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Breast Diseases

Skin Diseases

Adjuvant Radiotherapy delivered over 3 weeks

Adjuvant Radiotherapy delivered over 1 week

40 Gy in 15 fractions over 3 weeks to the whole breast or chest wall. Patients undergoing breast conservation therapy will receive additional boost radiotherapy to the tumor bed. The supraclavicular fossa will be treated in patient with node positive disease or those receiving neoadjuvant chemotherapy. IMC and Axillary radiotherapy will be given as per the institutional policy. Boost Dose schedule for BCS patients will be 8 Gy delivered in 15 fractions simultaneously with tangential EBRT. In institutions planning for sequential boost, a dose of 12 Gy in 4 fractions will be delivered after whole breast EBRT.

3 week RT

26 Gy in 5 fractions over 1 week to the whole breast or chest wall. Treatment volumes will be same as the control arm. Additional boost will be delivered to patients who have undergone breast conservation. Boost Dose schedule for BCS patients will be 6 Gy delivered in 5 fractions simultaneously with tangential EBRT. In institutions planning for sequential boost, a dose of 12 Gy in 4 fractions will be delivered after whole breast EBRT.

1 week RT

Sanjoy Chatterjee, FRCR

Rosina Ahmed, FRCS

Santam Chakraborty, MD

Sandip Ganguly, MD

Debdeep Dey, FRCPath

Anurupa Mahata, MSC Physics

Abha Kumari, DNB

Selvamani Bakianathan, MD

Patricia Solomon, MD

Rajesh Balakrishnan, MD

Punita Lal, MD

Shagun Misra, MD

KJ Maria Das, Phd

Background:Moderate three week hypofractionated adjuvant radiotherapy schedule is a standard care in breast cancers. A five day schedule has been demonstrated to be iso-toxic as a standard three week schedule. Recently studies have also demonstrated the safety and feasibility of simultaneous integrated boost in this setting. This randomized trial will investigate if a one-week course of hypofractionated breast radiotherapy is non-inferior to a three week course.

Aim: To determine if one-week schedule of adjuvant radiotherapy in breast cancer is non-inferior to a three week schedule.

Primary Objective: Locoregional Recurrence Rate (LRR) (Cumulative proportion of patients with locoregional recurrence) at 5 years

Secondary Objective:

1. Overall survival (OS) (Time from randomization to death)
2. Invasive Disease-free survival (iDFS) (Time from randomization to any invasive disease recurrence, death due to any cause or second invasive malignancy)
3. Late adverse events (AE)
4. Quality of Life (QoL)

Hypothesis:

1. 1 week schedule will be non-inferior to a three week schedule for Locoregional Recurrence Rate
2. 1 week schedule will be non-inferior to a three week schedule for OS
3. 1 week schedule will be not result in worse late adverse events as compared to 3 week schedule
4. Proportion of patients decrease in quality of life will not differ between the two arms at 12 months

Design: Open-label, parallel group, two arm, randomised, phase III, non-inferiority trial.

Population: Patients with breast cancer who need adjuvant radiotherapy after breast conservation or mastectomy.

Intervention: Patients will be randomized to 15 days or 5 days of radiotherapy to the whole breast or chest wall or reconstructed breast. Nodal radiation will be delivered as indicated. A simultaneous integrated boost (SIB) will be delivered to patients who need a tumor bed boost after breast cancer. The following dose schedules will be tested:

Control Group: 40 Gy in 15 fractions over 3 weeks (with SIB of 8 Gy)\*

Test Group: 26 Gy in 5 fractions over 1 week (with SIB of 6 Gy).\*

\* Use of Sequential Boost is allowed in both arms if prespecified by the institution. If used dose is 12 Gy in 4 fractions in 1 week in both arms.

Outcomes and measures:

1. LRR : Cumulative proportion of patients with ipsilateral Locoregional Recurrence after treatment at 5 years .
2. OS: Time from randomization to the time of death due to any cause. Cumulative proportion reported at 5 years.
3. iDFS: Time from randomization to any disease recurrence, death due to any cause or second primary invasive cancer.Cumulative proportion reported at 5 years.
4. AE: Proportion of patients with late Grade 2 or more AE as defined by the CTCAE 5 criteria
5. QoL: Proportion of patients with a worse summary score in the EORTC QLQ C30 at 12 months post-treatment as compared to the baseline score.

