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1 Robinson, D; Coupland, V; Mller, H (9) n analysis of temporal and generational trends in the incidence of anal and other HPVrelated cancers in Southeast England. ritish journal of cancer, (). pp ISSN 7-9 DOI:.8/sj.bjc Downloaded from: DOI:.8/sj.bjc Usage Guidelines Please refer to usage guidelines at or alternatively contact researchonline@lshtm.ac.uk. vailable under license:

2 ritish Journal of Cancer (9), 57 5 & 9 Cancer Research UK ll rights reserved 7 9/9 $. n analysis of temporal and generational trends in the incidence of anal and other HPV-related cancers in Southeast England D Robinson*,, V Coupland and H Møller Thames Cancer Registry, Division of Cancer Studies, King s College London, st Floor, Capital House, Weston Street, London SE QD, UK Patients diagnosed in 96 4 with cancer of the cervix, anus, vulva, vagina or penis were identified from the Thames Cancer Registry database, and age-standardised period (temporal) incidence rates calculated by direct standardisation. ge-cohort modelling techniques were used to estimate age-specific incidence rates in the earlier and later cohorts, enabling the calculation of agestandardised cohort (generational) rates. Incidence of anal cancer increased for both men and women over the period studied, mainly in those born from 94 onwards. Similar generational patterns were seen for cancers of the vulva and vagina, but those for penile cancer were different. For cervix cancer, the steep downward trend in cohort rates due to screening levelled off in women born from 94 onwards. Our findings are compatible with the hypothesis that changes in sexual practices were a major contributor to the increases of these cancers. Programmes of vaccination against HPV, aimed at reducing the burden of cervical cancer, may also help to reduce the incidence of cancer at other anogenital sites. ritish Journal of Cancer (9), doi:.8/sj.bjc Published online January 9 & 9 Cancer Research UK Keywords: human papillomavirus; anogenital cancers; cohort effects Human papillomavirus (HPV), a sexually transmitted pathogen infecting the anogenital epithelium, is the major cause of cervix cancer. In cervical cancer, HPV infection is the major cause (Schiffman et al, 99; International gency for Research on Cancer, 995; zur Hausen, 996; Walboomers et al, 999; Schlecht et al, ; osch et al, ; Schiffman et al, 7; osch and de Sanjosé, ), and positive associations have been found between HPV infection and cancers of the anus (Daling and Sherman, 99; Frisch et al, 997; Daling et al, 4; jørge et al, ), vulva and vagina (Madeleine et al, 997; Daling et al, ; Goffin et al, 6; Madsen et al, 8). Cancers of the anus, vulva and vagina occur more frequently than expected following cervical intraepithelial neoplasia III or invasive cervical cancer, suggesting a strong common aetiological factor (Evans et al, ). HPV infection may also play a role in a subset of penile squamous cell carcinomas (Iwasawa et al, 99; Rubin et al, ; Daling et al, 5; Heideman et al, 7; Tornesello et al, 8). Increasing trends in anal cancer have been reported, possibly due to changes in sexual practices (Daling et al, 987; Scholefield et al, 99; Frisch et al, 99, 997). If this were the case, a strong generational effect would be expected in the incidence trends of anogenital cancers. We have explored this hypothesis by plotting age-standardised period (temporal) and cohort (generational) rates for cancer sites linked to HPV infection. METHODS Patients diagnosed in 96 4 with cancer of the anus (ICD- code C), vulva (C5), vagina (C5), cervix uteri (C5) or penis *Correspondence: D Robinson; dave.robinson@kcl.ac.uk Received 7 October 8; revised 5 December 8; accepted 8 December 8; published online January 9 (C6) were identified from the Thames Cancer Registry (TCR) database. TCR is a population-based registry, which in this period covered a population of approximately million residents of London and southeast England. ll tumours are coded according to the ICD-O classification (World Health Organization, 976), and were retrospectively recoded to the ICD- classification in the case of tumours diagnosed before its introduction in the early 99s. Examination of proportional frequency plots revealed no coding discrepancies or inconsistencies over the period of the study. ge at diagnosis was categorised into 5-year groups ( 4, 5 9, y, 8 84, 85 þ ), and period of diagnosis into 5-year periods (96 964, , y, 4). Nominal birth cohort groups (875, 88, y, ) were then calculated by subtracting the midpoint of the age group from the midpoint of the period. For each site, an age-standardised incidence rate for each calendar period was calculated by direct standardisation, using the European standard population. s the earlier and later birth cohorts were missing data from the younger and older age groups, respectively, a Poisson regression age-cohort modelling technique (Clayton and Schifflers, 987) was used to estimate the unavailable rates, enabling the estimation of an age-standardised incidence rate for each cohort. s estimates for later cohorts (represented by younger patients diagnosed in recent periods) were based on small numbers of cases, and hence relatively unreliable, we report only estimates for birth cohorts between 885 and 96. RESULTS Table shows the total number of cancers diagnosed over the study period and the incidence by age for each site. Incidence increases with age at all sites, with few cases (other than cervical cancer cases) occurring before age 55.

