Before the era of effective chemotherapy, disseminated testicular cancer was uniformly fatal . Fortunately, new therapeutics emerged that have changed the face of testicular cancer [52,53]. The current regimen for chemotherapeutic intervention provides exceptional survival, greater than 80%, even in highly advanced stages of tes-ticular neoplasms . The standard of treatment for patients with disseminated germ-cell tumors is currently a regimen of bleomycin, an antibiotic with antineoplastic activity, etoposide, a DNA topoisomerase inhibitor, and cisplatin, an alkylating agent. This multidrug chemotherapeutic regimen is commonly referred to as BEP. Patients with resistant disease or those who experience relapse will undergo salvage chemotherapy with cisplatin, ifosfamide, and either vinblastine or etoposide. This salvage regimen provides a durable result in approximately 20% to 25% of these previously refractory patients . Even among patients unresponsive to salvage chemotherapy, approximately 25% of patients who undergo high-dose chemotherapy with bone marrow transplantation will have long-term survival. These remarkable and admirable high cure rates are accompanied by long-term sequela for these mostly young survivors of testicular neoplasms . The major categories of identified complications following chemotherapeutic treatment of testicular neoplasms are discussed in the following paragraphs.
The immediate toxicities associated with administration of BEP chemotherapy are well documented and may include hematologic toxicity (9%), mucositis (25%), sensory neuropathy (20%), ototoxicity (10%), fatigue (39%), and acute pulmonary toxicity (13%) . Salvage chemotherapy regimens that include ifosfamide additionally carry the risk of hemorrhagic cystitis and acute central nervous system toxicity [58,59]. In the mostly young and healthy patient population stricken with testicular cancer, their high performance status allows exceptionally good tolerance to the regimens. Rarely do testicular cancer patients fail to complete their chemotherapeutic cycles secondary to immediate toxicities.
One of the most devastating complications arising from treatment with BEP is the development of therapy-related leukemias, which are frequently refractory to treatment [60,61]. DNA topoisomerase inhibitors, such as etoposide, produce an acute leukemia with an onset 2 to 3 years following treatment. Alkylating agents such as cisplatin may produce leukemia with a prodromal myelodysplastic syndrome that manifests 5 to 7 years following treatment. The risk of leukemia from etoposide treatment is dose related . Risk-benefit analysis has revealed there is one case of therapy-related leukemia per approximately 20 cured patients, with the analysis revealing the benefits of chemotherapeutic intervention outweigh the risks of long-term malignancy . As mentioned above, this risk appears dose related and will thus likely decrease from the recorded 0.5% at 5 years seen with four cycles of BEP when data are available for patients treated with current therapies including lower doses and fewer cycles.
Postchemotherapy testicular cancer survivors are additionally at increased risk for development of secondary primary non-germ-cell malignancies at an incidence of 1.38% . The reported risk is increased over that of the general population for lung cancer, biliary cancer, gastrointestinal cancer, bladder cancer, stomach cancer, and sarcoma .
Nephrotoxicity is a recognized complication of cisplatin-based chemotherapies [7,65]. Clinical presentation may range from metabolic changes such as hypokalemia and hypomagnesemia to acute or chronic renal failure . Approximately one quarter of patients may have a permanent 20% to 30% reduction in glomerular filtration rate; however, most of these patients manifest only moderate clinical symptoms of electrolyte disturbances [66-68].
Cisplatin-based chemotherapy is commonly associated with peripheral neuropathies that are primarily sensory in character . Peripheral digit paresthesia and dysesthesia are common manifestations. Neuronal damage attributable to cisplatin may be present in up to 76% of patients, with clinical symptoms persisting in 20% to 40% [70,71].
A second troubling neurologic consequence of cisplatin-based therapy is ototoxicity, resulting in high-frequency hearing loss and tinnitus . This ototoxicity is dose related and fortunately most patients have subclinical damage or mild symptoms .
