REVIEW ARTICLE

Anna Niwińska1, Jacek Gałecki2

1Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Institute for Oncology, Warsaw

2Department of the Teleradiotherapy, Maria Sklodowska-Curie Institute for Oncology, Warsaw

Current indications and methods of postoperative radiation therapy — repetition before the exam

ABSTRACT

Radiation therapy is used in all stages of breast cancer: ductal carcinoma in situ, early and locally advanced breast cancer, locoregional recurrence, and in patients with bone and central nervous system relapse. This modality has been used for decades, and improvements in contemporary methods of target delineation, radiation techniques, and dose fractionation can be seen nowadays. Despite technological advancement, late cardiac and lung side effects after radiotherapy remain an unresolved problem. Potentially cardiotoxic targeted therapy and cytotoxic agents additionally elevate the risk of cardiotoxicity. The indications and the techniques of adjuvant radiation therapy after breast-conserving surgery and mastectomy, supported by ESMO, ESTRO, ASTRO, NCCN, and St Gallen recommendations, are discussed in this article. The review is dedicated to oncologists, especially non-radiotherapy specialists, who are in final stage of training before the speciality exams.

Key words: breast cancer, conformal radiation therapy, intensity-modulated radiation therapy (IMRT), hypofractionation, cardiotoxicity

Oncol Clin Pract 2016; 12, 1: 18–24

Introduction

Radiation therapy is used in all stages of breast cancer; it is applied in the treatment of pre-invasive cancer, loco-regional relapse of cancer, and in the dissemination of neoplastic disease to the bones and to the central nervous system. Although this modality has been used for decades, an important improvement of the target delineation methods, radiation techniques, and dose fractionation has been made in the last twenty years. This has led to an improvement in results in general technological progress (modern treatment planning and radiation devices, development of precise computer treatment planning systems). Despite the technologic advances the risk of late cardiac and lung side effects remains an important issue, especially due to the permanently evolving, highly effective, but cardiotoxic systemic treatment modalities that may additionally potentiate the damage to the normal tissue.

The major objective of this paper is to present to oncologists (non-radiotherapy specialists) the techniques of the radical radiotherapy, the actual principles of radiation dose fractionation, the indications and techniques of partial breast irradiation, the methods to limit heart exposure to radiation, the adjustment of radiotherapy to novel surgical requirements, and the failure risk, depending on the biologic breast cancer type. The presented data have been acknowledged by the recommendations of the following oncologic associations: The European Society for Medical Oncology (ESMO), the European Society for Radiotherapy and Oncology (ESTRO), the American Society for Radiation Oncology (ASTRO), and the National Comprehensive Cancer Network (NCCN), as well as by the recommendation of the experts at the St Gallen Conference in 2015.

Radiation techniques post breast-conserving surgery and post mastectomy

Breast-conserving surgery

The obstacles in planning and applying radiotherapy in breast cancer patients results from the irregular radiation target, from the proximity of important body organs (heart, lungs), and from the respiratory motion in the radiation field.

The indications for breast-conserving treatment in early breast cancer have not been modified for years. The target volume for radiotherapy to receive the prescribed homogenous radiation dose is the mammary gland itself without the skin and the chest wall (ribs, intercostal muscles). The radiation field is defined based on computer tomography (CT) scans. Three-dimensional conformal radiotherapy (3D CRT) with use of a computer system for treatment planning is the technique of choice in patients irradiated following breast-conserving surgery [1]. The technique consists of irradiation of the whole breast from two tangential fields or from several individually adjusted photon fields (a field-in-field technique) as well as adding a boost of electrons, photons, or brachytherapy to the primary tumour bed (sequential radiotherapy). A modification of this technique is 3D conformal radiotherapy with simultaneous integrated photon boost to the primary tumour bed (a simultaneous integrated boost; SIB) [2]. In the SIB technique, as practised in the Institute for Oncology in Warsaw (Dr. J Gałecki), five photon fields are commonly used: two tangential fields to the whole breast and usually three small fields to the primary tumour bed. During each irradiation session (fraction) a dose of 2.25 Gy is delivered to the whole breast and a dose of 2.7 Gy to 2.8 Gy is delivered to the primary tumour bed. Finally, total radiation dose delivered within four weeks consists of 45 Gy to the whole breast and 54–56 Gy to the tumour bed. This irradiation technique enables a precise dose distribution in the breast, planned by a radiotherapist, and reduces the total radiotherapy period from 5–6 weeks to 4 weeks.

