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ORIGINAL ARTICLE
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Evaluation of breathing-adapted radiation therapy for right-sided early stage breast cancer patients


 Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Gn.TevfikSaglam Cad., Etlik, 06018, Kecioren, Ankara, Turkey

Date of Submission14-Feb-2019
Date of Decision28-Apr-2019
Date of Acceptance06-May-2019

Correspondence Address:
Selcuk Demiral,
Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Gn.TevfikSaglam Cad., Etlik, 06018, Kecioren, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_140_19

  Abstract 


Background: Adverse effects of breast irradiation have been an important concern given the increased survival of early stage breast cancer (ESBC) patients with more effective treatments. However, there is paucity of data on the utility of Active Breathing Control (ABC) technique for right-sided ESBC patients. In this study, we assessed the incorporation of ABC into adjuvant Radiation Therapy (RT) of right-sided ESBC patients and report our dosimetric results.
Methods: Thirty-six patients receiving whole breast irradiation followed by a sequential tumor bed boost were included in the study. All patients received field-in-field intensity modulated radiation therapy with incorporation of active breathing control-moderate deep inspiration breath-hold (ABC-mDIBH) after breast conserving surgery. Dose–volume parameters in both plans with and without ABC-mDIBH were compared using Mann-Whitney U test.
Results: Mean lung dose decreased from 7 Gy to 5.2 Gy (26% reduction) for the total lung (p < 0.001) and from 12.6 to 9.4 Gy (25% reduction) for the ipsilateral lung (p < 0.001). Mean dose decreased from 4.6 Gy to 1.7 Gy (58% reduction) for liver (p < 0.001) and 1.7 Gy to 1.4 Gy (16% reduction) for the heart (p < 0.001).
Conclusion: Our study revealed that incorporation of ABC-mDIBH into adjuvant RT of right-sided ESBC patients results in significantly improved critical organ sparing.


Keywords: Active breathing control, breast cancer, breast-conserving surgery, breath-hold, radiotherapy
Key Message: Incorporation of breathing adapted radiation therapy for radiotherapeutic management of right-sided early stage breast cancer patients significantly improved critical organ sparing in our study. This viable strategy may be utilized for improving the toxicity profile of radiation therapy for right-sided early stage breast cancer patients.



How to cite this URL:
Demiral S, Sager O, Dincoglan F, Uysal B, Gamsiz H, Elcim Y, Dirican B, Beyzadeoglu M. Evaluation of breathing-adapted radiation therapy for right-sided early stage breast cancer patients. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297012





  Introduction Top


Breast cancer remains to be a major health concern as the most frequently diagnosed cancer in women and a leading cause of cancer-related deaths in females worldwide.[1],[2],[3] Radiation therapy (RT) plays a central role in breast cancer management with increased use of breast conserving therapy (BCT). While there is compelling evidence to justify the institution of RT after breast conserving surgery (BCS) to improve local control and survival, adverse effects of breast irradiation have been an important concern given the increased survival of early stage breast cancer (ESBC) patients with more effective treatments.[4],[5],[6]

Several studies have focused on improving the toxicity profile of radiation delivery for patients with breast cancer using different RT approaches, and dosimetric benefits of breathing-adapted RT have been reported in the era of contemporary RT techniques.[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20]

Among the several techniques used for improving the toxicity profile of radiation delivery for breast cancer patients, Active Breathing Control (ABC) system deserves utmost attention and has proved to be useful for left-sided breast cancer management particularly for cardiac sparing.[10],[11],[12],[13],[14],[15],[16],[17],[18] However, there is scant data on the utility of ABC for right-sided breast cancer patients. In this study, we assessed the impact of ABC technique on lung, heart, and liver doses in right-sided ESBC radiotherapy and report our comparative dosimetric results.


