Breast carcinoma has become an important global public health problem. In the United States of America (USA), breast carcinoma is now the most commonly detected cancer in women. According to The Global Cancer Observatory (GLOBOCAN) 2018, there were 20,88,849 newly diagnosed breast cancer cases, with 6,26,679 deaths globally. In India, there were 1,62,468 newly diagnosed breast cancer cases with 87,090 deaths.[
] Globally, breast cancer causes 25% of the cancer cases and 15% of the cancer deaths; the incidence and mortality rates vary resulting in high-incidence and low-incidence areas.[ 1 ] 2
The treatment modalities for patients with breast cancer include surgery, chemotherapy, radiotherapy, hormonal therapy, and targeted therapy. Adjuvant radiation has been used following mastectomy for decades. It has been well established that mastectomy without adjuvant radiation results in excellent locoregional control for most patients with non-invasive or early-stage, lymph node–negative disease. In contrast, patients with locally advanced breast cancer, that is, with four or more positive lymph nodes, or T3/T4 primary tumors have a clinically relevant risk of recurrence after surgery and benefit from adjuvant radiation in terms of a decreased risk of locoregional recurrence and a prolongation of survival.
[3–7] Postmastectomy radiotherapy also reduces the risk of locoregional recurrence in patients with the involvement of one to three axillary lymph nodes.[ ] Adjuvant radiotherapy is generally dosed at 45–50 Gy, given in conventional fractionation over 5 weeks. 8
Hypofractionation refers to the delivery of the radiotherapy dose in a smaller number of fractions than that of the conventional dosing scheme. The daily dose per fraction, therefore, is higher than that given conventionally.[
] The breast is a late-reacting tissue. Considering the theoretical radiobiological advantage of hypofractionated radiotherapy due to the low alpha/beta ratio (4) in carcinoma breast (around 4 Gy), studies have compared hypofractionation with conventional fractionation.[ 9 10 ] The UK Standardisation of Breast Radiotherapy Trial (START)-A and START-B trials have shown that hypofractionated radiotherapy is as effective as conventional fractionation radiotherapy.[ 11 12 ] Hypofractionated radiotherapy is now used in many countries as the standard adjuvant treatment in carcinoma breast. 13
The heart and lungs are two critical organs at risk that should be properly evaluated during postmastectomy radiation therapy. The most common radiotherapy-induced cardiac
toxicity is acute pericarditis. Radiation-induced cardiomyopathy results from dense and diffuse fibrosis. A case–control study reported that the risk of cardiac toxicity increased by 7.4% per Gy increase in the mean heart dose.[ ] This increment in cardiac 14 toxicity started within 5 years of the completion of radiotherapy. Most patients with node-negative breast cancer who have undergone breast conserving surgery receive a mean heart dose of 1 Gy or less, although higher doses are more common with left breast radiotherapy, in which the internal mammary lymph node region is also targeted.[ ] The expectation is that modern simulation and planning techniques, which reduce the cardiac radiotherapy dose, are associated with a very low risk of coronary artery disease. The risk of cardiac 15 toxicity is low compared with the survival advantage that results from radiotherapy in case of both breast-conserving surgery and mastectomy. A recent meta analysis reported that toxicities including cardiac events and secondary malignancies were of greater concern among patients who smoked, suggesting that smoking cessation may also be an important part of minimizing the treatment-related toxicities in these patients.[ ] 16
Radiotherapy also commonly affects the pulmonary endothelium and type 2 pneumocytes. Acute pneumonitis occurs weeks to months after radiation, and fibrosis occurs after several months to years. The symptoms of radiation pneumonitis include dyspnea, low-grade fever, and cough, which commonly develop within a few months after radiotherapy. Lung fibrosis can cause respiratory insufficiency. The lung tolerance decreases when radiation is combined with several chemotherapeutic agents.[
] The risk factors for radiation pneumonitis include smoking, advanced age, chronic lung disease, and diabetes. The use of concurrent chemotherapy has been reported to aggravate the risk of pneumonitis.[ 17 18 ] 19
To better evaluate the radiotherapy-induced complications in these two vital organs, we conducted a prospective, randomized study to compare the toxicities in the heart and lungs between patients who received conventional and hypofractionated radiotherapies following mastectomy for breast carcinoma.
