. 2024 Nov 12;15:646. doi: 10.1007/s12672-024-01549-1

Late side effects of testicular cancer and treatment: a comprehensive review

M Raheel Khan ^1,^✉, Patrice Kearney Sheehan ¹, Ashley Bazin ¹, Christine Leonard ¹, Umair Aleem ⁴, Lynda Corrigan ¹, Ray McDermott ^1,^2,³

PMCID: PMC11557811 PMID: 39532799

Abstract

Testicular cancer is a rare solid organ tumour associated with high cure rates and young age at diagnosis, hence it has a sizeable cohort of survivors worldwide. As it is one of the earliest tumours to be cured, a lot of studies have highlighted the late side effects of cancer and its different treatment modalities including surgery, radiotherapy and chemotherapy. While we are trying to identify the population at higher risk of platinum based chemotherapy and reduce its exposure, cisplatin based regimes remain an important tool to cure testicular cancer. The list of late side effects include a number of fatal and morbid conditions including but not limited to the second malignant neoplasms, cardiovascular disease, hypogonadism, infertility, metabolic syndrome, chronic respiratory disease, renal insufficiency, hearing loss, peripheral neuropathy, infertility and psychological illnesses like stress and anxiety. These complications eventually result in compromised social and economic health as well as lower life expectancy compared to the normal population. This article provides a comprehensive review of the latest data regarding the late side effects in testicular cancer survivors. A review of these conditions can help us develop recommendations and guidelines to improve the morbidity and mortality in survivors of testicular cancer.

Keywords: Testicular cancer, Cancer survivorship, Germ cell tumours, Chemotherapy late side-effect

Introduction

Testicular cancer (TC) is a rare tumour, accounting for only 1% of solid organ tumours, but its incidence has been increasing globally in the last two decades especially in the developed countries coupled with an improvement in mortality rates [1, 2]. Most of testicular cancers are germ cell tumours (97%) [3], usually diagnosed at an early age [4]. In general, the cure rates are around 95% [5], resulting in a large population of patients who will live for decades in the survivorship phase after the treatment of cancer. Different treatment modalities used in treatment, including surgery, radiotherapy and chemotherapy, are all associated with significant morbidity and mortality in the survivorship setting. Most commonly reported conditions include second malignant neoplasms, cardiovascular disease, persistent peripheral neuropathy, hypogonadism, chronic pulmonary disease, ototoxicity, nephrotoxicity and psychiatric disorders including anxiety and depression [6–8]. These late sequelae on one hand cause lower than normal life expectancy in TC survivors, while on the other hand severely affect their physical, social, psychological and economic health [7, 9]. Since the advent of cisplatin based chemotherapies in 1970s, cure rates have dramatically improved but late side effects in survivors still pose a big challenge for healthcare professionals [7, 10, 11]. In the last decade we have seen an abundant amount of research in this area. This increasing interest has generated an enormous amount of data which needs attention and review. In this article, we provide a comprehensive review of the incidence, prevalence and risk factors of the above mentioned complications. Similar review articles have established association of these complications with certain treatment modalities and risk factors [12]. We provide a thorough and complete landscape including all survivors and complications to help devise guidelines and care pathways.

Treatment overview

Over the last few years, efforts have been made to avoid exposure to platinum based chemotherapy and radiotherapy in patients with early stage cancers. In the section below we will briefly discuss current treatment options in TC.

For stage I seminomas, active surveillance after orchiectomy is recommended especially in the absence of risk factors, as only 15–20% of the patients experience the recurrence of disease [13, 14]. Known risk factors for recurrence of cancer in seminomas after orchiectomy include tumour size of more than 4 cm and involvement of rete testes or small vessels [13–15]. The risk of recurrence can be substantially reduced with one cycle of carboplatin in the adjuvant setting [13, 16, 17].

In stage I non-seminomatous germ cell tumours(NSGCT), the presence of lymph vascular invasion (LVI) or an embryonal component (EC) is associated with a higher risk of relapse after orchiectomy [14, 18]. In general the risk of relapse is around 30% at 5 years after orchiectomy alone, but in presence of risk factors it can rise up to 50% compared to only 12% without them [14, 19]. One cycle of chemotherapy with bleomycin, etoposide and cisplatin (BEP) can been used in stage I NSGCT [20, 21]. BEP given in one cycle after orchiectomy has shown to reduce the risk of recurrence compared to surveillance [20–23].

For stage IIA/IIB seminoma, both radiation and chemotherapy can be used, though chemotherapy is preferred as the latter results in a higher incidence of second malignant disease [14, 24]. Radiotherapy is usually given to the para-aortic and ipsilateral iliac lymph nodes and demonstrates excellent relapse-free survival (IIA 95.3%, IIB 88.9% at 6 years) [25]. For chemotherapy, three cycles of bleomycin, etoposide and cisplatin or four cycles of etoposide and cisplatin (EP) are recommended as preferred regimens with estimated five-year progression-free survival rates of 100% for IIA and 87% for IIB [14, 26]. Due to concerns regarding late side effects of chemotherapy and radiotherapy, primary RPLND is being evaluated as an alternative [27] but definitive data on efficacy is not available yet.

In the case of NSGCT stage IIA/IIB disease, it is recommended to either treat the patient upfront with chemotherapy or consider RPLND with adjuvant chemotherapy [28]. RPLND alone is not recommended due to high rate of recurrence especially in patients with elevated serum tumour markers [28]. Chemotherapy when given as primary treatment is prescribed according to the prognostic risk category [14].

Stage IIC and III of both seminomas and NSGCTs is treated as metastatic disease with chemotherapy based on IGCCCG prognostic risk groups [29]. In 2021, IGCCCG revised the prognostic groups by upgrading the overall survival of all risk groups and adding LDH as prognostic marker [29].

Metastatic seminomas are less common than NSGCT but carries better prognosis [14]. For good prognostic group three cycles of BEP (Bleomycin, Etoposide, Cisplatin) [14, 30, 31] or 4 cycles of EP (etoposide, cisplatin) have shown excellent results. Although BEP has been proven very effective with 2-year progression free survival of 90%, risk of pulmonary toxicity remains a concern [14, 30, 31]. Four cycles of EP can be safely used as an alternative if bleomycin is contraindicated [14, 31]. For intermediate group metastatic seminoma, four cycles of BEP or four cycles of etoposide, ifosfamide and cisplatin (VIP) can be used [32]. A summary of the recommended treatment options for seminoma and NSGCT are shown in Figs. 1 and 2.

Fig. 1 — Management of seminoma germ cell tumours

Fig. 2 — Management of non-seminomatous germ cell tumours

In good risk stage IIC and III NSGCT, either three cycles of BEP or four cycles of EP are recommended. R de Wit et, al. when compared the two, reported higher rates of complete response with BEP (95%) than EP(87%), but also a higher incidence of pulmonary toxicity, neurotoxicity and Raynaud’s phenomenon with bleomycin [30].

Given the better outcomes with BEP, replacing it with EP remains controversial. Current NCCN guidelines advise caution in patients more than 50 years of age, diminished renal function or underlying lung disease e.g., COPD [33]. Some oncologists use four cycles of EP in active smokers regardless of lung function [33]. Monitoring of DLCO and radiological changes have also been advocated, but the exact threshold prompting dose reduction of bleomycin is not clear yet [34, 35]. The role of concomitant use of granulocyte colony stimulating factors (GCSF) with bleomycin also needs further investigation. Data suggesting detrimental effect of GCSF with bleomycin mainly comes from animal models [36]. On the contrary, a retrospective study conducted in Australia, failed to establish any increased incidence of pulmonary complications with GCSF use [37]. While we wait for stronger evidence in this area, a shared decision between physician and patient is recommended [33].

