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ORIGINAL ARTICLE
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Comparison of two hypofractionated radiotherapy schedules in locally advanced postmastectomy breast cancer patients


1 Department of Radiotherapy and Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Radiation Oncology, Apex Cancer Institute, Apex Hospital, Varanasi, Uttar Pradesh, India
3 Department of Radiotherapy, SGPGIMS, Lucknow, Uttar Pradesh, India
4 Department of Radiotherapy and Oncology, Victoria Hospital, Port Louis, Mauritius
5 Department of Radiotherapy, National Cancer Institute, Jajjhar, Haryana, India
6 Department of Radiotherapy, AIIMS, Bhubaneshwar, Odisha, India
7 Department of Radiotherapy, AIIMS, New Delhi, India

Date of Submission08-Sep-2019
Date of Decision17-Nov-2019
Date of Acceptance07-Jan-2020
Date of Web Publication03-Nov-2020

Correspondence Address:
Neha Gupta,
Apex Cancer Institute, Apex Hospital, Varanasi - 2211 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_722_19

 > Abstract 


Introduction: The role of hypofractionated radiotherapy (HFRT) in postmastectomy breast cancer patients is not well established. This study was done to establish the role of two different HFRT schedules in the treatment of chest wall and regional lymph nodes after mastectomy.
Materials and Methods: Between 2012 and 2016, consecutively registered patients of locally advanced breast cancer patients having undergone mastectomy and adjuvant radiotherapy (RT) at a tertiary cancer center were analyzed. Locoregional recurrence (LRR) was the primary endpoint, whereas overall survival (OS), disease-free survival (DFS), and both acute and late adverse events were secondary endpoints.
Results: A total of 34 patients who were treated with 39 Gy in 13 fractions over 2½ weeks and 35 patients who were treated with 40 Gy in 15 fractions over 3 weeks were identified. The median follow-up period was 47 months and 63.5 months in the 39 Gy and 40 Gy arms, respectively. LRR was seen in 11.8% and 8.6% of patients in the 39 Gy and 40 Gy arms, respectively. OS at 4 years was 66% and 71.5% in the 39 Gy and 40 Gy arms, respectively. The mean DFS for 39 Gy and 40 Gy arms was 43.6 months and 66.4 months, respectively (P = 0.822). Acute skin toxicity was similar in the two groups. Arm edema was significantly more in the 40 Gy arm.
Conclusion: The two HFRT schedules are equivalent to each other in terms of survival outcomes. Arm edema is higher with 40 Gy arm as compared to 39 Gy arm.

Keywords: Adjuvant radiotherapy, altered fractionation, modified radical mastectomy



How to cite this URL:
Choudhary S, Gupta N, Misra S, Munnee NN, Kumar A, Ranjan R, Dhar SS, Kumar D, Mourya A, Aggarwal LM. Comparison of two hypofractionated radiotherapy schedules in locally advanced postmastectomy breast cancer patients. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299890




 > Introduction Top


Breast adenocarcinoma is known to have a low alpha/beta ratio of 4 Gy and therefore has high fractionation sensitivity. Hypofractionation in breast cancer has the potential to improve the satisfaction of the patients, employers, and payers as it shortens treatment time, saves medical resources, reduces medical costs, makes radiotherapy (RT) more convenient, and improves treatment compliance.

The UK and Canadian trials proved beyond doubt that hypofractionated RT (HFRT) is absolutely noninferior to conventional RT (CRT) both in terms of survival outcomes and late adverse events in patients with breast conservative surgery.[1],[2],[3],[4] Unfortunately, these trials failed to answer whether HFRT was equally safe and effective to CRT in postmastectomy patients. These landmark trials also did not address the effectiveness and safety profile of HFRT for regional lymph node irradiation (RLNI).

Therefore, this study was done to evaluate the safety and efficacy of two HFRT schedules in chest wall and RLNI irradiation in locally advanced breast cancer.


 > Materials and Methods Top


A database of histologically proven breast cancer patients registered between January 2012 and December 2016 in the RT outpatient department of a tertiary health-care center was studied. Those patients who met the following selection criteria were taken up for the study:

  1. Locally advanced nonmetastatic breast cancer patients (cT3-T4 or any cT with cN2+)
  2. Patients who had modified radical mastectomy (MRM) with or with axillary dissection
  3. Patients who had adjuvant RT to chest wall with or without RLNI.


Procedure

X-ray-based simulation was done for all the patients and RT portals were designed based on bony landmarks. Two tangential fields with half-beam block were used to cover the chest wall. Supraclavicular lymph nodes (LNs) were treated in patients who had four or more axillary LNs positive or had cT3–T4 disease. Direct anterior field was used to cover the supraclavicular fossa (SCF) with or without inclusion of axilla. Level I and II axillary LNs were treated in case of inadequate dissection of axilla, patients with unknown axillary LN status, and one who had very high axillary nodal burden. None of the patients in our study were treated for internal mammary chain LNs. The patients were treated to a dose of 40 Gy in 15 fractions over 3 weeks till December 2014. Thereafter, we decided to change the RT schedule to 39 Gy in 13 fractions over 2 weeks and 3 days to increase the machine throughput. All the patients were treated on a telecobalt unit. Bolus material was placed daily over the entire chest wall for cT4 disease and over the scar with T3 or less disease.

