NCCN Testicular Cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Testicular Cancer
Version 1.2020 — October 9, 2019
NCCN.org
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Version 1.2020, 10/09/19 © 2019 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Razvan Bardan on 10/22/2019 1:36:27 AM. For personal use only. Not approved for distribution. Copyright © 2019 National Comprehensive Cancer Network, Inc., All Rights Reserved.
NCCN Guidelines Version 1.2020 NCCN Guidelines Index

Table of Contents
Testicular Cancer Discussion
*Timothy Gilligan, MD/Chair † Ellis G. Levine, MD † Kanishka Sircar, MD ≠

Case Comprehensive Cancer Center/ Roswell Park Cancer Institute The University of Texas
University Hospitals Seidman Cancer MD Anderson Cancer Center
Center and Cleveland Clinic Taussig Thomas Longo, MD ω
Cancer Institute Duke Cancer Institute David C. Smith, MD †
University of Michigan Rogel Cancer Center
Daniel W. Lin, MD/Vice-Chair ω Will Lowrance, MD, MPH ω
Fred Hutchinson Cancer Research Center/ Huntsman Cancer Institute Katherine Tzou, MD §
Seattle Cancer Care Alliance at the University of Utah Mayo Clinic Cancer Center
Rahul Aggarwal, MD † ‡ Þ Bradley McGregor, MD † Daniel Vaena, MD ‡

UCSF Helen Diller Family Dana-Farber/Brigham and Women's St. Jude Children’s Research Hospital/
Comprehensive Cancer Center Cancer Center The University of Tennessee
Health Science Center
David Chism, MD, MS † Paul Monk, MD †
Vanderbilt-Ingram Cancer Center The Ohio State University Comprehensive David Vaughn, MD †
Cancer Center - James Cancer Hospital Abramson Cancer Center
Nicholas Cost, MD ω and Solove Research Institute at the University of Pennsylvania
University of Colorado Cancer Center
Joel Picus, MD ‡ Kosj Yamoah, MD, PhD §
Ithaar H. Derweesh, MD ω Siteman Cancer Center at Barnes- Moffitt Cancer Center
UC San Diego Moores Cancer Center Jewish Hospital and Washington
University School of Medicine Jonathan Yamzon, MD ω
Hamid Emamekhoo, MD City of Hope National Medical Center
University of Wisconsin Phillip Pierorazio, MD ω
Carbone Cancer Center The Sidney Kimmel Comprehensive NCCN
Cancer Center at Johns Hopkins Alyse Johnson-Chilla, MS
Darren R. Feldman, MD † Jennifer Keller, MSS
Memorial Sloan Kettering Cancer Center Soroush Rais-Bahrami, MD ω Lenora A. Pluchino, PhD
Daniel M. Geynisman, MD ‡ O'Neal Comprehensive
Fox Chase Cancer Center Cancer Center at UAB
Steven L. Hancock, MD § Þ Philip Saylor, MD †

Massachusetts General Hospital
Stanford Cancer Institute
Cancer Center
‡ Hematology/Hematology oncology
Chad LaGrange, MD ω Þ Internal medicine
Fred & Pamela Buffett Cancer Center † Medical oncology
≠ Pathology
Continue § Radiotherapy/Radiation oncology
ω Urology
NCCN Guidelines Panel Disclosures
* Discussion writing committee member

Table of Contents
NCCN Testicular Cancer Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Workup, Primary Treatment, and Pathologic Diagnosis (TEST-1) with cancer is in a clinical trial.
Pure Seminoma: Postdiagnostic Workup and Clinical Stage (TEST-2) Participation in clinical trials is
• Stage IA, IB (TEST-3) especially encouraged.
• Stage IS (TEST-3)
• Stage IIA, IIB (TEST-4) To find clinical trials online at NCCN
• Stage IIC, III (TEST-4) Member Institutions, click here:
• Postchemotherapy Management (TEST-5) nccn.org/clinical_trials/member_
Nonseminoma: Postdiagnostic Workup and Clinical Stage (TEST-6) institutions.aspx.
• Stage I with and without Risk Factors, Stage IS (TEST-7) NCCN Categories of Evidence and
• Stage IIA, IIB (TEST-8) Consensus: All recommendations
• Postchemotherapy Management (TEST-9) are category 2A unless otherwise
• Postsurgical Management (TEST-10) indicated.
• Stage IS, IIA S1, IIB S1, IIC, IIIA, IIIB, IIIC, and Brain Metastases (TEST-11)
See NCCN Categories of Evidence
• Postchemotherapy Management of Partial and Incomplete Response to Primary Treatment (TEST-12)
and Consensus.
Recurrence and Second-Line Therapy (TEST-13)
Prior Second-Line Therapy; Postchemotherapy Management (TEST-14) NCCN Categories of Preference:
Third-Line Therapy (TEST-15) All recommendations are considered
appropriate.
Follow-up for Seminoma (TEST-A)
Follow-up for Nonseminoma (TEST-B) See NCCN Categories of Preference.
Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C)
Risk Classification for Advanced Disease (TEST-D)
Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E)
Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F)
Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-G)
Principles of Surgery for Germ Cell Tumors (TEST-H)
Principles of Imaging (TEST-I)
Staging (ST-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2019.

Table of Contents
Updates in Version 1.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2019 include:
TEST-1 TEST-5
• Footnotes • Footnote cc added: In rare cases, nonseminomatous elements will
Footnote b modified: Mildly elevated, non-rising AFP levels may be identified, and if they are non-teratomatous then proceed in the
not indicate presence of germ cell tumor. Decisions to treat should same fashion as for viable seminoma above.
not be based on AFP values <20 ng/mL. Further workup should be
considered before initiating treatment for mildly elevated beta-hCG TEST-6
(generally <20 IU/L) since other factors, including hypogonadism • Clinical Stage
and marijuana use, can cause false-positive results. See IS moved from top pathway to bottom pathway
Discussion. • Footnotes
Footnote d added: Consider measuring baseline levels of gonadal Footnote removed: For select cases of clinical stage IIA disease
function. with borderline retroperitoneal lymph nodes, waiting 4–6 weeks
Footnote e added: Inguinal exploration with exposure of testis with and repeating imaging (chest/abdomen/pelvic CT with contrast) to
direct observation and directed biopsy. confirm staging before initiating treatment can be considered.
Footnote hh modified: Risk factors include lymphovascular
TEST-2 invasion or invasion of spermatic cord or scrotum. Some centers
• Footnote m added: The panel recommends staging tumors with consider predominance of embryonal carcinoma as an additional
discontinuous invasion of the spermatic cord as pT3 (high-risk stage risk factor for relapse.
I) and not as M1 (stage III) as is recommended in the 8th edition of
the AJCC Cancer Staging Manual. If surveillance is elected, the pelvis TEST-7
should be included in the imaging due to a higher risk of pelvic • Footnotes
relapses in these patients. See Discussion. Footnote jj added: Retroperitoneal lymph node dissection (RPLND)
is preferred as primary treatment for tumors with transformed
TEST-3 teratoma. Patients with stage I pure teratoma and normal markers
• Primary Treatment should receive either surveillance or RPLND. See Discussion.
Treatment modified: Surveillance for pT1-pT3 tumors (strongly Footnote kk modified: RPLND is recommended within 4 weeks of
preferred) CT scan and 7–10 days of marker measurement.
• RT (20 Gy, preferred or 25.5 Gy)
• Footnotes TEST-8
Footnote u modified: Elevated tumor markers increase the risk of • Footnote mm added: RPLND is preferred as primary treatment
disease outside of the retroperitoneum. Therefore, systemic therapy for stage II tumors with transformed teratoma, and should be
should be encouraged. See Primary Chemotherapy Regimens for considered for stage II tumors with teratoma predominance in
Germ Cell Tumors (TEST-E). patients with normal markers. See Discussion.
Continued
UPDATES

Table of Contents
TEST-11 TEST-15
• Primary Treatment • Third-Line Therapy, top pathway modified: Clinical trial (preferred) or
Response categories modified here and on TEST-12: Incomplete High-dose chemotherapy or Consider surgical salvage if solitary site
Partial response, residual masses with abnormal AFP and/or beta-
hCG levels
• Footnotes TEST-A 1 of 2
Footnote removed: Patients should receive adequate treatment for • Table 1, Clinical Stage I Seminoma: Surveillance After Orchiectomy
brain metastases, in addition to cisplatin-based chemotherapy. Year 2 column for H&P modified: Every 6-12 mo
Footnote removed: Salvage chemotherapy should be reserved Year 2 column for Abdominal ± Pelvic CT modified: Every 6-12 mo
for patients with rising AFP, beta-hCG, or other evidence of
progressive disease. TEST-B 1 of 3
• Table 5, Clinical Stage I without Risk Factors, NSGCT: Active
TEST-12 Surveillance
• Partial response categories added here and on TEST-14: Year 2 column for Abdominal ± Pelvic CT modified: Every 6-12 mo
Elevated and rising AFP and/or beta-hCG levels
Elevated but stable AFP and/or beta-hCG levels TEST-B 2 of 3
Mildly elevated and normalizing AFP and/or beta-hCG levels • Table 8, Clinical Stage II-III NSGCT: Surveillance After Complete
Response to Chemotherapy ± Post-Chemotherapy RPLND
TEST-13 Years 4 and 5 columns for Abdominal ± Pelvic CT added: As
• Recurrence and Second-Line Therapy with prior chemotherapy clinically indicated
This section has significant changes • Footnotes
• Footnotes Footnote f added: Patients who have an incomplete response to
Footnote removed: Examples of systems used to estimate chemotherapy require more frequent imaging than is listed on this
prognosis are: 1) Fossa SD, Cvancarova, Chen L, et al. J Clin Oncol table.
2011;29:963-970; 2) Fedyanin M, Tryakin A, Kanagavel D, et al. Urol Footnote j added: For patients with unresectable residual masses
Oncol 2013;31:499-504; and 3) Masterson TA, Carver BS, Shayegan or resected residual masses containing viable cancer.
B, et al. Urology 2012;79:1079-1084.
Footnote vv modified: Includes best supportive care and palliative TEST B 3 of 3
care. See NCCN Guidelines for Palliative Care. Footnote k modified: Patients who undergo RPLND and are found
to have pN0 disease or pN1 pure teratoma need only 1 CT scan
at postoperative month 3–4 and then as clinically indicated. See
Discussion.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
UPDATES

Table of Contents
TEST-C TEST-G 1 of 3
• General Treatment Information • Third-Line Chemotherapy Regimens for Metastatic Germ Cell
Sub-Bullet 2 modified: All patients, with the exception of those Tumors
who have undergone bilateral orchiectomy, should be treated with Other Recommended Regimens dosing added:
a scrotal shield. The legs should be separated by a rolled towel ◊◊Gemcitabine/paclitaxel/oxaliplatin
of approximately the same diameter as the scrotal shield and its ––Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
stand. ––Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
TEST-D ▪▪Administered on a 21-day cycle for 8 cycles
• Footnote b added: Referral to a high-volume center is recommended ◊◊Gemcitabine/oxaliplatin
for patients with extragonadal germ cell tumors. See Discussion. ––Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1
and 8 followed by
TEST-E ––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
• Primary Chemotherapy Regimens for Germ Cell Tumors ▪▪Administered on a 21-day cycle until disease progression or
Other Recommended Regimens unacceptable toxicity
◊◊Regimen instructions modified: Ifosfamide 1200 mg/m2 on Days ◊◊Gemcitabine/paclitaxel
1–5 with mesna protection ––Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and
15
TEST-F ––Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
• Second-Line Chemotherapy Regimens for Metastatic Germ Cell ▪▪Administered on a 28-day cycle for 6 cycles
Tumors ◊◊Etoposide (oral)
TIP Regimen instructions modified: Ifosfamide 1500 mg/m2 IV ––Etoposide 50–100 mg PO daily on Days 1–21
on Days 2–5 with mesna protection Mesna 300 mg/m2 IV over 15 ▪▪Administered on a 28-day cycle until disease progression or
minutes before ifosfamide, then at 4 and 8 hours from the start of unacceptable toxicity
each ifosfamide dose daily on Days 2–5 Regimens that are Useful in Certain Circumstances dosing added:
VeIP Regimen instructions modified: Mesna 240 mg/m2 IV over 15 ◊◊Pembrolizumab (for MSI-H/dMMR tumors)
minutes before ifosfamide, then at 4 and 8 hours from the start of ––Pembrolizumab 200 mg IV over 30 minutes on Day 1
each ifosfamide dose daily on Days 1–5 Ifosfamide 1200 mg/m2 IV ▪▪Administered on a 21-day cycle until disease progression or
on Days 1–5 with mesna protection unacceptable toxicity
Continued
UPDATES

Table of Contents
TEST-G 2 of 3 TEST-H
• Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumor • Principles of Surgery for Germ Cell Tumors
Preferred Regimens dosing added: Post-Chemotherapy Setting
◊◊Gemcitabine/paclitaxel/oxaliplatin ◊◊Bullet 5 added: Limited data suggest increased frequency
––Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8 of aberrant recurrences with the use of minimally invasive
––Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8 laparoscopic or robotic approaches to RPLND. Therefore,
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1 minimally invasive RPLND is not recommended as standard
▪▪Administered on a 21-day cycle for 8 cycles management at this time.
◊◊Gemcitabine/oxaliplatin • Reference added: Calaway AC, Einhorn LH, Masterson TA, et al.
––Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 Adverse surgical outcomes associated with robotic retroperitoneal
and 8 followed by lymph node dissection among patients with testicular cancer. Eur
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1 Urol 2019 June 4 [Epub ahead of print].
▪▪Administered on a 21-day cycle until disease progression or
unacceptable toxicity
◊◊Gemcitabine/paclitaxel ST-2 and ST-3
––Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and • Changes made on these pages to align with the American Joint
15 Committee on Cancer (AJCC) TNM Staging Classification for Testis
––Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15 Cancer 8th ed, 2017
▪▪Administered on a 28-day cycle for 6 cycles
◊◊Etoposide (oral)
––Etoposide 50–100 mg PO daily on Days 1–21
Regimens that are Useful in Certain Circumstances dosing added:
◊◊Pembrolizumab (for MSI-H/dMMR tumors)
◊◊Pembrolizumab 200 mg IV over 30 minutes on Day 1
• Footnotes
Footnote a added: If VIP or TIP received as second-line therapy,
high-dose chemotherapy is the preferred third-line option.

UPDATES

Table of Contents
WORKUP PRIMARY TREATMENTa PATHOLOGIC DIAGNOSIS
See
• Discuss sperm banking, if Pure seminoma (pure
Postdiagnostic
clinically indicated seminoma histology and AFP
Workup and
• Radical inguinal orchiectomy normal; may have elevated
Clinical Stage
• H&P • Consider inguinal biopsye of beta-hCG)b
(TEST-2)
• Alpha-fetoprotein (AFP)b contralateral testis if:
Suspicious
• beta-hCGb,c Ultrasound showing
testicular
• LDH intratesticular mass concerning Nonseminomatous germ
mass
• Chemistry profiled for testicular cancerf cell tumor (NSGCT) See
• Testicular ultrasound Cryptorchid testis (includes mixed seminoma/ Postdiagnostic
Marked atrophy nonseminoma tumors and Workup and
Suspicious mass seminoma histology with Clinical Stage
• Consider testicular prosthesis elevated AFP)b (TEST-6)
a Though rare, when a patient presents with rapidly increasing beta-hCG or AFP and symptoms related to disseminated disease with a testicular mass, chemotherapy
can be initiated immediately without waiting for a biopsy diagnosis or performing orchiectomy.
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further workup
should be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and marijuana use, can
cause false-positive results. See Discussion.
c Quantitative analysis of beta subunit.
d Consider measuring baseline levels of gonadal function.
e Inguinal exploration with exposure of testis, with direct observation and directed biopsy.
f Biopsies are not recommended for microcalcifications.

TEST-1

Table of Contents
Testicular Cancer - Pure Seminoma Discussion
PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUP CLINICAL STAGE
Stage
IA, IBm
See Primary Treatment
• Abdominal/pelvic CTi and Follow-up (TEST-3)
• Chest x-ray Stage
• Chest CTi if: IS
Pure seminomag Positive abdominal CT or
(pure seminoma histology abnormal chest x-ray
and AFP normal;h may • Repeat beta-hCG, LDH, and AFP
have elevated beta-hCGb) since TNM staging is based on post-
orchiectomy valuesb,j Stage
• Brain MRI,k if clinically indicatedl IIA,n IIB
• Recommend sperm banking, if clinically See Primary Treatment
indicated and Follow-up (TEST-4)
Stage
IIC, IIIm
g Mediastinal primary seminoma should be treated by risk status used for gonadal seminomas with etoposide/cisplatin for 4 cycles or bleomycin/etoposide/cisplatin for
3 cycles.
h If AFP is elevated, treat as nonseminoma.
i With contrast.
j Elevated values should be followed after orchiectomy with repeated determination to allow precise staging. Follow declining markers until normalization or plateau.
Staging is based on marker levels at the time that the patient starts postorchiectomy therapy (for example, for patients starting chemotherapy for disseminated disease,
prognostic category and staging should be assigned based on the serum tumor marker levels on day 1 of cycle 1 of chemotherapy).
k With and without contrast.
l Eg, beta-hCG >5000 IU/L, or extensive lung metastasis.
m The panel recommends staging tumors with discontinuous invasion of the spermatic cord as pT3 (high-risk stage I) and not as M1 (stage III) as is recommended in the
8th edition of the AJCC Cancer Staging Manual. If surveillance is elected, the pelvis should be included in the imaging due to a higher risk of pelvic relapses in these
patients. See Discussion.
n For select cases of clinical stage IIA disease with borderline retroperitoneal lymph nodes, waiting 4–6 weeks and repeating imaging (chest/abdomen/pelvic CT with
contrast) to confirm staging before initiating treatment can be considered.

