Testicular Cancer

Practice Essentials

Primary testicular tumors are the most common solid malignant tumor in men 20 to 35 years of age in the United States. For unknown reasons, the incidence of this cancer—principally, testicular seminomas—increased during the last century. Over the past decade, the incidence of testicular cancer has risen approximately 1.2% per year, although the rate of increase has been slowing. Germ cell cancers account for more than 90% of all testicular cancers. Approximately 9,000 new cases have been diagnosed in United States every year, although only about 400 deaths have occurred annually.

In patients with localized disease, painless swelling or a nodule in one testicle is the most common presenting sign. A dull ache or heavy sensation in the lower abdomen could be the presenting symptom. Patients with disseminated disease can present with manifestations of lymphatic or hematogenous spread. See Presentation.

Ultrasound can distinguish intrinsic from extrinsic testicular lesions and can identify masses within testes. Once the diagnosis of testicular cancer is suspected, a high-resolution CT scan of the abdomen and pelvis and a chest x-ray are ordered as part of the initial staging workup. Radical inguinal orchiectomy is the definitive procedure to permit histologic evaluation of the primary tumor and to provide local tumor control. See Workup.

Initial therapy is selected according to the following features of the cancer:

• Stage group
• Risk stratification (good, intermediate, or poor risk)
• Histology (seminoma versus nonseminoma)

With stage I seminoma, cure can sometimes be achieved by radical inguinal orchiectomy alone. Patients with more advanced disease require adjuvant chemotherapy or radiation therapy. See Treatment and Medication.

Testicular cancers are very sensitive to chemotherapy and are curable even when metastatic. Cure rates for good-risk disease are 90%-95%. However, patients cured of testicular cancer have approximately a 2% cumulative risk of developing a cancer in the opposite testicle during the 15 years after initial diagnosis. The risk of subsequent contralateral testis tumors appears to be higher in men whose primary tumor was a seminoma than in those with nonseminomatous primary tumors.^[1]

In the past, metastatic testicular cancer was usually fatal, but advances in treatment, including high-dose chemotherapy and stem cell rescue, have considerably improved the prognosis. Indeed, testicular cancer is a bright spot in the oncological landscape and is now considered the model for the treatment of solid tumors.

For patient education information, see Testicular Cancer. For information from the National Cancer Institute, see Testicular Cancer–Patient Version.

See also Testicular Seminoma, Testicular Choriocarcinoma, and Nonseminomatous Testicular Tumors.

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Pathophysiology

The cause of testicular cancer is not known. The characteristic genetic change found is an isochromosome of the short arm of chromosome 12 [i(12p)], which is often seen in sporadic cancers. This suggests that genes in this region are important in the development of germ cell tumors. A number of other genes that have a relatively weak effect are also involved in the development of testicular cancer.

That genetic factors have a role in the development of testicular cancer is shown by the fact that the risk for the disease is higher in first-degree relatives of cancer patients than in the general population. About 2% of testicular cancer patients report having an affected relative. Siblings are at particularly increased risk, with a relative risk of 8–10. For sons of affected men, the relative risk is 4–6.

Two models of testicular carcinoma in situ have been proposed. The first posits that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotropin stimulation.

The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. On occasion, this crossing over may lead to increased 12p copy number and overexpression of the cyclin D2 gene (CCND2). The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of the cell cycle and genomic instability.

Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p) or as tandem duplications of chromosome arm 12p. This abnormality is found in occult carcinoma in situ lesions as well as more advanced disease. Further studies indicate that CCND2 is present at chromosome band 12p13 and that CCND2 is overexpressed in most germ cell tumors, including carcinoma in situ. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

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Epidemiology

Frequency

United States

Testicular cancers are an uncommon malignancy, representing only 0.5% of all new cancer cases in the United States.^[2] The American Cancer Society (ACS) estimates that about 9560 new cases of testicular cancer will be diagnosed during 2019 in the United States.^[3] The lifetime chance of developing testicular cancer is about one in 250 and the risk of dying is very low—about one in 5,000.^[4] Most cases occur in young and middle-aged men; the median age at diagnosis is approximately 33 years.^[4]

In the United States, the incidence increased by 100% from 1988 to 2001. Diagnoses of seminomas increased 124% during that period and diagnoses of 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 increase was not due to more widespread screening or earlier detection.^[5] The rate of increase has slowed in recent years.^[4]

According to Surveillance, Epidemiology, and End Results (SEER) data from 18 geographic areas, the age-adjusted annual incidence of testicular cancer from 2012–2016 was 5.9 per 100,000 men.^[2] However, the incidence varies widely by race/ethnicity (see below).

International

Studies of testicular cancer in selected global populations from 1973-2007 have shown a clear trend toward an increased incidence in most populations evaluated.^{[6, 7]} In recent years, however, rates have plateaued in some areas and even decreased in a few.^[6]

 A review found that internationally, testicular cancer rates vary in adolescents and young adults (AYA; ages 15-39) and children under 15 years of age.^[8] In children, the incidence is highest in Asia (4.2 per million) and South America (5.0 per million) and lowest in Europe (2.1 per million) and North America (2.5 per million). Incidence rates in AYA are as follows:

1. Europe - 137.4 per million
2. Oceania - 116.9 per million
3. North America  - 94.9 per million
4. South and Central America - 66.5 per million
5. Asia  -  27.1 per million

Rates are highest in Northern Europe and in men descended from European populations—Northern European populations in particular. The incidence varies even in Northern Europe, however, with rates notably higher in Norway and Denmark than in Sweden and Finland.^[7] In recent years, rates in Eastern European countries have risen rapidly, approaching those in Northern European countries. Rates are lowest in Asia and Africa and intermediate in Central and South America.^[6]

Epidemiologic observations have suggested that environmental factors are instrumental in determining risk for testicular cancers. However, epidemiologic evidence does not consistently support any specific risk factor.^[7]

Race

The incidence of testicular cancer is fivefold higher in whites than in African Americans; however, African Americans tend to present with higher-grade disease and have much worse prognosis than whites.^[9] See the Table below.^[2]

Table. Incidence of Testicular Cancer by Race

View Table

See Table

A review of SEER data found that in Hispanic whites ages 15 to 39 years, the annual incidence of testicular germ cell tumors increased 58% between 1992 and 2010, from 7.18 to 11.34 cases per 100,000. By comparison, during that period the incidence in non-Hispanic white young adults increased 7%, from 12.41 to 13.22 cases per 100,000.^[10]

Age

Testicular cancer can occur at any age but is most common between the ages of 15 and 35 years; about 50% of cases occur in men 20-34 years old.^[2] There is also secondary peak in incidence after age 60. Seminoma is rare in boys younger than 10 years of age but is the most common histologic type in men older than 60.

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Prognosis

Testicular cancers are highly curable, even in patients with metastatic disease at diagnosis. According to SEER data from 2009-2015, overall 5-year survival is 95.2%.^[2]  The prognosis varies somewhat depending on the histologic type of cancer (seminoma versus nonseminoma), stage, and other features such as tumor marker and type of metastatic disease.

By stage, 5-year relative survival is 99.2% for patients with localized testicular cancer, which constitutes 68% of cases; 96.4% for patients with cancer that has spread to regional lymph nodes (19% of cases); 72.8% for patients with metastatic disease (12% of cases);, and 79.5% for unstaged disease (1% of cases).^[2]

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History

In patients with localized disease, painless swelling or a nodule in one testicle is the most common presenting sign. On physical examination, this mass/nodule cannot be separated from the testis. Patients with atrophic testes will feel enlargement. A dull ache or heavy sensation in the lower abdomen could be the presenting symptom. Patients who experience a hematoma with trauma should undergo evaluation to rule out testicular cancer.

Patients with disseminated disease can present with manifestations of lymphatic or hematogenous spread. With supraclavicular lymph node metastasis, the presenting sign can be a neck mass. Metastatic disease may also result in anorexia, nausea, and other gastrointestinal symptoms. Bulky retroperitoneal disease can present as back pain. Cough, chest pain, hemoptysis, and shortness of breath can be presenting symptoms of mediastinal adenopathy or lung metastasis. Central nervous system disease could rarely present as neurological symptoms. Bone pain is rare.