Similar to seminomas, intermediate group NSGCT can be effectively treated with 4 cycles of BEP or 4 cycles of VIP [14, 38]. VIP should be used with GCSF support to mitigate bone marrow toxicity. VIP doesn’t provide superior outcomes compared to BEP and should only be used where bleomycin needs to be avoided [14, 38].

Metastatic NSGCT in poor prognostic group carries 5-year overall survival of only 67% [29]. At present 4 cycles of BEP or VIP are widely used to treat this group of patients as no other treatment regimen successfully improved the outcomes [14, 39, 40]. However, intensification of treatment is recommended after initial BEP based on decline in serum tumour markers according to GETUG-13 phase 3 results [41].

Recurrence after initial chemotherapy can be treated with high dose chemotherapy (HDCT) followed by autologous stem cell transplant [42, 43]. Other treatment options include chemotherapy combinations like TIP (Paclitaxel, Ifosfamide, Cisplatin) [44] and GIP (gemcitabine, Ifosfamide, cisplatin) [45]. A prospective study (TIGER trial), currently in progress, will provide important information regarding efficacy of standard vs. high dose chemotherapy in this setting [46]. The International Prognostic Factor Study Group (IPFSG) has highlighted prognostic markers and estimated overall survival after recurrence of testicular cancer in a meta-analysis published in 2010 [47].

Relative survival and morbidity in TCS

Kvammen et al. in 2016 published a registry analysis of survival in TCS compared to the general population [9]. Patients diagnosed after the advent of cisplatin based chemotherapy in 1976 experienced a dramatic improvement in prognosis and survival. Unfortunately, their analysis also highlights that these gains didn’t last long, as the survival began to fall after 20–30 years of diagnosis. While the life expectancy of the general population has improved in last 50 years, it has worsened for TCS. Another analysis was performed to identify the causes of excess mortality in TCS [8]. Non-testicular second malignancies were identified as the most common cause of death after 5 years of diagnosis while TC remained the major cause of death before 5 years. Cardiovascular events were the second most common cause of mortality after 5 years of diagnosis.

Higher incidence of adverse health outcomes (AHO) was reported by Agrawal et al. in patients receiving chemotherapy compared to patients who were treated with surgery only [6]. Incidence of AHO increased with increasing the cycles of chemotherapy mainly BEP. In Platinum study [7] around 1200 patients, who had received platinum based chemotherapy were assessed for cumulative burden of morbidity (CBM). At median follow up of 4.2 years, 20% of patients had a high or very high score of CBM with another 30% having a medium score. The most common AHOs identified were obesity, neurotoxicity, ototoxicity and Raynaud’s phenomenon.

Long term complications in TCS

A brief list of late side effects in TCS is given in Table 1. In the headings below, we a provide detailed discussion on the major complications.

Table 1.

Summary of major late complications

Complications	Risk factors	Incidence (%)	Duration since Treatment	References
Second malignant neoplasm	− Chemotherapy − Radiotherapy − Age > 35 at diagnosis − NSGCT	6	4–7 years	− Groot et al. − Kvammen et al.
Cardiovascular disease	− Cisplatin chemotherapy − Presence of other CVD RF − Raynaud’s phenomenon	5.7	~ 15 years	− Lubberts et al.
Hypogonadism	− Chemotherapy − Baseline hypogonadism	~ 50	~ 9 years	− Sprauten et al.
Pulmonary disease	− Bleomycin, Cisplatin − Pulmonary mets/surgery − H63D gene variant − Smoking − Reduced renal function	~ 4–8	5–10 years	− Lauretsen et al. − Haugnes − Schoot et al.
Dyslipidaemia	− High BMI − Chemotherapy − Hypogonadism	86	~ 3 years	− Lubberts et al.
Hypertension	− Chemotherapy − High BMI − Smoking	50	~ 3 years	− Lubberts et al.
Raynaud’s phenomenon	− Cisplatin, Bleomycin	33	~ 2 years	− Glendenning et al. − Kerns et al.
Renal impairment	− Cisplatin − Baseline low renal function − Baseline high blood pressure	23	~ 1 year	− Hartmann et al. − Inai et al.
Ototoxicity	− Chemotherapy − Baseline hearing impairment	~ 40	~ 1 year	− Brydøy et al.

Open in a new tab

Second malignant neoplasms (SMN)

Second malignancy is the most common cause of death in TCS after 5 years of diagnosis [8]. Patients who received chemotherapy or radiotherapy are at greater risk of developing second cancers compared to those who had surgery only [48]. Also, more than 35 years of age at diagnosis carries a higher risk of developing cancer later in life [3]. With infra-diaphragmatic radiotherapy, risk increased by 2.6-fold, while with chemotherapy by 2.1-fold [48]. Relative risk is highest (2.9) among those who received both chemotherapy and radiotherapy [3]. A diverse set of malignancies including mesotheliomas, lung, thyroid, GI, GU and skin cancers are reported in large registry based studies [3, 8, 49]. Ondrus et al. reported testicular cancer as the most common second malignancy succeeded by prostate and kidney cancer [50]. A higher incidence of SMN was reported in patients who had seminoma as primary diagnosis.

Groot et al. in 2018 analysed registry data of around 6000 Dutch patients. They showed that compared to the general population TCS are at 1.8 fold higher risk of developing second cancers [49]. In this study, a higher risk was found in non-seminomas compared to seminomas.

Infra-diaphragmatic radiotherapy increases the risk of abdominal solid organ tumours, particularly those covered in the radiation field [49]. Radiotherapy is associated with an increased risk of stomach, pancreas, kidney, bladder, melanoma and squamous cell cancer [49]. Same study observed a linear association, with every Gray (Gy) of radiation increasing risk of second malignancy by 8% [49]. Dog-leg irradiation of more than 26 Gy raises the risk of non-colorectal GI cancers by 9.99 fold [49]. This increased risk of SMNs persists for 25 years after treatment [49].

In the same analysis performed by Groot et al. a higher incidence of GI cancers was reported among patients who received cisplatin based chemotherapy without radiotherapy [49]. A higher risk of solid organ malignancy (HR 2.40) including colorectal (HR 3.85) and non-colorectal cancers (HR 5.0) was observed with chemotherapy compared to surgery only. Increasing the dose of cisplatin resulted in a higher risk of malignancies [49].

Myeloid dysplasia and leukaemia are associated with both radiotherapy and chemotherapy [3, 51] with the majority of cases between 5 and 8 years after treatment [51, 52]. Travis et al. performed a comprehensive study capturing around 18,000 patients from US and Europe to investigate this subject in 2000. Radiotherapy alone without any chemotherapy increased the risk of developing leukaemia by 3 fold [51]. Radiotherapy to the chest (active bone marrow) in a dose of more than 19.5 Gy increases the risk by 11 fold. However, the relative risk was only 2.2 when radiation was limited to abdomen and pelvis [51].

Cisplatin and etoposide increases the predictive risk of leukaemia by 3.2 [51]. A higher risk of acute myeloid leukaemia is associated with chemotherapy [53] compared to radiotherapy alone. In particular, etoposide is known to be associated with the risk of developing secondary acute leukaemia [54].

