Germ Cell Tumors

Synonyms and related keywords: germ cell tumors, GCT, testicular cancer, seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor


INTRODUCTION

Background: Germ cell tumors (GCTs) are a morphologically distinct group of neoplasms with varied clinical presentation. Ninety-five percent of tumors arising in the testes are GCTs, indicating that they originate from the primordial germ cells. More than 90% of patients with GCT diagnosed early are cured. A delay in diagnosis correlates with a higher stage at presentation and, consequently, a lower cure rate. The success in treating GCTs in the past 2 decades is attributed largely to the effectiveness of cisplatin-containing combination chemotherapy in curing advanced disease.

Pathophysiology:

Biology

Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic.

GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53-dependent apoptotic pathway.

Mechanism of germ cell transformation

Almost 100% of tumors show increased copy numbers of 12p (i12p). This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. Two models have been proposed to explain the origin of CIS cells, as follows:

Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

Model 2: Increased 12p copy number, cyclin D2 expression, consistent near triploid-tetraploid chromosome numbers, and increased expression of wild-type p53 result in tumorigenesis. Abnormal chromatid exchanges during meiotic crossing over leads to increased 12p copy number and cyclin D2 overexpression. In cells containing unrepaired DNA strand breaks, cyclin D2 can block p53-dependent apoptosis and leads to re-initiation of cell cycle and genomic instability.

Recently, models involving other cyclins and inhibitory molecules have also been proposed.

Frequency:

• In the US: More than 9000 cases of GCTs are diagnosed each year.

• Internationally: For unknown reasons, worldwide incidence has more than doubled in the past 40 years. The incidence of GCT varies by geographic area. The highest incidence is in Scandinavia, Germany, and New Zealand. It is lower in the United States and lowest in Asia and Africa.

Mortality/Morbidity: For all patients with GCT, the 5-year survival rate is about 95%. Cure rates are highest for early stage disease and lower for advanced disease.

Race: GCTs are seen predominantly in whites and rarely in African Americans. The incidence ratio of whites to African Americans is approximately 5:1.

Despite this, a sharp increase in the incidence of germ cell tumors in men of African descent has occurred. In the United States, the incidence increased by 100% from 1988 to 2001. Diagnoses of seminomas increased 124% in that time period and nonseminomas increased by 64%. No significant increase occurred in the incidence of early-stage disease in proportion to all diagnoses in this population, indicating that the significant increase was not due to an increased prevalence of screening or earlier detection.

Age: GCT is the most common solid tumor in men aged 15-35 years. However, the disease has 3 modal peaks: infancy, ages 25-40 years, and age 60 years.

CLINICAL

History: Most patients present with a complaint of a painless testicular mass. Less common presenting symptoms, such as back pain, cough, and hemoptysis, arise from metastatic disease.

• Approximately 95% of GCTs occur in the gonads, and the rest occur in extragonadal tissues (see Extragonadal Germ Cell Tumors).

• A painless testicular mass is the most common presentation in patients with testicular cancer. However, about 20-40% of patients with primary testicular cancer present with pain, swelling, hardness, or a combination of these symptoms. Treating patients who have no palpable mass using a trial of antibiotics is reasonable, as infectious epididymitis or orchitis is more common than tumor. A testicular ultrasound examination is indicated if symptoms and signs are not controlled or do not revert in 2 weeks. Tumor-bearing testicles may be more susceptible to bleeding and hematoma development; therefore, patients who experience a hematoma with minor trauma should undergo evaluation for an underlying tumor.

• Testicular pain may be associated with epididymitis, torsion of the testes, tumor, or bleeding or infarction in the tumor. Flank pain, back pain, or abdominal pain can occur from metastatic disease.

• Gynecomastia may occur in patients with tumors that produce human chorionic gonadotropin (HCG), such as choriocarcinoma.

• Pulmonary symptoms such as shortness of breath, chest pain, and hemoptysis, although rare, can occur in patients with advanced pulmonary disease or primary mediastinal GCT.

• Symptoms due to central nervous system metastasis or to bone metastases are rare.

Physical:

• Physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular mass with or without pain is a finding that requires immediate attention.

