In this study we show that cancer mortality was much higher in males relative to females for a majority of cancer types ( and ). Conversely, cancer survival was generally similar between the sexes; even when differences were observed, these sex disparities were relatively modest.
Disparities of cancer mortality have largely paralleled those of cancer incidence, which we have described previously (2
). For example, the incidence and mortality rate ratios were largely similar, differing by more than 20% for only four cancer sites (lip: MRR=5.51, IRR=7.16; salivary gland: MRR=2.32, IRR=1.59; skin excluding basal and squamous: MRR=2.30, IRR=1.43; and ureter: MRR=1.86, IRR=2.45). Qualitatively, the patterns of sex-specific mortality rates and male-to-female MRRs by age and stratified by decade ( and Supplementary Figures
), appeared to be nearly identical to the patterns observed in cancer incidence rates (2
This supports the idea that sex disparities in cancer mortality arise from the sex differences in cancer incidence. Examples of risk factors that have been implicated in cancer sex disparities include tobacco smoking in lung and bronchus, oral HPV infection in tongue and oropharyngeal (20
), cosmetic and occupational UV radiation exposure in skin excluding basal and squamous (23
), and anal HPV infection in anus, anal canal and anorectum (6
). Universal mechanisms that may be causal in observed sex differences in cancer incidence and, thus, mortality include anti-oxidative capacity (26
), sex chromosome complement/aneuploidy/aberrations (28
), gene expression (30
), hormones (33
), and immunocompetence (35
). These issues relating to sex disparities in cancer incidence are discussed in further detail I our previous manuscript (2
For cancer survival, the largest sex differences occurred for the cancers: skin excluding basal and squamous; endocrine system; floor of mouth; retroperitoneum; salivary gland; small intestine; trachea, mediastinum and other respiratory organs; anus, anal canal and anorectum; lymphoma; nose, nasal cavity and middle ear; lung and bronchus; urinary bladder; and tongue. For all but the last two of these cancers, males had a higher risk of death from cancer. It is feasible that differential environmental exposures and/or physiological processes, such as sex hormones, could explain the observed sex disparities in survival (2
Alternatively, observed sex differences in survival may be artifactual. In analyses unadjusted for extent of disease, lead time bias could give the false impression of sex disparities in five-year survival rates. For cancers with the largest sex differences in survival, the sex with the poorer survival almost always presented with later stage and higher grade tumors. Additional adjustment for stage and grade substantially attenuated most observed sex differences. However, it is unlikely that categorical metrics of stage and grade fully account for variation in extent of disease, thus residual confounding remains a distinct possibility.
Over-diagnosis through screening could also disproportionately affect sex-specific cancer survival. For example, a large proportion of cancer is thought to be asymptomatic and undiagnosed (38
). If asymptomatic cancers tended to be diagnosed more frequently in females, relative to males, females could appear to have better cancer survival (39
). In support of this hypothesis, females typically present with earlier-stage, lower-grade, less-aggressive and unifocal cancers, compared with males (39
), perhaps because women more readily and more often utilize health resources available to them (37
). More research on this subject is required to accurately ascertain to what degree this may play a role in sex discrepant cancer survival.
Sex differences in co-morbidity at cancer diagnosis could also skew cancer survival in favor of one sex over the other. Some (45
), but not all (50
), studies have suggested that males have more co-morbid conditions at the point of cancer diagnosis than do females. As co-morbidities are independent prognostic indicators, pre-existing chronic conditions may contribute to poorer cancer survival.
Of our results for specific cancers, better survival for lung and bronchus among women is noteworthy. This concurs with previous studies which have addressed this question (40
), the results of which have piqued the idea that estrogen receptor β, expressed in lung cancer cells, may be causal to this observation (54
), though various other hypotheses have also been suggested (56
Urinary bladder cancer was unusual in that females had lower five-year survival, compared with males, an observation also made by others (8
). Given that US male urinary bladder cancer rates are much higher than female rates (2
) and that females often present with later stage and higher grade lesions (8
), the observed disparity in survival may partly be due to diagnostic misclassification. For example, when presenting with similar symptoms, males may be more readily referred for cystoscopy than women (60
Cancers of the anus, anal canal and anorectum show the opposite pattern to urinary bladder; these cancers are more common in females, yet males have lower rates of five-year survival. One hypothesis is that men may be more likely than women to have anus, anal canal and anorectum tumors caused by HIV infection (61
), and that such tumors may be more aggressive (25
Cancer of the tongue was unique, in that adjustment for stage and grade changed the HR estimate from indicating a higher risk of death in males to indicating a higher risk of death in females, in the five-years following diagnosis. These unusual observations are difficult to explain, mainly because the etiopathogenesis of this cancer is poorly understood (62
Strengths of this study include the use of a large, population-based cancer registry database. In addition, SEER has extensive quality control procedures (64
). Limitations of this analysis include use of cause of death extracted from death certificates which is known to have problems and imperfections (66
). However, inaccuracies are likely to be non-differential by sex. Other limitations include lack of information on co-morbidities and only having adjusted for stage and grade, which may be suboptimal for certain cancers. Lastly, although we utilized the largest US dataset currently available for cancer survival analyses, our results are not perfectly generalizable to the total US population due to the fact that the data are restricted to the 17 cancer registries currently in SEER (18
In conclusion, this analysis shows that male cancer mortality rates were higher than equivalent female rates for a majority of cancers and these differences largely mirror sex differences in cancer incidence. This analysis also demonstrates modestly, but appreciably, worse survival in men for a number of cancers. Future analytical studies should focus upon the etiological factors responsible for the systematically higher cancer incidence rates among men.