  Materials and Methods Top


Between January 2018 and October 2018, 36 patients with right-sided ESBC (pT1-2N0M0) were included in the study. Patients were treated with whole breast irradiation (WBI) followed by a sequential tumor bed boost using active breathing control-moderate deep inspiration breath-hold (ABC-mDIBH) after BCS. Written informed consents of all patients were acquired prior to treatment with institutional tumor board approval at our tertiary cancer center, and the study was performed in compliance with the Declaration of Helsinki principles and its later amendments. RT was delivered at mDIBH by using the ABC system (ABC, Elekta, UK) for all patients. Patient, tumor, and treatment characteristics are summarized in [Table 1].
Table 1: Patient, tumor, and treatment characteristics

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Radiotherapy technique

Before computed tomography (CT)-simulation, patients were trained for improving their compliance with the ABC system. Instructions about achieving reproducible mDIBH for precision RT and potential benefits of the ABC system were explained to the patients. Individual thresholds for mDIBH were determined and saved to be used for CT-simulation and treatment. The training session was completed after it was confirmed that the patients complied with breathing adapted RT procedure by achieving reproducible breath holding at moderate-deep inspiration with the ABC system.

After supine positioning and optimal immobilization of the patients using a breast board, CT-simulations with free breathing (FB) and ABC-mDIBH were performed at the CT-simulator (GE Lightspeed RT, GE Healthcare, Chalfont St. Giles, UK) in our department. Two sets of images were acquired with FB and ABC-mDIBH for all patients using a slice thickness of 3.75 to 5 mm. The FB scan was used for dosimetric comparison purposes and also served as a substitute in case of impaired patient compliance due to infections, etc., Radiation treatment planning (RTP) for actual treatment was based on CT-simulation images acquired at mDIBH.

For each patient, clinical target volume (CTV) contouring was performed in accordance with the European Society for Radiotherapy and Oncology (ESTRO) guidelines.[21] The planning target volume (PTV) was generated by adding a 5 mm margin to the CTV, but PTV was cropped up to 5 mm from the surface of the skin. All patients had surgical clips in the tumor bed, and CTV boost was obtained with an isotropic expansion of surgical clips by 1 cm clipping the volume 3 mm inside skin profile or at chest wall. PTV boost was obtained with an isotropic expansion of CTV boost clipping the volume 3 mm inside skin profile and not allowing for more than 4 mm inside lung. Right lung, left lung, whole lung, liver, heart, and contralateral breast were delineated as organs-at-risk (OARs). The same physician performed delineation of target volume and OARs on the two image sets of each patient (with FB and ABC-mDIBH) using Advantage-Sim MD simulation and localization software (Advantage-Sim MD, GE, UK) to prevent interobserver variability. The same physicist was involved in generation of two different RT plans (FB and mDIBH) for each patient using identical beam organization and target coverage with PrecisePLAN (Elekta, UK) Treatment Planning System.

All treatments were delivered at the linear accelerator (LINAC) (Synergy, Elekta, UK) at our department with image guidance for online set-up verification by use of Electronic Portal Imaging Device (EPID) (Iview, Elekta, UK) and kilo-Voltage Cone Beam Computed Tomography (kV-CBCT) (X-ray Volumetric Imaging (XVI), Elekta, UK). All patients received field-in-field intensity modulated radiation therapy (FIF-IMRT) with incorporation of ABC-mDIBH. After WBI to a dose of 50 Gy with daily fractions of 2 Gy was delivered over 5 weeks, a sequential boost dose of 10 Gy was delivered in five daily fractions of 2 Gy for all patients.

Statistical analysis

Dose–volume histograms (DVHs) acquired from two RT plannings of each patient were used in comparative assessment of dose–volume parameters in both plans, with and without ABC-mDIBH. Assessed dose–volume parameters included volume receiving ≥20 Gy (V20), lung volume and mean lung dose (MLD) for the lungs, volume receiving ≥5 Gy (V5), V20, lung volume and MLD for the right lung, V5 and mean heart dose (MHD) for the heart, volume receiving ≥10 Gy (V10), volume receiving ≥30 Gy (V30), mean liver dose, liver volume which received 50% of the prescribed dose and volume of liver within the treatment field for the liver. Mann–Whitney U test was used for comparison of dose–volume parameters. Statistical analysis was performed using Statistical Package for the Social Sciences, version 15.0 (SPSS, Inc., Chicago, IL) software with the level of significance set at P < 0.05.


