Testicle cancer survivorship


Testicular cancer is the most common cancer among men aged 18 to 39 years. 


It is highly curable, with a 10-year relative survival approaching 95% due to effective cisplatin-based chemotherapy. 


TC survivors (TCS) now account for approximately 4% of all US male cancer survivors. 


Complications have emerged as important survivorship issues: second malignant neoplasms, cardiovascular disease, hearing loss, tinnitus, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, infertility, anxiety, depression, cognitive impairment, and chronic cancer-related fatigue. 


Platinum chemotherapy analogue agents bind to and damage DNA , detectable up to 20 years after chemotherapy,and may contribute in part to several toxicities. 



Approximately 70% of patients with stage I nonseminoma and 80% to 85% with stage I seminoma are cured with orchiectomy alone and 97% to 99% of those who experience relapse are ultimately cured with chemotherapy.



Surveillance is a common  management strategy for stage I TC.



For stage I nonseminoma, adjuvant chemotherapy with 1 cycle of bleomycin/etoposide/cisplatin and retroperitoneal lymph node dissection (RPLND) are other options, whereas adjuvant chemotherapy with 1 cycle of carboplatin and adjuvant radiotherapy (RT; 20 Gy) to the para-aortic lymph nodes are other options for stage I seminoma. 



Reductions in both RT fields, to include ipsilateral para-aortic lymphatics vs ipsilateral iliac and para-aortic lymphatics and doses, 20 vs 30 Gy.



These changes were adopted in stage I seminoma as studies showed that these modifications caused no differences in 2-year TC relapse rates3.0% vs 2.3%, respectively.



For stage IIA and IIB seminoma, an RT dose of 30 to 35 Gy administered to the infradiaphragmatic area, which extends from the para-aortic region to the proximal ipsilateral iliac lymph nodes. 



For selected patients with stage IIB or IIC seminoma, chemotherapy  are other options.



Patients with good-risk metastatic TC typically receive chemotherapy for 3-4 cycles.



Approximately 20% of patients with  require salvage therapy.



Radiation therapy for TC is associated with significant risks of leukemia and solid cancers.



Abdominal and pelvic RT is associated with a significant 3-fold risk of leukemia.



Cisplatin and etoposide are associated with elevated risks of secondary leukemia in TC survivors.



Alkylating chemotherapeutic agent–induced leukemia develops 5 to 8 years after therapy.



Leukemia is usually preceded by myelodysplastic syndromes (MDS) with a karyotype involving long-arm deletions or monosomy of chromosomes 5 and 7. 



Topoisomerase II inhibitor–induced leukemia has a median onset of 2 to 3 years, usually presents without preceding MDS, and is often characterized by balanced translocations.



A significant dose–response relationship exists between cumulative cisplatin dose and leukemia risk:


A cumulative cisplatin dose of 650 mg was associated with a significant 3.2-fold risk of leukemia and doses (1,000 mg) associated with significant 6-fold risks in TC treated patients.



The 5-year cumulative incidence of leukemia after cumulative etoposide doses of <2,000 and ≥2,000 mg/m2 was 0.5% and 2.0%, respectively. 



There is a significant 6.3-fold risk of myeloid leukemia after bleomycin, etoposide and platinum (BEP) chemotherapy compared with age-matched population-based controls.



There is a significant associations of secondary malignancy risk in TCS with  cisplatin-based chemotherapy: 


overall 1.4-fold risk of solid cancer compared with surgery-only patients, with significant risks of kidney, thyroid and soft tissue cancers.



TCS administered chemotherapy showed significantly increased risk for CVD.



The incidence of angina, myocardial infarction (MI), or sudden cardiac death was 7% in a British investigation of 390 TCS given chemotherapy.



Compared with controls, the risk of diabetes is significantly higher in the RT and RT/chemotherapy groups compared with surgery only.



There is  significant risks of atherosclerotic disease after RT, chemotherapy and RT/chemotherapy.



The risk of coronary artery disease is significantly increased 5.7-fold compared with surgery only, and MI risk was significantly increased 3.1-fold compared with age-matched male controls.



TCS may have increased CVD mortality due to cancer treatments.



An international population-based investigation indicated a significant 1.6-fold risk of mortality due to circulatory disease with a median follow-up, 10 years among TCS who received chemotherapy.



Raynaud phenomenon (RP) is primarily a clinical manifestation of bleomycin-associated vascular damage.



Cisplatin may contribute to Raynaud phenomenon.



Approximately 18.7% to 39.0% of TCS develop Raynaud phenomenon within 4 to 12 months of chemotherapy, respectively.



A quarter  of patients  experience RP symptoms up to 20 years.



15.6%, 8.7%, and 9.1% experience grade 1, 2, and 3 RP, respectively.



