Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib
Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib
We found that compared with placebo, the cyclooxygenase 2 inhibitor celecoxib administered for 9 months was highly effective in preventing nonmelanoma skin cancers in subjects who had large numbers of actinic keratoses, some of whom had already developed one or more skin cancers, and thus were at high risk for these neoplasms. Our findings validate preclinical data that were the premise for the entry of celecoxib into clinical testing. However, this analysis of nonmelanoma skin cancers should be considered exploratory because it was not the primary endpoint of the randomized trial.
This study was initiated because of preclinical evidence suggesting that cyclooxygenase 2 is involved in the pathogenesis of sunlight-induced skin cancers. Specifically, expression of this enzyme is increased in the epidermis following UV exposure, and cyclooxygenase 2 can be detected in actinic keratoses and SCCs. In BCCs, cyclooxygenase 2 has been found in tumor islands and in the stroma surrounding the tumor islands. Moreover, cyclooxygenase 2 inhibitors have been successful at preventing UV-induced skin cancers in mouse models. There is also evidence from epidemiological studies that NSAIDs, which inhibit cyclooxygenases, are associated with a decreased risk of cutaneous SCCs. For example, in a case–control study conducted in Australia, subjects who had taken large doses of NSAIDs on a regular basis were less likely than subjects who had used NSAIDs infrequently or not at all to have had a cutaneous SCC. Another study reported that among individuals with a history of nonmelanoma skin cancers, those who were NSAID users had a reduced risk of nonmelanoma skin cancers, in particular SCCs, compared with nonusers. However, the protective effect of NSAIDs on nonmelanoma skin cancer was less striking in another study. In that study, in a cohort of high-risk patients, subjects who used NSAIDs for less than the study duration developed fewer BCCs and SCCs than subjects who used NSAIDs for the entire length of the study. However, another retrospective case–control study did not observe a statistically significant reduction in SCCs among individuals who reported taking any NSAID, ibuprofen, or nonaspirin NSAIDs. Similar conclusions were reached when pharmacy databases were examined for prescriptions for NSAID that were filled among patients with SCCs.
To our knowledge, no agents have been approved by either the FDA or governmental regulatory agents in other countries for the prevention of skin cancer. However, previous studies that were based in Australia, where the skin cancer rates are the highest in the world, and conducted in the general population have convincingly demonstrated that sunscreens are effective chemopreventive agents for actinic keratoses and cutaneous SCCs. They showed that the regular use of an SPF15 sunscreen for more than 5 years inhibited SCCs by approximately 35%, whereas the data for BCCs were limited. Despite the widespread use of sunscreens for skin cancer prevention, appreciable numbers of these malignancies still occur. The findings of this study, which showed that the celecoxib-treated individuals developed fewer nonmelanoma skin cancers than placebo-treated individuals, suggest that cyclooxygenase inhibitors may provide an additional benefit to sunscreens in the prevention of nonmelanoma skin cancers.
There has been substantial interest in the use of cyclooxygenase inhibitors for the prevention of other types of cancer besides nonmelanoma skin cancers. For example, celecoxib has been shown in clinical trials to inhibit the formation of sporadic colorectal adenomas and adenomas in familial adenomatous polyposis. Our results extend those findings to a second target organ system (ie, the skin) and to tumors caused by a different etiologic agent (ie, chronic UV exposure). In a recent study that examined NSAID use in subjects with basal cell nevus syndrome, which predisposes individuals to develop large numbers of BCCs because of a genetic defect in the patched 1 gene (PTCH1) of the sonic hedgehog signal transduction pathway, among patients with fewer than 15 BCCs at study entry, those who received celecoxib for 24 months developed statistically significantly fewer new BCCs than those treated with placebo.
Other agents have been evaluated for the chemoprevention of nonmelanoma skin cancer. Oral retinoid and topical application of the DNA repair enzyme T4 endonuclease V in liposomes have both been shown to have chemopreventive activity against nonmelanoma skin cancers in patients with predisposing conditions, but neither has been tested in the general population. It is interesting that low-fat diets have also been reported to reduce the number of actinic keratoses and nonmelanoma skin cancers in clinical trials. However, compliance with such a restrictive diet could prove challenging for individuals placed on the diet. Thus, there is clearly a need for new interventions that prevent these common malignancies.
