Cardiovascular events and survival of male patients with germline cell tumors

Abstract

Introduction and aim

Testicular germline tumors affect young male patients. Although they have high survival rates, they also have a higher risk of developing cardiovascular disease (CVD) compared to the general population. In this study we aim to evaluate the cardiovascular events and survival rates of a cohort of testicular cancer patients.

Methods

We included 274 consecutive testicular cancer patients treated at a university hospital, with an active cardio-oncology program – cardiovascular (CV) risk factors and CV events were evaluated. Survival rates were compared with its reference general population matched for age, sex, and region, using the Ederer II method.

Results

The prevalence of CV risk factors like high blood pressure and smoking, and CV events (acute myocardial infarction, pulmonary thromboembolism and exertional angina) were higher in testicular cancer patients. The survival analysis revealed that, in the first few years after diagnosis, there was a slight increase in mortality compared to their reference general population. However, from 7 years onwards, the survival of testicular cancer papers did not show any differences compared to its general reference population, according to age, sex, and geographical area.

Conclusion

Testicular germline cancer patients represent a young high-risk population, with CV risk factors and CV events. However, it carefully followed, long-term prognosis in terms of survival can be the same of a person who did not suffer this cancer. Therefore, it is important to strengthen cardio-oncology prevention strategies in this young population.

Resumen

Introducción y objetivo

Los tumores testiculares de células germinales afectan a pacientes varones jóvenes. Aunque tienen altas tasas de supervivencia, también presentan un mayor riesgo de desarrollar enfermedades cardiovasculares (CV) en comparación con la población general. En este estudio, nuestro objetivo es evaluar los episodios CV y las tasas de supervivencia en una cohorte de pacientes con cáncer testicular.

Métodos

Se incluyeron 274 pacientes consecutivos con cáncer testicular tratados en un hospital universitario con un programa activo de cardiooncología. Se evaluaron los factores de riesgo CV y los episodios CV. Las tasas de supervivencia se compararon con la población general de referencia, emparejada por edad, sexo y región, utilizando el método de Ederer II.

Resultados

La prevalencia de factores de riesgo CV, como hipertensión arterial y tabaquismo, y de episodios CV (infarto agudo de miocardio, tromboembolismo pulmonar, accidente cerebrovascular), fue mayor en los pacientes con cáncer testicular. El análisis de supervivencia reveló que, en los primeros años tras el diagnóstico, hubo un mínimo aumento de mortalidad en comparación con su población general de referencia. Sin embargo, a partir de los 7 años, la supervivencia de los pacientes con cáncer testicular se igualó a la de su población general de referencia, ajustada por edad, sexo y área geográfica.

Conclusión

Los pacientes con tumores testiculares germinales representan una población joven de alto riesgo CV, con factores de riesgo y episodios CV. No obstante, si se realiza un seguimiento cuidadoso, el pronóstico a largo plazo en términos de supervivencia puede ser equivalente al de una persona que no presentó este cáncer. Por lo tanto, es importante fortalecer las estrategias de prevención cardiooncológicas en esta población joven.

Introduction

Testicular cancer refers to cancers originating specifically in the testicles, and germ cell tumors (GCTs) account for up to 98% of all malignant tumors of the testis.¹ GCTs, which constitute approximately 1–2% of all malignant tumors, are more common in young patients, with an annual incidence of 4–5 cases per 100,000 population.² The two main types of testicular GCTs are divided into two large categories: seminomas and non-seminomas, with non-seminomas being even more prevalent in the young population.³ Although the five-year survival rate has improved significantly, reaching up to 95% in some types of GCTs, cancer survivors have a higher risk of developing cardiovascular (CV) disease compared to the general population.^3,4

Different treatment modalities are used in treatment, including surgery, radiotherapy and chemotherapy, including cisplatin. However, they can all be associated with significant morbidity and mortality in the survivorship setting, including cardiotoxicity.⁵ Chemotherapy, in particular, can induce cardiovascular damage through various mechanisms, such as oxidative stress, inflammation, and direct damage to heart cells, which can result in ventricular dysfunction and the development of heart failure.^6,7 Among the most common cardiovascular effects are heart failure, hypertension and coronary artery disease. As a result, young patients with GCTs have an increased cardiovascular risk, which can be up to three times higher compared to the general population.^8,9

This increase in cardiovascular morbidity has been linked to both the effects of chemotherapy and pre-existing risk factors, highlighting the importance of close follow-up and a comprehensive approach to the care of these patients.^10,11 In addition, cancer survivors have been shown to have an increased risk of developing peripheral artery disease, which can further complicate the assessment and management of their cardiovascular health.¹²

In this regard, cardio-oncology preventive strategies become of utmost importance. Since the very first publication of the Cardio-oncology guidelines,¹³ this new discipline has been revolutionary. There are specific recommendations based on the type of treatment and individual CV risk, which allow for the establishment of individualized short-, medium-, and long-term follow-up plans.¹⁴ In fact, these cardio-oncology evaluations can represent an opportunistic screening for not only classical CV risk factors, but also to detect CV concealed inherited conditions.^15,16

It is important to identify individual susceptibilities or risk factors before they have clinical manifestations in order to establish a personalized medicine plan.¹⁷ In addition, monitoring these CV factors in GT patients may contribute to improve their long-term quality of life and overall survival of patients.¹⁸ In this scenario, we aim to evaluate the CV profile and survival rates of a cohort of young patients treated for GCTs.

