By Jan Oldenburg, MD, PhD; Hege S. Haugnes, MD, PhD; Silke Gillessen, MD; and Torgrim Tandstad, MD, PhD
- Survivorship research and long-term side effects are areas of particular importance for testicular cancer survivors because of the high cure rate and the young median age at diagnosis.
- Long-term side effects in this population include secondary malignant neoplasms, pulmonary complications, cardiovascular toxicity, and fertility issues.
- Preventive measures, such as smoking cessation, a healthy diet, and an active lifestyle, may play an important role in reducing the risk of several treatment-related toxicities.
Long-term complications are of utmost importance and have to be recognized early or, ideally, prevented. It is crucial that health care personnel involved in follow-up care focus on signs and symptoms of known complications following treatment in addition to diagnosing possible relapse. This editorial provides an overview of the most important and frequent long-term complications.
Secondary Malignant Neoplasms
The most severe treatment-related late effects in testicular cancer survivors are secondary malignant neoplasms (SMN). The risk of SMN is not increased in patients treated with surgery alone (defined as orchiectomy with or without retroperitoneal lymph node dissection), such that a congenitally increased risk of SMN is unlikely.2 The development of solid SMN takes time, and an increased risk is usually not observed before 15 years of follow-up. Secondary hematologic malignancies, including acute leukemia, are rarer and occur earlier, usually within 10 years after treatment.3,4
In one large study including 40,576 testicular cancer survivors, the relative risk (RR) of second cancers was 1.8 after CT, 2.0 after radiotherapy (RT), and 2.9 after both CT and RT.5 The majority of patients in these studies received CT for metastatic disease, and henceforth we have no data on the risk of SMN for patients receiving adjuvant CT. The cumulative CT dose is low when one cycle of combination bleomycin, etoposide, and cisplatin (BEP) or carboplatin is used such that the risk of SMN is expected to be low. Adjuvant RT doses, however, do not differ much from those used in the treatment of metastatic disease, and the standardized incidence ratio (SIR) of SMN is 1.6 after adjuvant RT.6 SMNs following RT are located within or in proximity to the radiation fields—the most frequent being gastric, bladder, pancreatic, and colon cancers.7 Compared to CT, the odds ratio (OR) for gastric cancer after RT was 5.9 and reached 20.5 for doses of 50 Gy compared to doses less than 10 Gy, thereby establishing a clear dose–carcinogenesis gradient.8 SMNs following modern-era CT can be of any origin, but there seems to be an excess of cancers of soft tissue, kidney, and thyroid.2
The risk of dying of respiratory disease is increased nearly 3-fold for testicular cancer survivors after CT compared to the general population.9 Long-term bleomycin-induced lung toxicity may affect 7% to 21% of patients, resulting in death in 0% to 3%.10 The risk of long-term bleomycin-induced lung toxicity is associated with decreased renal function (hazard ratio [HR] 3.3), age older than 40 years (HR 2.3), initial stage III disease (HR 2.6), and cumulative bleomycin dose greater than 300,000 IU (300 units).10
Spirometric assessments of more than 1,000 Norwegian testicular cancer survivors revealed that men treated with large cumulative cisplatin doses and/or pulmonary surgery had, 11 years later, significantly decreased pulmonary function compared with men treated with surgery alone.11 However, these mostly subclinical alterations were significantly associated with cumulative cisplatin dose and age and not with the cumulative doses of bleomycin, etoposide, or vinblastine. Possibly aging and/or comorbidities increase the burden, as decreased pulmonary function has been shown to increase all-cause mortality in population-based epidemiologic studies.12,13
Mortality from cardiovascular disease (CVD) is higher in testicular cancer survivors than in the general population.9,14 An increased incidence of CVD, both fatal and non-fatal, has been observed in men previously treated with cisplatin-based CT in comparison to men treated with orchiectomy only.15-17 Infradiaphragmatic RT also is associated with an increased risk of CVD, fatal or non-fatal, in the majority of studies,6,17 although not all studies.16 Metabolic syndrome is a strong predictor for CVD, and its components (i.e., hypertension, obesity, and hypercholesterolemia) increase with treatment intensity (Fig. 1).18,19 Residual serum platinum is measurable decades after administration20 and, hypothetically, may exert endothelial stress.