In exceptional situations, when the 3D CRT radiotherapy treatment plan cannot be accepted due to either unsatisfying radiation dose distribution in the treated breast or due to exceeding the radiation dose limit delivered to the critical organs (heart, lungs), a patient post breast-conserving surgery can be irradiated with use of the IMRT technique (Intensity Modulated Radiation Therapy) [3]. This technique consists of delivering, during one fraction, different radiation doses to the different breast regions. It permits a better tailoring of the delivered radiation dose in the whole irradiated field. Due to the use of a multi-leaf collimator (MLC), a spatial, tree-dimensional dose distribution is adjusted to the shape and size of the target irradiated field. There are three IMRT varieties. The first is IMRT from static fields with use of a multi-leaf collimator. In this IMRT type the irradiation time during a given session is longer due to the necessity of configuring the subsequent fields. The second IMRT variant is a Volumetric Intensity-Modulated Arc Therapy (V-MAT). In this technique, during the irradiation session both the device treatment head and the collimator leaves are moving. The duration time of each radiation irradiation fraction is shorter. The third IMRT technique is Helical Tomotherapy. Its main advantage is the use of an additional axis of head rotation.

The main disadvantage of the IMRT technique compared to 3D CRT technique is the risk of unintended delivery of low irradiation doses to a relatively vast area of healthy tissues and a higher median irradiation dose to the critical organs. According to the radiotherapeutic and radiobiological data, the low radiation doses used in IMRT technique should not cause significant toxicity to the heart, lungs, healthy breast, or spinal cord. Nonetheless, a paper published in 2013 suggested that higher risk of cardiovascular complications is proportional to the rise in the median radiation dose delivered to the heart [4]. These data are particularly important in the subset of patients treated with anthracyclines and trastuzumab, who are potential future candidates for additional treatment of disseminated disease with lapatinib or trastuzumab emtansine.

Lately, heart-sparing techniques of breast or post-mastectomy irradiation have been developed [5–7]. These techniques include: deep inspiration breath hold, irradiation of large breasts in a prone position, accelerated partial breast irradiation, and modified IMRT techniques. Proton therapy seems to be a promising, future option due to its beneficial radiation distribution in the chest wall, although the cosmetic effect of this technique raises some doubts. In some subsets of elderly patients with low risk of relapse and high risk of cardiotoxicity it may be considered to resign from the post breast-conserving surgery radiotherapy in order to protect the heart (PRIME 2 study) [8].

Deep inspiration breath hold irradiation (DIBH) [9] can be applied in some patients with left breast cancer and an unfavourable heart position to the chest wall. Usually two treatment plans are prepared: on the easy and on the deep breath. If the differences in the doses delivered to the cardiac muscle and to the coronary vessels are substantially lower than in the standard plan and the patient is able to hold their breath on inspiration for a suitable time during the irradiation session, the aforementioned technique should be selected. Studies performed by a team of physicians and physicists from the Radiotherapy Department of the Institute for Oncology in Warsaw indicate a positive effect of DIBH on heart sparing. The DIBH technique allowed a reduction of the median irradiation dose to the heart from 4.4 Gy to 2.1 Gy and to the coronary vessels from 9.3 Gy to 3.1 Gy [10].

In the PRIME II study [8], omission of the radiotherapy post breast-conserving surgery in women aged of 65 years or older, with early breast cancer (tumour size up to 3 cm, N0), receiving adjuvant tamoxifen or aromatase inhibitors, increased the local relapses rate to 4.1% compared with 1.3% in the receiving radiotherapy (p = 0.002) but with no influence on the overall survival of the patients (93.8% vs. 94.2%, p = NS). The relapse risk was lower in patients with high expression of hormonal receptors. Therefore, the NCCN recommendations [11] contain a notation concerning the possibility to omit post breast-conserving surgery radiotherapy in some women aged more than 70 years, with breast cancer staged T1N0 and concomitant high expression oestrogen/progesterone receptors, receiving adjuvant hormonal treatment.

