Acute radiation dermatitis is a frequent adverse effect in patients with breast cancer undergoing radiotherapy, but there are only a small number of studies providing evidence-based interventions for this clinical condition. Adlay is a cereal crop that has been previously shown to have anti-inflammatory and antioxidant properties. In this study, we seek to evaluate the effectiveness of oral prophylactic treatment with adlay bran extract in reducing the risk of severe acute radiation dermatitis. A total of 110 patients with breast cancer undergoing radiotherapy were analyzed. Using a prospective, randomized, double-blind design, 73 patients received oral treatment with adlay bran extract and 37 patients received olive oil (placebo). Treatment was started at the beginning of radiation therapy and continued until the termination of radiation treatment. Our results showed that the occurrence of severe acute radiation dermatitis (RTOG grade 2 or higher) was significantly lower in patients treated with oral adlay bran extract compared to placebo (45.2% versus 75.7%, adjusted odds ratio 0.24). No serious adverse effects from adlay bran treatment were noted. In conclusion, prophylactic oral treatment with adlay bran extract reduces the risk of severe acute radiation dermatitis and may have potential use in patients with breast cancer undergoing radiotherapy.
Radiation therapy is commonly used for the treatment of various types of cancers. It can be used alone or in combination with other forms of treatment (such as surgery and chemotherapy). However, radiotherapy is limited by its potential to cause injury to normal tissues. The skin contains cells with high proliferative rate and is therefore one of the tissues most susceptible to radiation damage. Cells in the skin that are highly radiosensitive include the epidermal basal keratinocytes and hair follicle stem cells [
Radiation-induced skin injury may be categorized as acute or chronic [
Although various topical and oral agents have been used for the prevention or treatment of acute radiation skin reactions, only a small number of controlled trials have been performed, and some of the evidence is conflicting [
Adlay (
This is a prospective, randomized, double-blind controlled study performed at Kaohsiung Medical University Hospital. From December 2011 to August 2013, consecutive eligible female patients with unilateral breast cancer attending the Department of Radiation Oncology were asked to participate in this study. All patients received either breast conserving surgery or modified radical mastectomy followed by adjuvant radiation therapy. The exclusion criteria for this clinical trial were patients with recurrent breast cancer or distant metastases from breast cancer, pregnant women, patients receiving chemotherapy and radiotherapy at the same time, concurrent treatment with oral corticosteroids, prior radiation therapy to the breast or chest wall, past breast implants or reconstructions, and systemic connective tissue diseases (including scleroderma and lupus erythematosus). This clinical trial was approved by the ethics committee of our hospital, and all patients gave informed consent before participation in this study.
Adjuvant radiotherapy was administered following surgery for breast cancer. Planning for radiation therapy was performed using the Pinnacle three-dimensional treatment planning system. Each patient underwent computed tomography imaging from the level of the neck to the upper abdomen. The target volumes were defined according to the guidelines of the International Commission on Radiation Units and Measurements (ICRU) Reports 50 and 62 [
Patients who underwent breast conserving surgery were given external beam irradiation with photons to the entire breast. Patients who underwent modified radical mastectomy received irradiation with photons to the chest wall and regional lymph nodes. The total dose of radiotherapy delivered was 50.0–50.4 Gy, administered in 1.8–2.0 Gy fractions, five days a week. The radiation dose was prescribed to a point in the midplane of the breast or chest wall (defined as the ICRU reference point). Radiotherapy was administered using two opposed tangential 6 MV photon beams, with wedges and/or up to four small subbeams to obtain a homogeneous dose distribution. The radiation dose distribution of the PTV was designed to meet the ICRU dose uniformity guidelines. Patients who underwent breast conserving surgery received an additional 10–14 Gy boost dose to the tumor bed with three-dimensional photon beam technique. The total duration of radiotherapy was 5 to 6 weeks.
Adlay seed samples were obtained from farmers (in Taichung, Taiwan) who planted Taichung Shuenyu number 4 (TCS4) of
Patients were randomly allocated to one of two groups (adlay bran extract or olive oil) in a double-blind fashion in a 2 : 1 ratio using a computer-generated randomization list. We had elected to use unequal randomization ratios in this study in order to increase patient acceptability of the trial and therefore improve recruitment rates and because increased number of patients being allocated to the adlay group will allow us to better monitor any possible side effects which may arise from this new treatment [
Patients were instructed to take the assigned drug, four capsules a day in two divided doses (each capsule 500 mg), from the first day of radiotherapy, and to continue till the last day of radiotherapy. The total treatment period was 5-6 weeks. Patients were asked not to take oral anti-inflammatory medications or apply topical skin agents during the study period. Compliance to study medications was monitored at every follow-up visit. Patients who failed to take the assigned drug for ≥5 days were removed from the study for noncompliance.