Gynecomastia may occur in about 5% of patients with testicular germ cell tumors that produce human chorionic gonadotropin (hCG), such as choriocarcinoma. Marked overproduction of hCG can result in hyperthyroidism, since hCG and thyroid-stimulating hormone have a common alpha-subunit and a beta-subunit with considerable homology.

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Physical

Any solid, firm mass within the testis should be considered testicular cancer until proven otherwise. Prompt diagnosis and early treatment are required for cure.

Testicular cancer may be painless, in which case the patient may be unaware of its presence. In patients with scrotal pain, testicular cancer must be differentiated from epididymitis. The clinician should consider the full differential diagnosis of a testicular mass, which includes not only epididymitis but the following:

• Epididymo-orchitis
• Testicular torsion
• Hydrocele
• Hernia
• Hematoma
• Spermatocele
• Varicocele
• Syphilitic gumma

Unilateral or bilateral lower extremity swelling may be present in patients with iliac or caval venous obstruction or thrombosis.

Physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Examination should begin with bimanual examination of the scrotal contents, starting with the normal testis. This permits the examiner to evaluate the relative size, contour, and consistency of the normal testis. Other areas of emphasis include examination of the abdomen for lymphadenopathy and hepatomegaly. The examination should also include evaluation for supraclavicular nodes, bone tenderness, and gynecomastia.

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Causes

Various risk factors have been associated with testicular tumors, but the specific etiology is not known.

Cryptorchidism

In patients with cryptorchidism, the risk of developing germ cell tumor is increased fourfold to eightfold. The risk of developing germ cell tumor when a cryptorchid testis is intra-abdominal is about 5%. The risk is 1% if the testis is retained in the inguinal canal. Surgical placement of the undescended testis in the scrotum—orchiopexy—when the patient is younger than 6 years lowers the risk further. About 5%-20% of patients with a history of cryptorchid testis develop tumors in the normally descended testis.

In Sweden from 1965 to 2000, a total of 16,983 males underwent orchiopexy and 56 cases of testicular cancer were reported. The relative risk of testicular cancer among those who underwent orchiopexy before reaching 13 years of age was 2.23, compared with that of the Swedish general population. For those treated at 13 years of age or older, the relative risk was 5.4.^[11]

Prior Testicular Cancer

A previous history of testicular cancer is the strongest risk factor for germ cell tumor. Approximately 1-2% of testicular cancer patients will develop a second primary testicular cancer contralaterally—a 500-fold higher rate than in the general population.^{[12, 13]}

Genetics

Patients with Klinefelter syndrome (47XXY) have higher incidence of germ cell tumor, particularly primary mediastinal germ cell tumor. Family members of Klinefelter syndrome patients has a sixfold to 10-fold increased risk of germ cell tumor. Patients with Down syndrome also are at increased risk for germ cell tumors. Increased risk has also been reported in patients with any of the following:

• Cutaneous ichthyosis
• Mullerian syndrome
• Androgen insensitivity syndrome (testicular feminization)
• Mixed gonadal dysgenesis

Family history

First-degree relatives have a higher risk of developing testicular cancer than the general population, although the incidence is low. About 2% of testicular cancer patients report having an affected relative. Brothers are at particularly high risk, with a relative risk of 8–10. Among sons of affected men, twofold to sixfold increases in testicular cancer have been reported.

Infertility

Walsh et al have reported that men with male factor infertility are nearly 3 times more likely to develop subsequent testicular cancer.^[14] Intratubular germ cell neoplasia (testicular carcinoma in situ) has been found in 0.4%–1.1% of men undergoing testicular biopsy because of infertility.

Environmental exposure

Exposure to diethylstilbestrol (DES) in utero is associated with cryptorchidism. Increased risk has been suggested with Agent Orange exposure and numerous industrial occupations.

Recurrent activity such as horseback or motorcycle riding, local trauma, and increased scrotal temperature have not been associated with increased risk.

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Approach Considerations

The workup of patients with suspected testicular cancer starts with a complete history and physical examination. Lab tests and imaging studies include the following^[15] :

• Serum alpha-fetoprotein
• Serum beta subunit of human chorionic gonadotropin (beta-hCG)
• Lactate dehydrogenase (LDH)
• Chemistry profile
• Testicular ultrasound
• High-resolution computed tomography (CT) scan of the abdomen and pelvis
• Chest x-ray
• Magnetic resonance imaging (MRI) of the bBrain should be performed if brain metastases is suspected after clinical examination

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Imaging Studies

Testicular ultrasonography

Ultrasound can distinguish intrinsic from extrinsic testicular lesions and can identify masses within testes. A cystic or fluid-filled mass is unlikely to represent malignancy. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while nonseminomatous germ cell tumors (NSGCTs) are typically nonhomogeneous hyperechoic lesions with calcifications, cystic areas, and indistinct margins. Ultrasound is not reliable in local tumor staging.

Other radiographic imaging

Once the diagnosis of testicular cancer is made, a high-resolution computed tomography (CT) scan of the abdomen and pelvis and a chest x-ray are ordered as part of the initial staging workup. Chest CT is recommended if the chest x-ray is abnormal, or if metastatic disease in the thorax is strongly suspected clinically.

Magnetic resonance imaging (MRI) of the abdomen and pelvis or scrotum usually adds little to the information obtained by CT scan and ultrasound. MRI of the brain and a bone scan are performed if brain and bone metastases are suspected.

Because of frequent false negative results, positron emission tomography (PET) scans are of limited utility in the initial staging of patients with testicular cancers. However, PET scanning is gaining a significant adjunctive role in the evaluation of posttherapy residual masses, especially in seminoma. PET scans are negative in teratoma; therefore, PET scans could be used in some cases of nonseminoma.

Lymphangiography is currently rarely used to evaluate microscopic nodal involvement.

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Procedures

Radical inguinal orchiectomy and retroperitoneal lymph node dissection

Patients with a suggestive testicular mass, abnormal ultrasonographic findings, or both should undergo a radical inguinal orchiectomy. Radical inguinal orchiectomy is the definitive procedure to permit histologic evaluation of the primary tumor and to provide local tumor control. In patients with disseminated germ cell tumor, because of the incomplete penetration of the chemotherapeutic agent to the testes, orchiectomy must be performed sooner or later.

Intraoperative testicular and paratesticular frozen section assessments may be helpful in preserving patients' testicles. Results of a retrospective review of assessments performed on 45 testicular lesions and 20 paratesticular lesions show the procedure was successful in identifying benign lesions, therefore successfully avoiding orchiectomy. Frozen section assessment may be especially helpful in men with small, nonpalpable, incidentally found masses.^[16]

Biopsy of a suggestive testicular lesion is not recommended.

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

Retroperitoneal lymph node dissection (RPLND) is the gold standard and the only reliable method to identify nodal micrometastases and provide accurate pathologic staging of the retroperitoneal disease. Both the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In patients with early-stage nonseminoma, RPLND should be considered following radiographic evaluation of the retroperitoneum and radical inguinal orchiectomy. The transabdominal approach is technically more difficult but poses a lower risk of small bowel obstruction and requires a shorter hospital stay.

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Histologic Findings

Cellular Classification

Approximately 95% of testicular tumors are germ cell tumors. These are divided into two types: pure seminoma (no nonseminomatous element present) and nonseminomatous germ cell tumors. Less than 50% of malignant testicular germ cell tumors are of a single cell type; roughly 50% of these are seminomas. Determining the cell type of these tumors is important for estimating the risk of metastasis and the response to chemotherapy.

The World Health Organization uses following histologic classification of malignant testicular germ cell tumors.

1. Intratubular germ cell neoplasia, unclassified.

2. Malignant pure germ cell tumor (showing a single cell type):

   A. Seminoma

   B. Embryonal carcinoma

   C. Teratoma

   D. Choriocarcinoma

  E. Yolk sac tumor

3. Malignant mixed germ cell tumor (showing more than one histologic pattern):

   A. Embryonal carcinoma and teratoma with or without seminoma.

   B. Embryonal carcinoma and yolk sac tumor with or without seminoma.

   C. Embryonal carcinoma and seminoma.

   D. Yolk sac tumor and teratoma with or without seminoma.

   E. Choriocarcinoma and any other element.

4. Polyembryoma

Seminoma

In addition to pure seminomas, which constitute roughly 50% of pure germ cell tumors, a seminomatous component is present in 20% of mixed germ cell tumors. Serum tumor markers are usually at normal levels, but if syncytiotrophoblastic giant cells are present, beta-hCG may be elevated.

