Summary
Background
While testicular germ cell tumors (TGCT) survival exceeds 90%, many survivors of adult TGCT are at risk for treatment toxicities. Less is known about physical morbidities in children, adolescents, and young adults (CAYA) with TGCT.
Methods
We used the Pediatric Oncology Group of Ontario Networked Information System, the Initiative to Maximize Progress in Adolescent and Young Adult Cancer Therapy, and the Ontario Cancer Registry to identify all CAYA males diagnosed with TGCT from 1992 to 2021 at age 11–21 years in Ontario, Canada. We matched patients at TGCT diagnosis (one-to-five ratio) to cancer-free males from the general Ontario population who were identified from the Registered Person Database. We linked CAYA to health administrative databases to identify subsequent malignant neoplasms (SMN) and hearing loss/aid use after TGCT diagnosis. We assessed cardiovascular disease (CVD), dialysis, and kidney transplant that occurred <five years (early effect) and ≥five years (late effect) from TGCT diagnosis. We used the cumulative incidence function and cause-specific hazard models.
Findings
We identified 748 patients (404 chemotherapy-treated) and 3740 controls. Median age at diagnosis was 19.0 years [interquartile range (IQR): 18.0–21.0] and 29.7 years (IQR: 25.0–37.6) at the end of follow-up. Chemotherapy-treated patients had higher risk than controls for non-TGCT SMN [hazard ratio (HR) = 4.5, 95% CI: 1.8–11.4], hearing loss/aid (HR = 2.7, 95% CI: 1.8–4.2), early dialysis (HR = 7.7, 95% CI: 1.3–46.8), any early CVD (HR = 7.3, 95% CI: 4.1–13.0), and any late CVD (HR = 1.6, 95% CI: 1.1–2.4), particularly late stroke (HR = 7.4, 95% CI: 1.2–44.6). Compared to their controls, non-chemotherapy-treated patients had higher risk for late dialysis (HR = 10.5, 95% CI: 1.1–103.8), and lower risk for late hypertension (HR = 0.4, 95% CI: 0.2–1.0). Non-chemotherapy-treated patients had higher cumulative incidence of second contralateral TGCT than chemotherapy-treated patients (15-year incidence = 4.6% vs. 0.9%, p = 0.0049).
Interpretation
Chemotherapy-treated CAYA with TGCT are at elevated risks for non-TGCT SMN, hearing loss, and early CVD compared to the general population. The long latency for certain outcome risks indicate further research is needed to characterize the health outcomes of these survivors as they age.
Funding
Foundation grants-Canadian Institutes of Health Research, Ontario Graduate Scholarship-University of Toronto, and Research Training Competition (RESTRACOMP) award-The Hospital for Sick Children.
Keywords: Adolescents and young adults, Late effects, Testicular germ cell tumors, Real-world evidence
Research in context.
Evidence before this study
Survivors of testicular germ cell tumors (TGCT) diagnosed in adulthood are known to be at increased risk for treatment-related toxicities, including second malignant neoplasms and cardiovascular disease. However, a literature search performed in September 2021 revealed that not much is known about the risk of these toxicities among survivors diagnosed during childhood and adolescence. Previous large cohorts of childhood cancer survivors, such as the Childhood Cancer Survivor Study, did not include testicular cancer. It is imperative to characterize treatment-related toxicities in this younger patient population, as their risk profile may differ due to an earlier exposure to treatment.
Added value of this study
To our knowledge, this is the first population-level assessment of long-term toxicities among survivors of childhood, adolescence and early young adulthood testicular cancer. Despite a median age of 29.7 years at the end of follow-up, chemotherapy-treated survivors were at increased risk of subsequent malignancies as well as cardio-, renal- and oto-toxicities compared to the general population. Many survivors may continue to experience treatment-related complications as they age.
Implications of all the available evidence
Our findings highlight the need for long-term follow-up of TGCT survivors diagnosed at a young age to fully understand their disease burden across their lifespan. Furthermore, standard follow-up guidelines need to be developed to ensure appropriate screening for late effects, particularly for second malignancies.
Introduction
Testicular germ cell tumors (TGCT) are the most common cancers among adolescent and young adult (AYA) males aged 15–39 years, accounting for 18.5% of malignancies in this population.1 The survival rate exceeds 90%, with an estimate of >300,000 survivors in the United States in 2022.2 Many TGCT survivors are at risk for treatment-related toxicities, including subsequent malignant neoplasms (SMN), cardio-, renal-, and oto-toxicities. These toxicities have been attributed to cisplatin3 which, in addition to causing acute toxicities, can be detected in survivors' plasma up to 20 years after chemotherapy.4 Cisplatin-induced cardiotoxicity may be due to direct vascular endothelium damage and/or an increase in cardiovascular disease (CVD) risk factors, such as hypertension and hypercholesterolemia, whereas ototoxicity and renal toxicity are related to damaged cochlear hair cells and nephron epithelium, respectively.3
Prior studies focused predominantly on survivors of TGCT diagnosed during adulthood. This population has 1.3–2.0-fold and 12–27-fold increased risks for non-TGCT SMN and second primary TGCT, respectively.5, 6, 7, 8 Chemotherapy exposure has been linked to a 1.7–1.9-fold increased risk for CVD, including myocardial infarction (MI) and coronary artery disease (CAD),3 as well as reduced glomerular filtration rate (GFR), chronic kidney disease (CKD),9 and hearing loss.10,11 Toxicity risk in children and adolescents remains understudied and may differ from adults due to treatment exposure at a younger age.12 We designed a population-based retrospective matched cohort study to assess physical morbidities among children and AYA (CAYA) with TGCT.
Methods
Population
We identified all CAYA males diagnosed with a primary TGCT at age 11–21 years from 1992 to 2021 in Ontario, Canada. We matched patients to males from the general Ontario population (controls) in a one-to-five ratio (without replacement) based on birth date (±six months) and residential neighborhood at TGCT diagnosis. At TGCT diagnosis/matching date (defined as Index Date 1), both patients and controls had no history of a prior cancer and were Ontario residents. Controls' Index Date 1 was the date of TGCT diagnosis of their survivor match.
Data sources
Ontario's universal healthcare system provides free access to all essential healthcare services. We used several administrative databases associated with this system to examine outcomes (Supplement 1). These databases were linked using unique encoded identifiers and analyzed at ICES, an independent, non-profit research institute whose legal status under Ontario's health information privacy law allows it to collect and analyze anonymized healthcare and demographic data, without consent, for health system evaluation and improvement. Based on Ontario privacy legislation, the use of data in this project was authorized under section 45 of Ontario's Personal Health Information Protection Act (PHIPA) and did not require review by a Research Ethics Board.
