DOI: 0.054/ bjoc.999.0989, vilble online t http://www.idelibrry.com on Fertility in Norwegin testiculr cncer ptients SD Fosså nd Ø Krvdl 2 The Norwegin Rdium Hospitl, Montebello, N-030 Oslo, Norwy; 2 The Norwegin Cncer Registry nd Deprtment of Economics, Section for Demogrphy, University of Oslo, PO Box 095 Blindern, N-037 Oslo, Norwy Summry The intention ws to explore the reltionship between fertility nd testiculr cncer, including the possibly tretment-induced chnges over time in the post-dignostic fertility. Dt re from the Norwegin Cncer Registry, The Norwegin Popultion Register nd the Popultion Censuses. By estimting Poisson regression models, birth rtes mong testiculr cncer ptients were compred with those of other men who hd the sme ge, prity nd durtion since previous birth. Poisson regression models were lso estimted to check whether men s prity hs n effect on the cncer incidence. Fertility rtes mong testiculr cncer ptients born fter 935 nd treted before 99 decresed by roughly 30% when compred with the norml popultion. The introduction of cispltin chemotherpy nd of nerve-spring RPLND in the 980s seems to hve enbled more ptients with non-seminom to fther child fter tretment, or t lest shortened the time to conception. Moreover, the risk of being dignosed with seminom is reduced with incresing prity. This suggests tht the reltively low fertility fter dignosis my be prtly due to the continuing inherent influence of sub- or infecundity tht lso hd bering on the development of the disese. Keywords: fecundity; incidence; infecundity; infertility; prity; tretment In Norwy, the stndrdized incidence of testiculr cncer hs incresed from 2.7 per 00 000 in 955 to 8.5 per 00 000 in 992, with little difference between seminom nd non-seminom (Wnders et l, 995). The men ge of seminom nd nonseminom ptients t the time of dignosis is 40 nd 32 yers respectively. When confronted with such dignosis, most of these young men sk their responsible physicin bout their chnces of hving children fter tretment. Though mny monoinstitutionl studies hve demonstrted tht long-term sperm cell production nd ejcultion re preserved in the mjority of ptients treted during the lst decde (Petersen et l, 998; Jcobsen et l, 999), popultion-bsed studies on post-tretment fertility re rre. From clinicl prxis it hs been suspected for long time tht there re links between sub- or infertility nd the development of testiculr cncer (Giwermnn nd Petersen, 998). In 994, the United Kingdom Testiculr Cncer Study Group described significnt ssocition between low fertility or sterility nd the risk of being dignosed with testiculr cncer. Møller nd Skkkebæk (999) demonstrted tht pternity by itself nd incresing prity were ssocited with lower risk of testiculr cncer. The objective of this study ws to check whether Norwegin testiculr cncer ptients hd fewer children before dignosis thn men of the sme ge without this disese nd, more importntly, whether their fertility fter dignosis differed from tht of others. Stge nd histology, nd thereby lrgely the tretment modlity (rdiotherpy, chemotherpy, retroperitonel surgery), were tken into ccount. Also, the chnges over time were ssessed. Received 3 My 999 Revised 20 July 999 Accepted 23 August 999 Correspondence to: SD Fosså MATERIALS AND METHODS The nlysis ws bsed on individul sociodemogrphic life histories up to the end of 99 for ll men with Norwegin personl identifiction number (given to everyone who hs lived in Norwy for some time fter 960) who re born fter 935. These life histories were extrcted from the Norwegin Popultion Register nd the Popultion Censuses of 960, 970 nd 980, nd included informtion bout dte of deth nd emigrtion, dte of birth for ll children the mn fthered up to 99, mritl sttus, eduction nd vrious other socioeconomic chrcteristics t the time of the censuses. The dt were bsed on socil definition of prenthood, i.e. the fthers were linked with their socil rther thn biologicl offspring. These life histories were mtched with dt from the Norwegin