Testicular cancer survivors in the cisplatin era: Metachronous contralateral testicular cancer, second cancer and causes of death

Background/aims: Testicular cancer (TC) is the most common cancer among young men aged 20-40 years. The cure rates are excellent, an important factor being the chemotherapeutic agent cisplatin. This thesis aimed to investigate how TC treatment influenced the subsequent risk for metachronous contralateral (second) TC, non-TC second cancer (SC) and non-TC mortality. Methods: The Cancer Registry of Norway (CRN) identified all men diagnosed with TC 1980-2009. Complete TC treatment information was retrieved from medical journals for all eligible men (n=5724) and linked with the CRN and the Norwegian Cause of Death Registry. Crude cumulative incidences were estimated, and standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated to compare rates with the general population. Adjusted hazard ratios (HRs) were estimated to investigate the effect of treatment intensity. Results: Median follow-up time in the three papers was 16.6-18.7 years. Second TC developed in 218 (3.9%) men, and the 20-year cumulative incidence was 4% (95% CI 3.5-4.6). Treatment with cisplatin-based chemotherapy (CBCT) at first TC was associated with a significantly reduced second TC risk compared with surgery (HR 0.55). A dose-dependent relationship was observed, with a risk reduction for each additional CBCT cycle after 3, 4 and >4 cycles (HRs 0.53, 0.41 and 0.21, respectively). Additionally, older age at first TC was associated with a reduced second TC risk. Overall, 572 (10.2%) men developed a non-TC SC, and compared with the general population the risk was increased after treatment with surgery (SIR 1.28, 95% CI 1.05-1.56), CBCT (SIR 1.62, 95% CI 1.39-1.88) and radiotherapy (SIR 1.64, 95% CI 1.46-1.85). In total, 665 (12%) men died due to non-TC causes during follow-up, and the risk was increased after CBCT (SMR 1.23, 95% CI 1.07-1.43) and radiotherapy (SMR 1.28, 95% CI 1.15-1.43), but not after surgery. Compared with the general population, increased risk for suicide was observed after treatment with CBCT. The highest risk for SC and non-TC mortality was observed in those with young age at TC diagnosis. Compared with surgery, treatment with 1 CBCT cycle was not associated with increased risks, while increased risks were observed after ≥2 (SC) and ≥3 (mortality) CBCT cycles in those with >10 years follow-up. Conclusions: Previous TC treatment as well as age at diagnosis influenced the subsequent risks for second TC, SC and premature non-TC mortality. This information is important for all TC survivors and for health personnel involved in the follow-up.Bakgrunn: Testikkelkreft er den vanligste kreftsykdommen blant unge menn. Heldigvis kureres de aller fleste, og cellegiften cisplatin er en viktig årsak til dette. Målsetninga med denne avhandlinga var å undersøke hvordan testikkelkreftbehandling påvirker den seinere risiko for å utvikle metakron kontralateral testikkelkreft (ny testikkelkreft), sekundærkreft (ikke testikkelkreft) og risiko for død av andre årsaker enn testikkelkreft. Metode: Kreftregisteret identifiserte alle menn diagnostisert med testikkelkreft i perioden 1980-2009. Komplett informasjon om behandling ble samla fra medisinske journaler for alle menn inkludert i studien (n=5724) og koblet med data fra Kreftregisteret og Dødsårsaksregisteret. Kumulativ insidens ble estimert. For å sammenligne med den generelle befolkning kalkulerte vi standardisert insidensratio (SIR) og standardisert mortalitetsratio (SMR). Justerte hasard ratio (HR) ble estimert for å undersøke effekten av behandlingsintensitet. Resultater: Median oppfølgingstid i de tre arbeidene var 16.6-18.7 år. Det var 218 (3.9%) menn som utviklet en ny testikkelkreft, og 20 års kumulativ insidens var 4% (95% konfidensintervall (KI) 3.5-4.6). Behandling med cisplatin-basert cellegift (CBCT) ved første testikkelkreft var assosiert med en signifikant reduksjon i risiko for ny testikkelkreft sammenligna med kirurgi (HR 0.55). Vi observerte en dose-respons-sammenheng med en risikoreduksjon for hver påfølgende kur med CBCT etter 3 (HR 0.53), 4 (HR 0.41), >4 (HR 0.21). Alder >30 år ved første testikkelkreft var også assosiert med redusert risiko for en ny testikkelkreft. Totalt var det 572 (10.2%) menn som utviklet sekundærkreft, og sammenligna med den generelle befolkning var risikoen økt etter kirurgi (SIR 1.28, 95% KI 1.05-1.56), CBCT (SIR 1.62, 95% KI 1.39-1.88) og strålebehandling (SIR 1.64, 95% KI 1.46-1.85). Det var 665 (12%) menn som døde av andre årsaker enn testikkelkreft, og risikoen var forhøyet etter behandling med CBCT (SMR 1.23, 95% KI 1.07-1.43) og strålebehandling (SMR 1.28, 95% KI 1.15-1.43), men ikke etter kun kirurgi. Sammenligna med generell befolkning fant vi en økt risiko for selvmord etter behandling med CBCT. Den høyeste risikoen for sekundærkreft og død (ikke testikkelkreft) ble observert blant de som var yngst ved testikkelkreftdiagnosen. Konklusjon: Testikkelkreftbehandling og alder ved diagnose påvirker den seinere risikoen for ny testikkelkreft, sekundærkreft og for tidlig død. Dette er viktig informasjon for testikkelkreft-overlevere og helsepersonell involvert i oppfølginga av denne gruppa kreftoverlevere

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

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 < 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

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

Long-term serum platinum changes and their association with cisplatin-related late effects in testicular cancer survivors

<p><b>Background:</b> The long-term toxicities after cisplatin-based chemotherapy (CBCT) reveal a remarkable inter-individual variation among testicular cancer survivors (TCSs). Therefore, we assessed long-term platinum (Pt) changes and their associations with CBCT-related late effects in TCSs.</p> <p><b>Material and methods:</b> In 77 TCSs treated with CBCT from 1984 to 1990, blood samples for analyses of Pt and a questionnaire including self-reported neuro- and ototoxicity (NTX) symptoms were collected during two follow-up surveys at median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. Information about second cancers after SII was retrieved from the Norwegian Cancer Registry.</p> <p><b>Results:</b> A larger Pt decline from SI to SII was associated with a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62–0.99 per 10 ng/L/year), and worsening of paresthesias in hands (OR 1.98, 95% CI 1.09–3.59 per 10 ng/L/year) and tinnitus (OR 1.51, 95% CI 1.01–2.27 per 10 ng/L/year).</p> <p><b>Conclusion:</b> In summary, we found a significant association between a larger Pt decline and a reduced risk of second cancers and deterioration of paresthesias in hands and tinnitus.</p