We identified controls using the Registered Persons Database, which includes all Ontario residents with a valid health card number. We identified patients using three non-mutually exclusive databases: Pediatric Oncology Group of Ontario Networked Information System (POGONIS), a population-based registry that includes all patients aged 0–18 years who were diagnosed and treated at one of Ontario's five pediatric oncology programs13; The Initiative to Maximize Progress in Adolescent and Young Adult Cancer Therapy (IMPACT), a population-based cohort that includes AYA diagnosed with cancer at age 15–21 years from 1992 to 2012 in Ontario14; and the Ontario Cancer Registry (OCR), which includes all Ontario residents' cancer diagnoses data. POGONIS and IMPACT contain chart-abstracted disease and treatment data.
Ethics
The project data was accessed and analyzed at ICES. ICES is a prescribed entity under Ontario's PHIPA. Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to, or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA, and use no other data, are exempt from Research Ethics Board review. The use of the data in this project is authorized under section 45 and approved by ICES' Privacy and Legal Office.
Observation window
We assessed irreversible toxicities, SMN, and hearing outcomes, from Index Date 1 to the end of follow-up (first of death, loss of OHIP eligibility, or December 31, 2021). Since some patients might develop reversible short-term treatment-related toxicities, such as acute cardiovascular changes, we constructed two additional observation windows (Supplement 2) to differentiate between early and late effects. We defined early effects as morbidities that developed within five years from diagnosis, which we assessed from Index Date 1 to Index Date 2. Index Date 2 was defined as five years after Index Date 1, consistent with other cancer survivor studies.15 We assessed late effects from Index Date 2 to the end of follow-up. Late effects included prevalent cases (developed within five years from Index Date 1 but had records of healthcare system interactions for these conditions after Index Date 2) and incident cases (developed after Index Date 2).
We assessed pre-existing conditions using a two-year window prior to Index Date 1. Individuals with a pre-existing condition were excluded from that outcome definition (e.g., individuals with pre-existing hypertension were excluded from analyses of early/late hypertension but retained for all other outcome assessments).
Predictors
Demographic characteristics included age, vital status, as well as neighborhood income quintile and rurality using nearest census to Index Date 1 (rural, urban-Q1 [lowest income level] to urban-Q5 [highest income level]). TGCT patients' disease characteristics included tumor histology, tumor laterality, and presence and site of metastases at diagnosis. Treatment characteristics included surgery, chemotherapy exposure, cumulative doses (cisplatin, etoposide, and bleomycin), hematopoietic stem cell transplant (HSCT), and radiation exposure and site. OCR-identified patients lacked chart-abstracted data, so we used health administrative data to obtain limited treatment information (e.g., chemotherapy yes vs. no; Supplement 3).
Outcomes
The primary outcome was SMN incidence (first cancer in controls). Since chemotherapy is associated with an elevated risk for non-TGCT SMN16 but may protect against developing a subsequent contralateral TGCT,17,18 we assessed these two SMN subtypes separately. We identified new cancers in OCR for all patients and controls. Secondary outcomes were incidences of cardio-, renal-, and oto-toxicities (Supplement 4). We used health services records to identify CVD, including congestive heart failure (CHF), MI, CAD, pericardial disease, valvular abnormalities, arrhythmia, stroke, and hypertension. We defined renal toxicity as renal failure that required dialysis or kidney transplant, and ototoxicity as physician-diagnosed hearing loss or hearing aid use.
Statistics
We used descriptive statistics to summarize exposure and outcome frequencies and compared them between groups using chi-squared tests or Fisher's exact tests as appropriate. Due to privacy regulations, we suppressed cell sizes <six. We compared outcomes between TGCT patients and their controls and performed sub-analyses that stratified TGCT patients by chemotherapy exposure (yes vs. no). We used the cumulative incidence function and Gray's test to assess outcome incidence, including all-cause mortality, as follows: overall from Index Date 1 to the end of follow-up, and late from Index Date 2 to the end of follow-up. We assessed outcome rates using cause-specific hazard (CSH) models and accounted for the matched study design using the robust sandwich variance estimate. We used time-dependent CSH models to assess sociodemographic and treatment factors associated with outcome rates among survivors, including age at diagnosis, rurality and neighborhood income at diagnosis, cumulative cisplatin dose, HSCT, and hypertension (for non-hypertension CVD). We fit multivariable models using backward selection, with a 0.1 significance level for removing covariates from the model. We used the Efron method in CSH models to account for tied events. In all time-to-event outcome analyses, we censored event-free individuals at the end of follow-up (first of OHIP eligibility loss or December 31, 2021) and assessed death and SMN (controls' first cancer) as competing events. Additionally, non-TGCT SMN was considered a competing event for second TGCT (and vice versa). We defined statistical significance as p < 0.05 and performed all analyses using SAS statistical software (version 9.4).
Role of funding source
The analyses, conclusions, opinions, and statements expressed in this study are solely those of the authors and do not reflect those of the funding sources.
Results
Cohort description
We identified 748 patients and matched them to 3740 controls. The median age of patients and controls was 19 years [interquartile range (IQR) = 18–21] at Index Date 1 (Table 1). 83.6% of patients had non-seminoma histology, 98.0% had an orchiectomy, 24.7% had retroperitoneal lymph node dissection, and 54.0% received chemotherapy (Supplement 5). Of the 748 patients, we identified 521 from POGONIS and IMPACT (Supplement 6). Supplement 7 outlines differences between patients identified through IMPACT/POGONIS vs. OCR.
Table 1.