Cncer Registry, which from 953 hs received informtion on ll cncer cses in the country. This compulsory reporting system is bsed on pthology nd cytology reports, clinicl records nd deth certifictes, nd provides informtion bout site, bsis for the dignosis, histologicl grde nd type, nd the stge of the disese t the time of dignosis. The mtching of the dt ws pproved by the Norwegin Dt Inspectorte. The multiplictive Poisson regression model () f = exp(bx) exp(cy) ws estimted for the birth intensity f. x is vector of sociodemogrphic covrites ge, period, prity, durtion since previous birth, mritl sttus nd eductionl level. These covrites re ll ctegoricl nd time-vrying. A level for ech covrite is defined for ech month during the follow-up period, nd refers to the sitution t tht time (ge, period, prity, durtion) or tht in the lst previous census (eduction, mritl sttus). The vrible y is ctegoricl time-vrying disese indictor with one level up to the dignosis of testiculr cncer, if ny, nd 3 5 levels fterwrds, defined s combintion of stge nd 737
738 SD Fosså nd Ø Krvdl durtion since dignosis. In these dt, stge is defined s loclized (non-metsttic, stge I), regionl (spred to regionl lymph nodes, stge II), hemtogeneous distnt spred (i.e. to prenchymtous orgns or to non-regionl lymph nodes, stge III) or unknown (only %). Becuse of the smll size of the ltter ctegory, it is combined with loclized. The effect vectors re b nd c. The men were followed from ge 7 nd censored t the time of emigrtion, deth, or the end of 99. In principle, ll prity trnsitions cn be considered in such n nlysis (up to 8, which is the highest prity reched in these dt), but for prcticl resons limit ws set. It ws decided to censor t the birth of the third child, becuse few Norwegin men hve more thn three children (Krvdl, 994). For cncer ptients, censoring ws done t the time of the first birth fter dignosis. This is becuse fertility mong those who hve lredy proved their fertility by hving one child fter dignosis is much less interesting. In other words, c is mesure of how the chnce of hving child number n + differs between two groups of men who currently hve hd n children, the sme durtion since lst birth, the sme ge nd lso the sme other observed sociodemogrphic chrcteristics. One group comprises those who hd testiculr cncer nd hd ll their children before dignosis; the other group comprised those without such dignosis. Seprte models were estimted for seminom nd nonseminom, nd for ptients dignosed before 980 nd therefter. This cut-off point ws chosen becuse of the importnt tretment chnges initited t tht time (Fosså et l, 99). The following is brief summry of these chnges. Up to 980, ll ptients with stge I disese were treted by bdominl rdiotherpy (trget dose 40 50 Gy). Stge II ptients received the sme rdiotherpy in ddition to medistinl irrdition. Ptients with distnt metstses or with recurrent mlignncy were treted by vilble chemotherpy (without cispltin). From 980, non-seminom stge I ptients underwent retroperitonel lymph node dissection (RPLND). After 988, such ptients were included in surveillnce policy. Metsttic or recurrent ptients were given cispltin-bsed combintion chemotherpy followed by surgery. In stge I seminom ptients, the trget dose to the pr-ortic lymph nodes ws reduced from 40 Gy to 30 Gy. Metsttic seminom ws treted with cispltin-bsed chemotherpy nd smll-field irrdition. Five-yer reltive survivl rtes incresed from 6% in the lte 960s to 93% in the lte 980s (Cncer Registry, 993). As supplementry nd simple description of the impct of testiculr cncer on fertility, the probbilities of hving hd first child were clculted for different ges for persons who were childless t, sy, ge 20. If A is the integrl of the first-birth rtes from ge 20 up to the ge in focus, such probbility P (lso denoted s prtil probbility, becuse it is bsed on birth rtes exclusively, thus disregrding the chnces of not surviving up to tht ge) is given by (2) P = exp( A) Constnt birth rtes re ssumed for -yer intervls, nd