Hypofractionated radiation therapy comparing a standard radiotherapy schedule (over 3 weeks) with a novel 1-week schedule in adjuvant breast cancer: an open-label randomized controlled study (HYPORT-Adjuvant)-study protocol for a multicentre, randomized phase III trial

Sanjoy Chatterjee, Santam Chakraborty, HYPORT Adjuvant Author Group, Santam Chakraborty, Selvamani Backianathan, Punita Lal, Subhash Gupta, Rosina Ahmed, Shagun Misra, Patricia Solomon, Rajesh Balakrishan, Debashree Guha, K J Maria Das, Anurupa Mahata, Samar Mandal, Abha Kumari, Henry Finlay Godson, Sandip Ganguly, Debdeep Dey, Sanjoy Chatterjee, Sanjoy Chatterjee, Santam Chakraborty, HYPORT Adjuvant Author Group, Santam Chakraborty, Selvamani Backianathan, Punita Lal, Subhash Gupta, Rosina Ahmed, Shagun Misra, Patricia Solomon, Rajesh Balakrishan, Debashree Guha, K J Maria Das, Anurupa Mahata, Samar Mandal, Abha Kumari, Henry Finlay Godson, Sandip Ganguly, Debdeep Dey, Sanjoy Chatterjee

Abstract

Background: Hypofractionated radiotherapy is the current standard for adjuvant radiotherapy across many centres. Further hypofractionation may be possible but remains to be investigated in non-Caucasian populations with more advanced disease, with a higher proportion of patients requiring mastectomy as well as tumour bed boost. We are reporting the design of randomized controlled trial testing the hypothesis that a 1-week (5 fractions) regimen of radiotherapy will be non-inferior to a standard 3-week (15 fractions) schedule.

Methods: We describe a multicentre, randomized controlled trial recruiting patients at large academic centres across India. Patients without distant metastases who merit adjuvant radiotherapy will be eligible for inclusion in the study. Patients in the control arm will receive adjuvant radiotherapy to the breast or chest wall (with/without regional nodes) to a dose of 40 Gy/15 fractions/3 weeks, while those in the experimental arm will receive a dose of 26 Gy/5 fractions/1 week (to the same volume). The use of a simultaneous integrated boost (dose of 8 Gy and 6 Gy, respectively) is allowed in patients who have undergone breast conservation. A sample size of 2100 patients provides an 80% power to detect a non-inferiority of 3% in the 5-year locoregional recurrence rate with a one-sided type I error of 2.5%, assuming that the locoregional recurrence rate in the control arm is 5% at 5 years (corresponding to a hazard ratio of 1.63). Patients will be recruited over a period of 5 years and followed up for a further 5 years thereafter.

Discussion: If a five-fraction regimen of breast cancer is proven to be non-inferior, this will result in a significant improvement in the access to radiotherapy, as well as reduced costs of treatment. The trial gives an opportunity to standardize and quality-assure radiotherapy practices across the nation at the same time. Along with the results of the FAST-Forward trial, the safety of this intervention in advanced node-positive disease requiring regional nodal radiation will be established.

Trial registration: The trial has been registered at the Clinical Trial Registry of India (CTRI) vide registration number: CTRI/2018/12/016816 (December 31, 2018) as well as the ClinicalTrial.gov website at NCT03788213 (December 28, 2018).

Keywords: Adjuvant radiotherapy; Breast cancer; Hypofractionation; Non-inferiority trial; One-week radiotherapy.