Cohort baseline characteristics.
|
Any effects cohort (follow-up from Index Date 1 to end of study period) |
Late effects cohort (follow-up from Index Date 2 to end of study period) |
|||||
|---|---|---|---|---|---|---|
| Control (n = 3740) | TGCT patient (n = 748) | pa | Control (n = 2833) | 5-year survivor (n = 582) | pa | |
| Age at Index Date 1 | ||||||
| Mean (SD) | 18.9 (1.9) | 18.9 (1.9) | 0.90 | 18.8 (1.9) | 18.8 (1.9) | 0.88 |
| Median (Q1–Q3) | 19.0 (18.0–21.0) | 19.0 (18.0–21.0) | 19.0 (18.0–20.0) | 19.0 (18.0–20.0) | ||
| Age group at Index Date 1, n (%) | ||||||
| 11–17 | 886 (23.7) | 170 (22.7) | 0.57 | 697 (24.6) | 136 (23.4) | 0.53 |
| 18–21 | 2854 (76.3) | 578 (77.3) | 2136 (75.4) | 446 (76.6) | ||
| Age at end of follow-upb | ||||||
| Mean (SD) | 31.8 (8.1) | 31.3 (8.1) | 0.10 | 33.9 (7.2) | 33.9 (7.1) | 0.88 |
| Median (Q1–Q3) | 30.3 (25.5–37.9) | 29.7 (25.0–37.6) | 32.5 (28.1–39.4) | 32.7 (28.1–39.7) | ||
| Follow-up time (years)b | ||||||
| Mean (SD) | 13.0 (7.9) | 12.4 (8.0) | 0.089 | 15.0 (7.0) | 15.1 (6.9) | 0.91 |
| Median (Q1–Q3) | 11.4 (6.4–19.2) | 10.9 (5.8–18.8) | 13.4 (9.2–20.7) | 13.5 (9.3–20.7) | ||
| Rurality/neighborhood income, n (%) | ||||||
| Rural | 462 (12.4) | 101 (13.5) | 0.076 | 335 (11.8) | 78 (13.4) | 0.19 |
| UrbanQ1 | 666 (17.8) | 106 (14.2) | 482 (17.0) | 77 (13.2) | ||
| UrbanQ2 | 612 (16.4) | 114 (15.2) | 462 (16.3) | 91 (15.6) | ||
| UrbanQ3 | 635 (17.0) | 144 (19.3) | 489 (17.3) | 108 (18.6) | ||
| UrbanQ4 | 657 (17.6) | 120 (16.0) | 506 (17.9) | 96 (16.5) | ||
| UrbanQ5 | 694 (18.6) | 159 (21.3) | 550 (19.4) | 129 (22.2) | ||
| Missing | 14 (0.4) | <6 | 9 (0.3) | <6 | ||
| Death, n (%) | 35 (0.9) | 59 (7.9) | <0.0001 | 19 (0.7) | 21 (3.6) | <0.0001 |
Abbreviations: TGCT = testicular germ cell tumor.
p-values were generated using chi-squared test for categorical variables and t-test for continuous variables.
Follow-up ended at loss of OHIP eligibility, death, or December 31, 2021, whichever occurred first.
The late effects cohort included 582 five-year survivors (305 chemotherapy-treated) and 2833 controls (Table 1). Most individuals excluded from this cohort had a follow-up time <five years (66% of controls, 72% of survivors). Fig. 1 describes the late effects cohort creation.
Fig. 1.
Late effects cohort creation.
Compared to controls, patients had a significantly higher cumulative incidence of all-cause mortality (five-year incidence from Index Date 1 = 5.3% vs. 0.4%, p < 0.0001), Similarly, in the late effects cohort, the cumulative incidence of late all-cause mortality was higher in five-year survivors than controls (five-year incidence from Index Date 2 = 2.0% vs. 0.4%, p < 0.0001, Supplement 8).
Outcome frequencies
Supplements 9, 10.1, and 10.2 include frequencies of outcomes and pre-existing conditions. Pre-existing conditions were rare. A higher proportion of patients than controls had any pre-existing CVD (1.2% vs. 0.3%, p = 0.003).
SMN
Compared to controls, all patients had higher rates and 15-year cumulative incidences of any SMN (4.4% vs. 0.5%, p < 0.0001) and non-TGCT SMN (1.8% vs. 0.5%, p = 0.00030; Tables 2 and 3). Non-TGCT SMN incidence was only higher in chemotherapy-treated patients compared to controls (2.2% vs. 0.7%, p = 0.00070). While chemotherapy- and non-chemotherapy-treated patients did not differ statistically in the cumulative incidences of either outcome, chemotherapy-treated patients had a lower cumulative incidence of second contralateral TGCT (0.9% vs. 4.6%, p = 0.0049; Table 4). No sociodemographic or treatment factors were significantly associated with patients' rates of any SMN, non-TGCT SMN, or second TGCT in univariate models (Supplement 11); therefore, multivariable models were not estimated.
Table 2.
Comparison of the cumulative incidence of outcomes between patients and controls.
| All patients/5-year survivors |
Chemotherapy-treated patients/5-year survivors |
Non-chemotherapy-treated patients/5-year survivors |
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Incidence (95% CI) % | p | Incidence (95% CI) % | p | Incidence (95% CI) % | p | ||||||||||
| (follow-up from Index Date 1 to end of study) |
|||||||||||||||
|
15-year cumulative incidence % (15 years from Index Date 1) |
|||||||||||||||
|
Control n = 3740 |
Patient n = 748 |
Control n = 2020 |
Patient n = 404 |
Control n = 1720 |
Patient n = 344 |
||||||||||
| SMN | |||||||||||||||
| Any SMN | 0.5 | (0.3–0.9) | 4.4 | (2.8–6.5) | <0.0001 | 0.7 | (0.3–1.4) | 3.1 | (1.6–5.6) | <0.0001 | 0.3 | (0.1–0.7) | 6.0 | (3.2–9.9) | <0.0001 |
| Non-TGCT SMN | 0.5 | (0.3–0.9) | 1.8 | (0.9–3.3) | 0.00030 | 0.7 | (0.3–1.4) | 2.2 | (0.9–4.4) | 0.00070 | 0.3 | (0.1–0.7) | 1.4 | (0.4–3.8) | 0.12 |
| Ototoxicity | |||||||||||||||
