Hypofractionated Radiation Therapy for the treatment of breast cancer: Experience of National Institute of oncology, Rabat, Morocco

Hypofractionated radiation therapy has proven effective on locoregional control and tolerance in the adjuvant treatment of breast cancer. The aim of this study is to compare the results of hypofractionated radiation therapy versus conventional radiation therapy in terms of local control and tolerance. It was a retrospective study of patients observations collected from January 2007 to December 2008 in Department of Radiation Therapy in Institut National d’Oncologie de Rabat. The treatment results were evaluated by the rate of locoregional recurrence, distant recurrence and research of late toxicities. Radiotherapy was delivered using the same technique in both groups, by gamma photons of cobalt 60 with an energy of 1.25 MeV. They were 2 groups: the first group treated with standard dose rate and the second group treated by hypofractionated radiation therapy. The mean age of the patients was 42.8 ± 6.9 years old in the standard group and 43.22 ± 7.2 years old in the hypofractionation group. We noted a predominance of infiltrating ductal carcinoma. The majority of patients were pT2, pN0 and pN1. The majority of patients had radical surgery and chemotherapy with anthracyclines in both groups. We noted a statistically significant difference in the irradiation of chest wall between the standard (89.2%) and hypofractionated group (70.3%), with p = 0.043. The median duration of radiation therapy was statistically different in both groups: 39 days in the standard and 23 days in the hypofractionated group (p < 0.001). The local recurrences were statistically identical to 12 and 24 months (p = 0.999). Concerning toxicities, the frequency of adverse event was similar in both groups. Hypofractionated radiation therapy with a total dose of 42 Gy at 2.8 Gy per fraction in 5 fractions weekly is comparable to standard radiotherapy in terms of local control and tolerance and is therefore a very good alternative to standard treatment. How to cite this paper: Koné, A.S., Diakité, A., Ahid, S., Diarra, I.M., Diabaté, K., Abouqal, R., Cherrah, Y. and Benjaafar, N. (2016) Hypofractionated Radiation Therapy for the Treatment of Breast Cancer: Experience of National Institute of Oncology, Rabat. Morocco. Journal of Cancer Therapy, 7, 773-783. http://dx.doi.org/10.4236/jct.2016.710078 Received: June 20, 2016 Accepted: October 24, 2016 Published: October 27, 2016 Copyright © 2016 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Abstract
Hypofractionated radiation therapy has proven effective on locoregional control and tolerance in the adjuvant treatment of breast cancer. The aim of this study is to compare the results of hypofractionated radiation therapy versus conventional radiation therapy in terms of local control and tolerance. It was a retrospective study of patients observations collected from January 2007 to December 2008 in Department of Radiation Therapy in Institut National d'Oncologie de Rabat. The treatment results were evaluated by the rate of locoregional recurrence, distant recurrence and research of late toxicities. Radiotherapy was delivered using the same technique in both groups, by gamma photons of cobalt 60 with an energy of 1.25 MeV. They were 2 groups: the first group treated with standard dose rate and the second group treated by hypofractionated radiation therapy. The mean age of the patients was 42.8 ± 6.9 years old in the standard group and 43.22 ± 7.2 years old in the hypofractionation group. We noted a predominance of infiltrating ductal carcinoma. The majority of patients were pT 2 , pN 0 and pN 1 . The majority of patients had radical surgery and chemotherapy with anthracyclines in both groups. We noted a statistically significant difference in the irradiation of chest wall between the standard (89.2%) and hypofractionated group (70.3%), with p = 0.043. The median duration of radiation therapy was statistically different in both groups: 39 days in the standard and 23 days in the hypofractionated group (p < 0.001). The local recurrences were statistically identical to 12 and 24 months (p = 0.999). Concerning toxicities, the frequency of adverse event was similar in both groups. Hypofractionated radiation therapy with a total dose of 42 Gy at 2.8 Gy per fraction in 5 fractions weekly is comparable to standard radiotherapy in terms of local control and tolerance and is therefore a very good alternative to standard treatment.

