The severity of radiation dermatitis was correlated with external factors (dose, exposure area, etc.) and internal factors (age, sex, nutritional status, etc.) [12]. Bias will arise due to different internal and external factors if we make a comparative between different patients. Therefore, this study is designed as a self-controlled study to eliminate external factors as much as possible, comparing the left and right sides of each patient. For the skin area received radiotherapy of rectal and anal cancer are symmetrical due to the symmetric target area in these patients, self-comparison taking the midline as the dividing line can well balance the uneven brought by a series of factors, such as age, sex and so on. However, the dose distribution between the left and right sides could be asymmetrical for anal cancer patients with inguinal lymph nodes, as the side containing lymph nodes often received a higher dose. After the balance of influencing factors, the effect of treatment medicine of dermatitis will be better reflected.
Epidermal growth factor (EGF) is a polypeptide containing 53 amino acids [13]. EGF helps maintain homeostasis by regulating the proliferation, growth and migration of epithelial cells. rhEGF can also induce angiogenesis and provide nutritional support for tissue. Our previous study showed that EGF-triggered epidermal growth factor receptor (EGFR) internalization promoted radiation-induced DNA double-strand breaks [7]. Therefore, EGF may protect skin from radiation-induced skin injury by enhancing DNA damage repair and reducing radiation-induced cell death. Additionally, EGF has been shown to protect skin from radiation injury by promoting the proliferation of fibroblasts, epidermal stem cells, and keratinocytes [14, 15].
The purpose of this study was to observe the effectiveness of rhEGF for skin protection in patients with rectal and anal cancer during radiotherapy and to investigate factors associated with radiation dermatitis. The results showed that the incidence of radiation dermatitis for rectal and anal carcinoma patients receiving radiotherapy was 78.8%. Elder age, lower tumor location, no colostomy, higher biological effective dose and higher fractionated dose were all related to the development of radiation dermatitis during radiotherapy. RhEGF is a kind of medicine that is economical, easy to use with high compliance and could effectively reduce the area of radiation dermatitis. This study provides high-level evidence-based medical evidence for the application of rhEGF in skin protection of rectal and anal cancer during radiotherapy.
Pelvic tumors are often accompanied by radiation dermatitis when the tumor of the pelvis is irradiated by external radiation. The maximum dose delivered by modern radiotherapy equipment is often deposited subcutaneously at 0.5-4 cm. Dry peeling can occur after irradiation with 10 Gy. 15 Gy often causes wet peeling, accompanied by varying degrees of radiation mucosal damage, skin damage, pigmentation and other reactions. In 20–30 Gy, patients often have erythema, itching, dry peeling, severe skin blisters, epidermis exfoliation, exudate and ulcers, causing local or systemic infection, or even interrupting radiotherapy, affecting the effect of treatment [16]. Radiation injury of perianal skin is a common complication after pelvic radiotherapy. Due to the particularity of anorectal function and location, the perianal skin of the patients is prone to suffer infection, which further leads to the difficulty of wound healing and makes the patients suffer a great deal of pain.
The drugs to relieve radiation dermatitis include Essex cream, Calendula Weleda, glycerine cream and so on. RhEGF is one of the drugs for the prevention and treatment of radiation dermatitis [17, 18]. HONG and Lee suggested that rhEGF has a good effect on the prevention and treatment of oral mucositis in patients with head and neck tumors [19, 20]. KONG et al. found that it can be used in radiotherapy for patients with breast cancer. RhEGF can reduce the occurrence of radiation dermatitis and relieve the pain of patients [21]. In the current study, we also found that rhEGF can reduce the area of radiation dermatitis in patients with rectal and anal carcinoma during radiotherapy. At the end of radiotherapy, the RTOG grading of radiation dermatitis was not significantly reduced, while the area of radiation dermatitis was reduced. This may be related to the relative high radiation dose. In fact, it shows that although rhEGF cannot counteract and reverse the skin reaction caused by radiation dose, it could relieve the pain of radiotherapy and accelerate the healing of skin to some extent. Besides, different types of dressing have been shown as effective ways to prevent and treatment of radiation dermatitis [22]. A combination between rhEGF and dressing may be an efficient treatment, which could be studied in further assessment.
It was easily explained that the distance between the lower edge of the tumor and the perianal skin was related to the severity of radiation dermatitis. The closer target irradiation area from the anus, skin around the anus more prone to produce radioactive damage. The area of radiation dermatitis in patients with low tumor is about 3.5 times larger than that in patients with high tumor. Some patients had temporary colostomy due to obstruction before radiotherapy. After temporary colostomy, the patient's excretion is excreted only a small amount through the anus or not through the anus at all, which largely ensures the cleanliness of the perianal skin and reduces the area of radiation dermatitis. Therefore, patients with colostomy tend to have a mild degree of radiation dermatitis. The level of dose will affect the severity of radiation dermatitis, which is a more accepted view in many studies [23,24,25]. Behroozian et al. found that in breast cancer, radiation dose is a predictor of the severity of radiation dermatitis. Dose more than 50 Gy/25f is related to pain, and dose boost is the only factor related to bleeding [23]. Therefore, we should pay more attention to proper patient education and early prevention in patients with low tumor, receiving high dose of radiotherapy and without colostomy, who will be high-risk groups of severe dermatitis of rectal and anal cancer.
There are shortcomings in the present study. Firstly, as patients were usually discharged at the end of radiotherapy, so we did not observe and record the skin condition of patients after discharge. This may result in the lack of some important information because in some patients the most prominent radiation dermatitis occurs shortly after the end of irradiation. Consistently, the effect of rhEGF on the healing of radiation dermatitis remains to be further investigated, which needs a longtime of rhEGF treatment and follow-up after radiotherapy. Besides, we noticed the weakness of our study that the area of radiation dermatitis was only assessed at the end of radiotherapy, but not evaluated weekly, therefore leading to the absence of the data of continuous observation. Additionally, as the accurate data of the area/volume of irradiated skin which received at least 10, 30 or > 50 Gy in each patient is unavailable, we did not analyze the effect of radiation dose or the area/volume of the irradiated skin on radiation dermatitis, which could be the most objective factor related to radiation dermatitis.
In conclusion, our data showed that rhEGF is a skin protective reagent for rectal and anal cancer patients receiving radiotherapy.