1921-Breast ductal carcinoma in situ adjuvant EBRT

Indications and patient population

Non-invasive ductal carcinoma in situ (DCIS) of the breast.
Stage 0: Tis (DCIS) N0 M0.¹
Clear margins following breast conserving surgery: 2 mm optimally.²^,³^,⁴^,⁵

ECOG 0-3.

Cautions

Non-rheumatoid collagen vascular disorders.

Cardiac implantable electronic devices (CIEDs).

Radiosensitising genetic conditions e.g. ataxia telangiectasia (AT), p53 mutation.

Ipsilateral breast implants/augmentation/expanders.

Exclusions

Prior high dose radiation therapy to ipsilateral breast.

Pregnancy.

Indications notes

There is high level evidence that radiation therapy offers an advantage of local control in all groups; however, the benefit should be considered in the context of small absolute gains for certain subgroups.⁶ Refer to evidence subsection 'Low-risk subgroups’ for further discussion.

Consider the use of a DCIS recurrence risk tool to assist in decision making.

Clinical information

Genetic counselling is recommended if the patient is considered to be at high risk of hereditary breast cancer.⁷ See eviQ cancer genetics referral guidelines for breast cancer.

Patients should be encouraged to cease smoking as continuation can cause delayed wound healing and increases the risk of toxicity of treatment (including fibrosis, cardiac, skin, and risk of second malignancy).⁸^,⁹ Current smokers should be referred to a smoking cessation program. See eviQ general fact sheet - smoking cessation in oncology.

Radiation therapy should commence as soon as clinically appropriate given wound healing and other patient related factors. Ideally, radiation therapy commences within 4 weeks after completion of chemotherapy or 3-8 weeks after surgery if there is no chemotherapy.

Simulation

Simulation	Options	Notes
Position	Supine. Prone.
Arm/leg/head/neck/shoulder position	Arm(s) above head.
Immobilisation and supports	Breast board. Knee supports. Vacuum immobilisation device (e.g. vacuum bag). Breast positioning devices (e.g. breast cup).	As per departmental protocol.
Organ pre-requisites	N/A
Contrast	N/A
Radio-opaque markers	Yes.	Mark relevant surgical scars and/or palpable breast tissue and/or residual disease.
Bolus	N/A
Other imaging	Mammogram. Ultrasound. MRI. CT.	Any available pre-operative breast imaging.
CT acquisition	3D CT.	≤3 mm CT slices. Scan from neck to below diaphragm, include whole lungs. Consider the use of breath hold techniques to reduce heart, liver and/or lung dose.

Dose prescription

Hypofractionation

Two phase (sequential boost)

3DCRT/VMAT/IMRT
Phase	Target area	Dose prescription	Prescription point/volume	Beam type	Beam Energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/volume	Beam type	Beam Energy	Dose/#	Fractions	#/day	#/fortnight
1	Whole breast	40.05 Gy	ICRU 50/62/83	Photons	≥6 MV	2.67 Gy	15	1	9-10
OR
1	Whole breast	42.4-42.56 Gy	ICRU 50/62/83	Photons	≥6 MV	2.65-2.66 Gy	16	1	9-10
Boost*
2	Tumour bed	10 Gy	90-100% isodose/ICRU 50/62/83	Electrons/photons	≥6 MV/MeV (electron energy dependent on depth required)	2-2.5 Gy	4-5	1	N/A
OR
2	Tumour bed	16 Gy	90-100% isodose/ICRU 50/62/83	Electrons/photons	≥6 MV/MeV (electron energy dependent on depth required)	2 Gy	8	1	N/A

*A higher radiation boost dose of 16 Gy in 8 fractions may be used in the setting of strong risk factor(s) for local recurrence such as positive margins or young age and close margins.¹⁰^,¹¹

Single phase - simultaneous integrated boost** (SIB)

3DCRT/VMAT/IMRT
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam Energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam Energy	Dose/#	Fractions	#/day	#/fortnight
SIB	Whole breast	40 Gy	ICRU 50/62/83	Photons	≥6 MV	2.67 Gy	15	1	9-10
SIB	Tumour bed	48 Gy	ICRU 50/62/83	Photons	≥6 MV	3.2 Gy	15	1	9-10

**The reference committee considers SIB a reasonable technique for delivery of a boost. Refer to the adverse events table of the IMPORT HIGH trial opens in a new tab or window.¹²

Prescription notes

Tumour bed boost should be considered based on risk factor(s) for recurrence.
- For non-low risk DCIS treated with breast conserving surgery, a tumour bed boost following hypofractionated or conventional whole breast irradiation was found to reduce local recurrence rates.¹¹

In select patients diagnosed with DCIS, partial breast irradiation can be considered. Refer to eviQ protocol: 'Breast invasive cancer/ductal carcinoma in situ adjuvant partial breast EBRT'.

Over the past two decades, research has demonstrated that moderate hypofractionation schedules are equivalent to conventional breast irradiation (50 Gy in 25 fractions) in terms of local control. Furthermore, using moderate hypofractionation may result in reduced early and late adverse effects on normal tissues, and is now standard of care.¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸

Target volumes

Volume	Description
CTV_{(Whole breast)}	The target volume is normally regarded as the glandular tissue of the breast which can be difficult to identify on CT, therefore an anatomical definition is normally used. In practice, the CTV can be defined as the volume of breast tissue extending from the pectoralis major muscle to subcutaneous tissue (typically 5 mm deep to skin surface).
PTV_{(Whole breast)}	CTV + 0.5-1 cm margin. Smaller margins may be used if departmental set up error has been appropriately quantified. Note: A PTV Eval may be used to assess dosimetric coverage. This structure should NOT be used to guide beam aperture or shielding placement. PTV Eval = PTV clipped anteriorly 5 mm under skin and posteriorly to anterior surface of the ribs (excludes bony thorax and lung).
Tumour bed volume	Tumour bed description
CTV_{(Tumour bed)}	Tumour bed defined as location of prior primary site based on: the original location of primary on mammograms/ultrasound/palpation surgical changes and relevant scars (taking into consideration the type of surgery as the scar is often not representative of tumour bed in the setting of oncoplastic techniques) localisation clips placed by the surgeon. Consider including an additional 0.5-1 cm margin. Clip to anatomical boundaries.
PTV_{(Tumour bed)}	CTV + 0.5-1 cm margin. Smaller margins may be used if departmental set up error has been appropriately quantified.

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume notes

With modern treatment approaches it is appropriate to define target volumes.
CT volumes utilising a peer reviewed published contouring atlas is recommended although the use of traditional field borders to define radiation therapy fields is acceptable.
ESTRO guidelines include a “strong recommendation that there is no reason to enlarge the radiation fields beyond those obtained with conventional simulator based treatment set-up.”¹⁹

Target volume guides

Suggested contouring atlases and guidelines:
- ESTRO guidelines 2015 opens in a new tab or window ¹⁹ and 2016 update opens in a new tab or window ²⁰
- RTOG Atlas opens in a new tab or window ²¹
A comparison and systematic review of the consensus guidelines has been published by Gee et. al. 2019 opens in a new tab or window.²²

Organs at risk

Organ	Constraints	Additional information
Ipsilateral lung	V16 Gy <15%²³ V4 Gy <50%²³ For tangential fields it is recommended that central axis lung exposure should be <3 cm; ideally 2 cm or less if achievable.
Contralateral lung	V5 Gy <10%
Heart	V20 Gy <5%²³ Mean Heart Dose (MHD): <4 Gy²³	MHD <2 Gy is often achievable. Keep MHD as low as reasonably achievable (ALARA).²⁴ Please also refer to table S12 in Darby et al. supplementary material for additional information.²⁴ Use of deep inspiration techniques should be considered - several techniques exist that can be adapted to local departmental protocols.
Contralateral breast	Ideal: V3 Gy <10%²⁵ Acceptable: V5 Gy <10%²⁵	Dose should be ALARA. In cases where a VMAT technique is used or fields cross midline the NSABP-51 protocol may provide guidance.²⁵

OAR notes

If using inverse planned/non-tangential technique, particular attention should be paid to the low dose wash (e.g. to the contralateral breast and lung).