Spermatic seminomas are a variant of seminoma that differ in their clinical characteristics. They generally occur in older men (>60 years) and rarely metastasize without sarcomatous differentiation. They do not occur as part of mixed germ cell tumor and do not contain an isochromosome 12p.

Nonseminoma

Embryonal carcinomas constitute about 2% of all testicular germ cell tumors but are the histological type in 85% of mixed germ cell tumors. They have large pleomorphic cells with different architectural patterns.

Teratomas are part of the mixed germ cell tumor and are generally benign but have the potential for metastasis. They have elements from all three germ layers: ectoderm, endoderm, and mesoderm. In patients with residual disease after chemotherapy, teratoma is found in approximately 45% of resected specimens.

Choriocarcinomas are the least common type of nonseminoma but are very aggressive. Widespread hematogenous metastasis can occur very early in the disease course; the retroperitoneum may be spared. Choriocarcinomas are associated with increased levels of beta-hCG.

Yolk cell tumors, also called endodermal sinus tumor, are the most common testicular tumor in infants and young children. In adults, pure yolk cell tumors are rare, but yolk cell elements are found in approximately 40% of mixed germ cell tumors. Yolk cell tumors are associated with elevated alpha fetoprotein levels but they do not produce beta-hCG.

Mixed germ cell tumors (ie, those containing two or more germ cell types) constitute approximately one third of testicular cancer. Mixed germ cell tumors behave like nonseminomas. The average age at diagnosis is older than 30 years.

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Staging

Staging for testicular cancer follows the TNM (tumor, node, metastasis) system.

Tumor

The extent of primary tumor (pT) is classified after radical orchiectomy. Classifications are as follows:

• pTX – Primary tumor cannot be assessed (if radical orchiectomy has not been performed, Tx is used)
• pT0 – No evidence of primary tumor (eg, histologic scar in testis)
• pTis – Intratubular germ cell neoplasia (carcinoma in situ)
• pT1 – Tumor limited to the testis and epididymis without vascular/lymphatic invasion, or tumor invasion into the tunica albuginea but not the tunical vaginalis
• pT2 – Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
• pT3 – Tumor invades the spermatic cord with or without vascular/lymphatic invasion
• pT4 – Tumor invades the scrotum with or without vascular/lymphatic invasion

Node

Regional lymph node involvement is used for clinical (N) or pathologic (pN) staging, as follows:

• NX or pNX – Regional lymph nodes cannot be assessed
• N0 or pN0 – No regional lymph node metastasis
• N1 or pN1 – Metastases with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
• N2 or pN2 – Metastases with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension.
• N3 or pN3 – Metastases with a lymph node mass more than 5 cm in greatest dimension

Metastasis

Distant metastasis (M) is classified as follows:

• MX – Distant metastasis cannot be assessed
• M0 – No distant metastasis
• M1 – Distant metastasis
• M1a – Nonregional nodal or pulmonary metastasis
• M1b – Distant metastasis other than to nonregional lymph nodes and lungs

American Joint Committee on Cancer (AJCC) Stage Groupings

The AJCC stage groupings use both TNM staging and serum tumor marker levels. The designation SX indicates that markers were unavailable or not performed; S0 indicates normal levels. The table below defines other S categories.

Table 1. Serum Tumor Markers

View Table

See Table

AJCC stage groupings are as follows^[17] :

• Stage 0 - pTis, N0, M0, S0
• Stage I - pT1–4, N0, M0, SX
• Stage IA - pT1, N0, M0, S0
• Stage IB - pT2–4; N0, M0, S0
• Stage IS - Any pT/Tx, N0, M0, S1–3
• Stage II - Any pT/Tx, N1–3, M0, SX
• Stage IIA - Any pT/Tx, N1, M0, S0–1
• Stage IIB - Any pT/Tx, N2, M0, S0–1
• Stage IIC - Any pT/Tx, N3, M0, S0–1
• Stage III - Any pT/Tx, any N, M1, SX
• Stage IIIA - Any pT/Tx, any N, M1a, S0–1
• Stage IIIB - Any pT/Tx, N1–3, M0, S2; or any pT/Tx, any N, M1a, S2
• Stage IIIC - Any pT/Tx, N1–3, M0, S3; any pT/Tx, any N, M1a, S3; or any pT/Tx, any N, M1b, any S

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.

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Risk Classification

The International Germ Cell Consensus Classification (IGCCC),^[18]  an easily applicable, clinically based prognostic instrument, is used in clinical practice to guide treatment choice and is the current standard for all practice guidelines, including that of the National Comprehensive Cancer Network.^[15]

The IGCCC is based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous germ cell tumor (NSGCT) and 660 patients with metastatic seminomatous germ cell tumors from 10 countries, who were treated between 1975 and 1990. All patients received treatment with cisplatin- or carboplatin-containing therapy as their first chemotherapy course. Median followup was 5 years.

A subsequent meta-analysis of survival of patients with NSGCT, treated after 1989 and classified according to the IGCC classification, reported a small increase in survival for good-prognosis and intermediate-prognosis patients, and a large increase in survival for patients with a poor prognosis. Pooled 5-year survival estimates were 94% with good prognosis (n = 1087), 83% with intermediate prognosis (n = 232), and 71% with poor prognosis (n = 456). The researchers suggested that the improved survival most likely reflected both more effective treatment strategies and more experience in treating NSGCT patients.^[19]

Risk classification for both nonseminomas and seminomas is determined on the basis of tumor and metastasis characteristics and serum tumor marker levels. Nonseminomas are classified as good, intermediate, or poor risk. Seminomas are classified as good or intermediate risk; no patients with seminomas are considered to have a poor prognosis.

Good-risk nonseminoma

Nonseminomas are classified as good risk when all of the following are present:

• Testicular or retroperitoneal primary tumor
• No nonpulmonary visceral metastases
• Good markers

Good markers are defined as all of the following:

• Alpha-fetoprotein (AFP) < 1,000 ng/mL
• Human chorionic gonadotropin (hCG) < 5,000 IU/mL (1,000 ng/mL)
• Lactate dehydrogenase (LDH) < 1.5 times the upper limit of normal

Intermediate-risk nonseminoma

Nonseminomas are classified as intermediate risk when all of the following are present:

• Testicular or retroperitoneal primary tumor
• No nonpulmonary visceral metastases
• Any intermediate markers

Intermediate markers are defined as follows:

• AFP 1,000 to 10,000 ng/mL
• hCG 5,000 IU/L to 50,000 IU/L
• LDH 1.5 to 10 times the upper limit of normal

Poor-risk nonseminoma

Nonseminomas are classified as poor risk when any of the following are present:

• Mediastinal primary
• Nonpulmonary visceral metastases
• Any poor markers

Poor markers are as follows:

• AFP > 10,000 ng/mL
• hCG > 50,000 IU/mL (10,000 ng/mL)
• LDH > 10 times the upper limit of normal

Good-risk seminoma

Seminomas are classified as good risk when all of the following are present:

• Any primary site
• No nonpulmonary visceral metastases
• Normal AFP, any hCG, any LDH

Intermediate-risk seminoma

Seminomas are classified as intermediate risk when all of the following are present:

• Any primary site
• Nonpulmonary visceral metastases
• Normal AFP, any hCG, any LDH

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Lab Studies

Blood should be obtained for a chemistry profile including lactate dehydrogenase (LDH), complete blood count, and serum tumor markers including alpha fetoprotein (AFP), and the beta subunit of human chorionic gonadotropin (beta-hCG).

Serum levels of AFP and/or beta-hCG are elevated in approximately 80% to 85% of patients with nonseminomatous germ cell tumors (NSGCTs), even when nonmetastatic. Patients with pure seminoma may have elevated levels of beta-hCG but do not have elevated AFP levels. If AFP is elevated in patients with pure seminoma then the presence of an NSGCT component should be considered.

