Basalzellkarzinom-Chemopräventionsstudie (B3C)

Topical 5% Imiquimod cream will be applied once daily to the face in a thin layer for 12 weeks. Three packets of cream will be defined as one dose or application. The cream should be applied to the face prior to normal sleeping hours (it is readily absorbed) and left on the skin for 6-10 hours (i.e. overnight). Rest periods will be allowed if bothersome side effects occur.

Topical 5% Imiquimod cream will be applied once daily to the face in a thin layer for 12 weeks. Three packets of cream will be defined as one dose or application. The cream should be applied to the face prior to normal sleeping hours (it is readily absorbed) and left on the skin for 6-10 hours (i.e. overnight). Rest periods will be allowed if bothersome side effects occur.

• IMQ

The placebo vehicle control cream will be a virtually identical cream (to the Imiquimod cream) that contains no Imiquimod. This cream will be applied once daily to the face in a thin layer for 12 weeks. Three packets of cream will be defined as one dose or application. The cream should be applied to the face prior to normal sleeping hours (it is readily absorbed) and left on the skin for 6-10 hours (i.e. overnight). Rest periods will be allowed if bothersome side effects occur.

The placebo vehicle control cream will be a virtually identical cream (to the Imiquimod cream) that contains no Imiquimod. This cream will be applied once daily to the face in a thin layer for 12 weeks. Three packets of cream will be defined as one dose or application. The cream should be applied to the face prior to normal sleeping hours (it is readily absorbed) and left on the skin for 6-10 hours (i.e. overnight). Rest periods will be allowed if bothersome side effects occur.

• Placebo

Skin exams will occur at baseline and at 6-month intervals after study randomization. Diagnosis of a new BCC will be ascertained by a biopsy under local anesthesia in an outpatient setting, as is the standard of care. Every biopsy performed on the face of a participant during the trial will be processed per standard clinical operating procedures, as determined by their blinded clinician for the purposes of patient management. The biopsy will be sent for reading by a blinded central dermatopathologist with known high reliability (intra-rater and inter-rater with two other board-certified dermatopathologists) for diagnosing BCC. This central dermatopathologist diagnosis will be used for study purposes. Skin cancers diagnosed outside of the VA, and associated surgeries, will be systematically sought in all participants by participant interview and review of medical records to ensure that the outcome measure is complete.

Basal Cell Carcinoma (BCC) free time to a new BCC on the face over 3 years is defined as the time in years from treatment randomization to the first occurrence of a new BCC on the face. Participants who do not develop a new BCC on the face by 3 years will be considered censored observations. Skin exams will occur at baseline and at 6-month intervals after study randomization.

Diagnosis of a new SCC will be ascertained by a biopsy under local anesthesia in an outpatient setting, as is the standard of care. Every biopsy performed on the face of a participant during the trial will be processed per standard clinical operating procedures, as determined by their blinded clinician for the purposes of patient management, and the biopsy will also be sent for reading by a blinded central dermatopathologist with known high reliability (intra-rater and inter-rater with two other board-certified dermatopathologists) for diagnosing SCC. This central dermatopathologist diagnosis will be used for study purposes. Skin cancers diagnosed outside of the VA, and associated surgeries, will be systematically sought in all participants by participant interview and review of medical records to ensure that the outcome measure is complete.

Squamous Cell Carcinoma (SCC) free time to a new SCC on the face over 3 years is defined as the time in years from treatment randomization to the first occurrence of a new SCC on the face. Participants who do not develop a new SCC on the face by 3 years will be considered censored observations.

AK reduction persistence over time will be assessed using total AK counts (on the face only) evaluated at in-person visits at weeks 6 and 12 and months 6, 12, 18, 24, 30, and 36, and will be analyzed as a repeated measures outcome.

AK reduction in each Olsen grade on the face over time will be assessed using AK counts (on the face only) in each Olsen grade evaluated at in-person visits at weeks 6 and 12 and months 6, 12, 18, 24, 30, and 36, and will be analyzed as a repeated measures outcome.

The proportion of participants with any facial Actinic Keratosis (AK) biopsies or surgical removal on the face from the start of study treatment up to 1 year. Data collection regarding AK biopsies on the face will be assessed at weeks 6 and 12 during treatment, and months 6, 9, and 12 during active follow-up.

