Winter 2005 | The Canadian Journal of Medical Radiation Technology | Hiver 2005 •

INTRODUCTION

Breast cancer patients comprise approximately 20% of the total number of patients diagnosed with cancer.1 Predominantly, these patients are female, as 1 in 9 women will be diagnosed with breast cancer in their lifetime and only 1% of breast cancer patients are male. The scope of radiation therapy practice encompasses both radical and palliative intent. Radical therapy is delivered as adjuvant treatment to surgery and/or chemotherapy. Palliative therapy provides symptomatic control of advanced localized disease or distant metastasis.

Radiation therapy techniques are continually evolving with advancing technology and information based on clinical trials. Currently, external beam radiation therapy is the most prevalent method of delivering adjuvant treatment for breast cancer. Recent studies have shown that the majority of breast tumours recur at the original site, at the rate of 86% - 90%.2,3 There are now many long-term survivors; therefore, the potential side effects associated with treatment are a major consideration. Concerns regarding the necessity of treating the entire breast, and quality of life based on treatment outcomes, have inspired the ongoing search for new radiotherapy techniques.

Kerry James, RTT, ACT, BSc Radiography, Radiation Therapy Department, Vancouver Cancer Centre, BCKirsten Gielty, RTT, BSc Biology, Radiation Therapy Department, Vancouver Cancer Centre, BCLuminita Nica, RTT, BSc Chemistry, Radiation Therapy Department, Vancouver Cancer Centre, BC

ABSTRACT

The past two decades have seen dramatic changes in the treatment of breast cancer, the most important being the shift towards breast conservation. With

recent advances in diagnostic and treatment of breast cancer, the number of long-term survivors is increasing. The ongoing improvements and developments in radiotherapy techniques are leading to treatments, which offer both volume coverage and are minimizing the risk of treatment related side effects. In this article we review the role of radiation therapy in management of breast cancer, treatment techniques, as well as possible radiation induced sequelae.

RÉSUMÉ

Au cours des deux dernières décennies, des changements remarquables sont survenus en ce qui concerne le traitement du cancer du sein, le

plus important étant le virage vers la conservation du sein. Grâce aux progrès récents en matière de diagnostic et de traitement du cancer du sein, le nombre de survivantes à long terme sʼaccroît. Les améliorations et les perfectionnements continus des techniques de radiothérapie permettent de proposer des traitements qui, à la fois, offrent une couverture volumique et minimisent le risque lié aux effets secondaires. Dans cet article, nous examinons le rôle de la radiothérapie dans la prise en charge du cancer du sein, les techniques de traitement de même que les séquelles éventuelles induites par la radiation.

ROLE OF RADIATION THERAPY

Radical TherapyThe implementation of screening mammography, in addition to growing public awareness surrounding breast cancer, has greatly increased the number of cancers discovered at an early stage, allowing many women to conserve the affected breast. For the past decade, breast conserving surgery plus external beam radiation therapy has been the standard treatment for breast cancer patients. Studies have shown that the addition of radiation therapy reduces local recurrence rate from 27.2% to 8.8%.2 Radiation therapy is initiated after lumpectomy for ductal carcinoma in situ (DCIS) and early breast cancers (stage 1 and 2, some stage 3 patient dependent), or post-mastectomy for later stage breast cancers. Irradiation of the axillary and supraclavicular nodal area is offered to node-positive patients.

Although in some cases of DCIS mastectomy is still required, lumpectomy is often a practical alternative. Cases requiring mastectomy include those presenting with diffuse microcalcifications, a large volume of palpable disease, or involved surgical margins. The rationale for breast irradiation following excision is to eradicate occult residual disease within the breast. While the need for this has been debated, its value in reducing recurrence has been proven by multiple trials, with good to excellent cosmetic outcome for most patients.

RADIATION THERAPY

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The NSABP B 17 trial randomized breast cancer patients to excision alone or excision plus 5000 cGy of radiation.3 In this study a recurrence rate of 16% was seen in patients receiving excision alone and a 7% rate in patients receiving excision plus radiation at a follow-up of 43 months. A group of French oncology centers examined patterns of DCIS recurrence for a median of 97 months. Invasive recurrence of DCIS occurred in 2% treated with mastectomy, 18% of patients treated with lumpectomy alone, and 8% of patients treated with lumpectomy and radiation.4