re estimted by dividing the number of births in ech intervl by the corresponding exposure time. In ddition, the multiplictive Poisson regression model (3) i = exp(dz) ws estimted for the cncer incidence i. z is vector of sociodemogrphic covrites ge, period, mritl sttus, eductionl level (defined s in the fertility model) nd prity. Prity ws defined for ech month of follow-up nd referred to the totl number of children the mn hd fthered up to tht time. In other words, it ws estimted how the risk of being dignosed with testiculr cncer t given ge ws relted to prity t tht ge, net of differences in period, eduction nd mritl sttus. The men were followed from ge 7 up to time of emigrtion, deth or the end of 99. This method ws lso used with these dt in severl studies of other cncer types (Krvdl, 995; Hrvei nd Krvdl, 997). The models were estimted in the AMFIT module in the EPICURE progrm system (Preston et l, 993). A self-mde progrm (in the PASCAL lnguge), operting on the individullevel register nd census dt, ws used to compute the multidimensionl tbles of events (number of births or cncer cses) nd exposures tht were fed into AMFIT. RESULTS During the period under study, seminom nd non-seminom ptients fthered 7 nd 250 children, respectively, within 0 yers fter dignosis (Tble ). In comprison, there were.3 million births mong other men (not shown). Tble Fertility rtes for Norwegin men with testiculr cncer dignosis fewer thn 0 yers previously, reltive to men without such dignosis (with 95% confidence intervls) Seminom Men without testiculr cncer b.0.0 Men with testiculrcncer dignosed fewer thn 0 yers previously Locl 0.78 c (0.67 0.9) 72 0.69 c (0.59 0.8) 47 Regionl 0.45 c (0.34 0.60) 48 0.4 c (0.03 0.55) 9 Distnt 0.33 c (0.23 0.47) 30 0.35 c (0.8 0.67) 5 Only the effects of the disese vrible re shown in the Tble, but lso ge (5 levels), period (4 levels), prity (0,, or 2), durtion since lst previous birth (7 levels), eduction (4 levels) nd mritl sttus (4 levels) were included in the model. It ws censored 0 yers fter dignosis, if ny. b Reference ctegory. c Significntly different from t the 5% level. n, number of births mong men in this ctegory.
Fertility in testiculr cncer ptients 739 A B Probbility 0.9 0.8 0.7 0.6 0.5 0.4 Other men Men with testiculr cncer ge 7 20 Probbility 0.9 0.8 0.7 0.6 0.5 0.4 Other men Men with testiculr cncer ge 7 20 0.3 0.3 0.2 0.2 0. 0. 0 20 2 22 23 24 25 26 27 28 29 30 3 32 33 34 35 36 37 38 39 40 4 Age 0 20 2 22 23 24 25 26 27 28 29 30 3 32 33 34 35 36 37 38 39 40 4 Age Figure (A) Probbilities of hving hd first child, by ge, mong Norwegin men with or without testiculr cncer dignosis who were childless t ge 20. (B) Probbilities of hving hd first child, by ge, mong Norwegin men with or without testiculr cncer dignosis who were childless t ge 25 Tble 2 Fertility rtes for Norwegin men with testiculr cncer dignosis, reltive to men without such dignosis (with 95% confidence intervls) Before 980 After 980 Men without tesitculr cncer b.0.0 fewer thn 5 yers previously Locl 0.72 c (0.56 0.94) 58 0.85 (0.67.06) 78 Regionl/distnt 0.25 c (0.3 0.48) 9 0.49 c (0.36 0.64) 55 5 0 yers previously Locl.08 (0.64.59) 7 0.57 c (0.37 0.90) 9 Regionl/distnt 0.45 (0..82) 2 0.26 c (0.5 0.46) 2 more thn 0 yers previously Locl Regionl/distnt 0.65 (0.37.8) 0.7 c (0.53 0.97) 4 Seminom Men without testculr cncer b.0.0 fewer thn 5 yers previously Locl 0.77 (0.58.02) 49 0.6 c (0.49 0.77) 72 Regionl/distnt 0.4 c (0.7 0.99) 5 0.49 c (0.29 0.85) 3 5 0 yers previously Locl 0.63 (0.24.4) 6 0.75 (0.48.6) 20 Regionl/distnt 0.40 (0.06 2.86) 0.56 (0.23.35) 5 more thn 0 yers previously Locl Regionl/distnt 0.47 (0.5.46) 3 0.86 (0.55.34) 9 Only the effects of the disese vrible re shown in the Tble, but lso ge, period, prity, durtion since lst previous birth, eduction nd mritl sttus were included in the model. The ctegories re s described in note to Tble. b Reference ctegory. c Significntly different from t the 5% level. n, number of births mong men in this ctegory.
