Breast Cancer Pathway

Around one-third of breast cancers are detected through breast-screening initiatives in the United Kingdom. ^{Reference Sibbering and Courtney1} According to an audit carried out by the NHS breast-screening programme, it was responsible for detecting over 21,000 breast cancers per year, 2013–14. ⁵ That said, the major detection method remains that of referral by the General Practitioner (GP) where patients attend for consultation and physically describe the symptoms that they are experiencing. Best practice diagnostic guidelines for patients presenting with breast cancer symptoms were published in 2010. ^{Reference Willett, Michell and Lee6} Table 1 outlines the guidelines for GPs when considering referral options for patients presenting with suspected breast cancer symptoms. ^{Reference Sibbering and Courtney1}

Table 1. Best practice diagnostic guidelines 2010: referral of patient with breast cancer symptoms (Sibbering et al. p. 1 ^{Reference Sibbering and Courtney1} )

Once referred, ‘triple assessment’ in the form of clinical, radiological and pathological assessments is carried out. Clinical involved meeting with the patient and obtaining a full medical history as well as physically examining the breast. This is generally carried out by a surgeon or a breast cancer nurse specialist. Radiological assessment is carried out using diagnostic imaging tools such as mammography and ultrasound which can lead to a pathological assessment for those patients that are found to have an abnormality present. ^{Reference Sibbering and Courtney1} A fine needle aspiration (FNA) or punch biopsy is taken which provides primary information about the tumour, including pathological staging such as tumour type, grade and invasive status as well as measuring oestrogen receptor (ER) status, progesterone receptor (PgR) status and human epidermal growth factor (HER2) status. ^{Reference Sibbering and Courtney1,Reference Newman7} All the biopsy information plays a vital role in determining the treatment strategy of choice for the individual patient.

Treatment strategies are decided using a multi-disciplinary team (MDT) approach, where all aspects of the disease and the patient’s status (including social and physiological status) are taken into account by a wide range of professionals. Factors considered at this point include the extent and location of the tumour, whether there is lymph node involvement, the biology of the tumour including biomarkers and gene expression, the age and general health of the patient as well as the personal preferences of the patient. ^{Reference Senkus, Kyriakides and Penault-Llorca3} Depending on the results and data obtained, multimodal treatment options in the form of surgery, systemic therapy, hormonal therapies and radiotherapy are used in a variety of combinations and strengths to treat the disease. This mix of both local and systemic therapies is used to maximise the therapeutic benefit and minimise the risk for each individual patient. ^{Reference Vaidya and Joseph8}

Surgery

The term ‘local treatment’ in breast cancer refers mainly to surgery and radiotherapy, where the main aim of each is to (a) remove the cancer; (b) stop the cancer spreading and (c) reduce the likelihood of the cancer recurring locally within the breast, chest wall or axillary nodes. ^{Reference Vaidya and Joseph8} Surgery is generally used as the primary treatment for breast cancer as it is the main starting point in achieving the goal of long-term disease-free survival. ^{Reference Vaidya and Joseph8} Instances where this would not apply would be if local control of the disease was thought to be highly unlikely, for example, in patients presenting with distant metastases or a diagnosis of inflammatory carcinoma. ^{Reference Jacobs and Finlayson9} Several surgical options are available for the different types of breast cancer, but all are dependent on the type of breast cancer diagnosed. Most cases of ductal carcinoma in situ (DCIS) are treated using surgery due to the difficulty in predicting the cases that could potentially progress to invasive disease and when this might occur. ^{Reference Sibbering and Courtney1} For this type of potentially unpredictable breast cancer, mastectomy remains the most effective in achieving local control, although studies have shown that conservative breast surgery followed by radiotherapy can provide exceptional rates of local control. ^{Reference Sibbering and Courtney1,Reference Viani, Stefano and Afonso10} Many patients diagnosed with DCIS are offered a choice between mastectomy and breast-conserving surgery. For patients diagnosed with invasive breast cancer, surgery to the breast and related lymph nodes is a requirement and will determine post-operative treatment options by establishing final histology reports. ^{Reference Jacobs and Finlayson9} Identification of axillary node metastases is a very important factor in determining prognosis for the patient. If identified prior to surgery, an axillary lymph node dissection (ALND) is carried out at the time of surgery otherwise a node staging procedure is carried out by sentinel lymph node biopsy (SLNB) using radioisotope localisation techniques. ^{Reference Sibbering and Courtney1} A summary of the advantages and disadvantages of surgical techniques is shown in Table 2.