In higher stage disease where mastectomy has been performed, radiation therapy improves local control by treating subclinical disease in the remaining anterior chest wall and regional lymphatics. Recent reports from large prospective trials have shown superior loco-regional control, disease-free survival, and overall survival with the use of radiation therapy after mastectomy and chemotherapy. The Danish 82b trial evaluated the use of postoperative radiation therapy in premenopausal women with node-positive breast cancer, treated with mastectomy and methotrexate-based chemotherapy.5,6 At ten years, the patients who received radiation therapy to the chest wall and regional lymphatics had a decreased rate of loco-regional recurrence (9% vs. 32%) and improved cancer specific survival (48% vs. 34%) and overall survival rates (54% vs. 45%). This study confirmed that patients with larger tumours or extensive nodal involvement benefited from postmastectomy irradiation. A smaller trial from British Columbia also reported that the addition of radiation therapy after mastectomy and chemotherapy resulted in improved loco-regional control (87% vs. 67%) in premenopausal women with lymph node-positive disease.7

Palliative TherapyRadiation therapy is an effective tool in the management of advanced local disease or symptomatic breast cancer metastasis. The two main indications for palliative treatment are to prevent complications from local tumour growth, and to relieve symptoms such as pain or ulceration. In patients with unresectable disease that has not responded to systemic agents, radiation therapy may decrease tumour bulk, bleeding, or malodorous discharge. Painful bony metastases respond particularly well to radiation therapy. Whole brain irradiation is effective in controlling microscopic and small-volume macroscopic disease, although these benefits must be weighed against the potential late effects on normal brain parenchyma.

TREATMENT TECHNIQUES

Conventional TechniquesTypical external beam radiotherapy utilizes high energy x-rays, usually 6-10 MV, to treat the entire breast and any nodal regions at risk. Radiation beams are customized for each patient using treatment planning images. These images may be conventional x–rays or CT scans, depending on the resources available. Images are obtained with the patient

positioned to allow an optimal arrangement of treatment beams and ensure daily reproducibility throughout the course of treatment.

In order to calculate radiation dose, a transverse outline of the external breast surface is needed. CT imaging provides additional information regarding the location and density of underlying tissues, enabling accurate three-dimensional planning. The dose to lung tissue, as well as adjacent soft tissue, is affected by the difference in density between the two.

Conventionally, whole breast radiotherapy is accomplished with opposing tangential beams, blocked at the central axis to avoid divergence into the lung (Figure 1). The treated fields extend from the inferior head of the clavicle superiorly, to approximately 2cm beyond the breast tissue inferiorly. Medially, the field border is midline, and laterally it is the mid-axillary line. Individualized shielding, either cerrobend blocks or multi-leaf collimation within the head of the linear accelerator, shape the beam to protect the ipsilateral lung, and also the heart when treating the left breast.

The goal of treatment planning is to achieve a homogeneous dose distribution throughout the volume. This can be challenging, as the contour of the breast is irregular in all planes. Radiation dose will be higher in areas of smaller separation, namely at the apex of the breast, and near the superior and inferior extent of the treatment fields. Wedge filters or compensators are used to differentially attenuate the beam, and thus reduce undesirable ʻhot spots ̓ in which the dose exceeds the prescription by 7% or more (Figure 2).

The prescribed dose to the whole breast is 4000 to 5000 cGy, delivered in fractions of 180 to 200 cGy daily. An electron boost to the tumour bed may be added, sequentially or concurrent to the breast treatment, particularly for women with close surgical margins. Two randomized trials conducted in Europe have shown that a boost of 1000 to 1600 cGy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years, and from 7.3% to 4.3% at 5 years, respectively.8

Figure 1: Left medial tangent field, with indivi-dualized cerrobend block for heart. Y2 jaw is closed to avoid the divergence of the beam into the lung. Wedge in Y direction is used to compensate for the irregular shape of the breast.

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For node-positive patients, external beam radiation therapy is used to treat the supraclavicular and axillary lymph nodes (Figure 3). This is achieved using an anterior field, with or without a small posterior boost field, as determined by individual patient anatomy; namely the depth of the nodes and size of patient. High risk patients may require treatment of the internal mammary nodes. One option is to widen the breast tangent fields, by extending the medial border across midline. Depending on the depth of IMC nodes and shape of chestwall, this is an acceptable choice when the treated lung volume does not exceed a 3cm depth. Alternatively, a separate anterior beam may be used. The prescribed dose is delivered predominantly with electrons, (80%) with a small portion (20%) from photons. The electron beam exhibits a sharp dose falloff, thereby decreasing dose received by the underlying heart and lung. Junction issues must be addressed when any nodal area treated to avoid overdose or underdose in the treated volume.