To reduce the exposure of radiation used in surveillance CT scans, MRI abdomen is being investigated as an alternative [55–57]. So far, studies have successfully demonstrated non-inferiority of MRI to detect the recurrence of cancer specifically after stage I seminoma (TRISST study) [55–57]. In future MRI might become preferred modality for surveillance in TC patients.

Cardiovascular complications

A recent study conducted in the Netherlands, published in Journal of Clinical Oncology in July 2023, assessed cardiovascular disease (CVD) in TCS [58]. With a median follow up of 16 years, 5.73% patients had developed cardiovascular complications. TCS who received cisplatin had a higher risk of developing cardiovascular disease (HR 1.9) compared to orchiectomy alone. Even higher risks were found in patients who were smokers/obese (HR 4.6), had dyslipidaemia (HR 2.8) or a positive family history (HR 2.9). Chemotherapy in combination with radiotherapy posed even higher risk (HR 2.5) but radiotherapy alone was not found to be a risk factor for CVD (HR 1.1). Furthermore, patients who developed CVD showed lower quality of life (QoL) than other TCS [58]. Another Danish study including around 5000 TCS reported a high risk of myocardial infarction (HR 6.3), cerebrovascular accident (HR 6.0) and venous thromboembolism (HR 24.7) during first year of chemotherapy with BEP [59]. Interestingly, the same study reported no added risk of CVD in TCS when they had surveillance and risk factors controlled.

Cardiac complications are a major cause of mortality in TCS [60]. Cisplatin and bleomycin based chemotherapy causes damage to the endothelium and increases the levels of Von Willebrand Factor, which in turn can explain the long term cardiovascular complications [61, 62]. Available data suggests that increased inflammatory markers and microalbuminuria in TCS are could be an early sign of atherosclerosis [63] Regarding structural abnormalities, a higher incidence of diastolic dysfunction was found in TCS patients treated with cisplatin, although ejection fraction and systolic function were preserved [64].

Metabolic syndrome

Metabolic syndrome is a cluster of disorders including hypertension, dyslipidaemia, obesity and diabetes. It is a well-established major risk factor for cardiovascular disease [65]. A higher incidence of metabolic syndrome has been reported in TCS [66], particularly in patients with underlying hypogonadism [67]. The Platinum study also reported metabolic syndrome as a major cluster of co-morbidities in TCS after chemotherapy exposure (OR 9.8) [7].

In a Dutch study evaluating 304 TCS for cardiovascular risk factors, an alarming 86% were found to have dyslipidaemia of which 82% were untreated [58]. High levels of LDL (82%) and/or high levels of total cholesterol (55%) constituted the majority of cases. The same study reported 50% of TCS with underlying hypertension, of which only 48% was treated. Several other investigators have reported hypertension as a major undiagnosed complication in TCS [6, 7, 68].

During a major multi-institutional study to assess the cumulative burden of morbidity (CBM) after platinum based chemotherapy (PBCT), 41.7% TCS were found to have grade 2 obesity while 26% had grade 3 and 3.9% had grade 4 obesity(total 71.5%) [7]. Agarwal et al. also reported more than double (3.2% Vs 7.7%) the incidence of morbid obesity (BMI > 40) in patients treated with BEP compared to surgery alone [6]. Another study investigating CVD risk factors after PBCT, revealed an increase in visceral adipose tissue to subcutaneous adipose tissue (VAT -to- SAT ratio) after administration of chemotherapy. The resulting central adiposity leads to a higher incidence of cardiometabolic conditions [69].

At a median follow up of 4 years, 3% TCS were found to have diabetes [7]. However, studies comparing chemotherapy and orchiectomy have reported similar incidence of pre-diabetes and diabetes in both groups [6, 58].

Hypogonadism

Hypogonadism is a broad term to suggest loss of testicular function. It includes hormonal deficiency and disturbance in spermatogenesis [70]. In this section we will focus on dysregulation in gonadal hormones, while spermatogenesis will be discussed under the heading of infertility.

Most of the studies investigating TCS define gonadal dysfunction as low serum testosterone (< 10) and compensatory high LH/FSH with clinical manifestations of low testosterone such as erectile dysfunction, low libido and gynecomastia [58, 71]. It is important to make age related adjustments in the normal range when assessing these patients [72]. A higher incidence of hypogonadism, requiring testosterone treatment, is associated with cisplatin based chemotherapy compared to surgery alone(12.0% Vs 8.2%) [6]. Also, a higher incidence (28.4%) of erectile dysfunction has been reported after chemotherapy [7]. Cisplatin is known to damage Leydig cells which can cause this gonadal insufficiency in these patients [73].

A longitudinal study spanning over two decades and assessing hormonal levels in TCS, reported low levels of testosterone in all TCS independent of treatment modality. However, fewer patients in chemotherapy cohort recovered their hormonal levels, after 18 years of treatment, compared to surgery and radiotherapy [71]. Compared to healthy control group, the odds ratio for low testosterone level after 18 years was 2.1, 2.7 and 3.7 with surgery, radiotherapy and chemotherapy respectively [71].

Another study looking at hormonal levels in the first 5 years of treatment showed the highest incidence of hypogonadism at 6–12 months after orchiectomy. At 5 years follow up 25% remained hypogonadal while the rest recovered. Microlithiasis in the remaining testis and treatment with chemotherapy were found to be important risk factors for developing hypogonadism [74].

These reduced levels of serum testosterone and raised LH are associated with reduced bone mineral density in TCS population, causing osteopenia and osteoporosis [75].

A UK randomised trial has shown the benefit of testosterone replacement in young cancer survivors (88% testicular cancer) by improving whole body fat and truncal fat [76]. Unfortunately, no benefit was noticed in QoL (SF36-PF, EORTC QLQc30) with testosterone replacement [76, 77].

Pulmonary toxicity

Bleomycin is strongly associated with acute and chronic lung injury [78] as it causes alveolar damage which subsequently triggers pulmonary inflammation [79]. Some studies suggest that this dose dependent injury can be prevented by reducing BEP cycles in favourable prognosis tumours from four to three [80], but it remains debatable as we mentioned earlier in treatment section. For delayed toxicity of bleomycin, a Danish study recorded the pulmonary function tests (PFTs) of 565 patients who received treatment with BEP. Only one death was recorded of a 45 years old non-smoker, who died of acute bleomycin induced pneumonitis after 3 cycles of BEP. Data at 5-years follow up showed long term restrictive disease in 4.1%, obstructive disease in 2.7% and impaired diffusion capacity in 15.6% patients but 16-years follow up didn’t show any significant difference in lung function compared to patients who had surgery only. Pulmonary surgery, pulmonary embolism, smoking and reduced GFR were identified as risk factors for reduced lung function following BEP [81]. It is important to note that, HFE gene variant H63D is found to be associated with a higher risk of bleomycin induced pulmonary toxicity [82].

High doses of cisplatin especially when accompanied with pulmonary surgery can also cause long term lung injury [83].

Raynaud’s phenomenon

In TCS, Raynaud’s phenomenon is associated with an increased risk of cardiovascular disease and compromised QoL [58]. Its incidence in TCS is related to dose of bleomycin and cisplatin [6, 7]. In patients who received three cycles of BEP, the risk is increased by 12-fold and with 4 cycles of BEP by 21-fold compared to surgery alone [6]. For every 90,000IU of Bleomycin the risk increases by OR of 1.36 [6]. Cisplatin and Carboplatin also increase the risk in a dose dependent manner [84]. A multi-institutional study performed clinical assessment of more than 1200 TCS, who had received platinum based chemotherapy. They observed Raynaud’s Phenomenon in 33% of patients, including 15.6% with grade 1, 8.7% with grade 2 and 9.1% with grade 3 disease [7].

