Breast invasive cancer adjuvant whole breast EBRT

Cautions

• Collagen vascular disease e.g. active scleroderma or SLE.
• Pacemakers and implantable cardioverter defibrillators (ICDs).
  • Link to Management of pacemakers and implantable cardioverter defibrillators (ICDs) in patients receiving radiation therapy.
• Ipsilateral portacaths.
• Radiosensitising genetic conditions e.g. AT, p53.

• Ipsilateral breast implants/augmentation/expanders.

Exclusions

• Pregnancy.
• Prior high dose radiation therapy to ipsilateral breast.

• Genetic counselling is recommended if the patient is considered to be at high risk of hereditary breast cancer.^r See eviQ cancer genetics referral guidelines for breast cancer.
• Patients should be encouraged to cease smoking as continuation increases the toxicity of treatment (including fibrosis, cardiac, skin, and risk of second malignancy).^rr 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.

• If regional nodal irradiation (supraclavicular fossa, internal mammary chain, axilla) is indicated; refer to Breast invasive cancer adjuvant nodal irradiation EBRT protocol.

• Concurrent cytotoxic chemotherapy is not standard.
• Anti HER2 therapy may be given concurrently with radiation therapy.^r 
• The use of concurrent endocrine therapy with either tamoxifen or aromatase inhibitors is considered safe. The optimal timing of the commencement of endocrine therapy (anastrozole) in relation to radiation therapy is currently under investigation in the STARS Trial.^r

• CT voluming utilising a peer reviewed published contouring atlas is recommended although the use of traditional field borders to define radiation therapy fields is acceptable.
• With modern treatment approaches it is appropriate to define target volumes.
• 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.”^r

• Suggested contouring atlases and guidelines:
  • ESTRO guidelines 2015^r and 2016 update^r
  • RTOG Atlas^r
• A comparison and systematic review of the consensus guidelines has been published by Gee et. al. 2019.^r

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

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

Target volume notes

• If nodal irradiation is indicated, see Breast invasive cancer adjuvant nodal irradiation­ EBRT protocol for nodal target volumes.

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

OAR notes

• If using VMAT or non-standard fields consider dose to additional organs such as the liver, oesophagus, thyroid, etc.
• The OAR goals listed are the consensus of the RCM as there is a lack of high level evidence noting that there are several references where OAR goals may be obtained.

• If nodal irradiation is indicated see Breast invasive cancer adjuvant nodal irradiation­ EBRT protocol for organ at risk information.

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

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.

Efficacy for hypofractionation

The evidence supporting hypofractionation in this protocol is provided by a Cochrane review, three large phase III multi-centre international randomised trials with 10-year follow-up results, and the Cancer Australia guidelines systematic review update.^r

Cochrane review

The Cochrane review by Hickey et al. of 9 randomised trials (n = 8228) showed no significant differences in survival (local recurrence-free survival, breast cancer-specific survival or overall survival) between hypofractionated and conventionally fractionated radiation therapy.^r Three of the trials included in the review are discussed below.

Canadian trial

A Canadian study by Whelan et al. randomised 1234 women with completely excised invasive breast cancer (pT1-2, N0, M0) to 50 Gy/25fx or 42.5 Gy/16fx treating 5 fractions per week.^r The 10-year cumulative incidence of local recurrence was 6.7% among women in the conventional group versus 6.2% among women in the hypofractionated group (absolute difference 0.5 percentage points, 95% CI: -2.5 to 3.5). The 10-year probability of survival was similar (84.4% conventional vs. 84.6% hypofractionated group). There were no significant differences in the rate of good or excellent cosmetic outcomes.

UK START-A and START-B trials

The 10-year update^r on UK START-A^r and START-B^r trials confirmed the efficacy and safety of hypofractionated radiation therapy in women with completely excised invasive breast cancer (pT1-3a, N0-1, M0). START-A randomised 2236 women to receive 50 Gy/25fx compared with 41.6 Gy/13fx or 39 Gy/13fx all over 5 weeks. START-B randomised 2215 women to 50 Gy/25fx or 40 Gy/15fx with both regimens involving 5 fractions per week.

In both trials, there was no significant difference in 10-year locoregional control between the conventional and hypofractionated regimens. Both trials also showed a significant reduction in late normal tissue effects in the hypofractionated groups, with the START-A trial showing less breast induration, telangiectasia and oedema in the 39 Gy group, and START-B showing less breast shrinkage, telangiectasia and oedema in the 40 Gy group than the 50 Gy group.

For 10-year all-cause mortality, in the START-A trial there was no significant difference between 41.6 Gy and 50 Gy (18.4% vs. 19.8%, p = 0.74) or the 39 Gy and 50 Gy groups (20.3% vs. 19.8%, p = 0.69) In the START-B trial, the hypofractionated group had a significant reduction in the rate of distant metastases, which contributed to a small reduction in the rate of all-cause mortality in this group compared with conventional fractionation (15.9% vs. 19.2%, p = 0.042). However, this reduction cannot be readily explained in terms of radiation therapy-related factors. There were significantly fewer 10-year distant relapses in the 40 Gy group compared with the 50 Gy group (12.3% vs 16%, p = 0.014), which contributed to the significantly higher rate of OS in the 40 Gy compared with the 50 Gy group.