The concept of giving a boost to the primary tumour bed in patients with invasive breast cancer, post breast-conserving surgery, has changed recently. According to the recent NCCN [11] and ESMO [12] recommendations, the addition of a boost is not obligatory in all patients. It should be delivered in patients with risk factors of relapse: patients younger than 50 years, with G3 histological malignancy type, vascular invasion, or uncertain healthy tissue margins. In the Institute for Oncology in Warsaw all patients with invasive breast cancer receive a boost to the primary tumour bed.

Radiotherapy post mastectomy

Based on the ESMO 2015 conference [12] and the St Galen 2015 conference [13] recommendations, the indications for adjuvant radiotherapy post mastectomy include:

— presence of metastases to four or more axillary lymph nodes;

— primary tumour stage T3 or T4;

— non-radical surgery;

— presence of metastases in 1–3 axillary lymph nodes accompanied by additional risk factors of loco-regional relapse.

Usually the irradiation field contains the area of the chest wall post mastectomy and the area of the supraclavicular, axillary, and parasternal lymph nodes. Photon/electron beam techniques are used in post-mastectomy irradiation (in the Institute of Onco­logy in Warsaw these techniques were used until 2008) or photon IMRT techniques (static or V-MAT). The target field is delineated based on the CT imaging according to ESTRO recommendations [14]. Usually the total irradiation dose is 50 Gy, delivered in 25 fractions of 2 Gy each or 45 Gy delivered in 20 fractions of 2.25 Gy each.

Radiotherapy in patients with metastases in 1–3 axillary lymph nodes

Radiotherapy in patients post mastectomy with 1–3 metastases to axillary lymph nodes is the most controversial issue. It is not clear if currently practiced use of radiotherapy in patients with 1-3 involved lymph nodes combined with systemic treatment prolongs significantly survival of patients in view of potential cardiotoxicity of both therapeutic modalities.In the meta-analysis performed in 2014 by the Early Breast Cancer Trials Collaborative Group (EBCTCG) in a group of 8135 patients, included into 22 clinical trials [15], the decreased relapse and death risk after radiotherapy was proven in a subgroup of patients with metastases to 1–3 axillary lymph nodes. The aforementioned results constituted the basis to recommend post-mastectomy radiotherapy for patients with metastases in 1–3 axillary lymph nodes. However, it must be stressed that the patients included in that meta-analysis were treated in the years 1964–1986, and 86% of them received systemic therapy with use of CMF chemotherapy regimen or tamoxifen (a suboptimal systemic treatment). In these patients more cardiologic complications were detected than in the non-irradiated group [4]. The results of a randomised trial including 1832 patients treated in the years 2000–2007 were published in 2015 [16]. In 85% of patients the metastases in 1–3 axillary lymph nodes were detected; 91% received anthracycline-based chemotherapy regimens or a combination of anthracyclines and taxanes, and 75% received hormonotherapy. In the subset of irradiated patients treated the risk of relapse was lower; however, there was no statistically significant impact on overall survival (OS 92.3% vs. 90.7%, p = 0.07). It seems that, based on the results of some other studies suggesting the additive efficacy of chemotherapy and hormonotherapy in decreasing the risk of the loco-regional relapse [17, 18], in the era of the modern, intensive systemic adjuvant therapy, the independent gain from the radiotherapy, especially in the subgroup of patients with metastases in 1–3 axillar lymph nodes, may be lower nowadays compared to previous methods of suboptimal systemic treatment. Based on the aforementioned results, the ESMO 2015 and St Gallen 2015 recommendations were formulated [12, 13] concerning the necessity of individual relapse risk assessment and using the adjuvant radiotherapy for patients with 1–3 metastases in axillary lymph nodes with other concomitant risk factors of local and loco-regional relapse (young age, tumour size, the number of involved lymph nodes (1 or 3?), extracapsular spread of lymph nodes metastases, vascular invasion, histological grade, biological cancer type (triple negative, HER-2 positive), type of the systemic treatment, history of heart diseases, left breast cancer).