Elevation of serum beta-hCG and AFP levels, alone or in combination, is not sufficiently sensitive or specific to establish the diagnosis of testicular cancer in the absence of histologic confirmation, although markedly elevated levels are rarely found in normal individuals. However, AFP, beta-hCG, and LDH levels are vital in the evaluation and management of patients with testicular cancers. They are used for determining diagnosis, staging, and prognosis and for following response to therapy. Obtaining levels of AFP, beta-HCG, and LDH in patients in whom testicular cancer are suspected is mandatory prior to treatment, as is monitoring of these levels during and after treatment.

Serum alpha-fetoprotein features are as follows:

• Secretion is restricted to nonseminoma
• Reference adult concentration is < 10 ng/mL
• Serum half-life is 4-5 days
• Concentrations above 10,000 ng/ml are seen exclusively in germ cell tumor and hepatocellular carcinoma
• Levels may be elevated in patients with hepatic dysfunction, hepatitis, cirrhosis, and drug or alcohol abuse

B-hCG features are as follows:

• Increased levels of beta-hCG can be found in either seminoma or nonseminoma
• Serum half-life is 18-36 hours
• Patients with high levels of beta-hCG may experience nipple tenderness or gynecomastia
• Serum beta-hCG concentrations above 10,000 mIU/mL are seen exclusively in germ cell tumors
• Elevated levels may also be seen in patients with trophoblastic differentiation of a lung or gastric primary cancer or with hypogonadism
• False-positive elevations may result from marijuana use

LDH features are as follows:

• LDH has independent prognostic significance: increased levels reflect tumor burden, growth rate, and cellular proliferation
• Levels are elevated in 30% to 80% of patients with pure seminoma and 60% of patients with nonseminomatous tumors
• LDH is not a sensitive or specific indicator of disease recurrence and therefore is not a useful serum marker for posttreatment surveillance

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Medical Care

Testicular cancers are curable even in the presence of metastatic disease. If the cancer progresses or recurs despite initial chemotherapy, these patients are candidates for salvage therapy.

Nonseminoma is more aggressive than seminoma. When the elements of both seminoma and nonseminoma are present or the alpha-fetoprotein (AFP) concentration is elevated, the tumor should be treated as a nonseminoma.

Initial therapy is selected according to American Joint Committee on Cancer (AJCC) stage group; risk stratification (good, intermediate, or poor risk), as per the guidelines of the International Germ Cell Cancer Collaborative Group^[18] ; and histology (seminoma versus nonseminoma).^[20]  See Workup/Staging and Workup/Risk Classification.

Current guidelines from the National Comprehensive Cancer Network (NCCN)^[15] and the National Cancer Institute^[1] recommend a treatment approach keyed to AJCC staging. These treatment groups are as follows:

• Seminoma stage IA, IB
• Seminoma stage IS
• Seminoma stage IIA, IIB
• Seminoma stage IIC, III
• Nonseminoma stage IA, IB, IS
• Nonseminoma stage IIA, IIB
• Nonseminoma stage IIC, IIIA, IIIB, IIIC and brain metastases
• Recurrent disease and salvage treatment

Seminoma stage IA, IB

Clinical stage I seminomas have a very high cure rate. Cure can sometimes be achieved by radical inguinal orchiectomy alone. Options after orchiectomy include active surveillance, adjuvant chemotherapy, and adjuvant radiation therapy. Median time to relapse in patients who do not receive adjuvant treatment is 12 months, but relapse can occur even beyond 5 years.

Active surveillance is recommended for patients with horseshoe or pelvic kidney or inflammatory bowel disease and for those who have received prior radiotherapy. Surveillance can also be offered to selected patients with T1 or T2 or T3 disease. Surveillance consists of a history and physical exam and measurement of  aAFP and hCG every 3 to 4 months for the first 3 years, every 6 months for years 4 to 7, then annually up to year 10. A CT scan of the abdomen and pelvis is recommended at each visit and a chest x-ray at alternate visits. It is essential that patients maintain strict adherence to the surveillance program for at least 10 years.

Adjuvant radiation therapy consists of delivery of 20-30 Gy to the infradiaphragmatic area, including the para-aortic lymph nodes and in some cases the ipsilateral ileoinguinal nodes. According to surveillance data, the overall incidence of disease failure without radiation therapy is 15% to 27%, with median of 20%. With radiation therapy, failure rates were 2% to 5%, with a median of 3%.

Adjuvant chemotherapy with a single dose of carboplatin (see Medication) is currently recommended as an alternative to radiation therapy.^[21] In a randomized study in 1,477 patients, median followup of 6.5 years confirmed that single-dose carboplatin is noninferior to radiation therapy in terms of relapse-free rate (RFR), producing a statistically significant reduction in the medium-term risk of a contralateral germ cell tumor. RFRs at 5 years were 94.7% for carboplatin and 96.0% for radiation therapy.^[22] Acute toxicity such as lethargy and days missed from work was less with carboplatin than with radiation therapy.

A prospective, population-based, risk-adapted treatment protocol study by the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) concluded that stromal invasion in the rete testis and tumor diameter > 4 cm are risk factors for relapse in clinical stage I seminoma. Relapse rates in patients without those risk factors were 4.0% in patients managed with surveillance and 2.2% in those who received adjuvant carboplatin. The SWENOTECA researchers concluded that adjuvant therapy is not justified in those patients.^[23]

In patients with one or two risk factors, the relapse rate was 15.5% with surveillance versus 9.3% in patients receiving adjuvant carboplatin. However, the relapse rate was not higher in patients whose carboplatin dose was less than 7 × area under the curve (AUC) than in those who received a higher dose.^[23]

Seminoma stage IS

Stage IS seminoma is defined by persistent elevation of serum tumor markers (LDH, AFP, and beta-hCG). Current NCCN guidelines recommend repeating serum tumor marker assays in these patients and assessing with abdominal/pelvic CT for evaluable disease. However, the NCCN advises that stage IS pure seminoma is very uncommon and that other causes may be responsible for minimally elevated LDH or beta-hCG levels, so caution is warranted before intervening in those cases.^[15]

Seminoma stage IIA

Active surveillance is not an option. These patients receive adjuvant chemotherapy or radiation therapy.

For radiation therapy, 30 Gy is administered to the para-aortic and ipsilateral iliac lymph nodes. Mediastinal radiation is not recommended.

For adjuvant chemotherapy, four cycles of chemotherapy with etoposide and cisplatin (EP) or three courses of bleomycin, etoposide and cisplatin (BEP) is recommended.

Seminoma stage IIB

Primary chemotherapy with three cycles of bleomycin, etoposide and cisplatin (BEP) or four cycles of chemotherapy with etoposide and cisplatin (EP) is recommended. In select cases of non-bulky (≤3 cm) disease, radiation therapy that includes the para-aortic and ipsilateral iliac lymph nodes can be given, in a dose of 36 Gy.

Seminoma stage IIC and III

Stage IIC and III seminomas are categorized as good risk or intermediate risk. Intermediate-risk seminomas include nonpulmonary visceral metastatic disease. Chemotherapy is the option for both groups, with different regimens for the two categories, as follows:

• Good-risk seminoma stage IIC and III: Either three cycles of BEP or four cycles of EP 
• Intermediate-risk seminoma stage IIC and III: Four cycles of BEP is preferred, other option is VIP (VP 16/etoposide + ifosfamide + platinol/cisplatin) is another option for four cycles. 

Seminoma stage IIB, IIC, III after primary treatment with chemotherapy

For stage II and III seminoma after primary treatment with chemotherapy, recommended surveillance includes CT scans of the chest, abdomen, and pelvis along with serum tumor marker assays. For patients with a residual mass but normal markers, PET scanning should also be considered. In some cases of seminoma, a PET scan may detect nodal and extranodal disease that is not evident on CT scans.^[24]

PET scans for evaluating the response to chemotherapy in seminoma should be performed 3-4 weeks after the last course of chemotherapy. If the PET scan is negative, surveillance is recommended. Options for patients with a positive PET scan include the following:

• Surgery with biopsy
• Biopsy and salvage chemotherapy or radiation therapy

If a PET scan cannot be done and the residual mass is 3 cm or less in size, surveillance is recommended. When the mass is larger than 3 cm in size, surveillance could be considered but surgery and radiation therapy are options and should be discussed with the patient.

Patients who experience progressive disease with a growing mass or rising marker levels should receive salvage chemotherapy.

