8. FOLLOW-UP AFTER CURATIVE THERAPY
8.1. Minimal recommendations for follow-up
Based on different risks of relapse depending on diagnosis and initial treatment, three major follow-up groups can be defined:
3.all patients having received either adjuvant treatment or curative chemotherapy for “good”- and intermediate-prognosis metastatic disease (according to the IGCCCG) achieving a complete remission with, or without, surgery (for seminoma this includes residual lesions < 3 cm, or residual lesions > 3 cm that are PET-negative).
It is important to note that patients not achieving a complete remission or presenting with poor-prognosis disease should be followed up individually by specialised centres. Tables 8.1-8.3 show the minimal recommendations for follow-up of the three different groups based on recommendations developed at a European Society for Medical Oncology (ESMO) consensus conference .
Both CT and MRI can be used to evaluate the retroperitoneum, pelvis and inguinal regions for sites of metastatic disease from TC . Magnetic resonance imaging benefits from an absence of ionising radiation but is more time consuming and less readily available than CT . Given the frequency of follow-up, over a number of years some studies have estimated a risk of up to 1 in 300 of second malignancy related to CT imaging follow-up alone , although more recent dose saving protocols and limitations on field of view will have mitigated this somewhat. Nevertheless, this risk could be excluded by the use of MRI for follow-up.
Both CT and MRI rely predominantly on size cut-offs for evaluation given the excellent spatial resolution of both modalities, with morphological assessment for features such as necrosis and irregular shape an adjunct. Sensitivity and specificity vary according to the size cut-off used . However, studies have shown comparable excellent results between CT and MRI with up to 98% sensitivity on MRI for the detection of retroperitoneal nodal metastases in TGCT . It has, however, been demonstrated that reader experience is important when interpreting images . In the setting of TGCT, one study demonstrated decreased sensitivity for detection of retroperitoneal nodal disease on MRI when reported by a trainee radiologist with sensitivity of detection of 80% . However, experienced radiologists in the same study again achieved sensitivity for detection of nodal disease of 97% with good interobserver agreement. It was therefore suggested that if MRI is to be used instead of CT for follow-up this be done in centres/units with oncological radiologists who routinely report CT and MRI in patients with TGCT rather than general radiologists who may only occasionally see such imaging. Consequently, MRI of the abdomen can be used as an alternative to CECT in experienced centres .
Regarding the use of US examination of the contralateral testis, the majority of the consensus meeting participants did not support repeat US investigation, either with negative biopsy or if no contralateral biopsy has been performed .
A very late relapse (VLR) after five years is a rare event occurring in approximately 0.5% of patients based on a population-based analysis . The aim of follow-up beyond five years therefore shifts to detection of late side effects of treatment, and imaging tests are not routinely recommended.
Most patients with VLR are diagnosed due to symptoms, although up to 50% elevated tumour markers are present in both seminoma and NSGCTs [303,316]. Patient education regarding relapse symptoms and clinician awareness are important elements of survivorship management. Early use of imaging and tumour markers with suspicion of relapse is encouraged.
Table 8.1: Recommended minimal follow-up for seminoma clinical stage I on active surveillance or after adjuvant treatment (carboplatin or radiotherapy)
Years 4 & 5
After 5 years
± doctor visit
Further management according to survivorship care plan
Once at 36 months
Once at 60 months
Table 8.2: Recommended minimal follow-up for non-seminoma clinical stage I on active surveillance
Year 4 & 5
After 5 years
± doctor visit
Further management according to survivorship care plan
Once, in case of LVI+
At 60 months if LVI+
At 24 months**
Once at 36 months***
Once at 60 months***
* In case of high-risk (LVI+) a minority of the consensus group members recommended six times.
** In case of high-risk (LVI+) a majority of the consensus group members recommended an additional CT at eighteen months.
*** Recommended by 50% of the consensus group members.
LVI+ = Lymphovascular invasion present
Table 8.3: Recommended minimal follow-up after adjuvant treatment or complete remission for advanced disease (excluded: poor-prognosis and no remission)
Year 4 & 5
After 5 years
Tumour markers ± doctor visit
Further management according to survivorship care plan**
resonance imaging (MRI)
At 24 months
Once at 36 months
Once at 60 months
At 24 months*
Once at 60 months*
Once at 60 months*
* In conjunction with abdominopelvic CT/MRI in case of pulmonary metastases at diagnosis.