MATERIALS AND METHODS
General study details
This randomized, single-institutional, open-label, non-crossover study was conducted between February 2019 and August 2021, at the Department of Radiotherapy at the Institute of Postgraduate Medical Education and Research and Seth Sukhlal Karnani Memorial (SSKM) Hospital, Kolkata, India. The study (IEC/2019/089) was approved by the Institutional Ethics Committee on February 4, 2019 (Supplementary appendix 1). Patients were enrolled in the study after appropriate counselling and written informed consent. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki and Good Clinical Practice Guidelines. The study was not registered in a public clinical trials registry. No funding was received for this study.
We enrolled female patients with locally advanced carcinoma of the left breast with clinical stage T3-4, N1-2, or any T, N2 disease; with HER2/neu negative status. Patients with abnormal baseline electrocardiogram (ECG), that is, ECG suggestive of ischemic heart disease; echocardiography [left ventricular ejection fraction (LVEF) <55%, or the presence of valvular heart disease] or abnormal baseline pulmonary function test (PFT) [forced expiratory volume in the first second (FEV1) <80%, forced vital capacity (FVC) <80%, diffusion capacity of the lung for carbon monoxide (DLCO) <60%] were excluded. There were no exclusion criteria based on age, or any laboratory parameters.
Our primary objective was to assess the late toxicities in the heart and lungs in patients with locally advanced left breast carcinoma who had undergone surgery and were planned for adjuvant radiotherapy with conventional versus hypofractionated radiotherapy. Heart and lung toxicities were assessed functionally with serial echocardiography and PFTs, respectively.
Eligible patients were randomized, by a simple randomization method, to either arm A (hypofractionated radiotherapy) or arm B (conventional radiotherapy). Randomization was performed before the initiation of neoadjuvant therapy. Baseline evaluation included the PFTs to assess the FVC, FEV1, and DLCO, and cardiac assessment by ECG and echocardiography.
All patients received neoadjuvant chemotherapy with three cycles of 5-fluorouracil (500 mg/m
2), epirubicin (100 mg/m 2), and cyclophosphamide (500 mg/m 2) (FEC) all administered as intravenous infusions on day 1 and repeated every 21 days followed by three cycles of docetaxel (100 mg/m 2) administered as an intravenous infusion on day 1 and repeated every 21 days. Modified radical mastectomy was performed after the completion of neoadjuvant chemotherapy. One patient in each arm received tamoxifen (continued for at least 5 years) as adjuvant endocrine therapy; all other patients with hormone receptor positive disease in both arms received anastrazole (continued for at least 5 years).
Following surgery, the patients were treated with adjuvant radiotherapy. The patients in Arm A (study arm) received a dose of 39 Gy in 13 fractions (3 Gy per fraction, single fraction/day, 5 fractions/week). Patients in Arm B (control arm) received 50 Gy radiation in 25 fractions (2 Gy per fraction, single fraction/day, 5 fractions/week). All patients were treated by the three-dimensional radiotherapy technique (3DCRT). Radiation was given by the external beam radiotherapy (EBRT) machine “Bhabatron II” with a Cobalt 60 source. The Phillips computed tomography (CT) simulation system (Brilliance Big-Bore model) was used for treatment simulation. The Oncentra Treatment Planning System (version 4.5) was used for EBRT planning. The target volume was the chest wall on the side of the mastectomy. In patients with involved axillary lymph nodes, the ipsilateral supraclavicular and infraclavicular regions were included. Three patients in arm A and one patient in arm B additionally received radiation to the ipsilateral levels 1 and 2 axillary nodal regions due to the presence of extranodal extension. Medial and lateral tangential portals were used for the chest wall and the direct anterior beam was used for the ipsilateral supraclavicular field. The heart and lung were contoured along with the other organs at risk (OAR) and the dose volume histogram (DVH) was analyzed. During DVH analysis, coverage of 90% of the target volume by 90% of the isodose curve was accepted. Optimization to some extent of the heart and lung doses was done with the help of asymmetric jaw.
The cardiac doses were assessed by the volume of the heart which received a radiation dose equivalent to 30 Gy and 40 Gy in 2 Gy per fraction, that is, V30 (EQD2) and V40 (EQD2), respectively, and the maximum heart distance. Cardiac
toxicity was assessed by evaluating the LVEF on echocardiography (conducted at the Department of Cardiology at our institute) every 6 mo.