Introduction
The hypofractionated irradiation is currently a good alternative in the adjuvant treatment of breast cancer. It has demonstrated oncological efficacy and good tolerance [1]- [5].
Since the 1990s, the hypofractionated scheme has been proposed by several teams with the aim of exploring a shorter pattern. This hypofractionated radiotherapy reduces the total treatment time by decreasing the number of meetings and increasing the dose per fraction to obtain a biological equivalence of the total dose [6] [7]. Several recent tests have shown that the α ratio/β du breast cancer is low, around 4 Grays; breast adenocarcinoma would therefore offer a significant sensitivity to variations in the dose per fraction. This radiobiological argument strengthens the current interest of hypofractionated breast cancer irradiation [8].
Several trials compared conventional irradiation versus hypofractionated irradiation. Gy classic scheme in 25 fractions of 2 Gy; with a recurrence rate of 6% at 10 years, which was equivalent in both groups [9]. The British trial Yarnorld et al. had compared the classic pattern versus two hypofractionated schemes: 39 Gy in 13 fractions in 42, 9 Gy in 13 fractions, with a spread of five weeks in the three arms. Analysis of the results at ten years showed a similar rate of relapse in the three arms [10]. This scheme has proved effective in local control, with a net decrease of treatment duration which is a major benefit in countries where the waiting list is long. In Morocco, the Radiotherapy Department of the National Oncology Institute (INO) is confronting with a high number of patients awaiting treatment. The majority of patients came from far away to receive their radiation therapy for 5 weeks.
In view of previous clinical trials, the radiation therapy team adopted in 2007, the hypofractionated scheme in order to decongest the treatment posts and to facilitate access of treatment for patients with a shorter regimen of 42 Gy in 15 fractions over 21 days 2, 8 Gy.
The objective of this work is to compare the results of hypofractionated radiotherapy versus conventional radiotherapy in terms of locoregional control and toxicities.

Patients and Methods
This is a retrospective study on observations of patients collected from January 2007 to December 2008 at the radiotherapy department of INO in Rabat.
Patients with invasive tumor, without metastasis and who received standard radiotherapy and hypofractionated radiotherapy after surgery and chemotherapy were included in the study. The breast cancer patients who have not received radiotherapy were excluded from the study.
The treatment results were evaluated by the rate of locoregional recurrence, distant recurrence and research of late toxicities.
Surgical treatment consisted of radical surgery with mastectomy and axillary node dissection or conservative surgery with lumpectomy plus ipsilateral axillary node dissection.
Chemotherapy was administered to all patients with recurrence risk factors. The chemotherapy regimens were either anthracycline-based AC (Adriamycin 6 cycles: 60 mg/m 2 and cyclophosphamide: 600 mg/m 2 ); FEC (6 cycles of 5-fluorouracil: epuribicine: 100 mg/m 2 , cyclophosphamide); or combining anthracyclines and taxanes in sequential 4 AC courses, followed by 4 paclitaxel or 4 AC courses, followed by 4 cycles of docetaxel or 3 courses of FEC followed by 3 docetaxel.
Radiotherapy was delivered using the same technique in both groups, by gamma photons of cobalt 60 with an energy of 1.25 MeV.
The first group (A) receiving radiation therapy according to the standard scheme, with total dose of 50 Gy in a proportion of 2 Gy per fraction in 25 sessions over 5 weeks, associated with a boost on the tumor bed in the case of conservative surgery dose Total 15 -16 Gy the second group (B) received radiotherapy according to scheme hypofractionated total dose of 42 Gy in a rate of 2.8 Gy per fraction in 15 sessions on 3 weeks associated with an overlay 15 -16 Gy in case of conservative surgery. The supraclavicular area was irradiated when axillary dissection was positive, the internal mammary chain when the tumor was located in an internal quadrant or metastatic axillary lymph nodes (more than 3) were found during the analysis of the dissection piece.
The axillary irradiation was associated with the supraclavicular when the cleaning was inadequate and positive. The nodal irradiation, when indicated, delivered a dose of 50 Gy in 25 fractions in group A and 42 Gy in 15 fractions in group B. The boost was issued either by interstitial brachytherapy, either by photons or electrons.
Hormone therapy was prescribed in all patients hormone-sensitive. The positivity rate was 10%. Patients received for 5 years or tamoxifen or aromatase inhibitors according to their menopausal status and their financial means.
Monitoring and evaluation were performed in 6 to 12 -24 months and included: the clinical component through research recurrence of signs of the tumor bed and nodal areas and skin, heart, lung toxicities. Acute toxicities were not exploitable in the patient medical files.
Late toxicities were evaluated according to the SOMA-LENT scale (subjective objective management analytic-late effects of normal Tissues scale (SOMA-LENT) [11].
The radiological component of the evaluation included a mammogram, looking for locoregional recurrence in case of conservative treatment and in the controlateral breast. Chest radiography in search of metastasis and sequelae of radiation therapy.