Innovative TechniquesA variety of therapy techniques, including intensity modulated, modulated electron, intra-operative and brachytherapy have been explored in an attempt to restrict the volume of tissue irradiated and/or to deliver more homogeneous dose. These

techniques may result in better loco-regional control with a lower risk of long-term lung and cardiac problems.

Intensity Modulated Radiotherapy (IMRT)IMRT is a method of inverse planning, accomplished by providing the treatment planning computer with constraints as to acceptable planning target volume (PTV) coverage and normal tissue dose constraints. Dividing the beam into small beamlets optimizes the dose distribution in a volume of tissue. The dose delivered by each beamlet varies, allowing customized beam intensity across the field. In whole breast radiotherapy, IMRT can be used to eliminate hotspots throughout the volume, using dynamic multi-leaf collimation as a means of compensation for the irregular contour and tissue inhomogeneities. In partial breast radiotherapy, IMRT can be used to produce a dose distribution, which conforms to the PTV, while minimizing the dose to the heart and lung. Studies have shown that certain groups of patients are put at higher risk (as high as 9% depending on the volume of heart treated) of fatal cardiac events as a result of undergoing breast radiation therapy.9 Three-dimensional CT planning and alternative beam arrangements with IMRT optimization, enable more effective cardiac sparing without the compromise of PTV coverage.

Modulated Electron Radiation Therapy (MERT)Recently, energy and intensity modulated electron beams have been investigated in the treatment of superficial targets. This new technique uses an electron multi-leaf collimator to generate non-uniform intensity maps with several electron energies. In this way, conformal dose distributions are delivered to irregular targets located just a few centimetres below the surface while sparing deeper-lying anatomy. Studies have shown that MERT can reduce the maximum lung dose by up to 2000 cGy and maximum heart dose by up to 3500 cGy compared to conventional tangential wedged beams.10

Intra-operative Radiotherapy (IORT)Intra-operative radiation therapy is administered during surgery, immediately following excision of the tumour. A single high dose of radiation is delivered to a defined PTV, the extension and depth of which are directly determined in the operating room. The planning target volume (PTV) includes a 1-3cm margin around the tumour bed.

Intra-operative techniques have been described using either electron or low energy photon beams. IORT has the radiobiological advantage of reduced chance for tumour cell repopulation, by eliminating the delay between surgery and radiation, as well as delivering the dose in a single fraction.11 The dose is delivered directly in the tissue involved, while shielding uninvolved tissues. The limitation of this technique is that the time frame may not allow for pathology and nodal status to be reviewed before treatment.

Figure 2: External beam radiation therapy plan with standard wedges (thick end of the wedge towards the apex of the breast). Plan is optimized to 95% isodose line.

Figure 3: Anterior field used to treat supraclavicular and axillary nodes. Multileaf collimation is used to shield normal tissue. Y1 jaw is closed to avoid beam divergence.

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For IORT, a mobile linear accelerator (linac) equipped with a robotic arm produces electron beams with energies ranging between 3-9 MeV. The electron beam is collimated using a 5mm thick, round Perspex applicator. An aluminum-lead disk is placed between the breast and the pectoralis muscle to protect the thoracic wall. Doses between 1700-2100 cGy are prescribed. A single fraction of 2100 cGy has been estimated to be equivalent to 6000 cGy in 30 fractions delivered by external beam.12 IORT has also been investigated as an alternative to the external beam electron boost. The IORT boost has been demonstrated to prevent local recurrences in selected stage I and II breast cancer, without significant complications.13,14

A portable x-ray device (Photon Radiosurgery System) can also be used to deliver IORT. This unit can deliver doses of 500-2000 cGy to a distance of 0.2cm - 1cm beyond the tissue/applicator interface. As these are low energy x-rays, usually 50 KV, the beam attenuates rapidly. 1500 cGy prescribed at 2mm will deliver only 750 cGy at a 5mm depth. This dose gradient significantly limits the subset of patients in which this treatment is suitable.15

Despite the good short term results for both local control and tolerance for IORT, long term follow-up data are needed since the biological effects of the larger single fraction may significantly increase the incidence of late complications such as fibrosis and tissue necrosis.16,17

3D External Beam Conformal Partial Breast RadiotherapyCurrent trends in reducing the volume of breast tissue irradiated, have led to the design of partial breast external beam radiation using three dimensional conformal therapy. The target was again the lumpectomy cavity plus 2cm margins to account for the possibility of some motion. A dose of 3600 cGy in 10 fractions is given twice daily. A non-coplanar technique is employed using 4-5 beams (Figure 4). The feasibility of this technique was first reported in 2003 in the USA, and the acute toxicity has been minimal.18 British Columbia is currently using 3D partial breast radiotherapy in a province wide study. Additional studies will be needed to assess the long term effects of these larger fraction sizes on normal tissue, as well as the impact on treatment efficacy.

