Protective effects of doxepin cream on radiation dermatitis in breast cancer: A single arm double‐blind randomized clinical trial

Abstract

Aims

Breast cancer is the most frequently occurring cancer in women. Lumpectomy followed by radiotherapy is suggested to be as effective as a total mastectomy. Radiation‐induced dermatitis often occurs as a result of breast radiotherapy. Recent studies suggest that doxepin has promising anti‐inflammatory properties. This study was undertaken to evaluate the effects of doxepin therapy on radiation dermatitis.

Methods

A double‐blind randomized clinical trial was launched from 2016 to 2017, with a total of 48 patients who had undergone breast‐conserving surgery and received postoperative radiation therapy. Radiotherapy was applied 5 days per week for 5 weeks. Adverse dermatological effects were evaluated by a physician at the beginning of the fifth week of radiotherapy and the patients were then randomly assigned (1:1 ratio) to receive either doxepin (5%) or placebo cream for 7 days.

Results

There were no significant differences in the dermatitis grade between doxepin and placebo groups at baseline (P > .5). The occurrence of acute dermatitis (grade 2 or higher) was significantly lower with the use of doxepin than with placebo (P ≤ .0001, Z _α = 1.96 at 95% confidence interval).

Conclusion

Doxepin cream prevents dermatitis grade 2 or higher during post‐operative breast irradiation. Doxepin cream is easy to use, affordable and prevents pain and irritation.

What is already known about this subject

• Radiation dermatitis is an adverse reaction to breast cancer radiotherapy. Breast cancer outcomes vary and often negatively affect the patient's quality of life due to pain, resulting in disruption of treatment. Doxepin cream is frequently used to treat itchiness due to atopic dermatitis or lichen simplex chronicus.

What this study adds

• Doxepin prevents dermatitis (grade 2 or higher) after breast irradiation. Dermatitis was improved after treatment of patients with doxepin. Our findings suggest that doxepin as a potential treatment for patients experiencing postoperative radiotherapy for the management of breast cancer.

1. INTRODUCTION

Mammography allows for early detection of breast cancer, the most common malignancy in women.1 Radiotherapy is standard medical care after lumpectomy, a procedure that is as effective as a total mastectomy.2 Adjuvant radiotherapy decreases local relapse of breast cancer.3 Nearly 80% of women develop significant radiation dermatitis after whole breast irradiation.3 Dermatitis can reduce quality of life due to pain and irritation and can lead to disruption of treatment,4 and efforts to manage dermatitis have proved challenging.3

Delivery of high‐dose radiation, coupled with the large surface area of the breast, increases the risk of radiation dermatitis after conventional radiotherapy.5 Conventional radiotherapy techniques do not deliver a homogeneous dose throughout the 3‐dimensional shape of the breast and leads to the formation of radiation hot spots in areas experiencing high‐dose radiation.6 Intensity modulated radiation therapy, however, delivers a homogeneous dose of radiation to the breast.7

Increases in inflammation and oxidative stress, which can interact, are 2 important mechanisms associated with radiation dermatitis.8 During the first phase of radiation treatment, there is acute release of proinflammatory and inflammatory cytokines (such as interleukin [IL]‐1, IL‐6 and tumour necrosis factor‐α), chemokines and adhesions molecules. Histamine mediates the development of radiation‐induced erythema and oedema,9 as shown in experiments where irradiation of skin of mast cell‐deficient mice failed to cause erythema and oedema.10 Thus pharmacological blockage of histamine‐H1 receptors inhibited erythema and oedema induced by γ irradiation,10 and application of some topical corticosteroids decrease histamine release and depletes mast cells in the dermis.11

An effective standard management approach to inhibit radiation dermatitis does not exist, since treatment with topical ointments (such as water‐based moisturizing creams, aqueous ointments, steroid creams and anti‐inflammatory creams) provide inconsistent benefits.3, 12, 13

Doxepin is a tricyclic antidepressant used to treat various anxiety disorders, major depressive disorders and chronic hives. Doxepin functions as an antihistaminic, antimuscarinic and antiserotonergic agent.14 It is used in the form of a cream to treat itchiness due to atopic dermatitis or lichen simplex chronicus.15 It has greater antihistaminic potency than other antihistaminic products.16, 17

Its topical use causes sequential or simultaneous anaesthetic and analgesic effects in rodent models.18 According to several single‐arm trials and a more‐recent placebo‐controlled crossover study, topical doxepin use reduced oral mucositis pain.19 Randomized controlled trials demonstrated that doxepin reduced pruritus relief time compared to treatment with placebo.20 Some studies report that inhibition of H1 and H2 receptors and histamine release can suppress inflammation.21, 22, 23, 24 In addition, antidepressant medications such as doxepin decreased inflammatory cytokines such as IL‐2, IL‐1β, IL‐12, interferon‐γ tumour necrosis factor‐α, IL‐6 and IL‐1β levels in animal studies.25 On the basis of these findings, doxepin is proposed to have promising antihistaminic, anti‐inflammatory and analgesic properties.