Statistical Analysis
The variables were expressed as mean and standard deviation or median and interquartile or percentage. Patients who received standard or hypofractionated radiation were compared by univariate analysis using the χ 2 test or the Fisher exact test for variablesqualitatives and the Student t test for quantitative variables. Distribution distribution of quantitative variables was verified by the Kolmogorov-Smirnov. Mann-Whitney test was used for comparison of quantitative variables that did not have a normal distribution. P value < 0.05 was considered significant.
A propensity score, which is the probability of receiving the hypofractionated radiotherapy, was developed by a multiple logistic regression model including confounding factors vis-à-vis the propensity to receive hypofractionated radiotherapy: age patients, histological type, histological size, number of involved lymph nodes, SBR grade, hormone receptor positivity and surgical resections. Continuous variables, who was linear relation with the logit of the probability of hypofractionated radiotherapy were introduced in the model [12] [13] [14].
One patient of hypofractionated arm was matched to one patient of standard arm nearest propensity score using the method of five to one digit of the propensity score (technical greedy matching): the best match was obtained when the propensity score was identical to the fifth decimal score.
When a match was obtained, the pair hypofractionated/standard radiation therapy was removed from the process. When matching is not possible with an identical score to the fifth decimal place, it was made for an identical score to four decimal places, then three and so on up to a decimal.
If the match was not obtained at that point, the patient who received radiation therapy were excluded. The comparison of groups and evaluation of effects of standard and hypofractionated radiation therapy were performed by conditional univariate logistic regression.
Statistical analysis was performed with SPSS version 13.0 for Windows (SPSS Inc, Chicago, IL, USA).

Results
117 patients were selected on 329 eligible patients, with 54 in the standard arm and 63 in arm B hypofractionated (Figure 1). We noted a statistically significant difference between the two arms on age. The median age was 40.2 ± 7.7 years in the standard arm and 49 ± 9.7 years hypofractionated in the arm with p < 0.001. Other features such as histology, histologic tumor size, histologic node involvement, SBR grade, hormone receptors, surgical limits were comparable between the two arms. The propensity score has to match 37 patients in each arm on the various clinical and pathological features above-mentioned (Table 1).
After matching, the median age of patients was 42.8 ± 6.9 years in the standard arm and 43.22 ± 7.2 years in the hypofractionatedarm.
We noted a predominance of invasive ductal carcinomas. The majority of patients had pT2 and pN0 and pN1 (Table 2).
Therapeutic characteristics such as surgery and chemotherapy were statistically the same in both groups (p = 0.121 and p = 0.552). Over the majority of patients underwent radical surgery and anthracycline-based chemotherapy in both groups (Table 3). Re- garding radiotherapy, we observed a statistically significant difference of radiation to the chest wall between the standard arm (89.2%) and hypofractionné arm (70.3%), with p = 0.043. We did not find statistically significant differences in both groups for the irradiation of the lymph nodes, the supraclavicular area and internal mammary chain. The median duration of radiation therapy was statistically different in both groups: 39 days (37 -44) in the standard arm and 23 days (21 to 27) in the hypofractionated arm (p < 0.001).
We have found no recurrence at 6 months. Local recurrence were statistically identical at 12 and 24 months (p = 0.999).
For late toxicities, we did not find statistically significant difference in both arms; with 83.7% in the standard arm and 86.4% in the hypofractionned arm. The pain was 37.8% and 16.21% respectively in standard and hypofractionated arm; fibrosis was found in 21.6% of patients in the standard arm versus 16.21% in the hypofractionated arm; lymphedema at 16.21% versus 2.7%; atrophy at 5.4% versus 8.1% and cardiac arrhythmia was 2.7% in each arm. No late lung toxicity was observed (Table 4).
According to the SOMA-LENT scale, we found 51.35% and 24.32% of late grades I and II toxicities in the standard arm versus 29.73% and 16.21% in the hypofractionated arm. No Toxicity of grade III or IV have been find in the standard arm, while in the hypofractionated arm, there was only one case of toxicity, grade III with cardiac arrhythmia (Table 5).

