Relative Survival and Second Cancer Risk after Diagnosis of Testicular Germ Cell Tumor

Norsk sammendrag Testikkelkreft (TC) er den vanligste kreftformen blant yngre menn, med omtrent 300 årlige tilfeller i Norge. Nesten alle TC-tilfeller er testikulære germinalcellesvulster, som igjen inndeles i seminomer og nonseminomer. En viktig del av behandlingen er å fjerne den affiserte testikkelen, men de aller fleste blir kurert også hvis sykdommen har spredt seg til andre deler av kroppen. Hovedårsaken er cellegiften cisplatin, som har vært i bruk siden slutten av 70-tallet. Imidlertid har TC-overlevere økt risiko for å utvikle alvorlige tilstander som ny kreftsykdom (sekundær kreft, SC) og hjerte- karsykdom. Disse tilstandene kan oppstå flere tiår etter TCdiagnosen, og bidra til redusert overlevelse sammenlignet med normalbefolkningen (relativ overlevelse, RS). Hovedgrunnen er trolig senvirkninger av cellegift- og/eller strålebehandling, noe man derfor prøver å ta hensyn til i behandlingen. Før våre studier fantes det ikke RS-data for TC-overlevere fulgt lenger enn 20 år etter diagnosen. Det fantes heller ikke studier på SC-risiko basert på fullstendig informasjon om hvilken TCbehandling hver enkelt pasient fikk. Målene med denne avhandlingen var å undersøke RS og årsaker til overdødelighet blant ca. 9000 TC-pasienter diagnostisert i Norge mellom 1953 og 2015, også mer enn 20 år etter diagnosen (studie I og II). Et annet mål var å analysere SC-risiko blant 5600 ettårsoverlevere av TC diagnostisert i Norge mellom 1980 og 2009, basert på fullstendig behandlingsinformasjon (studie III). I studie I og II fant vi at selv om RS var betydelig høyere blant de som fikk TC-diagnosen etter 1979, fortsatte RS å falle også etter mer enn 15-30 års oppfølging. Det største fallet ble sett blant dem behandlet for seminom. Mens TC i seg selv var hovedårsak til redusert RS de første fem årene etter diagnosen, ble SC gradvis den viktigste årsaken etter denne perioden. Godartede magetarmsykdommer var en annen viktig årsak til overdødelighet, mens hjerte- karsykdom til sammenligning var av mindre betydning. Pasienter som fikk TC-diagnosen i 1990 eller senere hadde høyest RS, men hadde fortsatt overdødelighet av flere tilstander som noen former for SC, selvmord og infeksjoner. I studie III fant vi at overlevere av TC hadde økt risiko for SC etter visse former for cellegift og/eller strålebehandling. Imidlertid fant vi også noe økt risiko for SC blant dem som kun hadde blitt behandlet med kirurgi. Dette tyder på at faktorer som ikke skyldes behandlingen, som for eksempel genetiske årsaker, kan bidra til økt SC-risiko blant TC-pasienter og overlevere. Basert på funnene i denne avhandlingen bør TC-overlevere og deres leger være oppmerksomme på livslang økt risiko og dødelighet av flere tilstander etter en TC-diagnose. Dette bør føre til tettere livstidsoppfølging og en lavere terskel for utredning, spesielt hvis cellegift eller strålebehandling var del av behandlingen. Det bør også forskes mer for å redusere negative effekter av TCbehandlingen, uten å redusere den utmerkede sannsynligheten for å bli kurert

Causes of inferior relative survival after testicular germ cell tumor diagnosed 1953–2015: A population-based prospective cohort study