| Hearing loss or aid | 3.4 | (2.7–4.2) | 7.1 | (5.0–10.0) | 0.0049 | 2.8 | (2.1–3.8) | 10.6 | (7.1–14.8) | <0.0001 | 4.1 | (3.0–5.5) | 2.8 | (1.2–5.5) | 0.49 |
| Hearing loss | 3.3 | (2.6–4.0) | 6.6 | (4.6–9.2) | 0.0048 | 2.8 | (2.0–3.8) | 9.8 | (6.5–13.9) | <0.0001 | 3.9 | (2.8–5.2) | 2.8 | (1.2–5.5) | 0.56 |
| Hearing aid | 0.2 | (0.1–0.5) | 1.0 | (0.4–2.2) | 0.0021 | 0.1 | (0.0–0.5) | 1.1 | (0.3–3.0) | 0.030 | 0.3 | (0.1–0.9) | 0.9 | (0.3–2.4) | 0.031 |
|
Early effects (follow-up from Index Date 1 to Index Date 2) |
|||||||||||||||
|
5-year cumulative incidence % (5 years from Index Date 1) |
|||||||||||||||
|
Control n = 3740 |
Patient n = 748 |
Control n = 2020 |
Patient n = 404 |
Control n = 1720 |
Patient n = 344 |
||||||||||
| Cardiotoxicity | |||||||||||||||
| Any CVD | 1.2 | (0.9–1.6) | 4.1 | (2.8–5.7) | <0.0001 | 1.0 | (0.6–1.6) | 6.7 | (4.5–9.5) | <0.0001 | 1.4 | (0.9–2.1) | 1.0 | (0.3–2.6) | 0.52 |
| Non-hypertension CVD | 0.5 | (0.3–0.8) | 2.6 | (1.6–4.0) | <0.0001 | 0.4 | (0.2–0.7) | 4.8 | (3.0–7.3) | <0.0001 | 0.6 | (0.3–1.1) | 0.0 | (0.0–0.0) | 0.16 |
| CHF | 0.1 | (0.0–0.2) | 0.8 | (0.3–1.7) | <0.0001 | 0.0 | (0.0–0.3) | 1.5 | (0.6–3.1) | <0.0001 | 0.1 | (0.0–0.4) | 0.0 | (0.0–0.0) | 0.53 |
| Myocardial infarctiona | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| CADa | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Pericardial disease | 0.1 | (0.0–0.3) | 0.3 | (0.1–0.9) | 0.27 | 0.2 | (0.0–0.4) | 0.5 | (0.1–1.7) | 0.16 | 0.1 | (0.0–0.3) | 0.0 | (0.0–0.0) | 0.65 |
| Valvular abnormalitya | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Arrhythmia | 0.3 | (0.1–0.5) | 1.1 | (0.5–2.1) | 0.0016 | 0.2 | (0.1–0.5) | 2.1 | (1.0–3.9) | <0.0001 | 0.4 | (0.2–0.8) | 0.0 | (0.0–0.0) | 0.27 |
| Stroke | 0.0 | (0.0–0.2) | 0.7 | (0.3–1.5) | <0.0001 | 0.0 | (0.0–0.0) | 1.3 | (0.5–2.8) | <0.0001 | 0.1 | (0.0–0.4) | 0.0 | (0.0–0.0) | 0.65 |
| Hypertension | 0.8 | (0.5–1.1) | 1.7 | (0.9–2.9) | 0.014 | 0.7 | (0.4–1.2) | 2.4 | (1.2–4.3) | 0.0023 | 0.8 | (0.5–1.4) | 0.9 | (0.3–2.6) | 0.83 |
| Renal toxicity | |||||||||||||||
| Renal failure (dialysis or kidney transplant)b | 0.1 | (0.0–0.2) | 0.6 | (0.2–1.4) | 0.0010 | 0.1 | (0.0–0.3) | 1.0 | (0.3–2.5) | 0.0010 | – | – | – | – | – |
| Dialysisb | 0.1 | (0.0–0.2) | 0.4 | (0.1–1.2) | 0.0094 | 0.1 | (0.0–0.3) | 0.8 | (0.2–2.1) | 0.0094 | – | – | – | – | – |
| Kidney transplantb | 0.0 | (0.0–0.2) | 0.1 | (0.0–0.7) | 0.21 | 0.1 | (0.0–0.3) | 0.3 | (0.0–1.3) | 0.21 | – | – | – | – | – |
|
Late effects (follow-up from Index Date 2 to end of study) |
|||||||||||||||
|
15-year cumulative incidence % (15 years from Index Date 1) |
|||||||||||||||
|
Control n = 2833 |
Survivor n = 582 |
Control n = 1479 |
Survivor n = 305 |
Control n = 1354 |
Survivor n = 277 |
||||||||||
| Cardiotoxicity | |||||||||||||||
| Any CVD | 4.8 | (3.9–5.9) | 5.1 | (3.2–7.8) | 0.83 | 4.5 | (3.3–6.0) | 8.3 | (4.9–12.8) | 0.036 | 5.2 | (3.8–6.9) | 1.6 | (0.4–4.4) | 0.029 |
| Non-hypertension CVD | 1.1 | (0.7–1.7) | 1.4 | (0.6–2.9) | 0.21 | 1.2 | (0.6–2.0) | 2.2 | (0.8–4.9) | 0.051 | 1.1 | (0.5–2.0) | 0.5 | (0.0–2.6) | 0.56 |
| CHF | 0.2 | (0.1–0.4) | 0.2 | (0.0–1.0) | 0.97 | 0.3 | (0.1–0.7) | 0.4 | (0.0–1.9) | 0.68 | 0.1 | (0.0–0.5) | 0.0 | (0.0–0.0) | 0.52 |
| Myocardial infarctionc | 0.1 | (0.0–0.4) | 0.0 | (0.0–0.0) | 0.87 | 0.2 | (0.0–0.8) | 0.0 | (0.0–0.0) | 0.88 | – | – | – | – | – |
| CADc | 0.1 | (0.0–0.3) | 0.0 | (0.0–0.0) | 0.54 | 0.1 | (0.0–0.6) | 0.0 | (0.0–0.0) | 0.57 | – | – | – | – | – |
| Pericardial disease | 0.4 | (0.2–0.8) | 0.5 | (0.1–1.6) | 0.70 | 0.4 | (0.1–1.1) | 0.9 | (0.2–3.0) | 0.43 | 0.3 | (0.1–1.0) | 0.0 | (0.0–0.0) | 0.51 |
| Valvular abnormalityc | 0.1 | (0.0–0.3) | 0.0 | (0.0–0.0) | 0.44 | 0.2 | (0.0–0.6) | 0.0 | (0.0–0.0) | 0.44 | – | – | – | – | – |
| Arrhythmia | 0.5 | (0.3–0.9) | 0.9 | (0.3–2.3) | 0.15 | 0.3 | (0.1–0.9) | 1.3 | (0.3–3.6) | 0.065 | 0.7 | (0.3–1.5) | 0.5 | (0.0–2.6) | 0.91 |
| Stroke | 0.1 | (0.0–0.3) | 0.0 | (0.0–0.0) | 0.073 | 0.1 | (0.0–0.6) | 0.0 | (0.0–0.0) | 0.013 | 0.0 | (0.0–0.0) | 0.0 | (0.0–0.0) | 0.53 |
| Hypertension | 3.8 | (3.0–4.8) | 3.7 | (2.1–6.1) | 0.70 | 3.6 | (2.6–5.0) | 6.1 | (3.2–10.2) | 0.19 | 4.1 | (2.9–5.6) | 1.1 | (0.2–3.7) | 0.028 |
| Renal toxicity | |||||||||||||||
| Renal failure (dialysis or kidney transplant) | 0.0 | (0.0–0.0) | 0.6 | (0.2–1.7) | 0.0021 | 0.0 | (0.0–0.0) | 0.3 | (0.0–1.8) | 0.027 | 0.0 | (0.0–0.0) | 0.9 | (0.2–3.1) | 0.020 |
| Dialysis | 0.0 | (0.0–0.0) | 0.6 | (0.2–1.7) | 0.0021 | 0.0 | (0.0–0.0) | 0.3 | (0.0–1.8) | 0.027 | 0.0 | (0.0–0.0) | 0.9 | (0.2–3.1) | 0.020 |
| Kidney transplantb | 0.0 | (0.0–0.0) | 0.2 | (0.0–1.1) | 0.028 | 0.0 | (0.0–0.0) | 0.4 | (0.0–2.0) | 0.028 | – | – | – | – | – |
Abbreviations: TGCT = testicular germ cell tumor, SMN = subsequent malignant neoplasm, CVD = cardiovascular disease, CHF = congestive heart failure, CAD = coronary artery disease.
