Editing Germ Cell Tumours (section)

== Management ==

=== General principles ===

* Any post-pubertal male, regardless of age, should be treated according to adult treatment guidelines.
* Management decisions should be made in a multidisciplinary setting involving experienced clinicians in urology, medical oncology, radiation oncology, pathology, and radiology.
** '''Review of primary tumor specimens by experienced pathologists is recommended.'''
*** Expert review of pathologic specimens should be considered in clinical scenarios where treatment decisions will be impacted.
**** Studies have shown that expert pathology review can change the pathological subtype in 1-4% of cases.[https://pubmed.ncbi.nlm.nih.gov/16045777/][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704081/]
* '''<span style="color:#ff0000">Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days.</span>'''
** Due to the rapid growth of many GCT, particularly NSGCT, there is a risk of disease progression between staging studies and intervention. Therefore, risk adapted management decisions (i.e. RPLND for Stage IIA disease) should be made based on recent imaging and serum tumor marker levels to avoid undertreatment.
* '''In patients with normal serum tumor markers (hCG and AFP) and equivocal imaging findings for metastasis, consider repeat imaging in 6-8 weeks to clarify the extent of disease prior to making a treatment recommendation'''.
* '''<span style="color:#ff0000">Prior to definitive management, patients should be counseled about the risks of (3):</span>'''
*# '''<span style="color:#ff0000">Hypogonadism</span>'''
*#* '''<span style="color:#ff00ff">Hormone levels in long-term survivors of testicular cancer</span>'''
*#** Population: 1235 patients with history of unilateral orchiectomy for testicular cancer and adjuvant RPLND only, radiotherapy only, or chemotherapy
*#** Compared to healthy controls
*#** '''Results'''
*#*** '''Approximately 11 years follow-up'''
*#*** '''No significant difference in serum testosterone between testicular cancer patients and healthy controls'''
*#*** Significantly higher age-adjusted LH in testicular cancer patients
*#** Nord, Carina, et al. "[https://pubmed.ncbi.nlm.nih.gov/12932930/ Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer.]" ''European urology'' 44.3 (2003): 322-328.
*#* Over long-term follow-up, up to 10-15% of patients will have low serum testosterone levels or will require testosterone replacement therapy
*# '''<span style="color:#ff0000">Infertility</span>'''
*#* '''At diagnosis, up to 50% have impaired semen parameters and 10% are azoospermic'''
*#* '''<span style="color:#ff0000">Sperm cryopreservation</span>'''
*#** '''<span style="color:#ff0000">Timing</span>'''
*#*** '''<span style="color:#ff0000">Pre-orchiectomy</span>'''
*#**** '''Consider in patients without a normal contralateral testicle or with known subfertility'''
*#*** '''<span style="color:#ff0000">Post-orchiectomy</span>'''
*#**** '''Recommended before treatment (other than orchiectomy) is initiated in patients who are undecided or are planning future paternity.'''
*#***** '''Virtually all patients become azoospermic after chemotherapy, and 50-80% of patients with normal semen parameters at diagnosis return to these levels within 2 and 5 years, respectively.'''
*#***** '''Recovery of spermatogenesis after radiation therapy for seminoma may take 2-3 years or longer.'''
*#**** '''Consider in patients that do not require further treatment with a normal contralateral testicle or known fertility, who''' '''are undecided or are planning future paternity''', given the potential risk of pathologic process (testicular cancer, trauma) involving the normal contralateral testicle
*# '''<span style="color:#ff0000">Contralateral tumour</span>'''
*#* '''Patients with a history of GCT or GCNIS should be informed of risks of a second primary tumor, while rare, is significantly increased in the contralateral testis'''

=== Orchiectomy ===

* '''See [[Orchiectomy]] Chapter Notes'''

==== Radical inguinal orchiectomy ====

* '''<span style="color:#ff0000">Testicular prosthesis should be discussed prior to orchiectomy.</span>'''
* '''<span style="color:#ff0000">Approach: inguinal</span>'''
** '''<span style="color:#ff0000">Trans-scrotal orchiectomy: contraindicated due to risks of scrotal violation (see above)</span>'''
*** '''Patients who have undergone scrotal orchiectomy for malignant neoplasm should be counseled regarding the increased risk of local recurrence and may rarely be considered for adjunctive therapy (excision of scrotal scar or radiotherapy) for local control'''
**** In patients that have received systemic therapy following scrotal orchiectomy, local relapse is rare and adjuvant therapy is not needed
* '''<span style="color:#ff0000">Patients suspected of having a testicular neoplasm should undergo a radical inguinal orchiectomy with removal of the tumor-bearing testicle and spermatic cord to the level of the internal inguinal ring.</span>'''
** '''In very rare cases where there is a possibility of a benign tumour, excisional biopsy with a frozen section should be performed prior to definitive orchiectomy to allow for the possibility of organ-sparing partial orchiectomy.'''