If using VMAT or non-standard fields consider dose to additional organs such as the liver, oesophagus, and thyroid.

The OAR goals listed are the consensus of the reference committee as there is a lack of high level evidence there are several references where OAR goals may be obtained.

It is important to refer to the trial protocols for further details on planning techniques and dose constraints.

Target verification

Modality	Frequency	Match point
kV or MV or CBCT	Daily or Day 1-3 then weekly	Bone or soft tissue

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment and should only be used as a guide.

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Skin reaction/dermatitis	Including itch, erythema, dry or moist desquamation. Read more about skin reactions.
Fatigue	Read more about fatigue.
Breast/chest wall discomfort
Breast/chest wall oedema
Alopecia	Within treatment area. Read more about alopecia.
Pericarditis	Very rare. Read more about cardiac disease

Subacute: Mid term side effects - weeks to months post radiation therapy
Pneumonitis	Read more about pneumonitis.
Breast/chest wall discomfort
Breast/chest wall oedema

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Skin changes	Including telangiectasia, atrophy and changes to skin pigmentation.
Breast/chest wall discomfort and/or pain
Breast/chest wall fibrosis	Volume loss of the breast.
Breast/chest wall oedema
Pulmonary fibrosis	Usually subclinical.
Cardiac disease or complications	Read more about cardiac disease.
Rib fracture	Rare.
Second malignancy	Rare.

Evidence

Source	Study & year published	Supports use Yes/No/NA	Is the radiation dose and fractionation consistent with the protocol?	Comments
Meta-analysis	Goodwin et al. 2009²⁶	Yes	Yes	Adjuvant radiation therapy (RT) post breast conserving surgery (BCS) reduces ipsilateral breast tumour recurrence. No difference in overall survival (OS).
	Correa et al. 2010²⁷	Yes	Yes	Adjuvant RT post BCS reduces ipsilateral breast tumour recurrence. No difference in OS.
	Wapnir et al. 2011²⁸	Yes	Yes	Adjuvant RT post BCS reduces ipsilateral breast tumour recurrence. No difference in OS.
	Stuart et al. 2015²⁹	Yes	Yes	Adjuvant RT post BCS reduces ipsilateral breast tumour recurrence. No difference in OS.
	Dunne et al. 2009³⁰	Yes	Yes	Negative surgical margins should be obtained after BCS; a margin threshold of 2 mm seems as good as a larger margin for BCS plus radiation therapy to reduce ipsilateral tumour recurrence.
Phase III trials	Bijker et al. 2006³¹	Yes	Yes	Adjuvant RT post BCS reduces the risk of local recurrence (LR), with a 47% reduction at 10 years.
	Silverstein 2003³²	Yes	Yes	Tumour size, margin width, pathologic classification and age found to be independent risk factors of LR of DCIS.
	Warnberg et al. 2014³³	Yes	Yes	50 Gy/25 fx or 54 Gy given in two series with a gap of 2 weeks. Confirms the long-term (20-year) absolute reduction of ipsilateral breast recurrence by 10% with adjuvant RT post BCS.
	RTOG 9804 McCormick et al. 2021 ⁶	Yes	Yes	Omission of RT may be considered in patients with “good risk DCIS”. In "good risk DCIS" RT significantly reduced all and invasive IBR with 15-year durable results.
	TROG 07.01 Chua et al. 2022¹³	Yes	Yes	Tumour bed boost after whole breast radiation therapy (WBRT) for “non-low-risk" DCIS reduces local recurrence. Moderate hypofractionation is as safe and effective as conventional fractionation.
	IMPORT-HIGH Coles et al. 2023³⁴	Yes	Yes	Extrapolation from the treatment of invasive breast cancer. 48 Gy simultaneous integrated boost (SIB) to tumour bed, but not 53 Gy SIB, is associated with similar efficacy and rates of adverse events as compared to sequential boost of 16 Gy in 8 fractions to tumour bed.
Observational studies	Solin et al. 2015³⁵	N/A	N/A	Surgery series; no RT given. Shows ongoing risk of LR without plateau, even in "low risk" group through 12 years of follow up.
	Tadros et al. 2019³⁶	Yes	Yes	No difference in locoregional relapse in patients with margins <2 mm vs. ≥2 mm who underwent adjuvant RT.
	Van Zee et al. 2015³⁷	Yes	Yes	No association between negative margin width and risk of locoregional recurrence (LRR) for patients who received adjuvant RT. Significant LRR in patients with smaller negative margins who did not receive RT.
	Guidelines	Date published/revised	Supports use Yes/No/NA	Is the dose and regimen consistent with the protocol?	Comments
NCCN	V.2 2024³⁸	Yes	Yes
SSO, ASTRO & ASCO multidisciplinary panel	2016⁵	Yes	Yes
ASTRO	2018¹⁰	Yes	Yes	Hypofractionation may be used as an alternative to conventional fractionation.

Efficacy

The Ductal Carcinoma In Situ (DCIS) Cochrane review by Goodwin et al. included 4 randomised control trials: NSABP B-17, EORTC10853, UKCCCR and SweDCIS.²⁶ The review compared the addition of radiation therapy to breast conserving surgery (BCS) (n = 3925 women). They reported a statistically significant benefit from the addition of radiation therapy on all ipsilateral breast events (Hazard Ratio (HR) 0.49, 95% CI: 0.41-0.59, p <0.00001) and ipsilateral recurrence (HR 0.64, 95% CI: 0.41 to 1.01, p = 0.05).²⁶ The addition of radiation therapy reduced the risk of recurrence of either DCIS or invasive cancer in the treated breast by 51%.

The 15-year combined analysis of the NSABP B-17 and B-24 trials showed the reduction in risk of local recurrence appeared to persist in the long term.²⁸ The ipsilateral breast recurrence rate was reduced from 19.4% to 8.9% with radiation therapy at 15 years. The overall survival (OS) rate was similar, 83% versus 84%.

Further evidence supporting this protocol was provided by a second meta-analysis by Correa et al.²⁷ This meta-analysis reviewed individual patient data for the same 4 trials (n = 3925 women) and also compared BCS alone to BCS with adjuvant radiation therapy. The 10-year ipsilateral breast recurrence rate with surgery alone was statistically significant, 28% compared to 13% for BCS with radiation therapy. This benefit was greater in women >50 years old (28% versus 11%) compared with women <50 years old (29% versus 18%). Women with small, low-grade tumours and negative surgical margins still benefited (30% versus 12%, statistically significant). There was no effect on breast cancer specific mortality (~4%), other-cause mortality (~5%), and all-cause mortality (~8%).

A meta-analysis conducted by Stuart et al. included 9391 patients with follow-up at 10 years reported adjuvant radiation therapy after BCS was associated with greater local control when compared to patients who were managed with BCS and biopsy alone.²⁹ At 10 years, OS was similar in patients treated with mastectomy or breast conserving surgery with or without radiation therapy.