Almost 18% of TCS report severe to profound hearing loss.



Tinnitus was correlated with reduced hearing at each frequency.



Approximately 20% to 40% of TCS report peripheral neuropathy after cisplatin-based chemotherapy.



The incidence of neuropathy is related directly related to cumulative cisplatin dose and possibly residual serum platinum levels.



A Norwegian population-based study reported that 46%, 28%, and 10% of TCS experienced paresthesia after ≥5 cycles of cisplatin-based chemotherapy, 1 to 4 cycles of chemotherapy, and orchiectomy alone, respectively. 


The lower expression levels of RPRD1B are significantly associated with cisplatin-induced peripheral neuropathy.


Cisplatin causes primarily proximal and distal renal tubular dysfunction, leading to acute and chronic nephrotoxicity: There is  a persistently decreased glomerular filtration rate (GFR) in TCS for years after the end of treatment compared with baseline renal function. 


Treatment-related nephrotoxicity among long-term TCS may contribute to increases in incident CVD, including hypertension and MI.


Series reported no bleomycin-related deaths, likely attributable to bleomycin discontinuation at the earliest sign of pulmonary toxicity. 


Risk factors for late bleomycin-associated pulmonary toxicity include pulmonary surgery, tobacco use ≥20 pack years, and cumulative cisplatin dose >850 mg.


Danish study 16.1 years; reported that the cumulative risk of all pulmonary disease was comparable to that of TCS with stage I disease who remained on surveillance.


A Dutch study suggests that the HFE gene, may be involved in bleomycin-induced pulmonary toxicity. 


A multi-institutional investigation reported that approximately 38.5% of TCS had hypogonadism, defined by testosterone levels ≤300 ng/dL. 


Causes of hypogonadism in long-term TCS include orchiectomy, testicular dysgenesis syndrome, RT, and chemotherapy.


The intensity of treatment is directly associated with hypogonadism severity.


Cumulative cisplatin doses of >400 mg/m2 are associated with significant impairment of Leydig cell function compared with TCS who received no chemotherapy, whereas total cisplatin doses of ≤400 mg/m2 show no significant association.


Conception and paternity rates range from 49% to 88% among long-term TCS who intended to conceive a child after treatment.


Approximately half of the patients with newly diagnosed TC have low sperm counts (<20 million/mL), decreased motility indices (<40%), and large percentages of abnormal sperm cells before receipt of any treatment.


6% to 24% of TCS are azoospermic and 50% oligozoospermic at TC diagnosis. 


Most  patients (>90%) recover sperm counts by 24 months after radiation therapy.


Cisplatin-based chemotherapy is also associated with risk of infertility, and is dose related.


Sperm counts and serum level of inhibin B were significantly lower, and the serum follicle-stimulating hormone level was significantly higher in TCS who received a cumulative cisplatin dose >850 mg compared with those who received surgery only or ≤850 mg of cumulative cisplatin.


Retroperitoneal lymph nodes dissection(RPLND) may cause injury to the retroperitoneal postganglionic sympathetic nerve, causing infertility.


Rates of retrograde ejaculation after primary and postchemotherapy nerve-sparing RPLND were 1% to 9% and 21% to 29%,respectively.


Anxiety disorders are significantly associated with young age, peripheral neuropathy, economic difficulties, excess alcohol use, sexual concerns, and prior treatment of mental illness in TCS .


Significant anxiety was more prevalent among TCS, about 20%, than the general population, about 12.5%.


The prevalence of depression among TCS ranges from 7.9% to 29.2%.


Cisplatin-based chemotherapy may cause cognitive impairment, although the association of cisplatin-based chemotherapy with cognitive impairment in TCS remains unclear.


TCS who received chemotherapy have altered global and local brain network properties between baseline and follow-up and widespread brain gray matter reductions with prefrontal reductions on whole-brain MRI, compared with TCS who underwent surveillance.


The association of cisplatin-based chemotherapy with cognitive impairment in TCS is unclear, as prevalence of cognitive impairment in patients with newly diagnosed TC prechemotherapy ranges from 46% to 58%, which is higher than in normal populations.


The prevalence of chronic fatigue  among TCS is 17.1% compared with 9.7% in age-matched men in the general population.







Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7369



Table 2.


Multivariable Ordinal Logistic Regressiona of Factors Associated With CBM Scores



TCS had a significant 6% excess risk of mortality from noncancer causes compared with the general population; including 1.3- and 1.4-fold mortality from infections and digestive diseases, respectively. 



TCS given chemotherapy have significantly higher mortality from noncancer causes, including circulatory diseases, infections, and respiratory disease.



Premature physiologic aging develops in survivors of childhood cancer after cytotoxic therapies, with hypothesized mechanisms including increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity.




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