• Other areas of emphasis include examination for the following:

• Left supraclavicular lymphadenopathy

• Hepatomegaly

• Bone tenderness

• Gynecomastia

• Abdominal mass
• GCTs should be distinguished by seminoma versus nonseminoma subtypes because they are treated differently.

• Seminoma, a GCT subtype, has the following clinical features:

• This usually presents in the fourth decade of life. Seminoma is confined to the testes in about 70% of cases and metastasizes to the lymph nodes in about 25% of cases. Metastatic disease is present in 5% of cases at presentation. These testicular primary tumors are usually homogenous and large.

• Spermatocytic seminoma occurs in the sixth decade of life. It presents bilaterally more often than seminoma and is an indolent tumor that rarely metastasizes. Spermatocytic seminoma is not associated with CIS.

• Nonseminomatous germ cell tumor (NSGCT) is often composed of several histologic forms (mixed) and may contain any of the following forms:

• Embryonal carcinoma is characterized by rapid and bulky growth and by spread via lymphatic and hematogenous routes to distant viscera (eg, lungs, liver). More than 60% of patients have metastases at the time of presentation. Pain is a common feature in these patients.

• Teratoma is found commonly in residual or recurrent masses. It is the least aggressive form, but approximately 30% of patients with clinical stage 1 disease have relapse after orchiectomy.

• Choriocarcinoma is the most aggressive of the NSGCTs. It disseminates hematogenously to lungs, liver, brain, and other viscera very early in the disease process. Bleeding is common in patients with metastatic choriocarcinoma and may present as hemoptysis, gastrointestinal bleeding, or, rarely, intracerebral hemorrhage.

• Yolk sac tumors typically present as a large primary tumor.

Causes: No environmental exposures have been proven to lead to GCTs. However, a few congenital developmental defects are related to the development of GCTs.

• Cryptorchidism: Risk of developing GCT in the cryptorchid testis is 10- to- 40-fold higher than in the normally descended testis. About 5-20% of patients with a history of cryptorchid testis develop tumors in the normally descended testis. The risk of developing GCT when a cryptorchid testis is intraabdominal is about 5%. The risk falls to 1% if the testis is retained in the inguinal canal and decreases further if the undescended testis is surgically placed in the scrotum when the patient is younger than 6 years.

• Diethylstilbestrol: No clear association is seen between diethylstilbestrol and development of GCT.

• Klinefelter syndrome: Patients with Klinefelter syndrome have an increased incidence of mediastinal GCT.

DIFFERENTIALS

Epididymitis
Hydrocele
Lymphoma, Non-Hodgkin
Spermatocele
Testicular Torsion
Varicocele


WORKUP

Lab Studies:

• Tumor markers alpha-fetoprotein (AFP), beta-HCG, and lactate dehydrogenase (LDH) are vital in the evaluation and management of patients with GCTs. They are used for determining diagnosis, staging, prognosis, and response to therapy. Obtaining levels of AFP, beta-HCG, and LDH in patients in whom GCTs are suspected is mandatory prior to treatment, as is monitoring these levels during and after treatment.

• Alpha-fetoprotein

• Secretion is restricted to GCT of nonseminomatous histology.

• Reference adult concentration is less than 10 ng/mL.

• Serum half-life is 5-7 days.

• In patients with pure seminoma, increased AFP levels indicate an undetected nonseminomatous tumor component.

• Beta-human chorionic gonadotrophin

• Increased levels of beta-HCG can be found in either seminoma or nonseminoma. However, both nonseminoma can be beta-HCG negative however.

• Serum half-life is 18-36 hours.
• Patients with high levels of beta-HCG may experience nipple tenderness or gynecomastia.

• Lactate dehydrogenase

• LDH has independent prognostic significance. Increased levels reflect tumor burden, growth rate, and cellular proliferation.

• Increased LDH levels are found in about 60% of patients with advanced NSGCT and 80% of those with advanced seminoma.

Imaging Studies:

• Testicular ultrasonography: This study can reliably detect testicular masses and also distinguish a testicular mass from an extratesticular mass. Seminomatous tumors appear as hypoechoic lesions, and nonseminomatous tumors appear as hyperechoic lesions.

• CT scans of the chest, abdomen, and pelvis: These scans are a required part of the workup. Lymph nodes in the retroperitoneum measuring 10-20 mm are involved in GCTs 70% of the time, and lymph nodes measuring 4-10 mm are involved 50% of the time.