Our main objective is to compare survival rates with those of the reference general population. The secondary objective is to evaluate the rates of cardiovascular risk factors and cardiovascular events and compare them with the general population rates.

Materials and methods

Study population

This is a retrospective observational study. All consecutive patients treated for GCTs from to 1998 to 2024 were included. Those patients without available clinical records to review were excluded for analysis. Patients were recruited through the Oncology clinic of a university hospital, in northern Spain, with an active cardio-oncology program since 2020. This clinic is the reference center for GCTs treatment of all the region with a total population of approximately 1 million inhabitants. Oncologist of this center have always had a special interest regarding opportunistic control of classical CV risk factors of GCTs patients at every visit, including lifestyle intervention advise (smoking cessation, physical activity, weigh control, etc.).

Informed consent was waived because of the retrospective nature of the study and the analysis used anonymous clinical data. The institutional Ethical Committee evaluated and approved this study (CEImPA 2023.264).

Clinical information

Clinical data of patients was obtained from their digitalized medical records. We recorded date from: demographic characteristics, laboratory parameters (including cholesterol and HbA1c levels), and prevalence of CV risk factors: smoking, drug consumption, hypertension, diabetes, dyslipidemia and obesity. Moreover, we reviewed their evolution and treatment modification. In addition, specific CV tests available if performed, such as electrocardiogram (ECG), cardiac imaging test like transthoracic echocardiogram (TTE), ischemia detection tests or coronary angiograms were reviewed. CV events or death were also recorded.

Statistical analysis

Quantitative and categorical variables were described as mean ± standard deviation (SD) and n (%), respectively. A Chi-square test (χ²) was performed to compare the prevalence of cardiovascular events among the population studied and the prevalence values reported in the general population, and the Student's T-test (T-test) was performed to compare cholesterol values in the first analytical control with the cholesterol value of the last blood test.

To compare survival of patients who suffered GCT with its general reference population of the same sex, age, and territory. This is considered an optimal control cohort, because they share the same medical care system, environmental factors, etc. We calculated the following estimations: 1. Observed survival: is the real survival of the patients of our sample, 2. Expected survival: is considered the estimated life expectancy of a person from our region matched for the same characteristics (age and sex) of our GCTs patient. In other words, the theoretical survival of the patients if they had not suffered the germinal tumor. Its calculation was performed using the Ederer II method, which is the method of choice for the matching.¹⁹ This method uses the mortality rates for different intervals of age, sex, and region provided by the INE.²⁰ If the expected survival is included in the 95% confidence interval of the observed survival, no differences were considered to exist and 3. Accumulate excess of mortality: the difference between observed survival and expected survival. The “strs” command of STATA® v.15.1 (College Station, TX, USA) was used.²¹

In order to further study the influence of type of tumor and age on late survival, a Cox regression analysis was performed. A p value <0.05 was considered statistically significant. All analyses were performed with STATA® v.15.1 (STATA Corp, TX, USA).

STROBE Statement – Checklist of items for cohort studies can be consulted in Supplementary Table 1.

Results

A total of 274 patients with GCTs were included in this study (Fig. 1). This cohort represent a young population, with a mean age at diagnosis of 34.85 ± 9.34 years. Up to 43% of patients were or had been smokers and most patients were either overweight (38.50%) or obese (26.29%) (Table 1). The prevalence of smokers and patients with hypertension was higher when compared to the prevalence in general population (Table 2).

Fig. 1.

Flowchart of testicular cancer patients included in this study.

Table 1.

Baseline sample characteristics.

Basal characteristics	n = 274
Age (years)	34.85 ± 9.34
BMI	27.13 ± 4.58
Waist circumference (cm)	98.01 ± 13.09
CV risk factors
Smoking habit	118 (43.07%)
Dyslipidemia	65 (23.90%)
Hypertension	30 (10.95%)
Diabetes mellitus	15 (5.47%)
Overweight/obese	38.5%/26.29%

BMI: body mass index; CV: cardiovascular.

Table 2.

Differences in prevalence of cardiovascular risk factors between the sample and the general population.