Competing events include death/SMN.
Bolded p-values indicate statistical significance (p < 0.05).
No event in either group.
No event in non-chemotherapy-treated patients/survivors and their controls.
No event in chemotherapy-treated patients/survivors and/or their controls.
Table 3.
Patients' rate of outcomes (using controls as reference).
| All patients/survivors |
Chemotherapy-treated patients/survivors |
Non-chemotherapy-treated patients/survivors |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | (95% CI) | p | HR | (95% CI) | p | HR | (95% CI) | p | |
| (follow-up from Index Date 1 to end of study) |
|||||||||
| Patient n = 748, Control n = 3740 | Patient n = 404, Control n = 2020 | Patient n = 344, Control n = 1720 | |||||||
| SMN | |||||||||
| Any SMN | 7.9 | (4.3–14.6) | <0.0001 | 6.1 | (2.5–14.4) | <0.0001 | 10.4 | (4.4–24.5) | <0.0001 |
| Non-TGCT SMN | 3.7 | (1.8–7.6) | 0.00040 | 4.5 | (1.8–11.4) | 0.0013 | 2.6 | (0.8–8.9) | 0.12 |
| Ototoxicity | |||||||||
| Hearing loss or aid | 1.8a | (1.3–2.6) | 0.0017 | 2.7a | (1.8–4.2) | <0.0001 | 0.8 | (0.4–1.7) | 0.56 |
| Hearing loss | 1.8a | (1.3–2.7) | 0.0018 | 2.7a | (1.7–4.3) | <0.0001 | 0.8 | (0.4–1.8) | 0.63 |
| Hearing aid | 5.3 | (1.7–16.4) | 0.0035 | 5.6 | (1.1–28.1) | 0.035 | 5.0a | (1.0–25.0) | 0.048 |
|
Early effects (follow-up from Index Date 1 to Index Date 2) |
|||||||||
| Patient n = 748, Control n = 3740 | Patient n = 404, Control n = 2020 | Patient n = 344, Control n = 1720 | |||||||
| Cardiotoxicity | |||||||||
| Any CVD | 3.7a | (2.3–5.9) | <0.0001 | 7.3 | (4.1–13.0) | <0.0001 | 0.7 | (0.2–2.3) | 0.53 |
| Non-hypertension CVDc | 5.8 | (3.0–11.1) | <0.0001 | 14.3 | (6.0–34.1) | <0.0001 | – | – | – |
| CHFc | 10.2 | (2.6–40.6) | 0.0010 | 30.7 | (3.7–257.1) | 0.0016 | – | – | – |
| Myocardial infarctionb | – | – | – | – | – | – | – | – | – |
| CADb | – | – | – | – | – | – | – | – | – |
| Pericardial diseasec | 2.5 | (0.5–13.8) | 0.28 | 3.4 | (0.6–20.3) | 0.18 | – | – | – |
| Valvular abnormalityb | – | – | – | – | – | – | – | – | – |
| Arrhythmiac | 4.1 | (1.6–10.5) | 0.0028 | 10.7 | (3.2–35.2) | 0.00010 | – | – | – |
| Strokec,d | 25.5 | (3.0–215.6) | 0.0030 | – | – | – | – | – | – |
| Hypertension | 2.4 | (1.2–4.7) | 0.011 | 3.7 | (1.6–8.3) | 0.0018 | 1.2 | (0.3–4.1) | 0.83 |
| Renal toxicity | |||||||||
| Renal failure (dialysis or kidney transplant)c | 10.1 | (1.8–55.8) | 0.0077 | 10.3 | (1.9–57.1) | 0.0076 | – | – | – |
| Dialysisc | 7.6 | (1.3–45.8) | 0.027 | 7.7 | (1.3–46.8) | 0.027 | – | – | – |
| Kidney transplantc | 5.1 | (0.3–81.8) | 0.25 | 5.3 | (0.3–83.3) | 0.24 | – | – | – |
|
Late effects (follow-up from Index Date 2 to end of study) |
|||||||||
| Survivor n = 582, Control n = 2833 | Survivor n = 305, Control n = 1479 | Survivor n = 277, Control n = 1354 | |||||||
| Cardiotoxicity | |||||||||
| Any CVD | 1.1 | (0.8–1.6) | 0.64 | 1.6 | (1.1–2.4) | 0.020 | 0.5 | (0.2–1.0) | 0.049 |
| Non-hypertension CVD | 1.6 | (0.8–3.0) | 0.16 | 2.1 | (1.0–4.5) | 0.048 | 0.7 | (0.2–2.5) | 0.56 |
| CHFc | 1.0 | (0.1–8.4) | 0.99 | 1.6 | (0.2–15.9) | 0.67 | – | – | – |
| Myocardial infarctionc | 1.3 | (0.1–12.0) | 0.83 | 1.2 | (0.1–11.5) | 0.85 | – | – | – |
| CADc | 1.8 | (0.3–9.1) | 0.50 | 1.7 | (0.3–8.7) | 0.53 | – | – | – |
| Pericardial diseasec | 1.4 | (0.4–5.7) | 0.62 | 2.0 | (0.5–8.0) | 0.34 | – | – | – |
| Valvular abnormalityb | – | – | – | – | – | – | – | – | – |
| Arrhythmia | 2.0 | (0.8–4.6) | 0.12 | 2.8 | (0.9–8.5) | 0.071 | 1.1 | (0.3–4.6) | 0.86 |
| Strokec | 3.8 | (0.8–17.2) | 0.081 | 7.4 | (1.2–44.6) | 0.030 | – | – | – |
| Hypertension | 1.0 | (0.6–1.5) | 0.88 | 1.4 | (0.9–2.3) | 0.13 | 0.4 | (0.2–1.0) | 0.049 |
| Renal toxicity | |||||||||
| Renal failure (dialysis or kidney transplant)d | 15.0 | (1.6–140.0) | 0.018 | – | – | – | 10.5 | (1.1–103.8) | 0.044 |
| Dialysisd | 15.0 | (1.6–140.0) | 0.018 | – | – | – | 10.5 | (1.1–103.8) | 0.044 |
| Kidney transplantb | – | – | – | – | – | – | – | – | – |
Abbreviations: TGCT = testicular germ cell tumor, SMN = subsequent malignant neoplasm, HR = cause-specific hazard ratio, CVD = cardiovascular disease, CHF = congestive heart failure, CAD = coronary artery disease.