Ototoxicity

Ototoxicity is one of the most frequently reported long term complications in TCS especially after platinum based chemotherapy [6, 7]. Kern et al. found hearing loss and tinnitus in almost 40% of TCS at 4 years follow up [7]. Another study reported the rate of hearing loss with surgery alone as 11.5%, compared to 36.0% with BEP 3 and 41.8% with BEP 4 [6]. Increasing the cumulative dose of Cisplatin by 100mg/m² increases the risk by 1.4-fold. Hearing impairment is mainly in higher frequency ranges [85]. Hearing loss and tinnitus have frequently been reported as reason for unemployment and low QoL in TCS [11].

Renal insufficiency

At a median follow up of 4 years, 3.3% patients who received platinum based chemotherapy were found to have renal impairment compared to 0% who underwent surgery alone [6]. Even though hyperhydration has reduced the incidence of renal injury after cisplatin, yet a long term reduction in glomerular filtration rate (GFR) by 20–30% has been reported in almost a quarter of TCS [86]. Ifosfamide and aminoglycosides are other factors causing nephrotoxicity in TCS, with highest risk in those who received high dose chemotherapy (HDCT) in second line setting [86]. Elevated blood pressure and mild renal impairment before treatment are risk factors for developing long term nephrotoxicity [87]. Like ototoxicity and Raynaud’s Phenomenon, kidney disease is also a major contributor to unemployment and disability leave in TCS [11].

Neurotoxicity

Up to an 18 fold higher risk of peripheral neuropathy is reported in patients who received platinum based chemotherapy, with an increase in odds ratio of 1.75 for every 100 mg/m² of cisplatin [6] compared to surgery alone. Some studies have implicated certain genetic variations as risk factors for developing peripheral neuropathy after cisplatin [88]. Other risk factors include renal impairment, smoking and peripheral vascular disease [89]. Long term follow up has shown elevated serum platinum levels in TCS for up to 20 years, resulting in neurotoxicity along with ototoxicity, Raynaud’s Phenomenon and cardiovascular disease [90]. Peripheral as well as autonomic neuropathy are documented as a major factors contributing to higher incidence of unemployment and disability leave in TCS [11].

Central nervous system (CNS) metastases is found in 1–2% of patients of germ cell cancers [91]. They are usually treated with combined whole brain radiotherapy (WBRT) and chemotherapy [92]. As germ cell tumours can be cured even with brain metastases, long term consequences of WBRT have been widely reported. These include delayed symptoms of seizures, headaches, blindness, dementia and hemiparesis secondary to progressive multifocal leukoencephalopathy. D.M. Doyle et al. followed up 5 patients at 72 months after treatment with WBRT and found CNS gliosis and cerebral atrophy in all of them [93].

Psychological conditions

A recently published systemic review showed anxiety as the most common psychological problem in TCS. Most of the reviewed studies reported a anxiety in 20% of TCS after more than 5 years of follow up [94]. Although levels of depression and distress were similar to the general population, fear of recurrence of cancer was highly prevalent (33%) among them. Risk factors for psychological complications are single status, unemployment, low socioeconomic status, co-morbidities and presence of symptoms or side effects [94]. A Danish study reported higher levels of stress in TCS (OR 1.56) compared to the general population [95]. Another study reported a higher incidence of mental health services use in TCS during perioperative period continuing over 12 years of follow up [96]. Physical activity is found to be beneficial for psychological side effects in TCS, as it reduces the risk [97].

Registry based studies have reported a higher risk of suicide in TCS (HR 2.5) compared to cancer free population [98] and even higher risk with cisplatin based chemotherapy treatment [99]. Of note, suicide risk in TCS increases with follow up time, contrary to the trends of suicide in other cancers which decreases over time [100]. The standardised mortality ratio (SMR) of suicide compared to general population stands at 6 within first year, 12 from year 1 to 5 and 17 from year 5 onwards [100].

Socio-economic impact

A multi-institutional study of more than 1800 TCS showed 2.4% rate of disability and 6.8% of unemployment at median age of 37. Peripheral sensory neuropathy, renal dysfunction, pain and higher cumulative burden of morbidity (CBM) score were associated with these outcomes [11]. Compared to the normal population, the odds ratio for unemployment was 2.67 [11]. In another study of 562 TCS, 4 or more cycles of chemotherapy were associated with more chances of financial toxicity (OR 4.17) [101].

Infertility

TCS are less likely to father a child compared to the general population, particularly when diagnosed before age of 25 (HR 0.77). Multiple factors are involved in causing infertility in TCS. Almost half of newly diagnosed TC patients have a low sperm count (< 20 million/mL), low motility indices (< 40%) and high percentage of abnormal cells (> 80%) even before starting any treatment [102]. These findings explain the disappointing results with semen cryopreservation which is currently offered to all young patients before treatment. Orchiectomy reduces the quality of semen [103] and addition of cisplatin based chemotherapies further damage the gonadal function in a dose dependent manner [104].

Retroperitoneal lymph node dissection can cause retrograde ejaculation but nerve sparing techniques can be used to reduce the risk [105].

Other complications

In addition to the list above, a lot more complications are reported in the literature including thyroid disease, vertigo, peripheral vascular disease, substance abuse and chronic pain [6, 7].

A higher risk of hypothyroidism in TCS was reported in a Norwegian study, compared to general population, after three decades of treatment [106]. Of note, same study didn’t find any association with a particular treatment modality. Other studies have also reported similar findings [6, 7, 107].

Similar to cardiovascular disease, endothelial damage caused by cisplatin based chemotherapies is associated with the peripheral vascular disease (PVD) in survivors [108]. Therefore, a higher incidence of PVD is reported in studies assessing co-morbidities in TCS population [6, 7].

Substance abuse, chronic pain, fatigue and neuroticism in TCS has been widely described in literature. These conditions can negatively impact social, economic and sexual health of TCS [109].

Phantom testis syndrome is well recognised condition in patients after orchiectomy [110, 111]. A survey questionnaire conducted in University of Münster, investigated 238 TCS after a median 3.5 years of unilateral inguinal orchiectomy [111]. When 47% respondents didn’t report any symptoms, 25% reported phantom testis pain, 16% reported painless phantom sensation and 12% reported male gonad hallucinations [111].

Conclusions

The interest in survivorship of testicular cancer has grown recently, with many multi-institutional studies highlighting issues experienced by this cohort. This trend in research is possibly due to a rise in incidence, early age of diagnosis and improved cure rates, resulting in a continuously growing population of TCS. Also, this cohort represents the earliest solid organ tumours to be cured and can provide vital insight into survivorship of other cancers.