The dosimetric study of the lungs was conducted by calculating the volume of the lungs that received a radiation dose equivalent to 5, 10, 20, and 30 Gy, in 2 Gy per fraction, that is, V5 (EQD2), V10 (EQD2), V20 (EQD2), and V30 (EQD2), respectively; the central lung distance and the mean lung dose. The central lung distance was defined as the distance between the mid-point of the posterior edge of the tangential field and the edge of the chest wall; it was used as a predictor of the lung doses. The mean lung dose was defined as the average dose of radiation received by the lung.[
] Pulmonary 20 toxicity was assessed by PFTs (conducted at the Department of Respiratory Medicine at our institute) at 6, 12, and 18 mo after the completion of radiotherapy. FVC, FEV1, and DLCO were chosen for the assessment of lung toxicity. Statistics
The sample size in our study was calculated by the formula:
n = 4σ 2/ E 2, where σ is the standard deviation, E is the allowable error, and n is the calculated sample size.[ ] In the study by dos Santos 21 et al.,[ ] a reduction of the FVC on spirometry occurred in 23.52% (±5.98). Thus, 2 SD (σ) was assumed to be 5.98, and 1 SD would be 2.99. The allowable error was set at 1. Therefore, 22 n = 4σ 2/ E 2 would be n = 4*(2.99) 2/(1) 2, which was calculated as n = 35.76. As this was a rather small sample size, we a priori planned to include a few more patients in an attempt to increase the power of the study. The power of the study was 75.5%, and the beta error was 0.245.
Data were analyzed in the Statistical Package for the Social Sciences (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). We performed a per-protocol analysis, as we could only include the patients who were not lost-to-follow-up in the
toxicity assessment. The equality of variances of the two arms was compared using Levene’s test. Numerical variables were compared between the two arms using the independent sample t-test (unpaired t-test). Categorical variables were compared by the Chi-square test. The independent variable in the study was the different fractionation schedule of radiotherapy. The dependent variable was the change in the function of the lungs and heart, assessed by PFT and echocardiography, respectively. The level of significance in our study was set at 5%, that is, P ≤ 0.05 signified statistical significance. RESULTS
We enrolled 59 patients in the study, 31 to the hypofractionated radiation arm (Arm A) and 28 to the conventional radiation arm (Arm B). However, the data of 27 patients in arm A and 24 patients in arm B were analyzed [
Figure 1]. The mean follow-up period in arm A was 13.2 mo (range, 6 to 22) while that in arm B was 13.2 mo (range, 6 to 22.5). Patients enrolled in the two arms were well balanced in terms of their baseline clinicodemographic characteristics [ Table 1]. Figure 1:
Random assignment, therapy, and follow-up of the patients according to treatment group
Baseline characteristics of the patients
As the patients in the two arms received a different dose per fraction, the comparison of the dosimetry for the heart and lungs was done using the equivalent dose in 2 Gy per fraction (EQD2), that is, we compared the volume of the heart receiving 25.05 Gy (EQD2–30 Gy) and 33.4 Gy (EQD2–40 Gy) radiation in arm A with that in arm B receiving 30 Gy and 40 Gy radiation, respectively. Similarly, we compared the volume of the lungs receiving 3.93 Gy (EQD2–5 Gy), 8.35 Gy (EQD2–10 Gy), 16.7 Gy (EQD2–20 Gy), and 25.05 Gy (EQD2–30 Gy) radiation in arm A with that in arm B receiving 5 Gy, 10 Gy, 20 Gy, and 30 Gy radiation, respectively. There were no statistically significant differences between the means of V30 (EQD2) (
P = 0.52), and V40 (EQD2) ( P = 0.09) of the heart in the two arms. There were also no significant differences in the mean maximum heart distances between the two arms ( P = 0.43) [ Table 2]. Table 2:
Dosimetric analysis of the heart in the two types of radiation protocols, i.e., hypofractionated and standard radiation
There were no significant differences in the means of V5 (EQD2) (
P = 0.51), V10 (EQD2) ( P = 0.19), V20 (EQD2) ( P = 0.24), and V30 (EQD2) ( P = 0.77) of the lungs between the two arms. Similarly, there were no significant differences in the mean central lung distance ( P = 0.51) and the mean lung dose ( P = 0.62) between the two arms [ Table 3]. Table 3:
Dosimetric analysis of lungs in the two types of radiation protocols, i.e., hypofractionated and standard radiation
The follow-up data are provided in
Table 4. At 6, 12, and 18 mo of follow-up, there were no statistically significant differences in the cardiopulmonary toxicities between the patients treated with either conventional or hypofractionated radiation. In addition, there were no differences in the 2-year survivals of the patients treated with the two radiation techniques. Table 4:
Cardiac and pulmonary
toxicity analysis (functional) in the two types of radiation fractionation arms at 6, 12, and 18 months after the completion of radiotherapy DISCUSSION
For patients with breast cancer, hypofractionated radiotherapy has been shown to be as effective for locoregional control as the conventional fractionated schedule.[
12 ] Moreover, hypofractionation helps reduce the wait time and facilitates early rehabilitation resulting in less morbidity and better patient compliance.[ 13 ] Whelan 23 et al.[ ] had showed that hypofractionated adjuvant (following breast conservation surgery) radiotherapy (42.5 Gy in 16 fractions over 22 days) was comparable in terms of locoregional control to conventional fractionation (50 Gy in 25 fractions in 35 days). In our study on adjuvant breast radiation following surgery, we found no significant differences in the reduction of cardiac and pulmonary functions between conventional and hypofractionated radiotherapy. The cardiac and pulmonary toxicities were similar between the two arms. 24
The median age of the patients in our study was 54 years as compared to that in the study by Offersen
et al.,[ ] in which it was 59 years. The reason that our study included relatively younger patients may have been the fact that age was not a part of the eligibility criteria in our study, whereas only patients older than 40 years old were enrolled in the study by Offersen 25 et al.[ ] However, the median ages of the patients in the study by Rastogi 25 et al.[ ] were 46 years and 50 years in the two arms. In the study by Rastogi 26 et al., most of the patients were younger than 50 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 1. As opposed to the study by Rastogi et al., our study had included patients with an ECOG performance status 0 to 2, regardless of age.
We included only patients with left-sided breast carcinoma in our study, as the heart is on the left side, and we could, therefore, adequately compare the pulmonary and cardiac toxicities between the two radiotherapy schedules. Regarding the dosimetric analyses of the heart, the mean values of the cardiac V30 (EQD2) and V40 (EQD2) in the patients who received hypofractionated radiation were 27.44% and 11.25%, respectively. There was a difference in the DVH parameters of our study from that reported in the study by Deshmukh
et al.,[ ] in which the mean V25 to the heart was 6.6% in case of left-sided radiation, and 0% for radiation to the right side. This difference in DVH parameters was because we included only patients with left-sided disease. Thus, the mean radiation dose to the heart was higher in our study. In the study by Pattanayak 27 et al.[ ] the maximum heart distance for patients who received left-sided radiation was 2.9 cm. In our study, the maximum heart distance was 3.5 cm in the patients who received hypofractionated radiation and 3.4 cm in those who received conventional radiation. Our results were very similar to those reported by the two studies, as only patients with left-sided disease were compared. 28
In our study, the volume of the lung that received 20 Gy of radiation (V20) in the hypofractionated arm was 20.54%, versus 18.77% in those who received conventional fractionation. The mean lung dose in the patients who were treated with hypofractionated radiation was 7.75 Gy versus 7.48 Gy in those who received conventional fractionation. Thus, the dosimetric analysis of our study satisfied the recommendation from Krengli
et al.[ ] that it was desirable to minimize the lung volume receiving ≥ 25 Gy to reduce the pulmonary toxicities. 29
Similar to our finding of no difference in the pulmonary toxicities based on the type of radiotherapy, Kouloulias
et al.[ ] also reported that there was no difference in the occurrence of radiation pneumonitis between the patients who received hypofractionated radiotherapy and those who received conventional radiotherapy. In the study by Kouloulias 30 et al., CT scan-based criteria were used to grade pulmonary toxicities. We had assessed the pulmonary toxicities by serial PFTs. The development of clinical symptoms in patients with radiotherapy-induced lung toxicity is relatively uncommon. We chose functional assessment by PFT to properly assess the extent of pulmonary injury resulting from radiation. Anatomical injury ultimately leads to a decrease in the normal organ function. As our aim was to address the final step of toxicity, we chose PFT assessment rather than radiological investigation. The long-term follow-up data from the study by Shahid et al.[ ] suggested comparable pulmonary toxicities regardless of the fractionation schedules. Erven 31 et al.