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ORIGINAL ARTICLE
Ahead of print publication  

A comparative study of pulmonary toxicity between hypofractionated and conventionally fractionated radiation therapy in postmastectomy carcinoma breast


1 Department of Radiotherapy, Asansol District Hospital, Asansol, India
2 Department of Radiotherapy, Nil Ratan Sircar Medical College and Hospital, Kolkata, India
3 Department of Radiotherapy, Coochbehar Government Medical College and Hospital, Coochbehar, West Bengal, India
4 Department of Radiotherapy, College of Medicine and Sagore Dutta Hospital, Kolkata, India

Date of Submission13-Jul-2022
Date of Acceptance08-Aug-2022
Date of Web Publication01-Nov-2022

Correspondence Address:
Linkon Biswas,
Department of Radiotherapy, Nil Ratan Sircar Medical College and Hospital, Kolkata
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_44_22

  Abstract 

Background: Hypofractionated schedule has multiple advantages over conventional fractionation radiation therapy in terms of logistics and patient compliance. However, pulmonary toxicity is a major concern in breast cancer radiotherapy about which there are limited data comparing these two radiation regimens. Objective: This study aimed at comparing these two radiation schedules in terms of acute pulmonary toxicity and parameters of pulmonary function. Materials and Methods: Postmodified radical mastectomy patients with nonmetastatic carcinoma breast were randomized into two groups: study-arm patients received hypofractionated radiotherapy with 42.5 Gy in 16 fractions, over 3.5 weeks, whereas control-arm patients received conventionally fractionated radiotherapy with 50 Gy in 25 fractions, over 5 weeks. Patients underwent pulmonary function test (PFT) before radiotherapy (baseline), then at one and 3 months after completion of radiotherapy for changes in parameters of PFT and acute toxicities. Results: PFT changes were comparable in both the arms at day 30 and day 90 postradiation. Incidences of cough 1 month after radiotherapy and 3 months after radiotherapy were comparable (P = 0.3 and 0.07). Higher grade dyspnea at 3 months posttreatment, though numerically was higher in the study arm, was not significant (P = 0.44). In study arm at 90 days postradiation, Grade 2 and Grade 3 radiation pneumonitis were numerically more (15% vs. 3% and 3.5% vs. 0%), but not statistically significant (P = 0.08). Conclusion: Both conventional and hypofractionated arms showed almost similar results in terms of acute pulmonary toxicity and change in PFT parameters. Hence, considering the logistic advantages, the hypofractionated schedule can be considered an effective alternative to conventional radiotherapy for postmastectomy breast cancer patients.

Keywords: Carcinoma breast, conventional fractionation, hypofractionated radiotherapy, postmastectomy, pulmonary toxicity



How to cite this URL:
Manna D, Sharma S, Roy C, Biswas L, Dasgupta A, Das TK. A comparative study of pulmonary toxicity between hypofractionated and conventionally fractionated radiation therapy in postmastectomy carcinoma breast. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=360286


  Introduction Top


Breast cancer is the most common cancer (11.7% of all cancers) worldwide and also the most common cancer in women (24.5% of all cancers). According to the GLOBOCAN 2020, in India, breast cancer is the most prevalent cancer among women estimating around 1.5 lakh new cases in a year.[1]

Postoperative adjuvant radiation therapy (RT) remains one of the cornerstones of breast cancer management to reduce the risk of local recurrence and improve survival. This postmastectomy RT to the chest wall can be delivered by conventional or hypofractionated radiotherapy. Postmastectomy hypofractionated radiotherapy has demonstrated equivalent locoregional control, cosmetic and normal tissue outcomes, as compared to conventional radiation.[2],[3],[4],[5] Moreover, as hypofractionation reduces treatment length, it improves patient compliance, and allows to treat a large number of patients in a relatively shorter period enabling more judicious use of resources.

The adjuvant radiotherapy of the chest wall is achieved with tangential beams which include part of the anterior thoracic cavity, thereby potentially affecting the lung and heart significantly increasing the risk of cardiac and pulmonary toxicity.[3] Moreover, most of the reported studies provided data for pulmonary changes in patients who underwent breast-conserving therapy.[6] Data pertaining to adverse effects of hypofractionated RT on lung function in postmastectomy patients are scarce in the literature. Hence, the present study was intended to evaluate the impact of hypofractionated post-mastectomy radiotherapy on pulmonary toxicity and compare it with that of conventionally fractionated radiotherapy.