There is plenty of data available to suggest high incidence of comorbidities in TCS and risk factors to develop these complications. Though, platinum based chemotherapy is associated with a high incidence of complications, it is also the main reason for the high cure rates observed. Numerous efforts are going on to reduce the exposure of chemotherapy without making any negative impact on cure rates. Firstly, efforts should be made to avoid chemotherapy or reduce the number of cycles. We can achieve this by using less cycles in good prognostic risk groups and choosing more patients for active surveillance in clinical stage I. It is important to mention here that long term complications after 1 cycle of BEP or carboplatin are not yet investigated. Secondly, studies are investigating the efficacy of primary RPLND in clinical stage IIA and IIB in an attempt to avoid chemotherapy and radiotherapy. But, we have to wait for the results of these studies before making any changes to current practices [112]. Thirdly, use of more sensitive and specific tumour marker such as miR-371a-3p [113] will hopefully help with early detection of recurrence and save patients from systemic therapies. Some researchers have pointed out certain genetic variations to identify patients at higher risk of late side effects, but so far genetic testing is not being used in routine practice. Unlike many other cancers, novel agents including targeted therapies and immune check point inhibitors have failed to show any clinical benefit in testicular cancer treatment [114]. Therefore, in the foreseeable future, cisplatin based chemotherapy will continue to play pivotal role in the treatment of TC.

Given this outlook of TCS, there is a pressing need to develop care plans and clinical pathways for unmet needs of these patients. Survivorship clinics should be made a mandatory in all cancer centres and cancer control programs. A holistic approach is needed in survivorship programmes to deal with the physical, psychological as well as social aspects of problems. Cardiometabolic mortality can be reduced by regular screening, treating modifiable risk factors and promoting healthier lifestyles in TCS. Mortality from second malignant neoplasms can also be reduced with targeted screening and surveillance for early detection of cancers. Social issues can be mitigated by treating manageable co-morbidities like Raynaud’s phenomenon, hearing loss, metabolic syndrome, hypogonadism and anxiety. A specialised, purpose-built survivorship clinic can play an important role in improving the mortality and morbidity in TCS. Future research and quality improvement projects should work on these lines to help the TCS cohort.