Randomised, controlled, open-label, two arm, multicenter, randomized controlled trial with two parallel groups

One Week Versus Three Week in Adjuvant Radiotherapy in Breast Cancer

HYPOfractionated Radiation Therapy Comparing a Standard Radiotherapy Schedule (Over Three Weeks) With a Novel One Week Schedule in Adjuvant Breast Cancer: An Open Label Randomised Controlled Study (HYPORT- Adjuvant)

Cumulative proportion of patients with locoregional recurrence

Time from randomization to the time of death due to any cause. Cumulative proportion reported at 5 years

Time from randomization to any disease recurrence, death due to any cause or second primary invasive cancer. Cumulative proportion reported at 5 years.

Proportion of patients with late Grade 2 or more AE as defined by the CTCAE 5 criteria

Proportion of patients with a worse summary score in the health related quality of life as measured using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ C30) at 12 months post-treatment as compared to the baseline score. The total summary score may range between 0 - 100 with higher scores indicating better health related quality of life. This score is the mean of the 13 of the 15 items of the EORTC QLQ C30 questionnaire which include the scores related to all the domains excepting the Global quality of life scale and Financial impact scale.

Christian Medical College, Vellore, India

Sanjay Gandhi Postgraduate Institute of Medical Sciences

Tata Medical Center

Radiotherapy dose to chest wall, axilla level III and supraclavicular fossa will be of 26Gy in 5 fractions over 1 week in the study arm. BCS patients will receive a sequential boost of 8Gy/2#/2days or simultaneous integrated boost(SIB) to a total dose of 34Gy.Supraclavicular fossa(SCF) and axilla level III will be treated in patients with T3-4 disease with lymphovascular invasion, grade 3 or N2 disease and T3-4 disease treated with neoadjuvant chemotherapy after adequate axillary dissection. Level I and II axilla will only be irradiated in patients with inadequate axillary dissection(\<10 lymph nodes). Internal mammary node (IMNs) radiation will be done in T3-4 central and inner quadrant lesions and patients with N2 disease. IMNs will be irradiated with a separate single field. The first five intercostal spaces will be included in the IMN target volume.

Radiotherapy dose to chest wall, axilla level III and supraclavicular fossa will be 34Gy in 10 fractions over 2 weeks in the control arm. BCS patients will receive a sequential boost of 8Gy/2#/2days or simultaneous integrated boost(SIB) to a total dose of 42 Gy.

2 week RT

BUDHI S YADAV, MD

BUDHI S YADAV

BUDHI SINGH YADAV

We at PGIMER have been practicing hypofractionated radiotherapy in breast cancer patients for the last 4 decades. Our standard doses have been 35Gy/15#/3wks to the chest wall after mastectomy and 40Gy/16#/3wks after breast conserving surgery (BCS).It is also a routine practice in the UK and in a few centers in Canada. Hypofractionation reduces treatment time to half while maintaining cosmesis and gives control rates equal to conventional fractionation. As breast cancer is a leading cancer in females and radiation therapy is an important part of its local management, hypofractionation helps radiation centers worldwide to meet the growing need for radiation treatment in breast cancer, particularly in developing countries where resources are limited. It also reduces the financial burden on the patient and family. In this study we want to evaluate the impact of reducing the treatment duration from 3 weeks to 1 week. Eligible patients with breast cancer after mastectomy or BCS will be treated with a radiotherapy dose of 26Gy in 5 fractions over 1 week in the study arm and 40Gy in 15 fractions over 2 weeks in the control arm. The primary endpoint of this noninferiority study will be locoregional tumour control. Secondary endpoints will be early and late radiation toxicities, quality of life, contralateral primary tumours, regional and distant metastases, survival and second cancers. A total of 1018 patients will be randomised (1:1) to receive 1 week or 2 weeks of radiotherapy. An event-driven analysis will be performed after at least 94 patients have documented locoregional recurrences.

Aim: To test a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for loco-regional control, acute and late toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer.

Review of literature Four randomised trials involving a total of \>8000 women have compared a lower total dose in fewer larger fractions against 50Gy in 25 fractions, and all have reported favourable results in terms of local tumour control and late adverse effects.1-4 Appropriate adjustments to total dose allow 15- or 16-fraction schedules to be delivered over 3 weeks that are at least as safe and effective as standard 5-week regimens.