Evaluation of radiation-induced skin injury with clinical scoring criteria was performed before the start of radiotherapy and at the end of radiotherapy (on the last day of radiotherapy, i.e., 5-6 weeks after the first day of radiation therapy). Acute radiation dermatitis was graded using the Radiation Therapy Oncology Group (RTOG) scoring criteria. The acute radiation skin reactions were classified as mild (grade 1 and below) or severe (grade 2 and above). All patients were assessed jointly by an experienced radiation oncologist and a dermatologist who were blinded to the intervention received by the patients, and a consensus score for the skin reaction was determined.
The data were presented as mean ± standard deviation (SD). The two-sample
During the patient recruitment process, 172 patients were assessed for eligibility, and 58 patients were excluded (11 patients not meeting inclusion criteria and 47 patients declined to participate). The remaining 114 patients were randomly allocated in a 2 : 1 ratio to treatment with adlay bran extract or olive oil (placebo) (Figure
Flowchart of the participants’ progress through the randomized, double-blind, clinical trial. RT: radiotherapy.
Demographic and clinical characteristics for the intervention (adlay bran extract) and placebo (olive oil) groups including age, body mass index (BMI), education, marital status, annual income, breast cancer stage, the frequency of various comorbidities (diabetes mellitus and hypertension), pretreatment blood tests (hemoglobin, creatinine, cholesterol, and triglyceride), and different treatments for breast cancer (type of surgery, chemotherapy before radiotherapy, and hormone therapy) are shown in Table
Demographic and clinical characteristics of patients in the adlay bran extract and placebo groups.
Adlay bran group |
Placebo group |
|
|
---|---|---|---|
Age (mean ± SD) | 51.2 ± 10.5 | 52.1 ± 9.2 | 0.672 |
Body mass index (mean ± SD) | 22.4 ± 3.2 | 23.2 ± 2.8 | 0.247 |
Education | 0.933 | ||
Junior high school or lower | 19 (26.0%) | 9 (24.3%) | |
Senior high school | 25 (34.2%) | 14 (37.8%) | |
College or above | 29 (39.7%) | 14 (37.8%) | |
Marital status | 0.822 | ||
Single | 9 (12.3%) | 4 (10.8%) | |
Married | 50 (68.5%) | 24 (64.9%) | |
Widowed or divorced | 14 (19.2%) | 9 (24.3%) | |
Annual income (TWD) | 0.329 | ||
<400,000 | 30 (41.1%) | 13 (35.1%) | |
400,000–800,000 | 16 (21.9%) | 13 (35.1%) | |
>800,000 | 27 (37.0%) | 11 (29.7%) | |
Breast cancer stage | 0.326 | ||
0 | 11 (15.1%) | 3 (8.1%) | |
I | 30 (41.1%) | 17 (45.9%) | |
II | 15 (20.5%) | 12 (32.4%) | |
III | 17 (23.3%) | 5 (13.5%) | |
Diabetes mellitus | 0.730 | ||
Yes | 6 (8.2%) | 4 (10.8%) | |
No | 67 (91.8%) | 33 (89.2%) | |
Hypertension | 1.000 | ||
Yes | 9 (12.3%) | 5 (13.5%) | |
No | 64 (87.7%) | 32 (86.5%) | |
Pretreatment hemoglobin level | 11.99 ± 1.26 | 11.91 ± 1.29 | 0.748 |
Pretreatment creatinine level | 0.734 ± 0.908 | 0.628 ± 0.114 | 0.482 |
Pretreatment fasting cholesterol level | 193.1 ± 37.0 | 195.7 ± 45.0 | 0.750 |
Pretreatment fasting triglyceride level | 113.3 ± 78.9 | 136.9 ± 104.1 | 0.188 |
Surgery | 0.190 | ||
Breast conserving surgery | 61 (83.6%) | 27 (73.0%) | |
Modified radical mastectomy | 12 (16.4%) | 10 (27.0%) | |
Chemotherapy before radiotherapy | 0.458 | ||
Yes | 42 (57.5%) | 24 (64.9%) | |
No | 31 (42.5%) | 13 (35.1%) | |
Hormone therapy | 0.522 | ||
Yes | 51 (69.9%) | 28 (75.7%) | |
No | 22 (30.1%) | 9 (24.3%) |
TWD: Taiwan Dollar (1 Taiwan Dollar = 0.0325 United States Dollar).
