Hypofractionated versus Conventionally Fractionated Radiotherapy in Post-Mastectomy Breast Cancer Patients

Background & Objective: Hypofractionation has been used in curative setting in breast conservative surgery, but still no adequate information about its application in the adjuvant setting after mastectomy in breast cancer patients. The aim of this trial was to assess the efficacy and toxicity of hypofractionation radiotherapy (40 Gy in 15 fractions) in post mastectomy breast cancer patients and to compare these results with those of post mastectomy patients treated retrospectively by conventional radiotherapy (50 Gy in 25 fractions) as regard overall survival (OS), disease free survival (DFS), locoregional disease free survival (LDFS), and toxicities. Patients & Methods: One hundred post mastectomy breast cancer patients were included into this study, they were divided into 2 groups, the 1st included 50 patients treated prospectively with hypofractionated radiotherapy regimen (40 Gy in 15 fractions), and the 2nd (control group) included 50 patients treated retrospectively with conventionally fractionated radiotherapy regimen (50 Gy in 25 fractions). Results: The 2 year overall survival were 96% & 94% respectively (p = 0.7), while the disease free survival were 91% & 89.8%, respectively (p = 0.9), and the LDFS were 95.8% & 93.3%, respectively (p = 0.9), G1 acute dermatitis was observed in 22 (44%) & 25 (50%) patients in group I & II respectively, G2 in 8 (16%) & 10 (20%) patients respectively, no G4 skin toxicity was detected. Radiation pneumonitis was observed in 2 patients (4%) only in group II. Conclusion: post-mastectomy hypofractionated radiation therapy achieved comparable survival and toxicity to the conventionally fractionated radiotherapy with the advantage of reducing overall treatment time, treatment burden & cost.


Introduction & Objective
Breast cancer is the most commonly diagnosed cancer worldwide and it is the leading cause of cancer death in women.In 2016, 249,260 women have been diagnosed with breast cancer in the United States of America with 40,890 deaths [1].
Radiation therapy is a part of treatment in all breast conserving surgeries and for a large percentage of breast cancer patients after mastectomy, and it has been identified to decrease the local recurrence by 70% [2].
Also, it has a positive effect on overall survival, specifically in patients with a high incidence of loco-regional recurrence [3].
In spite of the established role of adjuvant radiotherapy, much debate remains about the ideal radiotherapy regimen to use.Several alternative fractionation regimens have recently been assessed and compared with the standard fractionation schedule (25 fractions, 2 Gy each/5 weeks) [4].
The alternative fractionation schedule that has received the most attention is hypofractionation, in which radiation is delivered using a lower number of fractions of more than 2 Gy each (40 Gy/15 daily fractions of 2.67 Gy to the whole breast, with a boost dose of 15 Gy in 3 Gy fractions) [5].
The theoretical advantages of hypofractionation include an improvement in cell killing from the increase in fraction size and a reduction in treatment duration.Furthermore, shortening the treatment duration means that more patients can be treated with a limited number of machines, a concern that arises in many countries in which access to radiation therapy is limited [6].
Many trials have confirmed that, hypofractionated radiotherapy schedules are equivalent to conventionally fractionated radiation of 50 Gy in 25 sessions irrespective of stage or breast surgery [5] [7], hypofractionated whole breast irradiation is a preferred option in United States of America, Canada and United kingdom because of its low cost and geographical convenience [8].
Due to these established data, hypofractionation has been used in curative setting in breast conservative surgery, but still no adequate information about its application in the adjuvant setting after mastectomy in breast cancer patients.
At our department, hypofractionated radiotherapy was applied first in late 2013 as an adjuvant treatment after breast conserving surgery in node negative patients, and since then, it was used.Currently, almost all patients needing adjuvant radiotherapy to the chest wall receive hypofractionated regimen (40 Gy in 15 fractions).
The aim of this trial was to assess the efficacy and toxicity of hypofractionation radiotherapy (40 Gy in 15 fractions) in post mastectomy breast cancer patients and to compare these results with those of post mastectomy patients treated retrospectively by conventional radiotherapy (50 Gy in 25 fractions) as regard overall, disease free and loco-regional disease free survival, and toxicities.