Bijker et al. reported the inclusion of radiation therapy resulted in a 48% reduction in the 10-year local recurrence (LR) rate in DCIS (14% with BSC versus 7% with BSC and radiation therapy, statistically significant). Factors that increased the risk for LR were age <40 years old, grade 2 or 3, cribriform or solid growth pattern, doubtful margin, and local excision alone. Size was not a prognostic factor. There was no difference reported in OS or distant metastases.³¹

In 20-year follow-up the sweDCIS trial showed the absolute risk reduction of ipsilateral breast recurrence in the radiation therapy arm was 12.0% at 20 years (95% CI: 6.5-17.7), with a relative risk reduction of 37.5%.³³ Absolute reduction was 10.0% (95% CI: 6.0-14.0) for DCIS. The cumulative incidence of invasive ipsilateral recurrences was found to continuously rise over the 20-year period before plateauing.

Role of hypofractionation and boost

TROG 07.01 was a phase III randomised control trial assessing the addition of sequential tumour bed boost following conventional or moderately hypofractionated whole breast irradiation in patients with non-low-risk DCIS.¹³ Non-low-risk DCIS included patients aged <50 years old, symptomatic presentation, palpable tumour, microscopic tumour size measuring ≥15 mm, multifocal disease, intermediate or high nuclear grade, central necrosis, comedo-histology, or a radial surgical margin of <10 mm, or a combination. The 5-year free from local recurrence rates were 93% in the no boost group and 97% in the boost group (HR 0.47, 95% CI: 0.31-0.72, p <0.001). There was no statistically significant difference in 5-year overall survival rates between the no-boost (98.2%) and boost (99.0%) groups. When comparing conventional fractionation to moderate hypofractionation, there were no significant differences observed in the 5-year free from local recurrence rates. Boost, but not hypofractionation, is associated with higher incidence of grade 2 or greater breast pain (10% in no-boost vs 14% in boost, p=0.003) and induration (6% vs 14%, p<0.001).

Simultaneous integrated boost (SIB) is safe and reduces patient visits for invasive breast cancer, and data could be extrapolated for DCIS. IMPORT-HIGH randomised 2621 women who completed breast conserving surgery for T1-3, pN0-3a, M0 tumours in a 1:1:1 fashion.³⁴ The control group received 40 Gy in 15 fractions to the whole breast followed by 16 Gy in 8 fractions sequential photon boost to the tumour bed volume, test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to partial breast and 48 Gy in 15 fractions concomitant photon boost to the tumour bed volume, and test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to partial breast and 53 Gy in 15 fractions concomitant photon boost to the tumour bed volume. 48 Gy SIB (test group 1) delivered in 3 weeks had similar efficacy to sequential boost delivered over 4-5 weeks, with similar or milder rates of adverse events. 53 Gy SIB (test group 2) had no additional benefit in local cancer control but a higher risk of moderate or marked breast induration.

Optimal margins

Although it is widely accepted that positive margins definitively increase the risk of locoregional recurrence (LRR) in patients who undergo BCS even with adjuvant radiation therapy, the exact optimal margin threshold is not yet defined at an international level.³⁰^,³⁹^,⁴⁰

ASTRO guidelines and other eminent groups recommend a >2 mm margin.³^,⁴^,³⁰^,¹⁰^,⁵ Other groups infer smaller margins may be acceptable in selected cases.⁵^,⁴¹^,⁴²

Tadros et al. recently published a retrospective analysis of a cohort of 1491 ‘contemporary’ patients with DCIS.³⁶ They reported no statistically significant difference in locoregional control between patients with <2 mm and ≥2 mm negative margins who underwent adjuvant radiation therapy. For patients who did not undergo adjuvant radiation therapy however, those with margins <2 mm were significantly more likely to develop LRR than those with margins ≥2 mm.

Van Zee et al. echoed the above in their retrospective analysis of 2996 patients.³⁷ They reported no significant association between negative margin width and risk of LRR for patients who received adjuvant radiation therapy, however, in patients with smaller negative margins who did not receive radiation therapy there was a significant risk of LRR.

The 2016 ASTRO guidelines noted that clinical judgement must be used when deciding on the need for re-excision in patients with >0-1 mm margins. Factors to consider include residual calcifications on post-excision mammography, extent of DCIS in proximity to margin, which margin is close (superficial/deep versus radial), cosmetic impact of re-excision, and overall life expectancy.⁵

The reference committee consensus is that clear margins ≥2 mm is optimal, however; narrower margins may be acceptable in selected cases.

Low-risk subgroups

Omission of radiation therapy may be considered in some low-risk patients such as those who were eligible for RTOG 9804 Good-Risk DCIS trial.⁴³ However, with longer follow-up (median 13.9 years), a steady increase of 1% per year of ipsilateral breast recurrence (IBR) was observed up to at least 15 years.⁶In this population, the use of radiation therapy reduced IBR with a HR of 0.36.

The RTOG 9804 eligibility criteria included:

mammogram detected DCIS or incidental finding of DCIS in tissue of an otherwise benign biopsy
unicentric disease
low or intermediate nuclear grade
size <2.5 cm
margin ≥3 mm to ink
negative post-excision mammogram.

Although the benefit of the addition of radiation therapy has been demonstrated in all sub-groups of patients, absolute benefit in these patients is small (1% risk of recurrence per year is halved by the addition of radiation therapy).⁴³The known and increasing long-term risk of a local recurrence must be considered in the context of a patient's longevity and wellbeing.

Consider the use of a DCIS recurrence risk tool to assist in decision making.

Chemoprevention

COSA provides a clinician guide for medications to lower the risk of breast cancer opens in a new tab or window.

Toxicity

There is limited evidence relating to toxicity in ductal carcinoma in situ (DCIS). Therefore toxicity data has been extrapolated from invasive breast cancer trials and combined with results from the TROG DCIS trial.¹³

Toxicity moderate hypofractionation

A summary of the most clinically significant toxicities associated with hypofractionation radiation therapy in this protocol are included below.

Toxicity	Study/Year	Incidence of event or %	Comment
Breast shrinkage	START A and B¹⁷	26%	In START-B, breast shrinkage, telangiectasia and breast oedema were less common in the 40 Gy group than the 50 Gy group.
Telangiectasia		4%
Oedema		5% at 10 years
Symptomatic rib fracture		1-2% at 10 years
Symptomatic lung fibrosis		1-2% at 10 years
Ischemic heart disease		0.7-0.8% confirmed at 10 years	A total of 48 patients in START-A and START-B with pre-existing heart disease were excluded from this final rate. Required >10 years follow up to

Boost doses

Boost radiation of 16 Gy in 8 fractions was associated with an increase in grade 2 or higher late breast pain and induration compared with no boost.¹³

Figure 1: Adverse events (grade 2 or higher) related to radiation therapy among the safety population¹³

The Cochrane review reported decreased acute skin toxicity with hypofractionation.⁴⁴ Late subcutaneous toxicity and cosmetic outcome did not differ with hypofractionated regimens. Hypofractionation was associated with less patient-reported and physician-reported fatigue at 6 months. There was no difference in patient-reported outcomes of physical, functional, emotional and social wellbeing.