Background Testicular germ cell tumor (TGCT) patients and survivors have excess mortality compared to the general male population, but relative survival (RS) has been scarcely studied. We investigated causes of excess mortality and their impact on RS among men diagnosed with TGCT in Norway, 1953–2015. Methods and findings Using registry data (n = 9541), standardized mortality ratios (SMRs) and RS were calculated. By December 31st, 2015, 816 testicular cancer (TC) and 1508 non-TC deaths had occurred (non-TC SMR: 1.36). Within five years of TGCT diagnosis, 80% were TC deaths. Non-TC second cancer (SC) caused 65% of excess non-TC deaths, of which 34% from gastric, pancreatic or bladder cancer. SC SMRs remained elevated ≥26 years of follow-up. In localized TGCT diagnosed >1979, SC SMRs were only elevated after seminoma. Cardiovascular disease caused 9% and other causes 26% of excess non-TC deaths, of which 58% from gastrointestinal and genitourinary disorders. RS continuously declined with follow-up. TGCT patients diagnosed >1989 had superior five-year TC-specific RS (98.3%), lower non-TC SMR (1.21), but elevated SMRs for several SCs, infections, Alzheimer’s disease, genitourinary disease and suicide. A limitation was lack of individual treatment data. Conclusions RS declines mainly from TC deaths <5 years after TGCT diagnosis. Later, excess SC mortality becomes particularly important, reducing RS even ≥26 years. Radiotherapy; standard adjuvant seminoma treatment 1980–2007, is likely an important contributor, as are chemotherapy and possibly innate susceptibilities. Vigilant long-term follow-up, including psychosocial aspects, is important. Further research should focus on identifying survivor risk groups and optimizing treatment

Causes of inferior relative survival after testicular germ cell tumor diagnosed 1953–2015: A population-based prospective cohort study

Background Testicular germ cell tumor (TGCT) patients and survivors have excess mortality compared to the general male population, but relative survival (RS) has been scarcely studied. We investigated causes of excess mortality and their impact on RS among men diagnosed with TGCT in Norway, 1953–2015. Methods and findings Using registry data (n = 9541), standardized mortality ratios (SMRs) and RS were calculated. By December 31st, 2015, 816 testicular cancer (TC) and 1508 non-TC deaths had occurred (non-TC SMR: 1.36). Within five years of TGCT diagnosis, 80% were TC deaths. Non-TC second cancer (SC) caused 65% of excess non-TC deaths, of which 34% from gastric, pancreatic or bladder cancer. SC SMRs remained elevated ≥26 years of follow-up. In localized TGCT diagnosed >1979, SC SMRs were only elevated after seminoma. Cardiovascular disease caused 9% and other causes 26% of excess non-TC deaths, of which 58% from gastrointestinal and genitourinary disorders. RS continuously declined with follow-up. TGCT patients diagnosed >1989 had superior five-year TC-specific RS (98.3%), lower non-TC SMR (1.21), but elevated SMRs for several SCs, infections, Alzheimer’s disease, genitourinary disease and suicide. A limitation was lack of individual treatment data. Conclusions RS declines mainly from TC deaths <5 years after TGCT diagnosis. Later, excess SC mortality becomes particularly important, reducing RS even ≥26 years. Radiotherapy; standard adjuvant seminoma treatment 1980–2007, is likely an important contributor, as are chemotherapy and possibly innate susceptibilities. Vigilant long-term follow-up, including psychosocial aspects, is important. Further research should focus on identifying survivor risk groups and optimizing treatment

Continuing increased risk of second cancer in long-term testicular cancer survivors after treatment in the cisplatin era

Using complete information on total treatment burden, this population‐based study aimed to investigate second cancer (SC) risk in testicular cancer survivors (TCS) treated in the cisplatin era. The Cancer Registry of Norway identified 5,625 1‐year TCS diagnosed 1980–2009. Standardized incidence ratios (SIRs) were calculated to evaluate the total and site‐specific incidence of SC compared to the general population. Cox regression analyses evaluated the effect of treatment on the risk of SC. After a median observation time of 16.6 years, 572 TCS developed 651 nongerm cell SCs. The SC risk was increased after surgery only (SIR 1.28), with site‐specific increased risks of thyroid cancer (SIR 4.95) and melanoma (SIR 1.94). After chemotherapy (CT), we observed 2.0‐ to 3.7‐fold increased risks for cancers of the small intestine, bladder, kidney and lung. There was a 1.6‐ to 2.1‐fold increased risk of SC after ≥2 cycles of cisplatin‐based CT. Radiotherapy (RT) was associated with 1.5‐ to 4.4‐fold increased risks for cancers of the stomach, small intestine, liver, pancreas, lung, kidney and bladder. After combined CT and RT, increased risks emerged for hematological malignancies (SIR 3.23). TCS treated in the cisplatin era have an increased risk of developing SC, in particular after treatment with cisplatin‐based CT and/or RT

Continuing increased risk of second cancer in long-term testicular cancer survivors after treatment in the cisplatin era