Discussion
Analysis of the results of this retrospective study showed that adjuvant radiotherapy with a hypofractionated scheme is comparable to the standard regimen in terms of local control and tolerance with a significant reduction in the median duration of radiation between the two arms. Several clinical trials have focused on the evaluation of local  versus two regimens hypofractionated 39 Gy in 13 fractions and 42.9 Gy in 13 fractions, with a spread of five weeks in the three arms. Analysis of the results at ten years showed a similar rate of relapse in the three arms [4] [5] [6]. The Start trial A, in 2236 randomized patients with localized breast cancer, three conservative arm after radical surgery or 50 Gy in 25 fractions versus 41.6 Gy in 13 fractions and 39 Gy in 13 fractions with a spreading 5 weeks. There was not a statistically significant difference in the three arms on the risk of recurrence. The Start B trial, randomized after conservative or radical surgery, patients in both arms in 2215: 50 Gy in 25 fractions versus 40 Gy in 15 fractions. Local recurrence at 6 years was 3.3% in the standard arm and 2.2% in the arm with a significant difference. Our results are consistent with those found in these studies. .95 Gy × 5 or 3.39 Gy × 10 had the same effectiveness as the classic pattern of 2 Gy × 25 [8].
The effective biological dose (Biological Effective Dose, BED) can quickly compare different requirements according to the following formula: BED = nd (1 + d/ (α/β) Using the α ratio/βde 4 Gy, proposed by Yamada et al. [14], the effective biological dose was 75 Gy for a prescription of 50 Gy in 25 fractions and 71.4 Gy for our prescription of 42 Gy in 15 fractions Thus the effective biological dose with a prescription of 42 Gy. 15 fractions is approximately 95% of that received by giving 50 Gy in 25 fractions.
In terms of effective dose, the two requirements are equivalent because the treatment in 15 fractions of 2.8 Gy is done on a shorter spreading.
Most studies have evaluated the hypofractionated scheme in patients who received conservative treatment, whereas in our series 7 patients in the standard arm and 13 in the hypofractionated arm had that conservative treatment. In each arm over half of the patients had lymph node involvement than 4 and the irradiation of lymph nodes was done according to the hypofractionated scheme, while in the Canadian trial patients had no lymph node involvement and thus no lymph node irradiation [15]. In tests Standardisation of Breast Radiotherapy (START) A and B, nodal involvement was less than or equal to 3 (N1) and less than 10% of patients underwent radical surgery, only 14 and 7% of patients respectively received a nodal irradiation [16]. Our results imply that the hypofractionated scheme is as effective and tolerated in case of radiation to the chest wall and lymph nodes.
In our study, the boost on the tumor bed was primarily via brachytherapy or by electrons. No studies have tested the overprint on a hypofractionatedscheme. In trying to Whelan there was no overprinting and English tests, she was under the classical scheme.
Acute toxicities were not evaluated in our study. A French prospective trial conducted at the Institut Curie showed a delayed skin reaction occurring within 14 days after the end of irradiation hypofractionated to the total dose of 42.9 Gy in 13 fractions [17].
Our study showed that there was no statistically significant difference in late toxicity in both arms. These same results were found in other studies. An Italian study comparing two arms: 45 Gy in 2.25 Gy/fraction in 85 patients, versus 50 Gy in 2 Gy/fraction in 70 patients; showed that the risk of late toxicity at 12 to 30 months were 5.9% and  Table 5. Late toxicities that the SOMA-LENT scale. 29.2% respectively in the hypofractionated arm; 8.7% and 10.6% in the standard arm; but not statistically significant.
Whelan et al. had found the late toxicities of grade I and II similar in the both arms and at 5 and 10 years. These data comply with our results; we essentially found similar late toxicities, grade I and II in both arms. No late lung toxicity had been found in patients, however we noted cardiac arrhythmia grade II was found in a patient's of standard arm, grade III in hypofractionated arm. We have not recovered grade IV toxicity.
Our study shows the low sampling-related limits. Indeed on 117 records selected in total, we had 37 selected in each arm, a total of 74 patients. Acute toxicities were not exploitable in the files where the interests of standardization regarding the postponement toxicities during treatment.

Conclusion
The hypofractionated radiotherapy with a total dose of 42 Gy at a rate of 2.8 Gy per fraction, 5 weekly fractions, gives results comparable to standard radiotherapy in local control and tolerance and is therefore a good alternative to standard treatment. Our results suppose that hypofractionated radiation therapy scheme can be as effective and well tolerated on the chest wall and the lymph nodes, but needs to be confirmed in a randomized trial.