Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

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

  • Øivind Kvammen ,

    Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

    oivind.kvammen@helse-mr.no

    Affiliations Department of Oncology, Ålesund Hospital, Ålesund, Norway, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

  • Tor Åge Myklebust,

    Roles Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliations Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway, Department of Registration, Cancer Registry of Norway, Oslo, Norway

  • Arne Solberg,

    Roles Funding acquisition, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliations Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway, The Cancer Clinic, St. Olav´s University Hospital, Trondheim, Norway

  • Bjørn Møller,

    Roles Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Department of Registration, Cancer Registry of Norway, Oslo, Norway

  • Olbjørn Harald Klepp,

    Roles Conceptualization, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Department of Oncology, Ålesund Hospital, Ålesund, Norway

  • Sophie Dorothea Fosså,

    Roles Conceptualization, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliations National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, The Radium Hospital, Oslo, Norway, Faculty of Medicine, Oslo University, Oslo, Norway

  • Torgrim Tandstad

    Roles Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliations Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway, The Cancer Clinic, St. Olav´s University Hospital, Trondheim, Norway

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

  • Øivind Kvammen, 
  • Tor Åge Myklebust, 
  • Arne Solberg, 
  • Bjørn Møller, 
  • Olbjørn Harald Klepp, 
  • Sophie Dorothea Fosså, 
  • Torgrim Tandstad
PLOS
x

Abstract

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.

Introduction

Despite today’s excellent cure rates for testicular germ cell tumor (TGCT), more than ten thousand men died from testicular cancer (TC) worldwide in 2012 [1]. Among TCGT survivors (TCS), excess mortality is also a concern. We previously reported a continuing decline in relative survival (RS) among men diagnosed with TGCT in Norway compared to the general male population, even beyond 25 years of follow-up [2].

TGCT treatment is associated with potentially life-threatening late effects such as second cancer (SC) and cardiovascular disease (CVD), which can manifest decades after chemo- or radiotherapy [3]. Indeed, several studies show excess mortality from these and other conditions among TCS [46]. However, to what extent such findings impact RS compared to the general male population is less clear.

We analyzed causes of excess mortality among TGCT patients diagnosed in Norway, 1953–2015, and examined the impact of these causes on RS.

Methods

Data sources

Data were obtained from the Cancer Registry of Norway (CRN) and the Norwegian Cause of Death Registry (NCDR). The study did not require institutional review board approval.

The CRN comprises data on all new cancers reported in Norway since 1953, collected prospectively. Data quality is considered to be high [7], but treatment and clinical follow-up data are incomplete. The NCDR contains cause of death information on all Norwegian inhabitants since 1951. Causes of death were recorded using the ICD-6 to ICD-9 coding systems until 1996, then ICD-10 (S1 Table).

Study population

We included all men diagnosed with histologically verified TGCT in Norway from January 1st, 1953 until December 31st, 2015, except extragonadal germ cell tumors and spermatocytic tumors [8, 9]. Because of incomplete individual treatment data, general treatment principles at the year of diagnosis were used as a proxy (Table 1).

thumbnail
Table 1. General treatment principles for testicular germ cell tumor patients diagnosed in Norway.

https://doi.org/10.1371/journal.pone.0225942.t001

Patients were classified into cohorts by time period of diagnosis: 1953–1979, 1980–1989 and 1990–2015. They were further classified as either seminoma, nonseminoma or unspecified TGCT. Disease extent at diagnosis was classified by CRN variables as either localized, metastatic or unknown [10]. Nonmetastatic tumors with direct micro- or macroscopic growth into neighboring tissues were classified as localized.

Follow-up was from the time of first TGCT diagnosis until death, emigration or December 31st, 2015, whichever occurred first.

Statistical analysis

In this population-based prospective cohort study, cause of death was the principal outcome parameter. Date and underlying cause of death were obtained from the NCDR for all deceased patients. Deaths were classified using the NCDR shortlist (S1 Table) by reported cause: TC, SC excluding TC, CVD and other causes including unknown (OC).