Patients were treated with anthracycline- and/or taxane-based chemotherapy regimens. Patients were started on RT after 3 weeks of completion of chemotherapy.

Tamoxifen or aromatase inhibitor (AI) was prescribed to premenopausal and postmenopausal females, respectively, with positive estrogen receptor and/or progesterone receptor for a period of 5 years. Patients with unknown receptor status were also given hormonal therapy for the same duration.

Her2neu receptor-positive patients were treated with trastuzumab for a period of 1 year.

Ethics committee approval

Because this was a retrospective study, approval of ethic committee was not required.

Statistical analysis

Locoregional recurrence (LRR) was considered as the principal endpoint. Disease-free survival (DFS), overall survival (OS), and late adverse events were the secondary endpoints. DFS and OS were calculated from the date of diagnosis of disease. Chi-square test was used to find out the differences in the characteristics in the two groups. DFS and OS were estimated using Kaplan–Meier survival plot. A comparison of survival curves was done using log-rank test. P<0.05 was considered statistically significant. Data analysis was done using SPSS Inc (Chicago, USA).


 > Results Top


We identified 69 patients who could fit into our selection criteria. Patients and tumor characteristics are mentioned in [Table 1], whereas treatment profile is mentioned in [Table 2]. In the 39 Gy arm, almost equal number of patients were below the age of 45 years and above. The other group had more number of young age patients (21 vs. 14). All the patients had infiltrative ductal carcinoma. Patients in the two groups were well balanced, except that lymphovascular invasion (LVI) positivity was significantly higher in the 40 Gy arm. Five patients in the 40 Gy arm had positive resection margin, whereas it was positive in one patient in the 39 Gy arm. Extranodal extension was seen in seven and eight patients in the 39 Gy and 40 Gy arms, respectively. Perinodal invasion was reported in one and four patients in the 39 Gy and 40 Gy arms, respectively. Twenty-two patients and 14 patients were in the poor prognostic group in the 39 and 40 Gy arms, respectively. The median time gap between surgery and start of RT was 5.5 months and 5.9 months for 39 Gy and 40 Gy arms, respectively. The number of patients with inadequate LN dissection was significantly high in the 40 Gy arm. All except 11 patients had RLNI. The median RT duration was 17.5 days and 20 days for 39 and 40 Gy arms, respectively. Twelve and seventeen patients in the 39 Gy and 40 arms, respectively, were not treated with standard combination of anthracycline and taxane. Most of the patients received few cycles before and after surgery. The median number of chemotherapy cycles in both the arms was six. Ten postmenopausal females were treated with anastrazole or letrozole and four had received tamoxifen. Out of 18 patients who were HER 2/neu receptor positive, only three had received trastuzumab. There were 23 patients alive in each arm at the time of analysis [Table 3]. The median follow-up (FU) period was 47 months and 63.5 months in the 39 Gy and 40 Gy arms, respectively. [Table 4] shows the pattern of failure. Of the seven patients who had LRR, six patients had stage IIIB disease and one patient had stage IIB disease. Visceral and bone metastasis were seen in almost equal number of patients in both the arms. OS at 4 years for 39 Gy and 40 Gy arms was 66% and 71.5%, respectively. The mean OS was 46.3 months and 70.7 months for 39 Gy and 40 Gy arms, respectively (P = 0.775). The median OS could not be reached [Figure 1]. DFS at 4 years was 67% and 66% for 39 Gy and 40 Gy arms, respectively. The mean DFS was 43.6 months and 66.4 months, respectively, for 39 Gy and 40 Gy arms (P = 0.822). The median DFS could not be reached [Figure 2].
Table 1: Patients and tumor characteristics

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Table 2: Treatment characteristics

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Table 3: Status of patients at the time of analysis

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Table 4: Pattern of disease failure

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Figure 1: Kaplan–Meier plot of overall survival

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Figure 2: Kaplan–Meier plot of disease-free survival

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Acute skin toxicity was similar among the two arms [Table 5]. Arm edema was found to be significantly high in the 40 Gy arm [Table 5]. None of the patients in both the groups had brachial plexopathy or cardiac morbidity. There was no case of rib or clavicular fracture.
Table 5: Adverse events