Ischemic heart disease

Concerns have been raised about doses to the heart with hypofractionated schedules. The heart is sensitive to radiation whatever fractionation is used, with no dose threshold for adverse effects. START-A and B showed no increased cardiac events with hypofractionated regimens, however, follow-up in these studies is considered too short to assess late cardiac events. The START-A and B trials excluded patients with pre-existing heart disease from the analysis – other studies have demonstrated that the absolute effect of radiation therapy on the heart is greater in patients with established cardiovascular system risk factors.²⁴ The risk of cardiovascular disease in breast radiation therapy patients increases with longer follow-up beyond 10 years.⁴⁵^,⁴⁶ In one of these 2 retrospective reviews patients were treated with 4.3 Gy per fraction.⁴⁶

Appelt et al. examined the predictions of the linear quadratic model on the estimated fraction size-corrected dose to heart for four hypofractionated regimens used in START-A, START-B and Canadian trials and conventional fractionation for a range of a/ß ratios.⁴⁷ The 40 Gy/15 fx, 39 Gy/13 fx and 42.5 Gy/16 fx regimens were estimated to have lower dose to heart, adjusted for fraction size using the linear quadratic model, compared to conventional fractionation. However, 41.6 Gy/13 fx was estimated to result in higher dose to heart if heart a/ß = 1.

References References

1

American Joint Commission on Cancer (AJCC). 2017. "Cancer Staging Handbook". 8th Edition. Springer, New York.

2

Dunne, C., J. P. Burke, M. Morrow, et al. 2009. "Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ." J Clin Oncol 27(10):1615-1620.

3

Merrill, A. L., R. Tang, J. K. Plichta, et al. 2016. "Should New "No Ink On Tumor" Lumpectomy Margin Guidelines be Applied to Ductal Carcinoma In Situ (DCIS)? A Retrospective Review Using Shaved Cavity Margins." Ann Surg Oncol 23(11):3453-3458.

4

Marinovich, M. L., L. Azizi, P. Macaskill, et al. 2016. "The Association of Surgical Margins and Local Recurrence in Women with Ductal Carcinoma In Situ Treated with Breast-Conserving Therapy: A Meta-Analysis." Ann Surg Oncol 23(12):3811-3821.

5

Morrow, M., K. J. Van Zee, L. J. Solin, et al. 2016. "Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma In Situ." Ann Surg Oncol 23(12):3801-3810.

6

McCormick, B, K. A. Winter, W. Woodward, et al. 2021. "Randomized Phase III Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG Oncology/RTOG 9804." Journal of Clinical Oncology 0(0):JCO.21.01083.

Read abstract

7

NCCN - Clinical Practice Guidelines in Oncology - Breast Cancer - Version 3.2015 https://www.nccn.org/

8

Pignol, J. P., T. T. Vu, G. Mitera, et al. 2015. "Prospective evaluation of severe skin toxicity and pain during postmastectomy radiation therapy." Int J Radiat Oncol Biol Phys 91(1):157-164.

9

Taylor, C., C. Correa, F. K. Duane, et al. 2017. "Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials." J Clin Oncol 35(15):1641-1649.

Read abstract

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence >/= 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

10

Smith, B.D., J.R. Bellon, R. Blitzblau, et al. 2018. "Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline." Practical Radiation Oncology 8(3):145-152.

11

Chua, B. H., E. Link, I. Kunkler, et al. 2021. "Abstract GS2-04: A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01)." Cancer Research 81(4 Supplement):GS2-04-GS02-04.

Read abstract

Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy.

Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age <50 years orage ≥50 years plus at least one of the risk factors for local recurrence (palpable tumor,multifocal disease, tumor size ≥ 1.5cm, intermediate or high nuclear grade, central necrosis, comedo histologyand/or surgical margin <10 mm). Patients were randomized to have tumor bedboost (16 Gy in 8 daily fractions) or no boost following conventional WBI (50Gy in 25 daily fractions) or hypofractionated WBI (42.5 Gy in 16 dailyfractions) in one of three randomization categories selected by centers priorto study activation. Randomization A was a 4-arm randomization of no boost vs. boostfollowing conventional WBI vs. hypofractionated WBI. Patients in RandomizationB and Randomization C were assigned no boost or boost following conventional WBIand hypofractionated WBI, respectively. The primary endpoint was time to localrecurrence, analyzed by intention to treat. The trial was designed to detect a3% difference in 5-year free-from- local recurrence rates between the no boostand boost groups (93% vs 96%; hazard ratio, 0.56) with 90% power and 2-sidedalpha level of 5%. The primary effect of boost was assessed on all randomizedpatients. The secondary effect of WBI dose-fractionation and the interactionbetween boost and WBI dose-fractionation were assessed on patients in RandomizationA and additionally on all patients.

Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P<0.001). Forty-four percent and 45% of LRs were invasive in the no boostgroup and boost group, respectively. The effect of boost did not vary significantlyby age, tumor size, nuclear grade, surgical margin or endocrine therapy. Therewere no significant differences in the 5-year free-from- local recurrence ratesbetween the conventional WBI group and hypofractionated WBI group inRandomization A (94% vs. 94%, P=0.84) and in all randomized patients (95% vs.95%, P=0.89). The test for interaction between boost and dose-fractionation wasnot significant in Randomization A or in all randomized patients (both P=0.89).The rates of grade ≥2 breastpain (12% vs. 16%, P=0.84) and skin and subcutaneous tissue fibrosis (6% vs.15%, P=0.14) did not differ significantly between the groups.

Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.)

12

Coles, C.E, C.L Griffin, A.M Kirby, et al. 2019. "Abstract GS4-05: 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)." Cancer Research 79(4 Supplement):GS4-05-GS04-05.

Read abstract

Background

IMPORT HIGH is a randomised, multi-centre phase III trial testing dose escalated simultaneous integrated boost (SIB) against sequential boost each delivered by intensity modulated radiotherapy (IMRT) for early stage breast cancer with higher risk of local relapse. The primary endpoint was initially breast induration at 3 years, requiring 840 patients; accrual was extended (target 2568) with the new primary endpoint of local relapse. We report adverse effects (AE) at 3 years.

Methods

Women age ≥18 after breast conservation surgery for pT1-3 pN0-pN3a M0 invasive carcinoma were eligible. Randomisation was 1:1:1 between 40Gy/15F to whole breast (WB) + 16Gy/8F sequential photon boost to tumour bed (40+16Gy), 36Gy/15F to WB, 40Gy to partial breast + 48Gy (48Gy) or + 53Gy (53Gy) in 15F SIB to tumour bed. AEs were assessed annually by clinicians in all patients and in a planned sub-set (840) of patients by photographs at 3 years and by patients at 6 months, 1 and 3 years. AE scores were dichotomised as none/mild vs marked for photographs and none/mild vs moderate/marked for patients and clinicians. Fisher's exact tests compared groups; principal comparison (protocol-specified) between 53Gy and 48Gy (p<0.01 defined as statistical significance).

Results

2617 women consented between 03/2009 and 09/2015 from 39 UK radiotherapy centres. Median follow-up was 49.1 (IQR 36.8-63.2) months. Median age was 49 (IQR 44-56); 9%, 38% & 53% were tumour grade 1, 2 & 3 respectively; 30% were node positive. 66% received chemotherapy and 73% endocrine therapy. 3-year AE data were available for 2017 clinician assessments, 641 photographs and 842 patient assessments. Proportions of patients with marked AEs were low overall. Rates of moderate/marked AEs at 3 years were broadly similar between the randomised groups; with a suggestion of a slightly increased risk for breast induration in 53Gy compared with control (borderline significance).

Conclusions

These results represent the largest and most mature reported AE outcomes of breast SIB within a clinical trial. At 3 years, rates of moderate/marked AEs were similar between SIB IMRT and WB + sequential boost IMRT delivered over 3 and 4.5 weeks respectively.