** In case of teratoma in resected residual disease: the patient should remain with the uro-oncologist.
8.2. Quality of life and long-term toxicities after cure of testicular cancer
The vast majority of patients will be cured with five-year relative survival rates of approximately 95% in Western Europe. Testicular cancer patients are usually between 18 and 40 years of age at diagnosis and life expectancy after cure extends over several decades . Patients should be informed before treatment of common long-term toxicities, which are avoided or minimised by adherence to international guidelines.
Treatment of stage I TC is controversial, with some experts advocating surveillance for all, thereby avoiding unnecessary adjuvant chemotherapy , whereas others highlight the importance of patient autonomy and consider the prospect of avoiding salvage treatment with long-term toxicities appealing . Unfortunately, it is not known which treatment spares most patients from long-term toxicities, which so far seem to be absent or mild after adjuvant chemotherapy. This observation is confirmed by the absence of excess mortality or late toxicities between stage I non-seminoma patients randomised to either primary RPLND or one cycle of adjuvant BEP .
During follow-up, patients should be screened and treated for known risk factors such as hypertension, hyperlipidaemia, and testosterone deficiency. Adverse health outcomes (AHOs) are more commonly found in TC patients who received chemotherapy than those cured by surgery alone. Further, modifiable risk factors do contribute to AHOs like hypertension and noise exposure to hearing impairment or smoking to Raynaud phenomenon . Therefore, a healthy lifestyle should be promoted during the follow-up consultations. Adverse health outcomes are associated with unemployment, which is found clearly increased in TCSs as compared to a male normative population . When follow-up by the TC clinician is terminated, a written cancer survivorship plan addressing late toxic effects, lifestyle recommendations, recurrence risk, and cancer-specific follow-up may be helpful [54,322].
8.2.1. Second malignant neoplasms (SMN)
Metachronous contralateral TC represents a particular SMN as it consists of a GCT. Further, cisplatin-based chemotherapy approximately reduces the risk of a subsequent contralateral TC as compared to surgery only
[323,324]. Second malignant neoplasms of different histologic origin usually occur after the first ten years and are considered to be induced by chemo- and/or radiotherapy . Testicular cancer is commonly diagnosed in adolescents and young adults (AYA), which have a higher absolute risk of developing a subsequent primary neoplasm than survivors of childhood or adult cancer . In a comprehensive study on second cancers in AYA cancer survivors (aged 15-39 years at AYA cancer diagnosis), 24,309 TC survivors with 1,435 second cancers were registered as opposed to 808 expected second cancers, yielding a standardised incidence ratio of 1.8. The second cancer incidence increased with time resulting in remarkably high and accelerating 35-year cumulative incidence rate of 20% (95% CI: 18·9–21·5) .
The risk for solid SMN increases with younger age at radio- or chemotherapy . Radiotherapy-related SMN are primarily localised within, or close to, the radiotherapy field (colon, stomach, pancreas, bladder, and the urinary tract) . A remarkably clear radiation-dose relationship to gastric- and pancreatic cancer has been demonstrated .
Modern cisplatin-based chemotherapy has been found to be associated with a 40% increased risk of a solid SMN . A relationship between cumulative dose of cisplatin and second SMN, especially in the GI tract, has been noted . As few studies have observation times beyond 25 years, the cumulative incidence of SMN may be underestimated. An increase from 6.5% after 25 years to 20% after 35 years has been
reported . Second malignant neoplasms were identified in 9.4% of Swedish TC survivors, with half these cancers considered uncommon in men in their 40s . Survival was 40% in TC survivors with a SMN as opposed to 80% in those without .
The European Society for Blood and Marrow Transplantation (EBMT) reported SMN in 59 of the 5,295 TC patients registered after receiving HDCT within a median follow-up of 3.8 years. Of them, 39% developed a hematologic SMN and 58% a solid SMN. Twenty-year cumulative incidence of solid and hematologic SMN was 4.2% and 1.4% respectively, with median OS shorter after diagnosis of hematologic vs. solid SMN (8.6 vs. 34.4 months). Age > 40 years at the time of HDCT was significantly associated with hematologic, but not with solid SMNs . Among 24,900 US TCSs, one out of six (16.9%) developed a solid SMN after 30 years of observation time .