The aim of this randomized, double‐blind, placebo‐controlled study is to assess the effectiveness and potency of topical doxepin for the improvement of radiation‐induced dermatitis during postoperative radiotherapy for breast cancer.

2. PATIENTS AND METHODS

2.1. Participant recruitment and sample size

Patients diagnosed with early‐stage breast cancer and who underwent breast surgery (lumpectomy) were referred to Milad Hospital (Isfahan, Iran) for radiotherapy. Patients were registered in a phase II, single arm, double‐blinded, randomized clinical trial between November 2016 and January 2017 (ClinicalTrials.gov Identifier: NCT02447211).

The sample size was calculated using the following formula:

$$n=\left(2{\left(\mathrm{Z\alpha }+\mathrm{Z\beta }\right)}^2\mathrm{p}\left(1-\mathrm{p}\right)\right)/\mathrm{p}1-\text{p2},$$

Where p₁ = 0.2; p₂ = 0.75; p = 0.2+0.75 ÷ 2; Z_α = 1.96 at 95% confidence interval; Z_β = 1.28 at 90% power; the sample size was calculated as 18 in each group. We included 24 patients in each arm.

Patients were eligible for participation in this study if they: (i) were diagnosed with early stage breast adenocarcinoma, and (ii) had undergone lumpectomy and who were then referred for postoperative radiotherapy with a total dose of 5000 cGy (25 fractions of 200 cGy, 5 days per week) for 5 weeks. Exclusion criteria were ongoing chemotherapy or hormonal therapy, pregnancy, hypersensitivity to doxepin, dermatological complications in the radiation area, constipation, xerostomia, blurred vision and urinary retention. All patients enrolled in this study were randomly assigned to the doxepin or placebo groups. A simple randomization method was applied using a table of randomized numbers (1:1 ratio). The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences. Written informed consent was obtained from patients prior to participation in this clinical trial.

2.2. Blinding

Patients and clinicians were blinded to treatment allocation (doxepin or placebo). Allocation was performed by a nonblinded member of staff who was not involved in either patient treatment or data analysis.

2.3. Radiation therapy

All patients were treated by 3D conformal radiation therapy using CT‐based treatment planning and multi‐leaf linear accelerators. Patients were treated by conventional fractionation regimens to a total dose of 5000 cGy (25 fractions of 200 cGy, 5 days per week, for 5 weeks).

2.4. Doxepin cream and placebo preparation

Doxepin cream (5%) was prepared with 5.6 g doxepin hydrochloride (histamine receptor, G‐protein couple receptor, blocker26) dissolved in glyceryl stearate, and 100 g cold cream.27 Each gram of the doxepin cream contained 50 mg of doxepin hydrochloride (equivalent to 44.3 mg of doxepin). The placebo cream was prepared identically but did not include doxepin hydrochloride.

2.5. Study protocol

The endpoint was the degree of severity of dermatitis. Adverse dermatological effects were evaluated at the beginning of the fifth week of radiotherapy by the same dermatologist throughout the study, using the RTOG Acute Radiation Morbidity Scoring Criteria. Scores are from 0 to 4, where grade 1 changes includes dry desquamation with generalized erythema, grade 2 changes includes brisk erythema or patchy moist desquamation, grade 3 changes includes extensive moist desquamation outside of the skin folds and grade 4 changes includes ulcers, bleeding and skin necrosis.28

The patients were then randomly assigned to receive either doxepin or placebo cream application for 3 times a day on affected areas for 7 days, starting from the last week of radiotherapy (fifth week). The patients were advised to rinse off the cream and dry off with a towel before undergoing radiotherapy. A 7‐day application period was used to determine any side effects of the cream.29 Assessments were performed at days 7 (end‐of‐radiation treatment), day 14 and day 21 (end‐of‐study). The scores were recorded at each follow‐up visit.

2.6. Statistical analysis

Data was analysed with SPSS software (version 24). Comparison of dermatitis grades between doxepin and placebo groups was done using the Mann–Whitney U nonparametric statistical test, and the exact Fisher test was used to reduce bias of a small sample size. P values <.05 were considered statistically significantly.