13

Chua, B. H., E. K. Link, I. H. Kunkler, et al. 2022. "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." Lancet 400(10350):431-440.

Read abstract

Summary

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.

14

Brunt, A. M., J. S. Haviland, D. A. Wheatley, et al. 2020. "Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial." The Lancet 395(10237):1613-1626.

Read abstract

Background

We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.

Methods

FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.

Findings

Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.

Interpretation

26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.

Funding

National Institute for Health Research Health Technology Assessment Programme.

15

Brunt, A. M., J. S. Haviland, M. Sydenham, et al. 2020. "Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer." J Clin Oncol 38(28):3261-3272.

Read abstract

Abstract

Purpose: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented.

Methods: Women ≥ 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 once-weekly fr of 6.0 or 5.7 Gy. The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens.

Results: A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. α/β estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred.

Conclusion: At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

Trial registration: ClinicalTrials.gov NCT00107497.

16

Offersen, B. V., J. Alsner, H. M. Nielsen, et al. 2020. "Hypofractionated Versus Standard Fractionated Radiotherapy in Patients With Early Breast Cancer or Ductal Carcinoma In Situ in a Randomized Phase III Trial: The DBCG HYPO Trial." J Clin Oncol 38(31):3615-3625.

Read abstract

Abstract

Purpose: Given the poor results using hypofractionated radiotherapy for early breast cancer, a dose of 50 Gy in 25 fractions (fr) has been the standard regimen used by the Danish Breast Cancer Group (DBCG) since 1982. Results from more recent trials have stimulated a renewed interest in hypofractionation, and the noninferiority DBCG HYPO trial (ClincalTrials.gov identifier: NCT00909818) was designed to determine whether a dose of 40 Gy in 15 fr does not increase the occurrence of breast induration at 3 years compared with a dose of 50 Gy in 25 fr.

Patients and methods: One thousand eight hundred eighty-two patients > 40 years of age who underwent breast-conserving surgery for node-negative breast cancer or ductal carcinoma in situ (DCIS) were randomly assigned to radiotherapy at a dose of either 50 Gy in 25 fr or 40 Gy in 15 fr. The primary end point was 3-year grade 2-3 breast induration assuming noninferiority regarding locoregional recurrence.

Results: A total of 1,854 consenting patients (50 Gy, n = 937; 40 Gy, n = 917) were enrolled from 2009-2014 from eight centers. There were 1,608 patients with adenocarcinoma and 246 patients with DCIS. The 3-year rates of induration were 11.8% (95% CI, 9.7% to 14.1%) in the 50-Gy group and 9.0% (95% CI, 7.2% to 11.1%) in the 40-Gy group (risk difference, -2.7%; 95% CI, -5.6% to 0.2%; P = .07). Systemic therapies and radiotherapy boost did not increase the risk of induration. Telangiectasia, dyspigmentation, scar appearance, edema, and pain were detected at low rates, and cosmetic outcome and patient satisfaction with breast appearance were high with either no difference or better outcome in the 40-Gy cohort compared with the 50-Gy cohort. The 9-year risk of locoregional recurrence was 3.3% (95% CI, 2.0% to 5.0%) in the 50-Gy group and 3.0% (95% CI, 1.9% to 4.5%) in the 40-Gy group (risk difference, -0.3%; 95% CI, -2.3% to 1.7%). The 9-year overall survival was 93.4% (95% CI, 91.1% to 95.1%) in the 50-Gy group and 93.4% (95% CI, 91.0% to 95.2%) in the 40-Gy group. The occurrence of radiation-associated cardiac and lung disease was rare and not influenced by the fractionation regimen.

Conclusion: Moderately hypofractionated breast irradiation of node-negative breast cancer or DCIS did not result in more breast induration compared with standard fractionated therapy. Other normal tissue effects were minimal, with similar or less frequent rates in the 40-Gy group. The 9-year locoregional recurrence risk was low.

17

Haviland, J. S., J. R. Owen, J. A. Dewar, et al. 2013. "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 14(11):1086-1094.

Read abstract

BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41.6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9.3 years (IQR 8.0-10.0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41.6 Gy and 50 Gy regimen groups (6.3%, 95% CI 4.7-8.5 vs 7.4%, 5.5-10.0; hazard ratio [HR] 0.91, 95% CI 0.59-1.38; p=0.65) or the 39 Gy (8.8%, 95% CI 6.7-11.4) and 50 Gy regimen groups (HR 1.18, 95% CI 0.79-1.76; p=0.41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41.6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9.9 years (IQR 7.5-10.1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4.3%, 95% CI 3.2-5.9) and the 50 Gy group (5.5%, 95% CI 4.2-7.2; HR 0.77, 95% CI 0.51-1.16; p=0.21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.

18

Whelan, T. J., J. P. Pignol, M. N. Levine, et al. 2010. "Long-term results of hypofractionated radiation therapy for breast cancer." N Engl J Med 362(6):513-520.

19

Offersen, B. V., L. J. Boersma, C. Kirkove, et al. 2015. "ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer." Radiother Oncol 114(1):3-10.

20

Offersen, B. V., L. J. Boersma, C. Kirkove, et al. 2016. "ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1." Radiother Oncol 118(1):205-208.

21

RTOG. "Breast Cancer Contouring Atlas."

22

Gee, H. E., L. Moses, K. Stuart, et al. 2019. "Contouring consensus guidelines in breast cancer radiotherapy: Comparison and systematic review of patterns of failure." J Med Imaging Radiat Oncol 63(1):102-115.

23

RTOG. "RTOG 1005 A Phase III Trial Of Accelerated Whole Breast Irradiation With Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost For Early-Stage Breast Cancer."

24

Darby, S. C., M. Ewertz, P. McGale, et al. 2013. "Risk of ischemic heart disease in women after radiotherapy for breast cancer." N Engl J Med 368(11):987-998.

25

NSABP B-51 - A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy - Clinical trial protocol.

26

Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000563. DOI: 10.1002/14651858.CD000563.pub6

Read abstract

Background The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs. Objectives To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms. Search strategy We searched the Cochrane Breast Cancer Group Specialised Register (January 2008), Cochrane Central Register of Controlled Trials (CENTRAL) ( The Cochrane Library 2008, Issue 1), MEDLINE (February 2008), and EMBASE (February 2008). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed. Selection criteria RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present). Data collection and analysis Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy. Main results Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported. Authors' conclusions This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

27

Early Breast Cancer Trialists' Collaborative, Group, C. Correa, P. McGale, et al. 2010. "Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast." J Natl Cancer Inst Monogr 2010(41):162-177.

28

Wapnir, I. L., J. J. Dignam, B. Fisher, et al. 2011. "Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS." J Natl Cancer Inst 103(6):478-488.

Read abstract

BACKGROUND: Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS. METHODS: In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients). RESULTS: Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM. CONCLUSIONS: Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

29

Stuart, K. E., N. Houssami, R. Taylor, et al. 2015. "Long-term outcomes of ductal carcinoma in situ of the breast: a systematic review, meta-analysis and meta-regression analysis." BMC Cancer 15:890.