In a series of 40,576 TC survivors, the observed ratio for developing leukaemia, mostly acute myeloid (AML) and lymphoblastic leukaemia was 2.6 . Among 24,900 US TCSs, the risk of developing leukaemia, mostly AML, after chemotherapy was 2.7 fold increased . The risk of AML seems to be related to both the dose of cisplatin and etoposide. Doses of etoposide exceeding 2 g/m2 have been shown to increase the subsequent risk of AML . The majority of TC patients receive much lower doses of etoposide than this so that the absolute risk of AML after three to four courses of BEP is very low. In patients requiring HDCT with cumulative etoposide doses exceeding this threshold, fewer than 1.5% have been reported to develop AML. There is a cumulative dose disease risk relationship with cisplatin and AML. Chemotherapy-induced leukaemia is usually diagnosed within the first ten years after treatment for TC and has a poor-prognosis .
Chemotherapy-treated TC survivors (TCSs) have a higher risk of dying from infections than the general population (standard mortality ratio 2.48, 95%; CI: 1.70-3.5) . This is possibly due to long-term bone marrow suppression, as well as complications of subsequent salvage treatment (which was not reliably registered). Alternatively, extensive or subsequent surgical treatment may be contributory. Furthermore, asymptomatic pulmonary fibrosis by mediastinal radiotherapy and/or bleomycin may render TCSs vulnerable to respiratory infections long after treatment.
8.2.4. Pulmonary complications
Chemotherapy exposed TCSs have a nearly three-fold increased risk of dying of pulmonary diseases than the normal population . Bleomycin-induced lung toxicity may affect 7-21% of patients in the long term, resulting in death in 1-3% . Testicular cancer survivors who received high cumulative cisplatin doses and/or pulmonary surgery, have a poorer pulmonary function than those cured with surgery alone . Intriguingly, long-term pulmonary complications were associated with the cumulative cisplatin doses but not with the dose of bleomycin . The data contrasts with a meta-analysis on chemotherapy for TC including 6,498 patients showing a significant effect of bleomycin administration on all-grade pulmonary toxicity . In a Danish cohort of 565 TC survivors, Lauritsen et al., found pulmonary function recovered with repeated assessments over five years in almost all patients . Pulmonary function was not associated with reduced renal function, age, tobacco-smoking, and cumulative chemotherapy, but rather pulmonary embolism, lung surgery, and poor IGCCCG risk group . In 234 good risk TCSs patients the inclusion of bleomycin did not seem to influence pulmonary morbidity, operative difficulty, or non-pulmonary post-operative complications after post-chemotherapy RPLND .
A Canadian study on 212 TC patients receiving bleomycin-containing chemotherapy revealed bleomycin-induced pneumonitis (BIP) in 73 patients (34%) with the majority of these (75%) asymptomatic . Granulocyte colony stimulating factor use was not associated with increased risk of BIP in multivariable analyses nor was it associated with increased severity of symptomatic BIP. There was a non-statistically significant trend towards greater risk of BIP in patients that developed renal impairment during chemotherapy treatment .
8.2.5. Cardiovascular toxicity
Thromboembolic events (mostly venous) occur more frequently in GCT patients receiving chemotherapy than in other young male adults treated with chemotherapy for other cancers . Low-dose heparins used during the course of chemotherapy may prevent the onset of thromboembolic events , though level 1 evidence is lacking. Mortality from cardiovascular disease (CVD) is higher in TCSs than in the general population
(OR: 5) [227,342,343]. Furthermore, CVD is more common in chemotherapy-treated TCSs than in those who underwent surgery only [182,344]. Feldman et al., applied the Framingham Risk Score (FRS) on 787 TC survivors and compared the results with controls : FRS did not differ by chemotherapy regimen (BEP 3 vs. EP 4) nor between control and TCSs, although the latter were three times less likely to smoke and generally more physically active. However, less educated, and less vigorously active TCSs had higher FRS representing a high-risk subgroup for intense follow-up and counselling .