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 > Discussion Top


Most of the breast cancer patients who come to our center have locally advanced disease. MRM with axillary clearance is the usual surgical practice in these patients. Due to limited medical resources, we have been practicing HFRT in these patients for the last few years. To further increase the machine throughput, we changed the RT schedule of 40 Gy in 15 fractions over 3 weeks to 39 Gy in 13 fractions over 2.5 weeks. Despite significantly high incidence of LVI positivity and inadequate axillary clearance in the 40 Gy arm compared to 39 Gy arm, the LRR was less in the 40 Gy arm though the difference was nonsignificant. This was probably because more number of patients in the 40 Gy arm were either in luminal A or B category compared to those in the 39 Gy arm. The cumulative LRR at the time of analysis was 10.1% in our patients whereas the same was 8.3% at 5 years in a similar group of patients in a study conducted by Wang et al.[5] About 27.5% of our patients had inadequate axilla dissection, and in 4.3%, axilla was surgically not addressed, whereas all the patients in the above study had adequate axillary LN dissection. Only 42% of our patients had received hormonal therapy, whereas 75% of patients in the above reference study were treated with estrogen or AI. These two differences in the treatment probably resulted in higher LRR in our patients.

OS and DFS at 5 years in the HFRT arm in the study by Wang et al. were 84% and 74%, respectively. These were higher than found in our study. Anthracycline- and taxane-based regimes were given in about 58% of our patients (vs. 88% in a study by Wang et al.). Only 3 of 18 patients with positive Her2neu receptor were given trastuzumab. Hormonal therapy was offered to about 43% of our patients (vs. 75% in a study by Wang et al.) as the rest were hormone receptor negative. The inadequate systemic treatment, due to financial constraints, in many of our patients may have resulted in lower OS and DFS in our study.

RLNI was done in 84.1% of our patients. SCF and axillary nodes were treated in 84.1% and 60.9% our patients, respectively. This did not result in any brachial plexopathy. The percentage of patients in the 39 Gy arm who had axillary RT was 52.9, whereas the same was 68.6% in the other arm. Longer median FU period in the 40 Gy arm may be the second reason for the same. These differences might have resulted in higher incidence of arm edema in the later. The incidence of arm edema was higher in our study compared to that by Wang et al., probably because many of our patients had Level III axillary LN dissection apart from Level I and II.

Start P and Start A trial had used 39 Gy in 13 fractions over 5 weeks, hereas Start B had tested 40 Gy in 15 fractions over 3 weeks. RT schedule of 39 Gy in 13 fractions has never been compared with 40 Gy in 15 fractions with both given over 3 weeks. EQD2 of these two schedules for normal tissue assuming alpha/beta ratio as 3 is 46.7 Gy and 45.3 Gy, respectively.[6] The same for breast cancer cells assuming alpha/beta ratio as 4 is 45.5 Gy and 44.5 Gy, respectively. Therefore, 39 Gy in 13 fractions seems to be less gentle than 40 Gy in 15 fractions both for breast cancer cells and for normal tissue. This study shows that both the RT schedules are equally efficacious and safe. In developing countries where the medical resources are limited and where patients suffer from serious financial constraints, 39 Gy in 13 fractions over 2.5 weeks seems to be a better alternative than 40 Gy in 15 fractions over 3 weeks.

Khan et al. had conducted a phase II study in 69 postmastectomy patients with Stage II and IIIa where chest wall and regional LNs were treated with a dose of 36.63 Gy in 11 fractions with 5 fractions per week.[7] They could demonstrate low toxicity and high tumor control rate. The 3-year estimated local recurrence-free survival in the study was 89.2%, which was very similar to our study. The EQD2 with alpha/beta ratio of 3 and 4 Gy was 47.4 and 44.8 Gy, respectively. These values were similar to that of our study.

The main caveat of the study was its retrospective nature with limited number of patients. Because most of the LRR and late adverse events occur within 5 years of treatment, we feel that the median follow-up period in the 39 Gy arm is short by 1 year.[8]


 > Conclusion Top


HFRT with a dose schedule of 39 Gy in 13 fractions over 2.5 weeks seems to be noninferior to 40 Gy in 15 fractions over 3 weeks with regard to survival outcomes and both acute and late adverse events. Phase 3 multicentric randomized controlled trial may be done to confirm the results of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
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. 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 B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008;371:1098-107.  Back to cited text no. 2
    
3.
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. 3
    
4.
Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002;94:1143-50.  Back to cited text no. 4
    
5.
Wang SL, Fang H, Song YW, Wang WH, Hu C, Liu YP, et al. Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: A randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2019;20:352-60.  Back to cited text no. 5
    
6.
Bentzen SM. The linear-quadratic model in clinical practice. Basic Clin Radiobiol 2002;CRC press:134-46.  Back to cited text no. 6
    
7.
Khan AJ, Poppe MM, Goyal S, Kokeny KE, Kearney T, Kirstein L, et al. Hypofractionated postmastectomy radiation therapy is safe and effective:First results from a prospective phase II trial. J Clin Oncol 2017;35:2037-43.  Back to cited text no. 7
    
8.
Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: Long-term results of a randomised trial. Radiother Oncol 2005;75:9-17.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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