Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib
Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib
Between January 18, 2001, and November 3, 2006, 240 patients were randomly assigned to treatment with celecoxib 200 mg twice daily or placebo. There were 122 participants in the celecoxib group and 118 in the placebo group (Table 1). Participants ranged in age from 37.5 years to 87.6 years at enrollment. Specifically, the mean age of the participants was 65.2 years (SD = 10.2 years), all participants had evidence of extensive actinic damage and a Fitzpatrick skin type of I, II, or III, and the average number of previous skin cancers was 2.3 (SD = 4.2). Of the 240 individuals who entered the study, 183 completed it, including 87 (71%) of those randomly assigned to celecoxib and 96 (81%) of those randomly assigned to placebo (Figure 1). The reasons participants withdrew from the trial are shown in Figure 1. The major differences between the celecoxib and placebo groups in reasons for participant withdrawal were withdrawal of consent (seven vs one participant, respectively) and termination of the study by the FDA (12 vs six participants, respectively). The main reason participants gave for withdrawing consent was the prohibition on taking pain medications for arthritis. The FDA terminated the study early after preliminary data from another study showed an association between another cyclooxygenase 2 inhibitor and an increased risk of cardiovascular adverse events because of concerns that the increased risk might extend to celecoxib, the cyclooxygenase 2 inhibitor used in this study. At the time that this study was terminated, there were more subjects in the celecoxib arm of the study than in the placebo arm (12 vs six participants, respectively).
(Enlarge Image)
Figure 1.
Study design and participant status by treatment arm. FDA = Food and Drug Administration.
We performed separate analyses to examine whether treatment with celecoxib influenced the number of actinic keratoses after 3, 6, and 9 months of therapy and at 2 months following the completion of therapy (ie, month 11). Specifically, we assessed the total number of actinic keratoses, the number of new actinic keratoses, and the ratio of total lesions to the number at baseline for the body as a whole and for the upper extremities, neck, face, and scalp individually. For each of these analyses, there was no difference in any of these measures between the celecoxib and placebo arms at month 9 (Table 2) or month 11 (data not shown) after randomization. After controlling for age, sex, sunscreen use, and Fitzpatrick skin type using Poisson regression, the ratio of new lesions to the number at randomization did not differ statistically significantly between the celecoxib and placebo groups (P = .69). A total of 29.3% of the actinic keratoses in both treatment groups regressed spontaneously, consistent with other reports.
The effect of treatment on the number of nonmelanoma skin cancers was evaluated by using Poisson regression and adjusting for patient time on study (Table 3). By month 11 after randomization (or at early study withdrawal), the mean number of nonmelanoma skin cancers per patient was statistically significantly less in participants who received celecoxib than in participants who received placebo (0.14 vs 0.35; rate ratio [RR] = 0.43, 95% CI = 0.24 to 0.75, P = .003), representing a 60% reduction in the mean number of nonmelanoma skin cancers. A decrease in nonmelanoma skin cancers was also observed at month 9 after randomization (Table 3). A difference in the number of nonmelanoma skin cancers between the two treatment groups was clearly evident by month 9 and was sustained for the rest of the time that the subjects were on the trial. In addition, we observed no rebound in the rate of development of nonmelanoma skin cancers in the celecoxib arm during the 2 months after subjects stopped taking celecoxib (Table 3). An inhibitory effect of celecoxib on nonmelanoma skin cancer development was also observed when cutaneous SCCs and BCCs were evaluated separately. By month 11 after randomization, the mean number of BCCs per patient in the celecoxib group was 0.07 (95% CI = 0.03 to 0.13) compared with 0.16 (95% CI = 0.1 to 0.25) in the placebo group (RR = 0.44; 95% CI = 0.19 to 0.99; P = .049) (Table 3). By month 11 after randomization, the mean number of SCCs per patient was 0.07 (95% CI = 0.04 to 0.14) in the celecoxib group compared with 0.19 (95% CI = 0.12 to 0.28) in the placebo group (RR = 0.42; 95% CI = 0.19 to 0.92; P = .03) (Table 3).