Facial regions will be dichotomized to forehead and cheeks versus other areas include the ear, eye (including eyebrows), and nose areas. The investigators will characterize subsites where BCC occurs and assess the effect of IMQ on preventing BCC on the forehead and cheek areas compared to elsewhere on the face.

Facial regions will be dichotomized to forehead and cheeks versus other areas include the ear, eye (including eyebrows), and nose areas. The investigators will characterize subsites where BCC occurs and assess the effect of IMQ on preventing BCC on the forehead and cheek areas compared to elsewhere on the face.

Higher risk histologic subtypes include infiltrative/morpheaform and nodular/infiltrative BCCs.

Higher risk histologic subtypes include infiltrative/morpheaform and nodular/infiltrative BCCs.

The proportion of participants who have experienced a facial primary Basal Cell Carcinoma (BCC) of high severity at 1 year will be determined. To be considered a high severity (i.e. high morbidity) BCC, the tumor must have at least moderate severity and of high severity one of the following features:

i.AJCC stage 3 or 4 BCC ii.BCC requiring radiation iii.BCC requiring multidisciplinary surgery (i.e. oculoplastics, ENT, or neurosurgery, with or without concomitant Mohs micrographic surgery) iv.BCC requiring systemic treatment

The proportion of participants who have experienced a high severity Basal Cell Carcinoma (BCC) at 3 years will be determined. To be considered a high severity (i.e. high morbidity) BCC, the tumor must have at least one of the following features:

i.AJCC stage 3 or 4 BCC ii.BCC requiring radiation iii.BCC requiring multidisciplinary surgery (i.e. oculoplastics, ENT, or neurosurgery, with or without concomitant Mohs micrographic surgery) iv.BCC requiring systemic treatment

The proportion of participants who have experienced a high or moderate severity Basal Cell Carcinoma (BCC) at 1 year will be determined. To be considered a high severity (i.e. high morbidity) BCC, the tumor must have at least one of the following features:

i.AJCC stage 3 or 4 BCC ii.BCC requiring radiation iii.BCC requiring multidisciplinary surgery (i.e. oculoplastics, ENT, or neurosurgery, with or without concomitant Mohs micrographic surgery) iv.BCC requiring systemic treatment

To be considered a moderate severity (i.e. moderate morbidity) BCC, the tumor must require surgical removal, which may include removal with Mohs micrographic surgery, but not meet the criteria for high severity. To be included in mild severity/morbidity, the tumor must not require surgical intervention.

The proportion of participants who have experienced a high or moderate severity Basal Cell Carcinoma (BCC) at 3 years will be determined. To be considered a high severity (i.e. high morbidity) BCC, the tumor must have at least one of the following features:

i.AJCC stage 3 or 4 BCC ii.BCC requiring radiation iii.BCC requiring multidisciplinary surgery (i.e. oculoplastics, ENT, or neurosurgery, with or without concomitant Mohs micrographic surgery) iv.BCC requiring systemic treatment

To be considered a moderate severity (i.e. moderate morbidity) BCC, the tumor must require surgical removal, which may include removal with Mohs micrographic surgery, but not meet the criteria for high severity. To be included in mild severity/morbidity, the tumor must not require surgical intervention.

The proportion of participants with any side effect of treatment during the 12 weeks of the active treatment period or the week following the end of active treatment (week 13).

Tolerability of treatment side effects will be assessed at the end of the treatment (week 12) and it will be a binary response (yes/no).

Photographs of the face will be taken at weeks 6 and 12 in-person visits and translated into a numerical score on the toxicity scale established and used in CSP #562 - the VA Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial.

The Skindex-16 is a 16-item scale to measure the effects of skin disease on a patient's quality of life. All item responses are transformed to a linear scale of 100, varying from 0 (no effect) to 100 (effect experienced all the time). Skindex scores are reported as three scale scores corresponding to the following three domains or subscales: Symptom, Emotional, Functional. A scale score is the average of a patient's responses to items in a given domain. Higher domain scale scores represent worse quality of life.

