Adjuvant radiotherapy for breast cancer

Background and history

Radiotherapy involves the delivery of ionising radiation to kill malignant cells. Radiotherapy is frequently used in the management of early breast cancer. The radiotherapeutic management of early breast cancer accounts for 20–40% of available resources in most UK radiotherapy departments.

Postmastectomy radiotherapy (PMRT) was one of the first medical interventions to be tested in prospective trials. These began around 50 years ago and have left a rich legacy of randomised evidence which has established the role of radiotherapy in patient management and provided insights into the natural history of breast cancer. Long-term follow up of these trials demonstrates that locoregional therapy can improve breast cancer mortality and overall survival. Consequently, early breast cancer cannot be considered as a disease whose outcome is solely determined by the presence or absence of micrometastatic disease at the time of diagnosis. Local as well as systemic therapy has the ability to improve survival.

Adjuvant radiotherapy whether given after breast-conserving surgery (BCS) or mastectomy substantially reduces local recurrence (LR) rates and contributes to improved outcomes in early breast cancer that we have seen over the last 20 years, but, like systemic adjuvant treatment, it is ultimately a treatment given based on the risk, rather than the existence, of recurrence. This of course means that thousands of patients with early breast cancer are irradiated unnecessarily as they would not have suffered recurrence without radiotherapy or they still develop recurrence despite its use.

The search for reliable predictive factors for recurrence and markers of tumour sensitivity will help to identify those who benefit most from this treatment.

Planning and treatment delivery

Modern radiotherapy for early breast cancer differs from the practice of 20–30 years ago. Radiotherapy planning allows precise definition and contouring of target volumes to be irradiated and organs that should be spared. This allows the delivery of a near homogenous dose of radiation, and modern linear accelerators (Linacs) ( Fig. 16.1 ) have the facility for multileaf collimation (MLC) to shape or block the beam and real-time on-treatment imaging to allow precise verification and treatment delivery within very tight tolerances, usually millimetres.

Inevitably the practice of radiotherapy involves compromise. Target volumes cannot be treated without acceptance that some organs will receive a radiation dose that results in common short-term toxicities and is associated with a smaller risk of more serious longer-term problems.

As is the case with systemic adjuvant therapies, improvements in treatment delivery create the well-known dilemma of ‘contemporary generalizability’ – namely whether (and by how much) the results of trials conducted decades previously should influence decision-making today. Since these trials, there have been many other improvements in imaging, diagnosis and management. A greater number of patients now have early-stage disease as a result of earlier presentation and breast screening.

Practicalities and treatment pathways

It is important to be aware of the likely need for postoperative radiotherapy when planning any surgical treatment and to discuss the pros and cons of radiotherapy in a preoperative multidisciplinary team (MDT) meeting with the clinical oncology team. The type and extent of proposed surgery will need to be reconsidered preoperatively for those patients unable to have adjuvant radiotherapy. It is particularly important to involve the clinical oncology team if immediate breast reconstruction for invasive breast cancer is being planned.

Factors that influence whether radiotherapy treatment is appropriate and practical include:

• Inability to adopt radiotherapy position including poor ipsilateral arm or shoulder movements.

• The presence of a cardiac pacemaker or ‘cardiac assist’ device, particularly if completely dependent.

• A very high body mass index (BMI), as weight may exceed maximum radiotherapy couch limits.

• Significant comorbidities.

• Previous radiotherapy.

• Severe skin or connective tissue disorders.

In most circumstances following an MDT decision to offer radiotherapy, consultation with the patient and obtaining informed consent are the next steps. A planning computed tomography (CT) scan ( Fig. 16.2 ) is then organised at which time positional parameters are recorded and permanent reference marks (tattoos) are usually placed to ensure consistent positioning and alignment throughout radiotherapy planning and treatment. New technologies using surface-guided radiotherapy (SGRT) are making it possible to deliver accurate radiotherapy without the need for tattoos, and for some patients, this is more acceptable.