Celecoxib was effective at reducing the incidence of cutaneous SCC but did not prevent its precursor, actinic keratosis. This finding was unexpected because results of preclinical studies on the prevention of SCC in mouse models suggested that celecoxib would reduce premalignant actinic keratoses as well as nonmelanoma skin cancers. This preferential effect of celecoxib against later stages of tumor development is consistent with findings of colorectal adenoma trials that tested celecoxib or aspirin. Although the precise mechanism for these unexpected results is not known, we envision three potential mechanisms by which celecoxib could inhibit the progression of premalignant keratinocytes to invasive malignancies. First, cyclooxygenase 2 is required for the synthesis of prostaglandin E2, which stimulates the proliferation of malignant cells. Celecoxib could thus have an antiproliferative effect, possibly by promoting apoptosis. The antiproliferative effect has been invoked to explain the regression of colorectal adenomas in a placebo-controlled trial of celecoxib in patients with familial adenomatous polyposis. Second, myeloid suppressor cells, which promote invasion and angiogenesis of human BCC cells, require cyclooxygenase 2 for production of the immunosuppressive molecule arginase-1. Celecoxib might render these cells less active and thereby inhibit the development of cutaneous SCCs and BCCs. Finally, celecoxib could suppress the epithelial–mesenchymal transition, a process through which malignant cells weaken intercellular adhesions, thereby enhancing their motility and allowing them to penetrate into surrounding tissues. In lung carcinogenesis, it has been proposed that cyclooxygenase 2 is intimately involved in this process.
The chemopreventive effect of celecoxib occurred rapidly. The numbers of new nonmelanoma skin cancers in the two treatment arms began to diverge within 3 months of the initiation of therapy for BCCs and within 6 months of the initiation of therapy for SCCs. This is not the first time that a chemopreventive agent has been shown to work this quickly to prevent BCCs: Kraemer et al. observed an inhibitory effect on skin cancer development in xeroderma pigmentosum patients within 3 months of administering oral isotretinoin, and, a recurrence of nonmelanoma skin cancers within 3 months after oral isotretinoin was stopped. In this study, nonmelanoma skin cancers did not recur during the 2-month follow-up period. However, the follow-up was short, and future studies will need to ascertain the durability of the response after cyclooxygenase inhibitors are discontinued.
Any beneficial effects of cyclooxygenase 2 inhibitors must be balanced against the adverse events associated with this class of compounds. Long-term use of rofecoxib and of celecoxib has been reported to increase the risk of serious cardiovascular events. The risk of serious cardiovascular events appears to depend on the dose and duration of exposure, and in six randomized trials it was greatest in patients who had the highest risk of cardiovascular disease at baseline. In this study, there was no statistically significant difference in the number of cardiovascular adverse events between participants who received celecoxib and those who received placebo. However, participants in this study took celecoxib for only 9 months, whereas increases in serious cardiovascular adverse events with the cyclooxygenase 2 inhibitor rofecoxib were not observed until patients had taken it for 1 or more years.
The dose selected for this study—200 mg twice daily—is the same as that used to treat arthritis. It would be interesting to examine whether lower doses of celecoxib, an intermittent dosing regimen, or combination regimens are as effective as the dose used in this study but with fewer toxic effects. Alternatively, it is possible that chemoprevention of skin cancer could be achieved by topical application of a cyclooxygenase 2 inhibitor or a nonspecific cyclooxygenase inhibitor.
The original intent of this trial was to examine the effect of celecoxib on actinic keratoses. Thus, one limitation of this study is that the effect of celecoxib on nonmelanoma skin cancers was not a primary or secondary endpoint. Therefore, additional studies will need to be conducted in which the effect of cyclooxygenase inhibitors on nonmelanoma skin cancer development is the primary endpoint to confirm this observation. A second limitation is that all of the participants in this study had extensive actinic damage. It is unclear whether celecoxib would have the same effect in subjects with less actinic damage.
In conclusion, this study demonstrates that the cyclooxygenase 2 inhibitor celecoxib is an effective chemopreventive agent for nonmelanoma skin cancer in patients who are at high risk for the disease. It is possible that a combination of medications that include sunscreens as well as cyclooxygenase inhibitors and/or other chemopreventive agents could be taken on a regular basis by individuals at risk for development of nonmelanoma skin cancers to reduce the incidence of this exceptionally common malignancy.