BrachytherapyInterest in accelerated partial breast irradiation following lumpectomy has increased over the past decade, including low dose rate and high dose rate brachytherapy. Brachytherapy is characterized by the use of radioactive sources placed close to the tumour in the treatment of malignant disease.

Brachytherapy is used for early breast cancer, clinical stage T1 or T2, node negative, with microscopic resection margins negative for both invasive and in situ disease. The main advantage of brachytherapy is based on the inverse square law inherent to radioactive sources, which allows the delivery of a very high dose of radiation to the tumour bed with a substantial sparing of the surrounding normal tissue. (Figure 5)

Interstitial brachytherapy involves implanting multiple catheters into the high-risk breast tissue. The catheters are loaded postoperatively with high dose rate radiation sources (Ir 192) (Figure 6 a & b). A total dose of 3200-3700 cGy is prescribed to the tumour bed, with 1-2cm margins, delivered over 4-5 days.19,20 Most investigators have adopted a protocol using 2 fractions daily, allowing 6 hours between fractions.

Figure 4: 3D Conformal Partial Breast Technique. 4 Field arrangement

Figure 5: Partial breast high dose rate brachytherapy – Planning treatment volume (Picture courtesy of dr. Kader HA, Vancouver Island Cancer Centre, BC).

a

b

Figure 6: a) & b): Catheters inserted under local anaesthesia are connected to the HDR remote afterloading system. (Picture courtesy of dr. Kader HA, Vancouver Island Cancer Centre, BC).

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Intracavitary brachytherapy uses a balloon-based catheter device, Mammosite. The balloon is inserted during surgery, and then inflated with saline to conform to the tumour bed cavity. A single radioactive source (Ir192) is remotely loaded. The prescription dose is 3400 cGy in 10 fractions given twice daily over 5 days. Upon completion of treatment, the balloon is deflated and removed.21

Research in the area of partial breast irradiation using permanent brachytherapy implants (Pd 103) made Toronto Sunnybrook Regional Cancer Centre the first in the world to use this technique. A dose of 9000 cGy was determined to be equivalent to 5000 cGy in 25 fractions delivered by external beam. This dose is prescribed to the target volume, which includes the surgical cavity and the fibrous scar plus a margin of 1cm. To date 40 patients were treated, and short term results are encouraging.22

RADIATION INDUCED SEQUELAE

The challenge of radiation therapy is to optimize the therapeutic ratio, by minimizing treatment-related morbidity, while maintaining or improving local control and survival. Radiation therapy is a localized treatment; therefore, anatomic location of the tumour is the most important factor determining side effects. Sensitivity to radiation varies between tissues and/or organs. The volume of irradiated tissue, total dose received, and overall delivery time are also important factors. Reaction severity may increase with the addition of chemotherapy to the treatment protocol.

There are two categories of response to radiation exposure; acute and chronic. Acute effects occur during or immediately following a course of radiation therapy and resolve within a few weeks after completion of treatment. These reactions are more prominent with high total doses. Chronic or late effects occur months to years after completion of radiation therapy. Late damage may arise without experiencing previous acute reactions. Reaction severity progresses with time, and usually cannot be halted or reversed. Larger dose per fraction increases the probability of late effects, more so than the total dose. Although for most cancers a 5 year follow up is appropriate, for breast cancer patients, follow up of 10 years or more is required.

SkinThe exposure of skin to radiation produces a variety of acute and chronic responses. Erythema will usually develop towards the end of treatment, presenting as a redness of the skin produced by a dilation of superficial capillaries. Erythema may cause burning, itching, and mild discomfort. Dry desquamation may follow and is caused by the partial loss of epidermal basal cells. The skin becomes dry, itchy and scaly, and may peel. There may also be hyperpigmentation in the area treated. Moist desquamation occurs when the basal cell layer is completely destroyed. This is characterized by blistering of the skin accompanied by a serous fluid exudate.

This most frequently occurs in areas of high dose or friction, such as in the axilla and the inframammary fold of large breasted women. Epidermal sloughing may leave nerves exposed and sensitive.

Chronic effects include permanent hyperpigmentation, telangiectasia, which is a permanent dilation of pre-existing blood vessels creating small focal red lesions, and an induration or hardening of the skin caused by fibrosis.

