Testicular%20cancer Treatment

Pure Seminoma

Stage I

• Orchiectomy is usually curative for stage I seminoma
• Postoperatively, surveillance is the preferred treatment for pT1-pT3 tumors especially for compliant patients since there is no survival advantage of radiation or chemotherapy over surveillance and treatment-related morbidity is avoided
  
  • Patients under surveillance need to be followed with periodic history review and PE, chest X-ray, and abdominal/pelvic CT scan 

• Risk factors for relapse or occult metastatic disease include tumor size >4 cm and rete testis invasion
  
  • Patients who relapse may be alternatively treated with chemotherapy or radiation

Nonseminomatous Germ Cell Tumor (NSGCT)

Stage I

• >70% of patients with stage I nonseminoma are cured with orchiectomy alone
• Predictors for relapse or occult metastatic disease include lymphovascular invasion, predominance of embryonal carcinoma component, or a T3-T4 primary tumor
• For patients with low-risk disease (vascular invasion absent), negative CT scan and tumor markers, and who are committed, surveillance is the preferred treatment option
  • Surveillance prevents acute and long-term adverse effects from overtreatment
  • Patients under surveillance need to be followed with periodic history review and PE, chest X-ray, abdominal/pelvic CT scan and serum tumor markers
  • For stage IB nonseminoma, consider surveillance for T2 only
  • Consider adjuvant chemotherapy or nerve-sparing RPLND in noncompliant patients or those unwilling to undergo surveillance
• May be an option for patients with risk factors

Chemotherapy
Pure Seminoma

Stage I

• A relapse-free survival is achieved by approximately 90% of patients with retroperitoneal masses <3 cm in diameter
• Patients who relapse are alternatively treated with chemotherapy
  
  • Single-agent Carboplatin given for 1-2 cycles is as effective as adjuvant radiation therapy in relapse prevention

Stage II

• Nonbulky retroperitoneal disease, eg stage IIA (lymph node mass <2 cm) and small IIB (lymph node mass 2-5 cm) may be treated with a Cisplatin-based chemotherapy which includes the following:
  
  • Bleomycin, Etoposide, and Cisplatin (BEP) chemotherapy for 3 cycles is the standard treatment
  • 4 cycles of Etoposide and Cisplatin (EP) are given to patients with contraindications to Bleomycin

• Bulkier disease (tumors >5 cm) has a higher relapse rate after radiation, thus a Cisplatin-based chemotherapy as above is the preferred treatment for some stage IIB and all IIC patients

Nonseminomatous Germ Cell Tumor (NSGCT)

Stage I

• Patients with or without risk factors may be treated with 1 cycle of BEP
• High-risk stage I patients (vascular invasion present) are treated with 1-2 cycles of BEP
  
  • Survival is the same as with surveillance

• Stage IS patients are treated with chemotherapy, eg 3 cycles of BEP or 4 cycles of EP
  
  • Chemotherapy is preferred over primary RPLND because of the high prevalence of disseminated disease

Stage II

• Treatment is based on the levels of serum tumor markers after orchiectomy and radiographic findings
• Chemotherapy is the preferred primary therapy in stage II patients with elevated serum markers and/or if lymph nodes are >3 cm in greatest dimension
• Primary chemotherapy with either 3 cycles of BEP or 4 cycles of EP is the recommended treatment for stage IIB patients with metastatic disease not confined within lymphatic drainage sites (eg multifocal or symptomatic lymph node metastases with aberrant lymphatic drainage sites)
• Disseminated disease is treated with chemotherapy due to the high relapse rate after RPLND
  
  • For patients with good prognosis, 3 cycles of BEP or 4 cycles of EP are acceptable combination chemotherapy regimens

• Patients with stage II nonseminoma and persistently elevated tumor markers are generally treated with 3 cycles of BEP or 4 cycles of EP