Parasternal lymph node irradiation

Controversies concerning the role of parasternal lymph node radiotherapy are due to the low risk of relapse in this lymph node group and the high risk of delivering a relatively high irradiation dose to the main coronary steam vessel, supplying both left (left anterior descending coronary artery) and right heart ventricle (right coronary artery). It was shown in three clinical studies that irradiation of the parasternal lymph nodes post breast-conserving surgery or post mastectomy decrease the risk of relapse and of distant metastases but without a significant influence on overall survival [16, 19, 20]. For that reason, according to the recent ESMO 2015 and St Gallen 2015 recommendations [12, 13], post-surgery of the parasternal lymph nodes is not obligatory in all patients. Based on the experience of the Institute for Oncology in Warsaw, this kind of radiotherapy is indicated in patients with tumour localised in the inner quadrants and in patients with multiple axillary lymph node metastases. The qualification to this procedure is made after exclusion of the risk of delivering an excessively high radiation dose to the heart.

Irradiation doses — hypofractionation

Different fractionation schedules of the irradiation dose have been studied for a long time in Canada and Great Britain, but the final and convincing results of these studies were first presented five years ago when the long-term results of the clinical trials — Ontario and START A and START B [21–23] — were published. The Ontario clinical trial compared the standard fraction size of 2 Gy and a total irradiation dose of 50 Gy to a dose of 2.67 Gy per fraction and a total dose of 42.5 Gy in the breast-conserving treatment. After a 12-year follow-up no difference was detected in the relapse rate, overall patient survival, cosmetic effect, or the rate of late side effects [21]. Based on the results of this study, the 2010 ASTRO trial accepted an alternative irradiation schedule in post breast-conserving surgery, with a total dose of 42.5 Gy delivered in 16 fractions of 2.67 Gy each in the patients over 50 years old, with breast cancer T1–T2 N0, not undergoing any systemic treatment, and not receiving radiotherapy to the primary tumour bed [24]. In the British START B clinical trial a fraction dose of 2 Gy with a total dose of 50 Gy (five weeks of therapy) was compared to a total dose of 40 Gy delivered in 15 fractions (three weeks of therapy). The 12-year observation did not reveal any difference in the relapse rate, cosmetic effect, or the late side effect rate (radiotherapy induced ribs fractures, lung fibrosis with clinical evidence, coronary disease, cardiac disease-related death, or brachial plexus palsy). The cosmetic effect was even slightly better in the group receiving a higher dose per fraction [25]. Based on the aforementioned studies, during the ESMO 2015 and St Gallen 2015 conferences [12, 13] a consensus was made that irradiation in 15–16 fractions of 2.5–2.67 Gy each has a comparable efficacy and safety compared to fractions of 2 Gy. By extension, hypofractionation has been accepted as a standard modality in breast-conserving treatment and post mastectomy, independent from patient age and the use of chemotherapy. There are ongoing clinical trials in Great Britain, aimed at further shortening of radical radiotherapy time [26].

In Poland a mild hypofractionation with 2.25 Gy fractions to a total dose of 45 Gy after breast-conserving surgery and post mastectomy has been introduced in the Institute of Oncology in Warsaw in 1999 by Dr. J. Gałecki. The treatment duration time was shortened to four weeks, and treatment results and complication rates are comparable to those after conventional 2 Gy fraction radiotherapy [27].

Accelerated partial breast irradiation (APBI)