RS was computed using the method developed by Pohar Perme et al [11]. Standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were computed for all non-TC causes of death. NCDR mortality data for the general male Norwegian population, matched on 5-year age groups and calendar year, constituted the reference population. Four follow-up time subintervals were defined: <16 years, 16–<26 years, ≥26 years and ≥5 years, the latter to assess the impact of surveillance bias.

Multiple comparisons correction was not performed due to the explorative nature of the study [12, 13]. Patients with partially missing data were not included in the respective subgroup analyses. The software used was Stata/MP version 15.1, copyright 1985–2017 StataCorp LLC.

Results

Patient characteristics and overall mortality

In total, 9541 patients were included, of whom 5278 were diagnosed with seminoma, 4126 with nonseminoma, and 47 with an unspecified TGCT (Table 2). Overall, 79% of seminomas and 60% of nonseminomas were localized at diagnosis. Disease extent was unknown in 457 patients. Median age at diagnosis was 38 and 29 years for seminoma and nonseminoma patients, respectively. Median follow-up times were 23.5 years for TGCT patients diagnosed <1980, 28.9 years when diagnosed in the 1980s and 10.0 years when diagnosed >1989.

thumbnail
Table 2. Persons at risk, cumulative deaths and relative survival by follow-up time.

https://doi.org/10.1371/journal.pone.0225942.t002

At end of follow-up, 2324 deaths had occurred. Of these, 816 were due to TC, 575 to SC, 440 to CVD and 493 to OC including 56 deaths of unknown cause (Table 2, S2 Table). Bilateral TC was registered in 2.9% of patients, and 102 patients had emigrated. The overall non-TC SMR was 1.36, 95% CI 1.30–1.44.

Testicular cancer mortality

During the first five years after TGCT diagnosis, 718 of 893 deaths (80%) were caused by TC. About 90% of TC deaths occurred within five years of follow-up. TC deaths were more common in patients diagnosed <1980, among nonseminoma patients and in patients with metastatic TGCT at diagnosis (Table 2, S2 Table).

Second cancer mortality, excluding testicular cancer

The overall SC SMR was 1.84 (95% CI 1.74–2.06), causing 262 (65%) of 402 excess non-TC deaths. Median time to SC death was 24.2 years after TGCT diagnosis (25th–75th percentile 14.5–32.5 years).

SC SMRs ranged from 1.39 among TCS diagnosed >1989 to 2.00 among TCS diagnosed <1980 (Table 3). In general, SC SMRs increased with follow-up and were higher among TCS with metastatic TGCT at diagnosis. TCS diagnosed with localized seminoma >1979 had elevated SC SMRs, while those with localized nonseminoma did not (S3 Table).

thumbnail
Table 3. Standardized mortality ratios for selected causes of death among testicular germ cell tumor patients diagnosed in Norway.

https://doi.org/10.1371/journal.pone.0225942.t003

Gastrointestinal and non-TC genitourinary cancer caused 38% and 15% of excess SC deaths, respectively. Gastric, pancreatic and bladder cancer caused 34% of excess SC deaths combined, with SMRs of 2.62–2.97 in TCS diagnosed <1980 and 3.98–4.74 among those diagnosed in the 1980s. For gastric and bladder cancers, SMRs were also elevated ≥16 years of follow-up among TGCT patients diagnosed >1989 (Table 3).

SMRs were generally threefold elevated in the “other malignant neoplasms” group. This group comprises several cancer forms, for which separate SMRs were not calculated (S1 Table). However, about half of deaths in this group were due to either sarcoma or cancer of unknown origin.

TCS diagnosed <1980 also had elevated SMRs for cancer of the large intestine, liver or intrahepatic bile ducts, prostate and central nervous system, melanoma, certain hematological malignancies, and esophageal cancer (the latter ≥26 years of follow-up only). Additionally, there was an about twofold risk of death from cancer of the lung, trachea or bronchus <16 years of follow-up.

TCS diagnosed in the 1980s had an SMR of 1.89 for cancer of the lung, trachea or bronchus. The SMR for cancer of the lip, oral cavity or pharynx was 3.44. ≥26 years of follow-up, there was an about twofold risk of death from cancer of the large intestine.

Among TCS diagnosed >1989, the SMRs for leukemia, esophageal and central nervous system cancer were 3.47, 2.61 and 1.98, respectively.