Table 2. Surgical options in breast cancer (Vaidya et al. ^{Reference Vaidya and Joseph8} p. 71)

Abbreviations: ER, oestrogen receptor; PgR, progesterone receptor; RT, radiotherapy.

Chemotherapy

Chemotherapy can be administered as adjuvant or neoadjuvant therapy. Neoadjuvant chemotherapy is given in instances where tumour control or shrinkage is necessary before more localised treatments are employed. ^{Reference Vaidya and Joseph8} Some studies have shown that there are little or minimal differences in disease-free or overall survival between the same regimes of systemic therapy given pre or post-surgery. ^{Reference Wolmark, Wang, Mamounas, Bryant and Fisher11–Reference Mauri, Pavlidis and Ioannidis13} The clinical benefits and obvious concerns associated with neoadjuvant-chemotherapy treatment are summarised in Table 3.

Table 3. Clinical benefits and potential concerns associated with neoadjuvant treatment for early breast cancer (Vaidya et al. ^{Reference Vaidya and Joseph8} p. 148)

The National Institute for Health and Care Excellence (NICE) has issued evidence-based recommendations on tumour profiling tests to guide adjuvant chemotherapy decisions for patients with early breast cancer. The tests include EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score and Prosigna. Gene expression profiling has been shown to be effective in predicting the course of disease in patients with ER-positive, HER2-negative and lymph node-negative early breast cancer who have been assessed as being at intermediate risk of distant recurrence.

The purpose of adjuvant chemotherapy is to reduce the risk of metastatic spread and recurrence and to improve the overall survival of the patient. ^{Reference Jacobs and Finlayson9} Breast cancer is seen as a systemic disease at diagnosis with a high rate of undetectable dormant micro metastases that have the potential to develop into clinically significant metastatic disease sometime after primary diagnosis, ^{Reference Vaidya and Joseph8} hence the need for systemic treatments in combination with local control. Features of the tumour that have been defined at surgery can help predict the risk of the development of metastatic disease in specific patient cases, including the grade and size of the tumour. ^{Reference Jacobs and Finlayson9} A wide variety of drugs and combinations maybe used to treat breast cancer and are selected based on a number of factors including tumour histology, stage and grade of disease and patient-specific conditions such as cardiac function. Overall, Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analyses cited by Jacobs et al. ^{Reference Jacobs and Finlayson9} conclude that

1. 1. ‘Combination therapy is more effective than single-agent therapy;

2. 2. Anthracycline-based chemotherapy appears superior to non-anthracycline regimens;

3. 3. Taxanes appear to add to anthracycline-based therapies;

4. 4. Maintenance chemotherapy beyond six or eight cycles does not increase survival and

5. 5. The targeted therapies (antioestrogen and anti-HER2) add significantly to chemotherapy when the targets are present in the tumour.’—(Jacobs et al. ^{Reference Jacobs and Finlayson9} p. 21)

Endocrine Therapies

Endocrine therapy or as it is also known, hormonal therapy, is indicated in patients with ER+ status irrespective of chemotherapy and/or targeted therapy. ^{Reference Senkus, Kyriakides and Penault-Llorca3} Patients with HER2+ status are treated using anti-HER2-targeted therapy, more commonly referred to as Herceptin. ^{Reference Henderson14} The type and length of endocrine therapy offered to patients are primarily dependant on the patient’s menopausal status, with factors such as side-effect profile and patients’ general health playing a role. ^{Reference Senkus, Kyriakides and Penault-Llorca3} Drugs most commonly used in adjuvant endocrine treatments include tamoxifen and aromatase inhibitors (AIs): Anastrozole, Letrozole and Exemestane. ^{Reference Senkus, Kyriakides and Penault-Llorca3} These can be prescribed to patients in various sequences. Henderson ^{Reference Henderson14} states that for postmenopausal women, one of the following options should be employed as an adjuvant treatment:

1. 1. ‘5 years of an AI alone

2. 2. 10 years of tamoxifen

3. 3. Sequential therapy with 2–5 years of tamoxifen, followed by 5 years of AI leading to a total treatment duration of 7–10 years’—(Henderson ^{Reference Henderson14} , p. 151)

Direct comparisons of each of these regimes have yet to be fully investigated and so the choice of which to use will mainly be dependent on the patient’s tolerance to the drugs themselves. ^{Reference Senkus, Kyriakides and Penault-Llorca3,Reference Henderson14} For premenopausal women, Henderson suggests that one of the following options be used as an adjuvant treatment:

1. 1. ‘10 years of tamoxifen

2. 2. Sequential therapy with 5 years of tamoxifen followed by 5 years of AI, leading to total treatment duration of 10 years. (Menopausal status should be confirmed by biochemical measurement before starting the AI since AIs may be harmful to premenopausal patients.)’—(Henderson ^{Reference Henderson14} , p. 152)

Henderson ^{Reference Henderson14} also goes on to state that the addition of ovarian suppression with the use of gonadotrophin-releasing hormone (GNRH) agonists or direct ovarian ablation maybe advantageous for disease-free survival. However, studies regarding ovarian suppression and its use in premenopausal patients have yet to provide sufficient consistent data, and many clinical professionals do not recommend its use as part of adjuvant therapy until more evidence has been published. ^{Reference Senkus, Kyriakides and Penault-Llorca3,Reference Henderson14}

Radiotherapy

Meta-analysis data published show that radiotherapy provides effective local control leading to the prevention of local recurrence in 50–75% of cases, as well as significantly improving survival after 10–15 -year follow-up. ^{Reference Vaidya and Joseph8,15} Radiotherapy may be given in various doses and fractionation patterns ranging from periods of 3 to 6 weeks, with a variety of treatment techniques being available, for example, intensity-modulated radiotherapy (IMRT), brachytherapy, conformal radiotherapy, breath hold radiotherapy and interstitial radiotherapy. The use of these techniques varies between departments and depends on the technology available at each centre. Whole-breast irradiation (WBI) is routinely delivered after surgery for patients with stage I–II breast cancer but is sometimes omitted due to factors such as patient age, low risk of disease recurrence or patient comorbidities. ^{Reference Henderson14} NICE guidelines for the treatment of early and locally advanced breast cancer suggest that radiotherapy be offered in 40 Gy over 15 treatments as a standard practice. ¹⁶ This is supported by the Standardisation of Radiotherapy (START) trials which have shown that at 5 -year follow-up patients who received the 40 Gy in 15 fractions experienced equivalent local regional tumour relapse and late adverse effects as those who received 50 Gy in 25 fractions. ¹⁷ Accelerated partial breast irradiation (APBI) is aimed to reduce radiation treatment to less than 1 week and improve local control by increasing the dose to the tumour bed only. ^{Reference Henderson14} Studies using APBI have employed both brachytherapy and external beam therapy techniques, and results have been challenging to interpret due to the inconsistency of techniques and short length of follow-up, averaging around 2·5 years (TARGIT trial). ^{Reference Vaidya and Joseph8,Reference Henderson14} None-the-less, advantages in the use of APBI as a standard treatment due to minimal side effects and reduced treatment time have the potential to have a significant impact on future radiation treatment strategies. ^{Reference Henderson14}

Radiotherapy Toxicity Management

Many side effects may ensue from most if not all the treatment modalities outlined. Each of the effects is managed by a range of health care professionals over a wide range of services to ensure a holistic care approach is adopted throughout the patient’s care pathway. The focus of this section is however solely to consider the toxicity management of the side effects experienced during the radiotherapy treatment aspect of the patient’s journey.