Nonseminoma stage IA, IB, IS

After radical inguinal orchiectomy, treatment options are active surveillance or chemotherapy. Retroperitoneal lymph node dissection (RPLND) is used to guide chemotherapy; the number of positive nodes present in the sample determines the number of chemotherapy cycles given. Open nerve-sparing RPLND is preferred over laparoscopic RPLND. RPLND has multiple complications, including retrograde ejaculation.

A long-term surveillance study by Daugaard et al in 1226 patients with stage I nonseminoma germ cell cancer who had been treated with orchiectomy only found that relapse occurred more often in patients with vascular invasion together with embryonal carcinoma and rete testis invasion in the testicular primary. Relapse risk at 5 years in patients with those features was 50%, versus 12% in patients without them. Relapses were diagnosed within the first year after orchiectomy in 80% of cases.^[25]

These findings suggest that the majority of stage I nonseminoma germ cell tumors can be safely managed without subjecting the patient to chemotherapy or RPLND; orchiectomy and followup surveillance will suffice. The small subset of patients at high risk for systemic recurrence may considered for adjuvant chemotherapy.

Nonseminoma stage IA

Active surveillance can be used in compliant patients and is preferred; see Follow-up for surveillance guidelines. The cure rate is 95%. Adherence to the surveillance program is the key to success. Noncompliant patients should be offered RPLND within 4 weeks of the CT scan and 7-10 days of tumor marker assays. If RPLND results are negative, primary chemotherapy BEP for one cycle is another option

Nonseminoma stage IB

Options are open nerve-sparing RPLND; chemotherapy with BEP for 1-2 cycles. Active surveillance, although not a preferred option, could be considered for compliant patients who have T2 or T3 disease. 

Nonseminoma stage IS

If persistent tumor marker elevation is present but no abnormality is visible on imaging studies, chemotherapy with EP for 4 cycles or BEP for 3 cycles is recommended.

Nonseminoma stage IIA, IIB

Treatment varies according to the stage and the results of tumor marker assays and CT scan. Chemotherapy in these cases consists of either EP for four cycles or BEP for three cycles. Treatment recommendations are as follows:

• Nonseminoma stage IIA with normal tumor markers: open nerve-sparing RPLND or chemotherapy BEP three cycles or EP for four cycles.
• Nonseminoma stage IIA with persistent elevation of tumor markers: chemotherapy
• Nonseminoma stage IIB with normal tumor markers and lymph node metastasis within lymphatic drainage site by CT scan: open nerve-sparing RPLND or chemotherapy BEP three cycles or EP for four cycles
• Nonseminoma stage IIB normal tumor markers and multifocal symptomatic lymph node metastases with aberrant lymphatic drainage by CT scan: Primary chemotherapy BEP three cycles or EP for four cycles
• Nonseminoma stage IIB with persistent elevation of tumor markers: chemotherapy

Nonseminoma stage IIC, IIIA, IIIB, IIIC and brain metastases

Patients with stage IIC and III are treated with chemotherapy, with the regimen choice based on risk status. Approximately 20-30% of patients with metastatic testicular cancer cannot be cured.

With nonseminoma stage IIC, IIIA good risk, 95% of patients are cured with chemotherapy, either EP for four cycles or BEP for three cycles. In nonseminoma stage IIIB intermediate risk, BEP for four cycles is given; the cure rate is 70%.

With nonseminoma stage IIIB poor risk, enrollment in clinical trials is preferred. Chemotherapy with four cycles with BEP can be considered, but fewer than 50% of patients will experience a durable complete response. In patients who cannot tolerate BEP because of pneumonitis from the bleomycin component, VIP (etoposide [VePesid], ifosfamide, mesna, cisplatin [Platinol-AQ]) is recommended.

Patients with brain metastases should receive primary chemotherapy plus radiation. Surgery should be performed if clinically indicated.

In nonseminoma stage IIC, IIIA, IIIB, or IIIC, a CT scan of the abdomen and pelvis and tumor marker assays are indicated after the completion of chemotherapy. With patients in whom these tests indicate a complete response, options are surveillance or open nerve-sparing RPLND. If residual disease is present but tumor marker levels are normal, all the residual disease should be resected. If the resection specimen shows only necrotic tissue or teratoma, no further therapy is recommended and active surveillance should be done. If residual embryonal, yolk sac, choriocarcinoma, or seminoma elements are present, the patient should receive two cycles of chemotherapy with EP, TIP (paclitaxel, ifosfamide and cisplatin), VIP, or VeIP (vinblastine, ifosfamide, mesna, cisplatin).

Patients who do not have a complete response to chemotherapy and/or whose disease cannot be resected should receive salvage chemotherapy.

Recurrent disease and salvage treatment

Patients who do not have a complete response to first-line therapy, or whose disease recurs after complete response, are categorized into favorable and unfavorable prognostic groups.

Salvage treatment for patients with a favorable prognosis

This group includes patients with low tumor marker levels, low-volume disease, complete response to first-line chemotherapy, and testis primary. These patients are treated with chemotherapy—VeIP or TIP. If they have an incomplete response or relapse, they should be considered for high-dose chemotherapy with autologous stem cell transplantation or enrollment in a clinical trial. In patients with a solitary metastatic site, salvage surgery should be considered. Patients who have a complete response should be followed closely and if they experience relapse, should be considered for clinical trials or high-dose chemotherapy.

Salvage treatment for patients with an unfavorable prognosis

This group includes patients with an incomplete response to first-line chemotherapy, high tumor marker levels, high-volume disease, extratesticular primary, and late relapse. In these patients, enrollment in a clinical trial is preferred. Other options include high-dose chemotherapy plus autologous stem cell support, conventional chemotherapy with either VeIP or TIP, or best supportive care. Third-line chemotherapy with or without cyclophosphamide/ifosfamide can produce a durable complete response in 15%-20% of patients and should be considered for patients with good performance scores.

High-dose chemotherapy and stem cell rescue

High-dose chemotherapy with tandem courses of carboplatin and etoposide followed by hematopoietic stem cell rescue can produce complete remission in 5%-10% of cisplatin-refractory testicular cancers.^[26] Non–cisplatin-refractory testicular cancers have much better responses; more than 60% of these patients can be cured with high-dose chemotherapy.

Palliative chemotherapy and radiation

Most patients who do not respond to high-dose chemotherapy probably have incurable disease; an exception is those with solitary metastatic disease that is surgically resectable. If surgery cannot be done, these patients can be considered for palliative chemotherapy or palliative radiation therapy. Gemcitabine and oxaliplatin (GEMOX) has shown efficacy in relapsed cisplatin-refractory disease and may offer a chance for long-term survival.^[27]

• References

Surgical Care

Surgical resection is recommended for patients with residual disease after chemotherapy. Retroperitoneal lymph node dissection (RPLND) should clear the region of residual disease. Open nerve-sparing RPLND is preferred over laparoscopic RPLND, although open nerve-sparing RPLND has multiple complications, including retrograde ejaculation and other infertility issues.

Patients in whom RPLND reveals viable cancer (in approximately 60% of patients, postchemotherapy residual masses are either viable cancer or teratoma) are treated with subsequent chemotherapy.

• References

Treatment-related Toxicity

Potential toxicity from testicular cancer treatment includes the following:

• Pulmonary
• Renal
• Cardiovascular
• Infertility
• Hematologic
• Bone loss

Pulmonary toxicity

Bleomycin can cause pneumonitis and pulmonary fibrosis; therefore, pulmonary function tests are done before starting chemotherapy that includes this agent. Bleomycin-induced lung toxicity is cumulative and although it can be fatal, it is rarely fatal if the total cumulative dose is less than 400 units.

Patients with bleomycin-induced pneumonitis present with nonproductive cough, dyspnea on exertion, and bibasilar rales. Chest x-ray may show pulmonary nodules. A decline in carbon monoxide diffusing capacity (DL_CO) is the earliest sign of lung toxicity; bleomycin should be discontinued if it occurs. Smokers should be counseled regarding smoking cessation.