740 SD Fosså nd Ø Krvdl Tble 3 Effects of prity on the risk of being dignosed with testiculr cncer (with 95% confidence intervls) Seminom 0 child b.00 596.00 379 child.03 (0.87.2) 23 0.76 c (0.63 0.92) 63 2 children 0.97 (0.8.6) 233 0.78 c (0.66 0.92) 289 3 children 0.83 (0.64.08) 76 0.60 c (0.47 0.75) 04 4 or more children.0 (0.75.62) 3 0.80 (0.58.09) 50 Only the effects of prity re shown in the Tble, but lso ge, eduction re mritl sttus were included in the model. The ctegories re s described in note to Tble. b Reference ctegory. c Significntly different from t the 5% level. n, number of dignoses mong men in this ctegory. In the regression estimtes presented, only the reltion between fertility nd the disese vrible is diplyed (Tble ) (controls for eduction nd mritl sttus were included, but were not importnt). Hving loclized cncer reduced fertility by bout 30% compred to the norml popultion, while stronger reduction ws seen mong men whose cncer hd spred t the time of dignosis. These estimtes re for the entire 0-yer period fter dignosis. The devition from norml fertility ws slightly more pronounced during the first few yers fter dignosis (not shown). As simple illustrtion, the probbilities of hving hd first child within different ges re plotted in Figure for men born 945 965. In Figure A, probbilities re shown for two groups of men who were still childless t ge 20. One group includes bout 00 men who were dignosed with testiculr cncer t ge 7 20 (regrdless of stge nd histology), nd the other group includes ll other men. In the ltter group, 76% hd child when they were 4 yers old, wheres the corresponding proportion mong the testiculr cncer ptients ws only 42%. Similr probbilities for two groups of men who were still childless t ge 25 re plotted in Figure B. One group includes bout 250 men with testiculr cncer dignosis t ge 7 25, nd the other group includes ll other men. Seprte regression models were estimted for periods before nd fter 980 (Tble 2). For non-seminom, there were quite strong indictions of n incresing reltive fertility over time when it ws focused on men who hd been dignosed with metstsis less thn 5 yers previously. Before 980, men in this sitution only hd nine children, wheres the corresponding number for the lter period ws 55. These differences reflect, of course, both fertility rtes nd the number of men under exposure for births, which in turn ws determined by testiculr cncer incidence s well s survivl. The fertility rtes were estimted to hve doubled, from one-qurter of the level mong other men before 980, to one-hlf in the lter period. The confidence intervls brely overlpped. With respect to fertility 5 0 yers fter dignosis, there were indictions, lbeit weker, of n opposite trend over time. For seminom, there were very modest differences in reltive fertility between the periods before nd fter 980. The risk of developing seminom depended significntly on prity. For exmple, the risk for mn with three children ws 40% lower thn tht for childless, but otherwise similr, mn. The risk for four-child fther ws not significntly reduced, but the group ws quite smll. When pooled together, reltive risk of 0.67, significntly different from, ppered for those with three or more children (Tble 3). On the other hnd, there ws no ssocition between prity nd the non-seminom incidence. DISCUSSION The birth rtes in this study reflect lmost exclusively the in vivo biologicl fertility. Adoptions re very rre in Norwy, nd ssisted fertiliztion lso counts very little. Furthermore, the few children born fewer thn 9 months fter their fther s dignosis of testiculr cncer re considered s post-tretment, lthough their conceptions most probbly hd tken plce prior to the dignosis nd tretment. Our strtegy of censoring t the time of first birth fter dignosis ws not criticl for the results. Also, those who lredy hd child fter dignosis, nd thus signl n bility to conceive, displyed subsequent fertility lower thn tht of men t the sme prity level without the testiculr cncer dignosis. This deficit ws similr to tht for the first birth fter dignosis. Testiculr cncer ws found to be ssocited with reltively low fertility before dignosis. Seminom ptients, but not those with non-seminom, hd significntly fewer children t the time of dignosis thn men with otherwise similr socio-demogrphic chrcteristics. We thus confirm the results of the two former comprble epidemiologicl studies (United Kingdom Testiculr Cncer Study Group, 994; Möller nd Shkkebæk, 999). The most plusible explntion for the reltionship between (predignostic) subfertility nd the seminom incidence is tht some types of primry hypogondism nd seminom my shre some etiologicl fctors during erly embryonl life, leding to disturbed differentition of primordil cells the cells from which the mle gonds develop. This