Cardiovascular disease mortality

The CVD SMR for all TCS was borderline significant at 1.09 (95% CI 0.99–1.22), causing 35 (9%) of excess non-TC deaths. Median time to CVD death was 21.4 years (25th–75th percentile 12.2–32.4 years). Thirty-one (89%) of the excess CVD deaths, mostly non-ischemic heart diseases, occurred among TCS initially diagnosed with metastatic TGCT.

Among TCS diagnosed <1980, the overall CVD SMR was 1.12, and 1.88 for TCS diagnosed with metastatic seminoma. The SMR for non-ischemic heart diseases was 1.59 (Table 3 and S3 Table).

TCS diagnosed in the 1980s had a 50% increased risk of death from acute myocardial infarction <16 years of follow-up, as had TCS diagnosed with localized seminoma (S3 Table). TCS diagnosed with metastatic seminoma had an about fivefold risk of death from non-ischemic heart diseases.

The only significant finding in TCS diagnosed >1989 was among TCS diagnosed with metastatic nonseminoma with <16 years of follow-up, where the CVD SMR was 2.23 (S3 Table). Five of seven deaths were due to heart diseases.

Other cause mortality

The OC SMR for all TGCT patients was 1.27 (95% CI 1.17–1.39), causing 105 (26%) of 402 excess non-TC deaths. Of these, 18 (17%) were of unknown cause (Table 3, S3 Table). Median time to OC death was 19.1 years (25th–75th percentile 7.7–31.0 years).

Digestive and genitourinary diseases caused 58% of excess deaths in the OC category. SMRs for digestive diseases were increased about threefold in TCS diagnosed <1990 (Table 3). Thirteen of 45 excess deaths by digestive diseases were due to ulcers or chronic liver disease, while intestinal disorders caused most of the remaining excess deaths.

Among TCS diagnosed <1980, the SMR for genitourinary diseases was 2.31. TCS diagnosed in the 1980s had a twofold risk of death from endocrine, nutritional and/or metabolic diseases and a threefold risk of death from a subgroup of respiratory disorders not including pneumonia and chronic lower respiratory disorders (S1 Table).

TCS diagnosed >1989 had elevated SMRs for genitourinary diseases (3.76) including diseases of the kidney and ureter (3.18), infections (3.06) and nervous system / sense organ diseases (1.72) including Alzheimer’s disease (3.85). Elevated SMRs for suicide (1.54) and accidents (1.46) were found, elevated also among nonseminoma patients with metastases at diagnosis (S3 Table). Median time to suicide among TCS diagnosed >1989 was 7.1 years (25th–75th percentile 2.8–12.7 years), and the median age at suicide was 40.1 years (25th–75th percentile 34.0–50.0 years).

Mortality among five-year TGCT survivors

In general, restricting SMR analyses to the 7111 five-year TCS caused only minor changes in SMRs from those of the entire study population (Table 3, S3 Table). Notable exceptions were that the SMRs for suicide and nervous system diseases in TCS diagnosed >1989 were no longer significantly elevated. This was also true for central nervous system cancer in TCS diagnosed <1980. Conversely, the SMR for stomach cancer became significantly elevated for five-year TCS diagnosed >1989, bladder cancer for TCS diagnosed <1980, as did the OC SMR among TCS diagnosed in the 1980s.

Relative survival by cause of death category, all TGCT patients

RS among TGCT patients generally declined with increasing follow-up time (Fig 1, Table 2). While TC deaths were the main cause of reduced RS during the first five years of follow-up, non-TC causes gradually became dominant beyond this time, with elevated SMRs among TCS increasing with follow-up even ≥26 years. Overall, SC was the prime non-TC contributor to reduced RS (Fig 1, Table 3). Patients diagnosed with localized seminoma >1979 had increased overall non-TC SC SMRs, while patients with localized nonseminoma did not, contributing to the inferior RS point estimates for this patient group.

thumbnail
Fig 1. Point estimates for relative survival among testicular germ cell patients diagnosed in Norway, by histology and disease extent at diagnosis, with cause of death category.