Author contributions

M Raheel Khan: Idea, literature search, data analysis, writing—draft, writing—review and editing Patrice Kearney Sheehan: literature search, writing—review and editing Ashley Bazin: idea, writing—review and editing Christine Leonard: idea, writing—review and editing Umair Aleem: idea, writing—review and editing Lynda Corrigan: critical analysis, writing – review and editing Ray Mc Dermott: idea, data analysis, critical analysis, writing—review and editing.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1.Park JS, Kim J, Elghiaty A, Ham WS. Recent global trends in testicular cancer incidence and mortality. Medicine. 2018;97(37):e12390. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Huang J, Chan SC, Tin MS, Liu X, Lok VT, Ngai CH, et al. Worldwide distribution, risk factors, and temporal trends of testicular cancer incidence and mortality: a global analysis. Eur Urol Oncol. 2022;5(5):566–76. [DOI] [PubMed] [Google Scholar]
3.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. J Natl Cancer Inst. 2005;97(18):1354–65. [DOI] [PubMed] [Google Scholar]
4.Mai PL, Chen BE, Tucker K, Friedlander M, Phillips KA, Hogg D, et al. Younger age-at-diagnosis for familial malignant testicular germ cell tumor. Fam Cancer. 2009;8(4):451–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Raghavan D. Testicular cancer: maintaining the high cure rate. Oncology. 2003;17(2):218–28. [PubMed] [Google Scholar]
6.Agrawal V, Dinh PC Jr, Fung C, Monahan PO, Althouse SK, Norton K, et al. Adverse health outcomes among US testicular cancer survivors after cisplatin-based chemotherapy vs surgical management. JNCI Cancer Spectr. 2020;4(2):pkz079. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Kvammen O, Myklebust TA, Solberg A, Moller B, Klepp OH, Fossa SD, et al. Causes of inferior relative survival after testicular germ cell tumor diagnosed 1953–2015: a population-based prospective cohort study. PLoS ONE. 2019;14(12):e0225942. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Kvammen Ø, Myklebust T, Solberg A, Møller B, Klepp OH, Fosså SD, et al. Long-term relative survival after diagnosis of testicular germ cell tumor. Cancer Epidemiol Biomark Prev. 2016;25(5):773–9. [DOI] [PubMed] [Google Scholar]
10.Lawrence H, Einhorn MD. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med. 1977;87(3):293–8. [DOI] [PubMed] [Google Scholar]
11.Kerns SL, Fung C, Fossa SD, Dinh PC Jr, Monahan P, Sesso HD, et al. Relationship of cisplatin-related adverse health outcomes with disability and unemployment among testicular cancer survivors. JNCI Cancer Spectr. 2020;4(4):pkaa022. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Fung C, Dinh PC, Fossa SD, Travis LB. Testicular cancer survivorship. J Natl Compr Cancer Netw. 2019;17(12):1557–68. [DOI] [PubMed] [Google Scholar]
13.Aparicio J, Germà JR, García del Muro X, Maroto P, Arranz JA, Sáenz A, et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol. 2005;23(34):8717–23. [DOI] [PubMed] [Google Scholar]
14.Honecker F, Aparicio J, Berney D, Beyer J, Bokemeyer C, Cathomas R, et al. ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018;29(8):1658–86. [DOI] [PubMed] [Google Scholar]
15.Kollmannsberger C, Tandstad T, Bedard PL, Cohn-Cedermark G, Chung PW, Jewett MA, et al. Patterns of relapse in patients with clinical stage I testicular cancer managed with active surveillance. J Clin Oncol. 2015;33(1):51–7. [DOI] [PubMed] [Google Scholar]
16.Oliver RT, Mead GM, Rustin GJ, Joffe JK, Aass N, Coleman R, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol. 2011;29(8):957–62. [DOI] [PubMed] [Google Scholar]
17.Patel HD, Srivastava A, Alam R, Joice GA, Schwen ZR, Semerjian A, et al. Radiotherapy for stage I and II testicular seminomas: secondary malignancies and survival. Urol Oncol. 2017;35(10):6061.e1-e7. [DOI] [PubMed] [Google Scholar]
18.Blok JM, Pluim I, Daugaard G, Wagner T, Jóźwiak K, Wilthagen EA, et al. Lymphovascular invasion and presence of embryonal carcinoma as risk factors for occult metastatic disease in clinical stage I nonseminomatous germ cell tumour: a systematic review and meta-analysis. BJU Int. 2020;125(3):355–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Daugaard G, Gundgaard MG, Mortensen MS, Agerbæk M, Holm NV, Rørth M, et al. Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort. J Clin Oncol. 2014;32(34):3817–23. [DOI] [PubMed] [Google Scholar]
20.Albers P, Siener R, Krege S, Schmelz HU, Dieckmann KP, Heidenreich A, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German testicular Cancer Study Group. J Clin Oncol. 2008;26(18):2966–72. [DOI] [PubMed] [Google Scholar]
21.Chevreau C, Mazerolles C, Soulié M, Gaspard MH, Mourey L, Bujan L, et al. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol. 2004;46(2):209–14. [DOI] [PubMed] [Google Scholar]
22.Cullen MH, Stenning SP, Parkinson MC, Fossa SD, Kaye SB, Horwich AH, et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol. 1996;14(4):1106–13. [DOI] [PubMed] [Google Scholar]
23.Pont J, Albrecht W, Postner G, Sellner F, Angel K, Höltl W. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol. 1996;14(2):441–8. [DOI] [PubMed] [Google Scholar]
24.Giannatempo P, Greco T, Mariani L, Nicolai N, Tana S, Farè E, et al. Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes. Ann Oncol. 2015;26(4):657–68. [DOI] [PubMed] [Google Scholar]
25.Classen J, Schmidberger H, Meisner C, Souchon R, Sautter-Bihl ML, Sauer R, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol. 2003;21(6):1101–6. [DOI] [PubMed] [Google Scholar]
26.Garcia-del-Muro X, Maroto P, Gumà J, Sastre J, López Brea M, Arranz JA, et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish germ cell Cancer Group Study. J Clin Oncol. 2008;26(33):5416–21. [DOI] [PubMed] [Google Scholar]
27.Hu B, Shah S, Shojaei S, Daneshmand S. Retroperitoneal lymph node dissection as first-line treatment of node-positive seminoma. Clin Genitourin Cancer. 2015;13(4):e265-9. [DOI] [PubMed] [Google Scholar]
28.Neuenschwander A, Lonati C, Antonelli L, Papachristofilou A, Cathomas R, Rothermundt C, et al. Treatment outcomes for men with clinical stage II nonseminomatous germ cell tumours treated with primary retroperitoneal lymph node dissection: a systematic review. Eur Urol Focus. 2023;9(3):541–6. [DOI] [PubMed] [Google Scholar]
29.Gillessen S, Sauvé N, Collette L, Daugaard G, de Wit R, Albany C, et al. Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG Update Consortium. J Clin Oncol. 2021;39(14):1563–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.de Wit R, Stoter G, Kaye SB, Sleijfer DT, Jones WG, ten Bokkel Huinink WW, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol. 1997;15(5):1837–43. [DOI] [PubMed] [Google Scholar]
31.de Wit R, Roberts JT, Wilkinson PM, de Mulder PH, Mead GM, Fosså SD, et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol. 2001;19(6):1629–40. [DOI] [PubMed] [Google Scholar]
32.Fizazi K, Delva R, Caty A, Chevreau C, Kerbrat P, Rolland F, et al. A risk-adapted study of cisplatin and etoposide, with or without Ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study. Eur Urol. 2014;65(2):381–6. [DOI] [PubMed] [Google Scholar]
33.Gilligan T, Lin DW, Aggarwal R, Chism D, Cost N, Derweesh IH, et al. Testicular cancer, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17(12):1529–54. [DOI] [PubMed] [Google Scholar]
34.Roncolato FT, Chatfield M, Houghton B, Toner G, Stockler M, Thomson D, et al. The effect of pulmonary function testing on bleomycin dosing in germ cell tumours. Intern Med J. 2016;46(8):893–8. [DOI] [PubMed] [Google Scholar]
35.Maruyama Y, Sadahira T, Mitsui Y, Araki M, Wada K, Tanimoto R, et al. Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors. Med Oncol. 2018;35(6):80. [DOI] [PubMed] [Google Scholar]
36.Adachi K, Suzuki M, Sugimoto T, Suzuki S, Niki R, Oyama A, et al. Granulocyte colony-stimulating factor exacerbates the acute lung injury and pulmonary fibrosis induced by intratracheal administration of bleomycin in rats. Exp Toxicol Pathol. 2002;53(6):501–10. [DOI] [PubMed] [Google Scholar]
37.Kwan EM, Beck S, Amir E, Jewett MA, Sturgeon JF, Anson-Cartwright L, et al. Impact of granulocyte-colony stimulating factor on bleomycin-induced pneumonitis in chemotherapy-treated germ cell tumors. Clin Genitourin Cancer. 2018;16(1):e193-9. [DOI] [PubMed] [Google Scholar]