Discussion
We found that compared with placebo, the cyclooxygenase 2 inhibitor celecoxib administered for 9 months was highly effective in preventing nonmelanoma skin cancers in subjects who had large numbers of actinic keratoses, some of whom had already developed one or more skin cancers, and thus were at high risk for these neoplasms. Our findings validate preclinical data that were the premise for the entry of celecoxib into clinical testing. However, this analysis of nonmelanoma skin cancers should be considered exploratory because it was not the primary endpoint of the randomized trial.
This study was initiated because of preclinical evidence suggesting that cyclooxygenase 2 is involved in the pathogenesis of sunlight-induced skin cancers. Specifically, expression of this enzyme is increased in the epidermis following UV exposure, and cyclooxygenase 2 can be detected in actinic keratoses and SCCs. In BCCs, cyclooxygenase 2 has been found in tumor islands and in the stroma surrounding the tumor islands. Moreover, cyclooxygenase 2 inhibitors have been successful at preventing UV-induced skin cancers in mouse models. There is also evidence from epidemiological studies that NSAIDs, which inhibit cyclooxygenases, are associated with a decreased risk of cutaneous SCCs. For example, in a case–control study conducted in Australia, subjects who had taken large doses of NSAIDs on a regular basis were less likely than subjects who had used NSAIDs infrequently or not at all to have had a cutaneous SCC. Another study reported that among individuals with a history of nonmelanoma skin cancers, those who were NSAID users had a reduced risk of nonmelanoma skin cancers, in particular SCCs, compared with nonusers. However, the protective effect of NSAIDs on nonmelanoma skin cancer was less striking in another study. In that study, in a cohort of high-risk patients, subjects who used NSAIDs for less than the study duration developed fewer BCCs and SCCs than subjects who used NSAIDs for the entire length of the study. However, another retrospective case–control study did not observe a statistically significant reduction in SCCs among individuals who reported taking any NSAID, ibuprofen, or nonaspirin NSAIDs. Similar conclusions were reached when pharmacy databases were examined for prescriptions for NSAID that were filled among patients with SCCs.
To our knowledge, no agents have been approved by either the FDA or governmental regulatory agents in other countries for the prevention of skin cancer. However, previous studies that were based in Australia, where the skin cancer rates are the highest in the world, and conducted in the general population have convincingly demonstrated that sunscreens are effective chemopreventive agents for actinic keratoses and cutaneous SCCs. They showed that the regular use of an SPF15 sunscreen for more than 5 years inhibited SCCs by approximately 35%, whereas the data for BCCs were limited. Despite the widespread use of sunscreens for skin cancer prevention, appreciable numbers of these malignancies still occur. The findings of this study, which showed that the celecoxib-treated individuals developed fewer nonmelanoma skin cancers than placebo-treated individuals, suggest that cyclooxygenase inhibitors may provide an additional benefit to sunscreens in the prevention of nonmelanoma skin cancers.
There has been substantial interest in the use of cyclooxygenase inhibitors for the prevention of other types of cancer besides nonmelanoma skin cancers. For example, celecoxib has been shown in clinical trials to inhibit the formation of sporadic colorectal adenomas and adenomas in familial adenomatous polyposis. Our results extend those findings to a second target organ system (ie, the skin) and to tumors caused by a different etiologic agent (ie, chronic UV exposure). In a recent study that examined NSAID use in subjects with basal cell nevus syndrome, which predisposes individuals to develop large numbers of BCCs because of a genetic defect in the patched 1 gene (PTCH1) of the sonic hedgehog signal transduction pathway, among patients with fewer than 15 BCCs at study entry, those who received celecoxib for 24 months developed statistically significantly fewer new BCCs than those treated with placebo.
Other agents have been evaluated for the chemoprevention of nonmelanoma skin cancer. Oral retinoid and topical application of the DNA repair enzyme T4 endonuclease V in liposomes have both been shown to have chemopreventive activity against nonmelanoma skin cancers in patients with predisposing conditions, but neither has been tested in the general population. It is interesting that low-fat diets have also been reported to reduce the number of actinic keratoses and nonmelanoma skin cancers in clinical trials. However, compliance with such a restrictive diet could prove challenging for individuals placed on the diet. Thus, there is clearly a need for new interventions that prevent these common malignancies.