Read abstract

BACKGROUND: To summarize data on long-term ipsilateral local recurrence (LR) and breast cancer death rate (BCDR) for patients with ductal carcinoma in situ (DCIS) who received different treatments. METHODS: Systematic review and study-level meta-analysis of prospective (n = 5) and retrospective (n = 21) studies of patients with pure DCIS and with median or mean follow-up time of >/=10 years. Meta-regression was performed to assess and adjust for effects of potential confounders - the average age of women, period of initial treatment, and of bias - follow-up duration on recurrence- and death-rates in each treatment group. LR and BCDR rates by local treatment used were reported. Outside of randomized trials, remaining studies were likely to have tailored patient treatment according to the clinical situation. RESULTS: Nine thousand four hundred and four DCIS cases in 9391 patients with 10-year follow-up were included. The adjusted meta-regression LR rate for mastectomy was 2.6 % (95 % CI, 0.8-4.5); breast-conserving surgery with radiotherapy (RT), 13.6 % (95 % CI, 9.8-17.4); breast-conserving surgery without RT, 25.5 % (95 % CI, 18.1-32.9); and biopsy-only (residual predominately low-grade DCIS following inadequate excision), 27.8 % (95 % CI, 8.4-47.1). RT + tamoxifen (TAM) in conservation surgery (CS) patients resulted in lower LR compared to one or no adjuvant treatments: LR rate for CS + RT + TAM, 9.7 %; CS + RT(no TAM), 14.1 %; CS + TAM(no RT), 24.7 %; CS(alone), 25.1 % (linear trend for treatment P < 0.0001). Compared to CS + RT + TAM, a significantly higher invasive LR was observed for CS(alone), odds ratio (OR) 2.61 (P < 0.0001); CS + TAM(no RT), OR 2.52 (P = 0.001); CS + RT(no TAM), OR 1.59 (P = 0.022). BCDR was similar for mastectomy, breast-conserving surgery with or without RT (1.3-2.0 %) and non-significantly higher for biopsy-only (2.7 %). Additionally, the 15-year follow-up was reported where all like-studies had >/= 15-year data sets; the biopsy-only patients had a meta-analysed total LR rate of 40.2 % and the invasive LR rate was 28.1 %. The biopsy-only patients had a >/= 15-year BCDR (that included women with metastatic disease) of 17.9 %; the >/= 15-year BCDR was 55.2 % for those with invasive LR. CONCLUSIONS: More local intervention was associated with greater local control for patients with DCIS at long-term follow-up. For patients undergoing breast-conservation, invasive LR was significantly lower when two rather than one adjuvant treatment modalities were given.

30

31

Bijker, N., P. Meijnen, J. L. Peterse, et al. 2006. "Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group." J Clin Oncol 24(21):3381-3387.

32

Silverstein, M. J. 2003. "The University of Southern California/Van nuys prognostic index for ductal carcinoma in situ of the breast." Am J Surg. 186:337-343.

Read abstract

33

Warnberg, F., H. Garmo, S. Emdin, et al. 2014. "Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS Trial." J Clin Oncol 32(32):3613-3618.

34

Coles, C. E., J. S. Haviland, A. M. Kirby, et al. 2023. "Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial." Lancet 401(10394):2124-2137.

Read abstract

Summary

Background

A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity.

Methods

IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1–3pN0–3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants.

Findings

Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm³ (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (–0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group).

Interpretation

In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits.

Funding

Cancer Research UK.

35

Solin, L. J., R. Gray, L. L. Hughes, et al. 2015. "Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study." J Clin Oncol 33(33):3938-3944.

36

Tadros, A. B., B. D. Smith, Y. Shen, et al. 2019. "Ductal Carcinoma In Situ and Margins <2 mm: Contemporary Outcomes With Breast Conservation." Ann Surg 269(1):150-157.

37

Van Zee, K. J., P. Subhedar, C. Olcese, et al. 2015. "Relationship Between Margin Width and Recurrence of Ductal Carcinoma In Situ: Analysis of 2996 Women Treated With Breast-conserving Surgery for 30 Years." Ann Surg 262(4):623-631.

38

National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology - Breast Cancer Version 2.2024 — March 11, 2024. Last accessed @ https://www.nccn.org/guidelines/category_1 on 15th of April 2024.

39

NCCN - Clinical Practice Guidelines in Oncology - Breast Cancer - Version 4.2018.

40

Wang, S. Y., H. Chu, T. Shamliyan, et al. 2012. "Network meta-analysis of margin threshold for women with ductal carcinoma in situ." J Natl Cancer Inst 104(7):507-516.

Read abstract

BACKGROUND: Negative margins are associated with reduced risk of ipsilateral breast tumor recurrence (IBTR) for women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS). However, there is no consensus about the best minimum margin width. METHODS: We searched the PubMed database for studies of DCIS published in English between January 1970 and July 2010 and examined the relationship between IBTR and margin status after BCS for DCIS. Women with DCIS were stratified into two groups, BCS with or without radiotherapy. We used frequentist and Bayesian approaches to estimate the odds ratios (OR) of IBTR for groups with negative margins and positive margins. We further examined specific margin thresholds using mixed treatment comparisons and meta-regression techniques. All statistical tests were two-sided. RESULTS: We identified 21 studies published in 24 articles. A total of 1066 IBTR events occurred in 7564 patients, including BCS alone (565 IBTR events in 3098 patients) and BCS with radiotherapy (501 IBTR events in 4466 patients). Compared with positive margins, negative margins were associated with reduced risk of IBTR in patients with radiotherapy (OR = 0.46, 95% credible interval [CrI] = 0.35 to 0.59), and in patients without radiotherapy (OR = 0.34, 95% CrI = 0.24 to 0.47). Compared with patients with positive margins, the risk of IBTR for patients with negative margins was smaller (negative margin >0 mm, OR = 0.45, 95% CrI = 0.38 to 0.53; >2 mm, OR = 0.38, 95% CrI = 0.28 to 0.51; >5 mm, OR = 0.55, 95% CrI = 0.15 to 1.30; and >10 mm, OR = 0.17, 95% CrI = 0.12 to 0.24). Compared with a negative margin greater than 2 mm, a negative margin of at least 10 mm was associated with a lower risk of IBTR (OR = 0.46, 95% CrI = 0.29 to 0.69). We found a probability of .96 that a negative margin threshold greater than 10 mm is the best option compared with other margin thresholds. CONCLUSIONS: Negative surgical margins should be obtained for DCIS patients after BCS regardless of radiotherapy. Within cosmetic constraint, surgeons should attempt to achieve negative margins as wide as possible in their first attempt. More studies are needed to understand whether margin thresholds greater than 10 mm are warranted.

41

Dixon, J.M & Cartlidge W.J. 2018. “Excision margins in breast conserving therapy.” Breast Cancer Manage. 6(3), 97-99.

42

Ekatah, G. E., A. K. Turnbull, L. M. Arthur, et al. 2017. "Margin width and local recurrence after breast conserving surgery for ductal carcinoma in situ." Eur J Surg Oncol 43(11):2029-2035.

43

McCormick, B., K. Winter, C. Hudis, et al. 2015. "RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation." J Clin Oncol 33(7):709-715

Read abstract

44

Hickey B.E., M.L. James, M. Lehman et al. "Hypofractionated radiation therapy for early breast cancer (Review)." Cochrane Database of Systematic Reviews 2016, Issue 7.

Read abstract

Background: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conserving surgery. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. This is an update of a Cochrane Review first published in 2008 and updated in 2009.ObjectivesTo assess the effect of altered radiation fraction size for women with early breast cancer who have had breast conserving surgery.

Search methods: We searched the Cochrane Breast Cancer Specialised Register (23 May 2015), CENTRAL (The Cochrane Library2015, Issue 4), MEDLINE (Jan 1996 to May 2015), EMBASE (Jan 1980 to May 2015), the WHO International Clinical Trials Registry Platform(ICTRP) search portal (June 2010 to May 2015) and ClinicalTrials.gov (16 April 2015), reference lists of articles and relevant conference proceedings. No language or publication constraints were applied.