Survival in the reference population is always 100%.

https://doi.org/10.1371/journal.pone.0225942.g001

Both short- and long-term RS improved significantly from TGCT patients diagnosed <1980 to patients diagnosed in the 1980s. Five-year RS increased from 69.0 to 94.5%, while 25-year RS increased from 59.2 to 88.4%. Further increases in RS point estimates were seen among TGCT patients diagnosed >1989 (Fig 1, Table 2). Five-year TC-specific RS increased from 70.1% (95% CI 68.0–72.1%) among patients diagnosed <1980 to 95.0% (95% CI 93.7–96.1%) in the 1980s and 98.3% (95% CI 97.9–98.6%) >1989.

Discussion

The primary objective of this study was to give an overview of causes of excess mortality and their impact on RS among men diagnosed with TGCT in Norway, 1953–2015, compared with the general Norwegian male population.

TC was, unsurprisingly, the main cause of declining RS during the first five years after diagnosis. Non-TC SC became the prime contributor to the continuing decline in RS beyond this time, particularly due to excess mortality from gastrointestinal and non-TC genitourinary cancer. Similarly, non-malignant digestive and genitourinary diseases were important contributors to excess OC mortality. CVD was a comparatively minor contributor, with most excess deaths occurring among TCS diagnosed with metastatic TGCT.

Other notable findings included the elevated non-TC SMRs among seminoma patients diagnosed with localized disease >1979, and the elevated SMR for suicide in patients diagnosed >1989.

Increased SMRs for central nervous system cancer and nervous / sensory system diseases including Alzheimer’s disease, were novel findings, though based on few cases. Many studies have shown an inverse relationship between cancer and dementia, although bias cannot be ruled out [14]. Prostate cancer excess mortality among TCS diagnosed <1980 was also a novel finding, though consistent with excess risks previously reported [15, 16]. Patients with a previous genitourinary cancer are perhaps more likely to be screened for prostate cancer, thus increasing detection.

To our knowledge, this is the first study to examine the impact of any cause of excess mortality on RS among TGCT patients. Study strengths are the inclusion of almost ten thousand patients diagnosed both in the pre- and post-cisplatin era regardless of disease extent and histology, inclusion of all causes of death, and the long follow-up times, all using high quality data sources. We believe our study has high external validity.

Several studies have reported long-term cause-specific mortality data among TC patients (S4 Table). Most of these studies are registry based and lack complete treatment data.

Mortality after radiotherapy

Radiation-induced DNA damage may lead to long-term effects such as stromal change with collagen deposition and neoangiogenesis causing organ dysfunction [17]. An increased SC risk within radiation fields with a dose-response relationship has been reported among TCS [18]. Increased mortality from SC, CVD, gastrointestinal diseases and infections has also been reported after radiotherapy (S4 Table). Zagars et al reported an SC SMR of 1.91 and a CVD SMR of 1.61 beyond 15 years of follow-up among stage I-II seminoma patients. Prophylactic mediastinal irradiation was the only factor correlated with survival in univariate analysis [19].

In Norway, most patients diagnosed in the pre-cisplatin era received infradiaphragmatic radiotherapy. Adjuvant radiotherapy was omitted in nonseminoma patients from 1980, whereas stage I seminoma patients continued to receive adjuvant irradiation to the paraaortic lymph nodes until about year 2007. Stage II seminoma patients received prophylactic mediastinal radiotherapy until about year 2000 (Table 1).

Thus, our findings suggest that infradiaphragmatic radiotherapy is a strong contributor to declining long-term RS by excess mortality from SC and OC in TCS diagnosed <1980, as well as in patients with localized seminoma. Mediastinal radiotherapy may likewise explain the excess CVD mortality among patients with metastatic seminoma diagnosed <1980, or the excess lung cancer mortality among corresponding patients diagnosed in the 1980s.

Mortality after chemotherapy

Cisplatin-based chemotherapy regimens are associated with a wide range of toxicities and late effects, including nephrotoxicity, CVD and SC [2022]. Such treatment might increase the CVD risk directly through vascular damage, or indirectly through modifying CVD risk factors, such as obesity, hypercholesteremia and hypertension [23]. Cisplatin can be detected in the blood and urine for decades after treatment, and serum levels have been positively correlated to SC risk [21, 24]. Cisplatin and etoposide have been linked to excess leukemia risk, often manifesting earlier than solid cancers [25]. Bleomycin can cause life-threatening pulmonary toxicity [20].