38.de Wit R, Stoter G, Sleijfer DT, Neijt JP, ten Bokkel Huinink WW, de Prijck L, et al. Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br J Cancer. 1998;78(6):828–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Kier MG, Lauritsen J, Mortensen MS, Bandak M, Andersen KK, Hansen MK, et al. Prognostic factors and treatment results after bleomycin, etoposide, and cisplatin in germ cell cancer: a population-based study. Eur Urol. 2017;71(2):290–8. [DOI] [PubMed] [Google Scholar]
40.Hinton S, Catalano PJ, Einhorn LH, Nichols CR, David Crawford E, Vogelzang N, et al. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer. 2003;97(8):1869–75. [DOI] [PubMed] [Google Scholar]
41.Fizazi K, Pagliaro L, Laplanche A, Fléchon A, Mardiak J, Geoffrois L, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol. 2014;15(13):1442–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Berger LA, Bokemeyer C, Lorch A, Hentrich M, Kopp HG, Gauler TC, et al. First salvage treatment in patients with advanced germ cell cancer after cisplatin-based chemotherapy: analysis of a registry of the German testicular Cancer Study Group (GTCSG). J Cancer Res Clin Oncol. 2014;140(7):1211–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Motzer RJ, Nichols CJ, Margolin KA, Bacik J, Richardson PG, Vogelzang NJ, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. 2007;25(3):247–56. [DOI] [PubMed] [Google Scholar]
44.Mead GM, Cullen MH, Huddart R, Harper P, Rustin GJ, Cook PA, et al. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. Br J Cancer. 2005;93(2):178–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Fizazi K, Gravis G, Flechon A, Geoffrois L, Chevreau C, Laguerre B, et al. Combining gemcitabine, cisplatin, and ifosfamide (GIP) is active in patients with relapsed metastatic germ-cell tumors (GCT): a prospective multicenter GETUG phase II trial. Ann Oncol. 2014;25(5):987–91. [DOI] [PubMed] [Google Scholar]
46.McHugh DJ, Feldman DR. Conventional-dose versus high-dose chemotherapy for relapsed germ cell tumors. Adv Urol. 2018;2018:7272541. [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Lorch A, Beyer J, Bascoul-Mollevi C, Kramar A, Einhorn LH, Necchi A, et al. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol. 2010;28(33):4906–11. [DOI] [PubMed] [Google Scholar]
48.van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. 2007;25(28):4370–8. [DOI] [PubMed] [Google Scholar]
49.Groot HJ, Lubberts S, Wit Rd, Witjes JA, Kerst JM, Jong, IJd, et al. Risk of Solid Cancer after treatment of testicular germ cell Cancer in the platinum era. J Clin Oncol. 2018;36(24):2504–13. [DOI] [PubMed] [Google Scholar]
50.Ondrus D, Ondrusova M, Friedova L. Second malignancies in long-term testicular cancer survivors. Int Urol Nephrol. 2014;46(4):749–56. [DOI] [PubMed] [Google Scholar]
51.Travis LB, Andersson M, Gospodarowicz M, van Leeuwen FE, Bergfeldt K, Lynch CF, et al. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst. 2000;92(14):1165–71. [DOI] [PubMed] [Google Scholar]
52.Fosså SD. Long-term sequelae after cancer therapy–survivorship after treatment for testicular cancer. Acta Oncol. 2004;43(2):134–41. [DOI] [PubMed] [Google Scholar]
53.Howard R, Gilbert E, Lynch CF, Hall P, Storm H, Holowaty E, et al. Risk of leukemia among survivors of testicular cancer: a population-based study of 42,722 patients. Ann Epidemiol. 2008;18(5):416–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Nichols CR, Breeden ES, Loehrer PJ, Williams SD, Einhorn LH. Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols. J Natl Cancer Inst. 1993;85(1):36–40. [DOI] [PubMed] [Google Scholar]
55.Joffe JK, Cafferty FH, Murphy L, Rustin GJS, Sohaib SA, Gabe R, et al. Imaging modality and frequency in surveillance of stage I seminoma testicular cancer: results from a randomized, phase III, noninferiority trial (TRISST). J Clin Oncol. 2022;40(22):2468–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Busch J, Schmidt S, Albers P, Heinzelbecker J, Kliesch S, Lackner J, et al. Can magnetic resonance imaging replace conventional computerized tomography for follow-up of patients with testicular cancer? A systematic review. World J Urol. 2022;40(12):2843–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Sohaib SA, Koh DM, Barbachano Y, Parikh J, Husband JE, Dearnaley DP, et al. Prospective assessment of MRI for imaging retroperitoneal metastases from testicular germ cell tumours. Clin Radiol. 2009;64(4):362–7. [DOI] [PubMed] [Google Scholar]
58.Lubberts S, Groot HJ, de Wit R, Mulder S, Witjes JA, Kerst JM, et al. Cardiovascular disease in testicular cancer survivors: identification of risk factors and impact on quality of life. J Clin Oncol. 2023;41(19):3512–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Lauritsen J, Hansen MK, Bandak M, Kreiberg MB, Skøtt JW, Wagner T, et al. Cardiovascular risk factors and disease after male germ cell cancer. J Clin Oncol. 2020;38(6):584–92. [DOI] [PubMed] [Google Scholar]
60.Fosså SD, Gilbert E, Dores GM, Chen J, McGlynn KA, Schonfeld S, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst. 2007;99(7):533–44. [DOI] [PubMed] [Google Scholar]
61.Nuver J, Smit AJ, Meer Jvd B, MPvd G, WTAvd, Meinardi MT, et al. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol. 2005;23(36):9130–7. [DOI] [PubMed] [Google Scholar]
62.Nuver J, De Haas EC, Van Zweeden M, Gietema JA, Meijer C. Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro. Oncol Rep. 2010;23(1):247–53. [PubMed] [Google Scholar]
63.Nuver J, Smit AJ, Sleijfer DT, van Gessel AI, van Roon AM, van der Meer J, et al. Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer. 2004;40(5):701–6. [DOI] [PubMed] [Google Scholar]
64.Bjerring AW, Fosså SD, Haugnes HS, Nome R, Stokke TM, Haugaa KH, et al. The cardiac impact of cisplatin-based chemotherapy in survivors of testicular cancer: a 30-year follow-up. Eur Heart J Cardiovasc Imaging. 2020;22(4):443–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Dobrowolski P, Prejbisz A, Kuryłowicz A, Baska A, Burchardt P, Chlebus K, et al. Metabolic syndrome—a new definition and management guidelines: a joint position paper by the Polish Society of Hypertension, Polish Society for the Treatment of Obesity, Polish Lipid Association, Polish Association for Study of Liver, Polish Society of Family Medicine, Polish Society of Lifestyle Medicine, Division of Prevention and Epidemiology Polish Cardiac Society, Club 30 Polish Cardiac Society, and Division of metabolic and Bariatric Surgery Society of Polish surgeons. Arch Med Sci. 2022;18(5):1133–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.de Haas EC, Altena R, Boezen HM, Zwart N, Smit AJ, Bakker SJ, et al. Early development of the metabolic syndrome after chemotherapy for testicular cancer. Ann Oncol. 2013;24(3):749–55. [DOI] [PubMed] [Google Scholar]
67.Bogefors C, Isaksson S, Bobjer J, Kitlinski M, Leijonhufvud I, Link K, et al. Hypogonadism in testicular cancer patients is associated with risk factors of cardiovascular disease and the metabolic syndrome. Andrology. 2017;5(4):711–7. [DOI] [PubMed] [Google Scholar]
68.Oh JH, Baum DD, Pham S, Cox M, Nguyen ST, Ensor J, et al. Long-term complications of platinum-based chemotherapy in testicular cancer survivors. Med Oncol. 2007;24(2):175–81. [DOI] [PubMed] [Google Scholar]
69.Wibmer AG, Dinh PC Jr, Travis LB, Chen C, Bromberg M, Zheng J, et al. Associations of body fat distribution and cardiometabolic risk of testicular cancer survivors after cisplatin-based chemotherapy. JNCI Cancer Spectr. 2022;6(4):pkac030. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Rey RA, Grinspon RP, Gottlieb S, Pasqualini T, Knoblovits P, Aszpis S, et al. Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach. Andrology. 2013;1(1):3–16. [DOI] [PubMed] [Google Scholar]
71.Sprauten M, Brydøy M, Haugnes HS, Cvancarova M, Bjøro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol. 2014;32(6):571–8. [DOI] [PubMed] [Google Scholar]
72.Bjerner J, Biernat D, Fosså SD, Bjøro T. Reference intervals for serum testosterone, SHBG, LH and FSH in males from the NORIP project. Scand J Clin Lab Investig. 2009;69(8):873–9. [DOI] [PubMed] [Google Scholar]
73.Aydiner A, Aytekin Y, Topuz E. Effects of cisplatin on testicular tissue and the Leydig cell-pituitary axis. Oncology. 1997;54(1):74–8. [DOI] [PubMed] [Google Scholar]
74.Eberhard J, Ståhl O, Cwikiel M, Cavallin-Ståhl E, Giwercman Y, Salmonson EC, et al. Risk factors for post-treatment hypogonadism in testicular cancer patients. Eur J Endocrinol. 2008;158(4):561–70. [DOI] [PubMed] [Google Scholar]