Selection criteria: Randomised controlled trials of altered fraction size versus conventional fractionation for radiation therapy in women with early breast cancer who had undergone breast conserving surgery.

Data collection and analysis: Two authors performed data extraction independently, with disagreements resolved by discussion. We sought missing data from trial authors

Main results: We studied 8228 women in nine studies. Eight out of nine studies were at low or unclear risk of bias. Altered fraction size (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not have a clinically meaningful effect on: local recurrence-free survival (Hazard Ratio (HR) 0.94, 95% CI 0.77 to 1.15, 7095 women, four studies, high-quality evidence), cosmetic outcome (Risk ratio (RR) 0.90, 95% CI 0.81 to 1.01, 2103 women, four studies, high-quality evidence)or overall survival (HR 0.91, 95% CI 0.80 to 1.03, 5685 women, three studies, high-quality evidence). Acute radiation skin toxicity(RR 0.32, 95% CI 0.22 to 0.45, 357 women, two studies) was reduced with altered fraction size. Late radiation subcutaneous toxicity did not differ with altered fraction size (RR 0.93, 95% CI 0.83 to 1.05, 5130 women, four studies, high-quality evidence). Breast cancer-specific survival (HR 0.91, 95% CI 0.78 to 1.06, 5685 women, three studies, high quality evidence) and relapse-free survival(HR 0.93, 95% CI 0.82 to 1.05, 5685 women, three studies, moderate-quality evidence) did not differ with altered fraction size. We found no data for mastectomy rate. Altered fraction size was associated with less patient-reported (P < 0.001) and physician-reported(P = 0.009) fatigue at six months (287 women, one study). We found no difference in the issue of altered fractionation for patient-reported outcomes of: physical well-being (P = 0.46), functional well-being (P = 0.38), emotional well-being (P = 0.58), social well-being (P = 0.32), breast cancer concerns (P = 0.94; 287 women, one study). We found no data with respect to costs.

Authors’ conclusions: We found that using altered fraction size regimens (greater than 2 Gy per fraction) does not have a clinically meaningful effect on local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance, late toxicity or patient-reported quality-of-life measures for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins.

45

Hooning, M. J., A. Botma, B. M. Aleman, et al. 2007. "Long-term risk of cardiovascular disease in 10-year survivors of breast cancer." J Natl Cancer Inst 99(5):365-375.

Read abstract

BACKGROUND: Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. METHODS: We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval [CI] = 1.22 to 1.38; corresponding to 62.9 excess cases per 10,000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P = .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039). CONCLUSIONS: Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.

46

Tjessem, K. H., S. Johansen, E. Malinen, et al. 2013. "Long-term cardiac mortality after hypofractionated radiation therapy in breast cancer." Int J Radiat Oncol Biol Phys 87(2):337-343.

47

Appelt, A. L., I. R. Vogelius and S. M. Bentzen. 2013. "Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart." Clin Oncol (R Coll Radiol) 25(3):147-152.

Read abstract

[%id%]

[%title%] [%url%]

Literature search

Flinders Filters has partnered with eviQ to build reliable, robust search filters to retrieve core high level evidence on topics of significance to eviQ. The project goal is the provision of a sustainable model for evidence retrieval to ensure ongoing currency of content.

These search filters have been developed to retrieve the most up to date evidence from PubMed, in real time, using specifically designed search filters built to meet our needs.

Searches can be used when a protocol is scheduled for review or at any time you choose. Please click on the Specific, Balanced and Sensitive tabs below to access the Pubmed searches.

Specific opens in a new tab or window	Balanced opens in a new tab or window	Sensitive opens in a new tab or window
restricted to retrieving randomised control trials and systematic reviews.	is the middle ground between sensitive and specific searches.	retrieves all clinically relevant evidence - generally a broader search on a given topic.

Access Flinders Filters opens in a new tab or window, a division of the Flinders Digital Health Research Centre at Flinders University to read more about research solutions to searching problems.

Troubleshooting

Occasionally the searches may not display correctly or take too long to load (and will eventually timeout). This may be caused by Internet Explorer being unable to handle long URL's. You can rectify this by using Firefox, Safari or Google chrome. It is always a good idea to clear the cache regularly to ensure you are getting the most up to date search.

Feedback

If you identify any new articles that you believe should be included in the content, please use the feedback button below to inform us of the name of the article(s).

History

Version 7

Date	Summary of changes
23/07/2024	Reviewed at the Breast reference committee meeting held on 28th of March 2024. Changes agreed to: Evidence: Evidence table: Phase 3 trials; Updated TROG trial 07.01 from abstract to published 2022 paper. Added 'Yes' to corresponding "Is the radiation dose and fractionation consistent with the protocol?" column. Included IMPORT-HIGH trial. Observational studies: Removed the following articles and associated notes: Omlin et al. 2006 Nilsson and Valachis 2015 Moran et al.2017. Guidelines: Updated NCCN (National Comprehensive Cancer Network) to most recent version: Version 2.2024. Toxicity: Removed the 2 Gy toxicity tables and associated written content. Changed toxicity heading from 'Toxicity hypofractionation' to “Moderate hypofractionation”. Statement regarding paucity of evidence from TROG 07.01 trial updated as results are now published, no longer pending. Included “Table 3: Adverse events (grade 2 or higher) related to radiation therapy among the safety population” from BIG 3–07/TROG 07.01 under the “Toxicity moderate hypofractionation” section. (Chua et al. 2022 BIG 3-07/TROG 07.01). Updated the comments under subheading ‘Boost doses’, as TROG 07.01 DCIS data now published. Indications and patient population: Indication notes: For statement regarding high-level evidence that radiation therapy offers an advantage of local control in all groups, include a reference that will direct readers to the efficacy protocol sub-section 'Low-risk subgroups'. Changed “nomogram” to risk tool to make a more universal term and removed example tools and associated references. Clinical Information Inclusion to cease smoking content: Patients should be encouraged to cease smoking as continuation 'can cause delayed wound healing' and increases the risk of toxicity of treatment (including fibrosis, cardiac, skin, and risk of second malignancy). Simulation: Simulation table: CT acquisition notes: Generic comment included across all breast protocols - ‘Consider the use of breath hold techniques to reduce heart, liver and/or lung dose’. Dose prescription: Prescription tables: Included VMAT as an option for treatment. Moved Hypofractionation table to first table in protocol order. Included an SIB option in hypofractionated table Whole breast- 40/15# (2.67 Gy/#). Tumour bed - 48Gy/15# (3.2 Gy/ #) Removed overarching statement : “The reference committee considers hypofractionation a reasonable technique prior to the results of ongoing studies.” Deleted 2 Gy fractionated schedule tables (2 phase and SIB) – based on evidence from TROG 07.01- 2023. Modified point under SIB table to read ** The reference committee considers SIB a reasonable technique for delivery of a boost. Refer to the adverse events table of the IMPORT HIGH . Prescription notes: Included “In select patients diagnosed with DCIS, partial breast irradiation can be considered (insert link to eviQ protocol ID 3658 V.2). Included a point noting that 2 Gy per fraction tables have been removed from DCIS protocol as hypofractionation is used in clinics, evidence is equivalent if not better for hypofractionated schedules. Target volumes: No content changes to tables. 'Whole breast traditional clinical borders’ table converted to additional clinical information - ID 4450, pop out nodal window; no change to content. Organs at risk: OAR table: Removed 2 Gy fractionation, first column in line with the dose prescription tables Contralateral breast constraint corrected to read: Ideal: V3 Gy <10% (reference NSABP B-51 trial) Acceptable: V5 Gy <10% (reference NSABP B-51 trial). Ipsilateral lung constraint corrected to read: V4 Gy <50% (reference RTOG 1005). OAR notes: Minor grammatical changes to OAR notes regarding techniques. Target verification: Removed the following overarching statement from above target verification table “Online image review is considered ideal and is preferable to offline review.” Target verification notes: Removed this statement from target verification notes - “Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs.” Patient information sheet: Side effects: Rephrased patient side effects to include user friendly terminology for the following: Short term - Pericarditis Long term - Telangiectasia. Version changed to V.7. Review in 4 years.