Competing events include death/SMN.
Bolded p-values indicate statistical significance (p < 0.05).
Indicates violations of the PH assumption. Average HRs are reported.
No event in one or both groups (all patients/survivors or all controls).
No event in non-chemotherapy-treated patients/survivors and/or their controls.
No event in chemotherapy-treated patients/survivors and/or their controls.
Table 4.
Comparison of the cumulative incidence of outcomes between chemotherapy and non-chemotherapy treated patients.
| Non-chemotherapy treated patients | Chemotherapy-treated patients | p | |||
|---|---|---|---|---|---|
| (follow-up from Index Date 1 to end of study) |
|||||
|
15-year cumulative incidence (95% CI) % (15 years from Index Date 1) |
|||||
| n = 344 | n = 404 | ||||
| SMN | |||||
| Any SMN | 6.0 | (3.2–10.0) | 3.1 | (1.6–5.6) | 0.16 |
| Non-TGCT SMN | 1.4 | (0.4–3.8) | 2.2 | (0.9–4.4) | 0.33 |
| Second primary TGCT | 4.6 | (2.2–8.2) | 0.9 | (0.3–2.6) | 0.0049 |
| Ototoxicity | |||||
| Hearing loss or aid | 2.8 | (1.2–5.5) | 10.6 | (7.1–14.8) | 0.0020 |
| Hearing loss | 2.8 | (1.2–5.5) | 9.8 | (6.5–13.9) | 0.0031 |
| Hearing aid | 0.9 | (0.3–2.4) | 1.1 | (0.3–3.0) | 0.82 |
|
Early effects (follow-up from Index Date 1 to Index Date 2) |
|||||
|
5-year cumulative incidence (95% CI) % (5 years from Index Date 1) |
|||||
| n = 344 | n = 404 | ||||
| Cardiotoxicity | |||||
| Any CVD | 1.0 | (0.3–2.6) | 6.7 | (4.5–9.5) | <0.0001 |
| Non-hypertension CVD | 0.0 | (0.0–0.0) | 4.8 | (3.0–7.3) | <0.0001 |
| CHF | 0.0 | (0.0–0.0) | 1.5 | (0.6–3.1) | 0.023 |
| Myocardial infarctiona | – | – | – | – | – |
| CADa | – | – | – | – | – |
| Pericardial disease | 0.0 | (0.0–0.0) | 0.5 | (0.1–1.7) | 0.19 |
| Valvular abnormalitya | – | – | – | – | – |
| Arrhythmia | 0.0 | (0.0–0.0) | 2.1 | (1.0–3.9) | 0.0087 |
| Stroke | 0.0 | (0.0–0.0) | 1.3 | (0.5–2.8) | 0.038 |
| Hypertension | 0.9 | (0.3–2.6) | 2.4 | (1.2–4.3) | 0.14 |
| Renal toxicity | |||||
| Renal failure (dialysis or kidney transplant) | 0.0 | (0.0–0.0) | 1.0 | (0.3–2.5) | 0.064 |
| Dialysis | 0.0 | (0.0–0.0) | 0.8 | (0.2–2.1) | 0.11 |
| Kidney transplant | 0.0 | (0.0–0.0) | 0.3 | (0.0–1.3) | 0.36 |
|
Late effects (follow-up from Index Date 2 to end of study) |
|||||
|
15-year cumulative incidence (95% CI) % (15 years from Index Date 1) |
|||||
| n = 277 | n = 305 | ||||
| Cardiotoxicity | |||||
| Any CVD | 1.6 | (0.4–4.4) | 8.3 | (4.9–12.8) | 0.00080 |
| Non-hypertension CVD | 0.5 | (0.0–2.6) | 2.2 | (0.8–4.9) | 0.042 |
| CHF | 0.0 | (0.0–0.0) | 0.4 | (0.0–1.9) | 0.34 |
| Myocardial infarctionb | 0.0 | (0.0–0.0) | 0.0 | (0.0–0.0) | 0.40 |
| CADb | 0.0 | (0.0–0.0) | 0.0 | (0.0–0.0) | 0.23 |
| Pericardial disease | 0.0 | (0.0–0.0) | 0.9 | (0.2–3.0) | 0.18 |
| Valvular abnormalitya | – | – | – | – | – |
| Arrhythmia | 0.5 | (0.0–2.6) | 1.3 | (0.3–3.6) | 0.37 |
| Strokeb | 0.0 | (0.0–0.0) | 0.0 | (0.0–0.0) | 0.14 |
| Hypertension | 1.1 | (0.2–3.7) | 6.1 | (3.2–10.2) | 0.0038 |
| Renal toxicity | |||||
| Renal failure (dialysis or kidney transplant) | 0.9 | (0.2–3.1) | 0.3 | (0.0–1.8) | 0.51 |
| Dialysis | 0.9 | (0.2–3.1) | 0.3 | (0.0–1.8) | 0.51 |
| Kidney transplant | 0.0 | (0.0–0.0) | 0.4 | (0.0–2.0) | 0.34 |
Abbreviations: TGCT = testicular germ cell tumor, SMN = subsequent malignant neoplasm, CVD = cardiovascular disease, CHF = congestive heart failure, CAD = coronary artery disease.