3 58 Figure shows a modest increase in age-standardised period rates for anal cancer in both men and women. In men, these increased from.79 in to.6 per in 4. In women, the increase was greater, from.45 in to.8 per in 4. In both sexes, rates for consecutive cohorts (Figure ) remained relatively constant (between.5 and. per ) for individuals born between 885 and 95. There was then a sharp increase in rates in the subsequent generations born from 94 onwards. In men, the rates increased from.9 in the 95 cohort to.7 per in the 96 cohort, whereas in women the increase was from.97 in the 95 cohort to 4.8 per in the 96 cohort. Figure and show age-standardised rates, by period and cohort, respectively, for cancers of the vulva and vagina. Period rates have remained fairly constant since the early 99s, whereas cohort rates have increased in recent generations: for vaginal cancer, from.4 in the 94 cohort to.8 per in the 96 cohort; the corresponding rise for vulval cancer was from.65 to.5. For penile cancer, period rates have remained fairly constant, whereas cohort rates have been erratic, with no clear pattern emerging (Figure and ). Figure 4 and show age-standardised period and cohort rates for cervical cancer. Period rates have shown a dramatic decline from.68 in those diagnosed between 985 and 99 to 6.66 per in 4. Cohort rates declined from.7 in the 885 cohort to 7.64 per in the 95 cohort, after which they remained relatively constant. Table summarises these results, showing the age-standardised rates and associated 95% confidence levels. DISCUSSION HPV cancer trends nal cancer incidence in southeast England increased in both men and women over the study period (96 4), by threefold in women and about.5-fold in men; the incidence is now higher in women than in men. Similar trends have been seen in Denmark (Frisch et al, 99), the United States of merica (Melbye et al, 994; Johnson et al, 4) and Sweden (Goldman et al, 989). Increases have also been reported in Scotland (rewster and hatti, 6), where the change in male rates has roughly paralleled that in the female rates from the mid-97s to the mid-99s. Male rates have since plateaued, whereas female rates have continued to rise. In Scotland the female rates were higher than the males rates throughout the period studied, whereas in our population these were initially lower than in men, but became higher from the early 99s onwards. Judson et al (6) found a % increase in invasive vulval cancer in the United States of merica between 97 and. No increase was seen in the period rates for vulval cancer in our data, nor any increase in the period rates for cancers of the vagina or penis. The dramatic decline in rates for cervical cancer from the late 98s onward is similar to that reported in the West Midlands (Clare et al, 8), and reflects the introduction of the National Health Service s screening programme around 988, which has led to the early detection of precancerous cervical lesions and the prevention of many invasive cancers. In our study, in both sexes a marked increase was found in the cohort rates for anal cancer in those born from around 94 onwards. Similar generational patterns were seen for cancers of the vulva and vagina, consistent with a common aetiology. The most likely causes are changes in sexual practice and greater exposure to infectious agents