Hypericum perforatum and neem oil for the management of acute skin toxicity in head and neck cancer patients undergoing radiation or chemo-radiation: a single-arm prospective observational study
© Franco et al.; licensee BioMed Central. 2014
Received: 9 October 2014
Accepted: 11 December 2014
Published: 29 December 2014
Radiation dermatitis is common in patients treated with combined radiotherapy and chemotherapy for head and neck malignancies. Its timely and adequate management is of uttermost importance for both oncological outcomes and global quality of life. We prospectively evaluated the role of hypericum perforatum and neem oil (Holoil®; RIMOS srl, Mirandola, Italy) in the treatment of acute skin toxicity for patients undergoing radiotherapy or chemo-radiotherapy for head and neck cancer.
A consecutive series of 28 head and neck cancer patients submitted to radiotherapy (RT) was enrolled onto this mono-institutional single-arm prospective observational study. Patients undergoing both definitive or post-operative radiotherapy were allowed, either as exclusive modality or combined with (concomitant or induction) chemotherapy. We started Holoil treatment whenever bright erythema, moderate oedema or patchy moist desquamation were observed. Holoil® was used during all RT course and during follow up time, until acute skin toxicity recovery.
The maximum detected acute skin toxicity was Grade 1 in 7% of patients, Grade 2 in 68%, Grade 3 in 25%, while at the end of RT was Grade 0 in 3.5%, Grade 1 in 32%, Grade 2 in 61%, Grade 3 in 3.5%. For patients having G2 acute skin toxicity, it mainly started at weeks 4-5; for those having G3, it began during weeks 5-6. Median times spent with G2 or G3 toxicity were 17.5 and 11 days. Patients having G2 acute skin toxicity had a dermatitis worsening in 27% of case (median occurrence time: 7 days). G3 events were reconverted to a G2 profile in all patients (median time: 7 days). Those experiencing a G2 skin event were converted to a G1 score in 23% of cases (median time: 14 days). Time between maximum acute skin toxicity and complete skin recovery after RT was 27 days.
Holoil® proved to be a safe and active option in the management of acute skin toxicity in head and neck cancer patients submitted to RT or chemo-radiotherapy. A prophylactic effect in the prevention of moist desquamation may be hypothesized for hypericum and neem oil and need to be tested within a prospective controlled study.
Radiation dermatitis is a frequent occurrence in patients undergoing radiotherapy (RT) for head and neck malignancies . Its adequate and timely management is of paramount importance as it may impact patients adherence to treatment protocol, with a consequent eventual effect on clinical outcomes and global quality of life. Acute skin toxicity generally appears within a few weeks from the start of radiation, with clinical manifestations varying from mild erythema to brisk moist desquamation and, rarely, to ulceration and necrosis . Several factors may potentially affect skin toxicity characteristics in terms of intensity, duration and recovery time. Some of them are related to RT characteristics such as total dose, fractionation, radiation energy and volume of treated regions. Others are patient’s specific depending on age, eventual comorbid conditions, skin phototype and genetic predisposition . The addition of standard chemotherapy and/or biological agents might consistently increase the toxicity profile ,. At present, there is no standard approach for the prevention and treatment of radiation-induced skin toxicity. Several medications have been proposed in this context such as topical agents, dressings and advanced medications. Holoil® is a medical compound made of hypericum flowers (Hypericum perforaturm) and neem oil (Azadirachta indica) extracts. Hypericum perforatum has been demonstrated to have anti-inflammatory properties . Neem oil has cicatrizing and anti-inflammatory effects . We herein report on a prospective observational study investigating the use of Holoil® (RIMOS s.r.l., Mirandola, Italy) as a local treatment for acute skin toxicity in patients undergoing radiotherapy or chemo-radiotherapy for head and neck malignancies.
Material and methods
Between November 2013 and June 2014, we enrolled a consecutive series of 28 patients affected with head and neck cancer and submitted to RT onto this single-arm prospective observational study designed to investigate the potential role of Hypericum perforatum and Neem oil in the treatment of acute skin toxicity during radiation. Written informed consent was obtained from all patients. Inclusion criteria included age > 18 and indication to RT as definitive treatment or as an adjuvant approach after radical surgery to the primary site. Patients receiving neck dissection and/or neck irradiation were enrolled as well as those submitted to combined modality treatment (induction and/or concurrent chemotherapy). Due to specific peculiarities in terms of skin toxicity, patients undergoing RT and cetuximab were excluded -.
Surgical approaches to the primary tumor and cervical lymphnodes varied according to the sites of presentation and eventual neck involvement, including partial or total laryngectomy, partial or emi- glossectomy, pharyngectomy, oral cavity excisions with partial mandibulectomies. Neck dissection, whenever needed, was always perfomed ‘en bloc’ with the excision of the primary sites, specifically radical or functional, bilateral or monolateral strictly depending on the clinical assessment of the nodal status of the neck at diagnosis. RT, either definitive or adjuvant, was delivered with an ‘intensity-modulated’ approach (IMRT), employing an Elekta 6 MV linear accelerator delivering volumetric IMRT (VMAT) (Elekta, Stockholm, Sweden). For definitive radiation, a ‘simultaneous integrated boost’ approach was used, with the macroscopic disease receiving 70 Gy/35 fractions (2 Gy daily), an ‘intermediate risk volume’ getting 63 Gy/35 fractions (1.8 Gy daily) and a ‘low risk volume’ receiving 54.25 Gy/35 fractions (1.55 Gy daily). Post-operative SIB-based RT generally included a ‘high risk volume’ (60–64 Gy 30–32 fractions; 2 Gy daily) and a low-risk volume (51.2-54.4 Gy; 1.6-1.8 Gy daily). For the post-operative setting, RT started no longer than 8 weeks from surgery. Image guided radiotherapy (IGRT) was employed for all treatments monitoring set up and interfraction motion with a daily cone-beam computed tomography (CBCT). Chemotherapy was given as induction treatment using the TPF regimen (Docetaxel 75 mg/m2 and Cisplatin 100 mg/m2 of body surface area on day 1 and 5-Fluorouracil 1000 mg/m2 of body surface are as a 24-hours continuous infusion on days 2–5) every 3 weeks or the Carboplatin (AUC 6) + Taxol (175 mg/m2 body surface area) on day 1 every 3 weeks regimen. Concurrent chemotherapy was given with weekly Cisplatin (30 mg/m2 body surface area) or weekly Carboplatin (AUC 2) for 6–7 weeks.
Medical evaluation during IMRT consisted of a weekly clinical evaluation with a visual examination of the neck region skin performed by the physician in charge of the patient and a consequent physician-rated score of acute skin toxicity. The RTOG⁄EORTC toxicity scale was used as reference . Non-skin toxicities were also assessed and managed during clinical assessment but are not object of this report. After the end of treatment patients were evaluated up to 90 days to evaluate and score skin toxicity. Oncological follow up continued over time according to our institutional protocol. The primary end-point of the study was the evaluation of the activity of Holoil® in the management of ≥ G2 acute skin toxicity in patients undergoing radiation or chemo-radiation for head and neck cancer. No patient-reported outcome measures have been analysed.
Acute skin toxicity management
All patients were given a moisturizing cream by the time of RT first fraction. They were instructed to carefully apply it on the bilateral neck 2–3 times a day, at least 3 hours before treatment session. Moreover patients were prohibited to use other creams or cosmetic products in the irradiated areas. No topical medications were prescribed prophylactically. All patients were educated to deterge the irradiated area only with a specific oil soap and to generally wear loose clothes. Holoil® ointment was started whenever bright erythema or moderate oedema or patchy moist desquamation were observed (G2 acute skin toxicity according to RTOG scoring scale). Concomitantly, moisturizing cream application was interrupted. Generally, for erythema and/or oedema the gel preparation was employed. For patchy moist desquamation, the oil preparation, with a higher concentration of active ingredients, was administered. Holoil® was used up to the end of RT and afterwards during follow up time, until complete recovery from acute skin toxicity. Twice a day applications were mostly given.
Patients and treatment characteristics
Highest prescribed dose
TPF x 3
CBDCA + TAX x 3
None (exclusive RT)
Acute skin toxicity
Acute skin toxicity rates
Acute skin toxicity
No change over baseline
Follicular, faint or dull erythema/epilation/dry desquamation/decreased sweating
Tender or bright erythema, patchy moist desquamation/moderate edema
Confluent, moist desquamation other than skin folds, pitting edema
Ulceration, hemorrage, necrosis
Acute skin toxicity timeline
Time to G2 acute skin toxicity
No G2 events
Time to G3 acute skin toxicity
No G3 events
Time spent with G2 acute skin tox (26 pts)
Time spent with G3 acute skin tox (7 pts)
Acute skin toxicity evolution
Toxicity conversion rate
G2 to G3
G3 to G2
G2 to G1
Time from Max to G0 toxicity
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