Editing Germ Cell Tumours (section)

==== 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