TEST-2

Table of Contents
CLINICAL PRIMARY TREATMENTo FOLLOW-UP

STAGE
Recurrence, treat
Surveillance for pT1-pT3 tumors according to extent
See Follow-up for Seminoma, Table 1 (TEST-A 1 of 2)
(strongly preferred) of disease at
relapsev
or
Stage Recurrence, treat

Single-agent carboplatinp,q See Follow-up for Seminoma, Table 2 (TEST-A 1 of 2) according to extent
IA, IB (AUC=7 x 1 cycle or AUC=7 x 2 cycles) of disease at
relapsev
or
Recurrence, treat
RTr (20 Gy or 25.5 Gy)s See Follow-up for Seminoma, Table 2 (TEST-A 1 of 2) according to extent
of disease at
relapsev
Repeat elevated serum tumor marker Recurrence, treat
Stage
measurementb and assess with chest/abdominal/ according to extent
IS
pelvic CT (with contrast) to scan for evaluable of disease at
diseaset,u relapsev
q There
are limited long-term follow-up data on the toxicity and efficacy of
carboplatin. A recent population-based study suggested patients with larger
tumors, rete testis involvement, or both derive a smaller reduction in relapse rate
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell with 1 cycle of carboplatin than previously reported. See Discussion.
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further r See Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C).
workup should be considered before initiating treatment for mildly elevated s For stage I seminoma, long-term follow-up studies indicate an increase in late
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and toxicities with radiation treatment. See Discussion.
marijuana use, can cause false-positive results. See Discussion. t For further information on stage IS, see Discussion.
o Discuss sperm banking prior to chemotherapy or radiation treatment. u Elevated tumor markers increase the risk of disease outside of the
p Recommend abdomen/pelvic CT scan and chest x-ray or CT scan within the 4 retroperitoneum. Therefore, systemic therapy should be encouraged. See Primary
weeks prior to the initiation of chemotherapy to confirm staging, even if scan was Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
done previously. See Principles of Imaging (TEST-I). v Patients should not be treated based upon an elevated LDH alone.

TEST-3

Table of Contents
CLINICAL PRIMARY TREATMENTo FOLLOW-UP

STAGEw Recurrence, treat
RT to include para-aortic and ipsilateral See Follow-up for Seminoma,
iliac lymph nodes to a dose of 30 Gyr according to extent of
Table 3 (TEST-A 2 of 2)
Stage disease at relapsev
or
IIA
Primary chemotherapy:z
BEPaa for 3 cycles or EP for 4 cycles
See Post-Chemotherapy
Primary chemotherapy (preferred):z Management and Follow-up (TEST-5)
BEPaa for 3 cycles or EP for 4 cycles
Stage or
IIB RT in select non-bulky (≤3 cm) cases Recurrence, treat
See Follow-up for Seminoma,
to include para-aortic and ipsilateral according to extent of
Table 3 (TEST-A 2 of 2)
iliac lymph nodes to a dose of 36 Gyr disease at relapsev
BEPaa for 3 cycles (category 1)
Good risky
or
EP for 4 cycles (category 1) See Post-Chemotherapy
Stage Management and Follow-up (TEST-5)
IIC, IIIx
Intermediate BEPaa for 4 cycles (category 1) Preferred Regimens
riskw,y or BEP = Bleomycin/etoposide/cisplatin
VIP for 4 cycles EP = Etoposide/cisplatin
Other Recommended Regimens
VIP = Etoposide/ifosfamide/cisplatin
o Discuss sperm banking prior to chemotherapy or radiation treatment.
r See Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C).
v Patients should not be treated based upon an elevated LDH alone. x All stage IIC and stage III seminomas are considered good-risk disease except for
w Intermediate risk in seminoma is based on metastases to organs other than the stage III disease with non-pulmonary visceral metastases (eg, bone, liver, brain),
lungs (stage IIIC). Stage IIIB does not apply to pure seminomas. Patients with which is considered intermediate risk.
elevated AFP have nonseminomas. In patients with a serum beta-hCG >1000 y See Risk Classification for Advanced Disease (TEST-D).
IU/L, consider the possibility of an NSGCT, re-review surgical specimen with z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
pathology, and consider discussion with a high-volume center. LDH and beta-hCG aa Consider a bleomycin-free regimen in patients with reduced or borderline GFR
alone should not be used to stage or risk stratify patients with pure seminoma. and in patients older than 50 years of age.

TEST-4

Table of Contents
STAGE IIA, IIB, IIC, III AFTER PRIMARY POST-CHEMOTHERAPY FOLLOW-UP

TREATMENT WITH CHEMOTHERAPY MANAGEMENT
No residual mass or
Recurrence,
residual mass See Follow-
See Second-Line
≤3 cm and normal Surveillance up for
Therapy (TEST-13)
serum AFP and Seminoma,
beta-hCG Table 3
(TEST-A 2 of
2)
Surveillance See Follow-up for
Seminoma, Table 4
Residual Negative Surveillance (TEST-A 2 of 2)
mass or
• Chest,
abdominal, (>3 cm) Complete 2 cycles adjuvant
pelvic CT and resection chemotherapydd
Consider
scani normal Positive
PET/CT scan
• Serum serum for viable
from skull
tumor AFP and seminomacc
base to mid- Resection of Incomplete
markers beta-hCG
thigh (6 wks residual mass resection Second-line
or more post- Positivebb or chemotherapyee
or
chemotherapy) Biopsy Progression
Negative See Follow-up for

for viable Seminoma, Table 4
seminomacc (TEST-A 2 of 2)
Progressive disease
(growing mass or See Second-Line Therapy (TEST-13) Recurrence,
rising markers) See Second-Line
i With contrast.
Therapy (TEST-13)
bb If PET/CT is borderline, consider surveillance and repeat PET/CT or CT. See Principles of Imaging (TEST-I).
cc In rare cases, nonseminomatous elements will be identified, and if they are non-teratomatous then proceed in the same fashion as for viable seminoma above.
dd If complete resection of all residual disease, consider chemotherapy for 2 cycles (EP or TIP or VIP or VeIP). If resection
incomplete, full course of second-line therapy
is recommended (see TEST-13). If a biopsy is performed and is positive, consider surgery if complete resection is possible or full course of second-line chemotherapy.
ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F).

TEST-5

Table of Contents
Testicular Cancer - Nonseminoma Discussion
PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUPff CLINICAL STAGE
Stage I with and

See Primary Treatment
without risk
(TEST-7)
factorsm,hh
• Chest/abdominal/pelvic CTi
• Repeat beta-hCG, LDH, AFP
NSGCT (includes mixed
because TNM staging is based on
seminoma/nonseminoma See Primary
post-orchiectomy valuesb,j Stage IIA,IIB
tumors and seminoma Treatment (TEST-8)
• Brain MRI,k if clinically indicatedgg
histology with elevated AFP)b
• Recommend sperm banking, if
clinically indicated
Stage IS, IIC, IIIA,m See Primary

IIIB,m IIIC,m and brain Treatment (TEST-11)
metastasis
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell k With and without contrast.
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further m The panel recommends staging tumors with discontinuous invasion of
workup should be considered before initiating treatment for mildly elevated the spermatic cord as pT3 (high-risk stage I) and not as M1 (stage III) as
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and is recommended in the 8th edition of the AJCC Cancer Staging Manual. If
marijuana use, can cause false-positive results. See Discussion. surveillance is elected, the pelvis should be included in the imaging due to a
i With contrast. higher risk of pelvic relapses in these patients. See Discussion.
j Elevated values should be followed after orchiectomy with repeated determination ff PET/CT scan is not clinically indicated for nonseminoma.
to allow precise staging. Follow declining markers until normalization or gg Eg, beta-hCG >5000 IU/L, extensive lung metastasis, choriocarcinoma,
plateau. Staging is based on marker levels at the time that the patient starts neurologic symptoms, non-pulmonary visceral metastasis, or AFP >10,000 ng/mL.
postorchiectomy therapy (for example, for patients starting chemotherapy for hh Risk factors include lymphovascular invasion or invasion of spermatic cord or
disseminated disease, prognostic category and staging should be assigned based scrotum. Some centers consider predominance of embryonal carcinoma as an
on the serum tumor marker levels on day 1 of cycle 1 of chemotherapy). additional risk factor for relapse.

TEST-6

Table of Contents
CLINICAL PRIMARY TREATMENTii,jj

STAGE
Surveillance (preferred) See Follow-up for Nonseminoma,
Table 5 (TEST-B 1 of 3)
or
Stage I without Nerve-sparing RPLNDkk,ll See Postsurgical Management
risk factorshh (TEST-10)
or
Primary chemotherapy:p,z See Follow-up for Nonseminoma,
BEP for 1 cycle Table 7 (TEST-B 2 of 3)
Surveillance See Follow-up for Nonseminoma,

or
Stage I with Primary chemotherapy:p,z See Follow-up for Nonseminoma,

risk factorshh BEP for 1 cycle Table 7 (TEST-B 2 of 3)
or
See Postsurgical Management
Nerve-sparing RPLNDkk,ll
(TEST-10)
Persistent
Stage
marker See Primary Treatment (TEST-11)
IS
elevationb
hh Risk factors include lymphovascular invasion or invasion of spermatic cord or
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell scrotum. Some centers consider predominance of embryonal carcinoma as an
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further additional risk factor for relapse.
workup should be considered before initiating treatment for mildly elevated ii Treatment options listed based on preference. See Discussion.
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and jj Retroperitoneal lymph node dissection (RPLND) is preferred as primary treatment
marijuana use, can cause false-positive results. See Discussion. for tumors with transformed teratoma. Patients with stage I pure teratoma and
p Recommend abdomen/pelvic CT scan and chest x-ray or CT scan within the 4 normal markers should receive either surveillance or RPLND. See Discussion.
weeks prior to the initiation of chemotherapy to confirm staging, even if scan was kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker
done previously. See Principles of Imaging (TEST-I). measurement.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). ll See Principles of Surgery for Germ Cell Tumors (TEST-H).

TEST-7

Table of Contents
CLINICAL STAGE PRIMARY TREATMENT

See Postsurgical
Nerve-sparing RPLNDkk,ll
Management (TEST-10)
or
Markers negative
Primary chemotherapyz: See Postchemotherapy
Stage
BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
IIAmm
Persistent marker
See Primary Treatment (TEST-11)
elevationb
Primary chemotherapy:z See Postchemotherapy

BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
Lymph node metastases,
within lymphatic drainage or
sites
Markers Nerve-sparing RPLNDkk,ll in highly See Postsurgical
negative selected cases Management (TEST-10)
Multifocal, symptomatic, or
Stage Primary chemotherapy:z See Postchemotherapy
lymph node metastases with
IIBmm BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
aberrant lymphatic drainage
Persistent marker elevationb See Primary Treatment (TEST-11)
Preferred Regimens
BEP = Bleomycin/etoposide/cisplatin
EP = Etoposide/cisplatin
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker measurement.
ll See Principles of Surgery for Germ Cell Tumors (TEST-H).
mm RPLND is preferred as primary treatment for stage II tumors with transformed teratoma, and should be considered for stage II tumors with teratoma predominance in
patients with normal markers. See Discussion.

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Table of Contents
POSTCHEMOTHERAPY MANAGEMENT
Negative markers, See Follow-up for

residual mass (≥1 cm) Nerve-sparing bilateral RPLNDkk,ll,nn Nonseminoma, Table 8
on CT scan (TEST-B 2 of 3)
Stage IIA, • Abdominal/pelvic

IIB treated CTi
with primary • Consider chest CTi
chemotherapy or chest x-ray
See Follow-up for
Surveillance Nonseminoma, Table 8
(TEST-B 2 of 3)
Negative markers, no
or
mass, or residual mass
<1 cm on CT scan See Follow-up for
Nerve-sparing bilateral RPLNDkk,ll,nn
Nonseminoma, Table 8
in selected cases (category 2B)
(TEST-B 2 of 3)
i With contrast.
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker measurement.
ll See Principles of Surgery for Germ Cell Tumors (TEST-H).
nn Referral to high-volume centers should be considered for surgical resection of masses post-chemotherapy.

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Table of Contents
POSTSURGICAL MANAGEMENT
See Follow-up for Nonseminoma,

pN0 Surveillance

Surveillance (preferred)
or
Chemotherapy:z
pN1
• BEP for 2 cycles See Follow-up for Nonseminoma,
or Table 9 (TEST-B 3 of 3)
Stage I with and
• EP for 2 cycles
without risk factors,hh
IIA, IIB treated with
primary nerve-sparing
RPLND Chemotherapy (preferred):z
pN2
• EP for 2 cycles
or
Surveillance
Chemotherapy:z
pN3
• EP for 4 cycles
pN1, pN2
Preferred Regimens
EP = Etoposide/cisplatin
BEP = Bleomycin/etoposide/cisplatin
pN3
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). Preferred Regimens
hh Risk factors include lymphovascular invasion or invasion of spermatic cordor scrotum. Some centers BEP = Bleomycin/etoposide/cisplatin
consider predominance of embryonal carcinoma as an additional risk factor for relapse. EP = Etoposide/cisplatin

TEST-10

Table of Contents
CLINICAL PRIMARY TREATMENTpp POST-CHEMOTHERAPY MANAGEMENT

STAGE
Primary If original
Good risky chemotherapy:z stage, Surveillance
Stage IS BEP for 3 cycles stage IS
Complete
Stage IIA, S1 (category 1) response, Surveillance
Stage IIB, S1 or negative If original See
Stage IIC EP for 4 cycles For recurrence,
markers stage, or Follow-up for
Stage IIIA (category 1) See Second-
T any N1-3, Nonseminoma,
Line Therapy
Primary M0-1 Nerve-sparing Table 8
(TEST-13)
chemotherapy:z bilateral (TEST-B 2 of 3)
Intermediate BEP for 4 cyclesqq RPLNDkk,ll,nn
Partial response, in selected cases
risky (category 1)
residual masses (category 2B)
Stage IIIB or
with normal AFP
VIP for 4 cyclesrr
and beta-hCG levels
(category 1)
OR
Primary
chemotherapy:z Partial response, See Post-Chemotherapy Management (TEST-12)
BEP for 4 cycles residual masses
Poor risky,oo (category 1) with abnormal AFP
Stage IIIC or and/or beta-hCG
VIP for 4 cycles in levelsss
selected patientsrr
(category 1)
Preferred Regimens
Brain Primary chemotherapyz ± RT ± surgery, BEP = Bleomycin/etoposide/cisplatin
metastases if clinically indicated EP = Etoposide/cisplatin
y See Risk Classification for Advanced Disease (TEST-D). oo Consider consultation with a high-volume center.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker and any other sites of disease is recommended.
measurement. qq If intermediate risk is based on LDH 1.5–3 times the upper limit of normal, then
ll See Principles of Surgery for Germ Cell Tumors (TEST-H). BEP for 3 cycles can be considered.
nn Referral to high-volume centers should be considered for surgical resection of rr Patients who may not tolerate bleomycin.
masses post-chemotherapy. ss Recommend referral to a high-volume center.

TEST-11

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RESPONSE AFTER POST-CHEMOTHERAPY

PRIMARY TREATMENT MANAGEMENT
Teratoma
Partial response, Surgical Surveillance
or necrosis
residual masses resection of
with normal AFP all residual Residual embryonal,
and beta-hCG levels massesnn yolk sac, Chemotherapy for 2
choriocarcinoma, or cycles (EPtt or TIP or VIP
seminoma element or VeIP)z,ee
Elevated and See Second-Line Therapy

rising AFP and/ (TEST-F)
or beta-hCG
Partial See For
levelsb
response, Follow-up for recurrence,
residual Nonseminoma, See Second-
masses with Elevated but Table 8 Line Therapy
abnormal stable AFP Close surveillance (TEST-B 2 of 3) (TEST-13)
AFP and/or and/or beta-
beta-hCG hCG levelsb
levelsss Teratoma or Surveillance
necrosis
Mildly
elevated and Consider
surgical Residual
normalizing embryonal, yolk
AFP and/ resection of Chemotherapy for 2
all residual sac, chorio-
or beta-hCG carcinoma, cycles (EPtt or TIP or VIP Preferred Regimens
levelsb massesnn or VeIP)z,ee EPtt = Etoposide/cisplatin
or seminoma
TIP = Paclitaxel/ifosfamide/cisplatin
element
VeIP = Vinblastine/ifosfamide/cisplatin
b Mildlyelevated, non-rising AFP levels may not indicate presence of germ cell tumor. ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors
Decisions to treat should not be based on AFP values <20 ng/mL. Further workup (TEST-F).
should be considered before initiating treatment for mildly elevated beta-hCG nn Referral to high-volume centers should be considered for surgical resection of
(generally <20 IU/L) since other factors, including hypogonadism and marijuana use, masses post-chemotherapy.
can cause false-positive results. See Discussion. ss Recommend referral to a high-volume center.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). tt Consider EP for low-volume residual disease.