• Regardless of histological type, the treatment for advanced or metastatic GCT is based upon the International Germ Cell Cancer Consensus Group (IGCCCG) risk stratification system which categorizes patients’ risk into good, intermediate or poor according to their pretreatment clinical features since treatment may bring about significant toxicities
• IGCCCG system assesses the histology, primary tumor site, metastatic disease and post-orchiectomy serum levels of tumor markers and provides prognosis for metastatic disease treated with chemotherapy
• Goals are to obtain maximum efficacy with minimal toxicity in patients with good risk and a more effective therapy with tolerable toxicity in patients with intermediate and poor risk
  
  

  Risk Status	Seminoma	Nonseminoma
  Good	5-year PFS1 89% 5-year survival 95%	5-year PFS1 90% 5-year survival 96%
  	All of the following: Any primary site No nonpulmonary visceral metastases Normal AFP Any hCG Any LDH	All of the following: Testis/retroperitoneal primary site No nonpulmonary visceral metastases AFP <1000 ng/mL hCG <5000 IU/L (1000 ng/mL) LDH <1.5 x ULN2
  Intermediate	5-year PFS1 79% 5-year survival 88%	5-year PFS1 78% 5-year survival 89%
  	All of the following: Any primary site Nonpulmonary visceral metastases Normal AFP Any hCG Any LDH	Testis/retroperitoneal primary site and No nonpulmonary visceral metastases and AFP 1000 - 10,000 ng/mL or hCG 5000 - 50,000 IU/L or LDH 1.5 - 10 x ULN2
  Poor	No patients are classified as poor prognosis	5-year PFS1 54% 5-year survival 67%
  		Mediastinal primary site or Nonpulmonary visceral metastases or AFP >10,000 ng/mL or hCG >50,000 IU/L (10,000 ng/mL) or LDH >10 x ULN2

¹PFS: Progression-free survival
²ULN: Upper limit of normal

• A durable complete response (complete absence of clinical evidence of tumor on PE and imaging along with normalization of serum AFP and hCG levels for ≥1 month) is achieved with the following:
  
  • 3 cycles of BEP or 4 cycles of EP in good-risk patients [stages IIC and III seminoma; stages IS, IIA and IIB (with persistent tumor marker elevation), IIC, and IIIA nonseminoma]
    • EP is preferred in patients >50 years old, with reduced estimated glomerular filtration rate (eGFR), chronic obstructive pulmonary disease or other lung disease resulting to reduced pulmonary function
  • 4 cycles of BEP is the standard treatment in intermediate- (stage IIIC seminoma with non-pulmonary visceral metastases and stage IIIB nonseminoma) and poor-risk patients (stage IIIC nonseminoma)
    • 4 cycles of Etoposide, Cisplatin and Ifosfamide (VIP) is reserved for stage IIIC seminoma and stage IIB nonseminoma patients with contraindications to Bleomycin
  • 4 cycles of VIP may be given in select patients with poor risk stage IIIC nonseminoma or to patients at risk of lung injury from or who may not tolerate Bleomycin

• A CT scan (eg abdominal, pelvic or chest) should be obtained after primary chemotherapy treatment especially in patients with evidence of retroperitoneal adenopathy initially as residual metastases resection is an important part of treatment; serum tumor markers are evaluated as well

Pure Seminoma

• If there is no residual disease or residual mass is present at ≤3 cm and tumor markers are normal, post-treatment surveillance is suggested
• If residual mass is >3 cm and tumor markers are normal, surveillance is an option or a PET scan is obtained ≥6 weeks after chemotherapy to assess presence of residual viable tumor
  
  • If PET scan is negative, do post-treatment surveillance
  • If PET scan is indeterminate, a repeat PET or CT scan is recommended after 6-8 weeks
  • If PET scan is positive, resect residual disease (RPLND if technically feasible); 2 additional cycles of chemotherapy either with EP or Paclitaxel, Ifosfamide, and Cisplatin (TIP) or VIP or Vinblastine, Ifosfamide, and Cisplatin (VeIP) are administered if viable tumor is found but is completely excised
    • If resection incomplete or progressive disease as shown in imaging or rising serum tumor markers is detected, 2nd-line chemotherapy is started with 4 cycles of VeIP or TIP

• If progressive disease is evident with a growing mass or rising tumor markers, patient may be given salvage therapy

Nonseminomatous Germ Cell Tumor (NSGCT)

• Do tumor marker level determination and imaging studies 4-8 weeks after the last cycle of therapy
  
  • If CT scan revealed no mass or residual mass <1 cm with normal tumor markers, ie complete response, may proceed with post-treatment surveillance or in select cases, nerve-sparing bilateral RPLND
  • If tumor markers have normalized but imaging revealed ≥1 retroperitoneal lymph nodes ≥1 cm in diameter, perform nerve-sparing bilateral RPLND

• Standard of care is resection of all residual masses apparent on scans in patients with normal tumor markers or those with partial response after chemotherapy
  
  • If a mature teratoma or necrotic debris is present, may do surveillance
  • If a viable tumor (choriocarcinoma, embryonal carcinoma, seminoma or yolk sac tumor) is present, 2 additional cycles of chemotherapy are administered, eg EP, TIP, VeIP, or VIP 

• If patient has incomplete response to primary treatment, consider salvage therapy
• If tumor markers are persistently elevated or are slowly decreasing, surveillance or post-chemotherapy RPLND may be done
  
  • Post-chemotherapy RPLND is warranted in metastatic nonseminoma with a residual retroperitoneal mass and normal post-chemotherapy serum tumor markers

• Considered 2nd-line therapy, it may be given to patients who failed to improve with 1st-line therapy or those who have developed recurrence
• Treatment is based on response to previous therapy, timing and location of relapse and tumor histology
  
  • Treat based on extent of disease at relapse

• Patients with NSGCT and recurrence ≤2 years after completion of primary chemotherapy have the following 2nd-line options:
  • Participation in a clinical trial is preferred or
  • Chemotherapy with conventional-dose therapy or high-dose chemotherapy or
  • Surgical salvage if present only on 1 site or
  • Best supportive care and palliative care
• Patients with NSGCT and with recurrence >2 years after completion of primary chemotherapy have the following 2nd-line options:
  • Surgical salvage is preferred if mass is resectable or
  • Participation in a clinical trial if mass is unresectable or
  • Chemotherapy with conventional-dose therapy or high-dose chemotherapy or
  • Best supportive care and palliation care
• Patients who have not received prior chemotherapy (chemotherapy-naïve patients) are treated based on their risk status
• 2nd-line chemotherapy regimens for metastatic germ cell tumors include the following:
  
  • Conventional-dose regimens: VeIP, TIP
  • High-dose regimens: Carboplatin + Etoposide with peripheral blood stem cell infusion for 2 cycles or Paclitaxel and Ifosfamide followed by high-dose Carboplatin + Etoposide with peripheral blood stem cell support for 3 cycles

• Favorable prognostic factors to conventional dose 2nd-line chemotherapy are testicular primary tumor, prior complete remission after having received 1st-line chemotherapy and low levels of post-orchiectomy tumor markers and volume of disease
  • Ifosfamide, Cisplatin and either Etoposide or Vinblastine can induce a long-term complete response in approximately 25% of patients
  • TIP was associated with durable remission in almost two-thirds of patients
  • Alternatives to above-mentioned conventional-dose chemotherapies include a clinical trial (preferred) or high-dose chemotherapy

• Patients with NSGCT with complete response after 2nd-line therapy may undergo surveillance or in selected cases a nerve-sparing bilateral RPLND
• Patients with NSGCT with incomplete response after 2nd-line therapy and with residual masses with normal or mildly elevated tumor marker levels should undergo surgical resection of all residual masses
  • If a mature teratoma or necrotic debris or if a viable tumor (choriocarcinoma, embryonal carcinoma, seminoma or yolk sac tumor) is present, may do surveillance
• Patients with NSGCT with incomplete response after 2nd-line therapy and with residual masses and progressively elevated tumor marker levels are recommended for 3rd-line therapy
  • Close surveillance should be done in patients with elevated but stable tumor markers
  • Surgical resection of all residual masses followed by surveillance should be performed in patients with mildly elevated but decreasing tumor marker levels
• If response is incomplete in patients with NSGCT or patient relapses following chemotherapy with 2nd-line conventional dose, give high-dose chemotherapy (if not previously given) or a clinical trial participation is preferred
  • Surgical salvage must be considered in highly selected patients with chemorefractory disease limited to a single resectable site
    • Resection of any residual mass after salvage chemotherapy remains a potential curative option

• Patients with NSGCT with recurrence after prior high-dose chemotherapy have the following 3rd-line options:
  • Participation in clinical trials (preferred) or
  • Conventional-dose salvage chemotherapy or
  • Surgical salvage if limited to a single site or
  • Testing for microsatellite instability/mismatch repair (MSI/MMR) or tumor mutation burden (TMB) if with progression after high-dose chemotherapy or 3rd-line therapy
• Patients with NSGCT with late-relapsing tumors, ie occurring after >2 years of achieving complete remission or completing 2nd-line chemotherapy, are treated with aggressive surgery if resectable (preferred) and or chemotherapy with conventional- or high-dose regimens if not previously received
• 3rd-line chemotherapy regimens for metastatic germ cell tumors in patients without previous high-dose chemotherapy include:
  • Preferred regimens (high-dose chemotherapy): Carboplatin + Etoposide with peripheral stem cell infusion for 2 cycles or Paclitaxel and Ifosfamide followed by Carboplatin + Etoposide with peripheral stem cell infusion for 3 cycles
  • Other recommended regimens
    • Etoposide
    • Gemcitabine + Paclitaxel + Oxaliplatin
    • Gemcitabine + Oxaliplatin (GEMOX)
    • Gemcitabine + Paclitaxel
  • Pembrolizumab for high MSI (MSI-H)/MMR deficient (dMMR) or TMB-high (TMB-H) tumors
• 3rd-line chemotherapy regimens for metastatic germ cell tumors in patients with previous high-dosechemotherapy include:
  • Preferred regimens: Gemcitabine + Paclitaxel + Oxaliplatin, GEMOX, Gemcitabine + Paclitaxel, or monotherapy with Etoposide
    • High-dose chemotherapy is the preferred option if VeIP or TIP was previously received as 2nd-line therapy
  • Pembrolizumab for MSI-H/dMMR or TMB-H tumors
• Patients with unfavorable prognostic features, ie extratesticular primary tumor, incomplete response to 1st-line chemotherapy, or high levels of tumor markers and volume of disease, may be given a clinical trial participation (preferred), 2nd-line conventional-dose therapy (VeIP or TIP) or high-dose chemotherapy; alternative options include palliative chemotherapy or salvage surgery if solitary site
  • High-dose therapy can be considered in patients with a testicular primary tumor and rising post-orchiectomy tumor markers during 1st-line chemotherapy
  • Consider stereotactic or conventional radiotherapy if refractory disease is unresectable but localized

• Palliative therapy with chemotherapy or radiation must be considered in patients with either persistent or recurrent disease
  • Regimens for metastatic germ cell tumors or patients with Cisplatin-resistant or refractory GCT (relapse occurring within 4-8 weeks following initial chemotherapy or patients with progressive disease despite platinum-based therapy or those relapsing shortly after high-dose chemotherapy) include Gemcitabine and Oxaliplatin; Gemcitabine and Paclitaxel; Gemcitabine, Paclitaxel and Oxaliplatin; and oral Etoposide

• Brain metastases are treated with a Cisplatin-based chemotherapy for poor-risk disease alone or in combination with radiation therapy and/or surgical resection if clinically indicated and feasible