The celecoxib treatment effect on skin cancer remained statistically significant after adjusting for age, sex, Fitzpatrick skin type, actinic keratosis history at screening, skin cancer history, and log-transformed patient time on study. The adjusted rate ratios for the celecoxib arm compared with the placebo arm were 0.41 (95% CI = 0.23 to 0.72, P = .002) for nonmelanoma skin cancers, 0.40 (95% CI = 0.18 to 0.93, P = .032) for BCCs, and 0.42 (95% CI = 0.19 to 0.93, P = .032) for cutaneous SCCs. In subgroup analyses according to Fitzpatrick skin type (I, II, or III) and stratified by history of skin cancers and median number of actinic keratoses (≤23 vs >23), we observed no statistically significant consistent difference between treatment arms with respect to nonmelanoma skin cancers, BCC, or SCC among subgroups (Supplementary Table 1, available online), possibly reflecting the small number of subjects in several of the subgroups.
There was no statistically significant difference between those who remained in the study and those who withdrew with regard to any of the demographic or clinical characteristics (Table 4).
Four patients in the placebo group had three or more nonmelanoma skin cancers compared with none in the celecoxib group (data not shown). One melanoma was diagnosed in the celecoxib group and none were diagnosed in the placebo group.
Eighty-four percent of celecoxib-treated subjects reported at least one adverse event compared with 85% of control subjects (P = .95) (Table 5). The most common adverse events were infections and infestations, followed by gastrointestinal, musculoskeletal, and skin disorders and hypertension (a frequent side effect of NSAIDs) (Supplementary Table 2, available online). The adverse effects that were more common in the celecoxib group than in the placebo group were those that are commonly attributed to cyclooxygenase inhibitors, that is, gastrointestinal disorders, skin rashes, hypertension, and hemorrhage. Serious events occurred in 16 subjects, nine of whom received celecoxib and seven of whom received placebo. This difference was not statistically significant. There were no deaths in either group.
Because cyclooxygenase 2 inhibitors have been reported to increase the risk of serious cardiovascular adverse events (ie, myocardial infarction, stroke, congestive heart failure, or cardiovascular deaths), we examined the occurrence of cardiovascular adverse events in greater detail (Table 5 and Supplementary Table 2, available online). A similar number of individuals experienced cardiovascular adverse events in the two treatment groups. There were nine adverse cardiovascular events in seven subjects treated with celecoxib compared with six adverse events in five subjects in the placebo group. The number of subjects in the two treatment arms who experienced a cardiovascular event was not statistically significantly different.
Results
Between January 18, 2001, and November 3, 2006, 240 patients were randomly assigned to treatment with celecoxib 200 mg twice daily or placebo. There were 122 participants in the celecoxib group and 118 in the placebo group (Table 1). Participants ranged in age from 37.5 years to 87.6 years at enrollment. Specifically, the mean age of the participants was 65.2 years (SD = 10.2 years), all participants had evidence of extensive actinic damage and a Fitzpatrick skin type of I, II, or III, and the average number of previous skin cancers was 2.3 (SD = 4.2). Of the 240 individuals who entered the study, 183 completed it, including 87 (71%) of those randomly assigned to celecoxib and 96 (81%) of those randomly assigned to placebo (Figure 1). The reasons participants withdrew from the trial are shown in Figure 1. The major differences between the celecoxib and placebo groups in reasons for participant withdrawal were withdrawal of consent (seven vs one participant, respectively) and termination of the study by the FDA (12 vs six participants, respectively). The main reason participants gave for withdrawing consent was the prohibition on taking pain medications for arthritis. The FDA terminated the study early after preliminary data from another study showed an association between another cyclooxygenase 2 inhibitor and an increased risk of cardiovascular adverse events because of concerns that the increased risk might extend to celecoxib, the cyclooxygenase 2 inhibitor used in this study. At the time that this study was terminated, there were more subjects in the celecoxib arm of the study than in the placebo arm (12 vs six participants, respectively).
(Enlarge Image)
Figure 1.
Study design and participant status by treatment arm. FDA = Food and Drug Administration.
Efficacy of Treatment
We performed separate analyses to examine whether treatment with celecoxib influenced the number of actinic keratoses after 3, 6, and 9 months of therapy and at 2 months following the completion of therapy (ie, month 11). Specifically, we assessed the total number of actinic keratoses, the number of new actinic keratoses, and the ratio of total lesions to the number at baseline for the body as a whole and for the upper extremities, neck, face, and scalp individually. For each of these analyses, there was no difference in any of these measures between the celecoxib and placebo arms at month 9 (Table 2) or month 11 (data not shown) after randomization. After controlling for age, sex, sunscreen use, and Fitzpatrick skin type using Poisson regression, the ratio of new lesions to the number at randomization did not differ statistically significantly between the celecoxib and placebo groups (P = .69). A total of 29.3% of the actinic keratoses in both treatment groups regressed spontaneously, consistent with other reports.
