Topical Perillyl Alcohol in Treating Patients With Sun Damaged Skin and Actinic Keratoses

• Safety of perillyl alcohol at the administered doses [ Designated as safety issue: Yes ]
• Statistically significant reductions in karyometric measurements (nuclear abnormality and discriminant function score) and biomarker expression (p53, apoptosis, and c-Fos) analyzed as percent immunohistochemical positive [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy, such as perillyl alcohol, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. It is not yet known which dose of topical perillyl alcohol is more effective in stopping the development of cancer in sun damaged skin.

PURPOSE: This randomized phase II trial is studying high-dose topical perillyl alcohol to see how well it works compared with low-dose topical perillyl alcohol in treating patients with sun damaged skin and actinic keratoses.

OBJECTIVES:

Primary

• To determine if topical administration of perillyl alcohol (POH) cream can reverse actinic damage as evidenced by normalization of quantitative skin histopathology scores in skin tissue biopsy samples from patients with moderate to severe sun damage.

Secondary

• To determine if topically administered POH results in significant alterations in surrogate endpoint biomarkers of epidermal cell proliferation, including optical coherence tomography, p53 expression, c-Fos expression, and apoptosis (as measured by activated caspase-3 expression).
• To determine if topically administered POH results in normalization of nuclear chromatin patterns in skin biopsy tissue from these patients, as determined by karyometric analysis.
• To determine if topical POH can be administered safely to the forearms of these patients.

OUTLINE: Patients are randomized to 1 of 3 arms.

• Arm I: Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.
• Arm II: Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.
• Arm III: Patients apply POH cream (0.76%) as in arm II. Patients undergo tissue sampling of the right or left dorsal forearm and of physician-selected representative actinic keratoses (AK) at baseline and after completion of study therapy. Tissue samples are assessed for changes in patterns of biomarker expression (i.e., p53, apoptosis, c-Fos histopathology) and karyometry. After completion of study therapy, patients undergo tissue sampling of the opposite forearm as well as blood sample collection to determine perillyl alcohol (POH) levels in blood and biopsy samples. Urine is also collected and analyzed for safety at the end of treatment. Digital photographs of the forearms and hands are obtained at baseline and after 3 months of study treatment. Optical coherence tomography imaging is also performed on pre- and post-biopsy sites to quantify the effect of POH on sun damage and AK in skin.

After completion of study treatment, patients are followed monthly.

• Drug: perillyl alcohol
  Applied as topical cream
• Other: placebo
  Applied as topical cream

• Placebo Comparator: Arm I
  Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.
  Intervention: Other: placebo
• Experimental: Arm II
  Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.
  Intervention: Drug: perillyl alcohol
• Experimental: Arm III
  Patients apply POH cream (0.76%) as in arm II.
  Intervention: Drug: perillyl alcohol

DISEASE CHARACTERISTICS:

• Resident of Pima or adjoining Southern Arizona county

  • Patients outside of Pima County are also eligible

• Sun damaged skin as judged by the study physician and quantifiable, clinically diagnosed, and visible actinic keratoses (AK) on both dorsal forearms, with at least two AK on each arm

  • AK lesions must not be clustered, confluent, or too numerous to count accurately
  • Presence of AK on sites other than the test area allowed
• No significant inflammation or irritation of the skin of the upper extremities that is not clinically diagnosed as sun damage or AK
• Patients must agree to limit sun exposure as much as possible and may continue their normal pattern of sunscreen use

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Females must not be of childbearing potential, and therefore must be post-menopausal or surgically sterile by hysterectomy
• Not pregnant or nursing

Exclusion criteria:

• Concurrent skin malignancy or disorder of the upper extremities

  • Patients with SCC or BCC in an area other than the test area are eligible upon excision of the SCC or BCC
• Patients who are immunosuppressed by virtue of medication or disease
• Serious concurrent illness that could interfere with study regimen
• Invasive cancer within the past 5 years

PRIOR CONCURRENT THERAPY:

• At least 30 days since prior topical medications to the skin of the upper extremities except for emollients or sunscreens

• At least 30 days since prior and no concurrent mega-doses of vitamins, defined as any of the following:

  • More than 5 times the recommended daily allowance
  • More than 5 capsules of multivitamins
  • 400 IU of vitamin E
  • 200 μg of selenium
  • 1 gm of vitamin C

• At least 6 months since prior and no concurrent therapy for squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) anywhere in the test area (i.e., the forearms or hands)

  • Treatment for SCC or BCC on sites other than the test area is allowed
• At least 4 weeks since prior surgical biopsy, surgical excision, or cryotherapy for AK in the test area and the sites must have healed
• At least 6 months since prior topical treatment (e.g., 5-fluorouracil or imiquimod) for AK
• No concurrent therapy that may interfere with clinical evaluations
• No concurrent topical drug treatment (e.g., retinoids, aminolevulinic acid, diclofenac sodium, imiquimod, or fluorouracil) to any area of skin, including test area
• No concurrent enrollment in another clinical trial
• No concurrent topical citrus peel or consumption of citrus peel
• No chemotherapy for cancer within the past 5 years