• Chest radiography

• CT scan or MRI of the brain: CNS evaluation should be included for all patients with stage III or IV disease or for patients with markedly elevated tumor markers.

• Positron emission tomography (PET) scans are generally not useful except in the case of seminomatous masses postchemotherapy. Teratomatous elements of a nonseminoma are generally considered to be PET negative, thus limiting the ability to conclude that a negative PET scan in a patient with a residual nonseminoma mass is of benign etiology.

Procedures:

• Patients with testicular mass, abnormal ultrasonographic findings, or both should undergo a unilateral radical transinguinal orchiectomy with ligation of the spermatic cord at the inguinal ring. Orchiectomy is the definitive procedure for both pathologic diagnosis and local control of the primary tumor. It should be undertaken even in patients with disseminated GCT, because the testes are a sanctuary site for chemotherapy.

• Testicular biopsy of a suggestive lesion is not recommended.

• Transscrotal orchiectomies are contraindicated, as they have been associated with local recurrence and spread to inguinal lymph nodes.

Histologic Findings: GCTs are classified on the basis of their histologic features into seminomas and nonseminomas. Seminomas account for about 40% of GCTs, of which classic and anaplastic cell types constitute the majority. The rest are classified as spermatocytic. Seminomas, both classic and anaplastic, occur in men aged 25-45 years, whereas spermatocytic seminoma occurs in men aged 65 years on average.

• Nonseminomas account for about 60% of GCTs.
  • The majority of these are embryonal (with or without seminoma) and teratoma with embryonal carcinoma, choriocarcinoma, or both.
  • Teratomas with or without seminoma account for a minority of tumors.
  • Pure choriocarcinoma and pure yolk sac tumors are extremely rare.
  • Nonseminomas occur in patients aged 15-35 years.
  • Lymphatic and vascular invasion is associated with a higher rate of relapse and predicts occult nodal metastases.

Staging:

• Stage I - Limited to the testis, epididymis, and spermatic cord

• Stage II - Limited to retroperitoneal lymph nodes

• Stage IIA - Nodes less than 2 cm in maximal diameter

• Stage IIB - Nodes 2-5 cm in diameter

• Stage IIC - Nodes greater than 5 cm in diameter

• Stage III - Metastatic to supradiaphragmatic nodal or visceral sites

TREATMENT

Medical Care: Virtually all germ cell tumors (GCTs) should be considered curable. Patients who undergo chemotherapy should be assessed according to the International Germ Cell Cancer Cooperative Group (IGCCCG) system of risk assessment. In this system, patients are classified as good, intermediate, or poor risk. Patients with a good-risk disease can receive 3 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy or 4 cycles of etoposide and cisplatin (EP). Patients with intermediate- and poor-risk disease should receive 4 cycles of BEP as initial therapy.