Competing events include death/SMN.
Bolded p-values indicate statistical significance (p < 0.05).
No event in either group.
Chemotherapy treated survivors had events over 19 years from Index Date 1.
Ototoxicity
Compared to controls, chemotherapy-treated patients had higher 15-year cumulative incidences of hearing loss (9.8% vs. 2.8%, p < 0.0001) and hearing aid use (1.1% vs. 0.1%, p = 0.030; Tables 2 and 3). Non-chemotherapy-treated patients had a higher cumulative incidence of hearing aid use compared to controls (0.9% vs. 0.3%, p = 0.031) but a lower cumulative incidence of hearing loss compared to chemotherapy-treated patients (2.8% vs. 9.8%, p = 0.0031; Table 4). Both cumulative cisplatin dose and HSCT were significantly associated with a higher rate of hearing loss or hearing aid use in the univariate model. However, only HSCT was significantly associated with a higher rate of hearing loss or hearing aid use in the multivariable model (HR = 6.8, 95% CI: 2.0–22.8; Supplement 12).
Renal toxicity
Compared to controls, chemotherapy-treated patients had higher cumulative incidences of early (five-year incidence = 0.8% vs. 0.1%, p = 0.0094) and late (15-year incidence) dialysis (0.3% vs. 0.0% p = 0.027) and late kidney transplant (0.4% vs. 0.0%, p = 0.028), whereas non-chemotherapy-treated patients only had a higher incidence of late dialysis (0.9% vs. 0.0%, p = 0.020; Table 2). Chemotherapy- and non-chemotherapy-treated patients did not statistically differ in the cumulative incidence of any renal outcome (Table 4).
Cardiotoxicity
Compared to controls, all patients had higher cumulative incidences and rates of these early CVD outcomes: any CVD, non-hypertension CVD, CHF, arrhythmia, stroke, and hypertension (Tables 2 and 3). All patients and controls did not statistically differ in the cumulative incidences of late CVD outcomes.
Compared to controls, chemotherapy-treated patients had significantly higher cumulative incidences of these early (five-year incidence) CVD outcomes: any CVD (6.7% vs. 1.0%, p < 0.0001), non-hypertension CVD (4.8% vs. 0.4%, p < 0.0001), CHF (1.5% vs. 0.0%, p < 0.0001), arrhythmia (2.1% vs. 0.2%, p < 0.0001), and hypertension (2.4% vs. 0.7%, p = 0.0023), in addition to any late (15-year incidence) CVD (8.3% vs. 4.5%, p = 0.036; Tables 2 and 3). In contrast, non-chemotherapy-treated patients had similar cumulative incidences to controls for early CVD, but a lower incidence of any late CVD (1.6% vs. 5.2%, p = 0.029), particularly late hypertension (1.1% vs. 4.1%, p = 0.028).
Compared to non-chemotherapy-treated patients, chemotherapy-treated patients had higher cumulative incidences of these early CVD outcomes (Table 4): any CVD (6.7% vs. 1.0%, p < 0.0001), non-hypertension CVD (4.8% vs. 0.0%, p < 0.0001), CHF (1.5% vs. 0.0%, p = 0.023), arrhythmia (2.1% vs. 0.0%, p = 0.0087), and stroke (1.3% vs. 0.0%, p = 0.038), in addition to these late CVD outcomes: any CVD (8.3% vs. 1.6%, p = 0.00080), non-hypertension CVD (2.2% vs. 0.5%, p = 0.042), and hypertension (6.1% vs. 1.1%, p = 0.0038). No sociodemographic or treatment factors were significantly associated with the rates of any late CVD or late non-hypertension CVD among survivors in univariate models (Supplement 11). Therefore, multivariable models were not estimated.
Discussion
In this study, the largest population-level assessment of physical morbidities in CAYA with TGCT thus far, we found that CAYA, particularly those treated with chemotherapy, have a considerably higher risk of SMN, ototoxicity, and renal toxicity compared to the general population. While we did not observe an elevated risk for late cardiotoxicity in all patients, they had an elevated risk for early CVD.
CAYA with TGCT had a 3.7-fold increased risk for non-TGCT SMN compared to the general population, a higher estimate than the 1.3–2.0-fold elevated risk reported in previous adult studies.5,6 Since we compared patients' SMN risk to age-matched controls from the general population, and cancer incidence increases with age,19 a higher SMN risk in CAYA might be related to a lower cancer incidence in our control group, which is younger than those in previous adult studies. While we cannot report the types of SMNs in our cohort due to privacy regulations that prevent the disclosure of rare outcomes, <six of the 13 non-TGCT SMNs were hematological malignancies.
Similar to previous studies,5,8 the majority of SMNs were second primary TGCTs, accounting for over 50% of all SMNs. Our observation of lower second TGCT incidence in chemotherapy-treated patients compared to non-chemotherapy-treated patients is also consistent with previous reports of a lower incidence with increasing chemotherapy dose (HR = 0.7).17,18 This is likely related to the impact of chemotherapy on germ cell neoplasia in situ, a TGCT precursor,20,21 and highlights the potential benefit of surveillance for earlier detection of second TGCT in non-chemotherapy-treated patients.
To our knowledge, hearing outcomes post-TGCT have not been compared to age-matched controls from the general population. We observed a higher incidence of hearing loss/aid use in patients than controls, particularly in chemotherapy-treated patients (HR = 2.7). Our observation of 10.6% 15-year cumulative incidence of hearing loss/aid in chemotherapy-treated patients is lower than expected, as chemotherapy exposure has been linked to prevalences of up to 39% subjective hearing loss11,22 and up to 80% objective hearing loss with varying levels of severity.10,23,24 Our low estimates are likely related to ototoxicity assessment method. Previous studies used patient-reported outcomes or audiometry to assess subjective and objective hearing loss, respectively. Use of health services records likely restricted our findings to clinically significant hearing loss requiring medical care. Additionally, previous studies assessed hearing loss in an older patient group (median age = 37–43 years10,11,22). In contrast, CAYA in our study were relatively young at the end of follow up (median age = 29.7 years). Since older age at hearing assessment is a risk factor for both subjective and objective hearing loss,22,25 the incidence of hearing loss in our cohort is expected to increase as survivors age. Our observation of higher risk of hearing aid use in non-chemotherapy-treated patients compared to controls is inconsistent with previous findings but given the small sample size (<six used hearing aids), this finding should be interpreted with caution.