The RTOG criteria were used to grade the severity of acute radiation dermatitis in patients with breast cancer. Before the start of radiation treatment, no patients exhibited clinically obvious erythema on the irradiation field, and all patients were scored as 0 on the RTOG scale. The severity of acute radiation dermatitis (assessed using the RTOG criteria) following radiotherapy is shown in Table
Comparison of acute radiation dermatitis severity in the intervention (adlay bran extract) and placebo (olive oil) groups assessed using the RTOG criteria.
RTOG grade | Adlay bran extract ( |
Placebo |
|
---|---|---|---|
Skin reaction | 0.006 | ||
Grade 0 | 4 (5.5%) | 0 (0.0%) | |
Grade 1 | 36 (49.3%) | 9 (24.3%) | |
Grade 2 | 25 (34.2%) | 25 (67.6%) | |
Grade 3 | 8 (11.0%) | 3 (8.1%) | |
Grade 4 | 0 (0.0%) | 0 (0.0%) | |
Skin reaction | 0.002 | ||
Grade ≤ 1 | 40 (54.8%) | 9 (24.3%) | |
Grade ≥ 2 | 33 (45.2%) | 28 (75.7%) |
In addition, when patients were grouped into those who developed mild radiation dermatitis (grade 1 and below) and severe radiation dermatitis (grade 2 and above), we found that the occurrence of severe radiation dermatitis (RTOG grade ≥ 2) was significantly lower in patients treated with oral adlay bran extract compared to placebo (45.2% versus 75.7%,
The great majority of patients did not report any adverse effects from oral ingestion of adlay bran extract throughout the treatment period. However, one patient reported abdominal bloating, and one patient reported mild watery stools following intake of adlay bran extract. These effects were mild and did not stop the patients from continuing to take the medications. No serious adverse reactions were noted.
Potential patient- and treatment-related factors which may be associated with the development of severe acute radiation dermatitis (RTOG grade ≥ 2) were analyzed, including age, body mass index, diabetes, hypertension, hemoglobin level, creatinine level, type of surgery, chemotherapy before radiotherapy, and hormone therapy. In the univariate analysis, body mass index was found to be significantly associated with the development of severe acute radiation dermatitis (Table
Univariate analysis to determine prognostic factors for the development of severe acute radiation dermatitis.
Factor | Skin reaction (RTOG) |
|
|
---|---|---|---|
Grade ≤ 1 |
Grade ≥ 2 |
||
Age | 50.3 ± 9.5 | 52.5 ± 10.4 | 0.246 |
Body mass index | 21.6 ± 2.3 | 23.5 ± 3.3 | <0.001 |
Diabetes mellitus | 0.180 | ||
Yes | 2 (4.1%) | 8 (13.1%) | |
No | 47 (95.9%) | 53 (86.9%) | |
Hypertension | 0.477 | ||
Yes | 5 (10.2%) | 9 (14.8%) | |
No | 44 (89.8%) | 52 (85.2%) | |
Pretreatment hemoglobin level | 11.90 ± 1.24 | 12.01 ± 1.29 | 0.654 |
Pretreatment creatinine level | 0.618 ± 0.178 | 0.764 ± 0.983 | 0.307 |
Surgery | 0.565 | ||
Breast conserving surgery | 38 (77.6%) | 50 (82.0%) | |
Modified radical mastectomy | 11 (22.4%) | 11 (18.0%) | |
Chemotherapy | 0.531 | ||
Yes | 31 (63.3%) | 35 (57.4%) | |
No | 18 (36.7%) | 26 (42.6%) | |
Hormone therapy | 0.612 | ||
Yes | 34 (69.4%) | 45 (73.8%) | |
No | 15 (30.6%) | 16 (26.2%) |
Multivariate analysis to determine prognostic factors for the development of severe acute radiation dermatitis (RTOG grade ≥ 2) (
Factor | Adjusted odds ratio | 95% CI |
|
---|---|---|---|
Age | 1.00 | 0.95–1.05 | 0.964 |
Body mass index | 1.31 | 1.11–1.56 | 0.002 |
Diabetes mellitus | 3.95 | 0.55–28.27 | 0.172 |
Hypertension | 0.96 | 0.20–4.62 | 0.955 |
Pretreatment hemoglobin level | 0.91 | 0.59–1.38 | 0.645 |
Pretreatment creatinine level | 1.77 | 0.51–6.12 | 0.368 |
Surgery (MRM versus BCS) | 0.82 | 0.26–2.60 | 0.736 |
Chemotherapy before radiotherapy | 0.44 | 0.13–1.49 | 0.189 |
Hormone therapy | 1.02 | 0.39–2.69 | 0.963 |
Intervention (adlay bran versus placebo) | 0.24 | 0.09–0.63 | 0.004 |
Multivariate analysis was performed using logistic regression.