Sub-groups

Planned sub-group analysis in the Canadian trial showed that treatment effect was similar regardless of age, tumour size, oestrogen-receptor status, or use of cytotoxic chemotherapy. The Canadian trial did not utilise a tumour boost, as it was initiated at a time prior to publication of studies supporting boost irradiation.^r The Canadian trial excluded patients with node positive disease and large breast (separation >25 cm).

Post-hoc subgroup analyses of the combined hypofractionated regimens versus conventional fractionation in the START-A and START-B trials showed that the treatment effect was not significantly different irrespective of age, breast size, tumour grade, axillary node status, cytotoxic chemotherapy or tumour bed boost. However, only a small proportion of patients in the START-A and START-B trials received regional nodal irradiation, or contemporary adjuvant chemotherapy.

A number of studies did not show any difference in rates of local relapse for grade 3 breast cancers treated with hypofractionated radiation therapy compared with conventionally fractionationated radiation therapy.^rrr Bane et al. found molecular subtype predicted for local recurrence in women enrolled in the hypofractionated whole breast irradiation trial after a median follow up of 12 years.^r However, tumour grade, molecular subtype and hypoxia did not predict response to hypofractionationated radiation therapy. This suggests patients with node-negative breast tumours of all grades and molecular subtypes may be safely treated with hypofractionated regimens. This is supported by the recent Cancer Australia guidelines.^r

Efficacy for conventional fractionation

The evidence supporting conventional fractionation in this protocol is provided by a meta-analysis of individual patient data from 17 phase III randomised trials involving 10801 patients.^r Between 1976 and 1999, trials randomised patients with stage I and II breast cancer to receive surgery alone (either lumpectomy or quadrantectomy) vs. surgery plus radiation therapy (dose/fractionation schedules ranged between 40-50 Gy in 2-2.5 Gy/fractions). The end points were locoregional recurrence and breast cancer death. After a median follow up of 9.5 years per woman, the addition of radiation therapy reduced the 10-year risk of locoregional or distant first recurrence from 35.0% to 19.3% (absolute reduction 15.7%, 95% CI 13.7–17.7, p<0.00001) and the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 95% CI 1.6–6.0, p = 0.00005).

Breast conserving surgery (BCS) used in conjunction with radiation therapy produces equivalent survival results when compared to mastectomy alone.^r Although the absolute recurrence reduction varies according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery,^r there has not been a low risk group identified who does not benefit from radiation therapy. The absolute benefit may be small enough in some patients to justify omission of radiation therapy based on patient/tumour factors.^rrr Results were significant for both node-positive and node-negative patients.^r The delivery of radiation therapy post BCS should be considered standard care in all women for the purposes of decreasing local recurrence and improving survival.

Figure 1: 10-year risk of any first recurrence and 15 year risk of breast cancer death and death from any cause

© Lancet 2011^r

Role of boost

The EORTC 22881-10882 trial found a tumour bed boost of 10-16 Gy significantly reduces the risk of local recurrence.^r In this trial, 5318 patients were randomised to receive BCS + whole breast radiation therapy (50 Gy) + 16 Gy tumour bed boost (n = 2661) or BCS + whole breast radiation therapy only (n = 2657). The addition of a boost reduced local recurrence from 7.3% to 4.3% at 5 years and 10.2% to 6.2% at 10 years (p<0.0001). At 20 years, the cumulative incidence of ipsilateral breast tumour recurrence was 16.4% in the no boost group vs 12% in the boost group. All age groups had a statistically significant relative risk reduction with the addition of a boost; with the largest risk reduction seen in those ≤ 40 years of age (23.9% to 13.5% at 10 years). Absolute benefit decreases with age. Survival was equivalent. These results were confirmed in the 20-year publication.^r

Timing of radiation therapy

Conclusions from individual studies are varied, however; some evidence suggests delays to the commencement of radiation therapy post BCS may be associated with increased risk of local recurrence.^r

Toxicity (hypofractionation)

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

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

Ischaemic 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.^r The risk of cardiovascular disease in breast radiation therapy patients increases with longer follow-up beyond 10 years.^rr In one of these two retrospective reviews, patients were treated with 4.3 Gy per fraction.^r

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

Toxicity (conventional fractionation)

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

Boost doses

• Boost doses >10 Gy resulted in an increase in adverse treatment effects such as fibrosis and telangiectasia.^r
• The EORTC breast boost trial investigating a 16 Gy boost in addition to 50 Gy in 2 Gy fractions to the whole breast, showed the cumulative incidence of severe fibrosis at 20 years was 5.2% (99% CI 3.9–6.4) in the boost group versus 1.8% (99% CI 1.1–2.5) in the no boost group (p<0.0001).^r