Patients undergoing breast radiotherapy are likely to develop many toxicities throughout their course of treatment with the most common being a radiation skin reaction. ^{Reference McAlinden, Mullan and Shepherd18,Reference Sharp, Johansson, Landin, Moegelin and Bergenmar19} These skin reactions can cause the patient to feel pain, discomfort, irritation, itching and burning in the treatment area throughout the course of treatment. ^{Reference McQuestion20} Radiation skin reactions maybe categorised as acute (hours or days) or late (months or years) and can occur at various rates and times during a course of radiotherapy. Table 4 shows a summary of acute and late skin reaction or changes in relation to the radiation dose during external beam radiotherapy. It demonstrates how skin reactions increase in severity as the dose of radiotherapy increases and how changes in the skin continue to occur even after the radiotherapy treatment has finished. Skin reactions generally peak during the last week of a patient’s treatment or around 1–2 weeks post treatment, with most acute reactions being fully resolved 4–5 weeks after that time. ^{Reference O’Donovan, Colemen, Harris and Herst21}

Table 4. Acute skin changes with localised radiation dose (Ryan ^{Reference Ryan22} p. 986)

Grading systems

Grading of toxicities caused by cancer treatments have been around since the 1980s, with National Cancer Institute (NCI) creating the Common Toxicity Criteria (CTC) for chemotherapy toxicities and Radiation Therapy Oncology Group (RTOG) creating the Acute Radiation Morbidity Scoring Criteria for radiation effects. ^{Reference Trotti, Byhardt and Stetz31} Much debate regarding these grading systems had arisen over the following years due to the creation and modification of older criteria for newer toxicities observed. This led to confusion and inconsistencies in grading and called for newer systems to be developed. ^{Reference Trotti, Byhardt and Stetz31} In 1997, the NCI called for both the CTC and RTOG to merge into one system, named ‘Common Toxicity Criteria Version 2’ (CTC v 2). ^{Reference Trotti, Byhardt and Stetz31} However, ongoing debate has continued to take place over a number of years which suggests that there is no clear agreement on which grading scale is more appropriate for clinical use. ^{Reference Feight, Baney, Bruce and Mcquestion24,Reference Schnur, Love, Scheckner, Green, Wernicke and Montgomery32–Reference Momm, Bartelt, Haigis, Grobe-Sender and Witucki34} The RTOG Acute Radiation Morbidity Scoring Criteria (Table 5) assesses the severity of the skin reaction on a scale from 0 to 4. This scale is one of the most popular scales used in departments across Europe and is the most commonly used scale in clinical trials. ^{Reference Feight, Baney, Bruce and Mcquestion24} The content only addresses the observation of physical changes and does not address symptoms or patient perspectives in any way. ^{Reference Feight, Baney, Bruce and Mcquestion24,Reference Huang, Hou and Luo35} CTC v 4.03 (updated version of CTC v2) (Table 6) is similar in that it also assesses the severity of skin reactions using a scale, but grades them from 0 to 5. It goes into more detail regarding the scale of desquamation and dermatitis associated with the radiation, but as with the RTOG system, it only observes the physical changes and does not take into account additional symptoms or the patient’s perspective. ^{Reference Feight, Baney, Bruce and Mcquestion24,Reference Huang, Hou and Luo35,Reference Schnur, Ouellette, DiLorenzo, Green and Montgomery36} Studies completed over the last number of years have shown that patient-reported outcomes have become valuable instruments in order to help document a more accurate assessment of toxicities. ^{Reference Neben-Wittich, Atherton and Schwartz37,Reference Ryan, Bole and Hickok38} The studies have shown that more locally devised skin assessment tools are not corresponding to the CTC or RTOG grading systems and that small but critical skin changes and patient-reported information are being missed. ^{Reference Ryan22} Using the grading systems alone in order to assess the toxicities experienced by patients having radiotherapy is not sufficient and a call for the development for of a more specialised system for breast cancer is required so that therapeutic radiographers can provide more superior symptom management. ^{Reference Sharp, Johansson, Landin, Moegelin and Bergenmar19,Reference Ryan22,Reference Huang, Hou and Luo35}