Several studies have analyzed long-term mortality among TGCT patients who received chemotherapy (S4 Table). Kier et al [26] reported a 1.6 times risk of SC death among Danish patients diagnosed between 1984 and 2008. Fung et al [5] reported a CVD SMR of 1.36 among nonseminoma patients diagnosed between 1980 and 2010.

Combined radio- and chemotherapy yields a higher risk of non-TC death than either treatment alone. Conversely, patients having undergone initial surgery only seem to be at lower risk [26]. Our findings of excess mortality from CVD, SC, respiratory and genitourinary diseases could thus partly be chemotherapy-related.

Treatment-independent mortality

SC has been reported to be more common among seminoma patients [15, 16, 27], who are approximately ten years older than nonseminoma patients at diagnosis, possibly causing a reduced long-term tolerance to treatment [28]. Moreover, previous TCGT treatment may hamper the possibility to provide effective SC treatment [29]. Repeated CT scans could be associated with elevated SC risks [30].

TC development occurs by an interaction between polygenetic, environmental and hormonal causes [31]. TGCT patients might genetically be more susceptible to developing life-threatening diseases such as cancer. A recent study on TC patients diagnosed 1980–2009 in Norway with complete treatment information, found increased SC risk even after surgery only [32].

Increased suicide risk has been reported among US TCS [3335]. In a recent Norwegian study, TCS born between 1965 and 1985, diagnosed before age 25, had a suicide hazard ratio of 2.9 [36].

Some evidence suggests increased prevalence of anxiety disorder [37] and fatigue [38] among TC patients. In a 2016 study, increased prevalence of depression and reduced health-related quality of life was also found [39], though other studies indicate that health-related quality of life in TCS is similar to the general population [40]. These findings could partly explain the increased suicide risk, as could changes in coding practices.

Conversely, general health care advances during the last decades have probably improved survival in the study population as well.

Study limitations

Incomplete CRN treatment and relapse data makes the long-term effects of a particular treatment difficult to assess.

Potential differences in comorbidity and smoking habits, for which we had no data, could affect SMRs and RS [41]. For instance, men with Down’s syndrome have increased risks for both TC and several other conditions such as Alzheimer’s disease [42]. With an overall median age of <40 years at diagnosis, we nevertheless expect little pre-TGCT comorbidity, and smoking habits were likely similar in the reference population [43].

TC deaths were not excluded from the NCDR reference population data, which could have led to a slight underestimation of overall SC SMRs. SMR and RS subgroup comparisons should be interpreted with caution due to potential differences in age distribution, follow-up time and reference population mortality rate. The decision to not perform multiple comparisons correction increases the risk of type I errors. Several SMRs are based on a relatively low number of cases, but there was no way of expanding the study sample as all eligible patients were included.

Surveillance bias must be considered, particularly during the first five years of follow-up. It is possible, for instance, that a patient that has previously been diagnosed with cancer is more likely to have any subsequent condition detected due to more vigorous follow-up. This could ultimately have an impact on survival. We included TGCT patients followed for <5 years in the analyses as to not infer a particular mechanism behind excess deaths (i.e., treatment-induced as opposed to genetic or other conditions), but also to provide the most complete estimate of RS across the entire follow-up period from time of TGCT diagnosis.

To investigate the extent of surveillance bias, we performed separate SMR analyses on five-year TCS only (Table 3, S3 Table). Because of the long MTD for most conditions, it was as expected that most SMRs did not significantly change for analyses restricted to five-year survivors. A few SMRs were no longer significantly elevated, perhaps most notably the important finding of increased suicide risk among TCS diagnosed >1989. As the MTD was 7.1 years and the number of cases was limited, such a result was not unexpected. The SMR point estimate of 1.54 remained unchanged. We conclude that the overall impact of surveillance bias on our results is negligible.

