DDI

May 29, 2023

Testicular Cancer: Pharmacologic Management

Testicular cancer is the most common solid tumor diagnosed in US men aged 20 to 34 years,1 and it is diagnosed with decreasing
frequency as men age (51% of all cases are diagnosed in men aged 20 to 34 years, 22.9% in those aged from 35 to 44 years, and
12.9% in those aged from 45 to 54 years).2 The incidence of testicular cancer is highest in non-Hispanic white men, followed by Black,
Hispanic, and Asian and Pacific Islander men.3 Testicular cancer is one of the most treatable and curable cancers, with a 5-year
relative survival rate of 95.2%1 and a cure rate exceeding 95%.2 However, the number of new cases in the United States has been
rising slowly (0.7% each year) during the past decade.1 Risk factors for testicular cancer include2:

Undescended testis (associated with a 2- to 4-fold increase in risk);

Family history of testicular cancer (associated with a 6- to 10-fold increased risk in brothers or sons);
Personal history of testis cancer or extragonadal germ cell tumor;
Infections (human papillomavirus (HPV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HIV);
Testicular trauma; and
Carcinoma in situ of the testis.

Early symptoms of testicular cancer are a unilateral lump and swelling, often without pain. Symptoms of advanced metastatic
testicular cancer include2:

Weight loss;
Anorexia;
Swollen lymph nodes;
Cough or shortness of breath;
Lower back pain;
Swelling in legs; and
Headache.

Types of Testicular Cancer

Testicular cancers are classified into 3 types according to their origin: germ cell tumors, which are further divided into seminomas
and nonseminomas; sex cord-stromal tumors; and carcinoma in situ.4

Testicular Germ Cell Tumors

More than 95% of testicular cancers are seminomas or nonseminomatous germ cell tumors (embryonal carcinomas, yolk sac tumors,
teratomas, and choriocarcinomas).2,5

Seminomas arise from transformed spermatogonia and make up approximately one-third of all testicular germ cell tumors.2 Patients
with seminomas have an excellent prognosis, with a survival rate of 98% to 99% when diagnosed in the early stage of the disease.6
Embryonal carcinomas are aggressive germ cell tumors that are the most common component in mixed germ cell tumors.7 Yolk-sac
tumors have extraembryonic differentiation and are nearly always found to be a part of nonseminomas, while teratomas have
somatic differentiation.2,8 Choriocarcinomas, which also have extraembryonic differentiation, are the most aggressive of the
nonseminomatous germ cell tumors.2

Tumors with a mixture of seminoma and nonseminoma cells and those that have histologic features of seminoma have elevations in
the tumor marker alpha-fetoprotein (AFP) are considered nonseminomas.4 Cell type composition of testicular tumors is an important
factor when considering treatment strategies and estimating the risk of metastasis.

Figure. Light microscopy of germ cell tumor of the testicle. Credit: Getty Images.

Sex Cord-Stromal Tumors

Approximately 5% of adult testicular cancers are sex cord-stromal tumors that arise from the stromal cells of testicles, including
Leydig cells that produce testosterone, Sertoli cells that support spermatogenesis, and granulosa cells.9 Leydig cell tumors are the
most frequently diagnosed (91% to 93%) sex cord-stromal tumors.

Carcinoma in Situ of the Testis

Carcinoma in situ of the testis is believed to be the precursor of all testicular germ cell tumors.10

Serum Tumor Markers in Testicular Cancer

In addition to histologic classification, levels of serum tumor markers — AFP, beta-human chorionic gonadotropin (beta-hCG), and
lactate dehydrogenase (LDH) — in patients with testicular cancer are a critical component in staging, treatment decision-making,
prognosis, and surveillance after treatment.5 Levels of serum tumor markers are the most significant predictors of prognosis for
patients with nonseminomas, and elevated levels of tumor markers are often the earliest sign of relapse.4

AFP. Seminomas do not produce AFP. Serum AFP levels are elevated in 40% to 60% of patients with nonseminomas.4 If the serum
AFP is elevated, even though histologic evaluation may indicate a tumor is a seminoma, it is considered a mixed germ cell tumor.