A 2008 Cochrane review of altered radiotherapy fractionation in early breast cancer1 including The Royal Marsden Hospital/Gloucestershire Oncology Centre and Ontario trials totalling 2644 women with mainly axillary node negative tumours \<5cm diameter concluded that radiotherapy fractions larger than 2Gy were at least as effective as 2Gy fractionation for a) local-recurrence free survival (absolute difference 0.4%, 95% CI 1.5% to 2.4%), b) breast appearance (risk ratio (RR)1.01, 95% CI 0.88 to 1.17; p=0.86), c) survival at five years (RR 0.97, 95% CI 0.78 to 1.19; p=0.75), d) late skin toxicity at five years (RR 0.99, 95% CI 0.44 to 2.22; p=0.98, or e) late radiation toxicity in subcutaneous tissue (RR1.0, 95% CI 0.78 to 1.28; p=0.99).1 The UK START A trial(N=2236) showed that the estimated absolute differences in 5-year local-regional relapse rates compared with the control schedule of 50Gy in 2Gy fractions were 0.2% (95% CI 1.3% to 2.6%) after41.6Gy and 0.9% (95% CI 0.8% to 3.7%) after 39Gy. In STARTA, photographic and patient self- assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with a hazard ratio(HR) for late change in photographic breast appearance of 0.69(95% CI 0.52 to 0.91,p=0.01).3 In the UK START B trial(N=2215) the estimated absolute difference in 5-year local-regional relapse rates for 40.05 Gy compared with 50Gy was -0.7% (95% CI 1.7% to 0.9%),and the HR for late change in photographic breast appearance was 0.83 (95% CI 0.66 to1.04). These START trials reported similar local tumour control with some evidence of lower rates of late adverse effects after schedules with fraction sizes larger than 2 Gy compared with the international standard 25-fraction regimen.4 The international standard regimen for whole breast radiotherapy prior to publication of these studies was a total dose of 50Gy in 25 fractions (daily doses) over 5weeks following surgical resection of the primary tumour in women with early breast cancer. With the establishment of safety and efficacy of moderate hypofractionation another 'new standard of care' using 40-41Gy in 15 to 16 fractions over 3 weeks has been established, as evidenced by recommendations by the National Institute for Health and Clinical Excellence(NICE). 5 Although interesting and practically helpful, such moderate hypofractionation is unlikely to represent the useful limits of hypofractionation for whole breast or even regional nodal radiotherapy.

Further hypofractionated radiotherapy has been tested using once weekly schedule to the whole breast in the UK FAST study.5 Assuming an α/β value between 3 and 4 two different schedules were hypothesised to be equally effective (28.5 Gy and 30Gy in 5 fractions over 5 weeks) to the 50Gy in 25 fraction over 5 weeks schedule. Initial analysis has shown a higher rate of moist desquamation using the 50Gy regimen; however photographic assessment after a median follow-up of 28.4 months has shown more mild or marked change in the photographic appearance with the hypofractionated schedule.4 Clinical assessments of breast appearance changes were similar to the 50Gy group when using the 28.5Gy schedule but worse with the 30Gy schedule. Final results from the study are awaited. The UK FAST Forward study randomly allocated 4096 patients to 40Gy/15#/3 weeks, 27Gy/5#/1 week, or 26Gy/5#/1 week to the whole breast or chest wall.6 They concluded that 26Gy/5#/1 week was non-inferior to the standard of 40Gy/15#/3 weeks for local tumour control, and was as safe in terms of normal tissue effects up to 5 years in patients with early-stage breast cancer.

Hypofractionated radiotherapy has been used at PGIMER and comparable clinical outcomes have been published with moderate hypofractionation.7-9 Although Indian breast cancer patients present at a younger age, with more advanced stage, and a higher percentage of grade 3 and triple negative tumours compared to the western population. These adverse factors may not be important when comparing hypofractionated radiotherapy with standard fractionation.9 Reservations exist for extreme hypofractionation to the regional nodes citing increasing risk of brachial plexopathy when hypofractionating to the supraclavicular fossa although moderate hypofractionation has been used at our institute for the last 5 decades without reports of any brachial plexopathy.10,11 Similarly, moderately hypofractionated 2-week regimes have been used in clinical trials and have been found to be safe.10 Given the above evidence, 40Gy in 15 fractions has been recommended as the standard of care in the UK even for cases that will include irradiation of the supraclavicular fossa.