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RECURRENCEuu SECOND-LINE THERAPYpp,vv
• Clinical trial (preferred)

Early relapse
• Chemotherapyee
(recurrrence ≤2 years
Conventional-dose therapy (VeIP or TIP)
after completion of
High-dose chemotherapy
primary treatment)
• Consider surgical salvage if solitary site
• Recommend sperm banking if clinically indicated
Prior chemotherapy Post Second-Line

Therapy (TEST-14)
• Surgical salvage, if resectable (preferred)

Late relapse • Clinical trial, if unresectable
(recurrence >2 years • Chemotherapyee
after completion of Conventional-dose therapy (VeIP or TIP)
primary treatment) High-dose chemotherapy
• Recommend sperm banking if clinically indicated
Treat per risk status on TEST-11

No prior
and
chemotherapy
Recommend sperm banking
Preferred Regimens
• High-dose chemotherapyee
• TIP = Paclitaxel/ifosfamide/cisplatin
• VeIP = Vinblastine/ifosfamide/cisplatin
ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F).
pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any other sites of disease is recommended.
uu It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative Care.

TEST-13

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RECURRENCEuu POST SECOND-LINE THERAPYpp,vv
Complete Surveillance
response, or
negative markers Nerve-sparing bilateral RPLNDkk,ll,nn
in selected cases (category 2B) Surveillance
Teratoma Surveillance
or necrosis
Partial response, Surgical
residual masses resection of
with normal AFP all residual Residual
Prior embryonal,
second-
and beta-hCG massesnn
levels yolk sac,
line choriocarcinoma, Surveillance
See Follow- For
therapy or seminoma up for
element recurrence,
Nonseminoma, See Third-
Elevated and rising AFP See Third- Table 8 line therapy
and/or beta-hCG levelb Line Therapy (TEST-B 2 of 3) (TEST-15)
(TEST-G)
Partial Elevated but
response stable AFP Close
residual and/or beta- surveillance
masses with hCG levelsb
abnormal Teratoma
AFP and/or or necrosis Surveillance
beta-hCG Mildly Consider
levelsss elevated and surgical
normalizing resection of Residual embryonal,
AFP and/ all residual yolk sac,
or beta-hCG massesnn choriocarcinoma, or Surveillance
levelsb seminoma element
nn Referral to high-volume centers should be considered for surgical resection of masses

b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. post-chemotherapy.
Decisions to treat should not be based on AFP values <20 ng/mL. Further workup should pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any
be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) other sites of disease is recommended.
since other factors, including hypogonadism and marijuana use, can cause false-positive ss Recommend referral to a high-volume center.
results. See Discussion. uu It is preferred that patients with recurrent nonseminoma be treated at centers with
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker expertise in the management of this disease.
measurement. vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative
ll See Principles of Surgery for Germ Cell Tumors (TEST-H). Care.
TEST-14

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RECURRENCEuu THIRD-LINE THERAPYpp,vv
Clinical trial (preferred)

Prior first- and second-line
or
conventional dose chemotherapy
High-dose chemotherapyww
or
Consider surgical salvage if solitary site
Clinical trial (preferred)

or
Conventional dose salvage chemotherapyww
Prior Prior high-dose or
chemotherapy chemotherapy Consider surgical salvage if solitary site
or
MSI/MMR testing if progression after high-dose chemotherapy
or third-line therapyww
Surgical salvage, if resectable (preferred)

Late relapse
or
(recurrence >2 years after
Chemotherapyww
completion of second-
• Conventional-dose therapy
line chemotherapy)
• High-dose chemotherapy (if not previously received)
pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any other sites of disease is recommended.
uu It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative Care.
ww See Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-G).

TEST-15

Table of Contents
FOLLOW-UP FOR SEMINOMA

No single follow-up plan is appropriate for all patients. The follow-up for seminoma tables are to provide guidance, and should be modified for the individual
patient based on sites of disease, biology of disease, and length of time on treatment and may be extended beyond 5 years at the discretion of the
physician. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time
interval from previous studies. Further study is required to define optimal follow-up duration. See NCCN Guidelines for Survivorship.
Table 1 Clinical Stage I Seminoma: Surveillance After Orchiectomy

Year (at month intervals)
1 2 3 4 5d
H&Pa,b Every 3–6 mo Every 6 mo Every 6–12 mo Annually Annually
Abdominal ± At 3, 6, If Recurrence, treat according to

Every 6 mo Every 6–12 mo Every 12–24 mo extent of disease at relapse
Pelvic CTc,e and 12 mo
Chest x-ray As clinically indicated, consider chest CT with contrast in symptomatic patients.
Table 2 Clinical Stage I Seminoma: Surveillance After Adjuvant Treatment (Chemotherapy or Radiation)
1 2 3 4 5d
H&Pa,b Every 6–12 mo Every 6–12 mo Annually Annually Annually
If Recurrence, treat according to

Abdominal ±
Annually Annually Annually —— extent of disease at relapse
Pelvic CTc,e
Chest x-ray As clinically indicated, consider chest CT with contrast in symptomatic patients.
a Serum tumor markers are optional. e Inselect circumstances, an MRI can be considered to replace an abdominal/pelvic CT. The
b Testicular ultrasound for any equivocal exam. MRI protocol should include all the nodes that need to be assessed. The same imaging
c With or without contrast. modality (CT or MRI) should be used throughout surveillance. See Principles of Imaging
d CT is not recommended beyond 5 years unless clinically indicated. (TEST-I).

TEST-A
Version 1.2020, 10/08/19 © 2019 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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FOLLOW-UP FOR SEMINOMA

Table 3 Clinical Stage IIA and Non-Bulky IIB Seminoma: Surveillance After Radiotherapy or Post-Chemotherapyf
1 2 3 4 5d
H&Pa,b Every 3 mo Every 6 mo Every 6 mo Every 6 mo Every 6 mo
Abdominal ± At 3 mo, then If Recurrence, treat according to

Annually Annually As clinically indicated extent of disease at relapse
Pelvic CTe,g at 6–12 mo
Chest x-rayh Every 6 mo Every 6 mo ——
Table 4 Bulky Clinical Stage IIB, IIC, and Stage III Seminoma: Surveillance Post-Chemotherapy
1 2 3 4 5d
H&P and
Every 2 mo Every 3 mo Every 6 mo Every 6 mo Annually
markersb
Abdominal/ As clinically If Recurrence, see TEST-13.

Every 4 mo Every 6 mo Annually Annually
Pelvic CTe,g,h,i,j,k indicated
Chest x-rayh Every 2 mol Every 3 mol Annually Annually Annually
a Serum tumor markers are optional. h Chest

x-ray may be used for routine follow-up, but chest CT with contrast is preferred
b Testicular ultrasound for any equivocal exam. in the presence of thoracic symptoms.
d CT is not recommended beyond 5 years unless clinically indicated. i Patients with PET-negative residual mass measuring >3 cm following chemotherapy
e In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. should undergo an abdominal/pelvic CT scan with contrast every 6 months for the first
The MRI protocol should include all the nodes that need to be assessed. The same year then annually for 5 years.
imaging modality (CT or MRI) should be used throughout surveillance. See Principles j Patients with residual masses may require more frequent imaging based on clinical
of Imaging (TEST-I). judgment.
f Assuming no residual mass or residual mass <3 cm and normal tumor markers. k PET/CT scan of skull base to mid-thigh as clinically indicated.
g With contrast. l Add chest CT with contrast if supradiaphragmatic disease present at diagnosis.

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FOLLOW-UP FOR NONSEMINOMA

No single follow-up plan is appropriate for all patients. The follow-up for nonseminoma tables are to provide guidance, and should be modified for the
individual patient based on sites of disease, biology of disease, and length of time on treatment and may be extended beyond 5 years at the discretion of the
physician. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time
interval from previous studies. Further study is required to define optimal follow-up duration.
Table 5 Clinical Stage I without Risk Factors, NSGCT: Active Surveillance

1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 4–6 mo Every 6 mo Annually
markersa
Abdominal If Recurrence, see TEST-13.
Every 4–6 mo Every 6 mo Annually As clinically indicated
± Pelvic CTb,c
At mo 4 and
Chest x-rayd Annually Annually Annually Annually
12
Table 6 Clinical Stage I with Risk Factors, NSGCT: Active Surveillance

1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 4–6 mo Every 6 mo Annually
markersa
Abdominal As clinically If Recurrence, see TEST-13.

Every 4 mo Every 4–6 mo Every 6 mo Annually
± Pelvic CTb,c indicated
As clinically
Chest x-rayd Every 4 mo Every 4–6 mo Every 6 mo Annually
indicated
a Testicular ultrasound for any equivocal exam.

b With contrast.
c In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. The MRI protocol should include all the nodes that need to be assessed. The
same imaging modality (CT or MRI) should be used throughout surveillance. See Principles of Imaging (TEST-I).
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is preferred in the presence of thoracic symptoms.

TEST-B
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Table 7 Clinical Stage IA/B NSGCT: Treated with 1 Cycle of Adjuvant BEP Chemotherapy or Primary RPLND
1 2 3 4 5
H&P and
markersa
Abdominal ± If Recurrence, see TEST-13.

Annually Annuallye — — —
Pelvic CTb,c
Chest x-rayd Every 6–12 mo Annually — — —
Table 8 Clinical Stage II–III NSGCT: Surveillance After Complete Response to Chemotherapy ± Post-chemotherapy RPLNDf
1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 6 mo Every 6 mo Every 6 mo
markera
Abdominal ±
Every 6 mo Every 6–12 mo Annually As clinically indicatedj
Pelvic CTb,c,g If Recurrence, see TEST-13.
Chest x-rayd,h Every 6 mo Every 6 mo Annuallyi Annuallyi —
a Testicular ultrasound for any equivocal exam.

b With contrast. e Optional for patients treated with primary RPLND.
c In select circumstances, an MRI can be considered to replace an abdominal/ g Patients with clinicalstage II disease treated with chemotherapy who undergo
pelvic CT. The MRI protocol should include all the nodes that need to be post-chemotherapy RPLND and are found to have pN0 disease or pN1 pure
assessed. The same imaging modality (CT or MRI) should be used throughout teratoma need only 1 CT scan at postoperative month 3–4 and then as clinically
surveillance. See Principles of Imaging (TEST-I). indicated. See Discussion.
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is h Chest CT with contrast if supradiaphragmatic disease at baseline.
preferred in the presence of thoracic symptoms. i Chest x-ray is optional at months 36 and 48.
f Patients who have an incomplete response to chemotherapy require more j For patients with unresectable residual masses or resected residual masses
frequent imaging than is listed on this table. containing viable cancer.

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Table 9 Pathologic Stage IIA/B NSGCT: Post-Primary RPLND and Treated with Adjuvant Chemotherapy
1 2 3 4 5
H&P and
Every 6 mo Every 6 mo Annually Annually Annually
markersa
Abdominal/ 4 mo after
As clinically indicated If Recurrence, see TEST-13.
Pelvic CTb,c,k RPLND
Chest x-rayd Every 6 mo Annually Annually Annually Annually
Table 10 Pathologic Stage IIA/B NSGCT: Post-Primary RPLND and NOT Treated with Adjuvant Chemotherapyl
1 2 3 4 5
H&P and
markersa
Abdominal/ If Recurrence, see TEST-13.

At 3–4 mom Annually As clinically indicated
Pelvic CTb,c
Every 3–6
Chest x-rayd Every 2–4 mo Annually Annually Annually
mo
a Testicular ultrasound for any equivocal exam. k Patients who undergo RPLND and are found to have pN0 disease or pN1 pure
b With contrast. teratoma need only 1 CT scan at postoperative month 3–4 and then as clinically
c In select circumstances, an MRI can be considered to replace an abdominal/ indicated. See Discussion.
pelvic CT. The MRI protocol should include all the nodes that need to be l Patients with clinical stage IIA/IIB nonseminoma who undergo primary RPLND
assessed. The same imaging modality (CT or MRI) should be used throughout and are found to have pN0 disease (no tumor or teratoma, pathologic stage I)
surveillance. See Principles of Imaging (TEST-I). should revert to the surveillance schedule for low-risk NSGCT with the exception
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is that only 1 CT scan is needed postoperatively around month 4 (Table 5).
preferred in the presence of thoracic symptoms. m This schedule assumes a complete resection has taken place.

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PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

General Principles
• Modern radiotherapy involves smaller fields and lower doses than were used in the past. References are provided to support current
recommended management.
• The mean dose (Dmean) and dose delivered to 50% of the volume (D50%) of the kidneys, liver, and bowel are lower with CT-based
anteroposterior-posteroanterior (AP-PA) three-dimensional conformal radiation therapy (3D-CRT) than intensity-modulated radiation therapy
(IMRT).1 As a result, the risk of second cancers arising in the kidneys, liver, or bowel may be lower with 3D-CRT than IMRT, and IMRT is not
recommended.2
• Timing of Radiotherapy:
Radiotherapy should start once the orchiectomy wound has fully healed.
Patients should be treated 5 days per week.
Patients who miss a fraction should be treated with the same total dose and with the same fraction size, extending the overall treatment
time slightly.
• Antiemetic medication significantly improves nausea. See the NCCN Guidelines for Antiemesis. Antiemetic prophylaxis is encouraged at
least 2 hours prior to each treatment, and some cases may require more frequent dosing.
Preparation for Radiotherapy

• A discussion of semen analysis and sperm banking prior to orchiectomy is recommended in patients who wish to preserve fertility.3,4
• If sperm banking is desired, it should be performed prior to imaging and the delivery of adjuvant therapy.
General Treatment Information

• Treatment Planning Principles
A non-contrast CT simulation should be performed with the patient supine, arms at his sides, in the treatment position.
◊◊Immobilization with a cast may be used to improve the reproducibility of patient setup.
◊◊All patients, with the exception of those who have undergone bilateral orchiectomy, should be treated with a scrotal shield.
Stage I (TEST-C 2 of 5)
Stage IIA, IIB (TEST-C 3 of 5)
References
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Stage I
• Dose: For stages IA, IB: Recommended radiation dose regimens are listed in the table below for the minority of patients who prefer adjuvant
treatment, realizing that there is a high likelihood of salvage should a relapse occur during surveillance.5
Table 1
Total Dose (Gy) Dose per Fraction (Gy) Number of Fractions
20 (preferred) 2.0 10
25.5 1.5 17
19.8 1.8 11
21.6 1.8 12
• Para-aortic (PA)-Strip Fields6 - Field Arrangement:
In patients with no history of pelvic or scrotal surgery, para-aortic strip irradiation may be delivered with opposed AP-PA fields. The weights
of the fields may be equal.
◊◊Recent nodal mapping studies suggest that fields should target the retroperitoneal lymph nodes but not necessarily the ipsilateral renal
hilar nodes (see Lateral borders).7,8
◊◊Superior and inferior borders: Borders may be determined by bony anatomy.
◊◊The superior border should be placed at the bottom of vertebral body T-10/11 T10/T11.9
◊◊The inferior border should be placed at the inferior border of vertebral body L-5 L5.6,10
◊◊Lateral borders:
◊◊Conventionally, PA-strip fields are approximately 10 cm wide, encompassing the tips of the transverse processes of the PA vertebrae.
◊◊The location of the kidneys within the PA-strip fields varies from patient to patient.
▪▪For patients whose kidneys are relatively medial, small renal blocks may be added at the level of T12. The right and left kidney D50%
should be ≤8 Gy (ie, no more than 50% of each kidney can receive 8 Gy or higher).1 If only one kidney is present, the kidney D15%
should be ≤20 Gy (ie, no more than 15% of the volume of the kidney can receive 20 Gy or higher).1
▪▪An alternative 3D-CRT planning technique is to base the lateral borders on vascular structures on a treatment planning CT scan
without contrast. The aorta and inferior vena cava (IVC) may be contoured on the CT scan; one should allow a 1.2- to 1.9-cm margin
on the aorta and IVC to include the para-aortic, paracaval, interaortocaval, and preaortic nodes in the clinical target volume.7,11
The planning target volume is then established by uniformly expanding the clinical target volume by 0.5 cm in all directions to
account for treatment setup errors.12 A uniform 0.7-cm margin should be provided on the planning target volume to the block edge to
take beam penumbra into account (Figure 1, see TEST-C 4 of 5).1
Special Considerations
• Ipsilateral pelvic surgery (eg, inguinal herniorrhaphy or orchiopexy) may alter the lymphatic drainage of the testis. As a result, irradiation of
the ipsilateral iliac and inguinal lymph nodes, including the surgical scar from prior surgery, has been advocated even in stage I patients.8,13
Stage IIA-IIB (TEST-C 3 of 5)
References
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Stage II PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