Table 5. RTOG criteria (modified version) (Huang et al. ^{Reference Huang, Hou and Luo35} p. 231)

Table 6. CTCAE criteria version 4.0 (Huang et al. ^{Reference Huang, Hou and Luo35} p 231)

Acute Effects

Late Effects

Late effects of breast cancer treatment can arise from around 3 months post treatment and some instances are permanent. They range in severity and are mainly dependent on the individual patient treatment previously delivered. Examples of effects include:

Telangiectasia—dilated superficial blood vessels that remain prominent on the irradiated skin area post treatment. Some studies have shown a correlation in the extend and severity of appearance and with the extend and severity of acute skin reaction experienced by the patient during treatment. ^{Reference Henderson14,Reference Fowble, Yom, Yuen and Arron44,Reference White and Joiner52} Other factors known to affect increased incidence include the total radiation dose and higher fraction size. ^{Reference White and Joiner52} Telangiectasia is permanent but tends to reduce in severity overtime. ^{Reference Fowble, Yom, Yuen and Arron44} A small study carried out by Lanigan et al. ^{Reference Lanigan and Joannides62} showed the effective use of pulsed dye laser (PDL) treatment in significantly reducing and even removing the appearance of telangiectasia in a number of patients who had received breast radiotherapy, thus demonstrating potential treatment for this in the future.

Fibrosis—is a skin thickening of breast or chest wall after radiotherapy. It can cause pain and discomfort for patients who experience it. Both treatment and patient-related risk factors are shown to increase the incidence of fibrosis post treatment. Studies have shown that patients with collagen vascular diseases such as scleroderma are at a higher risk of developing fibrosis after breast radiotherapy. ^{Reference Fowble, Yom, Yuen and Arron44} Treatment-related factors such as additional treatment fields (i.e., axilla), addition of boost treatments, total dose and fractionation and hypofractionation have also shown to increase the risk of development of fibrosis post treatment. ^{Reference Fehlauer, Tribius and Holler63}

Breast appearance—can change rapidly following breast cancer treatment. Changes in the size, shape and appearance of the breast can have a psychological effect on patients. Surgery, chemotherapy and radiotherapy have the potential to change the appearance of the breast, and an unsatisfactory cosmetic outcome can be seen as a late toxicity of breast cancer treatment. ^{Reference White and Joiner52} Studies have shown that there are several radiotherapy treatment factors that are associated with poor cosmetic outcome for patients including, radiotherapy dose, inclusion of boost treatment both interstitial and electron and addition of treatment fields (i.e., supraclavicular and axilla). ^{Reference White and Joiner52} Taylor et al. ^{Reference Taylor, Perez and Halverson64} looked at breast retraction and compared the size and shape of the treated and non-treated breast and found that patient factors such as age, weight, surgical technique and site of primary tumour (upper quadrant) were also contributing factors in breast retraction post treatment. Although some of these factors cannot be altered due to the stage and grade of disease being treated, it is important to note the potential late effects.

Cardiac toxicities—may be a consequence of left-sided radiotherapy. Damage may occur to the heart most commonly seen in the pericardium; however, with new advances in radiotherapy planning and delivery and the introduction of image-guided radiotherapy, incidences remain uncommon. ^{Reference Henderson14,Reference Mock, Hassey-Dow, Meares, Grimm, Dienemann and Haisfield-Wolfe53} Careful consideration should be employed when the use of cardiotoxic drugs is used concomitantly alongside radiotherapy treatment. ^{Reference Henderson14}

Radiation pneumonitis—is an uncommon clinical syndrome affecting the lung post treatment. ^{Reference Henderson14} It presents as a cough, fever, shortness of breath and will show radiographic changes in the previous radiotherapy field only. ^{Reference Mock, Hassey-Dow, Meares, Grimm, Dienemann and Haisfield-Wolfe53} Although uncommon risk factors for development include nodal irradiation and concomitant chemotherapy treatment. ^{Reference Mock, Hassey-Dow, Meares, Grimm, Dienemann and Haisfield-Wolfe53}