Most of the above studies are registry-based and thus limited. Lauritsen et al., took advantage of the
comprehensive prospective registration of cancer, diagnoses and drug prescription in Denmark comparing outcomes between 5,185 GCT patients and 51,850 men without GCT .
Cisplatin, etoposide, bleomycin (BEP) chemotherapy, applied in 1,819 GCT patients increased the risks of hypertension and hypercholesterolemia and thus CVD within one year after initiation of BEP: with hazard ratios (HRs) of 6.3, 6.0, and 24.7 for myocardial infarction, cerebrovascular accident, and venous thromboembolism, respectively. One year after BEP treatment, the risk of CVD decreased to normal levels, but after ten years, increasing risks were found for myocardial infarction (HR: 1.4; 95% CI: 1.0 to 2.0) and cardiovascular death (HR: 1.6; 95% CI: 1.0 to 2.5) .
Metabolic syndrome, a strong risk factor for CVD and its components, hypertension, obesity and hypercholesterolaemia, increases with treatment intensity (OR: 9.8) [343,346,347]. Hypogonadism increases the risk of insulin resistance, a proxy for metabolic syndrome, and an inherent risk of CVD. Bogefors
et al., showed, however, that most associations between TC treatment and metabolic parameters became statistically non-significant after adjustment for hypogonadism, indicating that hypogonadism might be the mediator of several toxicities which are usually attributed to the applied TC treatment . Circulating residual serum platinum might exert endothelial stress and thereby possibly lead to hypertension . Furthermore, exposure to circulating platinum is associated with paraesthesia, hypogonadism, and hypercholesterolaemia as well as major vascular events .
In a 30-year follow-up, chemotherapy treated TCSs used more often anti-hypertensive or lipid-lowering medications as controls. The TCSs’ diastolic heart function was impaired as compared to the controls, whereas no difference was found regarding systolic- or valvular function or prevalence of arrhythmias . The finding of increased vascular stiffness of TCSs more than 20 years after chemotherapy suggests accelerated vascular aging; thus, highlighting the need for intensive cardiovascular risk management .
Physical activity reduces the risk of metabolic syndrome and CVD. High-intensity aerobic interval training (HIIT) for twelve weeks improved cardiorespiratory fitness, multiple pathways of CVD risk, and surrogate markers of mortality in TCSs as compared to standard care, i.e., no supervised training . However, HIIT during cisplatin-based chemotherapy might be harmful as a planned study on 94 patients was closed early after recruiting nineteen patients and the finding of severe CVD complications among three out of nine patients undergoing HIIT . Two patients developed a pulmonary embolism (respectively at days seven and nine of BEP cycle 2) and the remainder a myocardial infarction (at day seven of BEP cycle 3). It is difficult to draw firm conclusions from such small patient numbers, but the observed CVD was well above the expected 5% risk of thromboembolic complications during or shortly after cisplatin-based chemotherapy such that the authors discourage HIIT during cisplatin-based chemotherapy for TC.
8.2.6. Raynaud-like phenomena, Neurotoxicity & Ototoxicity
Chemotherapy-related Raynaud-like phenomena were reported before the introduction of cisplatin and are usually attributed to bleomycin [354,355]. Cisplatin is believed to contribute to cold-induced vasospasms. Vogelzang et al., reported that the incidence of Raynaud’s phenomenon was higher after treatment with CVB than with vinblastine and bleomycin only, 41% vs. 21%, respectively .
Cisplatin induces a symmetric dose-dependent sensory, distal, length-dependent glove and stocking paraesthesia, affects 29% of TCSs who received cisplatin-based chemotherapy as opposed to 10% after orchidectomy alone [343,357]. Treatment with five or more cycles increases the frequency of this symptom to 46%. Paclitaxel-induced acute neuropathy consists of an acute pain syndrome, which usually develops within three to seven days following its administration. Platinum is measurable in the serum of TCSs many years after its application with the intensity of paraesthesia more strongly associated with platinum serum level than with the cumulative dose of applied cisplatin . Patients who experience a larger decline in circulating residual serum platinum during follow-up are at reduced risk of worsening of tinnitus or hand paraesthesia .