* '''<span style="color:#ff0000">Timing</span>'''
** '''<span style="color:#ff0000">In general, orchiectomy should be performed prior to any further treatment.</span>'''
*** '''<span style="color:#ff0000">Exception: in patients with life-threatening metastatic disease and an unequivocally elevated AFP and/or HCG, orchiectomy should not delay the start of chemotherapy and can be postponed until later in the treatment course</span>'''

==== Testis-sparing surgery (TSS)[https://www.auanet.org/guidelines/testicular-cancer-guideline] ====

* '''<span style="color:#ff0000">Not recommended in patients with a testicular lesion suspicious for malignant neoplasm and a normal contralateral testis; radical inguinal orchiectomy is recommended</span>'''
* '''<span style="color:#ff0000">Indications (3)</span>'''
*# '''<span style="color:#ff0000">Patients wishing to preserve gonadal function</span>'''
*# '''<span style="color:#ff0000">Mass <2cm</span>'''
*# '''<span style="color:#ff0000">And one of the following:</span>'''
*## '''<span style="color:#ff0000">Equivocal ultrasound/physical exam findings and negative tumor markers (hCG and AFP)</span>'''
*## '''<span style="color:#ff0000">Congenital, acquired or functionally solitary testis</span>'''
*## '''<span style="color:#ff0000">Bilateral synchronous tumors</span>'''
* '''Patients considering TSS should be counseled regarding (5):'''
*# '''Higher risk of local recurrence'''
*# '''Need for monitoring with physical examination and ultrasound'''
*# '''Role of adjuvant radiotherapy to the testicle to reduce local recurrence'''
*# '''Impact of radiotherapy on sperm and testosterone production'''
*# '''Risk of testicular atrophy and need for testosterone replacement therapy, and/or subfertility/infertility'''
* '''When TSS is performed, in addition to the suspicious mass, multiple biopsies of the ipsilateral testicle normal parenchyma should be obtained for evaluation by an experienced genitourinary pathologist to rule out GCNIS.'''
** 50-80% undergoing TSS have concomitant GCNIS in the ipsilateral testis
** '''GCNIS'''
*** '''Rationale for treatment is based on the high risk of developing invasive GCT.'''
*** Can be diagnosed by testicular biopsy performed for the investigation of infertility, contralateral testis biopsy in patients with GCT, or within the affected testis in a patient undergoing TSS
*** '''Management options'''
***# '''Orchiectomy'''
***# '''Low-dose (18-20 Gy) radiotherapy'''
***# '''Close observation'''
** '''If GSCNIS on testis biopsy or malignant neoplasm after TSS are found:'''
*** '''If patient prioritizes preservation of fertility and testicular androgen production, surveillance is recommended'''
**** '''For patients with abnormal semen parameters but sufficient for assisted reproductive techniques, close surveillance with periodic ultrasound evaluation of the testis is a reasonable strategy with deferred therapy until successful pregnancy and/or development of GCT.'''
*** '''If patient prioritizes reduction of cancer risk, testicular radiation (18-20 Gy) or orchiectomy is recommended'''
**** '''Radiation'''
***** '''Advantage'''
****** '''Reduced risk of hypogonadism compared to orchiectomy'''
******* '''Leydig cells are radioresistant compared with germinal epithelium.'''
******* Leydig cell function may decline over time, and 40% of men who receive radiation therapy require supplemental testosterone
***** '''Disadvantage'''
****** '''Increased risk of infertility compared to orchiectomy'''
******* '''For patients with a normal contralateral testis who desire future paternity, radical orchiectomy is preferred because scatter to the contralateral testis from radiotherapy may impair spermatogenesis.'''
******* Radiation at these doses causes permanent sterility of the treated testis, but can be delayed in patients who wish to father children.
**** '''Radical orchiectomy'''
***** '''Advantage'''
****** '''Most definitive treatment, although low-dose radiotherapy (≥20 Gy) is associated with similar rates of local control with the prospect of preserving testicular endocrine function'''
** '''If GCNIS is not found on biopsy:'''
*** '''It is highly likely that GCNIS is present outside of the sampled tissue, and the patient should be followed with serial self-testicular exam, ultrasound, and tumor markers as appropriate.'''
* '''Any local recurrence within the ipsilateral testis occurring with or without adjuvant therapy should be managed with completion radical orchiectomy'''

==== Contralateral testis biopsy ====

* An open inguinal biopsy of the contralateral testis may be considered in patients with risk factors for testicular cancer or patients with suspicious lesions on preoperative ultrasound scan

==== Delayed orchiectomy ====

* In a small subset of patients with widespread and/or symptomatic GCT, the diagnosis is made based on biopsy of a metastatic lesion or empirically based on clinical and serologic features. In these unique settings, initiation of systemic chemotherapy supersedes diagnostic orchiectomy. '''Because of high discordance of pathologic response rates within the testicle, a delayed orchiectomy is recommended for all patients with NSGCT after induction chemotherapy, even in the setting of a complete response in the retroperitoneum'''
* The role of delayed orchiectomy is more controversial in patients with presumed primary retroperitoneal/extragonadal GCT.
** Radical orchiectomy has been advocated when the metastatic pattern of retroperitoneal disease lateralizes to the expected distribution of a testicular primary.