75.Ondrusova M, Spanikova B, Sevcikova K, Ondrus D. Testosterone deficiency and bone metabolism damage in testicular cancer survivors. Am J Mens Health. 2018;12(3):628–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Walsh JS, Marshall H, Smith IL, Greenfield DM, Swain J, Best E, et al. Testosterone replacement in young male cancer survivors: a 6-month double-blind randomised placebo-controlled trial. PLoS Med. 2019;16(11):e1002960. [DOI] [PMC free article] [PubMed] [Google Scholar]
77.Huddart RA, Norman A, Moynihan C, Horwich A, Parker C, Nicholls E, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer. 2005;93(2):200–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med. 1990;11(1):1–20. [PubMed] [Google Scholar]
79.Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol. 1991;65(2):81–94. [DOI] [PubMed] [Google Scholar]
80.Einhorn LH, Williams SD, Loehrer PJ, Birch R, Drasga R, Omura G, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol. 1989;7(3):387–91. [DOI] [PubMed] [Google Scholar]
81.Lauritsen J, Kier MGG, Bandak M, Mortensen MS, Thomsen FB, Mortensen J, et al. Pulmonary function in patients with germ cell cancer treated with bleomycin, etoposide, and cisplatin. J Clin Oncol. 2016;34(13):1492–9. [DOI] [PubMed] [Google Scholar]
82.van der Schoot GGF, Westerink NL, Lubberts S, Nuver J, Zwart N, Walenkamp AME, et al. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients. Eur J Cancer. 2016;59:134–41. [DOI] [PubMed] [Google Scholar]
83.Haugnes HS, Aass N, Fosså SD, Dahl O, Brydøy M, Aasebø U, et al. Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol. 2009;27(17):2779–86. [DOI] [PubMed] [Google Scholar]
84.Glendenning JL, Barbachano Y, Norman AR, Dearnaley DP, Horwich A, Huddart RA. Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer. 2010;116(10):2322–31. [DOI] [PubMed] [Google Scholar]
85.Brydøy M, Oldenburg J, Klepp O, Bremnes RM, Wist EA, Wentzel-Larsen T, et al. Observational study of prevalence of long-term raynaud-like phenomena and neurological side effects in testicular cancer survivors. J Natl Cancer Inst. 2009;101(24):1682–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer. 1999;83(6):866–9. [DOI] [PubMed] [Google Scholar]
87.Inai H, Kawai K, Ikeda A, Ando S, Kimura T, Oikawa T, et al. Risk factors for chronic kidney disease after chemotherapy for testicular cancer. Int J Urol. 2013;20(7):716–22. [DOI] [PubMed] [Google Scholar]
88.Oldenburg J, Kraggerud SM, Brydøy M, Cvancarova M, Lothe RA, Fossa SD. Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study. J Transl Med. 2007;5(1):70. [DOI] [PMC free article] [PubMed] [Google Scholar]
89.Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155(12):2461–70. [DOI] [PubMed] [Google Scholar]
90.Sprauten M, Darrah TH, Peterson DR, Campbell ME, Hannigan RE, Cvancarova M, et al. Impact of long-term serum platinum concentrations on neuro- and ototoxicity in cisplatin-treated survivors of testicular cancer. J Clin Oncol. 2012;30(3):300–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Raj S, Parkinson C, Williams M, Mazhar D. Management of brain metastases from germ cell tumors: do we know what we are doing? Future Oncol. 2008;4(1):1–4. [DOI] [PubMed] [Google Scholar]
92.Spears WT, Morphis JG, Lester SG, Williams SD, Einhorn LH. Brain metastases and testicular tumors: long-term survival. Int J Radiat Oncol Biol Phys. 1992;22(1):17–22. [DOI] [PubMed] [Google Scholar]
93.Doyle DM, Einhorn LH. Delayed effects of whole brain radiotherapy in germ cell tumor patients with central nervous system metastases. Int J Radiat Oncol Biol Phys. 2008;70(5):1361–4. [DOI] [PubMed] [Google Scholar]
94.Smith AB, Rutherford C, Butow P, Olver I, Luckett T, Grimison P, et al. A systematic review of quantitative observational studies investigating psychological distress in testicular cancer survivors. Psychooncology. 2018;27(4):1129–37. [DOI] [PubMed] [Google Scholar]
95.Kreiberg M, Bandak M, Lauritsen J, Andersen KK, Skøtt JW, Johansen C, et al. Psychological stress in long-term testicular cancer survivors: a Danish nationwide cohort study. J Cancer Surviv. 2020;14(1):72–9. [DOI] [PubMed] [Google Scholar]
96.Raphael MJ, Gupta S, Wei X, Peng Y, Soares CN, Bedard PL, et al. Long-term mental health service utilization among survivors of testicular cancer: a population-based cohort study. J Clin Oncol. 2021;39(7):779–86. [DOI] [PubMed] [Google Scholar]
97.Thorsen L, Nystad W, Stigum H, Dahl O, Klepp O, Bremnes RM, et al. The association between self-reported physical activity and prevalence of depression and anxiety disorder in long-term survivors of testicular cancer and men in a general population sample. Support Care Cancer. 2005;13(8):637–46. [DOI] [PubMed] [Google Scholar]
98.Gunnes MW, Lie RT, Bjørge 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. [DOI] [PubMed] [Google Scholar]
99.Hellesnes R, Myklebust T, Fosså SD, Bremnes RM, Karlsdottir Á, Kvammen Ø, et al. Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort. J Clin Oncol. 2021;39(32):3561–73. [DOI] [PubMed] [Google Scholar]
100.Zaorsky NG, Zhang Y, Tuanquin L, Bluethmann SM, Park HS, Chinchilli VM. Suicide among cancer patients. Nat Commun. 2019;10(1):207. [DOI] [PMC free article] [PubMed] [Google Scholar]
101.Nezu K, Yamashita S, Kakimoto K, Uemura M, Kishida T, Kawai K, et al. Association of financial toxicity with quality of life in testicular cancer survivors. Int J Urol. 2022;29(12):1526–34. [DOI] [PubMed] [Google Scholar]
102.Fosså SD, Åbyholm T, Aakvaag A. Spermatogenesis and Hormonal Status after Orchiectomy for Cancer and before supplementary treatment. Eur Urol. 2017;10(3):173–7. [DOI] [PubMed] [Google Scholar]
103.Petersen PM, Skakkebaek NE, Rorth M, Giwercman A. Semen quality and reproductive hormones before, and after orchiectomy in men with testicular cancer. J Urol. 1999;161(3):822–6. [PubMed] [Google Scholar]
104.Soni KK, Kim HK, Choi BR, Karna KK, You JH, Cha JS, et al. Dose-dependent effects of cisplatin on the severity of testicular injury in Sprague Dawley rats: reactive oxygen species and endoplasmic reticulum stress. Drug Des Dev Therapy. 2016;10:3959–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Pettus JA, Carver BS, Masterson T, Stasi J, Sheinfeld J. Preservation of ejaculation in patients undergoing nerve-sparing postchemotherapy retroperitoneal lymph node dissection for metastatic testicular cancer. Urology. 2009;73(2):328–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
106.Nome RV, Småstuen MC, Fosså SD, Kiserud CE, Åsvold BO, Bjøro T. Thyroid hypofunction in aging testicular cancer survivors. Acta Oncol. 2021;60(11):1452–8. [DOI] [PubMed] [Google Scholar]
107.Fung C, Dinh PC Jr, Travis LB, Re. Thyroid hypofunction in aging testicular cancer survivors. Acta Oncol. 2022;61(3):386–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Vaughn DJ, Palmer SC, Carver JR, Jacobs LA, Mohler ER. Cardiovascular risk in long-term survivors of testicular cancer. Cancer. 2008;112(9):1949–53. [DOI] [PubMed] [Google Scholar]
109.Schepisi G, De Padova S, De Lisi D, Casadei C, Meggiolaro E, Ruffilli F, et al. Psychosocial issues in long-term survivors of testicular cancer. Front Endocrinol. 2019;10:113. [DOI] [PMC free article] [PubMed] [Google Scholar]
110.Selvi I, Basar H. Subcapsular orchiectomy versus total orchiectomy and LHRH analogue in the treatment of hormone-sensitive metastatic prostate cancer: a different perspective in evaluation of the psychosocial effects. Support Care Cancer. 2020;28(9):4313–26. [DOI] [PubMed] [Google Scholar]
111.Pühse G, Wachsmuth JU, Kemper S, Husstedt IW, Kliesch S, Evers S. Phantom testis syndrome: prevalence, phenomenology and putative mechanisms. Int J Androl. 2010;33(1):e216–20. [DOI] [PubMed] [Google Scholar]
112.Sigg S, Fankhauser CD. The role of primary retroperitoneal lymph node dissection in the treatment of stage II seminoma. Curr Opin Urol. 2023;33(4):245–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Dieckmann K-P, Radtke A, Spiekermann M, Balks T, Matthies C, Becker P, et al. Serum levels of MicroRNA miR-371a-3p: a sensitive and specific new biomarker for germ cell tumours. Eur Urol. 2017;71(2):213–20. [DOI] [PubMed] [Google Scholar]
114.Oing C, Kollmannsberger C, Oechsle K, Bokemeyer C. Investigational targeted therapies for the treatment of testicular germ cell tumors. Expert Opin Investig Drugs. 2016;25(9):1033–43. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No datasets were generated or analysed during the current study.

PERMALINK

Late side effects of testicular cancer and treatment: a comprehensive review

M Raheel Khan

Patrice Kearney Sheehan

Ashley Bazin

Christine Leonard

Umair Aleem

Lynda Corrigan

Ray McDermott