• Management of clinical stage I disease

• Seminoma
  • Surgical care of seminomas consists of inguinal orchiectomy. Adjuvant radiotherapy to para-aortic and ipsilateral pelvic lymph nodes is the historical treatment of choice. Recent studies have shown that about 15% of patients with clinical stage I disease have occult retroperitoneal disease.
  • Chemotherapy for stage I seminoma is now supported by randomized data. Two recent phase III studies have addressed the use of single-agent carboplatin chemotherapy in patients with stage I seminoma. In one randomized trial involving 1477 patients with stage I seminoma, the patients were randomly assigned to receive radiotherapy in either a para-aortic strip or dog-leg field (n = 904) or 1 injection of carboplatin administered at an area under the curve dose of 7 (n = 573). After 4 years of follow-up, relapse-free survival rates were similar comparing the 2 arms (96.7% vs 97.7%, respectively). Further, patients receiving carboplatin had lower rates of fatigue and had missed less work than those receiving radiation.
  • A second study used risk-adapted patient eligibility to determine whether the use of carboplatin in selected patients with higher-risk stage I disease could reduce the risk of relapse to that which would be expected of lower-risk patients. Risk factors for inclusion in the chemotherapy arm included tumors larger than 4 cm, rete testis involvement, or both factors. The study enrolled 131 patients (41.7%) with tumors larger than 4 cm, 33 patients (10.5%) with rete testis involvement, and 50 patients (15.9%) with both factors. Patients were treated with 2 courses of adjuvant carboplatin. As a control group, 100 patients with no risk factors were placed in a surveillance program. After a median followup of 34 months, relapses were observed in 6 patients (6.0%) on the surveillance arm and in 7 patients (3.3%) treated with carboplatin.
  • Although further follow-up is required to definitively suggest that carboplatin is equivalent to radiation, the preliminary reports from these 2 studies suggest that carboplatin is safe and is not inferior to radiation for stage I seminoma. Further, the reduced time required with this approach and the potential improvements in morbidity suggest that 1 or 2 cycles of carboplatin may ultimately become a preferred choice in this disease.
• Nonseminoma: Surgical care consists of inguinal orchiectomy alone and is curative in 60-80% of patients. Retroperitoneal lymph node dissection (RPLND) has diagnostic as well as therapeutic utility. Occult metastases can be found in about 30% of patients with clinical stage I disease and are classified as pathologic stage IIA. RPLND is accomplished through a thoracoabdominal approach.
• Nerve-sparing surgical technique can preserve ejaculatory capacity. Some patients choose surveillance over RPLND, with chemotherapy used at the time of recurrence. Patient compliance is absolutely vital for a surveillance strategy, and patients must be made aware of the 25-30% rate of disease relapse up to 4 years. A physical examination, chest radiograph, and determinations of AFP, LDH, and beta-HCG levels are required at monthly intervals in the first year, every other month for the second year, every 3 months in the third year, and less frequently thereafter. An abdominal CT scan is required every 3 months in the first year, every 4 months in the second year, and every 6 months in the third year. Office visits and evaluations should be annual in the fifth year and later.
• Patients with Stage I pure embryonal cell carcinoma have occult nodal metastases in fewer than 50% of cases. Further, because of hematogenous spread, the majority of relapses that occur in these patients after RPLND is outside of the surgical template. This has prompted many to advocate 2 cycles of BEP chemotherapy for patients with pure embryonal cell carcinoma with adverse features such as lymphovascular invasion. However, large-scale randomized trials do not support this approach.

• Management of clinical stage II disease
  • Seminoma (low tumor burden): The cure rate is 85-95%. This figure includes patients with retroperitoneal metastases that measure less than 5 cm in maximum transverse diameter. Radiation is the treatment of choice for most patients with stage II disease, with a relapse rate of less than 5%. Patients with horseshoe kidney or inflammatory bowel disease should not receive radiation. In these situations, a discussion with an experienced radiation oncologist is indicated. Primary chemotherapy is the treatment of choice if a decision is made not to administer radiation treatment. Chemotherapeutic agents used are bleomycin, etoposide, and cisplatin (BEP).
  • NSGCTs (low tumor burden): RPLND is a standard surgical therapeutic approach in patients with clinical stage IIA or IIB disease who have normal tumor markers. If patients with stage IIA or II B disease have elevated serum tumor markers, then systemic disease is present and should be treated with cisplatin-containing chemotherapy regimens. Two cycles of cisplatin-containing adjuvant chemotherapy is recommended if (1) more than 6 lymph nodes were involved, (2) any of the nodes are larger than 2 cm, or (3) extranodal extension is present. Observation is a treatment choice for patients with fewer than 6 lymph nodes involved and none greater than 2 cm. However, close monitoring is required. At the time of relapse, 3-4 cycles of cisplatin-based therapy are administered.
• Management of clinical stages II and III

• Seminoma (high tumor burden): This includes all patients with extensive, bulky, retroperitoneal, visceral metastases or supradiaphragmatic nodal disease, including patients with stage IIC seminomas. Cisplatin-based systemic chemotherapy cures 70-80% of these patients.
  • Good prognosis GCTs: These patients have a high likelihood of cure, and response ranges from 88-95%. Treatment regimens comprise 4 cycles of etoposide and cisplatin or 3 cycles of BEP.
  • Poor risk GCTs: In patients at intermediate risk, the response rate is 75%, and in patients considered poor risks, the response rate is about 40%. Treatment consists of 4 cycles of BEP.
• NSGCTs: Radiation is used in patients with metastatic NSGCT to the brain. Postchemotherapy resection is performed on patients with persistent radiographic abnormality and normal serum tumor marker levels 4-6 weeks following chemotherapy. If evidence of persistent carcinoma is noted, then 2 additional cycles of chemotherapy are indicated. Residual intrathoracic disease should be resected as well as all sites of residual disease.