The Skindex-16 is a 16-item scale to measure the effects of skin disease on a patient's quality of life. All item responses are transformed to a linear scale of 100, varying from 0 (no effect) to 100 (effect experienced all the time). Skindex scores are reported as three scale scores corresponding to the following three domains or subscales: Symptom, Emotional, Functional. A scale score is the average of a patient's responses to items in a given domain. Higher domain scale scores represent worse quality of life.

The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire designed to measure four domains of HRQOL in cancer patients: Physical, social, emotional, and functional well-being. Only the 7-item Physical Well-being subscale is being used in this study. The Physical Well-being score range is 0-28, and the higher score, the better the quality of life.

The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire designed to measure four domains of HRQOL in cancer patients: Physical, social, emotional, and functional well-being. Only the 7-item Physical Well-being subscale is being used in this study. The Physical Well-being score range is 0-28, and the higher score, the better the quality of life.

The proportion of participants indicating acceptability of their assigned treatment cream at 12 weeks will be summarized by treatment group. Acceptability will be assessed by asking participants at 12 weeks whether they would be willing to use the cream they received again in the future if the cream is determined to be effective in reducing their risk of developing future skin cancer on the face.

Medication compliance will be defined as a binary outcome (>=80% compliance vs <80% compliance). Individuals applying 67 or more of the expect 84 doses (67/84=80% with rounding) will be considered >=80% medication compliant, while those applying <67 doses will be considered <80% compliant.

Study treatment compliance status will be defined as a binary outcome (>=80% compliance vs <80% compliance). Individuals applying 67 or more of the expect 84 doses (67/84=80% with rounding) will be considered >=80% medication compliant, while those applying <67 doses will be considered <80% compliant.

The US Department of Veterans Affairs has developed an automated text message service application called Annie that can send automated treatment reminders to Veterans if they register/enroll in Annie and consent to receive Annie text messages. Nine of the 17 study sites will be randomly selected to offer the Annie application to their study participants. The medication compliance status during the 12 weeks of active treatment (as defined above) will be presented for the 9 study sites offering the Annie app and the 8 sites not offering it (irrespective of study treatment group).

Study treatment compliance status will be defined as a binary outcome (>=80% compliance vs <80% compliance). Individuals applying 67 or more of the expect 84 doses (67/84=80% with rounding) will be considered >=80% medication compliant, while those applying <67 doses will be considered <80% compliant.

Veterans Affairs has developed an application called Annie that can send text treatment reminders to Veterans if they enroll in Annie. Nine of the 17 sites will be randomly selected to offer Annie to their participants. Annie use is voluntary and not required for participation. Among the sites offering Annie, the investigators will ask participants whether they received any treatment reminders via Annie & a categorical Annie use variable will be created. Only for the 9 sites offering Annie, the medication compliance status (as defined above) will be presented for the participants that used Annie and those that didn't.

Skin exams will occur at baseline & 6 months after randomization. Diagnosis of a new facial BCC will be via biopsy under local anesthesia in an outpatient setting (standard of care). Every facial biopsy will be processed per standard operating procedures, as determined by the blinded clinician for the purposes of patient management. Biopsies will be read by blinded central dermatopathologist with known high reliability (intra-rater & inter-rater with 2 board-certified dermatopathologists) for diagnosing BCC. Central dermatopathologist diagnosis will be used for study purposes. BCC diagnosed outside VA & surgeries will be collected by participant interview and review of medical records to ensure the outcome measure is complete. Medication compliance will be defined as a binary outcome (>=80% vs <80%). Individuals applying 67 or more of the expect 84 doses (67/84=80% with rounding) will be considered >=80% compliant, while those applying <67 doses will be considered <80% compliant.

Basal Cell Carcinoma (BCC) free time to a new BCC on the face over 3 years is defined as the time in years from treatment randomization to the first occurrence of a new BCC on the face. Participants who do not develop a new BCC on the face by 3 years will be considered censored observations. Skin exams will occur at baseline and at 6-month intervals after study randomization.

Medication compliance status will be defined as a binary outcome (>=80% compliance vs <80% compliance). Individuals applying 67 or more of the expect 84 doses (67/84=80% with rounding) will be considered >=80% medication compliant, while those applying <67 doses will be considered <80% compliant.