such as HPV. For cancer of the cervix, for which HPV is generally recognised as the major cause, the steep downward trend in cohort rates due to screening levelled off in women born from 94 onwards. We found no clear-cut change in cohort rates for penile cancer, although on average the rates for generations born after 94 were Table Cancer incidence rates per by age at diagnosis ge Cancer site o Total cancers diagnosed nus, males nus, females Vulva Vagina Penis Cervix Rate per Figure Males Females nal cancer. (). () ge-standardised rates by cohort. Rate per ge-standardised rates by cohort Males Females irth cohort ritish Journal of Cancer (9) (), 57 5 & 9 Cancer Research UK

4 HPV cancer trends ge-standardised rates by cohort Rate per.5 Vulva Vagina Rate per.5 Vulva Vagina irth cohort Figure Vulval and vaginal cancers. (). () ge-standardised rates by cohort. ge-standardised rates by cohort Rate per Rate per irth cohort Figure Penile cancer. (). () ge-standardised rates by cohort. higher than in previous cohorts. It may be that the effect of HPV infection is less in penis cancer than in the other cancers, as recently suggested (Tornesello et al, 8). Several studies have linked sexual behaviour with cancer of the anus (Daling et al, 987; Scholefield et al, 99; Frisch et al, 99, 997). In both Denmark (Melbye and iggar, 99) and Scotland (rewster and hatti, 6) a higher prevalence of receptive anal intercourse in women than in men has been reported, and may explain in part the higher incidence of anal cancer in women in these countries. Sexual practices have also been implicated in cancers of the vagina and vulva (Sherman et al, 99; Madsen et al, 8) and of the penis (Maden et al, 99). It should be noted that the cohorts which show the recent increases in incidence are, of necessity, based partially on modelled data, because observational data in the older age groups are not available. However, the variability introduced by the modelling procedure has been included in the calculation of the standard errors of the estimated rates. s can be seen from Table, none of the estimates exhibits excessive variation. The generational patterns seen in the cohort rates presented in this paper, with a marked change from around 94, while not constituting proof, are compatible with the hypothesis that changes in sexual practices are a major contributor to the increases in anogenital cancers other than the cervix. Those born around 94 would have been in their early twenties at the start of the sexual revolution in the early 96s. Peto et al (4) have estimated that cervical cancer screening has prevented an epidemic that would have killed about one in 65 of all ritish women born since 95 and culminated in 6 deaths per year in this country. Trials of vaccination against HPV in teenage girls are currently underway in the United Kingdom. In ustralia, it has been predicted that the public vaccination programme begun in 7 will result in a reduction in the agestandardised incidence of HPV-6 infections of 56% by and 9% by 5 (Smith et al, 8). Programmes of vaccination, aimed at reducing the burden of cervical cancer, may also help to reduce the incidence of cancers of the vulva, vagina and anus in women. & 9 Cancer Research UK ritish Journal of Cancer (9) (), 57 5

