborative study between the Gustave-Roussy Institute and the Princess Margaret Hospital reviewed the use of radiotherapy alone as definitive breast cancer treatment. Patients who had inoperable disease or who were unable to undergo general anesthesia received definitive hypofractionated radiotherapy (40Gy in 16 fractions, 45Gy in 20 fractions, or 45Gy in 18 fractions). This retrospective study demonstrated tumor dose as being a highly significant factor for local control, with very low rates of disabling complications at 10 years. Van Limbergen et al. also performed a retrospective analysis of 221 patients withTis-T3N0-1 breast cancer treated with radiotherapy alone. The risk of local recurrence was significantly associated with tumor size, age, radiation dose, and length of radiation. They concluded that doses needed to provide local control similar to a combination of surgery and radiation are 10 Gy higher for T1 tumors and 35Gy higher for T2 tumors. Unfortunately, higher doses may result in worsened cosmetic outcomes. Van Limbergen et al reviewed 161 patients, and those that received dose higher than 75Gy recorded very poor cosmetic results in more than 30% of patients; if total dose was up to 80Gy only 15% of patients reported good cosmetic results. It is important to remember that these papers are more than 25 years old, using older radiotherapy techniques and larger treatment fields. With the development of modern radiation therapy techniques, and the adoption of Stereotactic Body RadioTherapy (SBRT) tumoricidal doses are delivered without severe complications. SBRT is a non-invasive cancer treatment with ablative intent delivered with highly focused and accurate radiation beams for few fraction (generally 3-5 fractions). Many trials established the safety and efficacy of SBRT in multiple organ sites including the lung, liver, spine, prostate and pancreas. SBRT is actually shared as standard treatment in inoperable lung tumors: Timmerman et al. published one of the earlier extracranial SBRT trials on its use in early stage lung cancer, demonstrating excellent local control rates and side effect outcomes. SBRT also offers a noninvasive alternative treatment for patients with liver metastases, who are not candidates for surgical resection. The Stanford group initially established the safety of single fraction SBRT in 6 patients with locally advanced pancreatic cancer, subsequently a multi-institutional phase II study, reported by Herman et al. demonstrated equivalent efficacy in 1-year local progression freedom with acceptable toxicity profile in 49 patients with LAPC treated with 5 fractions SBRT following gemcitabine. The scandinavian HYPO-RT-PC trial showed non-inferiority to conventionally fractionated radiotherapy for ultra-hypofractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival with similar late toxicity in both groups. To date, SABR to primary tumor in breast cancer treatment has been mainly investigated in neoadjuvant and adjuvant setting. Bondiau et al. conducted a Phase I study involving 25 patients to determine the maximum tolerable dose of SBRT concomitant with neoadjuvant chemotherapy before surgery. Thirty-six percent of patients had a pathological complete response, with the highest rate (67%) at dose level of 25.5 Gy in 3 consecutive fractions. However, the maximum tolerated dose was not reached (highest dose level 31.5 in 3 consecutive fractions) as the group found that early SABR related toxicities were rare. Also in other studies toxicity was limited. The first SBRT studies in the management of early stage breast cancer were post-operative studies. SBRT was used either as a boost, or for accelerated partial breast radiation therapy. Age was not an exclusion criterion, but mean ages were under 65 years. The proportion of patients aged >65 years were not given. SBRT has not yet been studied specifically in elderly patients who paradoxically most often have tumors with better histoprognostic factors than younger women. Instead, SBRT role as a definitive ablative therapy in breast cancer is less considered and there are no prospective studies. Therefore, in elderly patients (over 75y) eligible for hormone therapy only and unsuitable for surgery, SBRT could improve locoregional control by means of a short and highly effective treatment without any interruption of systemic treatment. The Aim of this trial is to evaluate dose limiting toxicity for SBRT in elderly patients elected to receive hormone therapy only for breast cancer.