• Patients should not receive primary RT if they have a horseshoe (pelvic) kidney, inflammatory bowel disease, or a history of RT.
• For clinical stage IIA–B patients, treatment is delivered in two consecutive AP-PA phases (modified dog-leg fields and cone down). There is
no break between the 2 phases.
• Modified Dog-Leg Fields:
Dose:
◊◊The initial phase consists of treatment of modified dog-leg fields to 20–25.5 Gy (see Table 1 on TEST-C 2 of 5 for dose fractionation
options).
◊◊Boost gross disease to achieve a total dose of approximately:
Table 2: Boost to Gross Disease
Stage Total Dose (Gy) Dose per Fraction (Gy)
IIA 30 1.8–2.0 Gy per fraction
IIB 36 1.8–2.0 Gy per fraction
Target: The fields should include the retroperitoneal and proximal ipsilateral iliac lymph nodes.
◊◊Modified dog-leg fields as described by Classen et al are preferred.14
◊◊Care should be taken to ensure coverage of the ipsilateral common, external, and proximal internal iliac lymph nodes down to the top of
the acetabulum.
◊◊The fields can be set up using bony landmarks or by contouring the vascular structures, as for stage I.
▪▪The superior border should be placed at the bottom of vertebral body T10/T11.15
▪▪The inferior border should be placed at the top of the acetabulum.14
▪▪The medial border for the lower aspect of the modified dog-leg fields extends from the tip of the contralateral transverse process of
the fifth lumbar vertebra toward the medial border of the ipsilateral obturator foramen.
▪▪The lateral border for the lower aspect of the modified dog-leg fields is defined by a line from the tip of the ipsilateral transverse
process of the fifth lumbar vertebra to the superolateral border of the ipsilateral acetabulum.
▪▪Preferably, one should contour the aorta and IVC from the bottom of the T10/T11 vertebra inferiorly and ipsilateral iliac arteries and
veins down to the top of the acetabulum. One should provide a 1.2- to 1.9-cm margin on these vascular structures for the clinical
target volume.7,11 The planning target volume is then established by uniformly expanding the clinical target volume by 0.5 cm in all
directions to account for treatment setup errors.12 A uniform 0.7-cm margin should be provided on the planning target volume to the
block edge to take beam penumbra into account (Figure 2, see TEST-C 4 of 5).1
▪▪It is not necessary to include the ipsilateral inguinal nodes or the inguinal scar in the AP-PA fields unless the patient has a history of
ipsilateral pelvic surgery (eg, inguinal herniorrhaphy or orchiopexy).
• Cone Down:
Dose: The second phase (cone down) of the radiotherapy consists of daily 1.8–2 Gy fractions to a cumulative total dose of approximately
30 Gy for stage IIA and 36 Gy for stage IIB.14
Target: The nodal mass (gross tumor volume) must be contoured. A uniform, 2-cm margin from the gross tumor volume to block edge
should be provided for the AP-PA cone down fields. (Figure 3, see TEST-C 4 of 5).
Note: All recommendations are category 2A unless otherwise indicated. References
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Treatment Modalities
• Linear accelerators with >6 MV photons should be used when possible.
Target Volumes by Stage (or location)

Figure 1: Figure 2: Figure 3:
Stage I RT Field Stage II RT Large Field Stage II Cone-down Field
Stage IIA, IIB (TEST-C 3 of 5)
References
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REFERENCES
1 Zilli T, Boudreau C, Doucet R, et al. Bone marrow-sparing intensity-modulated radiation therapy for Stage I seminoma. Acta Oncol 2011;50:555-562.
2 Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56:83-88.
3 Ragni G, Somigliana E, Restelli L, et al. Sperm banking and rate of assisted reproduction treatment: insights from a 15-year cryopreservation program for male cancer
patients. Cancer 2003;97:1624-1629.
4 Saito K, Suzuki K, Iwasaki A, et al. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005;104:521-524.
5 Garmezy B, Pagliaro LC. Choosing treatment for stage I seminoma: who should get what? Oncology (Williston Park) 2009;23:753-759.
6 Fossa SD, Horwich A, Russell JM, et al. Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical
Research Council Testicular Tumor Working Group. J Clin Oncol 1999;17:1146.
7 Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance
imaging. Int J Radiat Oncol Biol Phys 2009;74:844-851.
8 McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology 2010;254:31-46.
9 Bruns F, Bremer M, Meyer A, et al. Adjuvant radiotherapy in stage I seminoma: is there a role for further reduction of treatment volume? Acta Oncol 2005;44:142-148.
10 Classen J, Schmidberger H, Meisner C, et al. Para-aortic irradiation for stage I testicular seminoma: results of a prospective study in 675 patients. A trial of the
German testicular cancer study group (GTCSG). Br J Cancer 2004;90:2305-2311.
11 Shih
HA, Harisinghani M, Zietman AL, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvic nodal
irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63:1262-1269.
12 Boujelbene N, Cosinschi A, Khanfir K, et al. Pure seminoma: a review and update. Radiat Oncol 2011;6:90.
13 Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research
Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 2005;23:1200-1208.
14 Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol
2003;21:1101-1106.
15 Paly JJ, Efstathiou JA, Hedgire SS, et al. Mapping patterns of nodal metastases in seminoma: rethinking radiotherapy fields. Radiother Oncol 2013;106:64-68.

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RISK CLASSIFICATION FOR ADVANCED DISEASE

(post-orchiectomy)a
Risk Status Nonseminoma Seminoma

Good Risk Testicular or retroperitoneal primary Any primary site
tumorb and
and No nonpulmonary visceral metastases
No nonpulmonary visceral metastases and
and Normal AFP
Post-orchiectomy markers- all of: Any hCG
AFP < 1,000 ng/mL Any LDH
hCG < 5,000 iu/L
LDH < 1.5 x upper limit of normal
Intermediate Testicular or retroperitoneal primary Any primary site
Risk tumorb and
and Nonpulmonary visceral metastases
No nonpulmonary visceral metastases and
and Normal AFP
Post-orchiectomy markers- any of: Any hCG
AFP 1,000–10,000 ng/mL Any LDH
hCG 5,000–50,000 iu/L
LDH 1.5–10 x upper limit of normal
Poor Risk Mediastinal primary tumorb No patients classified as poor
or prognosis
Nonpulmonary visceral metastases
or
Post-orchiectomy markers- any of:
AFP > 10,000 ng/mL
hCG > 50,000 iu/L
LDH > 10 x upper limit of normal
Source: Figure 4 from the International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus
Classification: A Prognostic Factor-Based Staging System for Metastatic Germ Cell Cancers. J Clin Oncol
1997;15(2):594-603. Reprinted with permission of the American Society of Clinical Oncology.
a Markers used for risk classification are post-orchiectomy.

b Referral to a high-volume center is recommended for patients with extragonadal germ cell tumors. See Discussion.

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PRIMARY CHEMOTHERAPY REGIMENS FOR GERM CELL TUMORS

Preferred Regimens
• BEP
Etoposide 100 mg/m2 IV on Days 1–5
Cisplatin 20 mg/m2 IV on Days 1–5
Bleomycin 30 units IV weekly on Days 1, 8, and 15 or Days 2, 9, and 16
Repeat every 21 days1
• EP
(Option only for good-risk patients [see TEST-D], patients with pathologic stage II disease, and patients with viable germ cell tumor at
surgery following first-line chemotherapy)

• VIP3
(Option only for intermediate or poor-risk patients or patients with viable germ cell tumor at surgery following first-line chemotherapy
[See TEST-5 and TEST-11])
Ifosfamide 1200 mg/m2 on Days 1–5 with mesna protection
1 Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-
prognosis germ-cell tumors: The Indiana University Experience. J Clin Oncol 1998;16:702-706.
2 Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol 1997;15:2553-
2558.
3 VIP: This regimen is high risk for febrile neutropenia and granulocyte colony-stimulating factors (G-CSFs) should be used (See NCCN Guidelines for Hematopoietic
Growth Factors).
4 Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced
disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol
1998;16:1287-1293.

TEST-E

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SECOND-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS
Conventional-Dose Chemotherapy Regimens High-Dose Chemotherapy Regimens
Preferred Regimens Preferred Regimens

• TIP1 • Carboplatin/etoposide
Paclitaxel 250 mg/m2 IV on Day 1 Carboplatin 700 mg/m2 (body surface area) IV
Ifosfamide 1500 mg/m2 IV on Days 2–5 with mesna protection Etoposide 750 mg/m2 IV
Cisplatin 25 mg/m2 IV on Days 2–5 Administer 5, 4, and 3 days before peripheral blood stem cell infusion for
Repeat every 21 days2 2 cycles4
• VeIP1 • Paclitaxel/ifosfamide/carboplatin/etoposide
Vinblastine 0.11 mg/kg IV Push on Days 1–2 Paclitaxel 200 mg/m2 IV over 24 hours on Day 1
Ifosfamide 1200 mg/m2 IV on Days 1–5 with mesna protection Ifosfamide 2000 mg/m2 over 4 hours with mesna protection on Days 2–4
Cisplatin 20 mg/m2 IV on Days 1–5 Repeat every 14 days for 2 cycles followed by
Repeat every 21 days3 Carboplatin AUC 7–8 IV over 60 minutes on Days 1–3
Administer with peripheral blood stem cell support at 14- to 21-day
intervals for 3 cycles5
1 TIP, VeIP: These regimens are high risk for febrile neutropenia and G-CSFs should be used (See NCCN Guidelines for Hematopoietic Growth Factors).
2 Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular
germ cell tumors. J Clin Oncol 2005;23:6549-6555.
3 Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med
1988;109:540-546
4 Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340-348.
5 Feldman DR, Sheinfeld J, Bajorin DF et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
J Clin Oncol 2010;28:1706-1713.

TEST-F

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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORSa

High-Dose Chemotherapy NOT Previously Received
Preferred Regimens (High-Dose Chemotherapy)
• Carboplatin/etoposide
Carboplatin 700 mg/m2 (body surface area) IV
Etoposide 750 mg/m2 IV
Administered 5, 4, and 3 days before peripheral blood stem cell infusion for 2 cycles1
• Paclitaxel/ifosfamide/carboplatin/etoposide
Paclitaxel 200 mg/m2 IV over 24 hours on Day 1
Ifosfamide 2000 mg/m2 over 4 hours with mesna protection on Days 2–4
Repeat every 14 days for 2 cycles followed by
Carboplatin AUC 7–8 IV over 60 minutes on Days 1–3
Administered with peripheral blood stem cell support at 14- to 21-day intervals for 3 cycles2
• Gemcitabine/paclitaxel/oxaliplatin3
Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
Administered on a 21-day cycle for 8 cycles
• Gemcitabine/oxaliplatin4-6
Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 and 8
followed by
Administered on a 21-day cycle until disease progression or unacceptable toxicity
• Gemcitabine/paclitaxel7,8
Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and 15
Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
• Etoposide (oral)9
Etoposide 50–100 mg PO daily on Days 1–21
Useful in Certain Circumstances
• Pembrolizumab (for MSI-H/dMMR tumors)10,11
Pembrolizumab 200 mg IV over 30 minutes on Day 1
a If VeIP or TIP received as second-line therapy, high-dose chemotherapy is the preferred third-line option.

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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORSa

High-Dose Chemotherapy Previously Received
Preferred Regimens
• Gemcitabine/paclitaxel/oxaliplatin3
Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
• Gemcitabine/oxaliplatin4-6
Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 and 8
followed by
• Gemcitabine/paclitaxel7,8
Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and 15
Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
• Etoposide (oral)9
Etoposide 50–100 mg PO daily on Days 1–21
Useful in Certain Circumstances

• Pembrolizumab (for MSI-H/dMMR tumors)10,11
Pembrolizumab 200 mg IV over 30 minutes on Day 1
a If VeIP or TIP received as second-line therapy, high-dose chemotherapy is the preferred third-line option.

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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS

REFERENCES
1 Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340-348.
2 Feldman DR, Sheinfeld J, Bajorin DF et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
J Clin Oncol 2010;28:1706-1713.
3 Bokemeyer C, Oechsle K, Honecker F, et al; German Testicular Cancer Study Group. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in
patients with cisplatin-refractory or multiply relapsed germ-cell tumors: A study of the German Testicular Cancer Study Group. Ann Oncol 2008;19:448-453.
4 Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol
2004;15:493-497.
5 Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell
cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol 2004;22:108-114.
6 De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ
cell tumor. Eur Urol 2006;50:1032-1038.
7 Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following
high-dose chemotherapy with tandem transplant. J Clin Oncol 2007;25:513-516.
8 Mulherin BP, Brames MJ, Einhorn LH. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with
tandem transplant. Am J Clin Oncol 2015;38:373-376.
9 Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 1990;17:36-39.
10 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.
11 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.

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PRINCIPLES OF SURGERY FOR GERM CELL TUMORS
• RPLND is the standard approach to the surgical management of NSGCTs in both the primary and post-chemotherapy setting. Referral to
high-volume centers with experience in performing RPLNDs should be considered.
• A template dissection or a nerve-sparing approach to minimize the risk of ejaculatory disorders should be considered in patients undergoing
primary RPLND for stage I nonseminoma.
• The “split and roll” technique in which lumbar vessels are identified and sequentially ligated allows resection of all lymphatic tissue around
and behind the great vessels (ie, aorta, IVC) and minimizes the risk of an in-field recurrence.
Post-Chemotherapy Setting
• Referral to high-volume centers should be considered for surgical resection of masses post-chemotherapy.
• Completeness of resection is a consistent independent predictor of clinical outcome. In post-chemotherapy RPLND, surgical margins should
not be compromised in an attempt to preserve ejaculation. Additional procedures and resection of adjacent structures may be required.
• Post-chemotherapy RPLND is indicated in patients with metastatic NSGCT with a residual retroperitoneal mass following systemic
chemotherapy and normalized post-chemotherapy serum tumor markers.
• A full bilateral template RPLND should be performed in all patients undergoing RPLND in the post-chemotherapy setting, with the boundaries
of dissection being the renal hilar vessels (superiorly), ureters (laterally), and the common iliac arteries (inferiorly).
• Limited data suggest increased frequency of aberrant recurrences with the use of minimally invasive laparoscopic or robotic approaches to
RPLND. Therefore, minimally invasive RPLND is not recommended as standard management at this time.1
1 Calaway AC, Einhorn LH, Masterson TA, et al. Adverse surgical outcomes associated with robotic retroperitoneal lymph node dissection among patients with testicular
cancer. Eur Urol 2019 June 4 [Epub ahead of print].

TEST-H

Table of Contents
PRINCIPLES OF IMAGING
Staging
Pure Seminoma and Nonseminoma
• Abdominal/pelvic CT scan with contrast and chest x-ray or CT scan is recommended within 4 weeks prior to the initiation of chemotherapy to
confirm staging, even if scan was performed previously. (TEST-3, TEST-7)
Chest CT should be performed if abdominal/pelvic CT or chest x-ray is abnormal.
Treatment Response Assessment

Pure Seminoma
• Consider PET/CT scan (skull base to mid-thigh) for a residual mass >3 cm post primary chemotherapy. (TEST-5)
• PET/CT scan should be performed at least 6 weeks following completion of chemotherapy.
A negative PET/CT following chemotherapy is very reassuring. If PET/CT scan is positive, resection or interventional radiology-guided
biopsy should be considered. An alternative is to wait an additional 8–12 weeks and repeat PET/CT scan to assess for changes. If the mass
is persistently FDG-avid on PET, then resection or biopsy is recommended.
Surveillance
Pure Seminoma and Nonseminoma (TEST-A and TEST-B)
• MRI with contrast can be considered in select circumstances in place of an abdominal/pelvic CT.
MRI protocol should include visualization of retroperitoneal and pelvic nodes.
• Use the same imaging modality (CT or MRI) throughout surveillance.
• In stage I seminoma and nonseminoma, chest x-rays should be obtained when abdominal/pelvic CT scans are performed. Additional chest
imaging is not indicated under normal circumstances. In a retrospective review of nearly 560 patients, 76 patients relapsed with only four
patients having disease in the chest, one of whom had an abnormal chest x-ray (but also in the setting of an elevated AFP).1 Similar data
from Daugaard et al showed no role for chest x-ray in detecting relapse.2 Other series have also called into question the value of chest
x-rays in this and other surveillance settings for germ cell tumors.3,4
1 De La Pena H, Sharma A, Glicksman C, et al. No longer any role for routine follow-up chest x-rays in men with stage I germ cell cancer. Eur J Cancer 2017;84:354-
359.
2 Daugaard G, Gundgaard MG, Mortensen MS, et al. Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based
cohort. J Clin Oncol 2014;32:3817-3823.
3 Tolan S, Vesprini D, Jewett MA, et al. No role for routine chest radiography in stage I seminoma surveillance. Eur Urol 2010;57:474-479.
4 Gietema JA, Meinardi MT, Sleijfer DT, et al. Routine chest X-rays have no additional value in the detection of relapse during routine follow-up of patients treated with
chemotherapy for disseminated non-seminomatous testicular cancer. Ann Oncol 2002;13:1616-1620.