=== Post-orchiectomy management ===

* '''<span style="color:#ff0000">Based on histology (seminoma vs. NSGCT) and clinical stage</span>'''

==== General principles ====

* '''<span style="color:#ff0000">Newly elevated and/or rising serum tumor marker levels after orchiectomy indicate the presence of metastatic disease</span>, and these patients should receive induction chemotherapy.'''
* '''In the setting of a negative metastatic evaluation and slowly declining markers (i.e., not according to half-life), patients should be monitored closely and have levels checked periodically until the levels normalize or begin to rise.'''
* '''Surveillance for clinical stage I disease'''
** '''Advantages (1):'''
*** '''Potentially reducing treatment-related toxicity''' by restricting treatment to patients with a proven need for it.
**** '''Radical orchiectomy alone has high cure rate in patients with CSI GCT (80-85% for CS I seminoma and 70-80% for CSI NSGCT)'''
***** '''Patients that relapse on surveillance have excellent outcomes with salvage therapy'''.
** '''Disadvantages (4):'''
**# Highest risk of relapse (compared to adjuvant treatment)
**# Need for long-term (>5 years) surveillance
**# Risk of second malignant neoplasms owing to intensive surveillance CT imaging
**# More intensive therapy required to treat patients at the time of relapse than if they had received treatment at diagnosis
* '''<span style="color:#ff0000">Radiotherapy</span>'''
** '''<span style="color:#ff0000">Seminoma are sensitive to radiation therapy</span>'''
** '''<span style="color:#ff0000">Radiation therapy has no role in NSGCT with the exception of treatment for brain metastases.</span>'''
* '''<span style="color:#ff0000">Chemotherapy</span>'''
** '''<span style="color:#ff0000">International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification</span>'''
*** '''<span style="color:#ff0000">Used</span>''' over the TNM system '''<span style="color:#ff0000">to select the chemotherapy regimen and number of cycles in patients receiving chemotherapy for advanced disease</span>'''
**** '''<span style="color:#ff0000">Developed in patients with metastatic GCT at the time of diagnosis and is NOT applicable to patients with relapsed GCT</span>'''
*** '''<span style="color:#ff0000">Classified into (3): good, intermediate, and poor prognosis</span>'''
***'''<span style="color:#ff0000">Classification based on:</span>'''
****'''<span style="color:#ff0000">NSGCT (3):</span>'''
****# '''<span style="color:#ff0000">Presence of non-pulmonary visceral metastasis</span>'''
****# '''<span style="color:#ff0000">Primary mediastinal NSGCT</span>'''
****# '''<span style="color:#ff0000">TMs at the initiation of chemotherapy (not levels measured before orchiectomy)</span>'''
**** '''<span style="color:#ff0000">Seminoma (1):</span>'''
****# '''<span style="color:#ff0000">Presence of non-pulmonary visceral metastasis</span>'''
****#* '''<span style="color:#ff0000">No poor prognosis category</span>'''

{| class="wikitable"
|'''Histology'''
|'''Good prognosis'''
|'''Intermediate prognosis'''
|'''Poor prognosis''' (II or greater)
|-
|'''Non-seminoma'''
|
* '''Testis/retroperitoneal primary AND'''
* '''No non-pulmonary visceral metastases AND'''
* '''Good markers'''
** AFP < 1000 ng/mL AND
** hCG < 5,000 IU/L (1,000 ng/mL) AND
** LDH < 1.5 x upper limit of normal
** (CSI-IIIa)
|
* '''Testis/retroperitoneal primary AND'''
* '''No non-pulmonary visceral metastases AND'''
* '''Intermediate markers:'''
** AFP≥ 1,000 and ≤ 10,000 ng/mL OR
** hCG ≥ 5,000 IU/L and ≤ 50,000 IU/L OR
** LDH ≥ 1.5 x N and ≤ 10 x N
** (CSIIIb)
|
* '''Mediastinal primary OR'''
* '''Non-pulmonary visceral metastases OR'''
* '''Poor markers:'''
** AFP > 10,000 ng/mL OR
** hCG > 50,000 IU/L (10,000 ng/mL) OR
** LDH > 10 x upper limit of normal
** (CSII or greater)
|-
|'''Seminoma'''
|
* Any primary site AND
* '''No non-pulmonary visceral metastases''' AND
* Normal AFP, any hCG, any LDH
|
* Any primary site AND
* '''Non-pulmonary visceral metastases AND'''
* Normal AFP, any hCG, any LDH
| 
|}

** During chemotherapy, patients need to be monitored on a regular basis with serial tumour marker estimation.
** Post-chemotherapy, radiological restaging should be performed in all patients.
*** If the expected tumour marker decline is seen, all residual masses should be treated appropriately.
*** If the tumour markers plateau and are at a low level, they should be followed closely.
*** If there is a persistent plateau or tumour marker decline, residual masses should be treated appropriately.
** Markedly elevated HCG prior to treatment may take longer to normalize or plateau at the end of chemotherapy
* '''RPLND'''
** See [[Retroperitoneal Lymph Node Dissection|RPLND]] Chapter Notes

==== Seminoma ====

===== CSIA and IB Seminoma =====

* '''<span style="color:#ff0000">Options (3):</span>'''
** '''<span style="color:#ff0000">Preferred (1): surveillance</span>'''
** '''<span style="color:#ff0000">Alternatives (2):</span>'''
**# '''<span style="color:#ff0000">Adjuvant primary radiotherapy (20 Gy to the para-aortic region)</span>'''
**# '''<span style="color:#ff0000">Adjuvant primary chemotherapy with single-agent carboplatin (1 cycle)</span>'''
** '''<span style="color:#ff0000">Both 2019 AUA and 2010 CUA guidelines recommend surveillance, adjuvant as an alternative</span>'''
*** '''If adjuvant treatment is chosen'''
**** '''CUA recommends radiotherapy over chemotherapy'''
**** '''EAU recommends against radiotherapy'''
**** '''SWONTECA recommends radiotherapy only if chemotherapy not suitable'''
** Long-term survival rates approaching 100% for each approach
** '''<span style="color:#ff0000">Surveillance for clinical stage I seminoma</span>'''
*** 80-85% of patients with clinical stage I seminoma achieve cure with radical orchiectomy alone
*** Protocol varies by institution, no consensus
**** History and physical examination: every 4-6 months for the first 2 years, and then every 6-12 months in years 3-5.
**** Cross-sectional imaging of the abdomen with or without the pelvis: every 4-6 months for the first 2 years, and then every 6-12 months in years 3-5.
**** Imaging of the chest and serum tumor marker assessment can be obtained as clinically indicated.
***** Compared with NSGCT, surveillance for CS I seminoma is complicated by the limited utility of serum tumor markers to detect relapse
*** '''<span style="color:#ff0000">Risk factors for relapse on surveillance (2):</span>'''
**** '''<span style="color:#ff0000">Tumor size >4 cm</span>'''
**** '''<span style="color:#ff0000">Rete testis invasion</span>'''
*** Patients who relapse on surveillance should be fully restaged and treated based on their TNM-s status.
** '''Adjuvant primary radiotherapy'''
*** Delivered as dog-leg (retroperitoneum and ipsilateral pelvis) vs. para-aortic region
**** Dog-leg
***** Outcomes
****** In-field recurrence after dog-leg radiotherapy occurs in <1%.
******* Most common sites of recurrence are the thorax and left supraclavicular fossa.
******* Virtually all recurrences are cured with first-line chemotherapy.
****** Persistent oligospermia after dog-leg radiotherapy occurs in 8%
***** Advantage
****** Does not require serial follow-up CT imaging after treatment
**** Para-aortic
***** Advantage
****** Smaller field and dose.
***** Disadvantage
****** Requires serial follow-up CT imaging after treatment
**** Dog-leg vs. para-aortic
***** RTC found para-aortic to be non-inferior to dog-leg radiotherapy in CSI seminoma[https://pubmed.ncbi.nlm.nih.gov/21212385/ §]
** '''Adjuvant primary chemotherapy'''
*** Cisplatin is inferior to carboplatin for CSI seminoma
*** Patients require serial follow-up CT imaging

===== CS IIA and IIB Seminoma =====

* ≈15-20% of patients with seminoma have CS II disease at diagnosis; 70% of these patients have CS IIA and IIB.
* '''<span style="color:#ff0000">CSIIA:</span>'''
** '''CUA: Dog-leg radiotherapy (25-35 Gy) preferred over first-line chemotherapy (BEP×3 or EP×4)'''
** '''AUA: radiotherapy or chemotherapy'''
* '''<span style="color:#ff0000">CSIIB:</span>'''
** '''CUA: depending on bulk of disease and location of lymph nodes, radiation or chemotherapy [good risk chemotherapy BEP×3 or EP×4] can be used.''' 
*** '''First-line chemotherapy is recommended for bulky (>3 cm) and/or multifocal retroperitoneal metastases'''
** '''AUA:'''
*** '''CSIIB with lymph node ≤3cm: radiotherapy or chemotherapy'''
*** '''CSIIB with lymph node >3cm: chemotherapy'''
* Routine surveillance CT imaging is unnecessary after complete resolution of disease.
*'''<span style="color:#ff00ff">Surgery in Early Metastatic Seminoma (SEMS) Trial</span>'''
**Study design: Phase II trial
**55 patients with pure testicular seminoma after radical orchiectomy with isolated retroperitoneal lymphadenopathy 1-3 cm in greatest dimension. 
***No more than 2 lymph nodes could be enlarged radiographically and lymph nodes needed to be within the ipsilateral RPLND template
***Lymph node enlargement could be synchronous (stage IIA or IIB) or metachronous (stage I with recurrence).
***Open RPLND was performed by certified surgeons who performed ≥8 open RPLND surgeries in the year before site initiation or at least 25 open RPLND surgeries with the past 3 years
**Primary outcome: 2-year relapse-free survival
**Results
***Median follow-up after RPLND: 33 months
***In post-RPLND follow-up, one patient received a single cycle of carboplatin for pN2, all other patients were managed with surveillance
***Pathological nodal stage
****pN0: 16%
****pN1: 22%
****pN2: 56%
****pN3: 5%
***2-year relapse-free survival: 81% (86% cN1 vs. 64% cN2, p=0.04)
***2-year overall survival: 100%
**[https://pubmed.ncbi.nlm.nih.gov/36913642/ Daneshmand, Siamak, et al.] "Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy." ''Journal of Clinical Oncology'' (2023): JCO-22.

===== CSIIC and III seminoma =====

* '''Regimen and number of cycles are based on IGCCCG risk classification''' (see above)
** '''Good-risk: BEP×3 or EP×4'''
** '''Intermediate-risk: BEP×4'''

===== Special scenarios =====

====== Residual masses after chemotherapy for seminoma ======
* '''After first-line chemotherapy, 60-80% of patients have radiologically detectable residual masses.'''
* '''<span style="color:#ff0000">Histology of residual masses:</span>'''
** '''<span style="color:#ff0000">Necrosis 90%</span>'''
** '''<span style="color:#ff0000">Viable malignancy: 10%</span>'''
** '''Compared to NSGCT, residual masses after chemotherapy are much more likely to be necrosis (for NSGCT, histology of post-chemotherapy residual masses: necrosis in 40%, viable disease in 15%, and teratoma in 45% (see below)).'''
* '''<span style="color:#ff0000">Management</span>'''
** '''<span style="color:#ff0000">In seminoma, most residual masses do not need to be treated.</span>'''
*** '''Spontaneous resolution of post-chemotherapy residual masses is reported in 50-60% of cases, and the median time to resolution is 13-18 months.'''
*** <span style="color:#ff0000">'''Post-chemotherapy surgery for seminoma is technically difficult'''</span> (and frequently not feasible) because of the desmoplastic reaction that occurs after chemotherapy with resultant increased perioperative morbidity.
*** Teratoma and malignant transformation are much less of a concern with advanced seminoma.
** '''<span style="color:#ff0000">If residual masses > 3 cm, evaluate further with FDG-PET</span>'''
*** '''<span style="color:#ff0000">If FDG-PET positive: post-chemotherapy surgery</span>'''
*** '''<span style="color:#ff0000">If FDG-PET negative: observation.</span>'''
** '''<span style="color:#ff0000">If residual masses< 3 cm: observation.</span>'''
** Post-chemotherapy radiotherapy has no role in the management of residual masses

====== Residual masses after radiotherapy for seminoma ======

* '''Patients should undergo biopsy and histologic confirmation of the suspected lesion before management decisions are made.'''
** '''Although rare, seminoma may transform into NSGCT elements, and this should be considered in patients with metastatic seminoma who fail to respond to conventional therapy.'''
** Either an open or a robotic/laparoscopic biopsy of the para-aortic mass is an acceptable approach if CT-guided biopsy is not feasible or the result is non-diagnostic.
** RPLND should not be performed without histologic confirmation of NSGCT pathology.

====== Relapse of seminoma ======

* '''If chemo-naïve:'''
** '''Patients relapsing on surveillance should receive primary radiotherapy'''
** '''Patients with CSI or II seminoma treated with radiotherapy, or those on surveillance that relapse with bulky''' (>3 cm) '''retroperitoneal masses and systemic relapse should receive first-line chemotherapy based on ICCCG risk category'''
*** Salvage rates approach 100%.
* '''If early relapse after chemotherapy: salvage chemotherapy'''
** An important consideration for patients with advanced seminoma who relapse after first-line chemotherapy is the potential for teratoma at the site of relapse.
** Patients with normal serum tumor markers should undergo biopsy before starting second-line chemotherapy'''.'''

==== NSGCT ====

===== CSIA and IB NSGCT =====

* '''<span style="color:#ff0000">Options:</span>'''
*# '''<span style="color:#ff0000">Surveillance</span>'''
*# '''<span style="color:#ff0000">Adjuvant primary RPLND</span>'''
*# '''<span style="color:#ff0000">Adjuvant primary chemotherapy (BEPx1-2)</span>'''
*#* '''Newer guidelines, such as 2019 AUA guidelines, recommend 1 cycle for CSIA and 2 cycles for CSIB'''
*#* '''2010 CUA Consensus Statement: BEPx2'''
** Long-term survival approaches 100% for each
** '''Guidelines''':
*** '''2010 CUA Consensus Statement: surveillance preferred for all CSI NSGCT'''
*** '''<span style="color:#ff0000">2019 AUA Guidelines:</span>'''
**** '''<span style="color:#ff0000">CSIA NSGCT: surveillance recommended</span>'''
**** '''<span style="color:#ff0000">CSIB NSGCT: all options are recommended</span>'''
**** '''<span style="color:#ff0000">RPLND is recommended if there is any secondary somatic malignancy (e.g. rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor) in the primary tumor</span>'''
* '''<span style="color:#ff0000">Surveillance for clinical stage I NSGCT</span>'''
** 70-80% of patients with clinical stage I seminoma achieve cure with radical orchiectomy alone
** '''<span style="color:#ff0000">Risk factors for relapse on surveillance (2):</span>'''
**# '''<span style="color:#ff0000">Pre-dominant embryonal carcinoma</span>'''
**# '''<span style="color:#ff0000">Lymphovascular invasion</span>'''
*** The definition of EC predominance in the literature varies from 45-90%.
*** Other identified risk factors include advanced pT stage, absence of mature teratoma, absence of yolk sac tumor, presence of EC (regardless of the percent composition), percentage of MIB-1 staining, tumor size, and patient age.
** Surveillance protocol varies by institution, no consensus
*** History and physical examination: every 2-3 months in year 1, every 2-4 months in year 2, every 4-6 months in year 3, and every 6-12 months for years 4 and 5
*** Serum tumor markers (AFP, hCG +/- LDH): every 2-3 months in year 1, every 2-4 months in year 2, every 4-6 months in year 3, and every 6-12 months for years 4 and 5
*** Radiologic assessment (chest x-ray and imaging of the abdomen with or without the pelvis): every 3-6 months in year 1 starting at 3 months, every 4-12 months in year 2, once in year 3, and once in year 4 or 5.
**** Men at higher risk of relapse (e.g., lymphovascular invasion) should be imaged with shorter intervals.
**** >90% of relapses occur within the first 2 years, but late relapses (>5 years) are seen in 1% of patients; after this time, annual serologic and radiographic assessment may be performed as indicated based upon clinical concerns.
***** Compared with NSGCT, surveillance for CS I seminoma is needed for a longer period because 10% to 20% of relapses occur 4 years or more after diagnosis.
** Patients who relapse on surveillance should be fully restaged and treated based on their TNM-s status.
** Early and late relapses have similar prognosis
* '''Adjuvant primary RPLND'''
** Primary RPLND should be performed with curative (rather than staging) intent in all patients.
** Full, bilateral template dissection is associated with the lowest risk of abdominopelvic recurrence (<2%) and the highest rate of antegrade ejaculation (>90%) when nerve-sparing techniques are employed.
** A multi-center randomized trial comparing primary RPLND to chemotherapy for CS I found that chemotherapy was associated with a lower risk of relapse. The relapse rate after primary RPLND in this trial was 11%, higher than other published series, suggesting that RPLND should be performed in experienced centers.
* '''Adjuvant primary chemotherapy'''
** BEP x 1-2 is typically used.
** Advantages (2):
**# '''Highest relapse-free survival with any single treatment modality'''
**# Can be delivered at community-based institutions
** Disadvantages (4):
**# Does not treat retroperitoneal teratoma
**# Long-term surveillance CT imaging of the retroperitoneum is required
**# Potential risk of late toxicity (see below).
**#* The risk of late toxicity from 2 cycles of chemotherapy is poorly defined, although there appears to be no safe lower limit.
**# Exposes patients to the potential for chemoresistant and/or late relapse
**#* Although primary chemotherapy is associated with the lowest risk of relapse, these relapses are less amenable to salvage therapy because they are chemoresistant, particularly if they have received a regimen other than standard dose BEP. In contrast, patients who relapse after RPLND or on surveillance are chemotherapy-naive and are cured with chemotherapy in virtually all cases.

===== CSIS NSGCT =====

* '''<span style="color:#ff0000">Defined as the presence of elevated serum tumor markers after orchiectomy without clinical or radiographic evidence of metastatic disease.</span>'''
* '''Should''' be treated similarly to patients with CS IIC and III and '''receive <span style="color:#ff0000">induction chemotherapy according to IGCCCG classification.</span>'''

===== CS IIA and IIB NSGCT =====

* '''<span style="color:#ff0000">CSIIA with positive markers or CSIIB regardless of markers: primary chemotherapy (recommended by both CUA and AUA)</span>'''
** CUA: Elevated AFP or hCG levels after orchiectomy or bulky lymph nodes (>3cm) are risk factors for recurrence after primary RPLND. Therefore, patients with CS IIA and IIB NSGCT and elevated AFP or hCG levels or bulky lymph nodes (>3 cm) should receive induction chemotherapy.
** AUA: Clinicians may offer RPLND as an alternative to chemotherapy to select patients with clinical stage IIB NSGCT with normal post-orchiectomy serum AFP and hCG.
* '''<span style="color:#ff0000">CSIIA disease without marker elevation</span>'''
** Substantial proportion of men with clinical stage IIA NSGCT are over-staged
** Minority of men with clinical stage IIA are upstaged to pathological stage IIB and may be advised to receive two cycles of adjuvant chemotherapy
** '''<span style="color:#ff0000">CUA: RPLND (with or without adjuvant chemotherapy) or surveillance with surgery for stable or growing lesions (if becomes marker positive use primary chemotherapy)</span>'''
** '''AUA: RPLND or chemotherapy'''
* '''Management after primary RPLND for NSGCT based on pathology (2021 NCCN''' TEST-10'''/2019 AUA):'''
** '''pN0: surveillance'''
** '''pN1: surveillance (preferred) vs. chemotherapy''' (BEP x2 or EP x2)
** '''pN2: chemotherapy''' (BEP x2 or EP x2) '''(preferred) vs. surveillance'''
** '''pN3: chemotherapy''' (BEP x3 or EP x4)
** '''pN1-3 pure teratoma: surveillance'''
** '''<span style="color:#ff00ff">Immediate vs. deferred chemotherapy for pathological stage II disease after primary RPLND</span>'''
*** Population: 195 males found to have positive nodes, (pathologically stage II) after primary RPLND (in whom the procedure was indicated). Nodes had to be considered completely resected and tumor markers had to be normal after primary RPLND.
*** Randomized to immediate vs. delayed chemotherapy (cisplatin/vinblastine/bleomycin +/- dactinomycin/cyclophosphamide)
*** Results:
**** Median follow-up: 4 years
**** Relapse rate at 2 years: 6% immediate vs. 49% delayed chemotherapy
**** Cancer-specific deaths: 1 immediate vs. 3 delayed chemotherapy
**** Death from all causes: 5 immediate vs. 3 delayed chemotherapy
*** Conclusions: immediate chemotherapy in patients found to have pathological stage II after primary RPLND reduces risk of relapse, but no significant difference in cancer-specific or overall survival (though really few deaths)
*** Williams, Stephen D., et al. "[https://pubmed.ncbi.nlm.nih.gov/2446132/ Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer.]" ''New England Journal of Medicine'' 317.23 (1987): 1433-1438.
* '''Disadvantage of chemotherapy for metastatic NSGCT'''
*# '''Teratoma is resistant to chemotherapy'''
** '''RPLND is preferred as initial therapy in patients at risk for retroperitoneal teratoma who are at otherwise low risk for systemic disease''' (normal serum tumor markers, lymphadenopathy <3 cm).
** Unresected teratoma has the potential to exhibit rapid growth (growing teratoma syndrome), undergo malignant transformation, or cause late relapse, all of which may have lethal consequences.
* '''<span style="color:#ff0000">Growing teratoma syndrome</span>'''
** '''<span style="color:#ff0000">Should be considered if there is an expected tumour marker decline during chemotherapy but the metastases are growing radiologically</span>'''
** '''<span style="color:#ff0000">Management</span>'''
*** '''<span style="color:#ff0000">2010 CUA Guidelines: In most cases, the full course of chemotherapy should be completed and resection of the growing and residual masses should be done post-chemotherapy.</span>'''
**** Very rarely, rapid radiological progression in the setting of decreasing tumour marker decline is seen which would necessitate surgical resection prior to the completion of chemotherapy.
***** Similar description in 2018 AUA Update on on Medical and Surgical Management of Advanced Testis Cancer
***** Campbell's 11th edition, Chapter 34, page 805: Special mention is made of patients with declining or normalized serum tumor markers during first-line chemotherapy with enlarging (usually cystic) masses. These patients are considered to have growing teratoma syndrome. In these rare cases, chemotherapy is temporarily interrupted, and patients are taken for surgical resection. With complete surgical resection, the long-term prognosis for these patients is favorable

===== CS IIC and III NSGCT =====

* '''<span style="color:#ff0000">Induction chemotherapy with cisplatin-based regimens</span>'''
** '''<span style="color:#ff0000">Regimen and number of cycles are based on IGCCCG risk classification</span>''' (see above)
*** '''<span style="color:#ff0000">Good risk NSGCT: BEP×3 or EP×4</span>'''
**** 5-year OS is 91-94%
*** '''<span style="color:#ff0000">Intermediate or poor risk NSGCT: BEP×4</span>'''
**** 5-year OS is 79% for intermediate-risk patients and 48% for poor-risk patients.
**** VIP×4 may be substituted for BEP×4 in patients with compromised pulmonary function and in patients in whom extensive chest surgery is likely to be performed to remove residual disease after chemotherapy

===== Special scenarios =====

====== Residual masses after chemotherapy for NSGCT ======

* After receiving first-line cisplatin-based chemotherapy, 5-15% of patients will have partial remission with positive tumour markers or have disease progression.
* '''<span style="color:#ff0000">Management</span>'''
** '''<span style="color:#ff0000">If serum tumour markers elevated after induction chemotherapy, in general patients should receive salvage chemotherapy</span>'''
** ''''<span style="color:#ff0000">If serum tumour markers normal and</span>'''
*** ''''<span style="color:#ff0000">Residual mass >1 cm: resection of residual mass</span>'''
*** ''''<span style="color:#ff0000">Residual mass <1 cm: controversial management</span>'''
** If the mass was retroperitoneal, a full bilateral template RPLND should be performed.
** '''<span style="color:#ff0000">PC-RPLND in NSGCT</span>'''
*** '''<span style="color:#ff0000">Distribution of histology[https://pubmed.ncbi.nlm.nih.gov/2478726/]</span>:'''
***# '''<span style="color:#ff0000">Necrosis/fibrosis (≈40%)</span>'''
***# '''<span style="color:#ff0000">Teratoma (≈45%)</span>'''
***# '''<span style="color:#ff0000">Viable (≈15%) malignancy (with or without teratoma)</span>'''
***#* ≈6-8% of post-chemotherapy surgery specimens contain evidence of non-GCT malignancy arising from malignant transformation of teratoma
**** While those with necrosis could theoretically avoid post-chemotherapy surgery, '''necrosis only in the retroperitoneum cannot be predicted with sufficient accuracy to obviate safely the need for post-chemotherapy surgery in patients with residual masses.'''
***** '''Pure embryonal carcinoma in the primary tumour is the best predictor of fibrosis only in the retroperltoneum'''
**** 90% long-term survival with fibrosis and/or teratoma only at PC-RPLND vs. 50-70% for patients demonstrating viable GCT at PC-RPLND
*** '''<span style="color:#ff0000">If PC-RPLND pathology demonstrates</span>''' (2021 NCCN TEST-12)
**** '''<span style="color:#ff0000">Teratoma or necrosis/fibrosis: surveillance</span>'''
**** '''<span style="color:#ff0000">Viable disease (e.g. residual embryonal carcinoma, yolk sac, choriocarcinoma, seminoma) in PC-RPLND pathology: 2 cycles chemotherapy</span>''' (EP (etoposide/ciplatin), TIP (paclitaxel, ifosfamide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), or VeIP (vinblastine, ifosfamide, cisplatin) [2021 NCCN Guidelines]
* '''<span style="color:#ff0000">FDG-PET has NO role in the assessment of patients with NSGCT and residual masses after chemotherapy</span>'''
* '''Patients with residual masses at multiple anatomic sites (retroperitoneum, chest, and left supraclavicular fossa are the most common) and normal tumour markers should undergo resection of all sites of measurable residual disease.'''
** '''RPLND should be performed before post-chemotherapy surgery at other sites because the probability of residual disease in the retroperitoneum is highest, and RPLND histology is a strong predictor of histology at other sites.''' Therefore, if no disease in retroperitoneum, unlikely to have any disease elsewhere.
*** If RPLND histology shows
**** Viable malignancy, then patient should undergo chemotherapy
**** Fibrosis, then patient should undergo surveillance or resection
**** Teratoma, then patient should undergo resection.

====== Relapsing NSGCT ======

* '''Treatment depends on what treatment the patient previously received and, in certain cases, the location of the relapse.'''
* '''Chemotherapy-naïve:'''
** '''First-line chemotherapy based on ICCCG risk classification'''
** Cure rates > 95%
** Select CS I patients on surveillance who relapse in the retroperitoneum with non-bulky (<3 cm) tumor and normal serum tumor markers may be treated by induction chemotherapy or RPLND (particularly if teratoma was present in the primary tumor)
* '''Relapse after chemotherapy:'''
** '''Salvage-line chemotherapy.'''
** Patients with serologic complete response to second-line chemotherapy with residual masses should undergo surgical resection after salvage chemotherapy.
*** Patients with viable malignancy in post–salvage chemotherapy surgical specimens have a particularly poor prognosis, and their survival is not improved with the use of postoperative chemotherapy.
** In general, late relapse is resistant to chemotherapy, and the outcome is related to the ability to render patients disease-free by complete surgical resection

====== Scrotal exploration ======

* Patients found to have NSGCT in orchiectomy pathology following scrotal exploration require further treatment
** Low-stage NSGCT: wide excision of scrotal scar and removal of spermatic cord.
** High-stage NSGCT: systemic therapy will be given and therefore hemiscrotectomy is not needed

==== Treatment related sequelae ====

* '''Early toxicity'''
** '''Chemotherapy'''
*** '''Cisplatin is associated with fatigue, myelosuppression, infection, peripheral neuropathy, hearing loss, diminished renal function, and death.'''
***'''Etoposide is associated with myelosuppression'''
** '''Radiation'''
*** '''Associated fatigue, nausea and vomiting, leukopenia, and dyspepsia'''
* '''<span style="color:#ff0000">Late toxicity</span>'''
** '''<span style="color:#ff0000">Hypogonadism</span>'''
*** Occurs in
**** 10-20% of patients treated with orchiectomy alone
**** 15-40% of patients treated with radiation therapy
**** 20-25% of patients treated with first-line chemotherapy regimens
*** Serum AM testosterone and luteinizing hormone levels should be measured in patients with signs and symptoms of hypogonadism
** '''<span style="color:#ff0000">Infertility'''
*** Most males are able to have biological children after treatment for GCT but paternity rates are lower for men treated with radiation therapy and/or chemotherapy
** '''<span style="color:#ff0000">Cardiovascular disease</span>'''
*** Risk increased with either subdiaphragmatic radiation or platinum-based chemotherapy
*** Patients should establish regular care with a primary care physician so that modifiable risk factors for cardiovascular disease (e.g., diet, exercise, smoking, serum lipid levels, blood pressure, serum glucose) can be monitored.
** '''<span style="color:#ff0000">Secondary malignancy</span>'''
*** Risk increased with either subdiaphragmatic radiation or platinum-based chemotherapy
*** Patients should establish regular care with a primary care physician for appropriate health care maintenance and cancer screening as appropriate.
** '''<span style="color:#ff0000">Chemotherapy specific'''
*** '''<span style="color:#ff0000">Bleomycin'''
****'''<span style="color:#ff0000">Pulmonary complications (including pulmonary fibrosis)'''
****'''<span style="color:#ff0000">Raynaud phenomenon'''
****'''Mild myelosuppressive effects at high doses.'''
*** '''<span style="color:#ff0000">Cisplatin'''
****'''<span style="color:#ff0000">Nephrotoxicity'''
****'''<span style="color:#ff0000">Neurotoxicity'''
****'''<span style="color:#ff0000">Peripheral neuropathy'''
****'''<span style="color:#ff0000">Hearing loss'''