2.7. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY.

3. RESULTS

3.1. Patients

Sixty patients with early stage breast adenocarcinoma and after a lumpectomy were evaluated for eligibility. Seven patients did not agree to participate in this study, 3 withdraw because of doxepin hypersensitivity and 2 did not meet other participation criteria. A total of 48 patients were enrolled in phase II of the clinical trial (Figure 1). At day 14 of starting doxepin treatment, 2 patients in the doxepin group and 3 in the placebo group did not arrive for follow up visits. At day 21 of starting doxepin treatment, 3 patients in the doxepin group and 3 in the placebo group did not arrive for follow up (Figure 1). The mean age of the patients was 48 ± 9 years (range 21–65 years).

Figure 1.

Patient flow chart

The treatment and placebo groups were matched for age and there were no significant age differences between the 2 groups (48 ± 10 vs 47.8 ± 11 for treatment and control groups, respectively; P = .1). There were no smokers in either group. No signs of doxepin‐induced allergic responses were observed in the participants.

3.2. Evaluation of acute dermatitis

There were no significant differences in dermatitis grades between the doxepin and placebo groups (P = .5) before starting treatment. At day 7 of doxepin treatment (end of radiotherapy), the incidence of acute skin toxicity of grades 0–2 in the doxepin group was 33.3% (grade 0), 58.3% (grade 1) and 8.4% (grade 2), and was 4.2% (grade 0), 50% (grade 1) and 45.8% (grade 2) in the placebo group. Acute skin toxicity in the doxepin and placebo groups was significantly different (P = .001; Table 1).

Table 1.

Comparison of radiation dermatitis between doxepin and placebo groups in breast cancer patients after postoperative radiotherapy. Patients received doxepin or placebo cream for 7 days

Skin toxicity (grade)	Doxepin		Placebo		P (x2)
	No. of patients	(%)	No. of patients	(%)
Before doxepin or placebo therapy
0	10	(41.7)	8	(33.3)	.555
1	14	(58.3)	16	(66.7)
2	0	(0)	0	(0)
At day 7 after starting doxepin cream treatment
0	8	(33.3)	1	(4.2)	.001
1	14	(58.3)	12	(50)
2	2	(8.4)	11	(45.8)
At day 14 after starting doxepin cream treatment
0	7	(31.8)	0	(0)	<.0001
1	13	(59)	5	(23.8)
2	2	(9.2)	16	(76.2)
At day 21 after starting doxepin cream treatment
0	8	(38)	0	(0)	<.0001
1	11	(52.4)	3	(14.3)
2	2	(9.6)	13	(61.9)
3	0	(0)	5	(23.8)

There were significant differences in the rates of dermatitis of grade 0–2 (32% [grade 0], 59% [grade 1] and 9% [grade 2]) in the doxepin‐treated group vs the placebo treated group (0%, 24% and 76%, respectively) at day 14 of doxepin treatment (P = .0001) (Table 1 ). The dermatitis grade scores were 38% (grade 0), 52% (grade 1), 10% (grade 2) and 0% (grade 3) at day 21 of doxepin treatment, while the corresponding values for dermatitis grades were 0, 14, 62 and 24% respectively, in the placebo‐treated group. The incidence of radiation dermatitis was significantly lower in the doxepin treated placebo groups (P = 0.0001; Table 1). Grade 3 acute skin toxicity was not observed after 3‐weeks of starting doxepin‐treatment, while all patients in the placebo group exhibited toxic reactions at this time. There was a statistically significant effect of doxepin on dermatitis in patients undergoing radiotherapy after lumpectomy (Table 1).

4. DISCUSSION

To the best of our knowledge, this is the first randomized trial to demonstrate that doxepin improves acute radiation skin toxicity resulting from the use of breast intensity modulated radiation therapy in the treatment of breast cancer. We used a second phase clinical trial because topical use of doxepin has an analgesic effect in neuropathic pain, and compared with its oral administration, the related side effects are less frequent. Furthermore, doxepin has been frequently studied and is known to have the fewest side effects among active treatment creams. Its topical application has considerable antipruritic activity with a high safety profile, making it a strong candidate in the treatment of pruritus associated with eczematous dermatitis.30