TEST-I

Table of Contents
American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Testis Cancer 8th ed., 2017
Table 1. Definitions for T, N, M

Clinical T Primary Tumor
cTX Primary tumor cannot be assessed
cT0 No evidence of primary tumor
cTis Germ cell neoplasia in situ
cT4 Tumor invades scrotum with or without vascular/lymphatic invasion
Note: Except for Tis confirmed by biopsy and T4, the extent of the primary tumor is classified
by radical orchiectomy. TX may be used for other categories for clinical staging.
Pathological T Primary Tumor

pTX Primary tumor cannot be assessed
pT0 No evidence of primary tumor
pTis Germ cell neoplasia in situ
pT1 Tumor limited to testis (including rete testis invasion) without lymphovascular invasion
pT1a* Tumor smaller than 3 cm in size
pT1b* Tumor 3 cm or larger in size
pT2 Tumor limited to testis (including rete testis invasion) with lymphovascular invasion
OR
Tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer
covering the external surface of tunica albuginea with or without lymphovascular invasion
pT3 Tumor directly invades spermatic cord soft tissue with or without lymphovascular invasion
pT4 Tumor invades scrotum with or without lymphovascular invasion
*Subclassification of pT1 applies to only pure seminoma.
Continued
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
ST-1

Table of Contents

Table 1 (continued)
Clinical N Regional Lymph Nodes M Distant Metastasis
cNX Regional lymph nodes cannot be assessed M0 No distant metastases
cN0 No regional lymph node metastasis M1 Distant metastases
cN1 Metastasis with a lymph node mass 2 cm or smaller in greatest M1a Non-retroperitoneal nodal or pulmonary metastases
dimension
OR M1b Non-pulmonary visceral metastases
Multiple lymph nodes, none larger than 2 cm in greatest
dimension
cN2 Metastasis with a lymph node mass larger than 2 cm but not S Serum Markers
larger than 5 cm in greatest dimension SX Marker studies not available or not performed
OR
Multiple lymph nodes, any one mass larger than 2 cm but not S0 Marker study levels within normal limits
larger than 5 cm in greatest dimension S1 LDH <1.5 x N* and hCG (mIU/mL) <5,000
cN3 Metastasis with a lymph node mass larger than 5 cm in and AFP (ng/mL) <1,000
greatest dimension S2 LDH 1.5–10 x N* or hCG (mIU/mL) 5,000–50,000
or AFP (ng/mL) 1,000–10,000
S3 LDH >10 x N* or hCG (mIU/mL) >50,000
Pathological N Regional Lymph Nodes or AFP (ng/mL) >10,000
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or smaller in
greatest dimension and less than or equal to five nodes
positive, none larger than 2 cm in greatest dimension
pN2 Metastasis with a lymph node mass larger than 2 cm but
not larger than 5 cm in greatest dimension; or more than
five nodes positive, none larger than 5 cm; or evidence of
extranodal extension of tumor
pN3 Metastasis with a lymph node mass larger than 5 cm in
greatest dimension
Continued
*N indicates the upper limit of normal for the LDH assay.

ST-2

Table of Contents

Table 2. AJCC Prognostic Stage Groups Histologic Grade (G)

T N M S • Germ cell tumors are not graded
Stage 0 pTis N0 M0 S0
Stage I pT1-T4 N0 M0 SX
Stage IA pT1 N0 M0 S0
Stage IB pT2 N0 M0 S0
pT3 N0 M0 S0
pT4 N0 M0 S0
Stage IS Any pT/TX N0 M0 S1-3
Stage II Any pT/TX N1-3 M0 SX
Stage IIA Any pT/TX N1 M0 S0
Any pT/TX N1 M0 S1
Stage IIB Any pT/TX N2 M0 S0
Any pT/TX N2 M0 S1
Stage IIC Any pT/TX N3 M0 S0
Any pT/TX N3 M0 S1
Stage III Any pT/TX Any N M1 SX
Stage IIIA Any pT/TX Any N M1a S0
Any pT/TX Any N M1a S1
Stage IIIB Any pT/TX N1-3 M0 S2
Stage IIIC Any pT/TX N1-3 M0 S3
Any pT/TX Any N M1b Any S
ST-3

Table of Contents
NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

NCCN Guidelines Index

NCCN Guidelines Version 1.2020 Table of Contents
Discussion
Testicular Cancer
Discussion This discussion is being updated to correspond with the

newly updated algorithm. Last updated 10/22/18
Table of Contents
Overview .................................................................................... MS-2
Literature Search Criteria and Guidelines Update Methodology ... MS-4
Clinical Presentation ................................................................... MS-3
Workup, Primary Treatment, and Pathologic Diagnosis ............... MS-5
Pure Seminoma ......................................................................... MS-7
Pure Seminoma Stages IA and IB ........................................... MS-7
Pure Seminoma Stage IS ...................................................... MS-11
Pure Seminoma Stages IIA and IIB ....................................... MS-11
Pure Seminoma Stages IIC and III ........................................ MS-12
Nonseminoma .......................................................................... MS-12

Nonseminoma Stage I Without Risk Factors ........................ MS-135
Nonseminoma Stage I With Risk Factors ............................... MS-13
Nonseminoma Stage IS ........................................................ MS-15
Nonseminoma Stage IIA ....................................................... MS-15
Nonseminoma Stage IIB ....................................................... MS-16
Advanced Metastatic Nonseminoma ...................................... MS-17
Second-Line and Subsequent Therapy for Metastatic Germ Cell

Tumors .................................................................................... MS-18
Treatment of Brain Metastases....................................................MS-22
References............................................................................... MS-24
Version 1.2020, 10/09/2019 © National Comprehensive Cancer Network© (NCCN©). All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-1

Discussion
Testicular Cancer
Overview patients starting first-line chemotherapy for disseminated

nonseminomatous tumors.13 LDH, beta-hCG and AFP should be
Testicular cancer is relatively uncommon and accounts for <1% of all male
measured on the first day of the first cycle of first-line chemotherapy in
tumors.1 However, it is the most common solid tumor in men between the
these patients. LDH can also be used to monitor for relapse, but is
ages of 20 and 34 years,2,3 and the incidence has been steadily increasing
nonspecific resulting in a high false-positive rate. Serum tumor markers
over the last 6 decades.4-7 An estimated 9310 new cases of testicular
are very useful for monitoring all stages of nonseminomas and are also
cancer will be diagnosed in the United States in 2018 resulting in 400
useful in monitoring stage II and III seminomas, because elevated marker
deaths, which reflects the excellent 5-year survival rate for this disease
levels may be an early sign of relapse.
(~95%).1,2 Testicular germ cell tumors (GCTs) comprise 95% of malignant
tumors arising in the testes.3 GCTs also occasionally originate in Beta-hCG is the most commonly elevated serum tumor marker in
extragonadal primary sites (usually the retroperitoneum or anterior testicular cancer. Elevated serum concentrations of beta-hCG may be
mediastinum), and are managed similarly to testicular GCTs with regard to present with both seminomatous and nonseminomatous tumors. However,
systemic therapy and management of residual masses.8 Several risk in patients with beta-hCG levels >1000 IU/L, consider the possibility of a
factors for testis cancer development have been identified, including prior nonseminoma GCT and re-review the surgical specimen with pathology.
history of testis cancer, family history of testis cancer, and Consider discussion with a high-volume center experienced in the
cryptorchidism.3,9,10 management of these patients. Additionally, patients with post-
orchiectomy beta-hCG levels >5000 IU/L are at an increased risk of
Testicular GCTs are categorized into two main histologic subtypes:
having brain metastases and a brain MRI should be performed. It is
seminoma and nonseminoma.3,11,12 Seminomas are more common, while
essential to note that minor elevations of beta-hCG (generally <20 IU/L)
nonseminomas tend to grow faster and often include multiple cell types.
need to be interpreted with caution because hypogonadism,
The four types of nonseminomas are embryonal carcinoma,
hyperthyroidism, and marijuana use may cause serum elevations of beta-
choriocarcinoma, yolk sac tumor, and teratoma.11 Teratomas are
hCG.14-16 Intramuscular injection of 300mg of testosterone cypionate may
sometimes classified as either mature or immature, but this distinction is of
be administered in these cases of mild beta-hCG elevations of unclear
no clear significance in adult men and does not affect management in
etiology in order to exclude hypogonadism as a cause. Similarly,
these patients. Rarely, a teratoma may histologically resemble a somatic
heterophile antibodies have been reported to result in substantially
cancer, such as a sarcoma or adenocarcinoma, and is then referred to as
elevated false-positive beta-hCG results (>400 IU/L), so clinicians should
a teratoma with somatic type malignancy.
consider repeating the test using a different assay if a false positive is
The serum tumor markers alpha-fetoprotein (AFP) and beta-human suspected due to the absence of radiographic evidence of disease.17,18
chorionic gonadotropin (beta-hCG) are critical in diagnosing testicular
Elevated serum AFP is only associated with nonseminomatous GCTs,
GCTs, determining prognosis, and assessing treatment outcome. Serum
particularly embryonal or yolk sac carcinomas, and may be seen at any
tumor markers should be determined before and after treatment and
disease stage. When patients with a histologically “pure” seminoma have
throughout the follow-up period. In addition, lactate dehydrogenase (LDH)
an elevated level of AFP, it is generally interpreted as meaning the tumor
is important for determining prognosis and is used to help risk-stratify

Discussion
Testicular Cancer
is a mixed GCT and that undetected nonseminomatous GCT elements are resource for medical literature and indexes only peer-reviewed biomedical
present in addition to the seminoma.13,19-21 However, a small number of literature.22
people have a chronically elevated serum AFP level and clinicians should
The search results were narrowed by selecting studies in humans
be cautious about initiating treatment for a mildly elevated but stable AFP.
published in English. Results were confined to the following article types:
If an elevation of serum AFP is due to a metastatic GCT, then the AFP
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
typically will be steadily rising.
Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
Although serum LDH concentrations are elevated in about half of men with Reviews; and Validation Studies.
advanced testicular cancer, LDH is a less specific marker for testicular
The data from key PubMed articles as well as articles from additional
cancer compared to AFP and beta-hCG. Therefore, decisions about
sources deemed as relevant to these Guidelines and/or discussed by the
treatment should not generally be based on LDH elevations alone. The
panel have been included in this version of the Discussion section (eg, e-
primary use of LDH is to risk stratify patients with disseminated
publications ahead of print, meeting abstracts). Any recommendations for
nonseminomas on the first day of first-line chemotherapy.13 LDH should
which high-level evidence is lacking are based on the panel’s review of
not be used to risk stratify patients with pure seminoma.
lower-level evidence and expert opinion.
Standard care has been established for all disease stages and should be
The complete details of the development and update of the NCCN
closely followed to maximize the potential for cure and to avoid
Guidelines are available at www.NCCN.org.
unnecessary side effects, complications, and late toxicities. Nonseminoma
is the more clinically aggressive tumor type. When both seminoma and Clinical Presentation
elements of nonseminoma are present, management follows that of a
nonseminoma. Therefore, the diagnosis of a seminoma is restricted to Testicular cancer most often presents as a painless or painful testicular
pure seminoma histology and normal serum AFP levels. It is important to nodule, mass, enlargement, or induration (hardening). Often, patients will
note that pediatric GCTs are managed differently from adult GCTs and are present with testicular discomfort or swelling suggestive of epididymitis or
not covered in these guidelines. Additionally, testicular tumors arising from orchitis. A trial of antibiotics may be given in this circumstance, but
the stroma are also not covered in these guidelines, since they account for persistent tenderness, swelling, or any palpable abnormality warrants
<5% of cases and standards of care are not well established. further evaluation. Other patients may present with enlarged lymph nodes
of the lower neck or upper chest (supraclavicular), a retroperitoneal mass,
Literature Search Criteria and Guidelines Update gynecomastia, venous thrombosis, or pulmonary embolism. If testicular
Methodology cancer is being considered as a possibility, then a transscrotal ultrasound
should be performed. If the ultrasound findings show a mass concerning
Prior to the update of this version of the NCCN Guidelines for Testicular for malignancy, then an inguinal orchiectomy is generally performed to
Cancer, an electronic search of the PubMed database was performed make a diagnosis. Transscrotal biopsies of the testes should not be
using the following search terms: ‘testicular cancer’ and ‘germ cell tumor.’
The PubMed database was chosen as it remains the most widely used

Discussion
Testicular Cancer
performed because violating the scrotum can seed the cancer and Sperm banking should be discussed with patients of reproductive age, if
complicate management. clinically indicated, before undergoing any therapeutic intervention that
may compromise fertility, including surgery, radiation therapy (RT), or
Workup, Primary Treatment, and Pathologic Diagnosis chemotherapy.29-32 If sperm banking is desired, it may be performed either
before or after orchiectomy, but certainly prior to subsequent therapy.
Workup
Further management is dictated by histology, stage, and whether the
If an intratesticular mass is identified, the workup should include a
cancer is a pure seminoma or a nonseminoma (nonseminomas include
thorough history and physical examination. Testicular ultrasound serves to
mixed GCTs that are partially comprised of seminoma and tumors that are
confirm the presence of a testicular mass, determine whether a mass is
histopathologically described as pure seminomas in patients with elevated
intra- or extratesticular, and to explore the contralateral testis.23 If a
serum AFP). Though rare, when a patient presents with: 1) rapidly
testicular mass concerning for malignancy is confirmed on ultrasound,
increasing beta-hCG or AFP levels; 2) symptoms related to disseminated
serum tumor markers, including LDH, AFP, and beta-hCG, need to be
disease; and 3) a testicular mass or distribution of metastatic disease
assessed as they are used for diagnosis, prognosis, and staging.12 Marker
consistent with a testicular, retroperitoneal, or mediastinal GCT,
levels should be assessed both before and after orchiectomy. Elevated
chemotherapy may be initiated immediately without waiting for a biopsy
levels of beta-hCG, LDH, or AFP should be followed up with repeated
diagnosis if the risk of delaying treatment outweighs the benefit of a tissue
tests to allow precise staging. Testicular GCTs are typically
diagnosis.
heterogeneous and hypoechoic on ultrasound.
Staging
Primary Treatment
Staging of testicular GCTs is based upon determination of the extent of
Radical inguinal orchiectomy is considered the primary treatment for most
disease and assessment of post-orchiectomy levels of serum tumor
patients who present with a testicular mass that is concerning for
markers.12 The tumor (T), node (N), and metastasis (M) staging system
malignancy on ultrasound.24 Concurrent insertion of testicular prosthesis
used by the AJCC is the internationally accepted standard for cancer
may be considered during radical inguinal orchiectomy if desired by the
staging and is a major factor influencing prognosis and treatment
patient.25-27 In cases where the ultrasound shows an ambiguous
decisions. The AJCC TNM staging system incorporates serum tumor
abnormality that might be malignant, an open inguinal biopsy can be
marker elevation as a distinct category (S), which is unique to this organ
performed, but such cases are extremely rare. Similarly, an inguinal
site. The extent of the primary tumor is classified after orchiectomy, and
biopsy of the contralateral testis should be considered if an ambiguous
therefore pathologic (p) staging is assigned to the primary tumor (T). The
suspicious mass is identified on ultrasound. An open inguinal biopsy of the
8th edition of the AJCC Cancer Staging Manual introduced invasion of the
contralateral testis may also be considered when that testis is cryptorchid
epididymis and hilar soft tissue as new pathologic criteria used for T
or shows marked atrophy.28 However, biopsies are not recommended for
classification of stage I testicular GCTs.12,33 Due to the excellent clinical
microcalcifications.
outcomes seen in testicular cancer, large-scale follow-up studies have

Discussion
Testicular Cancer
historically used tumor relapse rather than tumor-specific survival to lung metastases. In patients who had elevated serum tumor markers prior
validate the relevance of pathologic parameters used for staging.12 to orchiectomy, it is important to obtain the half-life kinetics of the tumor
However, hilar soft tissue and epididymal invasion have not been validated markers after orchiectomy if the markers are declining because a slower-
for their association with relapse of stage I disease. Current data only than-expected decline often indicates the presence of metastatic disease.
support their association with having advanced-stage disease at the time
of diagnosis.34,35 Therefore, it is the opinion of the panel that these factors Risk Classification for Advanced Disease
should not be used for clinical decision-making in the management of
In 1997, the International Germ Cell Cancer Consensus Group (IGCCCG)
these patients. Instead, the NCCN Guidelines recommend managing
defined a classification system based on identification of clinically
patients with stage I nonseminoma based on the presence or absence of
independent prognostic features such as extent of disease and post-
lymphovascular invasion (LVI), invasion of the spermatic cord, or invasion
orchiectomy levels of serum tumor markers. This classification system
of the scrotum, which are risk factors known to be associated with an
categorizes patients with pure seminoma and nonseminoma GCTs into
increased risk of relapse.36-44 The NCCN Guidelines do not recommend good-, intermediate-, or poor-risk groups.53 When determining a patient’s
risk-adapted treatment for stage I pure seminoma.
risk classification, the relevant serum tumor marker value is the value on
Predominance of embryonal carcinoma has also been proposed as a day 1 of cycle 1 of first-line chemotherapy. Definitions of stage and risk
prognostic indicator of relapse in stage I nonseminoma, with several classification in these guidelines are done according to the IGCCCG
studies showing that a high volume of embryonal carcinoma in the primary classifications.
tumor (>50%) is associated with an increased risk of relapse.38,45-52
However, very few patients have a high volume of embryonal carcinoma Pure Seminoma
without also having LVI, and the value of embryonal carcinoma If a pure seminoma is found, an abdominal/pelvic CT scan with contrast
predominance in predicting relapse in the absence of LVI is should be performed to assess the retroperitoneal lymph nodes. A chest x-
unclear.38,45,48,52 Therefore, predominance of embryonal carcinoma is not ray is also recommended. A chest CT with contrast is indicated if the
used by the NCCN Guidelines to risk stratify stage I nonseminoma abdominal/pelvic CT or the chest x-ray shows evidence of metastatic
patients. Stage I nonseminoma patients with a high volume of embryonal disease.
carcinoma and no evidence of LVI are neither high-risk nor low-risk and
should be considered for adjuvant therapy. Measurement of beta-hCG, LDH, and AFP levels should be repeated
since TNM staging is based on marker levels at the time the patient starts
To assess for metastatic disease, imaging studies of the chest, abdomen, post-orchiectomy therapy. Elevated levels should be followed with
and pelvis should be performed. Such studies typically include CT scans repeated measurement to allow for precise staging. Declining markers
of the abdomen and pelvis and CT scan or x-ray of the chest. PET scans should be followed until normalization or plateau. Beta-hCG and LDH may
should not be used to stage testicular GCTs. In select patients, brain MRI be elevated in patients with seminoma; however, elevated LDH and beta-
should also be performed; these patients include those with neurologic HCG alone should not be used to stage or risk stratify patients with pure
symptoms, post-orchiectomy serum beta-hCG >5000 IU/L, or extensive seminoma. An elevated AFP indicates nonseminoma unless another