5 HPV cancer trends ge-standardised rates by cohort Rate per 5 Rate per irth cohort Figure 4 Cervical cancer. (). () ge-standardised rates by cohort. Table ge-standardised incidence rates (per,) and 95% confidence intervals Site nus, males nus, females Vulva Vagina Penis Cervix Period (.64.9).45 (.6.54). (.9.9).6 (.5.7). (.9.7).74 (..5) (.56.8).5 (.4.59).57 (.4.7).64 (.5.74).89 (.74.4). (.67.7) (.7.).7 (.59.8).9 (.7.8).5 (.4.6).94 (.78.9).74 (.4.4) (.76.5).79 (.67.9).5 (.87.4).46 (.7.55).89 (.74.4).48 (.97.99) (.6.88).75 (.6.87).95 (.77.).5 (.4.6).9 (.77.7).8 (.9.) (.78.98).8 (.7.9).85 (.7.98).58 (.5.66).96 (.85.7).68 (..6) 99.9 (.8.). (.9.).7 (.6.85).54 (.46.6).97 (.87.8) 9.98 (9.65.) (.94.6). (..4).75 (.6.87).5 (.4.57).94 (.84.5) 8.6 ( ).6 (.95.7).8 (.8.9).78 (.65.9).47 (.4.54).9 (.8.) 6.66 ( ) Cohort (.55.77).57 (.5.64).68 (.56.79).79 (.7.88).5 (..).7 (.4.) (.64.87).5 (.45.58). (.9.7).7 (.65.8). (.96.4) 8.65 (8. 9.9) (.84.).58 (.5.65).98 (.84.).6 (.5.67).96 (.8.9) 8.6 ( ) 9.85 (.7.96).55 (.47.6).7 (..).5 (.45.59).84 (.7.96) 5.58 (5. 6.) 95.7 (.6.8).55 (.47.6).4 (.99.9).48 (.4.55).4 (..7) 4.56 ( ) 9.79 (.68.9).59 (.5.67).96 (.8.).5 (.44.6). (.9.5) 5.8 ( ) 95.8 (.69.9).67 (.58.76).9 (.77.7).49 (.4.57).9 (.8.4) 6.9 ( ) 9.79 (.68.9).9 (.8.).64 (.5.78).5 (.4.58).8 (.7.9) 5.9 ( ) (.69.89).4 (.9.6).8 (.67.97).9 (..45).86 (.75.97).95 (.47.4) 9.97 (.85.8).8 (.97.9).64 (.5.78).49 (.4.57).86 (.76.96) 8.8 (8.8 9.) 95.9 (.8.).97 (.87.7).5 (.9.64).5 (.4.57).76 (.67.85) 7.64 (7.6 8.) 94. (..4).9 (.7.).65 (.5.78).4 (.6.49).8 (.7.9) 8.8 ( ) (..6).74 (.59.89).45 (..57).49 (.4.56).8 (.6.4) 8.9 ( ) (.48.8). (..4).7 (.57.86).5 (.45.59).6 (.4.8) 8.7 (8.4 9.) (.59.4).75 (.4.6). (..4).77 (.66.88).95 (.8.7) 9.5 ( ) 96.7 (.44.98) 4.8 ( ).5 (.6.77).8 (.67.96). (.88.8) 7.5 ( ) REFERENCES jørge T, Engeland, Luostarinen T, Mork J, Gislefoss RE, Jellum E, Koskela P, Lehtinen M, Pukkala E, Thoresen SØ, Dillner J () Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study. r J Cancer 87: 6 64 osch FX, de Sanjosé S () Chapter : Human papillomavirus and cervical cancer burden and assessment of causality. J Natl Cancer Inst Monogr : osch FX, Lorincz, Muñoz N, Meijer CJ, Shah KV () The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55: rewster D, hatti L (6) Increasing incidence of squamous cell carcinoma of the anus in Scotland, 975. r J Cancer 95: 87 9 Clare J, Edwards D, agnall H, Pearmain P, Lawrence G (8) The use of cervical screening history data to interpret cervical cancer incidence trends. J Public Health : 7 77 Clayton D, Schifflers E (987) Models for temporal variation in cancer rates. I: ge-period and age-cohort models. Stat Med 6: Daling JR, Madeleine MM, Johnson LG, Schwarz SM, Shera K, Wurscher M, Carter JJ, Porter PL, Galloway D, McDougall JK (4) Human papillomavirus, smoking and sexual practices in the etiology of anal cancer. Cancer : 7 8 Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera K, Wurscher M, Carter JJ, Porter PL, Galloway D, McDougall JK, Krieger JN (5) Penile cancer: Importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 6: Daling JR, Madeleine MM, Schwartz SM, Shera K, Carter JJ, McKnight, Porter PL, Galloway D, McDougall JK, Tamimi H () populationbased study of squamous cell vaginal cancer; HPV and cofactors. Gynecol Oncol 84: 6 7 ritish Journal of Cancer (9) (), 57 5 & 9 Cancer Research UK

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