While there was no statistically significant association between overall cisplatin dose and hearing loss/aid use after adjusting for HSCT, >400 mg/m2 was associated with higher rates of hearing loss/aid in multivariable analysis (HR = 3.8, 95% CI: 1.3–11.0). Others have reported significant associations between cisplatin dose (e.g., >300 mg/m2) and hearing loss.10,24,25 Loss of statistical significance for overall cisplatin dose after adjusting for HSCT should be interpreted carefully, as it might be related to outcome rarity, small sample size, or dose-intensive platinum used for HSCT conditioning. A previous study demonstrated that dose-intensive cisplatin, regardless of the number of chemotherapy cycles, was associated with a significantly higher risk for hearing loss than standard doses: 35% vs. 18% subjective and 69% vs. 28% objective hearing loss.22 We could not assess tinnitus using health services records. Based on previous estimates, up to 40% of survivors experience tinnitus,10,11,24 and it is reported more often by chemotherapy-treated patients.22
Compared to the general population, patients/survivors had higher incidences of late kidney transplant, and early and late dialysis, particularly those exposed to chemotherapy. However, all outcomes were rare (<1% of patients and controls). We could not assess other renal outcomes due to limitations in health services data. Previous studies demonstrated that TGCT patients are at risk for other renal toxicities, including stages II and III CKD.9,26 More cycles of chemotherapy increase patients' risk for CKD9 and for irreversible decline in renal function: ≥five cycles of cisplatin-based chemotherapy has been linked to a 20% reduction in GFR at five years post-treatment.26
The incidence of early CVD, including CHF, arrhythmia, stroke, and hypertension, was higher in chemotherapy-treated patients than controls. Our observation of similar early CVD incidence between non-chemotherapy-treated patients and their controls supports chemotherapy's role in inducing early cardiotoxicities. Chemotherapy has been linked to reduced left ventricular diastolic and stroke volumes27 and increased plasma von Willebrand factor levels and carotid artery thickness at 10 weeks post-chemotherapy.28 In another study, chemotherapy-treated survivors were at significant risk of CVD and cardiac death within one year of treatment.29 In our study, all late CVD subtypes, except for stroke, were similar in incidence between chemotherapy-treated survivors and controls. Unexpectedly, non-chemotherapy-treated survivors had a lower incidence of late hypertension than controls. Hypertension risk might be impacted by behavioral modifications after TGCT diagnosis. A recent Danish study demonstrated that while TGCT patients were more likely than the general population to be current smokers and have body mass index >25 kg/m2, patients reported more active lifestyles and less alcohol consumption.30
Our study has several strengths, including the population-level assessment of physical morbidities using real-world evidence, which makes our findings more generalizable than single-institution studies. We included all CAYA with TGCT in Ontario, which minimized sample selection bias. Furthermore, we used health services records, which reflect health services utilization and are not impacted by self-reporting bias. While health administrative data cannot reliably capture all TGCT-related toxicities, using this data allowed us to capture outcomes occurring in the entire population. However, outcome rarity and a small sample size might have lowered our statistical power, particularly in assessing the association between chemotherapy dose and outcome rates. Due to privacy regulations at ICES, we could not disclose the type of non-TGCT SMN, as each type occurred in frequency <six. Additionally, patients in our cohort were relatively young at the end of follow-up (median age = 29.7 years); they might continue to develop physical morbidities as they age. Finally, we lacked information on modifiable risk factors, such as smoking and physical activity level, which might impact toxicity risk.
In conclusion, we show that CAYA with TGCT treated with chemotherapy are at risk for non-TGCT SMN, hearing loss, renal failure, and early CVD, whereas non-chemotherapy-treated patients are at risk for developing second primary TGCT. As such, young survivors should receive risk-adapted follow-up care for early management of toxicities. Future research should continue following CAYA with TGCT, particularly chemotherapy-treated individuals, to characterize their long-term health.
Contributors
Rand Ajaj: Conceptualization; formal analysis; methodology; project administration; supervision; visualization; writing – review and editing; writing – original draft. Cindy Lau: Formal analysis; writing – review and editing. Sumit Gupta: Conceptualization; data curation; writing – review and editing. Nancy N. Baxter: Conceptualization; data curation; writing – review and editing. Jason D. Pole: Data curation; writing – review and editing. Furqan Shaikh: Conceptualization; writing – review and editing. Paul C. Nathan: Conceptualization; data curation; funding acquisition; methodology; project administration; supervision; writing – review and editing.
Rand Ajaj and Cindy Lau had access to and verified the underlying data. All authors read and approved the final version of the manuscript.
Data sharing statement
Project data are prohibited from being publicly available due to legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government).
Declaration of interests
The authors declare no conflict of interest.
Acknowledgements
This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care. Parts of this material are based on data and/or information compiled and provided by: MOH, Canadian Institute for Health Information, Ontario Health, Statistics Canada, and Ontario Registrar General (ORG). Adapted from Statistics Canada, CENSUS. This does not constitute an endorsement by Statistics Canada of this product. This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. Parts of this report are based on ORG information on deaths, the original source of which is Service Ontario. The views expressed therein are those of the author and do not necessarily reflect those of ORG or the Ministry of Public and Business Service Delivery. This research was facilitated by the Pediatric Oncology Group of Ontario's Networked Information System, financially supported by Ontario's Ministry of Health and Long-Term Care. This study received funding from two Canadian Institutes of Health Research Foundation Grants, awarded to PN and NB. Furthermore, RA was supported by the Ontario Graduate Scholarship through the University of Toronto and the Research Training Competition (RESTRACOMP) award through The Hospital for Sick Children. The analyses, conclusions, opinions, and statements expressed in this study are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Results from this study were partially presented at the American Society of Clinical Oncology Annual Meeting (Chicago, Illinois, USA, June 2023) and at the International Symposium on Late Complications After Childhood Cancer (Atlanta, Georgia, USA, June 2023). Some of the results were included in a Master of Science student thesis, titled “Evaluating the long-term morbidity of children, adolescents, and young adults with testicular germ cell tumours” at the University of Toronto's Institute of Medical Science (http://hdl.handle.net/1807/141299). The authors thank Ms. Emily Lam for her medical editing expertise, which enhanced the clarity and overall quality of this manuscript.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2025.103447.
Appendix A. Supplementary data
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