Radiation Therapy Techniques
Patients were planned in the supine position over a breast board with arms directed cranially using computerized tomography (CT) simulation, with CT slices of 5 mm thick.Standard two tangential fields were used to treat the breast; an additional supraclavicular field was added if lymph nodes treatment was indicated.All patients were planned by 3D-Conformal radiotherapy (3D-CRT) with ELEKTA Linear Accelerator, and precise treatment planning software.
The control CFRT group were given 5000 cGy/25 fractions/5 weeks at 200 cGy per fraction, 5 days per week.
The photon energy used in both groups was either 6 MV or 15 MV.

Radiation Toxicity and Its Grading
During the radiation therapy schedule; patients were weekly observed for the acute radiation reactions and it was reported and graded according to the Radiation Therapy Oncology Group (RTOG) toxicity criteria.
After ending radiation schedule, patients were followed up every 2 weeks for one month and then, every month to a minimum of 6-months for late reactions, shoulder movements restriction, and brachial plexopathy and radiation pneumonitis.

Statistical Analysis
Data was analyzed by SPSS, program statistical package for social science version 16.
To test the normality of data distribution, K-S (Kolmogorov-Smirnov) test was done, only significant data revealed to be nonparametric.However all tested data revealed to be parametric.The description of the data done in form of mean (+/−) SD for quantitative data, while frequency & proportion for qualitative data.The analysis of the data was done to test statistical significant difference between groups.For quantitative data, student t-test was used to compare between two groups.Chi square test was used for qualitative data.

Results
The patients , characteristics were matched in between the two groups.1).
All the patients ended their adjuvant radiotherapy schedule.All patients tolerated radiation treatment well, with no radiotherapy interruption because of toxicity in the 1 st group, while in the 2 nd group, treatment was interrupted for 3 patients (for 4 -6 days) because of G III skin toxicity.
The median duration of radiation interruption because of patient inconvenience & machine technical issues were 3 & 5 days in the 1 st & 2 nd groups, respectively.

Acute Radiation Toxicity
As regard skin reaction, G1 was observed in

Discussion
In breast cancer, radiotherapy is given to all patients after breast conservation and if indicated for patients after mastectomy [9].
Conventional adjuvant radiotherapy to chest wall after modified radical mastectomy is 25 fractions within 5 weeks.Hypo fractionated radiotherapy uses a smaller number of fractions and larger doses per fraction more than 2 Gy [4] [7].
Different hypofractionated schedules had been identified, one of the commonest hypofractionation protocols is 40 Gy/15 fractions/3 weeks, Therefore, this schedule leads to decrease in treatment time from 5 weeks to 3 weeks with nearly the same local control and cosmetic rate, also, it has more convenient and has financial advantages as it has lower costs due to fewer travels to treatment centers compared to conventional radiotherapy [10].
Also, breast cancer radiation therapy is responsible for 25% -30% of all radiotherapy treatment burden.The hypofractionation regimen offers more efficient use of resources, so that more patients can be treated with the existing machines and personnel [11].
The results of numerous randomized trials which compared conventional fractioned radiotherapy (50 Gy in 5 weeks/25 fractions) for patients with breast cancer with hypo fractionated radiotherapy (39 -42.9 Gy/13 -16 fractions in 3 -5 weeks) indicated that hypofractionation can be safely delivered to most patients [12].So, the use of hypofractionation has gained increasing popularity as a post operative treatment following breast conservation [4] [7] [13] [14], but the data on post-mastectomy hypofractionation is still limited.At our department, hypofractionation was first adopted as adjuvant treatment after breast conserving surgery in 2013, and then it has been increasingly used since then.Currently, almost all patients requiring adjuvant radiotherapy receive hypofractionation schedule (40 Gy/15 fractions/3 weeks).This trial was done to assess the efficacy and toxicity of hypofractionation schedule (40 Gy in 15 fractions) in post mastectomy breast cancer patients and to compare these results with those of post mastectomy patients treated retrospectively by conventional radiotherapy (50 Gy in 25 fractions) as regard OS, DFS and loco-regional control, and treatment toxicities.
Also START B is a randomized trial involved 2215 early breast cancer patients who were given adjuvant radiotherapy by different schedules, 50 Gy/25 fractions at 2 Gy in 5 weeks versus 40 Gy/16 fractions at 2.67 Gy/3 weeks, locoregional tumor recurrence rates were comparable with slighty superior cosmetic outcome in hypofractionation group [4].
The British Columbia randomized trial of adjuvant radiotherapy after mastectomy included 318 premenopausal women with node-positive disease, who were randomized to receive locoregional RT.Patients received 37.5 Gy in 16 fractions to the chest wall and 35 Gy in 16 fractions to the regional nodes, patients in the hypofractionated group had a lower incidence of loco-regional relapses (74% vs. 90%, p = 0.002) [20].
Our Another retrospective study included breast cancer patients, who were treated by surgery, radiotherapy and adjuvant systemic therapy, radiotherapy was given by two schedules; conventional (162 patients), and hypofractionated (181 patients).The 4 year overall & disease free survival for the whole group were 86.5% & 83.8% respectively [23].
A randomized trial involved postmastectomy breast cancer patients who were given 2 radiation schedules: Arm A (45) Arm B (46), 1 st arm was given 50 Gy/25 fractions and the 2nd was given 40 Gy/17 fractions.
In a prospective study, 56 patients treated by adjuvant HFRT (42.5 Gy/16 fractions in 3 weeks).Acute dermatitis of grade I, II and III were detected in 75%, 16% and 1.8%, respectively.Radiotherapy was not interrupted for any patient [29].
The current results are consistent with most of mentioned trials.