Discussion
Testicular Cancer
cause of the elevated AFP (such as liver disease) is identified. Patients managed by surveillance.65 In contrast, another recent systematic review
with seminoma arising from an extragonadal site, such as the found rete testis invasion to be significantly associated with relapse in only
mediastinum, are usually diagnosed via biopsy and treated with standard 4 out of the 13 studies analyzed.59 Due to these concerns, the NCCN
chemotherapy regimens according to risk classification. The NCCN Panel Panel discourages risk-adapted management in stage I pure seminoma
recommends performing a brain MRI if beta-hCG levels exceed 5000 IU/L and instead recommends surveillance for all patients who find it
or there is extensive metastatic disease in the lungs (as noted above, a acceptable and are able to adhere to the surveillance schedule.
beta-hCG >1000 IU/L is rare in seminoma and a value >5000 IU/L is
A retrospective study analyzing 2483 patients with clinical stage I GCTs
generally indicative of a nonseminomatous GCT). Sperm banking should
managed by active surveillance showed that 13% of patients with stage I
also be recommended to patients who will be undergoing chemotherapy,
seminoma relapsed. Median time to relapse was 14 months (range, 2–84
RT, or retroperitoneal lymph node dissection (RPLND), if clinically
months) and 92% of relapses were observed within 3 years. The overall 5-
indicated.
year disease-specific survival rate was 99%.66,67 Based on this and other
similar studies, surveillance is the preferred option for patients with stage I
Pure Seminoma Stages IA and IB
seminoma. If surveillance is not applicable, alternative options are either
Primary Treatment for Pure Seminoma Stages IA and IB adjuvant chemotherapy with carboplatin or adjuvant RT as described
Although most patients with stage I pure seminoma are cured by below. Each approach has distinct advantages and disadvantages that
orchiectomy alone, 15% to 20% of patients relapse. The standard should be discussed with patients and their families in order to pick the
management options after initial orchiectomy include active surveillance best approach on an individual basis.
(preferred), chemotherapy with one or two cycles of single-agent
Adjuvant Chemotherapy: Oliver et al reported the initial results of a trial
carboplatin, or RT (20 Gy, preferred or 25.5 Gy). Disease-specific survival
that randomized 1477 patients with stage I seminoma to receive either RT
for stage I disease is 99% irrespective of the management strategy used.54
(n = 885) or 1 cycle of intravenous carboplatin (n = 560) at the dose AUC x
Surveillance: Several prospective non-randomized studies on surveillance 7 (ie based on the formula 7 x [glomerular filtration rate (GFR, mL/min) +
for stage I seminoma have been conducted.55-58 The 5-year relapse rate 25 mg]).68 At a follow-up time of 3 years, the relapse-free survival rates for
seen in these studies have ranged from 15% to 20%, with most disease both groups were similar (95.9% for the RT group and 94.8% for the
relapse detected in the infra-diaphragmatic lymph nodes.56-58 The best carboplatin group), which established the noninferiority of carboplatin
established risk factor for relapse of pure seminoma is increased size of compared to RT.68 The mature results of this trial confirmed the
the primary tumor.59 As the tumor size increases the risk of relapse also noninferiority of single-dose carboplatin versus RT in terms of relapse-free
increases, but any cutoff point is arbitrary.57,60,61,62-64 Additionally, some survival.69 In an intent-to-treat analysis, the relapse-free survival rates at 5
studies have reported that rete testis invasion is an independent risk factor years were 96% in the RT arm and 94.7% in the carboplatin arm (hazard
for relapse in stage I pure seminoma while others have reported that it is ratio [HR], 1.25; P = 0.37). One seminoma-related death occurred after RT
not.57,59-62,65 A recent systematic review determined that rete testis invasion and none occurred after carboplatin. Additionally, patients given
is significantly associated with risk of relapse in stage I seminoma patients carboplatin were less lethargic and less likely to take time off work than

Discussion
Testicular Cancer
patients receiving RT. Therefore, the authors concluded that a single dose efficacy to control large tumors. Regardless of the regimen used,
of carboplatin is less toxic and as effective in preventing disease relapse performing abdominal/pelvic CT scan with contrast and chest x-ray or CT
as adjuvant RT in men with stage I pure seminoma after orchiectomy.69 scan is recommended within 4 weeks prior to the initiation of
However, it should be noted that there are limited long-term follow-up data chemotherapy to confirm staging, even if scans were previously
regarding the toxicity and efficacy of carboplatin.61,70 A recent non- performed. Chest CT should be performed if either abdominal/pelvic CT or
randomized population-based study of 897 patients with stage I seminoma chest x-ray shows evidence of metastatic disease.
suggested that patients with tumor size >4 cm, rete testis invasion, or both
derive a smaller reduction in relapse rate with one cycle of carboplatin Adjuvant Radiation Therapy: Numerous studies have found an increased
than previously reported.57,61,70 After a median follow-up of 5.6 years, the risk for secondary malignancies in seminoma patients treated with RT;
relapse rate in patients with one or both risk factors was 15.5% for patients however, many of these patients were treated at a time when treatment
managed by surveillance versus 9.3% for patients who received one cycle fields were larger and radiation doses were higher than those currently
of carboplatin.61 An absolute reduction in the risk of relapse by only 6.2% used.75,76 One population-based study reported that RT for stage I
may not be sufficient to justify the use of single-cycle adjuvant seminoma was associated with an 80% increase in the risk of death from
carboplatin.70 Therefore, more data are needed to assess the value of one secondary cancers.77 Another study found that moderate-dose
cycle of carboplatin in reducing the risk of relapse in patients with stage I infradiaphragmatic RT for stage I seminoma was associated with an
seminoma. increased risk for secondary cancers in organs within the radiation field.78
Additionally, one study reported that RT might increase the risk of a
Use of two cycles of adjuvant carboplatin in this setting has also been
subsequent cardiac event,79 but other analyses have not confirmed this
studied. The 2nd and 3rd Spanish Germ Cell Cancer Cooperative Group
risk.77 Platinum-based chemotherapy has also been associated with an
studies reported that two cycles of adjuvant carboplatin is effective in
increased risk for secondary cancers and cardiac toxicity.79,80 However,
reducing the rate of relapse in high-risk stage I seminoma patients, with a
whether such long-term risks ensue from single-agent carboplatin as
5-year relapse-free survival rate of 96.2% and a 5-year overall survival
dosed for seminoma remains unknown.
(OS) rate of 100%.71,72 The efficacy of two cycles of adjuvant carboplatin
was confirmed in a study by the Hellenic Cooperative Oncology Group, The NCCN Panel prefers active surveillance to the routine use of adjuvant
which reported a 5-year relapse-free survival rate of 96.8% among 138 therapy for stage I seminoma patients, because the risk of relapse is low
stage I seminoma patients treated with this regimen.73 A recent compared to the potential harms of adjuvant therapy. However, if adjuvant
prospective study reported the treatment outcomes of 725 stage I chemotherapy is given, the NCCN Panel recommends carboplatin (AUC x
seminoma patients managed by surveillance, one cycle of carboplatin, or 7) for either 1 or 2 cycles for patients with stage IA or IB pure seminoma. If
two cycles of carboplatin.74 Although disease-specific survival was 100% RT is delivered, the panel recommends a preferred total dose of 20 Gy
for all 3 strategies, crude relapse rates were significantly higher with the administered in 10 fractions of 2.0 Gy each.81 Alternatively, a total dose of
one-cycle regimen (5%) compared to the two-cycle regimen (1.5%) after a 25.5 Gy can be given in 17 fractions of 1.5 Gy each.82 Other RT dose
median follow-up of 30 months. The crude relapse rate for surveillance schedules are listed in the Principles of Radiotherapy for Pure Testicular
was 8.2%. Furthermore, one cycle of carboplatin demonstrated low Seminoma in the algorithm (see Table 1 on TEST-C 2 of 5). Patients at

Discussion
Testicular Cancer
higher risk for morbidity from RT, such as those with a history of in mind the potential for development of a second primary tumor in the
inflammatory bowel disease or prior RT, are generally not given primary contralateral testis.
RT.
Follow-up During Active Surveillance: Although no single follow-up plan is
Nodal mapping studies suggest that treatment fields should target the
applicable to all patients, the NCCN Panel has provided guidance for the
retroperitoneal lymph nodes but not necessarily the ipsilateral renal hilar
follow-up of patients with stage I seminoma managed with active
nodes.83,84 Special circumstances, such as ipsilateral pelvic surgery, may
surveillance after orchiectomy (see Table 1 on TEST-A 1 of 2 in the
alter the lymphatic drainage of the testis. Therefore, irradiation of the
algorithm). The recommendations outlined may be individualized and
ipsilateral iliac and inguinal lymph nodes has been advocated even in
extended beyond 5 years at the discretion of the physician. Follow-up for
stage I patients.83,85,86 It should be noted that patients treated with para-
patients on surveillance includes a history and physical examination, with
aortic RT have a slightly higher rate of pelvic relapse compared with those
optional measurement of serum tumor markers (AFP, beta-hCG, and
treated with “dog-leg’’ RT.86-89 Prophylaxis to the mediastinum is not
LDH), performed every 3 to 6 months for the first year, every 6 to 12
provided, because relapse rarely occurs at this site. Sperm banking should
months for years 2 to 3, and annually for years 4 and 5.72,91,92 The
be recommended beforehand, if clinically indicated, when patients are to
measurement of serum tumor markers is optional due to the rarity of
receive either chemotherapy or RT.
marker-only relapse, since most patients with elevated markers will also
have evidence of relapse on imaging. Additionally, in one of the largest
Follow-up for Pure Seminoma Stages IA and IB After Primary Treatment
prospectively maintained databases of stage I seminoma patients
Follow-up strategies vary according to the treatment modality received by managed with surveillance, it was reported that routine measurement of
the patient (surveillance vs. adjuvant therapy). An analysis of >5000 stage serum tumor markers did not aid in the early diagnosis of relapse.93
I seminoma patients from various trials reported that the 5-year relapse Therefore, routine measurement of serum tumor markers can be safely
rate was higher with surveillance (18.6%) compared to RT (4.8% with omitted from stage I seminoma surveillance schedules.
extended-field RT and 3.6% with para-aortic RT) or chemotherapy (6.1%
There is controversy regarding how many imaging studies should be
with 1 cycle of carboplatin and 2.3% with 2 cycles of carboplatin).88 An
performed in patients on active surveillance. The NCCN Panel
analysis of data from the National Cancer Database examined the survival
recommends an abdominal/pelvic CT scan with or without contrast at 3, 6,
outcomes of 33094 stage I seminoma patients who received surveillance,
and 12 months during the first year, every 6 to 12 months for years 2 and
chemotherapy, or RT as primary treatment after orchiectomy.90 Although
3, and then every 12 to 24 months for years 4 and 5. CT is not
OS was high for all strategies, results showed a small absolute survival
recommended beyond 5 years, unless clinically indicated. A clinical trial in
advantage for adjuvant therapy (RT or chemotherapy) over active
the United Kingdom entitled TRISST (MRC TE24/TRial of Imaging and
surveillance at 10 years (95% vs. 93.4%; HR, 0.58, P < .0005).
Schedule in Seminoma Testis) is currently investigating whether MRI or a
Independent of the modality, the risk of relapse is highest in the first 2
reduced CT schedule could be used as a safe and effective alternative to
years following treatment.88 In the event of relapse, clinicians should keep
standard CT-based surveillance in the management of stage I seminoma
(Clinical Trial ID: NCT00589537).94 The panel regards MRI as an

Discussion
Testicular Cancer
appropriate option that can be considered to replace abdominal/pelvic CT throughout surveillance. Chest x-rays should be obtained only when
in select circumstances. The MRI protocol should include visualization of clinically indicated and chest CT scans with contrast should be considered
all the nodes that need to be assessed, including the retroperitoneal and for symptomatic patients. CT is not recommended beyond 5 years, unless
pelvic nodes, and should be performed in centers with experience in clinically indicated. Relapses are treated according to the stage at
interpreting MRI results for testicular cancer. The same imaging modality relapse.54 However, patients should not be treated based upon an
(CT or MRI) should be used throughout surveillance. Several studies have elevated LDH level alone.
suggested that relapses in the lung are rarely detected by chest x-ray
alone in patients with stage I seminoma managed by active Pure Seminoma Stage IS
surveillance.66,95,96 In a recent retrospective analysis of 886 stage I Primary Treatment for Pure Seminoma Stage IS
seminoma patients, 83 patients experienced relapse.96 All relapses were
Stage IS pure seminoma is very uncommon and requires persistent
detected by either rising tumor markers or follow-up CT scan; not a single
elevation of serum tumor markers following orchiectomy. However,
relapse was detected by routine chest x-ray. Other studies have reported
physicians are cautioned against treating a patient based on minimally
similar results, calling into question the value of chest x-rays in
elevated LDH or beta-hCG alone, as other causes may be responsible for
surveillance settings for stage I seminomatous GCTs.66,95 Therefore,
elevation of these markers. Persistent elevation of serum markers is
routine chest imaging, including chest x-ray and chest CT with contrast,
usually evidence of metastatic disease, which will show up
should be reserved for patients with thoracic symptoms.
radiographically if doubt exists in the diagnosis.
Follow-up After Adjuvant Treatment: Follow-up of patients treated with
Follow-up for Pure Seminoma Stage IS
adjuvant therapy (chemotherapy or RT) is outlined in Table 2 on TEST-A 1
of 2 in the algorithm and includes a history and physical examination, with The NCCN Panel recommends repeating measurements of serum tumor
optional measurement of post-orchiectomy serum tumor markers (AFP, markers and performing imaging studies (chest/abdominal/pelvic CT with
beta-hCG, and LDH) performed every 6 to 12 months for the first 2 years contrast) to determine the extent of disease.
and annually for years 3, 4, and 5. A meta-analysis of 2466 patients
reported that relapse rarely occurred >3 years after treatment with RT or Pure Seminoma Stages IIA and IIB
carboplatin (0.2% of patients).54 Since the rate of relapse beyond 3 years Primary Treatment for Pure Seminoma Stages IIA and IIB
is very low for patients treated with chemotherapy or RT, the NCCN Panel
Stage IIA pure seminoma is defined as metastatic disease to lymph
recommends performing an abdominal/pelvic CT scan with or without
nodes, with a lymph node mass measuring ≤2 cm in greatest diameter.12 A
contrast annually for 3 years. In select circumstances, an MRI can be
lymph node mass measuring 2 to 5 cm in greatest diameter is classified as
considered to replace an abdominal/pelvic CT. The MRI protocol should
stage IIB disease.12 To confirm staging before treatment in select cases of
include visualization of the retroperitoneal and pelvic nodes and should be
stage IIA disease with borderline retroperitoneal lymph nodes, waiting 4 to
performed in centers with experience in interpreting MRI results for
6 weeks after initial imaging assessment and repeating
testicular cancer. The same imaging modality (CT or MRI) should be used

Discussion
Testicular Cancer
chest/abdominal/pelvic CT scans with contrast to confirm staging may be reported that the relapse rate was 6% among patients treated with
considered. chemotherapy compared to 12.6% among those treated with RT. It should
be noted that chemotherapy was used for more advanced stage disease
Options for the primary treatment of stage IIA and IIB seminomas include
than RT in this study.64 This has led some physicians to prefer
RT or chemotherapy with 3 cycles of bleomycin, etoposide, and cisplatin
chemotherapy for stage II patients; however, these results must be
(BEP) or 4 cycles of etoposide and cisplatin (EP).97-99 If chemotherapy is
interpreted with caution since this study was not a randomized trial and did
given, both EP and BEP are preferred regimens in this setting. However, a
not specifically compare the two treatment modalities for stage IIA
bleomycin-free regimen should be considered in patients with reduced or
disease. The NCCN Guidelines recommend either RT or chemotherapy as
borderline GFR and in patients over the age of 50. Different studies have
primary treatment for both stage IIA and IIB seminoma. However,
reported different outcomes with regard to whether chemotherapy or RT is
chemotherapy is preferred for stage IIB seminoma,99,102 with RT being
more effective in this setting. Two recent studies utilized data from the
reserved for select patients with non-bulky (≤3 cm) disease.97
National Cancer Database to assess survival outcomes according to
treatment strategy in stage IIA/B seminoma patients. A retrospective study The target fields for RT for stage IIA/B disease should include the
by Glaser et al compared RT with multi-agent chemotherapy in 1772 stage retroperitoneal and proximal ipsilateral iliac lymph nodes. Treatment is
IIA-C seminoma patients treated with orchiectomy.100 After a median delivered in two consecutive anteroposterior-posteroanterior (AP/PA)
follow-up of 65 months, 5-year OS was significantly higher with RT phases with no break in between. The initial phase consists of treatment of
compared to chemotherapy in stage IIA patients (99% vs. 93%; HR, 0.28; modified dog-leg fields at a dose of 20 Gy delivered in 10 fractions of 2.0
95% CI, 0.09–0.86; P = .027). However, no significant difference in 5-year Gy each or 25.5 Gy delivered in 17 fractions of 1.5 Gy each. The panel
OS was seen in stage IIB patients treated with post-orchiectomy RT or prefers modified dog-leg fields as described by Classen et al.97 The
chemotherapy (95.2% vs. 92.4%). A similar study by Paly et al evaluated second phase (cone down) consists of daily 1.8- to 2-Gy fractions to a
data from the same database during the same time period and reached cumulative total dose of 30 Gy for stage IIA patients and 36 Gy for stage
similar conclusions. This retrospective, non-randomized study evaluated IIB patients.97 Prophylactic mediastinal RT is not indicated for the
1885 stage IIA/B seminoma patients selected to receive either adjuvant management of stage II disease.103 For details on field arrangement, see
chemotherapy or adjuvant RT.101 Receipt of adjuvant chemotherapy was Principles of Radiotherapy for Pure Testicular Seminoma in the algorithm.
associated with decreased 5-year OS in stage IIA patients (HR, 13.33; P <
.01), but not in stage IIB patients (HR, 1.39; P = .45). These studies were
not randomized trials and treatment decisions were based on the treating Follow-up for Pure Seminoma Stages IIA and Non-bulky IIB After Primary
physician’s clinical judgment, which presumably was influenced by the Treatment
specific characteristics of each patient. Therefore, it is possible that
The recommended follow-up schedule for patients with stage IIA and non-
patients with more extensive disease were selected for chemotherapy.
bulky stage IIB seminoma after RT or chemotherapy is outlined in Table 3
Nevertheless, these studies provide some support for the use of RT over
on TEST-A 2 of 2 in the algorithm and includes a history and physical
chemotherapy to treat stage IIA seminoma. In contrast, a study by
examination with optional measurement of post-orchiectomy serum tumor
Mortensen et al evaluating 363 patients with stage II-III seminoma