Date

Summary of changes

23/07/2024

Reviewed at the Breast reference committee meeting held on 28th of March 2024.

Changes agreed to:

Evidence:
- Evidence table:
  - Phase 3 trials;
    - Updated TROG trial 07.01 from abstract to published 2022 paper. Added 'Yes' to corresponding "Is the radiation dose and fractionation consistent with the protocol?" column.
    - Included IMPORT-HIGH trial.
  - Observational studies:
    - Removed the following articles and associated notes:
      - Omlin et al. 2006
      - Nilsson and Valachis 2015
      - Moran et al.2017.
  - Guidelines:
    - Updated NCCN (National Comprehensive Cancer Network) to most recent version: Version 2.2024.
- Toxicity:
  - Removed the 2 Gy toxicity tables and associated written content.
  - Changed toxicity heading from 'Toxicity hypofractionation' to “Moderate hypofractionation”.
  - Statement regarding paucity of evidence from TROG 07.01 trial updated as results are now published, no longer pending.
  - Included “Table 3: Adverse events (grade 2 or higher) related to radiation therapy among the safety population” from BIG 3–07/TROG 07.01 under the “Toxicity moderate hypofractionation” section. (Chua et al. 2022 BIG 3-07/TROG 07.01).
  - Updated the comments under subheading ‘Boost doses’, as TROG 07.01 DCIS data now published.
Indications and patient population:
- Indication notes:
  - For statement regarding high-level evidence that radiation therapy offers an advantage of local control in all groups, include a reference that will direct readers to the efficacy protocol sub-section 'Low-risk subgroups'.
  - Changed “nomogram” to risk tool to make a more universal term and removed example tools and associated references.
Clinical Information
- Inclusion to cease smoking content: Patients should be encouraged to cease smoking as continuation 'can cause delayed wound healing' and increases the risk of toxicity of treatment (including fibrosis, cardiac, skin, and risk of second malignancy).
Simulation:
- Simulation table:
  - CT acquisition notes: Generic comment included across all breast protocols - ‘Consider the use of breath hold techniques to reduce heart, liver and/or lung dose’.
Dose prescription:
- Prescription tables:
  - Included VMAT as an option for treatment.
  - Moved Hypofractionation table to first table in protocol order.
  - Included an SIB option in hypofractionated table Whole breast- 40/15# (2.67 Gy/#). Tumour bed - 48Gy/15# (3.2 Gy/ #)
  - Removed overarching statement : “The reference committee considers hypofractionation a reasonable technique prior to the results of ongoing studies.”
  - Deleted 2 Gy fractionated schedule tables (2 phase and SIB) – based on evidence from TROG 07.01- 2023.
  - Modified point under SIB table to read ** The reference committee considers SIB a reasonable technique for delivery of a boost. Refer to the adverse events table of the IMPORT HIGH .
- Prescription notes:
  - Included “In select patients diagnosed with DCIS, partial breast irradiation can be considered (insert link to eviQ protocol ID 3658 V.2).
  - Included a point noting that 2 Gy per fraction tables have been removed from DCIS protocol as hypofractionation is used in clinics, evidence is equivalent if not better for hypofractionated schedules.
Target volumes:
- No content changes to tables.
- 'Whole breast traditional clinical borders’ table converted to additional clinical information - ID 4450, pop out nodal window; no change to content.
Organs at risk:
- OAR table:
  - Removed 2 Gy fractionation, first column in line with the dose prescription tables
  - Contralateral breast constraint corrected to read:
    - Ideal: V3 Gy <10% (reference NSABP B-51 trial)
    - Acceptable: V5 Gy <10% (reference NSABP B-51 trial).
  - Ipsilateral lung constraint corrected to read:
    - V4 Gy <50% (reference RTOG 1005).
- OAR notes:
  - Minor grammatical changes to OAR notes regarding techniques.
Target verification:
- Removed the following overarching statement from above target verification table “Online image review is considered ideal and is preferable to offline review.”
- Target verification notes:
  - Removed this statement from target verification notes - “Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs.”
Patient information sheet:
- Side effects:
  - Rephrased patient side effects to include user friendly terminology for the following:
    - Short term - Pericarditis
    - Long term - Telangiectasia.

Version changed to V.7.

Review in 4 years.

Version 6

Date	Summary of changes
22/12/2022	Prescription for single phase (SIB) tumour bed dose per fraction updated from 2 Gy to 2.28 Gy. Version increased to V.6. No change to review period.

Version 5

Date	Summary of changes
05/04/2022	Protocol reviewed and updated at breast reference committee meeting 11/11/2021. Summary of changes: Cautions: ipsilateral portacath removed. Clinical information: added information on concurrent trastuzumab emtansine and capecitabine timing, removed of chemotherapy timing. Simulation: removed PET from other imaging, addition of information on breath hold techniques. Dose prescription: "conventional fractionation" titles changed to "2 Gy fractionation", added hypofractionated regimen and notes on use of boost. OAR: added note to refer to trial protocols for further planning details. Target verification: added option for "Daily" imaging frequency. Evidence table: updated and included results of EORTC 22922/10925. Efficacy: Added TROG 07.01 trial abstract results, longer follow-up results for low-risk subgroups, and chemoprevention, and removed sub-groups section. Version change to V.4. Review in 2 years.

Date

Summary of changes

05/04/2022

Protocol reviewed and updated at breast reference committee meeting 11/11/2021.
Summary of changes:
- Cautions: ipsilateral portacath removed.
- Clinical information: added information on concurrent trastuzumab emtansine and capecitabine timing, removed of chemotherapy timing.
- Simulation: removed PET from other imaging, addition of information on breath hold techniques.
- Dose prescription: "conventional fractionation" titles changed to "2 Gy fractionation", added hypofractionated regimen and notes on use of boost.
- OAR: added note to refer to trial protocols for further planning details.
- Target verification: added option for "Daily" imaging frequency.
- Evidence table: updated and included results of EORTC 22922/10925.
- Efficacy: Added TROG 07.01 trial abstract results, longer follow-up results for low-risk subgroups, and chemoprevention, and removed sub-groups section.
Version change to V.4. Review in 2 years.

Version 4

Date	Summary of changes
01/07/2014	Approved and published to eviQ. Review Group - 2.
01/02/2015	Removed Follow Up section.
01/03/2016	Protocol reviewed by RCM and updated. Moved to new template.
31/05/2017	Transferred to new eviQ website.
02/09/2019	Protocol reviewed and updated at breast RCM 13/06/2019. Version change to V.4. Review in 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

Send feedback for this page

First approved:: 3 July 2014
Last reviewed:: 28 March 2024
Review due:: 30 June 2028

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1921

08 Jun 2025