[ ] reported a bimodal decline in lung functions, that is, a first dip at 3 to 6 mo, then a mild recovery at 1 year followed by another decline at 8–10 years. In our study, we found no improvement in the FVC at 12 mo compared to that at 6 mo of follow-up. However, by 18 mo, there was an improvement in the FVC in both the arms. This suggests that the lung injury was at least partially reversible; long-term data from global studies are not available regarding the degree of recovery of pulmonary functions. In the study by Erven 32 et al., on multivariate analysis, the use of tamoxifen may have contributed to the late decline of PFT. In this study, right-sided irradiation was also associated with late reduction in FEV1. As we had included only patients with left-sided breast cancer, we were unable to comment regarding the corresponding findings in our patients. Moreover, we had only one patient with hormone receptor positive disease in each arm who received tamoxifen, hence we could not independently assess the effect of tamoxifen on cardiac and pulmonary functions. Another study by Krengli et al.[ ] had reported a significant deterioration of the pulmonary functions as assessed by the PFTs at 3 mo, with a partial recovery by 9 mo. 29
Our findings regarding the functional cardiac toxicities were in concordance with the existing evidence. Alagizy
et al.[ ] had reported that the use of hypofractionated radiotherapy in the adjuvant treatment of breast cancer resulted in no extra cardiac 33 toxicity compared with conventional fractionation. Similarly, Shahid et al.[ ] found no difference in the cardiac toxicities based on the fractionation schedule. Hearteningly, the long-term 15-year follow-up data reported by Chan 31 et al.[ ] did not show any difference in mortality attributable to cardiac causes between patients treated with hypofractionated and conventional-fractionated radiation. 34
To the best of our knowledge, there are no other studies comparing the pulmonary and cardiac toxicities between patients treated with 50 Gy in 25 fractions and those treated with 39 Gy in 13 fractions. With the advancement in modern radiotherapy techniques, including higher energy machines,
toxicity of the lungs and heart have become uncommon, especially those that manifest as clinical signs and symptoms. To appropriately assess for pulmonary and cardiac toxicities, we used functional assessments in our study in the form of PFT and echocardiography, respectively. The inclusion of only patients with left-sided breast carcinoma was another unique feature of our study.
Our study was, however, limited by the small sample size, and the fact that it was conducted at a single institution. This could be overcome by performing a multi-institutional larger study in the future. The maximum follow-up period in our study was short at 18 mo. It would be important to continue to follow-up the patients long term to adequately assess for the development of long-term toxicities.
Hypofractionated radiotherapy leads to similar toxicities to the heart and lungs as compared with conventional fractionation radiation and is a reasonable alternative to conventional fractionation in patients with breast cancer. In India, considering the poor patient compliance to the conventional schedule given the long duration of radiation, and to optimally utilize the resources in terms of manpower and machine, hypofractionated radiotherapy protocols (39 Gy in 13 fractions) have evolved and may become a standard in the future.
Study conception and design: SS, KC, PM, SM, SP, DM; data collection: SS, KC, PM, SM, SP, DM; analysis and interpretation: SS, KC, PM, SM, SP, DM; manuscript writing: SS, KC, PM, SM, SP, DM; approval of final article: all authors; accountability for all aspects of the work: all authors.
Data sharing statement
Individual de-identified participant data that are related to the results of this study, the informed consent form, and the statistical analysis plan will be made available on reasonable request, from Dr. Santu Mondal (email ID:
[email protected]) starting from the date of publication, until three years following publication. Requests beyond this timeline will be considered on a case-by-case basis. Requests will be accepted from researchers with a methodologically sound research proposal, for an approved study protocol. In addition, the study protocol has already been made available as a Supplementary Appendix attached to this manuscript. Financial support and sponsorship
IPGMER and SSKM hospital is a Government Medical College and Hospital. Patients received all treatment (chemotherapy, surgery, radiotherapy) free of cost.
Conflicts of interest
There are no conflicts of interest.
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