PDE5 inhibitors may lower risk of colorectal cancer in men with benign colorectal neoplasms

Several factors are believed to be involved in development of colorectal cancer (CRC), such as advancing age, familial CRC, Western lifestyle factors and a diagnosis of colonic adenomatous polyps. More than 95% of CRC cases in Western countries are thought to develop from adenomatous polyps that grow slowly before turning malignant. Due to the high incidence of CRC among patients with colonic polyps, there is high interest in finding effective chemopreventive agents.(1)In vitro and in vivo studies have shown that phosphodiesterase (PDE) inhibitors—especially PDE5 inhibitors—have anticancer activity and therefore might have potential in the prevention of CRC. PDE5 has been found to be overexpressed in human CRC cell lines and in colon adenomas and adenocarcinomas compared with normal colonic mucosa.(1)A recent Swedish retrospective nationwide cohort study explored whether the use of PDE5 inhibitors (sildenafil, tadalafil, vardenafil) was associated with a reduced risk of CRC among men who were diagnosed with benign colorectal neoplasm. The study excluded women, as very few women take PDE5 inhibitors.(1)The study investigators used several national Swedish registers to compare the incidence rates of CRC among men who received PDE5 inhibitors and men who did not. They also examined whether there was any dose-response relationship, and whether the risk might be lower for CRC diagnosed at an advanced clinical stage compared with at an earlier stage.(1)A total of 36,020 men with benign colorectal neoplasm were identified during the 10-year study period; 4,849 of these men had taken PDE5 inhibitors and 31,171 men had not. The incidence rate of CRC was 2.64 per 1000 person-years for men prescribed PDE5 inhibitors compared with 4.46 per 1000 person-years for men without any PDE5 inhibitor intake. This translated to a significant negative association between PDE5 inhibitor use and risk of CRC (adjusted HR, 0.65; 95% CI, 0.49–0.85).(1)This association was more pronounced for higher cumulative doses PDE5 inhibitors (HR, 0.60; 95% CI, 0.36–1.01) compared with lower cumulative doses (HR, 0.75; 95% CI, 0.45–1.25; p = 0.003). In addition, the association was stronger for CRC diagnosed at stage III or IV (HR, 0.61; 95% CI, 0.37–1.00) compared with that diagnosed at stage I or II (HR, 0.70; 95% CI, 0.50–0.98). This suggests that the PDE5 inhibitors might reduce the metastatic potential of cancer cells.(1)The investigators conclude that the use of PDE5 inhibitors by men with a diagnosis of benign colorectal neoplasm is associated with a 35% reduced risk of CRC and the decrease is associated with increasing cumulative dose of PDE5 inhibitors. However, they caution that additional studies are needed to confirm the observed association.(1)An accompanying editorial notes that colonoscopy is highly effective in reducing the incidence of and mortality from colorectal cancer (CRC). However, suboptimal adherence and resource constraints are major limitations of this method. The use of acetylsalicylic acid (ASA) has been recommended to prevent CRC, but complications such as bleeding are an important concern.(2)The editorial cautions that although this new study offers novel evidence of a chemopreventive benefit for PDE5 inhibitors, these findings are not ready for clinical application. Prospective cohort studies would provide better evidence of a potential causal association. Additional clinical trials will also be required to determine the efficacy of PDE5 inhibitor use in women and the safety of long-term use. Further studies should also explore whether an additive chemopreventive effect could be achieved by combining ASA and PDE5 inhibitors.(2)ReferencesHuang W, Sundquist J, Sundquist K, et al. Use of phosphodiesterase 5 inhibitors is associated with lower risk of colorectal cancer in men with benign colorectal neoplasms. Gastroenterology 2019;157:672-81. https://www.gastrojournal.org/article/S0016-5085(19)40892-5/pdf (accessed September 6, 2019).Jovani M, Chan AT. Are phosphodiesterase-5 inhibitors a new frontier for prevention of colorectal cancer? Gastroenterology 2019;157:602-4. https://www.gastrojournal.org/article/S0016-5085(19)41109-8/pdf (accessed September 6, 2019).

PDE5 inhibitors may lower risk of colorectal cancer in men with benign colorectal neoplasms

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