Partial breast irradiation can be applied only in patients with early breast cancer with low relapse risk, treated with breast-conserving surgery. There are several methods of APBI: a multi seeds, multi-catheter applicators brachytherapy, modified brachytherapy (MammoSite, MammoSite ML, Contura, SAVI), conformal 3D partial radiotherapy, and electron-beam or Roentgen beam intraoperative radiotherapy. The treatment lasts 1–5 days depending on the irradiation technique [28]. Whereas APBI applied by the traditional brachytherapy method is accepted and has been used for a long time, and its value and safety have been proven [29], intraoperative radiotherapy is still a source of controversy. This is due to the statistically higher risk of local reoccurrence, as shown in the ELIOT study (4.4% vs. 0.4% after 5.8 years, p = 0.001) [30] and in the TARGIT study (3.3% vs. 1.3% after 5 years, p = 0.04) [31], compared to conventional whole-breast irradiation. In 2009 ASTRO [32] and Groupe Europeen de Curietherapie-European Society for Radiotherapy and Oncology (GEC-ESTRO) [33] published recommendations concerning indications for APBI with brachytherapy and teleradiotherapy techniques, excluding intraoperative radiotherapy. Both societies defined a group of patients in which APBI can be safely applied, a group of patients that can be treated with APBI only in clinical trials, and finally a group not being candidates for APBI due high relapse risk. Currently, after the publication of the results from further clinical studies, GEC-ESTRO, ASTRO, and NCCN recommend APBI in the group of patients with the lowest-risk disease and with adjuvant systemic treatment. According to NCCN from 2015, APBI can be safely used in so-called ‘suitable’ patients (age 60 years or over, with invasive ductal breast cancer or favourable histological type, in clinical stage T1N0, ER(+), without intraductal cancer component, with wide surgical margins, without mutations BRCA1/2), the irradiation can be delivered by brachytherapy or teleradiotherapy techniques with exclusion of intraoperative techniques [11]. The ESMO recommendations highlighted the increased relapse risk observed post intraoperative radiotherapy (ELIOT, TARGIT) compared to the other APBI techniques [12]. The Cochrane meta-analysis carried out in 2014, comparing APBI to conventional radiotherapy in terms of efficacy and safety, was inconclusive and advised to await the long-term results of important clinical trials [34].

Will advances in surgery modify the principles of radiotherapy?

A clinical study conducted by the American College of Surgeons Oncology Group Z0011 in 115 American centres and published in 2011 in the JAMA changed the principles of the surgical proceedings in early breast cancer [35]. This study evaluated the validity of the axillary lymphadenectomy post sentinel lymph node procedure in patients with breast cancer with tumour size up to 3 cm and macro-metastasis (metastasis with diameter > 2 mm) into one or two axillary lymph nodes. The group of 445 such patients underwent axillary lymphadenectomy, and the other 446 without axillary surgery received a further breast-conserving procedure — whole-breast radiotherapy from two tangential fields, including in the target volume the area of the previously operated sentinel lymph nodes. All patients received adjuvant systemic therapy. After the median observation time of 6.3 years no difference was found in the disease-free survival (DFS 82% vs. 84%) and in the overall survival (OS 92% vs. 92%). The relapse rate at five years reached 1.6% in patients undergoing only the sentinel lymph node procedure and 3.1% in those treated with axillary lymphadenectomy (p = 0.11). Based on the results of this study, it was accepted to resign from the axillary lymphadenectomy in breast cancer patients in clinical stage T1N0, post breast-conserving surgery, with a macro-metastasis to 1–2 axillary lymph nodes, if the adjuvant radiotherapy from two tangential fields to the whole breast and the area of the previously operated sentinel lymph nodes is planned.

The AMAROS study, published in 2014 in Lancet Oncology [36], included 1425 patients with macro-metastases (> 2 mm) to the axillary lymph node, detected during the sentinel lymph node procedure. Axillary lymphadenectomy was performed in 744 patients, and in 681 patients the axillary area was irradiated. After five years of observation the relapse rate reached 0.43% post axillary lymphadenectomy and 1.19% post axilla radiotherapy; no influence on the disease-free and overall survival was observed.

Based on the results of these studies the experts of the St Gallen 2015 conference [13] accepted to omit axillary lymphadenectomy in patients with macro-metastasis to 1–2 lymph nodes, post breast-conserving surgery and sentinel lymph node procedure, as these patients will receive adjuvant radiotherapy to the whole breast and the axillary lymph nodes area and adjuvant systemic treatment. If mastectomy has been performed in a patient with clinical stage I, and macro-metastasis is detected in 1–2 lymph nodes by histopathological examination (no radiotherapy is planned), this patient must have an axillary lymphadenectomy.