Conclusions

Despite the improved prognosis for cure, death by TC remains the main cause of excess mortality the first five years of follow-up among TGCT patients diagnosed in Norway. TCS also remain at increased long-term risk of death by SC in particular, negatively impacting RS even beyond 25 years of follow-up. Malignant and non-malignant diseases of the gastrointestinal and genitourinary organs are among the main long-term causes of excess mortality, while CVD is a comparatively minor cause. Late effects of radio- and chemotherapy are the main culprits. The elevated non-TC SMRs among seminoma patients diagnosed in the 1980s could be due to radiotherapy given in early-stage disease.

RS point estimates are highest among patients diagnosed >1989, but follow-up time is also the shortest. Excess mortality among these patients, including suicide, is a concern. Continuing optimization of TGCT treatment and appropriate follow-up schemes are thus required, covering psychosocial health as well. Particular focus should be on the follow-up of patients previously treated with radio- and/or chemotherapy. Further research should also be directed towards identifying subgroups of TGCT patients and survivors at particular risk of excess mortality.

Supporting information

S1 Table. Extended EU shortlist for causes of death, in use by the Norwegian Cause of Death Registry.

https://doi.org/10.1371/journal.pone.0225942.s001

(DOCX)

S2 Table. Cumulative deaths by cause of death, histology, disease extent at diagnosis and follow-up time.

https://doi.org/10.1371/journal.pone.0225942.s002

(DOCX)

S3 Table. Standardized mortality ratios for selected causes of death among testicular germ cell tumor patients diagnosed in Norway.

https://doi.org/10.1371/journal.pone.0225942.s003

(DOCX)

S4 Table. Summary of selected publications reporting long-term cause-specific mortality data among testicular cancer patients.

https://doi.org/10.1371/journal.pone.0225942.s004

(DOCX)

Acknowledgments

The study used data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the aforementioned registries is intended nor should be inferred.

Parts of the data presented herein were presented at a poster session during the American Society of Clinical Oncology Annual Meeting in Chicago, June, 2017. Abstract ID #4553.