Recently, Wang et al. published results from a randomised study in high-risk breast cancer patients after mastectomy.11 They reported similar 5-year clinical outcomes and late toxicities with conventional and hypofractionation. This study also established the safety of 3 weeks regional nodal irradiation(RNI) in patients with breast cancer. They reported a lymphedema rate of 19% at 5-years. We published our results of RNI with 40 Gy/15 fractions/3 weeks hypofractionation with 2D technique, at 15 years RNI was safe and comparable to historical data of conventional fractionation (ClinicalTrial.gov Registration No. NCT04175821).12

Against this background, a phase III randomised, non-inferiority study testing 1 week against 2 weeks of radiotherapy to the breast and chest wall with or without supraclavicular fossa adjuvant radiotherapy will include 1018 patients. The primary end point will be locoregional control and secondary end points will be acute and late radiation toxicity, QoL, survival and second cancers.

5. Preliminary work done: i) The consent form prepared. ii) CRF, PIS, evaluation sheet prepared Detailed Research Methodology This study will be a randomised, non-inferiority, open-label, phase 3 trial, with patients to be recruited from a single institute. Other institutes will be invited if they are willing to participate. Patients to be included in this study will be pre-operatively staged according to American Joint Committee on Cancer (AJCC) 8th edition, International Union against cancer (which uses TNM staging) as stage III breast carcinoma. For patients who receive adjuvant chemotherapy, pathological stage will be reflected and those with neoadjuvant chemotherapy the stage which is higher (clinical/pathological) will be reflected. A total of 1018 patients with histologically proven post lumpectomy/mastectomy cases of carcinoma breast suitable for radiotherapy will be enrolled in this study. Patients will be evaluated at the Department of Radiation Oncology Post Graduate Institute of Medical Education \&Research, Chandigarh, India. A thorough clinical examination followed by routine investigations which will include hemogram, liver function tests, kidney function tests, mammography, chest X-ray, ultrasound of abdomen/CECT chest, abdomen and pelvis and whole body bone scan. Written informed consent will be taken from all the patients.

Randomisation and masking Eligible patients will be randomly assigned (1:1) to receive either 1 week or 2 weeks of radiotherapy without stratification by simple randomisation according to a prescribed computer-generated central randomisation schedule. Radiation oncologists in the study team will enroll participants, and research staff members who will be involved in follow-up data collection will assign participants to interventions. Treatment allocation will not be masked.

Radiotherapy Radiotherapy dose to chest wall, axilla level III and supraclavicular fossa will be of 26Gy in 5 fractions over 1 week in the study arm and 34Gy in 10 fractions over 2 weeks in the control arm. BCS patients will receive a sequential boost of 8Gy/2#/2days or simultaneous integrated boost(SIB) to a total dose of 34Gy in the study arm and 42Gy in the control arm. Treatment will be done on a linear accelerator with 6 or 10MV photon energy. Boost can be with photons or electrons. 1cm bolus will be used in all postmastectomy patients, daily in study arm and in 50% of treatment in the control arm. Dose will be prescribed at mid-separation in 2D technique and the dose covering 95% of the planning target volume with three-dimensional conformal(3D-CRT) or intensity modulated radiotherapy(IMRT).

Supraclavicular fossa(SCF) and axilla level III will be treated in patients with T3-4 disease with lymphovascular invasion, grade 3 or N2 disease and T3-4 disease treated with neoadjuvant chemotherapy after adequate axillary dissection. Level I and II axilla will only be irradiated in patients with inadequate axillary dissection(\<10 lymph nodes). The prescribed dose to the area will be defined as the dose to the point at 3 cm beneath the skin in two-dimensional radiotherapy technique, or the dose covering 95% of the planning target volume with 3D-CRT or IMRT.

Internal mammary node (IMNs) radiation will be done in T3-4 central and inner quadrant lesions and patients with N2 disease. IMNs will be irradiated with a separate 12x5 cm single field. The first five intercostal spaces will be included in the IMN target volume. The medial border of the IMN field will be midline; lateral border 5 cm lateral to the midline; the superior border will abut the inferior border of the supraclavicular field; and the inferior border will be above the xiphoid. Dose will be 34Gy/10#/2weeks. Dose will be prescribed at 3cm depth. Imaging will be done for set-up verification on alternate days in the study arm and once weekly in the control arm.

Hormonal therapy may be given to oestrogen receptor-positive or progesterone receptor-positive tumours, and anti-HER2-targeted therapy (e.g., trastuzumab) for those with HER2-positive disease depending on the affordability.