Celecoxib was effective at reducing the incidence of cutaneous SCC but did not prevent its precursor, actinic keratosis. This finding was unexpected because results of preclinical studies on the prevention of SCC in mouse models suggested that celecoxib would reduce premalignant actinic keratoses as well as nonmelanoma skin cancers. This preferential effect of celecoxib against later stages of tumor development is consistent with findings of colorectal adenoma trials that tested celecoxib or aspirin. Although the precise mechanism for these unexpected results is not known, we envision three potential mechanisms by which celecoxib could inhibit the progression of premalignant keratinocytes to invasive malignancies. First, cyclooxygenase 2 is required for the synthesis of prostaglandin E2, which stimulates the proliferation of malignant cells. Celecoxib could thus have an antiproliferative effect, possibly by promoting apoptosis. The antiproliferative effect has been invoked to explain the regression of colorectal adenomas in a placebo-controlled trial of celecoxib in patients with familial adenomatous polyposis. Second, myeloid suppressor cells, which promote invasion and angiogenesis of human BCC cells, require cyclooxygenase 2 for production of the immunosuppressive molecule arginase-1. Celecoxib might render these cells less active and thereby inhibit the development of cutaneous SCCs and BCCs. Finally, celecoxib could suppress the epithelial–mesenchymal transition, a process through which malignant cells weaken intercellular adhesions, thereby enhancing their motility and allowing them to penetrate into surrounding tissues. In lung carcinogenesis, it has been proposed that cyclooxygenase 2 is intimately involved in this process.
The chemopreventive effect of celecoxib occurred rapidly. The numbers of new nonmelanoma skin cancers in the two treatment arms began to diverge within 3 months of the initiation of therapy for BCCs and within 6 months of the initiation of therapy for SCCs. This is not the first time that a chemopreventive agent has been shown to work this quickly to prevent BCCs: Kraemer et al. observed an inhibitory effect on skin cancer development in xeroderma pigmentosum patients within 3 months of administering oral isotretinoin, and, a recurrence of nonmelanoma skin cancers within 3 months after oral isotretinoin was stopped. In this study, nonmelanoma skin cancers did not recur during the 2-month follow-up period. However, the follow-up was short, and future studies will need to ascertain the durability of the response after cyclooxygenase inhibitors are discontinued.
Any beneficial effects of cyclooxygenase 2 inhibitors must be balanced against the adverse events associated with this class of compounds. Long-term use of rofecoxib and of celecoxib has been reported to increase the risk of serious cardiovascular events. The risk of serious cardiovascular events appears to depend on the dose and duration of exposure, and in six randomized trials it was greatest in patients who had the highest risk of cardiovascular disease at baseline. In this study, there was no statistically significant difference in the number of cardiovascular adverse events between participants who received celecoxib and those who received placebo. However, participants in this study took celecoxib for only 9 months, whereas increases in serious cardiovascular adverse events with the cyclooxygenase 2 inhibitor rofecoxib were not observed until patients had taken it for 1 or more years.
The dose selected for this study—200 mg twice daily—is the same as that used to treat arthritis. It would be interesting to examine whether lower doses of celecoxib, an intermittent dosing regimen, or combination regimens are as effective as the dose used in this study but with fewer toxic effects. Alternatively, it is possible that chemoprevention of skin cancer could be achieved by topical application of a cyclooxygenase 2 inhibitor or a nonspecific cyclooxygenase inhibitor.
The original intent of this trial was to examine the effect of celecoxib on actinic keratoses. Thus, one limitation of this study is that the effect of celecoxib on nonmelanoma skin cancers was not a primary or secondary endpoint. Therefore, additional studies will need to be conducted in which the effect of cyclooxygenase inhibitors on nonmelanoma skin cancer development is the primary endpoint to confirm this observation. A second limitation is that all of the participants in this study had extensive actinic damage. It is unclear whether celecoxib would have the same effect in subjects with less actinic damage.
In conclusion, this study demonstrates that the cyclooxygenase 2 inhibitor celecoxib is an effective chemopreventive agent for nonmelanoma skin cancer in patients who are at high risk for the disease. It is possible that a combination of medications that include sunscreens as well as cyclooxygenase inhibitors and/or other chemopreventive agents could be taken on a regular basis by individuals at risk for development of nonmelanoma skin cancers to reduce the incidence of this exceptionally common malignancy.