• Management of relapse after chemotherapy
  • About 20-30% of patients have a relapse or do not achieve a complete response to cisplatin-based chemotherapy. Treatment regimens for first-time salvage therapy consist of ifosfamide, mesna, and cisplatin plus either vinblastine or etoposide. The response rate for salvage chemotherapy is 25-35%.
  • Patients who relapse after achieving a complete response to initial chemotherapy can be successfully managed with either ifosfamide-, cisplatin-, and etoposide-containing regimens or the combination of paclitaxel, ifosfamide, and cisplatin. The latter regimen has been associated with durable complete responses in 70% of patients.

• The management of late relapsed (>2 y following initial therapy) GCT is not standardized and is associated with a poor prognosis due to high degrees of resistance to chemotherapy. Median survival in this setting has been reported to be approximately 2 years, and fewer than 50% of patients experience a complete response to chemotherapy.

Surgical Care: Postchemotherapy surgery should be considered in all patients with NSGCTs who have residual masses. Postchemotherapy surgery for seminoma is more difficult and is generally restricted to large masses. PET scanning may be useful in patients with seminoma following chemotherapy (see Imaging Studies).

Consultations: Sperm banking should be offered to all patients prior to chemotherapy because therapy for GCTs results in sterility in approximately 35% of patients.

MEDICATION

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Antineoplastic agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), and the final phase involves mitotic cell division (phase M).

The cell division rate varies for different tumors. The majority of common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant ones and is the rationale for current cyclic dosage schedules. Dosage cycles are determined by cancer stage and tolerance of adverse effects.

Antineoplastic agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Name	Cisplatin (Platinol) -- Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to produce cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in the cell, it binds to DNA, resulting in interstrand and intrastrand cross-linking. Modify dose on basis of CrCl. Avoid use if CrCl less than 60 mL/min.
Adult Dose	20 mg/m2/d IV over 20-60 min for 5 d; repeat q21d for 4 cycles
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid; other nephrotoxic drugs (eg, aminoglycosides, amphotericin B, cyclosporine) increase nephrotoxicity; bleomycin, cytarabine, methotrexate, and ifosfamide may accumulate because of decreased renal excretion; may enhance cytotoxicity of etoposide; mesna and sodium thiosulfate directly inactivate cisplatin; dipyridamole increases cytotoxicity by enhancing cellular uptake; paclitaxel-related peripheral neuropathy may be increased in patients previously treated with cisplatin
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; adverse effects include bone marrow suppression, nausea, vomiting, mucositis, and high-frequency hearing loss; major dose-limiting toxic effect is peripheral neuropathy; can cause acute or chronic renal failure in as many as a third of patients treated, but this usually can be prevented by vigorous hydration and saline diuresis; renal tubular wasting of potassium and magnesium are common (monitor closely); cellulitis and fibrosis rarely have occurred after extravasation; avoid aluminum needles

Drug Name	Etoposide, VP-16 (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 phase of cell cycle. Prodrug activated by dephosphorylation. Reduce dose in hepatic (increased total bilirubin [TB]) or renal (decreased CrCl) impairment.
Adult Dose	100 mg/m2/d IV for 5 d; repeat q21d for 4 cycles; adjust dose in hepatic or renal dysfunction TB 1.5-3 mg/dL: 50% dose reduction TB 3.1-4.9 mg/dL: 75% dose reduction TB >5 mg/dL: Avoid use CrCl 15-50 mL/min: 25% dose reduction
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT administration (may cause death)
Interactions	May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells; clearance decreased by high dose of cyclosporine (serum concentration >2000 ng/mL), leading to increased risk of neutropenia; zidovudine increases serum concentration, resulting in increased toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	IT administration may cause death Bleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur; reduce dose in hepatic (increased TB) or renal (decreased CrCl) impairment Note: small but real risk of secondary leukemia has been reported