Assessment Patients will be assessed for medical history, a physical examination, and a blood test before radiotherapy, once per week during radiotherapy, and 2 weeks after radiotherapy. Patients will be followed up every 3 months for 2 years after radiotherapy, then every 6 months from 3 to 5 years, and yearly thereafter. Skin, subcutaneous toxicity and cosmetic assessment will be done before treatment and then in regular follow up of the study. Acute radiation toxicity will be assessed and scaled according to the RTOG grading system. Late radiation toxicity will be assessed with the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer late radiation morbidity scale. Cosmetic assessment will be done using Harvard/NSABP/RTOG breast cosmesis grading scale at baseline, 3 and 5 years. Quality of life(QoL) will be assessed with EORTC QLQ -30, EORTC QLQ-BR 23 at baseline, 3 and 5 years.12

Statistical considerations The primary hypothesis of the study is that locoregional recurrence with 1 week is non-inferior to that with 2 weeks of radiotherapy. The primary endpoint will be locoregional recurrence (LRR). Based on historical data (Wang et al.), the 5-year LRR rate with 3 weeks of RT is expected to be approximately 8%. 1 week RT would be considered non-inferior to 2 weeks RT if the 5-year LRR rate does not exceed 13%. If LRR follows exponential distributions within each treatment group, this non-inferiority margin corresponds to a hazard ratio (HR) of 1.67.

Sample size calculations were performed using module STE0S-3 of nQuery version 8.5.2.0. A total of 94 LRR events will be required to provide at least 80% power using a one-sided test at the 5% level of significance. Under assumed failure rates and guarding against 10% ineligibility or loss to follow-up, the target accrual will be 1018 patients with an accrual period of 3 years. If the two schedules are equivalent, 5 years of follow-up after the last patient has been randomised will be required to observe 94 LRR events, resulting in total study duration of 8 years.

For the primary efficacy endpoint, we will use the cumulative incidence method to estimate the actual incidence of locoregional recurrence at different time points, with death without locoregional recurrence as a competing risk. We will use the log-rank test and Cox regression model for statistical inference based on cause-specific hazards. We will calculate overall survival and disease-free survival using the Kaplan-Meier method, and we will analyse these endpoints using the log rank test and Cox regression model. Acute and late toxicities will be summarised as frequency and severity on the basis of their association with protocol treatment; χ² tests will be used to compare the differences. The primary endpoint and all efficacy endpoints will be analysed in a modified intention-to-treat population (i.e., including all eligible patients who will undergo randomisation but exclude those who are considered ineligible. On the basis of the study design, the primary endpoint locoregional recurrence will be analysed at a one-sided significance level of 0•05 and reported with a two-sided 90% CI. All other statistical tests will be two sided, and p values of \<0.05 will be taken as significant. All tests will be performed using SPSS (Statistical Package for the Social Sciences) v.23.0.

Women with conformed invasive breast cancer

HYPofractionated Adjuvant RadioTherapy in 1 Versus 2 Weeks in High-risk Patients With Breast Cancer (HYPART).

HYPofractionated Adjuvant RadioTherapy in 1 Versus 2 Weeks in High-risk Patients With Breast Cancer (HYPART): A Non-inferiority, Open-label, Phase III Randomized Trial.

disease recurrence in the ipsilateral chest wall or regional lymph nodes from the time of randomization until the end of follow-up.

locoregional recurrence, distant metastasis, or death from any cause from the time of randomisation until the end of follow-up.

death from any cause from the time of randomisation until the end of follow-up

Any loco-regional toxicity assessed and scaled according to the RTOG grading system.

Any adverse event occurring after 6 months of RT

QoL will be assessed with EORTC QLQ -30. The QLQ-C30 is composed of both multi-item scales and single-item measures, as well as five functional scales, three symptom scales, a global health status/QoL scale, and six single items. The scores must be averaged and linearly transformed to obtain a range of scores from 0 to 100, with a higher score representing a greater response level.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
One Week Versus Three Week in Adjuvant Radiotherapy in Breast Cancer	NCT03788213	Breast Cancer F...	3 week RT 1 week RT	18 Years -	Tata Medical Center
HYPofractionated Adjuvant RadioTherapy in 1 Versus 2 Weeks in High-risk Patients With Breast Cancer (HYPART).	NCT04472845	Breast Cancer Hypofractionati... Radiotherapy Si...	1 week RT 2 week RT	18 Years -	PGIMER
One Week Versus Three Week in Adjuvant Radiotherapy in Breast Cancer	NCT03788213	Breast Cancer F...	3 week RT 1 week RT	18 Years -	Tata Medical Center

Spots Global Cancer Trial Database for 1 week rt

Every month we try and update this database with for 1 week rt cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for 1 week rt

Every month we try and update this database with for 1 week rt cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for 1 week rt cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.