  Results Top


The median age was 47 years (range: 41-57 years), median duration of mDIBH was 24.4 seconds, and the median threshold for mDIBH was 1.8 liters. 20 patients (55.6%) had stage I and 16 patients (44.4%) had stage IIA breast cancer. Reproducibility of setup has been secured by use of periodical image guidance with Electronic Portal Imaging Device (EPID) (Iview, Elekta, UK) or kilo-Voltage Cone Beam Computed Tomography (kV-CBCT) (X-ray Volumetric Imaging (XVI), Elekta, UK) before treatment fractions, and all patients completed RT with ABC-mDIBH as planned. Total volume of the lungs was 2349 cc (range 1576 to 3213 cc) with FB and 3892 cc (2712 to 4890 cc) with ABC-mDIBH. While the mean increase in total volume of the lungs with ABC-mDIBH was 1543 cc (37% mean increase), mean increase in lung V20 was 107 cc (27% mean increase) which is in favor of lung V20 (p < 0.001). Mean reduction in V20 was 4.1% for lungs and 6.1% for ipsilateral lung (p < 0.001).

MLD decreased from 7 Gy to 5.2 Gy (26% reduction) for the total lung (p < 0.001) with a difference larger than 1.0 Gy for 29 patients. There was no difference ≥3.0 Gy for total lung MLD. For the ipsilateral lung, MLD decreased from 12.6 to 9.4 Gy (25% reduction) with a difference larger than 2.0 Gy for 27 patients (p < 0.001). Mean dose decreased from 1.7 Gy to 1.4 Gy (16% reduction) for the heart (p < 0.001). For right-sided breast cancer patients, the heart doses are usually low as expected. The difference in heart doses is very low with the differences below 0.5 Gy for 34 patients. Mean dose decreased from 4.6 Gy to 1.7 Gy (58% reduction) for liver (p < 0.001). Mean reduction in the liver volume which received 50% of the prescribed dose was 56 cc (p < 0.001). The difference above 5.0 Gy was observed in nine patients. Dose–volume parameters of the both lungs, right lung, heart, and liver acquired from the dose–volume histograms of the two plans with and without ABC-mDIBH are shown in [Table 2]. [Figure 1] shows axial planning CT images of a patient with ABC-mDIBH and FB.
Table 2: Dose-volume parameters of the 2 plans with ABC-mDIBH and FB

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Figure 1:Axial planning CT images of a patient with ABC-mDIBH (a) and FB (b)

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  Discussion Top


Dosimetric results in our study based on comparative analysis of dose–volume parameters acquired from RT plans with FB and ABC-mDIBH revealed a statistically significant reduction in critical organ doses with incorporation of ABC-mDIBH [Table 2]. In the present study, MLD decrease was 1.8 Gy (26% reduction) for the total lung and 3.2 Gy for the ipsilateral lung (25% reduction). Mean reduction in V20 was 4.1% for lungs and 6.1% for in ipsilateral lung (p < 0.001). In the study by Essers et al, MLD reduction was very small (0.5 Gy) in the local breast radiotherapy.[22] In the previous studies, ipsilateral lung V20 reductions were reported between 1.7% and 5.2% in breast cancer radiotherapy and lung V20 Gy has been shown to be an important predictive parameter for pulmonary toxicity in breast cancer radiotherapy.[12],[16],[22],[23],[24],[25],[26]

There is little information relationship between pulmonary dose reduction and pulmonary side effects.[22],[25],[26],[27],[28] Reduction in lung doses may decrease pulmonary toxicity, such as radiation pneumonia, pulmonary fibrosis and secondary lung cancer. Lind et al. reported the incidence of pneumonia as 0.9% in locally treated breast cancer and 4.1% in locoregional radiotherapy.[29] Korreman et al. reported the rate of pneumonia probability as 28.1% for FB and 4.3% for DIBH.[30] In the study by Smith et al., the incidence of 5-year pneumonia was reported as 0.72% in whole breast radiotherapy.[27] Also, elimination of exposure of a given critical organ (lung, liver etc.) may lead to elimination of any risk for radiation induced secondary cancers. In a meta-analysis, increased risk of lung, esophageal cancer, and sarcoma were reported after breast cancer radiotherapy.[31] Grantzau et al. reported that the median time between diagnosis of lung cancer secondary to breast cancer treatment was 12 years (range 1–26 years) and the risk of lung cancer increased by 8.5% per Gy delivered to the lung.[32] Although the risk of lung cancer is relatively low (0.8%), the number of long-term survivors after breast cancer treatment is increasing, emphasizing the importance of the need for radiotherapy techniques that protect normal tissues.[32]