References

  1. 1. Park JS, Kim J, Elghiaty A, Ham WS. Recent global trends in testicular cancer incidence and mortality. Medicine (Baltimore). 2018;97(37):e12390. Epub 2018/09/15. pmid:30213007; PubMed Central PMCID: PMC6155960.
  2. 2. Kvammen O, Myklebust TA, Solberg A, Moller B, Klepp OH, Fossa SD, et al. Long-term Relative Survival after Diagnosis of Testicular Germ Cell Tumor. Cancer Epidemiology Biomarkers & Prevention. 2016;25:773–9. pmid:26908435
  3. 3. Maroto P, Anguera G, Martin C. Long-term toxicity of the treatment for germ cell-cancer. A review. Crit Rev Oncol Hematol. 2018;121:62–7. Epub 2017/12/28. pmid:29279100.
  4. 4. Fosså SD, Gilbert E, Dores GM, Chen J, McGlynn KA, Schonfeld S, et al. Noncancer causes of death in survivors of testicular cancer. Journal of the National Cancer Institute. 2007;99:533–44. pmid:17405998.
  5. 5. Fung C, Fossa SD, Milano MT, Sahasrabudhe DM, Peterson DR, Travis LB. Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study. Journal of Clinical Oncology. 2015;33:3105–15. pmid:26240226
  6. 6. Fosså SD, Aass N, Harvei S, Tretli S. Increased mortality rates in young and middle-aged patients with malignant germ cell tumours. British journal of cancer. 2004;90:607–12. pmid:14760372.
  7. 7. Larsen IK, Småstuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. European journal of cancer (Oxford, England: 1990). 2009;45:1218–31. pmid:19091545.
  8. 8. Eble JN. Spermatocytic seminoma. Human Pathology. 1994;25(10):1035–42. pmid:7927308
  9. 9. Khan O, Protheroe A. Testis cancer. Postgrad Med J. 2007;83(984):624–32. Epub 2007/10/06. pmid:17916870; PubMed Central PMCID: PMC2600126.
  10. 10. CRN. Documentation of CRN Variables (Norwegian) 2015. Available from: https://www.kreftregisteret.no/contentassets/6b389374314344d8a37726aa4d79c732/dokumentasjon_av_variabler-v4.1.pdf.
  11. 11. Perme MP, Stare J, Estève J. On estimation in relative survival. Biometrics. 2012;68:113–20. pmid:21689081.
  12. 12. Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology (Cambridge, Mass). 1990;1(1):43–6. Epub 1990/01/01. pmid:2081237.
  13. 13. Althouse AD. Adjust for Multiple Comparisons? It's Not That Simple. Ann Thorac Surg. 2016;101(5):1644–5. Epub 2016/04/24. pmid:27106412.
  14. 14. van der Willik KD, Schagen SB, Ikram MA. Cancer and dementia: Two sides of the same coin? Eur J Clin Invest. 2018;48(11):e13019. Epub 2018/08/17. pmid:30112764; PubMed Central PMCID: PMC6220770.
  15. 15. Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. Journal of the National Cancer Institute. 2005;97:1354–65. pmid:16174857.
  16. 16. Zhang L, Hemminki O, Chen T, Yu H, Zheng G, Chattopadhyay S, et al. Second cancers and causes of death in patients with testicular cancer in Sweden. PLoS One. 2019;14(3):e0214410. Epub 2019/03/29. pmid:30921367; PubMed Central PMCID: PMC6438485.
  17. 17. Hwang WL, Pike LRG, Royce TJ, Mahal BA, Loeffler JS. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat Rev Clin Oncol. 2018. Epub 2018/06/07. pmid:29872177.
  18. 18. Fung C, Dinh P Jr., Ardeshir-Rouhani-Fard S, Schaffer K, Fossa SD, Travis LB. Toxicities Associated with Cisplatin-Based Chemotherapy and Radiotherapy in Long-Term Testicular Cancer Survivors. Adv Urol. 2018;2018:8671832. Epub 2018/04/20. pmid:29670654; PubMed Central PMCID: PMC5835297.
  19. 19. Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22:640–7. pmid:14726503.
  20. 20. Haugnes HS, Oldenburg J, Bremnes RM. Pulmonary and cardiovascular toxicity in long-term testicular cancer survivors. Urologic oncology. 2014:1–8. pmid:25554583.
  21. 21. Chovanec M, Abu Zaid M, Hanna N, El-Kouri N, Einhorn LH, Albany C. Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann Oncol. 2017;28(11):2670–9. Epub 2017/10/19. pmid:29045502.
  22. 22. Kerns SL, Fung C, Monahan PO, Ardeshir-Rouhani-Fard S, Abu Zaid MI, Williams AM, et al. Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study. J Clin Oncol. 2018;36(15):1505–12. Epub 2018/04/05. pmid:29617189; PubMed Central PMCID: PMC5959198.
  23. 23. Haugnes HS, Bosl GJ, Boer H, Gietema Ja, Brydøy M, Oldenburg J, et al. Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012;30:3752–63. pmid:23008318.