The effect of treatment on the number of nonmelanoma skin cancers was evaluated by using Poisson regression and adjusting for patient time on study (Table 3). By month 11 after randomization (or at early study withdrawal), the mean number of nonmelanoma skin cancers per patient was statistically significantly less in participants who received celecoxib than in participants who received placebo (0.14 vs 0.35; rate ratio [RR] = 0.43, 95% CI = 0.24 to 0.75, P = .003), representing a 60% reduction in the mean number of nonmelanoma skin cancers. A decrease in nonmelanoma skin cancers was also observed at month 9 after randomization (Table 3). A difference in the number of nonmelanoma skin cancers between the two treatment groups was clearly evident by month 9 and was sustained for the rest of the time that the subjects were on the trial. In addition, we observed no rebound in the rate of development of nonmelanoma skin cancers in the celecoxib arm during the 2 months after subjects stopped taking celecoxib (Table 3). An inhibitory effect of celecoxib on nonmelanoma skin cancer development was also observed when cutaneous SCCs and BCCs were evaluated separately. By month 11 after randomization, the mean number of BCCs per patient in the celecoxib group was 0.07 (95% CI = 0.03 to 0.13) compared with 0.16 (95% CI = 0.1 to 0.25) in the placebo group (RR = 0.44; 95% CI = 0.19 to 0.99; P = .049) (Table 3). By month 11 after randomization, the mean number of SCCs per patient was 0.07 (95% CI = 0.04 to 0.14) in the celecoxib group compared with 0.19 (95% CI = 0.12 to 0.28) in the placebo group (RR = 0.42; 95% CI = 0.19 to 0.92; P = .03) (Table 3).
The celecoxib treatment effect on skin cancer remained statistically significant after adjusting for age, sex, Fitzpatrick skin type, actinic keratosis history at screening, skin cancer history, and log-transformed patient time on study. The adjusted rate ratios for the celecoxib arm compared with the placebo arm were 0.41 (95% CI = 0.23 to 0.72, P = .002) for nonmelanoma skin cancers, 0.40 (95% CI = 0.18 to 0.93, P = .032) for BCCs, and 0.42 (95% CI = 0.19 to 0.93, P = .032) for cutaneous SCCs. In subgroup analyses according to Fitzpatrick skin type (I, II, or III) and stratified by history of skin cancers and median number of actinic keratoses (≤23 vs >23), we observed no statistically significant consistent difference between treatment arms with respect to nonmelanoma skin cancers, BCC, or SCC among subgroups (Supplementary Table 1, available online), possibly reflecting the small number of subjects in several of the subgroups.
There was no statistically significant difference between those who remained in the study and those who withdrew with regard to any of the demographic or clinical characteristics (Table 4).
Four patients in the placebo group had three or more nonmelanoma skin cancers compared with none in the celecoxib group (data not shown). One melanoma was diagnosed in the celecoxib group and none were diagnosed in the placebo group.
Safety
Eighty-four percent of celecoxib-treated subjects reported at least one adverse event compared with 85% of control subjects (P = .95) (Table 5). The most common adverse events were infections and infestations, followed by gastrointestinal, musculoskeletal, and skin disorders and hypertension (a frequent side effect of NSAIDs) (Supplementary Table 2, available online). The adverse effects that were more common in the celecoxib group than in the placebo group were those that are commonly attributed to cyclooxygenase inhibitors, that is, gastrointestinal disorders, skin rashes, hypertension, and hemorrhage. Serious events occurred in 16 subjects, nine of whom received celecoxib and seven of whom received placebo. This difference was not statistically significant. There were no deaths in either group.
Because cyclooxygenase 2 inhibitors have been reported to increase the risk of serious cardiovascular adverse events (ie, myocardial infarction, stroke, congestive heart failure, or cardiovascular deaths), we examined the occurrence of cardiovascular adverse events in greater detail (Table 5 and Supplementary Table 2, available online). A similar number of individuals experienced cardiovascular adverse events in the two treatment groups. There were nine adverse cardiovascular events in seven subjects treated with celecoxib compared with six adverse events in five subjects in the placebo group. The number of subjects in the two treatment arms who experienced a cardiovascular event was not statistically significantly different.
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