Discussion
Testicular Cancer
markers (AFP, beta-hCG, and LDH), performed every 3 months for year 1 Management of Pure Seminoma Stages IIA, IIB, IIC, and III After
and then every 6 months for years 2 through 5. Chemotherapy
An abdominal/pelvic CT scan with contrast is recommended at 3 months After primary treatment with chemotherapy, patients with stage IIA, IIB,
and 6 to 12 months for year 1; annually for years 2 and 3; and then as IIC, or III seminoma are evaluated by CT scan with contrast of the chest,
clinically indicated for years 4 and 5. In select circumstances, an MRI can abdomen, and pelvis as well as measurement of serum tumor markers.
be considered to replace an abdominal/pelvic CT. The MRI protocol Patients are then classified according to the presence or absence of a
should include visualization of the retroperitoneal and pelvic nodes and residual mass and the status of serum tumor marker levels. Patients with
should be performed in centers with experience in interpreting MRI results normal serum AFP and beta-hCG levels and either no residual mass or a
for testicular cancer. The same imaging modality (CT or MRI) should be residual mass ≤3 cm should undergo surveillance as described in Table 3
used throughout surveillance. CT is not recommended beyond 5 years, on TEST-A 2 of 2 in the algorithm and discussed in the section above on
unless clinically indicated. Chest x-ray is recommended every 6 months Follow-up for Pure Seminoma Stages IIA and Non-bulky IIB After Primary
for the first 2 years only. Treatment.
Surveillance is also recommended for patients with a residual mass >3 cm
Pure Seminoma Stages IIC and III
and normal serum AFP and beta-hCG levels. Additionally, a PET/CT scan
Primary Treatment for Pure Seminoma Stages IIC and III from skull base to mid-thigh can be considered to better delineate the
Patients with stage IIC or stage III seminomas are classified as either presence of viable residual tumor since CT alone cannot discriminate
good or intermediate risk. Intermediate risk in seminoma is based on between residual neoplastic lesions and necrotic or fibrotic tissue.113-117
metastases to organs other than the lungs. All stage IIC and stage III PET can provide useful metabolic information on these lesions, which may
seminomas are considered good risk except for stage IIIC disease, which aid in the early detection of recurrent disease in patients with normal CT
involves non-pulmonary visceral metastases (eg, bone, liver, brain) and is findings, since functional abnormalities usually precede morphologic
considered intermediate risk. Standard chemotherapy is used for both ones.117 However, testicular GCTs are typically slow-growing and have low
groups of patients. However, 3 cycles of BEP or 4 cycles of EP are uptake of 18-fluorodeoxyglucose (FDG) on PET scans, often resulting in
recommended for patients with good-risk disease (both preferred),104-106 unclear images of testicular lesions.118 Additionally, the abdomen and
while more intensive chemotherapy with 4 cycles of BEP (preferred) or 4 retroperitoneal space are sites of non-specific FDG uptake, which can lead
cycles of etoposide, mesna, ifosfamide, and cisplatin (VIP) is to false-positive results.118 Possible sources of false-negative results
recommended for patients with intermediate-risk disease.107-112 VIP should include small malignant lesions (<3 cm) and lesions with low proliferative
be reserved for patients with a contraindication to bleomycin. Additionally, indices.117 Therefore, accurate interpretation of PET scans is paramount
a bleomycin-free regimen should also be considered in patients with and possible positive findings should be corroborated with the
reduced or borderline GFR and in patients over the age of 50. All of these corresponding CT results. PET/CT is not indicated for residual masses ≤3
chemotherapy options are category 1 recommendations except for VIP, cm.
which is a category 2A recommendation.

Discussion
Testicular Cancer
To reduce the incidence of false-positive results due to inflammation, the are recommended every 4 months for year 1, every 6 months for year 2,
PET/CT scan should be performed at least 6 weeks after the completion of annually for years 3 and 4, and then as clinically indicated for year 5.124 In
the last cycle of chemotherapy in patients with a residual mass >3 cm and select circumstances, an MRI can be considered to replace an
normal serum tumor marker levels.117,119 A negative PET/CT following abdominal/pelvic CT. The MRI protocol should include visualization of the
chemotherapy is very reassuring. If the PET/CT is negative, surveillance is retroperitoneal and pelvic nodes and should be performed in centers with
recommended as described in the next section on Follow-up for Pure experience in interpreting MRI results for testicular cancer. The same
Seminoma Bulky Stage II and Stage III After Chemotherapy. If the PET/CT imaging modality (CT or MRI) should be used throughout surveillance.
is positive, resection or interventional radiology (IR)-guided biopsy of the Patients with residual masses may require more frequent imaging based
residual mass should be considered. If the biopsy results show viable on clinical judgment. However, CT is not recommended beyond 5 years
seminoma and the resection is complete, 2 cycles of adjuvant unless clinically indicated. Chest x-ray is recommended every 2 months
chemotherapy with the following regimens: EP, TIP (paclitaxel, ifosfamide, for year 1, every 3 months for year 2, and annually for years 3 through 5.
cisplatin),120 VIP, or VeIP (vinblastine, mesna, ifosfamide, cisplatin) is While chest x-ray may be used for routine follow-up, chest CT with
recommended.121,122 If the resection is incomplete or there is progressive contrast is preferred for patients with thoracic symptoms. Since viable
disease (growing mass or rising markers), a full course of second-line tumor cells have been found in tumors >3 cm with a negative post-
chemotherapy (4 cycles of TIP or 4 cycles of VeIP; both preferred) is chemotherapy PET scan,125 the NCCN Panel recommends that patients
recommended.120-123 Borderline PET/CT results require careful with a residual mass measuring >3 cm and negative PET results after
interpretation by experienced clinicians. If the PET/CT is borderline, chemotherapy should undergo an abdominal/pelvic CT scan with contrast
consider surveillance and repeat PET/CT in 8 to 12 weeks to assess for every 6 months for the first year and then annually for 5 years.
changes. If the mass is persistently FDG-avid on PET/CT, then resection
or biopsy is recommended. Following adjuvant or second-line Nonseminoma
chemotherapy, patients should undergo follow-up as discussed in the next
Nonseminomatous GCTs include nonseminoma tumors, mixed
section. Patients should also adhere to this follow-up schedule if their
seminoma/nonseminoma tumors, and seminoma tumors in patients with
biopsy results are negative for viable seminoma.
elevated serum AFP levels. The post-diagnostic workup for nonseminoma
includes CT scans with contrast of the chest, abdomen, and pelvis.
Follow-up for Pure Seminoma Bulky Stage II and Stage III After
PET/CT scan is not clinically indicated for nonseminoma.126,127 Elevated
Chemotherapy
levels of serum beta-hCG, LDH, or AFP should be followed up with
The recommended follow-up schedule for patients with bulky stage II or repeated tests. Repeated measurement of serum tumor markers is
stage III seminoma after treatment with chemotherapy is outlined in Table important because TNM staging is based on post-orchiectomy values. The
4 on TEST-A 2 of 2 in the algorithm and includes a history and physical NCCN Panel emphasizes that mildly elevated AFP levels may not indicate
examination as well as measurement of serum tumor marker levels every the presence of a GCT. Therefore, decisions to treat should not be based
2 months for year 1, every 3 months for year 2, every 6 months for years 3 on AFP levels <20 ng/mL. MRI of the brain, with and without contrast,
and 4, and once during year 5. Abdominal/pelvic CT scans with contrast should be performed if clinically indicated (ie, beta-hCG >5000 IU/L,

Discussion
Testicular Cancer
extensive lung metastasis, choriocarcinoma, neurologic symptoms, non- relapse. Therefore, patients who choose surveillance should adhere to the
pulmonary visceral metastasis, AFP >10000 ng/mL). follow-up schedule. When nerve-sparing RPLND is performed, it should be
done within 4 weeks of a CT scan and within 7 to 10 days of repeat serum
Sperm banking should be recommended to patients of reproductive age, if
marker testing to ensure accurate presurgical staging.133
clinically indicated, before undergoing any therapeutic intervention that
may compromise fertility, including surgery, RT, and chemotherapy.29-32 If A phase III trial by Albers et al randomized stage I nonseminoma patients
desired, sperm banking may be performed either before or after to undergo unilateral RPLND (n = 191) or 1 course of adjuvant BEP (n =
orchiectomy, but certainly prior to adjuvant therapy. 191) after orchiectomy.131 After a median follow-up of 4.7 years, 2 relapses
were reported in the BEP arm compared to 13 in the RPLND arm (P =
Stage-dependent treatment options after inguinal orchiectomy include
.0011). This indicates that 1 course of BEP is active in stage I
surveillance, primary chemotherapy, and RPLND. Although the timing of
RPLND may vary, most patients with nonseminoma will undergo RPLND nonseminoma and could be an appropriate option for select patients.131 In
for either diagnostic or therapeutic purposes at some point during another prospective trial (SWENOTECA), stage I nonseminoma patients
treatment. The major morbidity associated with bilateral dissection is with or without LVI received 1 course of adjuvant BEP.132 The relapse rate
retrograde ejaculation, resulting in infertility. Nerve-sparing dissection at 5 years was 3.2% for patients with LVI and 1.6% for patients without
techniques preserve antegrade ejaculation in 90% of cases.128 Therefore, LVI. Five-year OS was 100% in both groups.36 The results after a median
nerve-sparing RPLND is recommended. follow-up of 7.9 years confirmed the low relapse rate with 1 course of
adjuvant BEP, especially in patients with LVI.36 In this setting, the NCCN
Nonseminoma Stage I Without Risk Factors Panel considers 1 cycle of BEP an appropriate option to reduce the risk of
relapse. However, performing abdominal/pelvic CT scan and chest x-ray
Primary Treatment for Nonseminoma Stage I Without Risk Factors
or CT scan is recommended within 4 weeks prior to the initiation of
The NCCN Panel recommends treating stage I nonseminoma patients chemotherapy to confirm staging, even if scans were done previously.
based on the presence or absence of risk factors known to be associated Chest CT should be performed if either abdominal/pelvic CT or chest x-ray
with an increased risk of relapse (LVI, invasion of the spermatic cord, or shows evidence of metastatic disease.
invasion of the scrotum).36-44 Stage I nonseminoma patients with or without
these risk factors are managed similarly after orchiectomy and can receive Follow-up for Nonseminoma Stage I Without Risk Factors
surveillance,41,48,129,130 nerve-sparing RPLND, or chemotherapy (1 cycle of The long-term follow-up for stage I nonseminoma patients without risk
BEP)131,132 as primary treatment. The major difference in the management factors includes a history and physical examination, serum tumor marker
of these two patient populations is that surveillance is preferred for assessment, abdominal/pelvic CT scan, and chest x-ray. In select
patients with stage I nonseminoma without risk factors. The survival rate circumstances, an MRI can be considered to replace an abdominal/pelvic
for stage I nonseminoma managed with surveillance or nerve-sparing CT. The MRI protocol should include visualization of the retroperitoneal
RPLND exceeds 98%. However, the high survival rate associated with and pelvic nodes and should be performed in centers with experience in
surveillance depends on adherence to periodic follow-up examinations interpreting MRI results for testicular cancer. The same imaging modality
and subsequent chemotherapy for the 20% to 30% of patients who

Discussion
Testicular Cancer
(CT or MRI) should be used throughout surveillance. All imaging in this BEP as primary treatment for stage I nonseminoma have similarly
setting is performed with contrast. The frequency of these tests varies with reported relapse-free survival rates >95%.130,135-139 However, late
the primary treatment modality received by the patient (see Tables 5 and 7 consequences of cisplatin-based chemotherapy, such as hearing damage
on TEST-B in the algorithm). It should be noted that routine chest x-ray and loss, cardiovascular conditions, hypertension, and neuropathy, have
may have limited value for detecting relapse in stage I nonseminoma. In a been reported during long-term follow-up.79,140-146 Therefore, one cycle of
recent retrospective study, a total of 76 relapses were detected among BEP is recommended due to its lower toxicity. Surveillance is also a
561 stage I nonseminoma patients managed by active surveillance recommended primary treatment option for stage I nonseminoma patients
following orchiectomy.96 All relapses were detected by either rising serum with risk factors. However, it should be noted that LVI is a significant
tumor markers or abnormal routine follow-up CT scans; not a single predictor of relapse when orchiectomy is followed by surveillance alone.24
relapse was detected by chest x-ray alone. Similar results have been
reported in other studies, calling into question the value of chest x-rays in
surveillance settings for stage I nonseminomatous GCTs.48,66,134 The Management of Nonseminoma Stage I After RPLND
current schedule for routine chest x-ray in the follow-up of stage I
If the resected lymph nodes are negative for malignancy (pN0) after nerve-
nonseminoma patients without risk factors is two chest x-rays in year 1
sparing RPLND, the patient should undergo surveillance. For positive
and one chest x-ray in years 2 through 5 in patients managed by
lymph nodes (pN1 to pN3), the decision whether to use adjuvant
surveillance. Chest x-ray is not indicated in years 3, 4, and 5 for stage I
chemotherapy is based on the degree of nodal involvement. Surveillance
nonseminoma patients without risk factors treated with adjuvant BEP or
is the preferred option for patients with pN1 disease, while chemotherapy
primary RPLND.
is the preferred option for patients with pN2 disease. However,
Nonseminoma Stage I With Risk Factors chemotherapy is the only option for patients with pN3 disease.
Recommended chemotherapy regimens include two cycles of either EP
Primary Treatment for Nonseminoma Stage I With Risk Factors
(preferred) or BEP for patients with pN1 or pN2 disease139,147 and 3 cycles
Surveillance, adjuvant chemotherapy (1 cycle of BEP), or nerve-sparing of BEP or 4 cycles of EP (both preferred) for patients with pN3 disease.
RPLND are the recommended primary treatment options to reduce the risk
of relapse in stage I nonseminoma patients with LVI, invasion of the Follow-up for Nonseminoma Stage I With Risk Factors
spermatic cord, or invasion of the scrotum. In a prospective trial The long-term follow-up for stage I nonseminoma patients with risk factors
(SWENOTECA), stage I nonseminoma patients with or without LVI includes a history and physical examination, serum tumor marker
received 1 course of adjuvant BEP.132 The relapse rate at 5 years was assessment, chest x-ray, and abdominal/pelvic CT scan. In select
3.2% for patients with LVI and 1.6% for patients without LVI. Five-year OS circumstances, an MRI can be considered to replace an abdominal/pelvic
was 100% in both groups.36 The results after a median follow-up of 7.9 CT. The MRI protocol should include visualization of the retroperitoneal
years confirmed the low relapse rate with 1 course of adjuvant BEP, and pelvic nodes and should be performed in centers with experience in
especially in patients with LVI.36 Several other studies using two cycles of interpreting MRI results for testicular cancer. The same imaging modality