Cisplatin-induced ototoxicity comprises tinnitus and hearing impairment, particularly frequencies of 4,000 Hz and higher, and is caused by damage to the outer hair cells in the inner ear . Encouragingly, hearing impairment deteriorated not considerably after the first decade after chemotherapy and quite normal speech perception tests 30 years after treatment indicated a limited clinical relevance of the high-frequency hearing loss [359,360]. Both hearing impairment and tinnitus are considerably increased after application of 50 mg/m2 cisplatin over two days as compared to 20 mg/m2 over five days (OR: 5.1 and 7.3, respectively), indicating a higher impact of serum peak concentrations than cumulative doses . A significant association between Glutathione S-transferases (GST) genotypes and the risk of cisplatin-induced ototoxicity has been demonstrated [361,362].
A comprehensive clinical and genome-wide analysis of multiple severe cisplatin-induced neurotoxicities has revealed a correlation between neurotoxicity, ototoxicity, and Raynaud phenomena in TCSs . Of particular interest was the observation that certain TCSs seem to be particularly vulnerable to develop multiple and serious neuro-otological toxicities. TCSs without toxicities comprised the 196 controls and TCSs with two to three severe toxicities represented the 104 cases. Only three controls (1.5%) reported fair/poor health as compared to 18 (17.5%) of the cases.
Patients with multiple severe neurotoxicities were also more likely to report symptoms of peripheral motor neuropathy. Current smoking had a clearly negative impact on severe neurotoxicities. No genome-wide significant SNPs for developing severe cisplatin-induced neurotoxicities were identified. The authors concluded that metastatic TC patients with good-risk features should preferably be treated with 3 x BEP instead of 4 x EP in order to avoid neurotoxicities by the fourth cycle of cisplatin .
8.2.7. Cognitive function
There are concerns that chemotherapy may reduce the cognitive function leading to “chemo-brain.” Amidi et al., could show an alteration of brain structural networks after cisplatin-based chemotherapy for TC . Impaired brain networks may underlie poorer performance over time on both specific and non-specific cognitive functions in TC survivors following chemotherapy.
Cisplatin-based chemotherapy may lead to long-term renal dysfunction in 20-30% of TCSs [234,344,346]. In TC patients, reduced renal excretion of cisplatin and bleomycin might increase the risk of other toxicities, e.g., bleomycin-related pneumonitis [365,366]. A comprehensive assessment of 1,206 Danish TCSs, however, did not reveal a significant association between chemotherapy-induced impaired renal function and other toxicities . Renal recovery was poor after five or more cycles of BEP as compared to after BEP x 3 . The estimation of glomerular filtration rate (eGFR) depends on whether creatinine or cystatin is applied, with the latter substance leading to an overestimation of eGFR in cisplatin treated TCSs, whereas this discrepancy was not found in patients with chronic kidney failure due to medical disease . Genomic markers are related to the risk of cisplatin-induced nephrotoxicity . How these results will impact selection and/or modification of chemotherapy remains to be seen.
Testicular endocrine dysfunction comprises insufficient testosterone production and/or compensatory increased LH levels. Subnormal testosterone levels have been reported in TCSs treated with chemotherapy, when compared to those treated with surgery only or the general population [343,365,369,370]. Compensated Leydig cell dysfunction in TCSs (testosterone within normal limits & increased LH values) was not associated with symptoms of depression, anxiety, sexual dysfunction, fatigue or impaired overall self-evaluated QoL, such that testosterone substitution seems not to be indicated in these patients .
Hypogonadism increases the risk of insulin resistance and hence the risk of metabolic syndrome, which, in turn, might lead to CVD in the long term . Wiechno et al., could show a decline in testosterone and an increase in LH and FSH within one year after treatment for unilateral TC . Although there are clear indications of hypogonadism-related complications, and despite an established association between low testosterone and metabolic syndrome, no clear association between Leydig cell dysfunction and the risk of metabolic syndrome during a median ten-year follow-up could be established .
