Highly Accelerated Dose-Integrated Radiotherapy in 5 Fractions in Breast Cancer (HAI-5)

Evaluation of Dose Integrated Accelerated Irradiation in Older Women (≥ 70 Year) With Early and Loco-regionally Advanced Stages of Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Radiotherapy
• Intervention / Treatment: Radiation: Dose-integrated accelerated EBRT in pN0 breast cancer; Radiation: Dose-integrated accelerated EBRT in pN+ breast cancer

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • University Hospital - Radiotherapy Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Accelerated dose-integrated radiotherapy - pN0; Lymph node negative breast cancer	Radiation: Dose-integrated accelerated EBRT in pN0 breast cancer; WBI: 5 x 5.7Gy Thoracic wall: 5 x 5.7Gy R0 boost: 5 x 6.5Gy R1 boost: 5 x 6.9Gy
Experimental: Accelerated dose-integrated radiotherapy - pN1; Lymph node positive breast cancer	Radiation: Dose-integrated accelerated EBRT in pN+ breast cancer; WBI: 5 x 5.7Gy Thoracic wall: 5 x 5.7Gy R0 boost: 5 x 6.5Gy R1 boost: 5 x 6.9Gy Lymph node region: 5 x 5.4Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast retraction (LENTSOMA)	Breast Cancer Conservative treatment.core (BCCT.core) objective measurement	6 weeks post-radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute toxicity: number of patients with clinical relevant dermatitis (CTCAE v. 4.0)	Assessment of grade of dermatitis	1-8 weeks
Acute toxicity: number of patients with pain (CTCAE v. 4.0)	Grade 1: mild; Grade 2: moderate, limiting activity of daily living (ADL); grade 3: severe, limiting ADL	1-8 weeks
Acute toxicity: number of patients with pruritus (CTCAE v. 4.0)	Grade 1: mild, localized topical intervention; Grade 2: intense, oral intervention, skin changes	1-8 weeks
Acute toxicity: number of patients with fatigue (MFI-20)	Questionnaire (20 questions)	1-8 weeks
Chronic toxicity: prevalence of fibrosis	LENT Soma: fibrosis (score 0-3)	2 and 5 years
Chronic toxicity: prevalence of pain	LENT Soma: score 0-4	2 and 5 years
Chronic toxicity: prevalence of telangiectasia	LENT Soma: Score 0-3	2 and 5 years
Chronic toxicity: prevalence of lymphedema	LENT Soma: score 0-4	2 and 5 years
Chronic toxicity: prevalence of fatigue (MFI-20)	Questionnaire (20 questions)	2 and 5 years
Chronic toxicity - prevalence of radiation induced brachial plexopathy (RIBP) (standardized screening questionnaire), confirmed by electromyogram (EMG)	If a screening reveals unilateral pain, loss of function or muscular atrophy in the ipsilateral arm, an EMG will be performed to confirm/exclude RIBP	2 and 5 years
Loco-regional tumor control	Ipsilateral or regional breast recurrence	2 and 5 years
Distant tumor control	Distant metastases free survival	2 and 5 years
Breast cancer specific survival	Number of patients alive and without breast cancer recurrence at 2 and 5 years after adjuvant radiotherapy	2 and 5 years
Overall survival	Number of patients alive, 2 and 5 years after adjuvant radiotherapy	2 and 5 years
Acute toxicity: number of patients with moist desquamation (CTCAE v. 4.0 (grade 3)		1-8 weeks
Chronic toxicity: measurement of patient satisfaction with breast esthetic outcome: BREAST-Q questionnaire	BREAST-Q questionnaire: Patient reported outcome, evaluating satisfaction with esthetic outcome.	Before radiotherapy and after 2 and 5 years

Collaborators and Investigators

• Sponsor: University Hospital, Ghent

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 13, 2018

Study Registration Dates

• First Submitted: June 2, 2015
• First Submitted That Met QC Criteria: September 20, 2019
• First Posted (Actual): September 23, 2019

Study Record Updates

• Last Update Posted (Actual): September 23, 2019
• Last Update Submitted That Met QC Criteria: September 20, 2019
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Accelerated radiotherapy; Older women; Dose-integrated radiotherapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: EC/2014/1167