Little evidence is available to guide treatment of bleomycin-induced pneumonitis. Prompt and permanent discontinuation of the drug remains the mainstay of management. Corticosteroid therapy may be beneficial,especially in patients with acute inflammatory disease. Animal studies and case reports have described treatment with a variety of agents (eg, imatinib, infliximab), but with mixed results.^[28]

An increase in the incidence of restrictive lung disease has also been reported in patients who receive cisplatin-based chemotherapy for testicular cancer. The effect was dose dependent, with no increase in risk for men who received up to 850 mg of cisplatin but a three-fold increase in men who received over 850 mg of cisplatin. In absolute terms, the incidence of restrictive lung disease in men receiving over 850 mg of cisplatin was nearly 18%.^[29]

Renal toxicity

Approximately 20-30% of patients who receive cisplatin have a reduction in glomerular filtration rate. Cisplatin can also cause hypomagnesemia, hypophosphatemia, and hypokalemia.

Cardiovascular toxicity

Cardiovascular disorders are late complications of radiation therapy and/or chemotherapy (particularly platinum based). They include hypertension, dyslipidemia, coronary artery disease, thromboembolic events, and Raynaud phenomenon. However, the risk of cardiovascular disease appears to be of only borderline significance with the newer regimen of bleomycin, etoposide, and cisplatin (BEP), compared with the older regimen of cisplatin, vinblastine, and bleomycin (PVB), which was used until the mid-1980s.^[1]

Infertility

Many patients have oligospermia or sperm abnormalities before treatment, but semen analysis results generally become more normal after treatment. Data on the effect of chemotherapy on fertility remain uncertain; most men can father children after treatment, and the risk of congenital malformations does not seem to be increased, but waiting for at least 3 months after completion of chemotherapy before attempting to conceive a child has been recommended.^[1]

Hematologic toxicity

Anemia, leukopenia/neutropenia, and thrombocytopenia may occur. Prophylactic treatment with hematopoietic growth factors is recommended to avoid the need for dose attenuation or treatment delays.

Bone loss

In patients who had metastatic germ cell tumors, Willemse et al reported a significant decrease in bone mineral density (BMD) in the first year after curative chemotherapy, with no recovery of BMD in the 5 years afterward. These researchers note that whether this bone loss is associated with increased fracture risk and whether it could be prevented by bone-modifying treatment remains uncertain.^[30]

Other complications

Other complications include the following:

• Gastrointestinal toxicity: Nausea and vomiting
• Neurological toxicity: Cisplatin and oxaliplatin can cause neuropathy
• Ototoxicity: Tinnitus and high-frequency sensorineural loss may occur

• References

Fertility and Sperm Banking

Because 45% to 55% of testicular cancer patients have azoospermia or oligospermia at or beyond 2 years after therapy, those patients who wish to preserve fertility should be offered semen cryopreservation before the start of therapy.^[31] Some experts recommend performing a baseline sperm count and sperm banking prior to the radiographic diagnostic evaluation, to avoid radiation exposure of the sperm. An increased rate of fetal malformations has not been reported in the subsequent offspring of men who have retained fertility after treatment for testicular cancer.

• References

Guidelines Summary

The following organizations have released guidelines on the diagnosis, staging and treatment of testicular cancer:

• National Comprehensive Cancer Network (NCCN)^[15]
• European Association of Urology (EAU)^[32]
• European Society for Medical Oncology (ESMO)^{[33, 34]}

• References

Diagnosis and Staging

All guidelines concur with the following diagnosis and staging recommendations^{[15, 33, 32, 34]} :

• Sperm banking should be discussed with all men before embarking on treatment for testicular cancer.
• Testicular ultrasonography should be performed on all patients in whom testicular cancer is suspected.
• Biopsy of the contralateral testis should be performed in patients with ultasound findings of intratesticular mass suggestive for testicular cancer, cryptorchid testis, marked atropy or any suspicious mass
• Orchiectomy should be performed and the testis should undergo pathological examination in order to confirm the diagnosis and to define the local extension (pT category).
• In the rare cases of a patient presenting with rapidly increasing beta-hCG or AFP and symptoms of extensive metastasis, chemotherapy can be started before a biopsy diagnosis or orchiectomy.
• For staging and prognostic purposes, serum determination of tumor markers (ie, alpha-fetoprotein, human chorionic gonadotrophin, lactate dehydrogenase) should be performed before orchiectomy, 5-7 days after orchiectomy, and until normalized. Staging is based on marker levels at the time that the patient starts potorchiectomy therapy.
• The state of retroperitoneal, mediastinal, and supraclavicular nodes, as well as the viscera, should be assessed in testicular cancer.

Patients and family members with a familial history of testicular cancer should be advised to perform regular testicular self-examination.^[32]

• References

Recommendations for treatment of seminoma

Stage I

All guidelines are in general agreement with the following treatment recommendations for stage I seminoma^{[15, 32, 33]}

• Patients should be fully informed about all available management options. This should include surveillance or adjuvant chemotherapy after orchiectomy, treatment-specific recurrence rates, and short- and long-term adverse effects.
• Surveillance: NCCN and ESMO preferred treatment for for pT1-pT3 tumors^{[15, 33]} , while EAU recommends if there are facilities available and the patient is compliant.^[32]
• Carboplatin chemotherapy: EAU and ESMO recommend one cycle at area under the curve (AUC) 7^{[33, 32]} ; NCCN recommends 1 or 2 cycles.^[15]
• Radiotherapy (RT): NCCN and ESMO recommend 20 Gy/10 fractions^{[15, 33]} ; EAU recommends against RT as adjuvant treatment.^[32]

EAU also recommends against adjuvant treatment for patients at very low risk (ie, no risk factors).^[32]

Stage II

All guidelines agree that patients with clinical stage IIA seminoma should be offered radiotherapy or chemotherapy; they should also be informed about the possible long-term adverse effects of both management options.^{[15, 32, 33]}

For clinical stage IIB, primary chemotherapy with BEP x 3 or etoposide/cisplatin (EP) x 4 is preferred by all guidelines.^{[15, 33, 32]}  NCCN also recommends RT in slect non-bulky (≤3cm) cases at a dose of 36Gy.^[15]

For good risk clinical stage IIC or III, NCCN gives a category 1 recommendation for chemotherapy with either BEP x 3 or EP x 4; for intermediate risk, the category 1 recommendation is BEP x 4.  Esposide/ifosfamide/cisplatin (VIP) x4 is an alternative regimen.^[15]  ESMO guidelines are in agreeement with these recommendations.^[33]

According to EAU guidelines, patients with seminoma at stage IIC and higher should be treated with primary chemotherapy according to the same principles used for NSGCTs (see below).^[32]

• References

Recommendations for surveillance of seminoma

In patients with clinical stage I seminoma, the National Comprehensive Cancer Network (NCCN) recommends surveillance with history and physical examination (H&P) and abdominal and pelvic computed tomography (CT). The NCCN guidelines advise that follow-up for seminoma should be modified for the individual patient and may be extended beyond 5 years.^[15]

Serum tumor marker assays are optional. Testicular ultrasound should be performed in patients with an equivocal exam. Chest x-rays should be performed as clinically indicated, with chest CT considered in symptomatic patients.

The NCCN surveillance schedule for clinical stage I seminoma patients treated with orchiectomy only is as follows:

• Year 1 - H&P every 3-6 mo; abdominal/pelvic CT at 3, 6, and 12 mo
• Years 2-3 - H&P and abdominal/pelvic CT every 6-12 mo
• Years 4-5 - H&P annually; abdominal/pelvic CT every 12-24 mo

The NCCN surveillance schedule for clinical stage I seminoma patients treated with adjuvant chemotherapy or radiation therapy is as follows:

• Years 1-2 - H&P every 6-12 mo; abdominal/pelvic CT annually
• Year 3 - H&P and abdominal/pelvic CT annually
• Years 4-5 - H&P annually

In patients with clinical stage IIA and non-bulky stage IIB seminomas, the NCCN recommendations for surveillance are as follows:

• H&P
• Abdominal and pelvic CT
• Chest x-ray, with chest CT preferred in patients with thoracic symptoms
• Serum tumor marker assays are optional
• Testicular ultrasound should be performed in patients with an equivocal exam

In clinical stage IIA and non-bulky stage IIB seminoma, the NCCN surveillance schedule after radiotherapy or chemotherapy is as follows:

• Year 1 - H&P every 3 mo; abdominal/pelvic CT at mo and then 6-12 mo; chest x-ray every 6 mo
• Year 2 - H&P every 6 mo, abdominal/pelvic CT annually, chest x-ray every 6 mo
• Year 3 - H&P every 6 mo, abdominal/pelvic CT annually
• Years 4-5 - H&P every 6 mo, abdominal/pelvic CT as clinically indicated

In patients with bulky clinical stage IIB, IIC and stage III seminomas, the NCCN surveillance post-chemotherapy with no residual mass or residual mass < 3 cm and normal tumor marker recommend abdominal and pelvic CT scan with contrast at 3-6 months, then as clinically indicated. PET/CT scan as clinically indicated. The surveillance schedule is as follows:

• Year 1 - H&P, tumor markers, and chest x-ray every 2 mo
• Year 2 - H&P, tumor markers, and chest x-ray every 3 mo
• Years 3-4 - H&P and tumor markers every 6 mo and chest x-ray annually
• Year 5 - H&P, tumor markers, and chest x-ray annually

• References

Recommendations for treatment of nonseminoma

Stage I 

For stage I nonseminomatous germ cell tumors (NSGCTs), the guidelines are in agreement that patients should be informed about all adjuvant treatment options after orchiectomy (ie, surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection [RPLND]). Information should include treatment-specific recurrence rates and short- and long-term adverse effects.^{[15, 33, 32]}

Stage I without risk factors

For the treatment of stage 1 NSGCTs with no risk factors (pT1), the guidelines recommend surveillance as the preferred treatment.^{[15, 33, 32]}  If surveillance is not feasible, e.g. due to difficulties with repeated imaging, low compliance or patient's preferenceerred treatment, the guidelines vary in their treatment recommendations as follows:

• NCCN recommends RPLND (preferred) or chemotherapy with one course of bleomycin/etoposide/cisplatin (BEP).^[15]
• EAU recommends adjuvant chemotherapy with one course of BEP.^[32]
• ESMO recommends adjuvant chemotherapy with one or two cycles of BEP. In patients not suitable for surveillance or adjuvant chemotherapy, RPLND in highly experienced centres is an option. The guidelines note that some experts consider nerve-sparing RPLND the preferred treatment of patients with teratoma and somatic transformation in the primary tumour.^[33]

According to EAU guidelines, patients who have a marker-positive recurrent and/or progressing lesion during surveillance should receive salvage treatment that includes three or four courses of BEP chemotherapy according to the International Germ Cell Cancer Collaborative Group classification; this should be followed by postchemotherapy RPLND as necessary.^[32]

Stage I with risk factors

Recommendations for treatment of stage I NSGCTs with risk factors (pT2-pT4), are as follows^{[15, 33, 32]} :

• NCCN: Surveillance or primary chemotherapy with BEP for one cycle, or nerve-sparing RPLND^[15]
• ESMO: Surveillance or adjuvant chemotherapy for one or two cycles of BEP. Nerve-sparing RPLND may be carried out if serveillance and chemotherapy are contraindicated.^[33] ​ 
• EAU: Primary chemotherapy with one course of BEP chemotherapy. In adjuvant chemotherapy, discuss advantages and disadvantages of one versus two cycles of BEP chemotherapy. Surveillance for patients not willing to undergo adjuvant chemotherapy. Nerve-sparing RPLND for highly selected patients only, to include patients with contraindications to adjuvant chemotherapy and those not willing to accept surveillance.^[32]

​Stage II and III

Stage IIA/IIB (markers negative): NCCN and ESMO recommend nerve-sparing RPLND or primary chemotherapy with BEP x 3 or EP x 4.^{[15, 33]} EAU recommends excluding marker-negative embryonal carcinoma by histological examination after either RPLND or biopsy. If this is not possible, staging should be repeated after 6 weeks of surveillance before any final decisions are made on further treatment.^[32]

Stage IIA/IIB (persistent marker elevation), IIC and IIIA: NCCN gives category 1 recommendations for primary chemotherapy with BEP x 3 or EP x 4.^[15]  ESMO and EAU guidelines concur.^{[33, 32]}

Stage IIIB (intermediate risk): NCCN gives category 1 recommendations for primary chemotherapy with BEP x 4 or VIP x 4.^[15]  ESMO and EAU guidelines concur.^{[33, 32]}

Stage IIIC (poor risk): NCCN gives category 1 recommendations for primary chemotherapy with BEP x 4 or VIP x 4 (in selected patients).^[15]  ESMO guidelines concur.^[33]  EAU recommends one cycle of BEP or cisplatin/etoposide/ifosfamide (PEI) in case of poor lung function, followed by an assessment of tumor markers after 3 weeks. If tumor markers decline favorably, BEP (or PEI) should be continued for up to four cycles. If tumor markers decline unfavorably, chemotherapy intensification should be initiated.^[32]

Surgical resection of residual masses should be performed after chemotherapy for NSGCTs when visible residual masses are noted and when serum levels of tumor markers are normal or normalizing.^{[15, 32]}

• References

Recommendations for surveillance of nonseminoma

In patients with clinical stage I-III nonseminomas, the NCCN recommends surveillance with H&P, serum tumor markers, abdominal/pelvic CT, and chest x-ray, with chest CT preferred in patients with thoracic symptoms. Testicular ultrasound should be performed in patients with an equivocal exam.^[15]

In clinical stage IA nonseminoma, the NCCN active surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 2 mo; abdominal/pelvic CT every 4-6 mo; chest x-ray at 4 and 12 mo
• Year 2 - H&P and tumor markers every 3 mo; abdominal/pelvic CT every 6-12 mo; chest x-ray annually
• Year 3 - H&P and tumor markers every 4-6 mo; abdominal/pelvic CT annually; chest x-ray annually
• Year 4 - H&P and tumor markers every 6 mo; chest x-ray annually
• Year 5 - H&P, tumor markers, and chest x-ray annually

In clinical stage IB nonseminoma, the NCCN active surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 2 mo; abdominal/pelvic CT every 4 mo; chest x-ray every 2 mo
• Year 2 - H&P and tumor markers every 3 mo; abdominal/pelvic CT every 4-6 mo; chest x-ray every 3 mo
• Year 3 - H&P and tumor markers every 4-6 mo; abdominal/pelvic CT every 6 mo chest x-ray every 4-6 mo
• Year 4 - H&P and tumor markers every 6 mo; abdominal/pelvic CT annually; chest x-ray every 6 mo
• Year 5 - H&P, tumor markers, and chest x-ray annually

In clinical stage IB nonseminoma treated with 1-2 cycles of adjuvant BEP chemotherapy, the NCCN surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 3 mo; abdominal/pelvic CT annually; chest x-ray every 6-12 mo
• Year 2 - H&P and tumor markers every 3 mo; abdominal/pelvic CT annually; chest x-ray annually
• Years 3-4 - H&P and tumor markers every 6 mo
• Year 5 - H&P and tumor markers annually

In clinical stage II-III nonseminoma that has shown a complete response to chemotherapy, with or without post-chemotherapy RPLND, the NCCN surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 2 mo; abdominal/pelvic CT every 6 mo; chest x-ray every 6 mo
• Year 2 - H&P and tumor markers every 3 mo; abdominal/pelvic CT annually; chest x-ray every 6 mo
• Year 3 - H&P and tumor markers every 6 mo; chest x-ray annually (optional at month 36 and 48)
• Year 4 - H&P and tumor markers every 6 mo; chest x-ray annually (optional at month 36 and 48)
• Year 5 - H&P and tumor markers every 6 mo

In pathologic stage IIA-B nonseminoma, after primary RPLND and treatment with adjuvant chemotherapy, the NCCN surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 6 mo; abdominal/pelvic CT after RPLND; chest x-ray every 6 mo
• Year 2 - H&P and tumor markers every 6 mo; abdominal/pelvic CT as clinically indicated; chest x-ray annually
• Years 3-5 - H&P and tumor markers annually; abdominal/pelvic CT as clinically indicated; chest x-ray annually

In pathologic stage IIA-B nonseminoma, after primary RPLND and NOT treated with adjuvant chemotherapy, the NCCN surveillance schedule is as follows:

• Year 1 - H&P and tumor markers every 2 mo; abdominal/pelvic CT at 3-4 mo (assuming complete resection has taken place); chest x-ray every 2-4 mo
• Year 2 - H&P and tumor markers every 3 mo; chest x-ray every 3-6 mo
• Year 3 - H&P and tumor markers every 4 mo; abdominal/pelvic CT as clinically indicated; chest x-ray annually
• Year 4 - H&P and tumor markers every 6 mo; abdominal/pelvic CT as clinically indicated; chest x-ray annually
• Year 3 - H&P and tumor markers annually; abdominal/pelvic CT as clinically indicated; chest x-ray annually

• References

Medication Summary

Chemotherapy regimens for testicular cancers are divided into initial and salvage chemotherapy, according to tumor stage, status, and risk stratification.

Initial Chemotherapy Regimens

Carboplatin (for stage I seminoma)

• Carboplatin area under the curve (AUC) 7 (see Carboplatin AUC Dose Calculation [Calvert Formula]) for one or two cycles

BEP (5-day schedule)

• Bleomycin 30 U or 30 mg IV bolus day 1, 8, 15 or day 2, 9, 16
• Etoposide (VP-16) 100 mg/m²/day IV for 5 days
• Cisplatin (CDDP) 20 mg/m²/day IV for 5 days

This regimen is administered for three to four cycles at 21-day intervals

EP

• Etoposide (VP-16) 100 mg/m²/day IV daily for 5 days
• Cisplatin (CDDP) 20 mg/m²/day IV daily for 5 days

This regimen is administered for four cycles at 21-day intervals

VIP (for patients with underlying lung disease)

• Etoposide (VP-16) 75 mg/m²/day IV daily for 5 days
• Ifosfamide 1.2 g/m²/day IV daily for 5 days
• Cisplatin (CDDP) 20 mg/m²/day IV for days 1-5

Mesna 120 mg/m² slow IV bolus is given before ifosfamide day 1, followed by 1200 mg/m²/day continuous infusion on days 1-5

This regimen is administered for four cycles at 21-day intervals

Salvage Chemotherapy Regimens

VeIP (for patients who received prior etoposide)

• Vinblastine 0.11 mg/kg/ IV daily for 2 days
• Ifosfamide 1,200 mg/m² IV daily for 5 days
• Mesna 400 mg/m² IV every 8 hours for 5 days
• Cisplatin (CDDP) 20 mg/m² IV daily for 5 days

This regimen is administered for four cycles at 21-day intervals

TIP

• Paclitaxel 250 mg/m2 IV day 1 followed by ifosfamide 1500 mg/m² IV daily days 2-5 and cisplatin (CDDP) 25 mg/m² IV daily on days 2-5
• Mesna 500 mg/m² IV before ifosfamide, and then 4 and 8 hrs after each dose of ifosfamide daily on days 2-5

This regimen is administered for four cycles at 21-day intervals

GEMOX (palliative second-line)

• Gemcitabine 1000 or 1250 mg/m² IV on days 1 and 8, plus oxaliplatin 130 mg/m² IV on day 1, administered every 3 weeks

• References

Etoposide (Toposar)

• Dosing, Interactions, etc.

Clinical Context:  Glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect through stabilization of the normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks. This causes cell proliferation to arrest in late S or early G₂ portion of the cell cycle.

Therapy should be withheld or suspended if platelet counts are < 50,000 or absolute neutrophil counts are < 500/mm³. Reduce dose 20% for granulocytic fever or previous radiotherapy. Reduce dose in hepatic (increased total bilirubin [TB]) and renal (decreased CrCl) impairment.

• References

Class Summary

These agents may cause DNA strand breaks, which may result in the inhibition of cell growth and proliferation.

• References

Bleomycin

• Dosing, Interactions, etc.

Clinical Context:  Group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. Planar end intercalates with DNA, while amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.

Not absorbed when given orally; peak levels reached in about 30-60 min when given IM and are only one third of levels obtained after IV administration; approximately 50% of drug absorbed systemically after intrapleural or intraperitoneal administration; systemic absorption after intracavitary administration for craniopharyngioma not negligible.

Volume of distribution is 20-30 L both in intracellular and extracellular fluid.

Less than 10% is bound to plasma proteins.

Bleomycin has plasma half-life of less than 1 h and terminal half-life of 2-4 h, but it could be as long as 22 h in patients with renal dysfunction or those previously treated with cisplatin.

About 50% eliminated in urine within 24 h. Most tissues (known exceptions—skin and lungs) contain an enzyme, bleomycin hydrolase (most active tissues are liver and kidney), which readily inactivates drug; therefore, toxicity is tissue specific, occurring in tissues lacking this enzyme. Bleomycin mostly used systemically in combination with other drugs (mostly with cisplatin and vincristine).

Principal mechanisms of resistance include high levels of bleomycin hydrolase, cell mutations altering DNA sequences to prevent intercalation, poor cell accumulation of drug, and rapid plasma removal. None of these factors plays important role when bleomycin administered locally in residual cyst.

Toxicity is age dependent and cumulative dose related; systemic administration mostly causes pulmonary toxicity. This consists of pneumonitis, which can progress to fatal pulmonary fibrosis.

Maximum recommended total cumulative dose for systemic use is 400 U. Unit measurement based on toxicity to bacteria; 1 U equals approximately 1.7 mg.

Administered systemically, does not produce significant bone marrow toxicity. Toxicity with local administration due to both systemic contamination (when anaphylactoid reactions, transient fever, nausea, and vomiting could occur) and leakage into surrounding neural tissue. Fatal outcome has been reported with leakage, due to subsequent diffuse diencephalon and brainstem edema.

Contrast CT cystography is required prior to intracavitary administration to ensure cyst wall integrity; when inconclusive, MR cystography with gadopentetate dimeglumine has been advocated.

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Class Summary

Agents in this class may cause single and double DNA strand breaks and may inhibit RNA and protein synthesis.

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Cisplatin

• Dosing, Interactions, etc.

Clinical Context:  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 cause cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell, binds to DNA, resulting in interstrand and intrastrand cross-linking and denaturation of double helix.

Modify dose on basis of CrCl. Avoid use if CrCl < 60 mL/min.

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Ifosfamide (Ifex)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Oxaliplatin (Eloxatin)

• Dosing, Interactions, etc.

Clinical Context:  Platinum-based antineoplastic agent forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.

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Carboplatin

• Dosing, Interactions, etc.

Clinical Context:  Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.

Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity.

Dose is based on the following formula: total dose (mg) = (target AUC) x (GFR+25) where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.

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Class Summary

These agents may inhibit DNA synthesis and disrupt DNA function.

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Paclitaxel

• Dosing, Interactions, etc.

Clinical Context:  Mechanisms of action are tubulin polymerization and microtubule stabilization.

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Class Summary

Agents in this class may distort mitotic spindles and result in breakage of chromosomes.

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Vinblastine

• Dosing, Interactions, etc.

Clinical Context:  Vinca alkaloid, inhibits microtubule formation, which disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.

• References

Class Summary

These agents may inhibit microtubule formation.

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Gemcitabine (Gemzar)

• Dosing, Interactions, etc.

Clinical Context:  Cytidine analog, after intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Cell-cycle specific for S phase.

This drug has been shown to have activity in a phase 2 trial against relapsed germ cell tumors.

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Class Summary

Agents in this class are pyrimidine antimetabolites that inhibit DNA synthesis.

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Mesna (Mesnex)

• Dosing, Interactions, etc.

Clinical Context:  Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

• References

Class Summary

Agents in this class may inactivate acrolein, the urotoxic metabolite from ifosfamide and cyclophosphamide.

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Complications

Secondary malignancy

Secondary malignancies are the most common cause of death in testicular cancer survivors. A second testicular cancer develops in 1% to 2% of testicular cancer survivors.

Solid tumors

A followup study of more than 40,000 testicular cancer survivors in Europe and North America showed that the relative risk of developing a secondary tumor was 1.9 (95% confidence index, 1.8 to 2.1) for 10 years and 1.7 for 35 years.^[12] Cancers of the lung, colon, bladder, pancreas, stomach, mesothelioma, and esophagus were found. Testicular cancer patients who were treated with radiation alone were at higher risk of having bladder, stomach, pancreas, and kidney cancers.

Leukemia

Patients treated with regimens that contain etoposide have an increased risk of developing leukemia, mainly of the myeloid lineage. In such cases, the Hallmark chromosomal translocation involving the long arm of chromosome 11 (11q23) occurs 2 to 3 years following treatment. Leukemia develops in 16 per 10,000 patients treated with standard-dose chemotherapy.

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