Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3–07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study,The Lancet

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Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3–07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study
The Lancet ( IF 168.9 ) Pub Date : 2022-08-04 , DOI: 10.1016/s0140-6736(22)01246-6
Boon H Chua ₁ , Emma K Link ₂ , Ian H Kunkler ₃ , Timothy J Whelan ₄ , A Helen Westenberg ₅ , Guenther Gruber ₆ , Guy Bryant ₇ , Verity Ahern ₈ , Kash Purohit ₉ , Peter H Graham ₁₀ , Mohamed Akra ₁₁ , Orla McArdle ₁₂ , Peter O'Brien ₁₃ , Jennifer A Harvey ₁₄ , Carine Kirkove ₁₅ , John H Maduro ₁₆ , Ian D Campbell ₁₇ , Geoff P Delaney ₁₈ , Joseph D Martin ₁₉ , T Trinh T Vu ₂₀ , Thierry M Muanza ₂₁ , Anthony Neal ₂₂ , Ivo A Olivotto ₂₃ ,

Affiliation

Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
Edinburgh Cancer Research Centre, Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
McMaster University, Department of Oncology, Hamilton, ON, Canada; Juravinski Cancer Centre, Hamilton, ON, Canada.
Radiotherapiegroep Arnhem, Arnhem, Netherlands.
Institute for Radiotherapy, Klinik Hirslanden, Zurich, Switzerland.
University of Queensland, Brisbane, QLD, Australia.
University of Sydney, Sydney, NSW, Australia; Westmead Hospital, Westmead, NSW, Australia.
University of Sheffield, Sheffield, UK; Weston Park Hospital, Broomhall, Sheffield, UK.
Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; St George Hospital, Kogarah, NSW, Australia.
University of Manitoba, Winnipeg, MB, Canada; Cancer Care Manitoba, Winnipeg, MB, Canada.
Cancer Trials Ireland, Dublin, Ireland; St Luke's Radiation Oncology Network, Beaumont Hospital, Beaumont, Dublin, Ireland.
University of Newcastle, Newcastle, NSW, Australia; GenesisCare, Gateshead, NSW, Australia.
University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
Université Catholique de Louvain, Brussels, Belgium; Cliniques Universitaires St Luc, Bruxelles, Belgium.
Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
University of Auckland, Auckland, New Zealand; Waikato Hospital, Hamilton, New Zealand.
Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Liverpool Hospital, Liverpool, NSW, Australia.
National University of Ireland, Galway, Ireland; University Hospital Galway, Galway, Ireland.
Université de Montréal, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada.
Department of Oncology, McGill University, Montreal, QC, Canada.
Royal Surrey County Hospital, Guildford, UK.
University of Calgary, Calgary, AB, Canada.

Background

Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS.

Methods

The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236).

Findings

Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6–94·4%) in the no-boost group and 97·1% (95·6–98·1%) in the boost group (hazard ratio 0·47; 0·31–0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8–12%] vs 14% [12–17%], p=0·003) and induration (6% [5–8%] vs 14% [11–16%], p<0·001).

Interpretation

In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results.

Funding

National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

中文翻译：

非低风险乳腺导管原位癌的辐射剂量和分割方案（BIG 3–07/TROG 07.01）：一项随机、析因、多中心、开放标签、3 期研究

背景

导管原位癌 (DCIS) 保守手术后的全乳照射 (WBI) 可减少局部复发。我们调查了 WBI 后肿瘤床推量是否改善了结果，并检查了非低风险 DCIS 的辐射剂量分割敏感性。

方法

该研究是一项国际性、随机化、未设盲的 3 期试验，涉及 11 个国家（澳大利亚、新西兰、新加坡、加拿大、荷兰、比利时、法国、瑞士、意大利、爱尔兰和英国）的 6 个临床试验组织的 136 个参与中心英国）。符合条件的患者是年龄在 18 岁或以上的女性，患有单侧、经组织学证实的非低风险 DCIS，并通过保乳手术治疗，至少有 1 毫米的清晰放射状切除边缘。他们被分配到四组 (1:1:1:1) 中的一组 (1:1:1:1)中心预先指定的常规或大分割 WBI。使用的常规 WBI 是 50 Gy，分 25 次，大分割 WBI 为 42·5 Gy，分 16 次。WBI 后，如果分配了八个部分的 16 Gy 加强剂量。患者和临床医生并未对治疗分配设盲。主要终点是局部复发的时间。该试验已在 ClinicalTrials.gov (NCT00470236) 注册。

发现

2007 年 6 月 25 日至 2014 年 6 月 30 日期间，1608 名患者被随机分配到未加强（805 名患者）或加强（803 名患者）组。831 名患者接受了常规 WBI，777 名患者接受了大分割 WBI。中位随访时间为 6·6 年。未加强治疗组的 5 年无局部复发率为 92·7%（95% CI 90·6–94·4%）和 97·1%（95·6–98·1% ) 在加强组中（风险比 0·47；0·31–0·72；p<0·001）。加强组的 2 级或更高级别乳房疼痛发生率更高（10% [8–12%]对14% [12–17%]，p=0·003）和硬结（6% [5–8%]对14% [11–16%]，p<0·001）。