Radiotherapy and a biological breast cancer subtype

The risk of local and loco-regional relapse depends on the biological breast cancer subtype. Clinical trials including 500 breast cancer patients in clinical stage I post breast-conserving surgery demonstrated that the risk of the local or loco-regional relapse after 10 years of observation in the luminal A, luminal B, HER-2 positive, and triple negative cancer type was, respectively, 4.8%, 8.6%, 15.3%, and 17.3% [37]. Also, in another study including 618 patients treated with breast-conserving surgery or with mastectomy, the risk of loco-regional relapse was significantly higher in the HER-2 positive and triple negative cancer subtypes [38].

Regardless of the aforementioned results, until now there has been no advice in any international recommendations concerning individual adjustment of the radiotherapy dose to a breast cancer subtype. There are some ongoing studies aiming to precisely define the indication for APBI depending on the biological breast cancer subtype (use of APBI especially in the type luminal A) [39] and a randomised clinical trial, LUMINA, concerning to omit from radiotherapy post breast-conserving surgery in patients > 60 years old, with the breast cancer in I clinical stage T1N0, luminal A, receiving tamoxifen [personal communication — Ian Kunkler, seminary at the SABCS St Antonio 2014 conference].

In everyday clinical practice in the Institute of Onco­logy in Warsaw, the biological breast cancer subtype upon qualification for radiotherapy concerns patients with 1–3 involved lymph nodes. In these patients, a biological cancer subtype HER-2 positive or triple negative is considered as one of many risk factors influencing the qualification to adjuvant, postoperative radiotherapy.

Radiotherapy after neoadjuvant treatment

According to the latest St Gallen 2015 and ESMO 2015 conference recommendations, patients with primary locally advanced breast cancer, who had received neoadjuvant chemotherapy before mastectomy, have indications for postoperative radiotherapy regardless of the overall pathological cancer regression [12, 13]. The decision to use radiotherapy depends on baseline staging of the tumour and relevant indications for post-operative radiotherapy.

If the locally advanced breast cancer post induction chemotherapy remains unresectable then one may consider the use of radical radiotherapy to the whole breast and to the regional lymph nodes in a standard dose of 50 Gy with the boost onto the tumour tissue to 60–76 Gy depending on the doses tolerated by the healthy tissues [12].

The decision to use radiotherapy depends on baseline staging of the tumour and relevant indications for post-operative radiotherapy.

If a patient with a primary resectable — but extensively advanced for primary breast-conserving surgery — breast cancer starts a preoperative systemic treatment, the radiotherapy post breast-conserving surgery typically involves the whole breast, but the additional boost is delivered to the primary tumour volume (tattoo marks should be placed prior to the treatment) regardless of the tumour mass reduction post induction systemic treatment [13].

Conclusions

In recent years substantial advances have been made in planning and radiation treatment techniques. Nonetheless, not all radiotherapy problems have been solved. A priority is to continue to improve radiotherapy techniques in order to further limit the cardiotoxicity risk. There is no clear evidence whether low radiation doses delivered to relatively vast healthy tissue areas, especially in combination with intensive chemotherapy, will have a negative influence on patients’ health condition in the future. A second issue requiring further investigations and implementation into everyday clinical practice is to define a precise relation between the biological subtype of breast cancer and the effective radiotherapy dose or target radiotherapy volume in order to individualise the local treatment depending on the cancer biology. The preliminary results of clinical trials suggest the possibility to decrease the doses or the target radiotherapy volume, or even to resign from radiotherapy in patients with favourable biological luminal type A in the early clinical stages of the cancer, while in the HER-2 positive and triple-negative cancer type the actual treatment rules must be completely preserved.

Risk-adapted radiation therapy has become a new challenge for oncologists and radiotherapists, and the individualised attitude to treatment in the patients has led to the development of personalised medicine.

This paper has not been supported by any financial sources

Address for correspondence:

Dr hab. n. med. Anna Niwińska

Klinika Nowotworów Piersi i Chirurgii Rekonstrukcyjnej

Centrum Onkologii — Instytut im. Marii Skłodowskiej-Curie w Warszawie

e-mail: annaniwinska@gmail.com

Oncology in Clinical Practice

2016, Vol. 12, No. 1, 18–24

Translation: dr n. med. Aleksandra Hołowiecka

Copyright © 2016 Via Medica

ISSN 2450–1654

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