Figures

Fig. 1
Fig. 1
HYPORT-Adjuvant trial schema

References

    1. India State-Level Disease Burden Initiative Cancer Collaborators The burden of cancers and their variations across the states of India: the Global Burden of Disease Study 1990-2016. Lancet Oncol. 2018;19(10):1289–1306.
    1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)s. Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707–1716.
    1. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) McGale P, Taylor C, Correa C, Cutter D, Duane F, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127–2135.
    1. Punglia RS, Saito AM, Neville BA, Earle CC, Weeks JC. Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis. BMJ. 2010;340:c845.
    1. Munshi A, Ganesh T, Mohanti BK. Radiotherapy in India: history, current scenario and proposed solutions. Indian J Cancer. 2019;56(4):359–363.
    1. Lam J, Cook T, Foster S, Poon R, Milross C, Sundaresan P. Examining determinants of radiotherapy access: do cost and radiotherapy inconvenience affect uptake of breast-conserving treatment for early breast cancer? Clin Oncol. 2015;27(8):465–471.
    1. Cohen L. Radiotherapy in breast cancer. I. the dose-time relationship theoretical considerations. Br J Radiol. 1952;25(300):636–642.
    1. Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol. 2005;75(1):9–17.
    1. Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006;7(6):467–471.
    1. Whelan TJ, Pignol JP, Levine MN. Are three weeks of whole-breast radiotherapy as good as five weeks in early breast cancer?–10 year follow-up in the Canadian Trial of Hypofractionated. Breast Care. 2010; Available from: .
    1. Haviland JS, Mannino M, Griffin C, Porta N, Sydenham M, Bliss JM, et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: results from the UK START (Standardisation of Breast Radiotherapy) trials. Radiother Oncol. 2017; Available from: 10.1016/j.radonc.2017.10.033.
    1. Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14(11):1086–1094.
    1. Valle LF, Agarwal S, Bickel KE, Herchek HA, Nalepinski DC, Kapadia NS. Hypofractionated whole breast radiotherapy in breast conservation for early-stage breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat. 2017;162(3):409–417.
    1. Courdi A, Ortholan C, Hannoun-Lévi J-M, Ferrero J-M, Largillier R, Balu-Maestro C, et al. Long-term results of hypofractionated radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients. Radiother Oncol. 2006;79(2):156–161.
    1. FAST Trialists group. Agrawal RK, Alhasso A, Barrett-Lee PJ, Bliss JM, Bliss P, et al. First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015) Radiother Oncol. 2011;100(1):93–100.
    1. Sanz J, Zhao M, Rodríguez N, Granado R, Foro P, Reig A, et al. Once-weekly hypofractionated radiotherapy for breast cancer in elderly patients: efficacy and tolerance in 486 patients. Biomed Res Int. 2018;2018:8321871.
    1. Dragun AE, Ajkay NJ, Riley EC, Roberts TL, Pan J, Rai SN, et al. First results of a phase 2 trial of once-weekly hypofractionated breast irradiation (WHBI) for early-stage breast Cancer. Int J Radiat Oncol Biol Phys. 2017;98(3):595–602.
    1. Brunt AM, Wheatley D, Yarnold J, Somaiah N, Kelly S, Harnett A, et al. Acute skin toxicity associated with a 1-week schedule of whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward Trial. Radiother Oncol. 2016;120(1):114–118.
    1. Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 2015;16(1):47–56.
    1. Paelinck L, Gulyban A, Lakosi F, Vercauteren T, De Gersem W, Speleers B, et al. Does an integrated boost increase acute toxicity in prone hypofractionated breast irradiation? A randomized controlled trial. Radiother Oncol. 2017;122(1):30–36.
    1. Versmessen H, Vinh-Hung V, Van Parijs H, Miedema G, Voordeckers M, Adriaenssens N, et al. Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy. BMC Cancer. 2012;12:495.
    1. Coles CE, Griffin CL, Kirby AM, Haviland JS, Titley JC, Benstead K, et al. Dose escalated simultaneous integrated boost radiotherapy for women treated by breast conservation surgery for early breast cancer: 3-year adverse effects in the IMPORT HIGH trial (CRUK/06/003) [Internet] San Antionio: San Antonio Breast Cancer Symposium; 2018.
    1. Mukesh MB, Duke S, Parashar D, Wishart G, Coles CE, Wilson C. The Cambridge post-mastectomy radiotherapy (C-PMRT) index: a practical tool for patient selection. Radiother Oncol. 2014;110(3):461–466.
    1. Feng M, Moran JM, Koelling T, Chughtai A, Chan JL, Freedman L, et al. Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2011;79(1):10–18.
    1. Yi SK, Hall WH, Mathai M, Dublin AB, Gupta V, Purdy JA, et al. Validating the RTOG-endorsed brachial plexus contouring atlas: an evaluation of reproducibility among patients treated by intensity-modulated radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2012;82(3):1060–1064.
    1. Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC, Sola AB, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1. Radiother Oncol. 2016;118(1):205–8.
    1. Giesinger JM, Kieffer JM, Fayers PM, Groenvold M, Petersen MA, Scott NW, et al. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol. 2016;69:79–88.
    1. START Trialists’ Group. Bentzen SM, Agrawal RK, EGA A, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008;9(4):331–341.
    1. Kundu S, Chakraborty S, Chatterjee S, Das S, Achari RB, Mukhopadhyay J, et al. De-identification of Radiomics data retaining longitudinal temporal information. J Med Syst. 2020;44(5):99.
    1. Murray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, et al. Lancet. 2020; Available from: 10.1016/S0140-6736(20)30932-6.
    1. Brunt AM, Haviland JS, Sydenham M, Agrawal RK, Algurafi H, Alhasso A, et al. Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer. J Clin Oncol. 2020. p. JCO1902750.

Source: PubMed

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