Walsh et al., reported a RCT demonstrating a benefit of testosterone replacement therapy in young male survivors of TC, lymphoma, and leukaemia aged 25–50 years who had low morning serum testosterone. Under the six months of replacement therapy, cancer survivors that received testosterone experienced a decrease in trunk fat mass and whole-body fat mass and an increase in lean-body mass, but no effect on reported physical functioning or other QoL scores when compared to those that received a placebo gel . The absence of improved QoL and the issue of rendering TCSs sub- or infertile by testosterone replacement therapy is the reason why the TC panel does not recommend this strategy until more compelling endpoints are reported. An ongoing Danish RCT might yield new level 1 evidence .
Erectile dysfunction (OR: 4.2) has been significantly associated with chemotherapy in a recent multicentre study . Of 481 North American TCSs treated with modern cisplatin-based chemotherapy, 38% were hypogonadal (defined as on testosterone substitution or serum testosterone level < 3.0 ng/mL) . Hypogonadism was associated with the number of adverse health outcomes and its risk increased with age and obesity .
Chronic fatigue (CF) is described as a subjective feeling of emotional, physical and/or cognitive tiredness that is not relieved by rest and persists for more than six months. Significantly higher levels of C-reactive protein and interleukin-1 receptor antagonist are measured in TCSs with CF . Also, a significantly higher frequency of CF (16%) was reported in a cross-sectional Norwegian study of long-term TCSs at a median of twelve years after treatment for TC when compared with the age-matched Norwegian population (10%) . Of note, the prevalence of CF increased from 15-27% during a ten-year period in long-term TCSs .
8.2.11. Quality of life
Quality of life is transiently reduced by chemotherapy, during which patients experience a loss of appetite, increased fatigue, increased dyspnoea and reduced social- and physical function . When comparing three or four cycles of BEP in good-risk patients, all outcomes favour treatment with three courses . After one and two years, one-third of patients reported an improvement in global QoL after chemotherapy, while one fifth of patients reported deterioration, with no difference between treatment groups. After adjuvant treatment of non-seminoma stage I patients, there was no difference in short-term or long-term (five years) QoL between RPLND, or one course of BEP .
Anxiety, depression, fear of cancer recurrence (FCR), and distress may impair the health-related quality of life (HRQoL) in TCSs. A recent review identified a considerable variation in both severity and prevalence of each of these issues, probably due to use of different questionnaires and also cultural variations . Clinically significant anxiety is reported in approximately one out of five TCSs and distress in one out of seven; therefore, it is more frequent among TCS than in the general population. Depression was not uniformly found to be more frequent, whereas every third TCSs reported fear of recurrence. Importantly, poorer psychological outcomes were more common among single, unemployed TCSs with a low socio-economic status and co-morbidities, as well as those experiencing worse symptoms/side effects, and those using passive coping strategies.
A German study found clinically significant anxiety in 6.1% and depression present in 7.9% of TC patients, with both a higher number of physical symptoms and the prospect of having children being related to higher levels of anxiety and depression .
Among 2,479 Danish long-term TCSs, higher anxiety was reported by those who experienced bilateral TC as compared to unilateral TC . For a subset of approximately 11% of TCSs, the diagnosis of TC was traumatic. This subset was found to suffer from post-traumatic stress disorder in the long term, which resulted in significant QoL reduction . Kreiberg et al., recommend stress symptoms at follow-up visits in order to timely identifyTCSs requiring support . This recommendation is supported by the finding of an increased mental health service utilisation as compared to healthy controls . Testicular cancer survivors who developed bilateral TC had a higher degree of anxiety compared to survivors of unilateral TC but did not report otherwise impaired QoL .
Erectile dysfunction was found in men who underwent radiotherapy, BEP chemotherapy with subsequent surgical resection of residual masses, or more than one line of treatment. The latter group also reported orgasmic dysfunction. After radiotherapy, significantly more men reported overall decreased sexual satisfaction, whereas all other groups reported no difference in overall satisfaction, intercourse satisfaction, and sexual desire .
Testicular cancer survivors were more likely to have high levels of stress compared to the reference population with a prevalence ratio of 1.56 (95% CI: 1.40 – 1.73), according to a big cohort study with 2,252 patients, with a median of nineteen years from diagnosis .