CT-related Raynaud-like phenomena were reported before the introduction of cisplatin and are usually ascribed to bleomycin.21,22 Cisplatin is believed to contribute to cold-induced vasospasms, as the incidence of Raynaud’s phenomenon is higher after treatment with CVB than after vinblastine and bleomycin only (41% vs. 21%).23 Intriguingly, CT-related Raynaud’s phenomenon may be associated with erectile dysfunction.24
Cisplatin induces symmetric dose-dependent sensory, distal, length-dependent “glove and stocking” paraesthesias, affecting 29% of testicular cancer survivors who received cisplatin-based CT as opposed to 10% after orchiectomy alone.25 Application of five or more cycles increases the frequency of this symptom to 46%. Interestingly, self-reported paraesthesias 20 years after treatment were more strongly associated with serum platinum levels measured 10 years after application than with the initially applied cumulative dose, indicating an ongoing neuronal damage.20
Both the risk of hearing impairment and tinnitus are considerably increased after application of 50 mg/m2 cisplatin over 2 days as compared to 20 mg/m2 over 5 days (OR 5.1 and 7.3, respectively), indicating a higher effect of serum peak concentrations than cumulative doses.25
In a recent large Danish cohort, a median decrease of glomerular filtration rate (GFR) of −11.3%, −15.4%, and −25.9% after three, four, and five or more cycles of BEP has been demonstrated.29 There was a substantial rebound after treatment, but the renal function remained subnormal. However, this decrease in GFR was not associated with an increased risk of CVD or death. Reduced renal elimination of cisplatin and bleomycin might increase the risk of other toxicities (e.g., bleomycin-related pneumonitis).30,31
Chronic fatigue is a common and distressing adverse effect of cancer and its treatment.32 The prevalence of chronic fatigue 11 years after treatment was more common in testicular cancer survivors (16%) than in the general male population (10%).33 A subsequent survey 19 years after treatment revealed a surprisingly high chronic fatigue prevalence of 26%.34 Intriguingly, chronic fatigue was not associated with testicular cancer treatment, level of education, smoking, diabetes, pulmonary disease, or age. However, testicular cancer survivors who were physically active or had high testosterone levels had a lower prevalence of chronic fatigue.
The prevalence of primary hypogonadism increases in long-term testicular cancer survivors and is associated with treatment intensity35: 11 years after treatment, the OR for hypogonadism was 3.7 as compared to age-matched males without testicular cancer. The prevalence of hypogonadism does increase considerably from 10 years to 20 years after treatment (Fig. 3). Twenty years after treatment, ORs for lower testosterone were 3- and 5-fold increased after RT and CT, respectively. The ORs for increased LH and FSH were even higher, implying accelerated hormonal aging of testicular cancer survivors.
Conception rates of 554 testicular cancer survivors who wished to father children after testicular cancer treatment are shown in Figure 4.39 Survivors were grouped into five categories according their prior testicular cancer care: active surveillance, retroperitoneal lymph node dissection only, RT, cisplatin-based CT (< 850 cumulative cisplatin) and cisplatin-based CT (> 850 cumulative cisplatin). The overall actuarial post-treatment paternity rate 15 years after treatment was 71% without the use of cryopreserved semen. This rate was highest in the surveillance group (92%) and lowest in survivors who received more than 850 mg cisplatin (48%).
Lifestyle Interventions and Implications for Follow-Up
Treatment modality and intensity are recognized as risk factors for development of several long-term toxicities. However, apart from treatment burden, there is a lack of data on genetic or molecular factors that can identify testicular cancer survivors at high risk for treatment-related toxicities.
Low testosterone levels are associated with an increased prevalence of metabolic syndrome and increased risk for CVD. Yet, there are no data supporting testosterone substitution in order to prevent CVD.40 However, most clinicians agree that men with endocrine hypogonadism and symptoms such as reduced libido or loss of energy should be offered androgen replacement therapy unless there are contraindications.
Smoking, a significant risk factor for CVD and second malignancies, is also associated with decreased pulmonary function and neurologic adverse events in testicular cancer survivors.41 Other risk factors, including hypertension, obesity, hypercholesterolemia, and diabetes, are more prevalent in testicular cancer survivors who were treated with CT as compared to those cured by surgery only. Such factors may increase the development of several severe long-term complications.
Although the treatment burden represents an unchangeable risk factor for long-term toxicities, lifestyle factors are amenable to change. Consequently, follow-up of cancer survivors should include regular assessments of lifestyle factors and tools for achieving a healthy lifestyle. Preventive measures, such as smoking cessation, a healthy diet, and an active lifestyle, may play an important role in reducing the risk of several treatment-related toxicities.42 Importantly, regular physical activity is crucial in reducing the level of fatigue, which is one of the most distressing symptoms among testicular cancer survivors.32 Every patient should receive a survivorship care plan including tools for lifestyle interventions and regular checks for CVD risk factors and gonadal function.