Following planning, any changes to patient shape can be problematic. This can be an issue if there is a persistent large postoperative seroma or wound healing problems. Similarly, inflation of any expander implant needs to be completed before radiotherapy is planned as otherwise the dose distribution may become sub-optimal.

The clinical oncologist or appropriately trained therapy radiographer then delineates the appropriate target volume on the relevant dedicated CT data set:

Whole breast (+/- tumour ‘bed’ boost) or postmastectomy chest wall – regional nodal areas (axilla, supraclavicular or internal mammary regions).

Placement of titanium clips at the time of surgery at the limits of the tumour bed and at the apex of axillary surgery can be helpful to delineate target volume particularly if a tumour bed radiotherapy ‘boost’ is planned ( Fig. 16.3 ). Oncoplastic breast surgery with tissue re-arrangement can complicate target volume definition in these circumstances and clip placement, imaging and operation notes are particularly helpful.

Following delineation of the target volume/s and any organs at risk (e.g. the heart and lungs) the treatment planning/physics team determines the optimum beam shapes, arrangements, energies and units of dose for each beam. The goal is to treat the target volume homogenously and limit, as far as possible, radiation to normal tissues. Compromises are inevitable. A very common arrangement to treat the breast or postmastectomy chest wall is to use tangential beams that ‘glance across’ these target volumes ( Fig. 16.3 ).

It may take 1–2 weeks for treatment to start to allow time for careful treatment planning and for stringent quality assurance that accompanies this process. When treatment begins, the patient is set up in an identical position to that which was assumed for CT planning and each session takes usually 10–15 minutes, although only a fraction of this time is involved in the actual delivery of radiation. The total radiation dose prescribed for adjuvant therapy in breast cancer has been defined in clinical trials and is based on the radiosensitivity of breast cancer cells. The total dose is delivered in small fractions over a certain time period and in most cases daily fractions are administered on weekdays.

Irradiation of the skin, underlying ribs and some lung tissue is unavoidable but with modern treatments it can be limited and long-term problems are rare. One of the main concerns is cardiac irradiation as there is irrefutable evidence that this will increase rate of ischaemic heart disease starting a few years after exposure and continues for at least 20 years. Heart-sparing techniques are widely available and avoiding or minimising heart irradiation is now possible in most cases. One of the most effective and simple techniques is deep inspiration breath hold (DIBH). In this technique, patients hold a deep breath for 20–30 seconds while treatment is planned and delivered, and this will inflate the lungs moving the heart backwards, away from the chest wall and radiation beam ( Fig. 16.4 ).

Other heart-sparing methods include angling the beam or using MLCs to block the heart without compromising breast tissue. For most women being considered for radiotherapy today, the absolute 30-year risk of having a major coronary event as a result of the radiotherapy is <2% so in almost all cases the benefits of the radiotherapy far outweigh the risks.

Radiotherapy after breast conserving surgery for invasive cancer

The use of whole breast irradiation (WBI) after BCS for invasive cancer has been the default intervention for decades since randomised trials that compared mastectomy with BCS and breast irradiation (BCS + RT) were completed and published. These randomised trials are now a routine and accepted part of the history of developments in breast surgical oncology but in their time, they were controversial and revolutionary. They established beyond question the long-term safety of breast conservation. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) individual patient-level meta-analysis of these studies has confirmed that overall and breast cancer-related mortalities were not affected by the type of local treatment employed, but that there was a moderate increase in LR risk in the BCS + RT group. The higher risk of LR in these early trials has not translated into a detriment in breast cancer mortality, possibly because of the opportunity to treat within-breast recurrence after BCS + RT by further surgery (usually mastectomy), which is often curative. Data from a large series of recent non-randomised studies suggest that now, there may no longer be an excess of LR following breast conservation treatment compared with mastectomy. A full discussion of these recent studies can be found in the breast conservation chapter (see Chapter 7).