Risk factor	Prevalence in germinal cell tumor patients (%)	CI prevalence in GCT	Prevalence in general population (%)	Observed number	Expected number	p-Value
Smoking habit	43.07%	37.2–48.9%	30%	118	82.20	<0.001*
Dyslipidemia	23.90%	18.8–29.0%	20%	65	54.80	0.108
Hypertension	10.95%	7.3–14.6%	25%	30	68.50	<0.001*
Diabetes mellitus	5.47%	2.8–8.2%	7%	15	19.18	0.323

*

p value <0.05 was considered statistically significant.

Although most patients had no personal nor family history of CV disease, 4 patients (1.4%) did have a history of ischemic heart disease and other 4 of heart failure, and 9 of them presented family history of CV disease (3.28%). Only 3 patients (1.1%) presented prior atrial fibrillation. During oncological treatment, in up to 6.5% of patients, CV treatment to address detected CV risk factors (mostly dyslipidemia and hypertension) was stated. Smoking cessation advice and recommendations for lifestyle improvements, including diet and exercise, was given in all GCTs patients.

CV-events during follow-up

The mean time of follow-up since GCT diagnosis was 13.85 years (±15.65). During this period, we observed a higher incidence of acute myocardial infarction (AMI), acute pulmonary thromboembolism (APE) and deep vein thrombosis (DVT) in GCT's patients when compared to the general population (Table 3) (Fig. 2A and B).

Table 3.

Differences in prevalence of cardiovascular events between the sample and the general population.

Cardiovascular event	Prevalence in sample	CI prevalence sample	Prevalence in general population (33–34 y.)	z-Score	p-Value
Myocardial infarction	1.82% (5/274)	0.76–4.3%	0.2%	6.02	<0.001*
Cerebrovascular accident	1.46% (4/274)	0.55–3.8%	0.1%	7.13	<0.001*
Deep vein thrombosis	0.73% (2/274)	0.18–2.9%	0.1%	3.30	0.001*

*

p value <0.05 was considered statistically significant.

We analyze the rate of CV events between 2 groups – patients aged 35 years or younger and those older than 35 years at diagnosis – the rate of cardiovascular events was higher in the older group (Fig. 3, HR: 7.00, 95% CI: 1.96–24.88).

Fig. 3.

Comparison of cardiovascular events occurrence in patients with testicular GCT, depending on age.

Survival analysis

The overall mortality rate was low 4.38% (12 patients). Most of them died due to oncological causes (91.67%) and none of them from CV ones.

Long term survival rate analysis compared with its general reference population matched for age, sex, and region (Table 4). It showed that there was a slightly higher mortality in the first 7 years. However, from 7 years onwards, the survival of our sample did not show differences compared to the general population, according to age, sex, and geographical area (Fig. 2C and D).

Table 4.

Survival comparison with its reference geographical population matched by gender and age.

Follow-up	Observed survival in germinal tumors patients	Expected survival	Accumulated excess mortality
1st year	98.90% (95% CI 96.77–99.79%)	99.86%	0.96% (95% CI 0.21–3.23%)
5th year	97.40% (95% CI 95.61–99.79%)	99.78%	1.80% (95% CI 0.43–4.60%)
10th year	95.58% (95% CI 93.87–99.89%)	99.73%	1.18% (95% CI −0.42–4.33%)
20th year	94.89% (95% CI 95.99–102.82%)	99.55%	0.08% (95% CI −2.35–4.45%)

Fig. 2.

(A) Cardiovascular risk factors and events in the distribution of the; (B) cardiovascular risk factors and events in the control cohort. (C) 95% confidence interval of the Kaplan–Meier observed survival (blue line) compared with the expected survival (green line) of the sample. (D) Graphical representation of the accumulated excess mortality (red circles) and its 95% confidence interval (blue squares) compared with expected survival. DL: dyslipidemia; HBP: high blood pressure; DM: diabetes mellitus; AMI: acute myocardial infarction; DVT: deep vein thrombosis; CI: confidence interval.

Discussion

In this cohort of patients with GCT, once the first period of oncological-related complications has passed, they recover the expected survival rates of their control population. The strength of this study relies on the comparison with the control cohort that enables to match patients form the same region with the same age and gender, sharing the same environment characteristics, including the same healthcare system with universal access to insurance.²² For patients with testicular cancer, disparities based on insurance status have been reported.²³ In fact, prior studies have demonstrated that insurance status can be related with worse survival.^24,25 Moreover, drastic geographical disparities have also been noted, even within Europe.²⁵ In European Nordic countries, are known to have the highest incidence rates, while Eastern European countries have been reported to have the highest mortality rates.²⁶