Bleomycin administration has been associated with chronic lung damage that can result in pulmonary fibrosis, and in a small percentage of patients, may eventually result in death. Toxicity is related to total bleomycin dose, exposure to high oxygen concentrations, thoracic radiation, decreased renal function, older age, and history of smoking . Pneumonitis induced by bleomycin typically manifests in the first few months of therapy with symptoms of a nonproductive cough and dyspnea with exertion . Once infectious pneu-monitis is excluded, bleomycin is usually discontinued in these patients. Patients receiving bleomycin therapy with suggestions of drug-induced pneumonitis are monitored with pulmonary function tests. A 40% to 60% fall from baseline of the diffusion capacity of carbon monoxide (DLCO), a marker of significant pulmonary compromise, usually terminates bleomycin therapy. Corticosteroids are additionally administered to reduce lung inflammation. In patients who have received bleomycin therapy, it is imperative to perform adequate pulmonary evaluation before future surgical interventions such as RPLND to reduce potential perioperative morbidity . Careful monitoring of fluid management in the bleomycin-treated patient is accomplished by giving a minimal volume to support urine output and hemodynamic stability . In addition, many anesthesiologists promote restriction on the concentration of forced inspired oxygen during surgery; however, studies have demonstrated that inspired oxygen concentration is not an independent risk factor for postoperative pulmonary complications .
A strikingly high percentage of patients who undergo chemotherapy with vinblastine and bleomycin for testicular neoplasms manifest episodic vasoconstriction of the digital arteries, commonly referred to as Raynaud's phenomenon [78,79]. These painful spasms manifest on average 10 months following therapy and 20% to 25% of patients may have persistent symptoms for more than 10 years . Neurovascular complications, including cerebrovascular hemorrhage, have been reported following the administration of cis-platin-based therapy for testicular cancer [59,81]. This central nervous system toxicity is postulated to be related to metabolic and vascular abnormalities induced by the chemotherapeutic agent. Clinician awareness of this phenomenon is important in the differential diagnosis of neurologic symptoms in the face of potential brain metastasis.
Although the mechanism is unknown, patients undergoing cisplatin- and bleomycin-based chemotherapy for testicular cancers are at a greater than twofold increased risk for cardiovascular disease [80,82,83]. Interplay of a variety of metabolic and vascular factors may accelerate atherosclerosis or impact autonomic function . This postchemotherapy cardiac toxicity has been reported to manifest as a devastating myocardial infarction [81,85]. Increases in markers of endothelial injury following cisplatin administration implicate this agent in damage to the endo-thelium that may contribute to its cardiovascular toxicity .
Profound derangements of plasma and intra-cellular ion concentrations have been demonstrated following treatment with cisplatin-based chemotherapies [87,88]. Alterations in the balance of magnesium and potassium may present as simple fatigue or life-threatening Torsades des pointes. Changes in plasma values may precede a measurable compromise of renal function. Hy-pomagnesemia may lead to vasospasm of coronary arteries and contribute to the increased incidence of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapies .
Metabolic abnormalities such as increases in serum cholesterol may contribute to long-term cardiovascular pathology in patients treated with chemotherapy, including changes in total testosterone and urinary cortisol .
Striking men in their prime reproductive years, fertility is a crucial issue to address for the survivor of testicular cancer. Curiously, up to 60% of patients diagnosed with testicular cancer have abnormal semen analysis including lower sperm counts and higher serum follicle-stimulating hormone (FSH) levels . Chemotherapy has well-documented adverse effects on semen quality, particularly with platinum-based regimens . The effects of chemotherapy on fertility have been reported to be less profound than those seen with radiation therapy ; however, recent paternity data revealed low-dose chemotherapy and radiation treatments to be equally deleterious to fertility with high-dose chemotherapy resulting in the lowest paternity rates . Hormonal dysfunction, including elevation of FSH following chemotherapy has been correlated with this decreased paternity . The most common manifestations on seminal parameters are impairment of spermatogenesis leading to azoospermia. This phenomenon was found to be dependent on the total dose of cisplatin given . Much of this tes-ticular damage appears to be transient, and may resolve in up to 80% of cases by 5 years . Although decreased sperm counts do not preclude fathering children , discussion on sperm cryo-preservation and assisted reproductive technologies should be initiated in all patients who must undergo chemotherapy for testicular cancer [99,100].
A number of case reports of unusual complications following chemotherapy for testicular cancer exist. Osteonecrosis of the femoral head was reported in three testicular cancer patients following BEP chemotherapy and treatment with the commonly prescribed antiemetic ondansetron, a serotonin receptor antagonist, in conjunction with dexamethasone . Bilateral spontaneous pneumothorax was reported after implementation of a salvage chemotherapy regimen . One case of gynecomastia has been reported in a young man in complete remission with normal values of beta-human chorionic gonadotropin (BHCG) following BEP combination chemotherapy .
This postchemotherapy gynecomastia resolved spontaneously over an 8-month time period.
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