Trials of BCS + RT vs BCS without RT have shown that radiotherapy is associated with a substantial reduction in within-breast recurrence and a modest reduction in breast cancer deaths. The effect of radiotherapy on first recurrence is seen within 5 years of radiotherapy; the effect on breast cancer deaths is not seen until 10–15 years ( Fig. 16.5 ).

One of the great strengths of individual patient-level meta-analysis is the ability to explore treatment effects in subgroups, given the large number of patients involved. The EBCTCG meta-analysis of BCS vs BCS + RT revealed that radiotherapy produced similar proportional reductions in recurrence risk, irrespective of tumour size, grade, oestrogen receptor (ER) status, degree of nodal involvement or patient age. The absolute benefits of radiotherapy were however different for patients with different tumour characteristics. The greater the risk of breast cancer recurrence, the greater is the absolute benefit from radiotherapy.

Some patients are at low risk of recurrence (e.g. patients ≥65 years old), with small, low-grade, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative and node-negative tumours. Some other patients may be at higher risk of radiation-induced morbidity. In some of these women, the benefit of radiotherapy in reducing LR is small, with no evidence that radiotherapy improves metastatic free and overall survival and so it may be reasonable to consider omission of radiotherapy in such patients. ^,

Irrespective of the effect of radiotherapy following BCS, within-breast recurrence rates have fallen substantially over the last 10–20 years, and for many women irradiated in the 2000s, 5-year risks of within-breast recurrence are only around 1–2%. These low recurrence rates may be due to the rising incidence of lower-risk (often screen-detected) cancer, improved imaging and surgery, greater pathological rigour, the routine achievement of adequate margins and an increasing use of systemic adjuvant therapy that reduces local (as well as systemic) recurrence risk.

Despite the success of breast conservation in early breast cancer, there has been an increase in the use of both therapeutic and prophylactic mastectomy particularly in the USA. The reasons are multiple but include increased genetic testing, the use of magnetic resonance imaging (MRI), greater access to reconstructive surgery and possibly the existence of misconceptions about contralateral breast cancer risk. In many ways this seems a retrograde step given the proven success of oncologically safe organ preservation afforded by modern locoregional treatment.

Radiotherapy after breast conserving surgery for ductal carcinoma in situ (DCIS)

DCIS is an increasingly common disease that is largely identified by mammographic screening. Around 25% of breast ‘cancer’; detected mammographically represent DCIS.

Many aspects of the management of DCIS are controversial due to limitations in knowledge of its natural history. The effect of whole breast radiotherapy following BCS was tested in five individual randomised trials, four of which were combined in a meta-analysis conducted by the EBCTCG. Radiotherapy approximately halved the risk of within-breast recurrence of in situ or invasive disease, but it had no effect on breast cancer mortality ( Fig. 16.6 ).

The use of radiotherapy for DCIS is variable. An analysis of patterns of care from the UK Sloane Project has confirmed a wide variability in radiotherapy practice. National Institute for Health and Care Excellence (NICE) guidelines advise consideration of adjuvant radiotherapy after BCS with clear margins after discussing risk and benefits in individual cases.

There are ongoing efforts to develop an improved means of selecting radiotherapy by the identification of risk scores developed from routine demographic and pathological data. A number of nomograms to predict the benefit of radiotherapy can be used to aid decision-making, and the (modified) van Nuys Index is one of the most widely used. This index uses tumour size, margin proximity, pathological classification (grade and the presence of comedo necrosis) and age to predict the benefit from radiotherapy. Another useful prediction tool from the Memorial Sloan Kettering Cancer Center (MSKCC) takes into consideration family history and the number of excisions to achieve clear margins. It estimates the probability of recurrence at 5 and 10 years and provides an estimate of the benefit of adjuvant radiotherapy and/or endocrine therapy. Molecular pathological profiling (e.g. Oncotype Dx DCIS or PreLudeDx DCIS test) has been studied and has a role in selecting patients for adjuvant radiotherapy although in practice few use these tests.