eMedicine Specialties > Oncology > Carcinomas of the Genitourinary Tract

Testicular Cancer

Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Mansoor Javeed, MD, FACP, Clinical Assistant Professor of Medicine, University of California Davis; Consultant, Sierra Hematology-Oncology Medical Center; Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center

Updated: Jul 29, 2009

Introduction

Background

Primary testicular tumors are the most common solid malignant tumor in men between the ages of 20 and 35 years in United States. For unknown reasons, the incidence of this cancer increased during the last century. Over the past decade, the incidence of testicular cancer has risen approximately 1.2% per year but the absolute mortality rate has been stable or decreasing; approximately 9,000 new cases have been diagnosed in United States every year, and only about 350 to 400 deaths have occurred annually. The American Cancer Society estimates that about 8,400 new cases of testicular cancer will be diagnosed during 2009 in the United States.¹ It is estimated that 380 men will die of testicular cancer in 2009. The lifetime chance of developing testicular cancer is about 1 in 300 and the risk of dying is very low—about 1 in 5,000.

In the past, metastatic testicular cancer was usually fatal, but recent 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 are now considered the model for the treatment of solid tumors.

Testicular cancers are very sensitive to chemotherapy and are curable even when metastatic. Cure rates for good-risk disease cure rates are 90-95%. On , there were approximately 190,265 men alive in the United States who had a history of cancer of the testis.

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.

Frequency

United States

Testicular cancers are not a common malignancy. Approximately 9,000 new cases are diagnosed in the United States each year. From 2002–2006, the median age at diagnosis was 34 years of age.

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.²

According to Surveillance, Epidemiology, and End Results (SEER) data from 17 geographic areas, the age-adjusted annual incidence of testicular cancer from 2002–2006 was 5.4 per 100,000 men. However, the incidence varies widely by race/ethnicity (see below).

International

Studies published between 1980 and 2002 showed a clear trend towards an increased testicular cancer incidence in the last 30 years in the majority of industrialized countries in North America, Europe, and Oceania. Differences in incidence were seen between neighboring countries (2.5/100,000 cases in Finland versus 9.2/100,000 cases in Denmark) as well as among regions of the same country (2.8 to 7.9/100,000 within France). The increase in incidence was significantly associated with a birth cohort effect in the United States and in European countries. Substantial differences in the incidence and trends were observed among ethnic groups. Incidence by race are described above.

Mortality/Morbidity

Testicular cancers are highly curable, even in patients with metastatic disease at diagnosis. The prognosis depends upon the histologic type of cancer (seminoma versus nonseminoma), stage, and other features such as tumor marker and type of metastatic disease.

Patients with seminomas that confer a good prognosis, which constiute about 90% of seminomas, have a 5-year survival of 86%; patients with good-prognosis nonseminomas (56% of nonseminomas) have a 5-year survival of 92%. With intermediate-prognosis cancers (28% of nonseminomas), 5-year survival is 72% with seminomas and 80% with nonseminomas. With poor-prognosis nonseminomas (about 16% of nonseminomas) 5-year survival is 48%.  

Those survival data are based on patients treated between 1975 and 1990; more recent studies has shown much better survival with nonseminomatous germ cell tumors (NSGCT). Pooled 5-year survival estimates for NSGCT were 94% for good-prognosis, 83% for intermediate-prognosis, and 71% for poor-prognosis tumors.
   

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.³

Age

Testicular cancer can occur at any age but is most common between the ages of 15 and 35 years. 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.

Clinical

History

Localized disease:
 
Painless swelling or nodule of one testicle is the most common presenting symptom. On the physical exam this mass/nodule can not be separated from the testis. Patients with atrophic testes will feel enlargement. Dull ache or heavy sensation in the lowed abdomen could be presenting symptom. Patients who experience a hematoma with trauma should undergo evaluation to rule out testicular cancer.
 
Metastatic disease:
 
Disseminated disease have symptom of lymphatic or hematogenous spread. Presenting symptom could be neck mass in supraclavicular lymph node metastatic disease, anorexia, nausea and other gastrointestinal symptom. Bulky retroperitoneal disease could present as back pain. Cough, chest pain, hemoptysis and shortness of breath could be presenting symptom of mediastinal adenopathy or lung metastatic disease. 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 tumor that produce human chorionic gonadotropin (HCG), such as choriocarcinoma and is a systemic manifestation. Marked overproduction of hCG can develop hyperthyroidism since hCG and thyroid stimulating hormone have a common alpha-subunit and a beta-subunit with considerable homology.

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 they are sometimes ignored by the patient. In patients with scrotal pain, testicular cancer must be differentiated form epididymitis. The clinician should consider the full  differential diagnosis of a testicular mass, which includes not only epididymitis but epididymo-orchitis, testicular torsion, hydrocele, hernia, hematoma, spermatocele, varicocele, and syphilitic gumma. 

Unilateral or bilateral lower extremity swelling may be present in 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.

Causes

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

Cryptorchidism
In patients with cryptorchidism, the riskof 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 men 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 5.4.⁴

Differential Diagnoses

Other Problems to Be Considered

Epididymo-orchitis
Hematoma
Leukemia
Metastasis from other cancers such as lung cancer, melanoma, and prostate cancer
Syphilitic gumma
Trauma
Tuberculosis and other testicular infections

Workup

Laboratory Studies

The workup of patients with suspected testicular cancer includes a complete history and physical examination. 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
  • 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.
  • May be elevated in patients with hepatic dysfunction, hepatitis, cirrhosis, and drug or alcohol abuse.
• Beta-human chorionic gonadotropin
  • 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 tumor.
  • 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.
• Lactate dehydrogenase
  • 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.

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 is 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. PET scans are negative in teratoma; therefore, PET scans could be used in some cases of nonseminoma.

Lymphangiograhy is currently rarely used to evaluate microscopic nodal involvement.

Procedures

Radical inguinal orchiectomy and r etroperitoneal 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.
• 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.

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 hematological 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 tumor behave like nonseminomas. The average age at diagnosis is older than 30 years.

Staging

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

• Primary tumor (pT) – The extent of primary tumor is classified after radical orchiectomy
  • 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
• Regional lymph nodes – Clinical (N) or pathologic (pN) staging
  • 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
• Distant metastasis (M)
  • 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. Serum Tumor Markers

• Stage 0
  • pTis, N0, M0, S0
• Stage I
  • pT1–4, N0, M0, SX
• Stage IA
  • pT1, N0, M0, S0
• Stage IB
  • pT2, N0, M0, S0
  • pT3, N0, M0, S0
  • pT4, 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
  • Any pT/Tx, N1, M0, S1
• Stage IIB
  • Any pT/Tx, N2, M0, S0
  • Any pT/Tx, N2, M0, S1
• Stage IIC
  • Any pT/Tx, N3, M0, S0
  • Any pT/Tx, N3, M0, S1
• Stage III
  • Any pT/Tx, any N, M1, SX
• Stage IIIA
  • Any pT/Tx, any N, M1a, S0
  • Any pT/Tx, any N, M1a, S1
• Stage IIIB
  • Any pT/Tx, N1–3, M0, S2
  • Any pT/Tx, any N, M1a, S2
• Stage IIIC
  • Any pT/Tx, N1–3, M0, S3
  • Any pT/Tx, any N, M1a, S3
  • Any pT/Tx, any N, M1b, any S

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

• Testicular or retroperitoneal primary tumor, and
• No nonpulmonary visceral metastases, and
• Good markers; all of:
  • Alpha-fetoprotein (AFP) < 1,000 ng/mL, and
  • Human chorionic gonadotropin (hCG) < 5,000 IU/mL (1,000 ng/mL), and
  • Lactate dehydrogenase (LDH) < 1.5 times the upper limit of normal

Intermediate- risk nonseminoma

• Testicular or retroperitoneal primary tumor, and
• No nonpulmonary visceral metastases, and
• Intermediate markers; any of:
  • AFP 1,000 to 10,000 ng/mL, or
  • hCG 5,000 IU/L to 50,000 IU/L, or
  • LDH 1.5 to 10 times the upper limit of normal

Poor-risk nonseminoma

• Mediastinal primary, or
• Nonpulmonary visceral metastases, or
• Poor markers; any of:
  • AFP > 10,000 ng/mL, or
  • hCG > 50,000 IU/mL (10,000 ng/mL), or
  • LDH > 10 times the upper limit of normal

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

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

• No patients are classified as poor prognosis.

Treatment

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 AFP concentration is elevated, the tumor should be treated as a nonseminoma.
 
Initial therapy is selected according to AJCC stage group; risk stratification (good, intermediate, or poor risk), as per the guidelines of the International Germ Cell Cancer Collaborative Group⁷ ;  and histology (seminoma versus nonseminoma). 

Current guidelines from the National Comprehensive Cancer Network (NCCN) and the National Cancer Institute recommend 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

• 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 disease. Surveillance consists of a history and physical exam and measurement of AFP 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. In a randomized study in 1,477 patients, after a median followup of 4 years there was no difference in relapse-free survival between patients receiving single-dose carboplatin and those receiving radiation therapy.⁸ Five-year followup in 1,148 patients from this trial showed relapse-free rates of 96% for the radiation arm and 94.7% for the carboplatin arm. However, there were 15 new germ cell tumors in the radiation therapy arm versus two in the carboplatin arm, giving a hazard radio of 0.22 (95% CI 0.05, 0.95 p = 0.33).⁹  Acute toxicity such as lethargy and days missed from work was less with carboplatin than with radiation therapy.

• Adjuvant radiation therapy, 20-30 Gy, is administered to the infradiaphragmatic area, including para-aortic lymph nodes, with or without ipsilateral ileoinguinal nodes.

Seminoma stage IIA and IIB 
Active surveillance is not an option. These patients receive adjuvant chemotherapy or radiation therapy.

• Radiation therapy: 35-40Gy is administered to the infradiaphragmatic area, including the para-aortic and ipsilateral iliac lymph nodes. Mediastinal radiation is not recommended.
• Adjuvant chemotherapy: Four courses of chemotherapy with etoposide and cisplatin (EP) may be given .

• Seminoma stage IIC and III, good risk: Either four cycles of EP or three cycles of bleomycin, etoposide, and cisplatin (BEP)
• Seminoma stage IIC and III, intermediate risk: Four cycles of BEP

• No disease: surveillance is recommended.
• Residual mass with normal markers: Consider PET scanning. In some cases of seminoma, a PET scan may detect nodal and extranodal disease that is not evident on CT scans.¹⁰ PET scans for evaluating the response of 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 surgery with biopsy or 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. 
• Progressive disease with a growing mass or rising marker levels: salvage chemotherapy

• Nonseminoma stage IA: Active surveillance can be used in compliant patients. The Surveillance should include an abdominal and pelvic CT scan every 2-3 months for the first year and every 3-4 months in the second year; history and physical examination, chest x-ray, and tumor marker assays should be done every 1-2 months for the first year and every 2 months during the second year. The cure rate is 95%. Adherence to the surveillance program is the key to success. Noncompliant patient should be offered RPLND within 4 weeks of the CT scan. If RPLND results are negative, no adjuvant chemotherapy is recommended. If RPLND results are positive, adjuvant chemotherapy is recommended.
• Nonseminoma stage IB: Options are open nerve-sparing RPLND; chemotherapy with BEP for 2 cycles; or active surveillance for compliant patients who have T2 disease without any vascular invasion.
• 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 with normal tumor markers: open nerve-sparing RPLND or chemotherapy, either EP for 4 cycles or BEP for 3 cycles.
• Nonseminoma stage IIA with persistent elevation of tumor markers: chemotherapy, either EP for 4 cycles or BEP for 3 cycles.
• Nonseminoma stage IIB with normal tumor markers and lymph node metastasis within lymphatic drainage site by CT scan: open nerve-sparing RPLND or chemotherapy, either EP for 4 cycles or BEP for 3 cycles.
• Nonseminoma stage IIB normal tumor markers and multifocal symptomatic lymph node metastases with aberrant lymphatic drainage by CT scan: chemotherapy, either EP for 4 cycles or BEP for 3 cycles.
• Nonseminoma stage IIB with persistent elevation of tumor markers: chemotherapy, either EP for 4 cycles or BEP for 3 cycles.

• Nonseminoma stage IIC, IIIA good risk: 95% of patients are cured with chemotherapy, either EP for 4 cycles or BEP for 3 cycles.
• Nonseminoma stage IIIB intermediate risk: BEP for 4 cycles is given; the cure rate is 70%.
• Nonseminoma stage IIIB poor risk: Enrollment in clinical trials is preferred. Chemotherapy with 4 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.       
• Brain metastases: Primary chemotherapy plus radiation. Surgery should be performed if clinically indicated.
• Nonseminoma stage IIC, IIIA, IIIB, IIIC post-chemotherapy management: 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 2 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.¹¹ 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.¹²     

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. 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. Open nerve-sparing RPLND has multiple complications, including retrograde ejaculation and other infertility issues.

Consultations

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.¹³ 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.

Medication

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  AUC 7 x 1 cycle or 2 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 five days
Cisplatin (CDDP) 20 mg/m²/day IV for five days
This regimen is administered for 3 to 4 cycles at 21-day intervals

EP
Etoposide (VP-16) 100 mg/m²/day IV daily for five days
Cisplatin (CDDP) 20 mg/m²/day IV daily for five days
This regimen is administered for 4 cycles at 21-day intervals

VIP (for patients with underlying lung disease)
Etoposide (VP-16) 75 mg/m²/day IV daily for five days
Ifosfamide 1.2 g/m²/day IV daily for five days
Cisplatin (CDDP) 20 mg/m²/day IV for days one through five
Mesna 120 mg/m2 slow IV bolus is given before ifosfamide day one, followed by 1,200 mg/m²/day continuous infusion on days one through five
This regimen is administered for 4 cycles at 21-day intervals

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 five days
Mesna 400 mg/m² IV every 8 hours for 5 days
Cisplatin (CDDP) 20 mg/m² IV daily for five days
This regimen is administered for 4 cycles at 21-day intervals

TIP
Paclitaxel 250 mg/m2 IV day one followed by Ifosfamide 1500mg/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 4 cycles at 21-day intervals

GEMOX (palliative second line)
Gemcitabine 1,000 or 1,250 mg/m² IV on days 1 and 8, plus oxaliplatin 130 mg/m² IV on day 1 administered every 3 weeks

Antineoplastic Agent, Irritant

Etoposide

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.

Dosing

Adult

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

Not established

Interactions

May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; significant hypotension; IT administration may cause death

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur

Antineoplastic Agent, Antibiotic

Bleomycin

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.

Dosing

Adult

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 <20 mL/min: 40% of normal dose

Pediatric

Not established

Interactions

May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically

Contraindications

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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; vaso-occlusive phenomenon with distal necrosis of digit; permanent damage to nail matrix may occur

Antineoplastic Agent, Alkylating Agent

Cisplatin

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.

Dosing

Adult

20 mg/m²/d IV over 20-60 min for 5 d; repeat q21d for 4 cycles

Pediatric

Not established

Interactions

Increases toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity, pre-existing renal insufficiency, myelosuppression, and hearing impairment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea and vomiting, may occur

Ifosfamide

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.

Dosing

Adult

1200 mg/m²/d IV continuous infusion on days 1-5; repeat q21d for 4 cycles

Pediatric

Not established

Interactions

Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P-450 activity, may alter effects of ifosfamide

Contraindications

Documented hypersensitivity; depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause hemorrhagic cystitis and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve

Oxaliplatin

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

Dosing

Adult

Oxaliplatin 130mg/m2 IV on day one with Gemcitabine administered every three wks

Pediatric

Not established

Interactions

Contraindications

Documented hypersensitivity to oxaliplatin or other platinum compounds

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Anaphylaxis may occur within minutes of administration; may cause neuropathy, pulmonary fibrosis, bone marrow suppression, GI tract symptoms (eg, nausea, vomiting, stomatitis), renal or hepatic toxicity (decrease dose), or thromboembolism; dilute IV only in dextrose-containing solution

Carboplatin

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.

Dosing

Adult

AUC 7

Pediatric

600 mg/m² IV on day 2 of therapy, or the following formula has been used in clinical trials: 6 X (uncorrected GFR + [15 X surface area])

Interactions

Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs

Contraindications

Documented hypersensitivity; bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor bone marrow function

Antineoplastic Agent, Antimicrotubular

Paclitaxel

Mechanisms of action are tubulin polymerization and microtubule stabilization.

Dosing

Adult

250 mg/m² IV over 24 h q3wk

Pediatric

200 mg/m² IV infused over 24 hours has been used in pediatric trials

Interactions

Coadministration with cisplatin may further increase myelosuppression

Contraindications

Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Premedicate with steroids, H1, and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur

Antineoplastic Agent, Vesicant

Vinblastine

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

Dosing

Adult

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

Not established

Interactions

Phenytoin plasma levels may be reduced when administered concomitantly with vinblastine; with mitomycin, the toxicity of vinblastine may significantly increase; CYP450 3A4 inhibitors (eg, itraconazole, erythromycin,
quinupristin/dalfopristin) may decrease clearance, thus increasing toxicity

Contraindications

Documented hypersensitivity and bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients diagnosed with impaired liver function and neurotoxicity; when patient is receiving mitomycin C, monitor closely for shortness of breath and bronchospasm

Antineoplastic Agent, Antimetabolite

Gemcitabine

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.

Dosing

Adult

1000 or 1200 mg/m² day 1 and 8 every three wks

Pediatric

1.2 g/m² IV infused over 30 min on days 1, 8, and 15 of 28-d cycles has been used in pediatric trials

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause myelosuppression (particularly thrombocytopenia); toxicities include flu like syndrome, LFT abnormality, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic uremic syndrome; clearance reduced in women and elderly individuals

Antidote, Cyclosphosphamide-induced Hemorrhagic Cystitis

Mesna

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

Dosing

Adult

1200 mg/m²/d IV continuous infusion on days 1-6 of each cycle; IV dose of mesna equivalent to ifosfamide dose

Pediatric

Not established

Interactions

May increase warfarin effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Does not prevent hemorrhagic cystitis in all patients (monitoring for hematuria in the morning prior to ifosfamide or cyclophosphamide dose required); does not prevent or alleviate other toxicities associated with ifosfamide or cyclophosphamide; common adverse effects include hypotension, headache, GI toxicity, and limb pain

Follow-up

Further Outpatient Care

Surveillance:

Seminoma stage IA, IB: History and physical examination (H & P) and AFP, beta-hCG, and LDH assays every 3 to 4 months for the first three years, every 6 months for years 4 to 7, then annually up to 10 years. Abdominal and pelvic CT scan is recommend at each visit and chest x-ray at alternate visits. Strict adherence to this surveillance program for at least 10 years is vital.

Seminoma stage IS: H & P, AFP, beta-hCG, LDH, and chest x-ray every 3 to 4 months for the first year, every 6 months for year 2, then annually. Pelvic CT scan is recommended annually for three years for patients who received only para-aortic radiation.

Seminoma stage IIA, IIB: H&P, AFP, beta-hCG, LDH, chest x-ray every 3 to 4 months for years 1 to 3, every 6 months for year 4, then annually. Abdominal CT scan is recommended at month 4 of year 1.

Seminoma stage IIC, III: H&P, chest x-ray, AFP, beta-hCG, and LDH every 2 months for year 1, every 3 months for year 2, every 4 months for year 3, every 6 months for year 4, then annually. Abdominal/pelvic CT at month 4 of year 1 status post surgery; otherwise, abdominal/pelvic CT every 3 month until stable. PET scan could be considered when clinically indicated.

Nonseminoma stage IA, IB: H&P, chest x-ray, AFP, beta-hHG, and LDH every 1-2 months for year 1, every 2 months for year 2, every 3 months for year 3, every 4 months for year 4, every 6 months for year 5, then annually. Abdominal/pelvic CT scan every 2-3 months for year 1, every 3-4 months for year 2, every 4 months for year 3, every 6 months for year 4, every 12 months for year 5, then annually.

Nonseminoma stage IIA, IIB, IIC, IIIA, IIIB, IIIC after complete response to chemotherapy and/or retroperitoneal lymph node dissection: H&P, chest x-ray, AFP, beta-hHG, and LDH every 2-3 months for year 1, every 2-3 months for year 2, every 4 months for year 3, every 4 months for year 4, every 6 months for year 5, then annually. Abdominal/pelvic CT scan every 6 months for year 1, every 6-12 months for year 2, every 12 months for year 3, every 12 months for year 4, every 12 months for year 5, then every 12-24 months.

Complications

Treatment-related toxicity 
 
Pulmonary: 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.
 
Renal toxicity: 20-30% of patients who receive cisplatin have a reduction in glomerular filtration rate. Cisplatin can also cause hypomagnesemia, hypophosphatemia, and hypokalemia.
 
Cardiovascular: Cardiovascular disorders are late complications of cisplatin treatment. They include hypertension, dyslipidemia, coronary artery disease, thromboembolic events, and Raynaud phenomenon.
 
Infertility
 
Hematological: 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.
 
Gastrointestinal: Nausea and vomiting.
 
Neurological: Cisplatin and oxaliplatin can cause neuropathy.

Ototoxicity: tinnitus and high-frequency sensorineural loss. 
 
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.¹⁴ 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.

Prognosis

The International Germ Cell Consensus Classification (IGCCC),⁷ an easily applicable, clinically based prognostic instrument, is now used in clinical practice for risk classification and is the current standard for all practice guidelines, including that of the National Comprehensive Cancer Network.

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. For NSGCT, independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein, human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH); and presence of nonpulmonary visceral metastates (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM.

The IGCCC distinguishes NSGCT patients with a good, intermediate, or poor prognosis; these have reported 5-year overall survival of 92%, 80%, and 48%, respectively. 
 
A subsequent meta-analysis of survival of patients with NSGCT, treated after 1989 and classified according to the IGCC classification, included 10 papers describing 1775 patients with NSGCT with good (n = 1087), intermediate (n = 232), or poor (n = 456) prognosis. Pooled 5-year survival estimates were 94%, 83%, and 71%, respectively. There was a small increase in survival for good-prognosis and intermediate-prognosis patients, and a large increase in survival for patients with a poor prognosis. The researchers suggested that the improved survival was most likely due to both more effective treatment strategies and more experience in treating NSGCT patients.¹⁵

Good-prognosis nonseminoma (56% to 61% of nonseminomas): 5-year progression-free survival (PFS) is 89%; 5-year survival is 92% to 94%

• Testis/retroperitoneal primary, and
• No nonpulmonary visceral metastases, and
• Good serum tumor markers; all of:
  • Alpha-fetoprotein (AFP) less than 1,000 ng/mL, and
  • Human chorionic gonadotropin (hCG) less than 5,000 IU/mL (1,000 ng/mL), and
  • Lactate dehydrogenase (LDH) less than 1.5 times the upper limit of normal