Male patients affected by GCT are characteristically younger compared to other types of cancer. Although they are considered rare tumours, incidence has also increased over time²⁷ and it is expected to reach 28% by 2025.⁶ Fortunately, excellent 5-year survival rates are reported.²⁸ However, long term survivals patients may face a number of long-term related complications. Incidence of adverse health outcomes is increased with increasing the cycles of chemotherapy mainly Platinum based regimens. Most commonly reported conditions include second malignant neoplasms, CV disease, persistent peripheral neuropathy, hypogonadism, chronic pulmonary disease, ototoxicity, nephrotoxicity and psychiatric disorders.²⁹

In our cohort, and in consistency with the literature, patients with GCT have a higher prevalence of both CV risk factors and CV events compared to the general population, enhancing their high-risk CV profile. A recent study with a median follow-up of 16 years reported a rate of CV complications over 5%.²⁸ Moreover, they identified testicular cancer patients who were smokers, obese, had dyslipidemia or a positive family history had an even higher CVD risk.²⁸ Therefore, CV assessment becomes a major concern. An extra effort to assess CV risk factors and stablish preventive strategies both in primary and secondary prevention is of utmost importance.

In 2016, a registry analysis of survival in testicular cancer patients compared to the general population²⁹ showed a dramatic improvement in prognosis and survival after the advent of cisplatin-based chemotherapy in 1976. However, the survival began to fall after 20–30 years of diagnosis.²⁹ Another interesting study focused on evaluating the causes of excess mortality.³⁰ They found that testicular cancer itself remained the major cause of death in the first 5 years.³⁰ However, after 5 years of diagnosis, non-testicular second malignancies were identified as the most common cause of death, being CV events the second most common.²⁹

Accordantly, in our cohort, cancer-related complications remained the major cause of death in the first 7 years after treatment, when the survival rates were slightly lower that the general control population. However, in contrast to other series,²⁹ after these first years, the mortality rates level out to the expected in the general population. What it is more, although not statistically significant, the long term (20–25 years) survival rates (Fig. 2C and D) of our GCT patient cohort seem to be even better than the general population. In this regard, a Danish study including about 5000 testicular cancer patients reported a high risk of AMI, CVA and venous thromboembolism during first year of chemotherapy with platin regimen.³⁰ However, interestingly, in patients followed in a surveillance program, CV risk factors, CV disease, and CV death data were comparable to that of the normal population.³⁰ These encouraging findings should inspire the establishment of strong cardio-oncology surveillance programs, focused on providing personalized care for both the treatment and prevention of CV diseases in GCT patients.

Limitations

The main limitation of this study is that this is a single-center study with a relatively small sample size, which might not be applicable to other populations or centers.

Conclusion

Patients with testicular GCT represent a high-risk young population, with higher prevalence of CV risk factors and CV events than the general population. However, once overpassed the first 7 years associated with oncological problems, the survival rates in our cohort reaches that in the general population. Therefore, to reduce long-term CV morbidity and mortality, an optimal CV assessment is essential.

What is known?

• -

  Testicular germline tumors are considered rare tumours, but its incidence is increasing over time. They affect young male patients and have overall excellent survival rates. However, those patients do have a high CV risk profile that may impact their long-term survival.

What is new

• -

  Testicular cancer patients do present a high CV risk profile with a higher incidence of CV events than their general control population. However, in our cohort, once the first years of oncological related problems are overcome, they achieve the life expectancy expected for their reference population, form the same age, gender and geographical region. These encouraging findings should inspire the establishment of strong cardio-oncology surveillance programs to address the CV risk of these patients.

CRediT authorship contribution statement

Design and writing of the original draft: Rebeca Lorca, Rut Álvarez-Velasco, Maria Fernandez, and Carlos Álvarez.

Conceptualization and final approval: Rebeca Lorca, Emilio Esteban, Pablo Avanzas and Carlos Álvarez.

Image preparation: Rut Álvarez Velasco, Marcel Almendárez and Rebeca Lorca.

Interpretation of the data: Rebeca Lorca, María Fernández and Rut Álvarez-Velasco.

Critical revision: Alfonso Revuelta, Sena Valcárcel, Emilio Esteban and Pablo Avanzas.

Data recollection: Maria Fernández, Luis Gutiérrez, Daniel Morena, Reyes López-Triviño, Alfonso Revuelta, Sena Valcárcel and Marcel Almendárez.

Interviewing the patients: Alfonso Revuelta and Sena Valcárcel.

Ethical approval

The institutional Ethical Committee evaluated and approved this study (CEImPA 2023.264).

Funding

This research was funded by Instituto de Salud Carlos III (ISCIII) (grant number PI22/00705).

Conflicts of interest

Pablo Avanzas is an associate editor of Revista Española de Cardiología. The rest of the authors have no conflicts of interest to declare.