Using complete information on total treatment burden, this population‐based study aimed to investigate second cancer (SC) risk in testicular cancer survivors (TCS) treated in the cisplatin era. The Cancer Registry of Norway identified 5,625 1‐year TCS diagnosed 1980–2009. Standardized incidence ratios (SIRs) were calculated to evaluate the total and site‐specific incidence of SC compared to the general population. Cox regression analyses evaluated the effect of treatment on the risk of SC. After a median observation time of 16.6 years, 572 TCS developed 651 nongerm cell SCs. The SC risk was increased after surgery only (SIR 1.28), with site‐specific increased risks of thyroid cancer (SIR 4.95) and melanoma (SIR 1.94). After chemotherapy (CT), we observed 2.0‐ to 3.7‐fold increased risks for cancers of the small intestine, bladder, kidney and lung. There was a 1.6‐ to 2.1‐fold increased risk of SC after ≥2 cycles of cisplatin‐based CT. Radiotherapy (RT) was associated with 1.5‐ to 4.4‐fold increased risks for cancers of the stomach, small intestine, liver, pancreas, lung, kidney and bladder. After combined CT and RT, increased risks emerged for hematological malignancies (SIR 3.23). TCS treated in the cisplatin era have an increased risk of developing SC, in particular after treatment with cisplatin‐based CT and/or RT

Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based Cohort Study

PURPOSE It is hypothesized that cisplatin-based chemotherapy (CBCT) reduces the occurrence of metachronous contralateral (second) germ cell testicular cancer (TC). However, studies including treatment details are lacking. The aim of this study was to assess the second TC risk, emphasizing the impact of previous TC treatment. PATIENTS AND METHODS Based on the Cancer Registry of Norway, 5,620 men were diagnosed with first TC between 1980 and 2009. Treatment data regarding TC were retrieved from medical records. Cumulative incidences of second TC were estimated, and standardized incidence ratios were calculated. The effect of treatment intensity was investigated using Cox proportional hazard regression. RESULTS Median follow-up was 18.0 years, during which 218 men were diagnosed with a second TC after median 6.2 years. Overall, the 20-year crude cumulative incidence was 4.0% (95% CI, 3.5 to 4.6), with lower incidence after chemotherapy (CT) (3.2%; 95% CI, 2.5 to 4.0) than after surgery only (5.4%; 95% CI, 4.2 to 6.8). The second TC incidence was also lower for those age ≥ 30 years (2.8%; 95% CI, 2.3 to 3.4) at first TC diagnosis than those age &lt; 30 years (6.0%; 95% CI, 5.0 to 7.1). Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general male population (standardized incidence ratio, 13.1; 95% CI, 11.5 to 15.0). With surgery only as reference, treatment with CT significantly reduced the second TC risk (hazard ratio [HR], 0.55). For each additional CBCT cycle administered, the second TC risk decreased significantly after three, four, and more than four cycles (HRs, 0.53, 0.41, and 0.21, respectively). CONCLUSION Age at first TC diagnosis and treatment intensity influenced the second TC risk, with significantly reduced risks after more than two CBCT cycles

Testicular cancer in the cisplatin era: Causes of death and mortality rates in a population-based cohort

PURPOSE Using complete information regarding testicular cancer (TC) treatment burden, this study aimed to investigate cause-specific non-TC mortality with impact on previous treatment with platinum-based chemotherapy (PBCT) or radiotherapy (RT). METHODS Overall, 5,707 men identified by the Cancer Registry of Norway diagnosed with TC from 1980 to 2009 were included in this population-based cohort study. By linking data with the Norwegian Cause of Death Registry, standardized mortality ratios (SMRs), absolute excess risks (AERs; [(observed number of deaths − expected number of deaths)/person-years of observation] ×10,000), and adjusted hazard ratios (HRs) were calculated. RESULTS Median follow-up was 18.7 years, during which non-TC death was registered for 665 (12%) men. Overall excess non-TC mortality was 23% (SMR, 1.23; 95% CI, 1.14 to 1.33; AER, 11.14) compared with the general population, with increased risks after PBCT (SMR, 1.23; 95% CI, 1.07 to 1.43; AER, 7.68) and RT (SMR, 1.28; 95% CI, 1.15 to 1.43; AER, 19.55). The highest non-TC mortality was observed in those 10 years of follow-up. CONCLUSION TC treatment with PBCT or RT is associated with a significant excess risk of non-TC mortality, and increased risks emerged after more than two cisplatin-based chemotherapy cycles after > 10 years of follow-up