  Materials and Methods Top


This was a single-institutional, double-arm, prospective, and comparative study in postmodified radical mastectomy patients of Stage II–III carcinoma breast aged between 20 and 70 years having adequate hematological, hepatic, and renal parameters and an Eastern Cooperative Oncology Group score of 0–2. Patients with bilateral, recurrent, or metastatic breast carcinoma and history of any other malignancy, chemotherapy, or radiotherapy were excluded from the study. This study was done between January 2018 and April 2019.

Ethical clearance was obtained from the Institutional Ethical Committee.

Study technique

Patients were randomized into two groups [Figure 1].
Figure 1: Flow Diagram of Study Protocol

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Study arm

Patients in this arm received 42.5 Gy in 16 fractions over 3.5 weeks, single fraction/day, 5 fractions per week.

Control arm

Patients in this arm received 50 Gy in 25 fractions over 5 weeks, single fraction/day, 5 fractions per week.

Radiotherapy technique

Telecobalt machine (Theratron 780E) was used to deliver external beam radiotherapy with conventional two-dimensional fields based on anatomical landmarks.

Patient positioning

Supine position with face turned toward the opposite side.

The upper limb of the diseased site was abducted at the shoulder joint at 90°. The opposite arm was by the side of the body.

The radiation portals used were:

  1. Two tangential chest wall fields (medial and lateral tangential)
  2. Supraclavicular field alone or supraclavicular and axillary fields (depending on indication).


Dose:

  • 42.5 Gy/16 fractions over 3.5 weeks in the study arm
  • 50 Gy/25 fractions over 5 weeks in the control arm.


Follow-up

All patients were evaluated for pulmonary function status before start of radiotherapy (baseline), then followed up at 1 month after completion of radiotherapy, and at 3 months after completion of radiotherapy with history, clinical examination, pulmonary function test (PFT), and imaging of thorax. Toxicities were graded as per the Radiation Therapy Oncology Group (RTOG) grading. PFT parameters evaluated were forced expiratory volume in 1st second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow 25%–75% (FEF 25%–75%). Symptoms corresponding to pulmonary function that were assessed during follow-up were cough and dyspnea. Radiation pneumonitis was assessed by imaging and clinical symptoms.

Statistical analysis

Data were analyzed and compared according to appropriate statistical tests using SPSS (Chicago, Illinois, United States) V.24 software and Microsoft Word–Excel. The significance of prognosis was statistically evaluated using nonparametric statistical methods. Any P < 0.05 was considered statistically significant.


  Results Top


Baseline characteristics

Both the arms of the study were comparable in terms of mean age of the patients, area of residence, laterality of disease, stage of disease at presentation, and performance status of the patients at the initiation of the study [Table 1].
Table 1: Distribution of baseline characteristics between two arms

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Pulmonary function test changes

The comparative analysis of PFT parameters including FVC%, FEV1%, FEV1/FVC, and FEF 25%–75% showed that most of the mean values were comparable between the two arms except FEV1 after 3 months of radiation. FEV1% at day 90 had dropped significantly in the study arm (P = 0.02). Although in conventionally fractionated radiotherapy, arm PFT parameters are better during the 1-month and 3-month follow-up, the differences were not statistically significant [Table 2].
Table 2: Comparison of pulmonary function test parameters between two arms

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Incidences of cough at 1 month (33% vs. 42%) and 3 months (38% vs. 55%) after radiotherapy were higher in the study arm than the control arm, but not significantly different (P = 0.3 and 0.07, respectively). Dyspnea was also comparable 1 month after completion of radiotherapy (P = 0.8). Although Grade 3 dyspnea at 3 months after treatment was numerically higher in the study arm, the difference was not statistically significant (P = 0.44).