Drug Name	Bleomycin (Blenoxane) -- Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single-stranded or double-stranded DNA breaks by ability to form oxygen free radicals.
Adult Dose	Test dose (optional): 1-2 U IV/IM prior to full dose 30 U IV bolus every wk on days 2, 9, and 16; repeat q21d for 4 cycles; modify dose based on CrCl CrCl 20-30 mL/min: 50% of normal dose CrCl less than 20 mL/min: 40% of normal dose
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; erythema, rash, vesiculations, hyperpigmentation, stomatitis, alopecia, and nail changes may occur

Drug Name	Ifosfamide (Ifex) -- Alkylating agent activated in liver to phosphoramide mustard and acrolein. Phosphoramide mustard cross-links DNA strands and is responsible for therapeutic effect. Acrolein related to bladder toxicity.
Adult Dose	1200 mg/m2/d IV continuous infusion on days 1-5; repeat q21d for 4 cycles
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; depressed bone marrow function; uncontrolled infection
Interactions	Phenobarbital, phenytoin, chloral hydrate, and other drugs that induce CYP-450 activity may enhance metabolism of ifosfamide to its active metabolites
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause hemorrhagic cystitis (use with mesna to decrease risk) and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve; nausea, vomiting, diarrhea, and constipation may occur; CNS toxic effects include somnolence, confusion, depressive psychosis, and hallucinations; seizures and coma may occur

Drug Name	Vinblastine (Velban) -- Vinca alkaloid, inhibits microtubule formation, which disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Adult Dose	0.11 mg/kg IV on days 1 and 2; repeat q21d for 4 cycles; adjust dose in hepatic impairment TB >3 mg/dL: 50% dose reduction
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression; IT administration (may cause death) Careful administration in patients with underlying neurological disorders
Interactions	May reduce plasma phenytoin levels; previous or concurrent use of mitomycin-C increases pulmonary toxicity; drugs that inhibit P-450 CYP3A isoform (eg, erythromycin) may decrease vinblastine metabolism, causing increased toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	IT administration may cause death Careful administration in patients with underlying neurological disorders Reduce dose in impaired liver function; mitomycin-C may cause shortness of breath and bronchospasm; extravasation precautions necessary due to vein irritation (is a vesicant and should be given exclusively via side port of freely flowing IV); if extravasation occurs, antidote is hyaluronidase, 150 mg SC around needle site, and apply warm compresses at site of extravasation; adverse effects include neurotoxicity, myelosuppression, alopecia, nausea, vomiting, anorexia, constipation, and paresthesia; dose reduction not required in impaired renal function

Drug Category: Uroprotective antidote -- Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Drug Name	Mesna (Mesnex) -- Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Adult Dose	1200 mg/m2/d IV continuous infusion on days 1-6 of each cycle; IV dose of mesna equivalent to ifosfamide dose
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase warfarin effect, adjust dose according to INR target
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor morning urine for hematuria prior to ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain

FOLLOW-UP

Further Outpatient Care:

• Observation

• Patients with clinical stage I NSGCT who prefer surveillance instead of RPLND should have a physical examination, chest x-ray, and measurement of AFP and beta-HCG levels on a monthly basis for the first year, every 2 months in the second year, every 3 months in the third year, and less often subsequently.

• Abdominal CT scan is required every 3 months in the first year, every 4 months in the second year, and every 6 months in the third year.

• Office visits and evaluations should be every year through the fifth year and beyond.

• Patients with clinical stages I, IIA, or IIB seminoma, or clinical stage I NSCGT after RPLND without adjuvant chemotherapy

• After radiation therapy, perform a chest radiography, determine AFP and beta-HCG levels, and perform a physical examination every 6-12 weeks in the first year, every 3-4 months in the second year, and less often thereafter.

• Abdominal CT scan should be performed at the conclusion of radiation therapy.

• Following RPLND, a chest radiography, AFP and beta-HCG tumor marker levels, and a physical examination are required every 4-8 weeks in the first year, every 8-12 weeks in the second year, and less frequently in the third year and beyond, with yearly visits to detect late relapse and second primary tumors after the fifth year.