Conclusion
Post-mastectomy hypofractionated radiation therapy achieved comparable OS, DFS, LDFS and toxicity to the conventionally fractionated radiotherapy with the advantage of reducing overall treatment time, treatment burden & cost.

Limitations
This study is limited by the relatively small number of patients and short follow-up period and the retrospective nature of the control group.

Figure 1 .
Figure 1.The overall survival of the 2 treatment groups.

Figure 2 .
Figure 2. The disease free survival of the 2 treatment groups.

F
. M. F. Akl, A. Khater DOI: 10.4236/jct.2018.911078949 Journal of Cancer Therapy cancer but they could not accept it as a tumor bed boost [17].In a study by Ciammella et al. they involved 212 women with early breast cancer underwent conserving surgery.Patients received 40.05 Gy in 15 daily fractions, with boost to the tumor bed of 9 Gy in 3 consecutive fractions in 55 patients, they detected higher incidence of G I dermatitis, in 79% of patients and G II in 12% of patients, in contrast to the results of the 1 st group in the current study (44% & 16%) respectively [18].There have been 4 large randomized controlled trials evaluating the results of hypofractionated versus conventionally fractionated radiotherapy following breast conservation, Canadian, START A, START B and Royal Marsden Hospital (RMH) [4] [7] [13] [14] [19].
In a phase II trial byKhan  et al., patients with stage II to IIIa breast cancer were treated by postmastectomy hypofractionated radiation, in 15 fractions, they F. M. F. Akl, A. Khater DOI: 10.4236/jct.2018.911078951 Journal of Cancer Therapy After acceptance of the Mansoura Faculty of Medicine, institutional research F. M. F. Akl, A. Khater DOI: 10.4236/jct.2018.911078943 Journal of Cancer Therapy board MFM IRB, 100 female patients with breast cancer treated at the Clinical Oncology & Nuclear Medicine department in collaboration with the Oncosurgery department, Oncology center, Mansoura University, were included into this study in the period between January, 2015 till January, 2017.

Table 2 .
Treatment-related acute toxicity.Skin &subcutaneous tissue toxicity were the common side effects in both groups, with most patients of G1 & 2 toxicity, no G 3 or 4 toxicity.Grade 1was detected in (4/8%) patients & in (3/6%) patients in the 1 st & 2 nd groups respectively, while grade 2 was expressed in 2 patients in group II only & formed 4%.
results are in accordance with Shaltout and Abd El Razek 2012, and El-