Radiation pneumonitis of higher grades (Grade 2 and Grade 3) was numerically more (15% vs. 3% and 3.5% vs. 0%) in hypofractionated radiation arm at 3 months after radiation. However, the finding was not statistically significant (P = 0.08) [Table 3].
Table 3: Comparison of postradiation therapy (day 90) radiation pneumonitis

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  Discussion Top


A longer treatment duration in conventional fractionation leads to delay for many patients getting timely radiation in many institutions with a huge patient load and limited resources. However, as the treatment duration is less in hypofractionated regimen, this would result in substantial economic and logistic benefits for treating a large number of patients and becomes a compliable option for patients. However, hypofractionation with a larger radiation dose per fraction increases the possibility of late normal tissue damage. However, the linear-quadratic model predicts that the normal tissue toxicity is not increased when the fraction dose is modestly increased and the total dose is reduced, as in our case. It was seen that hypofractionated radiotherapy protocols are as effective as conventional radiotherapy, regardless of disease stage or type of breast surgery. In our study, patients treated with hypofractionated radiotherapy showed acceptable and manageable toxicity and locoregional control.

Due to their close proximity to the chest wall, radiation-induced heart and lung toxicity is a matter of concern. Pulmonary toxicity, mainly radiation pneumonitis, is directly related to the volume of lung tissue irradiated. Radiation pneumonitis is characterized by interstitial inflammation within the irradiated field, a nonproductive cough and/or low-grade fever. Radiation-induced pulmonary changes have been investigated in a majority of the trials for conventionally fractionated radiotherapy. Moreover, these studies provided literature for pulmonary changes in patients who underwent breast conservative surgery. Data pertaining to adverse effects of hypofractionated radiotherapy on lung function assessed using PFT in postmastectomy carcinoma breast patients are scarce. In the present study, we utilized PFT and certain symptoms such as cough and dyspnea to assess acute pulmonary toxicity using RTOG toxicity criteria.

In our study, the baseline values for FEV1%, FVC%, FEF 25%–75%, and the ratio of FEV1/FVC were statistically insignificant between the control and study arm (P values being 0.089, 0.338, 0.298, and 0.10, respectively). On day 30 postradiotherapy, the values for the above-mentioned PFT parameters were again comparable between the two arms (P > 0.05).

A study conducted by AlSaeed et al. showed a significant drop in FVC% and FEV1% at day 90 after completion of radiotherapy in postmastectomy carcinoma breast patients (P value for FEV1% = 0.042 and P value for FVC% = 0.033), but FEF (25%–75%) was not affected that much.[7] Spyropoulou et al. reported a reduction in the values of FVC, FEV1, and DLCO at 3 months after treatment.[8],[9] In a study conducted by Blom Goldman et al., the median-matched vital capacity, FEV1, and total lung capacity were reduced by 15%, 9%, and 7%, respectively, at the long-term follow-up (P < 0.001).[10] However, Jaén et al. showed in a prospective study with 7-year follow-up that PFT values decreased in the first 2 years, but practically recovered their baseline values in the long term.[11] Our study also showed that at day 90 postradiation, there was a significant drop in FEV1% and FVC% in both the arms, but the difference was not statistically significant between the arms (P = 0.02 and 0.189, respectively).

For symptoms like cough, 30 days postradiotherapy, incidences were not significantly different in the two arms. However, on day 90 postradiation, the hypofractionated radiation arm showed more incidences of Grade 2 (21% vs. 13%) and Grade 3 (21% vs. 3%) cough, but the results were not statistically significant (P = 0.087).

In the case of dyspnea, 30-day postradiation, the maximum grading for dyspnea found was Grade 2. In the control arm, two patients (6%) developed Grade 2 dyspnea, while in the study arm, it was three (9.3%), although it was statistically insignificant (P = 0.434). On day 90 postradiation, Grade 3 dyspnea was the highest grade for both the arms, and it was only numerically higher in the study arm (9% vs. 3%).

Shaaban et al. have reported a 4.7% incidence of radiation pneumonitis with the 40 Gy/15 fraction protocol.[12] Rastogi et al. found that Grade II or higher radiation-induced pneumonitis was found in 6% of the conventional fractionation group and 2% of the hypofractionated radiotherapy group.[13] Lingos et al. have reported incidences of radiation pneumonitis to be 2.9%.[6] Shaltout et al. and Plataniotis et al. evaluated the incidences of radiation pneumonitis after hypofractionated radiotherapy in early stage carcinoma breast patients. They used HRCT (high resolution computed tomography) thorax as a tool to monitor radiation pneumonitis and reported minimal effects of radiation on underlying lung parenchyma.[14],[15]

In our study, it was found that 1 month after irradiation, only Grade 1 pneumonitis was seen, which was more in the control arm (21% vs. 10%) evidenced by only radiographic findings. At 3 months (day 90) postirradiation, the maximum grade of pneumonitis in the control arm is Grade 1 (16.6%), whereas around 15.6% of Grade 2 and 3% of Grade 3 pneumonitis were observed in the study arm.