• For seminoma with bulky nodal metastases, a PET scan following the conclusion of chemotherapy may be useful. A prospective study of PET scans in residual tumors larger than 3 cm 1-2 months following the completion of chemotherapy revealed no false-negative scan results. A positive PET scan in this setting was likewise associated with a 100% positive predictive value. Because postchemotherapy surgery is morbid in seminoma patients, these scans may be useful in justifying a more conservative surveillance approach in patients with posttreatment residual masses.

• In postchemotherapy masses smaller than 3 cm, the resolution of PET scans is decreased, and false-negative results were detected in 2 of 33 patients studied.

Complications:

• Secondary malignancies

• Metachronous GCT appears in the contralateral testis in 2-3% of patients.

• Etoposide causes secondary leukemia after a latent period of 2-4 years in 0.8-1.3% of patients.

• GI malignancies can occur secondary to radiation therapy, chemotherapy, or both. Relative risk increases with time and is greater after 10 years. Stomach cancer is of the most concern.

• Soft-tissue sarcoma, melanoma, and genitourinary cancers also can occur.

• Chemotherapy-related toxic effects

• Acute
  • Nausea and vomiting may occur. Postcisplatin delayed emesis is treated by oral administration for 2-4 days of metoclopramide, benzodiazepine, and dexamethasone in combination with a serotonin-receptor antagonist.
  • A certain degree of cisplatin-related nephrotoxicity is almost always present and is cumulative. Hypomagnesemia is common.

• Subacute
  • Toxic effects related to vinblastine are arthralgias, myalgias, peripheral neuropathy, and paralytic ileus. Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. Hearing aids are rarely required.
  • Neutropenic fever and severe thrombocytopenia are relatively uncommon with etoposide and cisplatin (EP) as first-line chemotherapy. The addition of bleomycin and salvage chemotherapy results in significant increase of these complications (50%), requiring prophylactic use of hematopoietic growth factors after the first episode of neutropenic fever.
  • Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated patients) and dose and age dependent (eg, rate is higher in patients >70 y and after a cumulative dose >1200 IU or 400 mg). Progression to pulmonary fibrosis is uncommon and occasionally fatal (1%). Although carbon monoxide diffusing capacity (DLCO) may not predict clinically significant lung damage, its use was recommended along with chest x-ray as a screening test in patients treated with bleomycin. If radiographic changes or a decrease of DLCO greater than 30% are detected, discontinue the drug.
  • Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction have been reported after use of bleomycin.
  • Accelerated coronary artery disease is a well-recognized complication of mediastinal radiotherapy.
  • Infertility is seen in as many as 50% of patients after chemotherapy. Standard bilateral RPLND almost always is associated with retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior approaches decrease the occurrence of, but do not abolish, this complication.
  • The frequency of etoposide-related secondary leukemia is dose dependent. It is seen in less than 0.5% of patients who receive a total dose less than 2000 mg/m² and in about 6% of those who receive more than 3000 mg/m². Abnormalities of band 11q23 are very common in this setting. The latency period varies from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric cancers and soft-tissue sarcomas, is increased slightly after combined radiation and chemotherapy. The latency period is about 10 years or more.
  • A high rate of thromboembolic events (8.4%) is seen during chemotherapy in patients with GCTs. Liver metastases and high-dose corticosteroids were identified as risk factors for these complications.

Prognosis:

• GCT risk classification, international consensus: The management of GCTs is determined by the clinical stage, size, serum marker level elevation, and histologic features.

• Seminoma
  • Good prognosis - No nonpulmonary visceral metastases
  • Intermediate prognosis - Nonpulmonary visceral metastasis present

• Nonseminoma
  • Good prognosis (all of the following): (1) AFP less than 1000 ng/mL, (2) beta-HCG less than 5000 IU/L, (3) LDH less than 1.5 X upper limit of normal, (4) no nonmediastinal primary, and (5) no nonpulmonary visceral metastasis
  • Intermediate prognosis (all of the following): (1) AFP = 1000-10,000 mg/mL, (2) beta-HCG = 5000-50,000 IU/L, or LDH = 1.5-10 X normal limit, (3) nonmediastinal primary site, (4) no nonpulmonary visceral metastasis
  • Poor prognosis (any of the following) (1) AFP higher than 10,000 mg/mL (2) HCG >50,000 IU/L, or LDH 10 X normal limit (3) mediastinal primary site (4) nonpulmonary visceral metastasis present