Clinical trial NCT04098926: Highly Accelerated Dose-Integrated Radiotherapy in 5 Fractions in Breast Cancer
Official title: Evaluation of Dose Integrated Accelerated Irradiation in Older Women (≥ 70 Year) With Early and Loco-regionally Advanced Stages of Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Breast Cancer
Radiotherapy
Keywords: Older women
Accelerated radiotherapy
Dose-integrated radiotherapy
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
First posted: 2019-09-23
Enrollment: 70
Sex: FEMALE
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Adjuvant radiotherapy in breast cancer improves local control, also in the elderly. Hormonal therapy in hormone sensitive tumors improves results but can not substitute radiotherapy. Improved local control leads to less breast cancer related morbidity and mortality, also in an older population (Schonberg, JCO, 2011).

Unfortunately, in older patients with lower life expectancy, adjuvant radiotherapy is often omitted. Following reasons are invoked:

* frailty of the patient
* fear for toxicity
* impaired mobility, rendering transportation and positioning more difficult
* dependency for transportation to and from the radiotherapy departement
* negative cost effectiveness ratio, due to high cost (especially for complex techniques and long schedules) and lower benefit (lower life expectancy)

Hypofractionation is feasible without increased toxicity, and combines better local control with patient comfort and lower costs. Further lowering the number of fractions (from 15-21 to 5) will further improve patient comfort, but is challenging when different doses are needed in the same target volume. This problem is addressed using advanced techniques permitting dose-integration.

In the elder with cancer, several unrecognized geriatric problems, including depression and cognitive impairment, can be detected by CGA . Some problems do interact with cancer treatment. In this study screening and assessment is provided to support patients and to develop an inventory of radiotherapy obstacles.

Our study includes breast cancer patients, ≥70 years old, referred for adjuvant radiotherapy after surgical treatment. A schedule of 5 fractions is offered, encompassing different targets of treatment.

Detailed description: Adjuvant radiotherapy in breast cancer improves local control and overall survival, also in the elderly. Hormonal therapy in hormone sensitive tumors improves results but can not substitute radiotherapy (EBCTCG, Lancet, 2011). Improved local control, leads to less breast cancer related morbidity and mortality, also in an older population (Schonberg, JCO, 2011).

Unfortunately, in older patients with lower life expectancy, adjuvant radiotherapy is often perceived as too cumbersome. As a consequence, patients who could have benefit from breast conserving therapy are referred for mastectomy. Even when breast-conserving surgery is chosen, adjuvant radiotherapy is sometimes omitted in frail patients over 70 years fearing the burden of daily transportation to the radiation department. However, omitting radiotherapy results in a higher risk of loco-regional recurrence. It has been shown that older patients have a worse prognosis due to suboptimal treatment, especially in locally advanced breast cancer (Schonberg, JCO, 2011).

Following reasons are invoked by the patients or the care-givers:

* frailty of the patient
* fear for (mostly acute) toxicity
* impaired mobility, rendering transportation and positioning more difficult
* dependency on third parties (family, services) for transportation to and from the radiotherapy departement
* negative cost effectiveness ratio, due to high cost (especially for complex techniques and long schedules) and lower benefit (lower life expectancy)

Hypofractionation and acceleration are proven to be feasible in recent trials (cf. Start Trial, Fast Trial).

Based on these data and in order to overcome above mentioned obstacles for radiotherapy in breast cancer, we start a study with accelerated radiotherapy in women above 70 years old.

As we are experienced in advanced techniques as IMRT, VMAT, simultaneous dose-integration and IGRT, we will use simultaneous dose integrated protocols to permit inclusion of early as well as locally advanced breast cancer.

Integration of doses within one global volume encompasses several advantages:

* number of fractions can be maintained, regardless of the indication
* imprevisible high doses due to overlap of adjacent fields in tangential techniques is avoided
* high dose volume is more adequately limited to the actual region of high risk, as dose difference is smaller.

In order to evaluate the impact of accelerated radiotherapy on the well being of the patient and on the treatment cost, quality of life (QoL) will be measured and a cost-analysis will be performed.

Methodology of research At the radiotherapy intake consultation, patients with age ≥70 years are extensively informed on the advantages and the possible risks of accelerated irradiation. A written documentation of the study is provided to permit consultation of family and general practitioner before consent for participation. Until 1 week before the start of radiotherapy, patients can decide wether or not to participate in this study without impact on the starting day. Inclusion is performed after signing the informed consent.

The aim is to include 70 patients aged ≥ 70 years, who, after signing the informed consent, will be treated with the accelerated schemes over 10 days (5 sessions, every other day). Following doses are prescribed

* Breast: 5x5,7Gy
* R0 boost: 5x6.5Gy
* R1 boost: 5x6.9Gy
* Thoracic wall: 5x5.7Gy
* Lymph nodes: 5x5.4Gy --\> these doses are simultaneously integrated, and regions are prescribed according to our standard protocol .