This study had its limitation: our sample size was small, so any statistical data have to be interpreted with caution. It was a single-institutional study; hence, the result derived cannot be extrapolated on the entire population. The entire study duration was about 15 months including patient accrual, intervention, and assessment. Hence, the late toxicity and the locoregional control and survival could not be assessed.


  Conclusion Top


In our study, both the control group and the study group showed almost similar results in terms of acute pulmonary toxicity. However, conventional fractionation is associated with higher costs and longer waiting lists, whereas short hypofractionated schedules have shown the same response in terms of tumor control, increased patient compliance, and reduced cost of treatment. Hence, hypofractionated radiotherapy can be offered as an effective and safe alternative to conventional radiotherapy for postmastectomy breast cancer patients.

Acknowledgment

We acknowledge our head of the department of radiotherapy for his guidance and all the patients who participated in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2020;68:394-424.  Back to cited text no. 1
    
2.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-41.  Back to cited text no. 2
    
3.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008;371:1098-107.  Back to cited text no. 3
    
4.
Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: Long-term results of a randomised trial. Lancet Oncol 2006;7:467-71.  Back to cited text no. 4
    
5.
Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362:513-20.  Back to cited text no. 5
    
6.
Lingos TI, Recht A, Vicini F, Abner A, Silver B, Harris JR. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1991;21:355-60.  Back to cited text no. 6
    
7.
AlSaeed EF, Balaraj FK, Tunio MA. Changes in pulmonary function tests in breast carcinoma patients treated with locoregional post-mastectomy radiotherapy: Results of a pilot study. Breast Cancer (Dove Med Press) 2017;9:375-81.  Back to cited text no. 7
    
8.
Spyropoulou D, Leotsinidis M, Tsiamita M, Spiropoulos K, Kardamakis D. Pulmonary function testing in women with breast cancer treated with radiotherapy and chemotherapy. In Vivo 2009;23:867-71.  Back to cited text no. 8
    
9.
Fleckenstein K, Gauter-Fleckenstein B, Jackson IL, Rabbani Z, Anscher M, Vujaskovic Z. Using biological markers to predict risk of radiation injury. Semin Radiat Oncol 2007;17:89-98.  Back to cited text no. 9
    
10.
Blom Goldman U, Svane G, Anderson M, Wennberg B, Lind P. Long-term functional and radiological pulmonary changes after radiation therapy for breast cancer. Acta Oncol 2014;53:1373-9.  Back to cited text no. 10
    
11.
Jaén J, Vázquez G, Alonso E, León A, Guerrero R, Almansa JF. Changes in pulmonary function after incidental lung irradiation for breast cancer: A prospective study. Int J Radiat Oncol Biol Phys 2006;65:1381-8.  Back to cited text no. 11
    
12.
Shaaban L, Elkholy M, Abbas H. Pulmonary toxicity of postoperative adjuvant chemo-radiotherapy for breast cancer. Egypt J Chest Dis Tuberc 2010;4:59-63.  Back to cited text no. 12
    
13.
Rastogi K, Jain S, Bhatnagar AR, Bhaskar S, Gupta S, Sharma N. A comparative study of hypofractionated and conventional radiotherapy in postmastectomy breast cancer patients. Asia Pac J Oncol Nurs 2018;5:107-13.  Back to cited text no. 13
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14.
Shaltout EA, El Razek A. Adjuvant post-mastectomy hypofractionated radiotherapy in Egyptian cancer patients: A 2 years follow-up. Ann Oncol 2012;23:34-6.  Back to cited text no. 14
    
15.
Plataniotis G. Hypofractionated radiotherapy in the treatment of early breast cancer. World J Radiol 2010;2:197-202.  Back to cited text no. 15
    


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