MRM: modified radical mastectomy, BCS: breast conserving surgery, and CI: confidence interval.
Acute radiation dermatitis is a common side effect in patients with breast cancer receiving radiation therapy. Although some patients develop only mild skin erythema, the skin reaction in a subset of patients may progress to moist desquamation and ulceration. Acute radiation-induced skin damage may have major adverse impacts on a patient’s well-being and quality of life [
Currently, the mechanism of skin injury due to ionizing radiation is only partially understood. Acute radiation exposure causes single- and double-stranded DNA breaks and induces direct injury to cells of the epidermis and hair follicle (particularly stem cells), dermal fibroblasts, and endothelial cells [
Various clinical scoring systems have been developed to grade the severity of acute radiation dermatitis, the most common of which are the Radiation Therapy Oncology Group (RTOG) and the Common Terminology Criteria for Adverse Events (CTCAE) criteria [
Although acute radiation dermatitis is a frequent adverse effect of radiotherapy, there is currently no standard management for this condition [
It is therefore clear that there is insufficient evidence in the literature to support the use of any single agent for the prevention or treatment of acute radiation dermatitis [
Adlay seed had been previously shown to have anti-inflammatory and antioxidant properties. In particular, the bran part of adlay had been demonstrated to have greater anti-inflammatory and antioxidant activities compared to other parts of adlay seed [
In this study, we had elected to use unequal randomization ratios (2 : 1 in favor of the experimental group) to increase patient acceptability of the trial and therefore improve recruitment rates and because increased number of patients being allocated to the adlay group will allow us to better monitor any possible side effects which may arise from this new treatment. Since the treatment allocation process is entirely random, the use of unequal group sizes in this clinical trial is not expected to affect the validity of our data. In fact, some investigators have argued that unequal randomization has been underutilized in the design of clinical trials and recommended that it should be used more often in appropriate situations [
In the present study, the occurrence rate of severe acute radiation dermatitis (RTOG grade ≥ 2) was higher compared to previous reports [
Adlay bran contains a substantial amount of neutral oil (around 25% of the dry weight) [
Previously, adlay seed has been used for centuries in certain Asian countries as a food supplement without obvious adverse effects. In our study, the great majority of patients also did not report any side effects from oral ingestion of adlay bran extract throughout the treatment period. This indicates that adlay bran extract may be a safe form of treatment for acute radiation dermatitis.
In terms of patient- and treatment-related factors, multivariate analysis in our study showed body mass index to be a significant prognostic factor for the development of severe acute radiation dermatitis (RTOG grade ≥ 2). This is in agreement with a previous study demonstrating an association between higher body mass index and acute radiation dermatitis of grade 2 or higher [
In summary, the results of this prospective, randomized, double-blind study indicate that oral prophylactic therapy with adlay bran extract may reduce the risk of acute radiation dermatitis of grade 2 or higher in patients with breast cancer undergoing radiotherapy. No serious adverse effects due to adlay bran treatment were noted. Therefore, adlay bran extract may have potential use in the future for the prevention of severe acute radiation skin reactions. Further clinical studies with larger numbers of patients will be required to determine the optimal dosage and duration of administration for patients receiving radiotherapy.
The authors declare that they have no conflict of interests.
The authors would like to thank Professor Yi-Hsin Yang and Professor Tsu-Nai Wang (Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Medical University Hospital) for assistance with statistical analysis. They would also like to thank Professor Wenchang Chiang (Graduate Institute of Food Science and Technology, National Taiwan University) for providing the adlay bran extract and olive oil. This work was supported by grants from the National Science Council (100-2622-B-002-001-CC2QC094002) and the Ministry of Health and Welfare (Contract no. MOHW103-TD-B-111-05), Taiwan.