In the previous studies, DIBH has been reported to reduce cardiac doses in left breast cancer radiotherapy, but the effect of DIBH on cardiac dose varies in right breast cancer radiotherapy.[12],[23],[30],[33],[34],[35] In the study by Pedersen et al., the median heart volume receiving >50% of the prescription dose was reduced from 8% for FB to 1% for DIBH but there was no meaningful change or slight difference in other studies.[22],[23],[36]

In our study, mean dose reduced from 1.7 Gy to 1.4 Gy (16% decrease) for the heart (p < 0.001). For right-sided breast cancer patients, the heart doses are usually low as expected. The difference in heart doses are very low with the differences below 0.5 Gy for 34 patients in our study. The importance of limiting cardiac doses has been reported in many studies.[23],[37],[38] In the study by Darby et al., rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy.[37] SEER data showed that the risk of cardiac events is reduced by modern techniques.[38] Small decreases in cardiac doses may have long-term benefits.

In right-sided breast cancer radiotherapy, liver doses are expected to be higher than left-sided breast cancer radiotherapy because liver and right breast are adjacent organs. With deep inspiration, liver moves away from the breast. There is little data on radiation-associated liver toxicity in breast cancer radiotherapy. In the study by Prabhakar et al., with analysis of only four patients, an average of 50% reduction in the dose of the liver with DIBH was reported.[24] Conway et al. showed that an average of 42 cc reduction in the liver volume which received 50% of the prescribed dose.[23] In our study, mean dose decreased from 4.6 Gy to 1.7 Gy (58% reduction) for liver (p < 0.001). The difference above 5.0 Gy was observed in nine patients. The volume of liver within the target volume decreased by 77% to 57.7 cc and mean reduction in the liver volume which received 50% of the prescribed dose was 56 cc. In the literature, if a mean dose of 30–32 Gy is applied to the liver, there is a risk of 5% radiation-induced liver disease (RILD) and the risk of RILD increases to 50% if the mean dose is 42 Gy.[39] These doses administered to the partial liver do not have clinical significance for RILD development, but irradiation of the liver with FB is undesirable in patients with this excellent prognosis. As per the ALARA principle, reducing the exposure of normal tissues may have several benefits. It is not clear that a decrease in irradiated liver volume will reduce treatment-related side effects but may be important in patients with poor hepatic functional reserve. In addition, functional and radiographic changes in liver have been reported to be common with incidental irradiation.[40]

Absence of clinical follow up to comment on treatment outcomes of the patients is an important limitation of this study which precludes assessing the clinical benefit of improved critical organ sparing with the ABC technique. Nevertheless, our dosimetric results which revealed improved critical organ sparing by use of ABC-mDIBH in this study may add to the current literature given the limited available data on the utility of breathing adapted RT with ABC-mDIBH for right-sided ESBC patients. With a relatively larger sample size, our study reports dosimetric results of a homogeneous patient group with right-sided ESBC receiving breathing adapted RT using the ABC technique. Reduced critical organ doses by incorporation of ABC-mDIBH may potentially translate into improved toxicity profile, and may allow for dose escalation particularly in the setting of focused RT delivery. Minimizing normal tissue exposure without comprimising target volume coverage is an excellent goal of RT in the millenium era to improve quality-of-life of cancer patients, and incorporation of ABC-mDIBH may potentially offer a viable strategy to achieve this goal for right-sided ESBC patients.


  Conclusion Top


Our study revealed that incorporation of ABC-mDIBH into adjuvant RT of right-sided ESBC patients results in significantly improved critical organ sparing. This viable strategy may be used to improve the toxicity profile of RT delivery but studies with long-term follow-up are warranted to assess clinical translations of improved critical organ sparing with ABC-mDIBH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

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