Official Title
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Stereotactic Ablative Body Radiotherapy in Elderly Women With Early Breast Cancer Unsuitable for Surgery and Elected to Receive Primary Endocrine Therapy Alone

Conditions
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Breast Neoplasm Female

Intervention / Treatment
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* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 75 years Histologically confirmed diagnosis of local disease only (cT1-T2 N0 M0) Luminal like A or B (estrogen receptor positive and/or progesterone receptor positive and Her2 negative Tumors) SBRT within 2 months after hormonal therapy start Exclusion Criteria: Metastatic Disease Evidence of loco-regional nodal disease Multifocal or multicentric tumors Prior radiotherapy to the region of the study cancer that would result in overlap of therapy fields Concurrent systemic disorders that contraindicate radiotherapy

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Time to Event Key-Board, a dose escalation design study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 40Gy/5fx<br>The starting dose level will be 8Gy x 5 fractions, i.e., 40 Gy/5 nonconsecutive once-daily fractions. | Radiation: Stereotactic Body Radiation Therapy<br>* In every group, the dose is prescribed at the edge of the PTV. To be approved, 95% of the PTV will be conformally covered by the prescription isodose surface and 99% of PTV will receive a minimum of 90% of the prescription dose.<br>* Other names: Stereotactic Radiotherapy;|
| Experimental: 42.5Gy/5fx<br>The intermediate dose level will be 8.5Gy x 5 fractions, i.e. 42.5Gy/5 nonconsecutive once-daily fractions. | Radiation: Stereotactic Body Radiation Therapy<br>* In every group, the dose is prescribed at the edge of the PTV. To be approved, 95% of the PTV will be conformally covered by the prescription isodose surface and 99% of PTV will receive a minimum of 90% of the prescription dose.<br>* Other names: Stereotactic Radiotherapy;|
| Experimental: 45Gy/5fx<br>The higher dose level will be 9Gy x 5 fractions, i.e. 45Gy/5 nonconsecutive once-daily fractions | Radiation: Stereotactic Body Radiation Therapy<br>* In every group, the dose is prescribed at the edge of the PTV. To be approved, 95% of the PTV will be conformally covered by the prescription isodose surface and 99% of PTV will receive a minimum of 90% of the prescription dose.<br>* Other names: Stereotactic Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | DLT is determined as any grade 3 or worse toxicity (per CTCAE v5.0) that occurs within 6 months from the start of SBRT | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional disease control (LRC) | Absence of progressive tumor within the radiation field, it also requires evidence of an objective response (50% reduction in the product of two dimensions of the dominant tumor mass for measurable disease, as per RECIST criteria) | 5 years | 
| Clinical complete response (cCR) | Disappearance of the target lesion; ideally, this determination will be made based on clinical evaluation and US and Rx Images | 6 months | 
| Cosmesis assesed by Harvard scale | Cosmesis evaluation will be carried out before treatment, at last day of treatment and at every clinical examination with Harris scale scoring system. The Harvard scale proposed by Harris et al., which has been used to evaluate cosmetic outcome after BCT, is a 4-point scale that describes the global esthetic appearance of breasts as excellent, good, fair, or poor. | 5 years | 
| Cosmesis assesed by BREAST-Q v2.0 | Cosmesis evaluation will be carried out before treatment, at last day of treatment and at every clinical examination with Breast-Q v2.0 questionnaire. The BREAST-Q v2.0 is a rigorously developed patient-reported outcome (PRO) measure designed to evaluate outcomes among women undergoing different types of breast treatment. Among the 6 BREAST-Q modules we will use Physical well-being chest Module, Satisfaction with breast Module and Adverse Effects of Radiation Module. All scales are transformed into scores that range from 0-100, a higher score means greater satisfaction or better QOL | 5 years | 
| Progression-free survival (PFS) | The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. | 5 years | 
| Overall survival (OS) | The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. | 5 years | 
| patient reported global health status assesed by EORTC QLC-C30 | Patient reported quality of life will be evaluated using the EORTC QLC-C30 v3.0 at time zero, at the end of treatment, at 6 and 12 months, and then yarly. The EORTC quality of life questionnaire (QLQ) is composed of both multi-item scales and single-item measures, which include functional scales, symptom scales, a QoL scale, and specific single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | 5 years | 
| patient reported therapy side effects assesed by EORTC QLQ-BR23 | Patient reported breast specific satisfaction will be evaluated using the EORTC QLQ-BR23 v3.0 at time zero, at the end of treatment, at 6 and 12 months, and then yarly. QLQ-BR23 is a supplementary questionnaire module for specific breast cancer populations; it incorporates 5 multi-item scales to assess systemic therapy side effects, arm and breast symptoms, body image and sexual functioning. In addition, single items assess sexual enjoyment, hair loss and future perspective. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy