Oral Isotretinoin Versus Topical Tretinoin for Actinic Keratosis

This study is a randomized controlled trial with 60 men and women (already in menopause for at least one year), aged 50-75 years. At the beginning, the number of actinic keratosis (AKs) of face and forearms will be counted and treated with cryotherapy with liquid nitrogen (LN).The patients will be randomized in two groups: one receiving oral isotretinoin 10mg/day every day and other receiving tretinoin 0,05% cream applied in the face and arms every other night, for six months. Along with these treatments, patients will use sunscreens FPS 60 with UVA and UVB protection. The inclusion criteria will be the presence of at least 10 and maximum 40 AKs (visible or palpable). Skin biopsies will be performed twice (before and after treatment with retinoids) for all patients, in the left forearm at a standardized site. Histological and immunohistochemical with blinded- evaluator analysis will be done. The main objective of the study is to evaluate clinical, histological and immunohistochemical effects of retinoids for AK prevention on face and forearms of immunocompetent individuals. Efficacy evaluation will be measured by improving clinical (AK counting before and after treatments), histopathological (Hematoxilin-eosin and Verhoeff staining) and immunohistochemical parameters (markers for carcinogenesis - p53 protein, Bcl-2 and Bax). The secondary objective is evaluate the tolerability and safety of the drugs and their impact in quality of life. The safety analysis will be related to adverse events of the two drugs and the blood tests will be performed in the ISO group patients. Indirectly, by decreasing the number of AKs and the expression of cutaneous carcinogenesis markers, a decrease in the risk of squamous cell carcinoma could be infered . This principle is used by many drugs called chemoprophylactic drugs, and the retinoids are considered in this group.

Inclusion criteria

• Signature of the Free and Clarified Consent Term before any procedure of the study;
• Men and women, aged 50-75 years, in good health;
• Women in menopause for 1 year or more;
• Phototypes I-IV by Fitzpatrick classification;
• Glogau photodamage classification scale from moderate to severe
• At least 10 and maximum 60 visible and/or palpable actinic keratosis, in the face and forearms, in a standardized distribution;
• Absence of topical treatment in the face and forearms, except sunscreens, with:

• tretinoin in the last 6 months;
• alphahydroxyacids, polyhydroxyacids, betahydroxyacids and ascorbic acid in the last 3 months;
• drugs or procedures that may change the natural evolution of actinic keratosis, such as imiquimod 5% cream, diclofenac 3% in hyauronic acid gel, photodynamic therapy, 5-FU, in the last 6 months;
• Absence of previous treatment in the face and forearms with chemical peels and microdermabrasion, in the last 6 months;
• Absence of previous treatment with oral retinoids in the last 6 months;
• Absence of anti-cancer chemotherapy in the last 3 months;
• Absence of hypersensitivity to parabens (present in the majority of drugs as a preserving agent);
• Absence of infectious or inflammatory diseases in the face and forearms;
• Absence of immunossupression;
• Absence of photodermatosis;
• Agreement in avoiding sun exposure during the research;
• Agreement in not performing any other kind of treatment that could change the natural history of actinic keratosis; and
• Agreement with the study conditions, ability to understand and follow strictly the given orientations, availability to attend the periodical evaluations.

For the isotretinoin group (ISO):

• Absence of history of isotretinoin hypersensitivity;
• Avoid alcohol intake and;
• Absence of previous and actual history of rheumatologic diseases.

For the tretinoin group (AR):

• Absence of history of tretinoin hypersensitivity;

Exclusion criteria

For all patients:

• Men and women who dón't agree with the terms of the research or without ability to understand and/or follow strictly the conditions of the study, without availability to understand and attend the periodical evaluations or who decline to sign the Free and Clarified Consent Term;
• Patients with less than 10 and more than 60 actinic keratosis in the face and forearms;
• Fertile, pregnant or lactating women;
• Fitzpatrick phototypes V e VI ;
• Topical treatment in the face and forearms, except sunscreens, with:

• tretinoin in the last 6 months;
• alphahydroxyacids, polyhydroxyacids, betahydroxyacids and ascorbic acid in the last 3 months;
• drugs or procedures that may change the natural evolution of actinic keratosis, such as imiquimod 5% cream, diclofenac 3% in hyauronic acid gel, photodynamic therapy, 5-FU, in the last 6 months;
• Previous treatment in the face and forearms with chemical peels and microdermabrasion, in the last 6 months;

• Previous treatment with oral retinoids in the last 6 months

For the isotretinoin group (ISO):

• Presence of significative hepatic laboratory alterations (elevated liver enzymes twice ashigh as the upper normal limit;
• Diabetic patients, with fast glucose values superior to 110mg/dl;
• Significant lipid profile alterations (triglycerides > 300 mg/dl; total cholesterol> 250 mg/dl);
• Low count of white blood cells (leukocytes < 3000/mm3);
• History of hypersensitivity to isotretinoin and parabens;
• Alcohol intake;
• Previous or actual history of rheumatologic diseases;
• Anticancer chemotherapy in the last 3 months;
• Previous history of hypervitaminosis A;
• Previous history of bone or muscular diseases;
• Patients who are in use or may use the following drugs (risk of drug interaction):

• tetracyclines and derivatives - in the last 7 days;
• vitamin A - in the last 30 days;
• carbamazepine - in the last 7 days.