Dermatitis caused by radiation is a side‐effect of radiotherapy for breast cancer. Radiation injures keratinocytes, resulting in oxidative stress from the production of reactive oxygen species associated with tissue damage.31 Mast cell degranulation occurs in mice exposed to ionizing irradiation,4 resulting in histamine release that prompts oedema and erythema.3 Moreover, azelastine (which has antihistaminic and antiallergic actions) decreased radiation dermatitis in mice.5

Numerous trials report that creams or sanitation to inhibit radiation dermatitis are ineffective in either delaying or inhibiting skin reactions.3, 32, 33 Our randomized double‐blinded trial demonstrates that doxepin, which has anti‐inflammatory, antiallergic and antihistaminic properties, reduced radiation dermatitis after breast radiotherapy. We report that radiation dermatitis was improved in patients using topical doxepin cream. Patients in the study had no contact sensitivity to doxepin cream and tolerated it well. Doxepin activates a descending antinociceptive system by inhibiting the reuptake of serotonin and noradrenaline from the synaptic cleft. Doxepin also inhibits adenosine receptors and sodium channels and N‐methyl‐D‐aspartate.34 It is unclear if treatment with a more selective agent (e.g. highly potent and selective histaminergic receptor antagonist) would provide greater benefit in the treatment of radiation dermatitis.

A meta‐analysis harbouring 20 clinical trials examined topical ointments for the prevention and treatment of radiotherapy dermatitis. This study of 3098 patients concluded that currently available topical ointments failed to inhibit or treat radiation complications.35 Systematic reviews on the prevention and management of radiation dermatitis are available.12, 36, 37, 38 Chan et al. suggested that the different approaches used in the studies may have created biases in the clinical findings.39 Our findings suggest that patients should consider the use of doxepin to prevent radiotherapy complications.

A nonsteroid topical ointment was shown to potently inhibit radiation dermatitis during radiotherapy of breast cancer.40 The largest randomized clinical trial to date demonstrated that the incidence of radiotherapy dermatitis was significantly lower after calendula consumption compared to trolamine. Patients receiving calendula had fewer interruptions of radiotherapy and experienced significantly less radiation induced pain. However, the application of calendula was more difficult, but self‐assessed satisfaction was higher.13 The results of another randomized, blinded trial reported no differences between calendula cream and placebo (aqueous cream).41

A study by Nasser et al. compared the effect of topical vitamin D and aqua cream on radiation dermatitis; both treatments had similar effects, with vitamin D not being not superior to aqueous cream in the prevention of skin toxicity during radiotherapy after lumpectomy.3 A study in mice showed that a topical steroid ointment (mometasone furoate) markedly reduced radiation‐induced dermatitis.42

Our study shows that doxepin significantly reduces the prevalence and severity of dermatitis compared to placebo. After 3 weeks of treatment, the incidence of grade 3 dermatitis was 13% in the placebo treated group but dermatitis was not detected in the treated group. Importantly, there was no radiation dermatitis in 50% of patients after 3 weeks of treatment with doxepin while all patients in the placebo group had dermatitis (grades 2 and 3).

Limitations of our study include the relatively small sample size and the relatively short period of monitoring for dermatitis. We followed the patients for 14 days after radiotherapy and doxepin treatment. We will monitor patients for the chronic effects of doxepin cream in future studies, and will obtain details on the breast sizes and skin types of patients.

In conclusion, we designed a randomized, double blind trial to demonstrate that doxepin is significantly more effective than placebo in preventing dermatitis of grade 2 or higher during postoperative breast irradiation. Doxepin is easy to use, affordable and prevents pain and irritation. We propose that doxepin be used as a potential treatment of dermatitis in patients experiencing postoperative radiotherapy of the breast.

COMPETING INTERESTS

There are no competing interests to declare.

CONTRIBUTORS

Laleh Shariati ^3,6,7,8, Alireza Amouheidari ⁴, Hajar Naji Esfahani and Alireza Abed ^3,5, Shaghayegh Haghjooy Javanmard ^1,2, Ismail Laher ^8,9, Ahmad Ghasemi ⁶, Golnaz Vaseghi^1,2,6,7,8.

1. Formulated the research question; 2. designed the study; 3. carried it out; 4. clinical examination of patients; 5. data collecting, 6. analysed the data; 7. interpretation of data 8. wrote the article; 9. revised the article.

Shariati L, Amouheidari A, Naji Esfahani H, et al. Protective effects of doxepin cream on radiation dermatitis in breast cancer: A single arm double‐blind randomized clinical trial. Br J Clin Pharmacol. 2020;86:1875–1881. 10.1111/bcp.14238

DATA AVAILABILITY STATEMENT

Research data are not shared.