disturbnce my be expressed s infecundity, reduced spermtogenesis, nd my even contribute to the development of testiculr cncer, in prticulr seminom, ffecting one or both of the testicles. The fct tht prity effects re less pronounced in non-seminom ptients could perhps be prtly due to their generlly lower ge. At reltively low ge, low prity is more signl of choice, while it is more likely to indicte physiologicl limittions t higher ge. A clinicl impliction of this result is tht especilly the childless older seminom ptients should undergo tretment which is s fertility-sving s possible in order to llow mximum recovery of the spermtogenesis. These rguments strongly fvour the ppliction of wit-nd-see policy in ptients who wnt to fther child fter dignosis (Wrde et l, 993). In ddition to low predignostic fertility for seminom ptients, birth rtes were low lso fter testiculr cncer dignosis compred to those of other men t the sme ge nd prity in the sme period. Among men with loclized cncers, of either histologicl type, the birth rtes fter dignosis were bout
Fertility in testiculr cncer ptients 74 one-qurter lower thn in the remining popultion, while the gp ws more thn twice s lrge in cses of metstsized cncers. There re severl possible resons for this lowered fertility fter dignosis nd tretment. One reson, which is relevnt only for the seminom ptients, is continuing influence of n inherent sub- or infecundity tht lso existed before dignosis. Another reson is reduced desire for more children fter n exhusting tretment for life-thretening mlignncy. A perceived risk of mlformtions of the offspring due to prior cytotoxic therpy of the fther my lso contribute to weken fertility desires nd my led not only to postponement but lso rejection of further childbering. Any such voluntry postponement of post-tretment ftherhood is, of course, of greter significnce for the generlly older seminom ptients (nd their prtners) thn for those with non-seminom. Possibly the most importnt reson for the low post-dignostic fertility mong testiculr cncer ptients is the tretment. The use of bdomino-pelvic rdiotherpy nd cytosttics leds to decresed spermtogenesis, which, depending on the type of tretment nd cumultive doses nd the ptient s ge, my or my not recover. Secondly, trditionl RPLND, performed in mny nonseminom ptients before 985 with the complete resection of sympthetic nerve fibres, leds to dry ejcultion nd thus to infecundity. The chnge of tretment modlities fter 980 is expected to hve reduced the risk of tretment-induced infecundity for ptients treted fter 980 (Petersen et l, 998; Jcobsen et l, 999). The Registry dt support the expecttions, nd demonstrte tht this effect is most pronounced in metsttic non-seminom ptients, though the picture is not entirely consistent. When the focus is on the first 5 yers fter dignosis, there re indictions of improvement in fertility for the observtion period 980 99. On the other hnd, there re lso wek indictions of grdully lrger fertility deficit during recent yers mong men dignosed with testiculr cncer 5 0 yers previously. This might be explined by chnging force of selection: with current stndrd chemotherpy, spermtogenesis recovers fter 2 3 yers, wheres the recovery took plce lter, if ever, in the 960s nd 970s. The ptients treted fter 980 who hd still not hd child 5 yers fter dignosis, in spite of the improved therpy, my to much lrger extent thn before comprise group of persons with tretment-independent infecundity problems or wek fertility desires. The fvourble time trend will probbly continue mong nonseminom ptients s result of the surveillnce policy nd nervespring RPLND since 989. In seminom ptients, improvement of fertility will presumbly be less pronounced, s long s chnges in the tretment remin more limited. In summry, this study shows, first, tht the fertility rtes mong Norwegin testiculr cncer ptients born fter 935 nd treted before 99 decresed by roughly 30% when compred with the norml popultion. Secondly, there re quite strong indictions tht the introduction of cispltin-bsed chemotherpy nd limited or nerve-spring RPLND in the 980s mde it possible for more non-seminom ptients to hve (nother) child fter dignosis, or t lest to hve child erlier. Thirdly, the risk of being dignosed with seminom is reduced with incresing prity. This suggests tht the reltively low fertility fter dignosis my be prtly due to the continuing influence of sub- or infecundity problems tht lso hd bering on the development of the disese. Consequently, introduction of wit-nd-see policy for childless ptients with stge I seminom my be dvntgeous in n ttempt to preserve pre-existing (though low) fertility s much s possible. ACKNOWLEDGEMENTS Thnks re due to Sttistics Norwy for llowing the use of the dt. 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