  24. 24. Hjelle LV, Gundersen POM, Hellesnes R, Sprauten M, Brydoy M, Tandstad T, et al. Long-term serum platinum changes and their association with cisplatin-related late effects in testicular cancer survivors. Acta Oncol. 2018:1–9. Epub 2018/05/19. pmid:29775128.
  25. 25. Travis LB, Beard C, Allan JM, Dahl Aa, Feldman DR, Oldenburg J, et al. Testicular cancer survivorship: research strategies and recommendations. Journal of the National Cancer Institute. 2010;102:1114–30. pmid:20585105.
  26. 26. Kier MG, Hansen MK, Lauritsen J, Mortensen MS, Bandak M, Agerbaek M, et al. Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer: A Danish Nationwide Cohort Study. JAMA Oncol. 2016;2(12):1624–7. Epub 2016/10/07. pmid:27711914.
  27. 27. Hemminki K, Liu H, Sundquist J. Second cancers after testicular cancer diagnosed after 1980 in Sweden. Annals of Oncology. 2009;21:1546–51. pmid:20019089.
  28. 28. Fosså SD, Cvancarova M, Chen L, Allan AL, Oldenburg J, Peterson DR, et al. Adverse prognostic factors for testicular cancer-specific survival: a population-based study of 27,948 patients. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2011;29:963–70. pmid:21300926.
  29. 29. Curreri SA, Fung C, Beard CJ. Secondary malignant neoplasms in testicular cancer survivors. Urol Oncol. 2015;33(9):392–8. Epub 2015/06/16. pmid:26072728.
  30. 30. Hall EJ, Brenner DJ. Cancer risks from diagnostic radiology: the impact of new epidemiological data. Br J Radiol. 2012;85(1020):e1316–7. Epub 2012/11/24. pmid:23175496; PubMed Central PMCID: PMC3611740.
  31. 31. De Toni L, Šabovic I, Cosci I, Ghezzi M, Foresta C, Garolla A. Testicular Cancer: Genes, Environment, Hormones. Frontiers in Endocrinology. 2019;10. pmid:31338064
  32. 32. Hellesnes R, Kvammen O, Myklebust TA, Bremnes RM, Karlsdottir A, Negaard HFS, et al. Continuing increased risk of second cancer in long-term testicular cancer survivors after treatment in the cisplatin era. Int J Cancer. 2019. Epub 2019/10/10. pmid:31597192.
  33. 33. Alanee S, Russo P. Suicide in men with testis cancer. European journal of cancer care. 2012;21:817–21. pmid:22624649.
  34. 34. Beard CJ, Travis LB, Chen M-H, Arvold ND, Nguyen PL, Martin NE, et al. Outcomes in stage I testicular seminoma: a population-based study of 9193 patients. Cancer. 2013;119:2771–7. pmid:23633409.
  35. 35. Zaorsky NG, Zhang Y, Tuanquin L, Bluethmann SM, Park HS, Chinchilli VM. Suicide among cancer patients. Nature Communications. 2019;10(1). pmid:30643135
  36. 36. Gunnes MW, Lie RT, Bjorge T, Ghaderi S, Syse A, Ruud E, et al. Suicide and violent deaths in survivors of cancer in childhood, adolescence and young adulthood-A national cohort study. Int J Cancer. 2017;140(3):575–80. Epub 2016/10/27. pmid:27750385.
  37. 37. Dahl AA, Haaland CF, Mykletun A, Bremnes R, Dahl O, Klepp O, et al. Study of anxiety disorder and depression in long-term survivors of testicular cancer. J Clin Oncol. 2005;23(10):2389–95. Epub 2005/04/01. pmid:15800331.
  38. 38. Sprauten M, Haugnes HS, Brydoy M, Kiserud C, Tandstad T, Bjoro T, et al. Chronic fatigue in 812 testicular cancer survivors during long-term follow-up: increasing prevalence and risk factors. Ann Oncol. 2015;26(10):2133–40. Epub 2015/08/13. pmid:26265167.
  39. 39. Smith AB, Butow P, Olver I, Luckett T, Grimison P, Toner GC, et al. The prevalence, severity, and correlates of psychological distress and impaired health-related quality of life following treatment for testicular cancer: a survivorship study. J Cancer Surviv. 2016;10(2):223–33. Epub 2015/07/17. pmid:26178326.
  40. 40. Cappuccio F, Rossetti S, Cavaliere C, Iovane G, Taibi R, D'Aniello C, et al. Health-related quality of life and psychosocial implications in testicular cancer survivors. A literature review. Eur Rev Med Pharmacol Sci. 2018;22(3):645–61. Epub 2018/02/21. pmid:29461592.
  41. 41. O'Donnell E, Markt SC, Miller R, Bernard B, Albiges L, Beard C, et al. Smoking and Disease Outcomes in Patients With Malignant Germ Cell Tumors. Clin Genitourin Cancer. 2017. Epub 2017/08/31. pmid:28851592.
  42. 42. Hill DA, Gridley G, Cnattingius S, Mellemkjaer L, Linet M, Adami HO, et al. Mortality and cancer incidence among individuals with Down syndrome. Arch Intern Med. 2003;163(6):705–11. Epub 2003/03/18. pmid:12639204.
  43. 43. Haugnes HS, Wethal T, Aass N, Dahl O, Klepp O, Langberg CW, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:4649–57. pmid:20855830.