Beta-hCG. Beta-hCG is the most commonly elevated serum tumor marker in patients with testicular cancer. It is elevated in
approximately 14% of patients with stage I pure seminomas prior to orchiectomy, in 50% of patients with metastatic seminomas, and
in 40% to 60% of patients with nonseminomas.4 Significant and definitive elevations in AFP and/or beta-hCG levels indicate relapse
and warrant treatment even if radiographic imaging does not show metastasis.

LDH. Serum LDH levels are elevated in approximately one-half of patients with advanced testicular cancer. However, LDH is less
specific than AFP or beta-hCG, and elevated LDH level should not be used alone to make treatment decisions.5

Treatment of Testicular Cancer

Treatment of testicular cancer is tailored according to the type of cancer (seminoma or nonseminoma), subtype composition of the
tumor, and clinical stage of disease.4 In general, seminomas are more responsive to radiation therapy and chemotherapy, and are less
prone to metastasis. Nonseminomas are often resistant to chemotherapy and require surgical treatment. As such, each type of
testicular cancer requires a different treatment strategy. Treatment recommendations outlined in the National Comprehensive
Cancer Network (NCCN) Clinical Practice Guidelines® for Testicular Cancer (Version 1.2023)5 are presented below.

Pure Seminoma Stages IA and IB

Most stage I pure seminomas can be cured with orchiectomy alone. Although surveillance is recommended as the preferred
management approach after surgery, adjuvant chemotherapy with 1 or 2 cycles of single-agent carboplatin or adjuvant radiation
therapy may reduce the risk of relapse (15% to 20%) following orchiectomy. Disease-specific survival for stage I pure seminoma is
close to 100%.5

Pure Seminoma Stage IS

Due to the increased risk of metastasis as indicated by elevated levels of serum tumor markers, orchiectomy followed by systemic
therapy is recommended for the treatment of stage IS pure seminoma.5

Pure Seminoma Stages IIA and IIB

Treatment options for patients with stage IIA and IIB seminomas consist of radiation therapy or chemotherapy with the preferred
regimens: 3 cycles of bleomycin, etoposide, and cisplatin (BEP) or 4 cycles of etoposide and cisplatin (EP). For patients with stage IIB
seminoma, radiotherapy is only recommended for nonbulky (≤3 cm) disease.5

Pure Seminoma Stages IIC and III

Stage IIIC seminomas with nonpulmonary visceral metastases are classified as intermediate risk, while all other stage IIC and stage III
seminomas are considered good risk. For patients with good-risk pure seminoma, standard primary chemotherapy with 3 cycles of
BEP or 4 cycles of EP is the recommended treatment, with the choice based on the patient’s pulmonary fitness (associated with
bleomycin) and the risk of developing a secondary malignancy (associated with etoposide). For patients with intermediate-risk
disease, 4 cycles of BEP is recommended.
A regimen consisting of 4 cycles of VIP (etoposide, mesna, ifosfamide, and cisplatin) can be used for patients with a contraindication
to bleomycin.5 For residual masses, surgical resection followed by 2 cycles of adjuvant chemotherapy with EP (etoposide and
cisplatin), TIP (paclitaxel, ifosfamide, cisplatin), VIP, or VeIP (vinblastine, ifosfamide, cisplatin with mesna) is recommended. If the
resection is incomplete, if there is a growing mass, or if the serum tumor marker levels are rising, second-line chemotherapy with 4
cycles of TIP or 4 cycles of VeIP is indicated.5

Nonseminoma Stage I Without Risk Factors

Patients with stage I nonseminoma who have undergone orchiectomy and have normal serum AFP and beta-hCG levels have 3
primary treatment options: surveillance, nerve-sparing retroperitoneal lymph node dissection (RPLND), or chemotherapy with 1
cycle of BEP. For patients with no known risk factors for relapse, such as lymphovascular invasion or invasion of the spermatic cord or
scrotum, surveillance is the preferred option. All 3 treatment options should be considered for patients with known risk factors for
relapse. Survival rates for patients with stage I nonseminoma exceed 98%.5

For management of patients with stage I nonseminoma without risk factors, surveillance is the preferred option if the resected lymph
nodes are unaffected (pN0) after nerve-sparing RPLND. Depending on the degree of nodal involvement, surveillance (for pN1) or
chemotherapy (pN2) are recommended as management of stage I nonseminoma without risk factors for relapse. The recommended
chemotherapy regimens are 2 cycles of EP for patients with pN1 or pN2 disease and 3 cycles of BEP or 4 cycles of EP for patients
with pN3 disease.5

Nonseminoma Stage I With Risk Factors

For patients with risk factors (lymphovascular invasion or invasion of the spermatic cord or scrotum), surveillance, adjuvant
chemotherapy (1 cycle of BEP), and nerve-sparing RPLND are the primary treatment options. Although 2 cycles of BEP has been
shown to be effective at preventing relapse and led to survival rates exceeding 95%, 1 cycle of BEP is recommended to avoid
increased risk of toxicity.5

The same management strategies indicated for patients without risk factors (surveillance and chemotherapy) are recommended for
patients with stage I nonseminoma with risk factors.5

Nonseminoma Stage IS
Primary chemotherapy with 3 cycles of BEP or 4 cycles of EP is recommended for patients with stage IS nonseminoma with serum
tumor marker levels in the S1 range (AFP >1000 ng/mL, beta-hCG >5000 IU/L). Elevated AFP or beta-hCG in the S1 range is
considered a good/reliable indicator of metastasis.5

Nonseminoma Stage IIA

For patients with stage IIA nonseminoma with normal levels of AFP and beta-hCG following orchiectomy, nerve-sparing RPLND or
chemotherapy with 3 cycles of BEP or 4 cycles of EP is recommended as the primary treatment. If AFP and/or beta-hCG levels are
elevated, primary chemotherapy with 3 cycles of BEP or 4 cycles of EP is recommended.5

Treatment options for management of stage IIA nonseminoma following nerve-sparing RPLND include surveillance and
chemotherapy. Surveillance is preferred for patients with pN0 and pN1 diseases. For patients with pN2 disease, 2 cycles of adjuvant
chemotherapy with EP and surveillance is recommended. For patients with pN3 disease, full-course chemotherapy with 3 cycles of
BEP or 4 cycles of EP is recommended. Two cycles of adjuvant chemotherapy with cisplatin reduces the risk of relapse to less than
1%.

Surveillance is recommended for patients with pure teratoma. Surveillance is also recommended for patients with no residual mass
or residual mass measuring less than 1 cm, as well as for patients with only necrotic debris or teratoma in the resected tissue. For
patients with residual mass containing embryonal, yolk sac, choriocarcinoma, or seminoma elements/tissue, 2 cycles of TIP, VIP, VeIP,
or EP chemotherapy regimen are recommended.5

Nonseminoma Stage IIB

If imaging studies reveal metastases that are confined within the lymphatic drainage sites in the retroperitoneum and serum tumor
marker levels are normal, primary treatment options for patients with stage IIB nonseminoma are chemotherapy with either 3 cycles
of BEP or 4 cycles of EP, or nerve-sparing RPLND. RPLND is also indicated for patients with stage II tumors with somatic-type
malignancy. Both chemotherapy (3 cycles of BEP or 4 cycles of EP) and nerve-sparing RPLND are associated with relapse-free
survival rates approaching 98%.5

If metastases are not limited to the lymphatic drainage sites, the recommended treatment is primary chemotherapy with 3 cycles of
BEP or 4 cycles of EP. The same primary chemotherapy regimens are recommended for patients with stage IIB nonseminoma with
persistently elevated tumor marker levels. For patients with a contraindication to bleomycin, a bleomycin-free regimen should be
given.5

The same management strategies indicated for patients with stage IIA nonseminoma (surveillance and chemotherapy) are
recommended for patients with stage IIB nonseminoma.5

Advanced Metastatic Nonseminoma

The primary treatment strategies for patients with advanced metastatic nonseminoma are based on the International Germ Cell
Cancer Collaboration Group (IGCCCG) risk classification. Patients are categorized as good, intermediate, or poor risk based on the
extent of metastases and serum tumor marker levels.

The recommended primary treatment for patients with good-risk nonseminoma (stages IS, IIA [S1], IIB [S1], IIC, and IIIA) is either 3
cycles of BEP or 4 cycles of EP, both of which have an approximate cure rate of 90% in this population. For patients with
intermediate-risk disease (stage IIIB), 4 cycles of BEP is recommended, which yields an approximately 70% cure rate. Four cycles of
VIP can be used for patients with contraindications to bleomycin. For patients with poor-risk nonseminoma (stage IIIC), 4 cycles of
BEP or 4 cycles of VIP (to avoid bleomycin toxicity) are recommended. However, poor-risk nonseminoma is fatal in up to 50% of
patients with the disease.5

Following primary chemotherapy, if there is no residual disease and tumor marker levels are normal, surveillance is recommended. If
tumor marker levels are normal but there are residual masses, surgical resection is recommended. For necrotic debris and teratomas,
surveillance is advised. If embryonal, yolk sac, choriocarcinoma, or seminoma elements remain in the residual mass, 2 cycles of
chemotherapy with either EP, TIP, VIP, or VeIP is recommended.

If there are residual masses and the tumor marker levels are persistently elevated and rising following primary chemotherapy, a full
course of second-line chemotherapy is recommended. Close surveillance is recommended for patients with elevated but stable
tumor marker levels. Mildly elevated or normal-level tumor markers call for resection of residual masses.5

Second-line therapy options for metastatic germ cell tumors with early relapse (within 2 years of primary treatment) include
enrollment in a clinical trial, surgical salvage, conventional-dose chemotherapy (TIP or VeIP), or high-dose chemotherapy. High-dose
chemotherapy regimen options include5:

High-dose carboplatin plus etoposide followed by autologous stem cell transplant; or

Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide with stem cell support.

Clinical trials, surgical salvage, and chemotherapy (conventional-dose or high-dose) are treatment options for unresectable late
relapses.

If tumor-marker levels are elevated and rising after second-line therapy, the following third-line therapy is recommended: close
surveillance for patients with elevated but stable marker levels, and surgical resection followed by surveillance for patients with
mildly elevated and normalizing marker levels.5

For patients experiencing relapse after second-line therapy, third-line therapy options are clinical trials, high-dose chemotherapy for
those who previously had conventional-dose chemotherapy, and surgical salvage. For patients who previously had high-dose
chemotherapy, third-line treatment options are conventional-dose salvage chemotherapy, surgical salvage, and microsatellite
instability/mismatch repair (MSI/MMR) or tumor mutation burden (TMB) testing.5

If the patient had received high-dose chemotherapy previously, third-line treatment is palliative chemotherapy. Immunotherapy with
pembrolizumab can be used for patients with MSI-high or MMR-deficient tumor mutational burden-high (TMB-high) tumors. For
patients with cisplatin-resistant or refractory germ cell tumors, combination third-line palliative chemotherapy with gemcitabine
with paclitaxel and/or oxaliplatin or oral etoposide is recommended.5

Pharmacologic Treatment of Testicular Cancer

The remarkably high cure rate (>95%) for testicular cancer has been largely made possible by the effectiveness of chemotherapy,
primarily seen in combination regimens that are the gold standard in testicular cancer treatment.

Chemotherapy Agents
Chemotherapy agents used in the treatment of testicular cancer include cytotoxic antibiotics, platinum agents, topoisomerase
inhibitors, and cell cycle inhibitors that induce cell death in cancer cells.

Bleomycin sulfate. Bleomycin is a mixture of cytotoxic glycopeptide antibiotics that cause DNA damage in cancer cells, leading to cell
death. It is indicated for the treatment of testicular cancer, including embryonal cell carcinoma, choriocarcinoma, and
teratocarcinoma. The recommended dose schedule of bleomycin for testicular cancer treatment is 0.25 to 0.50 units/kg (10 to 20
units/m2) intravenously, intramuscularly, or subcutaneously weekly or twice weekly.11

Severe adverse reactions to bleomycin include:

Pulmonary toxicity (reported in 10% of patients receiving bleomycin);

Severe idiosyncratic reaction (reported in 1% of lymphoma patients receiving bleomycin); and
Renal or hepatic toxicity.

The most common side effects associated with bleomycin include:

Integument and mucous membranes;

Skin toxicity;
Vascular toxicity;
Fever;
Chills;
Vomiting;
Weight loss; and
Anorexia.

Coadministration of bleomycin with nephrotoxic drugs should be avoided to prevent impairing renal clearance of bleomycin.

Pregnant patients should be warned of the potential risk of harm to the fetus, and female patients with reproductive potential should
use birth control to avoid becoming pregnant during treatment with bleomycin. Breastfeeding should be discontinued during
treatment with bleomycin. The safe and effective use of bleomycin has not been established in pediatric patients. Pulmonary toxicity
was found to occur at a higher rate in patients older than 70 years. The risk of bleomycin-associated renal toxicity may be increased
in patients of advanced age. Dose reduction should be considered for patients with renal impairment.
Cisplatin. Cisplatin is a platinum chemotherapy agent that induces DNA damage in cancer cells by inhibiting DNA repair, leading to
apoptosis. It is used for the treatment of advanced testicular cancer. The recommended dose schedule of cisplatin for treatment of
advanced testicular cancer is 20 mg/m2 given intravenously daily for 5 days per cycle. Antiemetics and hydration pretreatment and
antiemetics following treatment are advised.13

Severe adverse reactions reported with cisplatin use include:

Renal toxicity;
Peripheral neuropathy;
Nausea and vomiting;
Bone marrow suppression;
Hypersensitivity reactions;
Ototoxicity;
Ocular toxicity;
Secondary leukemia; and
Embryo-fetal toxicity.

Other side effects associated with cisplatin include:

Anemia;
Blood clot;
Diarrhea;
Muscle cramps;
Alopecia; and
Rash.

Concurrent use of cisplatin with nephrotoxic drugs or ototoxic drugs should be avoided.

The pregnancy status of female patients should be verified before treatment, and pregnant patients should be advised of the risk of
fetal harm. Contraception should be used by female patients with reproductive potential during treatment and for 14 months
following the last dose of cisplatin. Male patients with female partners with reproductive potential should use contraception during
treatment and for 11 months after the treatment. Cisplatin may impair fertility in female and male patients. Breastfeeding should be
discontinued during treatment with cisplatin.

Cisplatin-associated ototoxicity may be more severe and more common in pediatric patients. Audiometric and vestibular function
should be monitored in all patients receiving cisplatin. The risk of cisplatin-associated renal toxicity may be increased in patients of
advanced age. Alternative treatments or reduction of cisplatin dose should be considered for patients with renal impairment.

Dactinomycin. Dactinomycin is a cytotoxic antibiotic that induces cell death in cancer cells by binding to DNA and preventing RNA
synthesis. It is used in the treatment of metastatic nonseminomatous testicular cancer in combination with vinblastine,
cyclophosphamide, bleomycin, and cisplatin in what is known as a VAB-6 regimen.13

Dactinomycin is administered intravenously at 1000 mcg/m2 on day 1 in combination with cyclophosphamide, bleomycin, vinblastine,
and cisplatin.

Dactinomycin is contraindicated in patients with hypersensitivity to dactinomycin and in patients with active chickenpox or herpes
zoster infection. The use of live virus vaccines should be avoided during treatment with dactinomycin.

Severe adverse reactions reported with the use of dactinomycin with radiotherapy include:

Gastrointestinal toxicity;
Bone marrow suppression; and
Second primary tumors (including leukemia).

Common side effects associated with dactinomycin include:

Liver toxicity;
 Low leukocyte and platelet counts;
Anemia;
Pneumonitis;
Alopecia;
Nausea and vomiting;
Severe skin damage; and
Sepsis.

Pregnant patients should be advised of the risk of harm to the fetus, and female patients should use birth control during treatment
with dactinomycin. Breastfeeding mothers should be warned of the risk of serious adverse reactions in nursing infants via excretion
of dactinomycin in milk.

Dactinomycin is only recommended for use in pediatric patients older than 6 to 12 months. Bone marrow suppression was found to
be more common in patients of advanced age. The dose may need to be reduced for elderly patients because of higher rates of
decreased renal, hepatic, or cardiac function.

Etoposide phosphate. Etoposide is a topoisomerase inhibitor that leads to cell death in cancer cells by inducing DNA damage and cell
cycle arrest. It is indicated for the treatment of refractory testicular tumors, in combination with other chemotherapy drugs. It is
administered as an intravenous infusion at the following doses14:

50 to 100 mg/m2 per day over 5 minutes to 3.5 hours on days 1 through 5; or
100 mg/m2 over 5 minutes to 3.5 hours on days 1, 3, and 5.

Severe adverse reactions reported with etoposide use include:

Bone marrow suppression;

Secondary leukemias;
Hypersensitivity reactions; and
Embryo-fetal toxicity.

The most common side effects associated with etoposide are:

Low neutrophil counts;

Nausea and vomiting;
Fever;
Constipation;
Vision problems;
Interstitial pneumonitis/pulmonary fibrosis;
Severe skin reactions; and
Hepatotoxicity.

Etoposide should not be administered concurrently with warfarin due to the risk of bleeding or decreased coagulation.

Pregnant patients should be advised of the risk of fetal harm. Contraception should be used to avoid pregnancy by female patients
with reproductive potential during treatment and for 5 months after treatment and by male patients with female partners with
reproductive potential during treatment and for 4 months after treatment. Etoposide may impair fertility in female and male
patients. Breastfeeding should be discontinued during treatment.

The safe and effective use of etoposide has not been established in pediatric patients.

Ifosfamide. Ifosfamide is a cytotoxic chemotherapy agent that causes apoptosis in cancer cells by inducing DNA damage.16 It is used
as third-line chemotherapy treatment of germ cell testicular cancer, in combination with other antineoplastic agents. The
recommended dosage is 1.2 g/m2 per day administered intravenously for 5 consecutive days, repeated every 3 weeks or following
hematologic toxicity recovery.15

Severe adverse reactions reported with the use of ifosfamide include:

 Urotoxicity;
Severe bone marrow suppression;
Confusion; and
Coma.

Other side effects associated with ifosfamide include:

Alopecia;
Nausea;
Vomiting;
Hematuria; and
Hallucination.

Ifosfamide can cause embryotoxicity and fetal damage. Patients should be warned of the risk of harm ifosfamide can cause to the
fetus and nursing infants.

The safe and effective use of ifosfamide has not been established in pediatric patients. Clearance of ifosfamide through the kidney
may be affected in patients of advanced age.

Vinblastine sulfate. Vinblastine is a chemotherapy agent that induces apoptosis in cancer cells by interfering with microtubule
assembly, leading to cell cycle arrest.17 It is used in the treatment of advanced testicular germ cell cancers, including embryonal
carcinoma, teratocarcinoma, and choriocarcinoma, as a single agent or in combination with other antineoplastic agents. Vinblastine
enhances the cell cycle arrest effect of bleomycin when administered prior to bleomycin treatment.18

Vinblastine administration is initiated as a single intravenous injection at 3.7 mg/m2 of body surface area (BSA) followed by
sensitivity assessment with a leukocyte count. The following are the recommended doses and administration of vinblastine for
testicular cancer.

First dose: 3.7 mg/m2 BSA

Second dose: 5.5 mg/m2 BSA
Third dose: 7.4 mg/m2 BSA
Fourth dose: 9.25 mg/m2 BSA
Fifth dose: 11.1 mg/m2 BSA

The maximum dose should be the dose at which the leukocyte count decreases to approximately 3000 cells/mm3 and not exceed 18.5
mg/m2 BSA. A dose of 1 increment smaller than this determined maximum dose should be given weekly for maintenance.

Severe adverse reactions reported with vinblastine use include:

Severe leukopenia at high doses;

Bone marrow suppression; and
Severe bronchospasm.

Common side effects associated with vinblastine include:

Alopecia;
Constipation;
Hypertension;
Jaw pain;
Bone pain; and
Pain in tumor-containing tissue.

Medications that may amplify toxicities when taken concurrently with vinblastine include:

Phenytoin;
P450 CYP3A inhibitors; and
Erythromycin.
Pregnant patients should be advised of the risk of fetal harm, and birth control should be used by female patients with reproductive
potential during treatment with vinblastine. Breastfeeding mothers should be warned of the risk of harm of vinblastine to nursing
infants. Vinblastine may impair fertility in male patients.

For treatment of testicular germ cell carcinomas in pediatric patients, the recommended initial dose of vinblastine is 3 mg/m2 in a
combination regimen. The dose should be modified based on hematologic tolerance.

Combination Chemotherapy Regimens

Combination chemotherapy has led to significant improvements in survival and has been the gold standard in treatment of testicular
cancer, often resulting in cure rates surpassing 95%.2 The remaining challenge of combination chemotherapy is managing the
increased risk of toxicity from multiple cytotoxic agents.

BEP. BEP is a combination chemotherapy regimen consisting of bleomycin, etoposide, and cisplatin.5 It is the preferred regimen for
first-line treatment of germ cell tumors and has been the standard regimen for first-line therapy for disseminated testicular cancer
since 1984.19 BEP is administered according to the following schedule5:

Etoposide: 100 mg/m2 intravenously on days 1 through day 5;

Cisplatin: 20 mg/m2 intravenously on days 1 through day 5; and
Bleomycin: 30 units intravenously weekly on days 1, 8, and 15, or days 2, 9, and 16.

TIP. TIP is a combination chemotherapy regimen consisting of paclitaxel, ifosfamide, and cisplatin. It is used as a second-line
conventional-dose chemotherapy regimen for metastatic germ cell tumors. TIP is administered at the following doses and schedule5:

Paclitaxel: 250 mg/m2 intravenously on day 1;

Ifosfamide: 1500 mg/m2 intravenously on days 2 through day 5 with mesna protection; and
Cisplatin: 25 mg/m2 intravenously on days 2 through day 5.
Repeat every 21 days.

VeIP. VeIP is a combination chemotherapy regimen consisting of vinblastine, ifosfamide, and cisplatin. It is used as a second-line
therapy for treatment of metastatic germ cell tumors as the conventional-dose chemotherapy option. The recommended doses and
schedule of VeIP are as follows5:

Vinblastine: 0.11 mg/kg intravenous push on days 1 through day 2;

Ifosfamide: 1200 mg/m2 intravenously on days 1 through day 5 with mesna protection; and
Cisplatin: 20 mg/m2 intravenously on days 1 through day 5.
Repeat every 21 days.

VIP. VIP is a combination chemotherapy regimen consisting of etoposide, ifosfamide, and cisplatin. It is a first-line treatment for germ
cell tumors for patients at higher risk of developing bleomycin-related complications. It is also used for treatment of patients with
intermediate or poor-risk disease or patients with residual viable malignant cells at surgery following first-line chemotherapy. The
recommended doses and schedule for VIP are5:

Etoposide: 75 mg/m2 intravenously on days 1 through day 5;

Ifosfamide: 1200 mg/m2 intravenously on days 1 through day 5 with mesna protection; and
Cisplatin: 20 mg/m2 intravenously on days 1 through day 5.
Repeat every 21 days.

Testicular Cancer Treatment Guidelines

Recommendations for the diagnosis and treatment of testicular cancer have been made available by national organizations to assist
in clinical decision-making:

National Comprehensive Cancer Network (NCCN Clinical Practice Guidelines in Oncology – Testicular Cancer. Version 1.2023
 American Society of Clinical Oncology (ASCO) Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males
With Germ Cell Tumors

American Urological Association (AUA) Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline (2019)

References

1. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: testicular cancer. National Cancer Institute. Accessed
May 15, 2023.
2. Gaddam SJ, Chesnut GT. Testicle cancer. StatPearls. Updated October 16, 2022. Accessed May 15, 2023.
3. Li Y, Lu Q, Wang Y, Ma S. Racial differences in testicular cancer in the United States: descriptive epidemiology. BMC Cancer.
2020;20(1):284. doi:10.1186/s12885-020-06789-2.
4. Testicular Cancer Treatment (PDQ®)–Health Professional Version. National Cancer Institute. Updated March 9, 2023.
Accessed May 15, 2023.
5. National Comprehensive Cancer Network®. Testicular Cancer. Version 1.2023. Updated January 26, 2023. Accessed May 15,
2023.
6. Cedeno JD, Light DE, Leslie SW. Testicular seminoma. StatPearls. Updated November 28, 2022. Accessed May 15, 2023.
7. Khan L, Verma S, Singh PK, Agarwal A. Testicular embryonal carcinoma presenting as chest wall subcutaneous mass. J Cytol.
2009;26(1):39-40. doi:10.4103/0970-9371.54868
8. Katabathina VS, Vargas-Zapata D, Monge RA, et al. Testicular germ cell tumors: classification, pathologic features, imaging
findings, and management. Radiographics. 2021;41(6):1698-1716. doi:10.1148/rg.2021210024.
9. Kapoor M, Leslie SW. Sex cord stromal testicular tumor. StatPearls. Updated January 2, 2023. Accessed May 15, 2023.
10. Hoei-Hansen CE, Rajpert-De Meyts E, Daugaard G, Skakkebaek NE. Carcinoma in situ testis, the progenitor of testicular germ
cell tumours: a clinical review. Ann Oncol. 2005;16(6):863-868. doi:10.1093/annonc/mdi175
11. Blenoxane. Highlights of Prescribing Information. Bristol-Myers Squibb Company; 2010. Accessed May 15, 2023.
12. Cisplatin. Highlights of Prescribing Information. WG Critical Care, LLC; 2019. Accessed May 15, 2023.
13. Cosmegen [package insert]. Lundbeck; 2012. Accessed May 15, 2023.
14. Etopophos. Highlights of Prescribing Information. Bristol-Myers Squibb Company; 2017. Accessed May 15, 2023.
15. Ifex. Highlights of Prescribing Information. Baxter Healthcare Corporation; 2018. Accessed May 15, 2023.
16. Gangireddy M, Nookala V. Ifosfamide. StatPearls. Updated March 23, 2023. Accessed May 15, 2023.
17. Dhyani P, Quispe C, Sharma E, et al. Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine,
vindesine, vinorelbine and vincamine. Cancer Cell Int. 2022;22(1):206. doi:10.1186/s12935-022-02624-9
18. Vinblastine sulfate [package insert. Bedford Laboratories; 2012. Accessed May 15, 2023.
19. Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci USA. 2002;99(7):4592-4595. doi:10.1073/pnas.072067999

Author Bio

Bora Lee, PhD, earned a Bachelor of Science in biology from Boston College and a PhD in Molecular and Cellular Biology from the
University of Massachusetts Amherst. She has more than 10 years of translational research experience in reproductive medicine and
women’s health, with a focus on fertility and placental health. She is passionate about improving people’s lives by helping them to
make informed health decisions.

TOPICS: DDI TESTICULAR CANCER TREATMENT REGIMENS

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