LungLung is an intermediate to late responding tissue, for which at least two radiation induced effects are observed: acute pneumonitis, and fibrosis. Acute radiation pneumonitis is an inflammatory response, which occurs 1-6 months after radiation treatments. When symptomatic, radiation pneumonitis may present with dyspnea, dry cough, pain, and low-grade fever. Fibrosis develops slowly over a period of several months to years.23

The impairment of pulmonary function is primarily dependent on the proportion of lung that receives a dose above its tolerance. Therefore, although the lung is among the most sensitive of the late-responding organs, because of its functional units it only becomes a dose limiting organ when large volumes of lung are irradiated.

Including some lung in the treatment field is unavoidable when treating the breast. Studies have shown that radiation pneumonitis is an uncommon complication after either local (0.9%) or loco-regional radiation therapy (4.1%).24

The incidence of radiation pneumonitis increases with the addition of a supraclavicular field, prior chemotherapy, concurrent tamoxifen and increased age. Smoking habits and pre-radiation therapy performance status are also important factors.

HeartRadiation therapy to the left breast has been associated with potential cardiotoxicity.25 The development of ischemic heart disease has been correlated with the volume of heart irradiated and the total radiation dose.26,27 Minimizing radiation dose to the heart muscle and the coronary arteries is necessary to avoid later effects of ischemic cardiovascular disease. The early manifestation of cardiac injury is inflammation of the pericardium and myocardium. Pericarditis results from radiation damage to mesothelial cells lining the pericardium and usually develops within weeks. Chronic effects include ischemic heart disease and coronary artery disease. Adverse effects to coronary arteries and small myocardial vessels are due to the injury of slowly evolving endothelial cells, loss of capillaries, ischemia at the microcirculatory level and progressive fibrosis.28

These side effects were particularly prominent in earlier treatment studies based on outdated techniques. Since then, the importance of reducing cardiac dose has been recognized,

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and recent clinical studies involving current techniques have not shown an increase in radiation induced cardiac complications with a median follow up of 4.5 years.29

LymphaticsLymphedema is an accumulation of fluid in the intercellular spaces due to obstruction of lymph vessels or disorders of lymph nodes. Lymphedema is often permanent and generally occurs within 4 years of treatment, although transient lymphedema may occur in 7% of women. The addition of radiation to axillary dissection may increase the risk of arm swelling by 5-10%.30 Arm edema is associated with increased age, axillary radiation and extent of surgery.31

Brachial PlexusThe hypothesized mechanism of brachial plexus neuropathy (BPN) is nerve compression resulting from the radiation-induced fibrosis. Normal connective tissue becomes more dense and inelastic, constricting the nervous tissues. The neurological manifestations of this syndrome could be paresthesia of fingers and hands, hyporeflexia and muscular atrophy. Pain is not always a feature of BPN, although it is often a symptom. Studies have shown that the evolution of neuropathy can take up to 10 years to manifest.32

ThyroidHypothyroidism is a rare side effect of radiation treatment to the breast. The few reported cases have generally occurred following a direct field to the internal mammary chain, supraclavicular, or infraclavicular nodes. The main symptoms are fatigue and rapid weight gain. Hypothyroidism is often associated with constipation, dry skin and sensitivity to cold. These symptoms develop weeks after treatment, and result from direct damage to follicular cells, thyroid vessels, or the induction of an immunologic reaction.33

EsophagusIf regional lymph nodes are treated, esophagitis may occur. This is generally mild and may develop around the third week of treatment, and will disappear 2-3 weeks after the completion of radiation therapy.

Secondary MalignancyThe link between radiation exposure and carcinogenesis is well established. Studies have been done to assess the risks and patterns of second malignancy in women treated with conservative surgery and radiation therapy. Young age and family history predicted for an increased risk of contralateral breast cancer, and older age predicted for an increased risk of non-breast malignancies, such as skin cancers and endometrial cancers.34 While the benefits of radiotherapy outweigh the risks of developing secondary cancers, the presence of such risks indicates the need for further investigation of methods aimed at minimizing the dose to, and volume of, normal tissue irradiated.

FatigueFatigue is commonly reported amongst most radiation therapy patients. This may be due to the disease or treatment, which affects normal cells as well as cancer cells. The stress of the illness, as well as attending daily treatments, patients may experience chronic fatigue, which may be attributed to physical, psychological, social, cognitive and behavioural

factors.

CONCLUSION

Radiation therapy is an integral component of the multimodality treatment of breast cancer. The survival rate for this patient group is high, 86% at 5 years; therefore, a focus on reducing the morbidity of treatment is critical. Anticipated results from ongoing clinical trials will provide clearer evidence regarding choice of radiation therapy technique to provide the best outcome for this group of patients.

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