Positioning of the patient depends on technical possibilities and patient rigidity:

* for breast irradiation without lymph nodes, prone positioning is preferred if feasible, if not the patient is positioned in supine
* for thoracic irradiation with or without lymph node irradiation, patient is always installed in supine position
* for breast + lymph node irradiation, patients are installed in supine position.

End points of our study are acute and chronic toxicity, loco-regional control and QoL.

The study is divided in two different strata (first group without lymph node irradiation, second group with lymph node irradiation) for following reasons:

1. these groups represent different outcomes with lymph node invasion having a negative impact on morbidity, loco-regional control and overall survival
2. a higher frequency of acute moist desquamation might occur in the second group (lymph nodes included) as compared to the first group, due to a larger target volume.
3. the brachial plexus is a special concern, as it lies close or even within the target volume. Therefore we will monitor closely the effects on the brachial plexus for the second group. Nevertheless, as the total dose is lower than with normo-fractionation, the risk for brachial neuropathy is maximally reduced.

Groups

* 40 patients in group 1: irradiation of breast/thoracic wall with or without integrated boost without lymph node irradiation
* 30 patients in group 2: irradiation of breast/thoracic wall with or without integrated boost and with lymph node region irradiation

An application for funding to perform geriatric assessment is introduced. In the elder with cancer, several unrecognized geriatric problems, including depression and cognitive impairment, can be detected bij CGA . Some of these problems even interact with cancer treatment. In this study screening and assessment is provided to develop an inventory of obstacles for undergoing radiotherapy.

When screening scores positive (G8 score ≤ 14/17) geriatric assessment will be performed to evaluate the problems and needs of the patient. Patients will be referred for appropriate treatment and support. As described by Schönberg, treatment in early stage breast cancer might even lead to improved morbidity and mortality when compared to a non-cancer population, due to the 'healthy user' effect, detecting otherwise unrevealed problems. In the scope of this study, this effect can not be evaluated.

Power analysis To estimate the number of patients needed, we applied the Wilson score confidence interval test for binomial proportion, which is a 2-sided exact method for power analysis, using "SAS Power and Sample Size".

Group 1:

To achieve a conditional probability of 87% with an alpha-error of 0,1, a number of 35 patients would be needed. To compensate for drop-outs, we include 40 patients in this study-arm.

Group 2 To achieve a conditional probability of \>95% with an alpha-error of 0,1, a number of 25 patients would be needed. To compensate for drop-outs, we include 30 patients in this study-arm.

Eligibility criteria: Inclusion Criteria:

* ≥ 70 years old
* AND breast conserving surgery or mastectomy for breast carcinoma
* AND multidisciplinary decision of adjuvant irradiation
* AND absence of distant metastases
* AND informed consent obtained, signed and dated before specific protocol procedures

Exclusion Criteria:

* Bilateral breast irradiation
* In case of mastectomy: positive resection margin, needing boost
* Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study
* Patient unlikely to comply with the protocol; i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study
* History of previous radiation treatment to the same region

Primary outcomes:
measure: Breast retraction (LENTSOMA)
timeFrame: 6 weeks post-radiotherapy
Secondary outcomes:
measure: Acute toxicity: number of patients with clinical relevant dermatitis (CTCAE v. 4.0)
timeFrame: 1-8 weeks
measure: Acute toxicity: number of patients with moist desquamation (CTCAE v. 4.0 (grade 3)
timeFrame: 1-8 weeks
measure: Acute toxicity: number of patients with pain (CTCAE v. 4.0)
timeFrame: 1-8 weeks
measure: Acute toxicity: number of patients with pruritus (CTCAE v. 4.0)
timeFrame: 1-8 weeks
measure: Acute toxicity: number of patients with fatigue (MFI-20)
timeFrame: 1-8 weeks
measure: Chronic toxicity: measurement of patient satisfaction with breast esthetic outcome: BREAST-Q questionnaire
timeFrame: Before radiotherapy and after 2 and 5 years
measure: Chronic toxicity: prevalence of fibrosis
timeFrame: 2 and 5 years
measure: Chronic toxicity: prevalence of pain
timeFrame: 2 and 5 years
measure: Chronic toxicity: prevalence of telangiectasia
timeFrame: 2 and 5 years
measure: Chronic toxicity: prevalence of lymphedema
timeFrame: 2 and 5 years
measure: Chronic toxicity: prevalence of fatigue (MFI-20)
timeFrame: 2 and 5 years
measure: Chronic toxicity - prevalence of radiation induced brachial plexopathy (RIBP) (standardized screening questionnaire), confirmed by electromyogram (EMG)
timeFrame: 2 and 5 years
measure: Loco-regional tumor control
timeFrame: 2 and 5 years
measure: Distant tumor control
timeFrame: 2 and 5 years
measure: Breast cancer specific survival
timeFrame: 2 and 5 years
measure: Overall survival
timeFrame: 2 and 5 years
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: University Hospital - Radiotherapy Department
Study officials:
References: