Treatment Protocols

Treatment protocols for nonseminoma testicular cancer are provided below, including the following:

Recommendations for treatment of stage I-III disease
Second-line recommendations for metastatic disease
Recommendations for persistent or recurrent disease

Treatment recommendations for stage I nonseminoma testicular cancer

Stage IA:

Recommendations after orchiectomy include surveillance in compliant patients or use of nerve-sparing retroperitoneal lymph node dissection (RPLND)^{[1, 18]}
If the dissected lymph nodes are not involved with tumor (pN0), there is no need for adjuvant chemotherapy after RPLND
If resected lymph nodes do involve the tumor, a decision must be made as to whether to give adjuvant chemotherapy based on degree of nodal involvement; chemotherapy is preferred in patients with pN2 or pN3 disease^[1]
Recommended chemotherapy includes two cycles of EP (etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d) or
One cycle of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d)^[2]

Stage IB:

Treatment recommendations after orchidectomy include nerve-sparing RPLND or chemotherapy
Chemotherapy includes one or two cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d) or
Surveillance for compliant patients with T2 or T3 disease
Adjuvant therapy after a nerve-sparing RPLND is the same as in stage IA

Stage IS:

Persistent elevation of seurm tumor marker levels characterizes this stage; patients are treated with four cycles of EP^[3](etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 12d^[3]) or
Three cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d)

Treatment recommendations for stage II nonseminoma testicular cancer

Stage IIA:

Treatment recommendations are based on serum tumor marker results after orchiectomy
Patients with normal marker levels should be treated with nerve-sparing RPLND or chemotherapy with four cycles of EP^[3](etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 12d^[3]) or
Three cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d)
In patients who underwent RPLND and were found to have pN1 or pN2 disease, adjuvant chemotherapy with two cycles of EP or two cycles of BEP is preferred^{[3, 1]}
Those with pN3 disease should receive three cycles of BEP or four cycles of EP

Stage IIB:

As with stage IIA, treatment recommendations are based on serum tumor marker levels
Treatment for patients with negative tumor markers but lymph node metastases within lymphatic drainage sites is nerve-sparing RPLND plus adjuvant therapy (as in stage IIA) or chemotherapy
Chemotherapy includes four cycles of EP^[3](etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d) or
Three cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d)
For patients with multifocal symptomatic disease or lymph node metastases within lymphatic drainage sites, recommended treatment is chemotherapy with four cycles of EP and three cycles of BEP; nerve-sparing RPLND is not recommended

Treatment recommendations for advanced metastatic nonseminoma testicular cancer

The International Germ Cell Cancer Consensus Group (IGCCCG) developed a risk classification for advanced nonseminoma testicular cancer based on identifying clinically independent prognostic features, including extent of disease and levels of serum tumor markers. In testicular cancer patients who have undergone orchiectomy, markers are used to determine risk classification.^{[4, 1]}

Stages IS, IIA-S1, IIB-S1, IIC, IIIA (good risk):

Good risk is classified as the presence of testicular or retroperitoneal primary tumors with no nonpulmonary visceral metastases and S1 markers; 5-y progression-free survival (PFS) is 89%; 5-y survival is 92-94%
Primary chemotherapy includes four cycles of EP^[3](etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d) or
Three cycles of BEP (bleomycin 30 U IV on days 1,8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d^[5][5-day schedule]; or bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 165 mg/m² IV on days 1-3 plus cisplatin 50 mg/m² IV on days 1-2; every 21d^[5][3-day schedule])

Stage IIIB (intermediate risk):

Intermediate risk is classified as presence of testicular or retroperitoneal primary tumors with no nonpulmonary visceral metastases and S2 markers; 5-y PFS is 75%; 5-y survival is 80-83%
Patients with stage IIIB intermediate risk should be treated with 4 cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d^[5][5-d schedule]; or bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 165 mg/m² IV on days 1-3 plus cisplatin 50 mg/m² IV on days 1-2; every 21d^[5][3-d schedule])
Tumor markers should be measured immediately before each cycle of chemotherapy regimen and ongoing response should be assessed via continued reduction in tumor marker levels
In patients with intermediate-risk disease, chemotherapy can be followed by surveillance or RPLND for those with complete tumor response and negative markers
Residual masses in patients with normal marker levels should be resected; depending on the pathology, further chemotherapy should be considered with regimens such as VIP (etoposide 75 mg/m² IV on days 1-5 plus ifosfamide 1.2 g/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5 plus mesna 400 mg/m² IV infused over 30 min before ifosfamide, then 4h and 8h after the start of each ifosfamide dose (or 1200 mg/m²/24h) on days 1-5; every 21d for four cycles^{[6, 7]})
If marker levels are persistently abnormal after the completion of initial chemotherapy, second-line therapy should be considered

Stage IIIC (poor risk):

Poor risk is classified as the presence of a mediastinal primary tumor, nonpulmonary visceral metastases, or S3 markers; 5-y PFS is 41%; 5-y survival is 71%
Patients with stage IIIC poor risk should be treated with four cycles of BEP (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d^[5][5-day schedule]; or bleomycin 30 U IV on days 1, 8 and 15 plus etoposide 165 mg/m² IV on days 1-3 plus cisplatin 50 mg/m² IV on days 1-2; every 21d^[5][3-day schedule])
In patients with brain metastases, cisplatin-based chemotherapy should be combined with surgery and radiation therapy as clinically indicated
Tumor markers should be measured immediately before each cycle of chemotherapy, and ongoing response should be assessed via continued reduction in tumor markers
In patients with poor-risk disease, chemotherapy can be followed by surveillance or RPLND for those with complete tumor response and negative markers
Residual masses with normal markers should be resected; depending on the pathology, further chemotherapy should be considered with regimens such as VIP (etoposide 75 mg/m² IV on days 1-5 plus ifosfamide 1.2 g/m² IV on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5 plus mesna 400 mg/m² IV infused over 30 min before ifosfamide, then 4h and 8h after the start of each ifosfamide dose (or 1200 mg/m²/24h) on days 1-5; every 21d for four cycles^{[6, 7]})
If markers are persistently abnormal after the completion of initial chemotherapy, second-line/salvage therapy should be considered

Second-line treatment recommendations for metastatic disease

Favorable prognosis:

Patients with a favorable prognosis^[1]—defined as those with low marker levels, low tumor volume, and complete response to first-line therapy—should be treated with conventional doses of VeIP^[8](vinblastine 0.11 mg/kg IV push on days 1-2 plus ifosfamide 1200 mg/m² IV on days 1-5 plus mesna 400 mg/m² IV infused over 30 min before ifosfamide, then 4h and 8h after the start of each ifosfamide dose (or 1200 mg/m²/24h) on days 1-5 plus cisplatin 20 mg/m² IV on days 1-5; every 21d for four cycles) or
TIP^[9](paclitaxel 250 mg/m² IV continuous infusion over 24h on day 1 plus ifosfamide 1500 mg/m² IV on days 2-5 plus cisplatin 25 mg/m² IV on days 2-5 plus mesna 500 mg/m² IV infused over 30 min before ifosfamide and then 4h and 8h after each dose of ifosfamide on days 2-5; every 21d for four cycles) or
High-dose chemotherapy^[10]with carboplatin 700 mg/m² IV plus etoposide 750 mg/m² IV; administer 5, 4, and 3 days before peripheral blood stem cell infusion for two cycles; or
Paclitaxel 200 mg/m² IV over 24h on day 1 plus ifosfamide 2000 mg/m² over 4h with mesna protection on days 2-4; every 14d for two cycles; followed by carboplatin area under the curve (AUC) 7-8 IV over 60min on days 1-3 plus etoposide 400 mg/m² IV on days 1-3; administer with peripheral blood stem cell support every 14-21d for three cycles^[11]

Unfavorable prognosis:

Unfavorable prognosis^[1]is defined by incomplete response, high marker levels, high tumor volume, an extratesticular primary tumor, and late relapse
Treat these patients with chemotherapy; clinical trials or conventional-dose VeIP or TIP regimens are preferred; consider high-dose chemotherapy (as above)
Consider surgical salvage therapy or best supportive care^[1]

Treatment recommendations for persistent or recurrent disease

See the list below:

All patients should be considered for palliative chemotherapy or radiation therapy.
Patients who have been pretreated, cisplatin-resistant disease, or have refractory germ cell tumors may be given combination chemotherapy with GEMOX (gemcitabine 1000 or 1250 mg/m² IV on days 1 and 8 plus oxaliplatin 130 mg/m² IV on day 1; every 21d^{[12, 13]}) or
High-dose chemotherapy and stem-cell rescue^{[14, 15]}

Special considerations

See the list below:

Pulmonary function studies to ensure adequate function should be confirmed before initiation of any regimen that includes bleomycin
Smokers should be counseled regarding smoking cessation
If significant thoracic surgery is anticipated (eg, for a mediastinal tumor), a VIP regimen can be considered as an alternative to a BEP regimen
Surgical resection of residual or recurrent disease should be considered (including RPLND or resection of pulmonary masses) in patients whose markers have normalized or remain normal
Sperm banking should be discussed with patients before initiation of therapy
Secondary malignancies are the most common cause of death in testicular cancer survivors
A second testicular cancer develops in 1-2% of testicular cancer survivors; treatment with etoposide can increase the risk of secondary leukemia^{[16, 17]}

[Guideline] National Comprehensive Cancer Network. Testicular Cancer. NCCN Clinical Practice Guidelines in Oncology. Available at http://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf. Version 2.2022 — January 4, 2022; Accessed: January 29, 2022.
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[Guideline] Stephenson A, Eggener SE, Bass EB, Chelnick DM, Daneshmand S, Feldman D, et al. Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline. J Urol. 2019 Aug. 202 (2):272-281. [QxMD MEDLINE Link]. [Full Text].