Discussion
Testicular Cancer
(CT or MRI) should be used throughout surveillance. All imaging in this S2-3 disease should be individualized. The vast majority of stage IS
setting is performed with contrast. The frequency of these tests varies with patients have serum tumor markers in the S1 range, and they should
the primary treatment modality received by the patient (see Tables 6 and 7 receive primary chemotherapy for good-risk disease: either 3 cycles of
on TEST-B in the algorithm). BEP or 4 cycles of EP (both preferred). Both regimens are category 1
recommendations, and either is preferable to initial RPLND as these
Nonseminoma Stage IS patients nearly always have disseminated disease.148,149
Patients with stage IS nonseminoma exhibit persistent elevation of serum
Management of Nonseminoma Stage IS After Primary Treatment
tumor markers post-orchiectomy, but no radiographic evidence of disease.
However, mildly elevated levels of AFP or beta-hCG after orchiectomy The management of patients with stage IS nonseminoma after primary
must be interpreted with caution, as the reason for marker elevation may treatment with chemotherapy is described below in Advanced Metastatic
be hepatobiliary disease, marijuana use, or hypogonadism. Mildly elevated Nonseminoma (see Management of Good, Intermediate, and Poor-Risk
AFP levels (<20 ng/mL) may not indicate the presence of a GCT and Nonseminoma After Chemotherapy).
should not be used to guide treatment decisions. In addition, in very rare
instances, heterophile antibodies can result in significant false-positive Nonseminoma Stage IIA
elevations of beta-hCG. Elevated beta-hCG due to metastatic disease Primary Treatment for Nonseminoma Stage IIA
typically rises steadily on serial measurements. In a patient with stable (ie,
Treatment for patients with stage IIA nonseminoma depends on post-
not rising) elevated beta-hCG and no other evidence of metastatic
orchiectomy serum tumor marker levels. For patients with normal post-
disease, repeating the test using a different assay should be considered.
orchiectomy levels of AFP and beta-hCG, the NCCN Panel recommends
Furthermore, many different conditions can result in an elevation of LDH,
either nerve-sparing RPLND or chemotherapy with 3 cycles of BEP or 4
including many benign conditions. Therefore, patients should not be
cycles of EP as primary treatment options (both BEP and EP are preferred
treated with chemotherapy for systemic disease if the only evidence of
regimens).150,151 Chemotherapy is considered particularly appropriate if the
systemic disease is an elevation of LDH.
patient has multifocal disease. For stage IIA patients with persistently
Primary Treatment for Nonseminoma Stage IS elevated AFP or beta-hCG levels, the NCCN Panel recommends primary
chemotherapy with 3 cycles of BEP or 4 cycles of EP (both category 1;
The NCCN Panel recommends that stage IS nonseminoma patients be
both preferred).152,153 A bleomycin-free regimen should be considered in
treated with primary chemotherapy if the elevated marker is either AFP or
patients with reduced or borderline GFR and in patients over the age of
beta-hCG. For the purposes of this guideline, the NCCN Panel assumes
50. For select stage IIA nonseminoma patients with borderline
that patients with stage IS disease have markers in the S1 range. It would
retroperitoneal lymph nodes, repeating imaging (chest/abdominal/pelvic
be extraordinarily rare for a patient to have an AFP >1000 ng/mL or a
CT scan) after 4 to 6 weeks to confirm staging before the initiation of
beta-hCG >5000 IU/L and yet have no evidence of metastatic disease on
treatment can be considered.
imaging studies. These guidelines cannot address every possible
situation, and the management of those rare patients with T any, N0, M0,

Discussion
Testicular Cancer
Management of Nonseminoma Stage IIA After Primary Treatment Follow-up for Nonseminoma Stage IIA
Treatment options following primary nerve-sparing RPLND include either The long-term follow-up for stage IIA nonseminoma patients includes a
surveillance or chemotherapy, depending on the number of positive lymph history and physical examination, serum tumor marker assessment, chest
nodes identified. Since RPLND is likely a curative procedure in patients x-ray, and abdominal/pelvic CT scan. In select circumstances, an MRI can
with pN0 disease, surveillance is recommended for this group. be considered to replace an abdominal/pelvic CT. The MRI protocol
Surveillance is also the preferred option for patients with pN1 disease, should include visualization of the retroperitoneal and pelvic nodes and
although chemotherapy with 2 cycles of either EP or BEP can also be should be performed in centers with experience in interpreting MRI results
considered.153,154 If chemotherapy is given, EP is the preferred regimen in for testicular cancer. The same imaging modality (CT or MRI) should be
this setting. The risk of relapse in stage IIA nonseminoma patients with used throughout surveillance. All imaging in this setting is performed with
pN2 or pN3 disease after RPLND is >50%.153,155 This risk is reduced to contrast. The frequency of these tests varies with the primary treatment
<1% with 2 cycles of adjuvant cisplatin-based chemotherapy.153,156,157 modality and post-surgical management received by the patient (see
Therefore, the NCCN Panel prefers 2 cycles of adjuvant chemotherapy Tables 8, 9, and 10 on TEST-B in the algorithm).
with EP (preferred) or BEP to surveillance for pN2 disease and
recommends full-course chemotherapy (and not surveillance) for pN3 Nonseminoma Stage IIB
disease (either 3 cycles of BEP or 4 cycles of EP; both preferred). Primary Treatment for Nonseminoma Stage IIB
Subsequent management after primary chemotherapy depends on the Treatment for patients with stage IIB nonseminoma depends on post-
size of the residual mass on CT scan. Patients should thus undergo orchiectomy tumor marker levels and radiographic findings. When tumor
abdominal/pelvic CT scan with contrast after completing chemotherapy. marker levels are normal, the CT findings determine the proper course of
Chest CT with contrast or chest x-ray may also be considered. If the treatment. If abnormal radiographic findings are limited to lymph node
residual mass is ≥1 cm after chemotherapy, nerve-sparing bilateral metastases within lymphatic drainage sites in the retroperitoneum (ie, the
RPLND is recommended. A bilateral RPLND involves removal of landing zone), patients should receive primary chemotherapy with either 3
lymphatic tissue between both ureters, spanning from the diaphragmatic cycles of BEP or 4 cycles of EP (both preferred). Primary treatment with
crus to the bifurcation of the common iliac arteries. The rationale for this nerve-sparing RPLND should be reserved for highly selected cases. Both
extended region of dissection is the greater likelihood of bilateral disease options of primary chemotherapy or primary nerve-sparing RPLND are
with greater tumor burden.158 Referral to high-volume centers should be comparable in terms of outcome, but side effects and toxicity are
considered for surgical resection of masses post-chemotherapy. different.151 The reported relapse-free survival with either approach is
Surveillance is recommended for patients with no residual mass or a close to 98%.155-157,159,160 If metastatic disease (based on radiographic
residual mass <1 cm. Nerve-sparing bilateral RPLND is a category 2B findings) is not confined to within the lymphatic drainage sites (ie,
recommendation in this setting and may be performed in selected cases. multifocal lymph node metastases with aberrant lymphatic drainage sites),
primary chemotherapy is recommended with either 3 cycles of BEP or 4
cycles of EP (both preferred). For stage IIB nonseminoma patients with

Discussion
Testicular Cancer
persistent marker elevation, the recommended treatment option is also bleomycin-free regimen should be considered in patients with reduced or
primary chemotherapy with either 3 cycles of BEP or 4 cycles of EP (both borderline GFR and in patients over the age of 50.
category 1; both preferred). A bleomycin-free regimen should be
considered in patients with reduced or borderline GFR and in patients over Primary Treatment for Good-Risk Nonseminoma
the age of 50. The IGCCCG good-risk group includes patients with stages IS, IIA (S1),
IIB (S1), IIC, and IIIA disease. Treatment for good-risk GCTs is designed
Management of Nonseminoma Stage IIB After Primary Treatment
to decrease toxicity while maintaining maximal efficacy. Presently, two
The management of patients with stage IIB nonseminoma after primary regimens are recommended by the NCCN Panel: 3 cycles of BEP104,106,161
treatment with either nerve-sparing RPLND or chemotherapy is similar to or 4 cycles of EP105,106,161 (both category 1; both preferred). Both regimens
the post-primary management scheme outlined above for patients with are well tolerated and cure approximately 90% of patients with good-risk
stage IIA nonseminoma (see Management of Nonseminoma Stage IIA disease.161,162
After Primary Treatment).
Primary Treatment for Intermediate-Risk (Stage IIIB) Nonseminoma
Follow-up for Nonseminoma Stage IIB
For patients with intermediate-risk disease, the cure rate is approximately
The long-term follow-up schedule for stage IIB nonseminoma patients is 70% with the standard chemotherapy regimen of 4 cycles of BEP.163,164
similar to the follow-up schedule outlined above for patients with stage IIA Therefore, the NCCN Panel recommends 4 cycles of BEP (preferred), or 4
nonseminoma and is dependent upon the primary treatment modality and cycles of VIP163,165 for patients who may not tolerate bleomycin, for the
post-surgical management received by the patient (see Follow-up for treatment of intermediate-risk nonseminoma. Both regimens are category
Nonseminoma Stage IIA and Tables 8, 9, and 10 on TEST-B in the 1 recommendations. However, if intermediate-risk status is based on LDH
algorithm). levels 1.5 to 3 times the upper limit of normal, then 3 cycles of BEP can be
considered.
Advanced Metastatic Nonseminoma
Primary Treatment for Poor-Risk (Stage IIIC) Nonseminoma
The primary chemotherapy options for patients with advanced metastatic
nonseminoma are based on the IGCCCG risk classification, which The standard chemotherapy regimen for poor-risk disease is 4 cycles of
categorizes patients as good, intermediate, or poor risk.53 When BEP (preferred). Alternatively, 4 cycles of VIP can be used to treat select
determining a patient’s risk classification, the relevant serum tumor marker patients who may not tolerate bleomycin.165 Both regimens are category 1
value is the value on day 1 of cycle 1 of first-line chemotherapy (see Risk recommendations. However, between 20% and 30% of patients with poor-
Classification for Advanced Disease in the algorithm).13 Patients with an risk nonseminoma are not cured with conventional cisplatin-based
extragonadal primary site, whether retroperitoneal or mediastinal, are also chemotherapy and <50% experience a durable complete response to 4
treated with primary chemotherapy. As previously mentioned, a cycles of BEP. Therefore, consultation with a high-volume center should
be considered for these patients.162

Discussion
Testicular Cancer
Management of Good-, Intermediate-, and Poor-Risk Nonseminoma Follow-up for Good-, Intermediate-, and Poor-Risk Nonseminoma
After Chemotherapy
The recommended follow-up tests and their frequencies during
At the conclusion of primary chemotherapy, chest/abdominal/pelvic CT surveillance of good-, intermediate-, and poor-risk nonseminoma after
scan with contrast and measurement of serum tumor marker levels are chemotherapy (with or without post-chemotherapy RPLND) are outlined in
indicated to assess treatment response. If a complete response to Table 8 on TEST-B 2 of 3 in the algorithm.
chemotherapy is found by radiographic imaging and the tumor marker
levels are normal, the NCCN Panel recommends surveillance. Nerve- Second-Line and Subsequent Therapy for Metastatic
sparing bilateral RPLND can be considered in select cases for patients Germ Cell Tumors
who had retroperitoneal lymphadenopathy prior to chemotherapy
(category 2B).166 RPLND is recommended within 4 weeks of the CT scan Second-Line Therapy
and 7 to 10 days of marker measurement. Referral to high-volume centers Patients with disease relapse following first-line therapy, or those who do
should be considered for surgical resection of residual masses following not experience a durable complete response to first-line therapy, are
chemotherapy. divided into favorable or unfavorable prognostic groups based on
prognostic factors.171-173 Favorable prognostic factors include low levels of
If there is a partial response to chemotherapy and the tumor marker levels
post-orchiectomy serum tumor markers, low-volume disease, complete
are normal, then surgical resection of all residual masses is
response to first-line therapy, and the presence of a testicular primary
recommended.167-170 As previously stated, referral to high-volume centers
tumor. Unfavorable prognostic features include an incomplete response to
should be considered for surgical resection of masses post-chemotherapy.
first-line therapy, high levels of serum tumor markers, high-volume
If only necrotic debris or mature teratoma is present in the resected tissue,
disease, and the presence of an extratesticular primary tumor. Regardless
the patient should be put under surveillance. If embryonal, yolk sac,
of prognosis, sperm banking should be recommended to patients before
choriocarcinoma, or seminoma elements are found in the residual mass, 2
the initiation of second-line therapy, if clinically indicated. Patients with
cycles of chemotherapy (EP, TIP, VIP, or VelP) should be administered.
recurrent disease who have not been treated with prior chemotherapy
All regimens are preferred in this setting, though EP should be reserved
should be managed per their risk status, as described in the preceding
for low-volume residual disease.
sections. It is preferred by the panel that patients with recurrent
Patients who experience an incomplete response to chemotherapy with nonseminoma be treated at centers with expertise in the management of
persistently elevated AFP and/or beta-hCG levels should be referred to a this disease. Second-line therapy options for those with favorable or
high-volume center experienced in the management of this disease. unfavorable prognosis include enrollment in a clinical trial (preferred), or
Management of these patients should include close surveillance. Surgical conventional-dose or high-dose chemotherapy. If chemotherapy is given,
resection of residual masses, as described in the previous paragraph, can both conventional-dose and high-dose regimens are preferred in this
also be considered. Salvage chemotherapy should be reserved for setting. The conventional-dose regimens are TIP or VeIP.120,174-176 The
patients with rising markers or other evidence of progressive disease. high-dose regimens include high-dose carboplatin plus etoposide followed
by autologous stem cell transplant,177 or paclitaxel plus ifosfamide followed

Discussion
Testicular Cancer
by high-dose carboplatin plus etoposide with stem cell support.178 followed by surveillance. Referral to high-volume centers should be
Alternatively, a surgical salvage may be considered in patients with an considered for surgical resection of residual masses following
unfavorable prognosis if the relapse is in a solitary resectable site.179 chemotherapy.
It is not known whether high-dose chemotherapy is better than Patients who do not experience a complete response to second-line
conventional-dose chemotherapy in the second-line setting for patients therapy should be managed according to the NCCN Panel’s
with relapsed disease. Therefore, the NCCN Panel recommends clinical recommendations for third-line therapy, summarized below.
trial enrollment as the preferred management option for these patients. An
ongoing, randomized, international phase III trial (TIGER) will compare Third-Line Therapy
second-line standard-dose chemotherapy with high-dose chemotherapy in
Participation in a clinical trial is the preferred treatment option for patients
patients with relapsed GCTs, with OS as the primary endpoint.180,181
who experience relapse following first- and second-line therapy. Patients
Participation in this trial is highly encouraged (Clinical Trial ID:
previously treated with conventional-dose chemotherapy should be
NCT02375204). considered for high-dose regimens. Alternative options for patients
Late relapses (>2 years after completion of primary therapy) occur in 2% previously treated with high-dose regimens include conventional-dose
to 3% of testicular cancer survivors.182,183 The NCCN Panel prefers salvage chemotherapy, surgical salvage (if solitary site of relapse), and
surgical salvage for patients with late relapse, if technically feasible.179 microsatellite instability/mismatch repair (MSI/MMR) testing (if disease
Conventional-dose and high-dose chemotherapy are also options for progresses after high-dose chemotherapy or third-line therapy).
patients with late relapse.
The preferred treatment option for patients who experience a late relapse
(>2 years after completion of second-line therapy) is surgical salvage, if
Management of Metastatic Germ Cell Tumors After Second-Line Therapy
the recurrent mass is resectable. Conventional-dose or high-dose
To assess response after second-line therapy, a CT scan with contrast of chemotherapy (if not previously given), are also options for patients with
the chest, abdomen, pelvis, and any other sites of disease is late relapse.
recommended. Levels of serum tumor markers should also be measured.
In order to maintain optimal efficacy and limit treatment-related toxicities,
Patients experiencing a complete response to second-line therapy with
the chemotherapy regimens previously received by the patient should be
normal marker levels should be put under surveillance. Alternatively,
taken into account when deciding on third-line chemotherapy options.
select patients may receive nerve-sparing bilateral RPLND (category 2B),
High-dose chemotherapy is the preferred third-line option if it has not been
followed by surveillance. For patients with a partial response to second-
previously received. High-dose chemotherapy is also preferred if VIP or
line therapy (as indicated by residual mass on CT scan) and normal
TIP was received as second-line therapy. If high-dose chemotherapy was
marker levels, surgical resection of all residual masses is recommended,
previously received by the patient, then palliative chemotherapy is the
followed by surveillance. Patients with an incomplete response to second-
preferred third-line treatment option. Additionally, the panel considers
line therapy and persistently elevated marker levels should be managed
with either close surveillance or surgical resection of residual masses

Discussion
Testicular Cancer
pembrolizumab immunotherapy to be useful in certain circumstances (ie, salvage regimen (high-dose or conventional-dose chemotherapy) were
in patients with MSI-high/deficient MMR [MSI-H/dMMR] testicular GCTs). treated with pembrolizumab.195 Two patients achieved stable disease for
28 and 19 weeks, respectively, but no partial or complete responses were
The recommended third-line palliative chemotherapy options for patients
observed. There were 6 grade 3 adverse events, but no immune-related
with intensively pretreated, cisplatin-resistant, or refractory GCTs are
adverse events were reported. Therefore, pembrolizumab was well
combinations of gemcitabine with paclitaxel and/or oxaliplatin,184-190 or oral
tolerated but appears to have limited single-agent activity in refractory
etoposide.191 The recommendation for gemcitabine and oxaliplatin
GCTs. However, larger phase II and phase III trials of pembrolizumab in
(GEMOX) is based on data from phase II studies investigating the efficacy
patients with metastatic or refractory testicular cancers are needed to fully
and toxicity of GEMOX in patients with relapsed or cisplatin-resistant
assess the value of this therapy, especially in treating MSI-H/dMMR
GCTs.185,187,189 These studies showed that GEMOX is safe for patients
testicular GCTs.
with cisplatin-resistant testicular GCTs and may offer a chance of
long-term survival.185,187,189 Gemcitabine and paclitaxel is another option
Treatment of Brain Metastases
that has shown promising results in a phase II study.186 Follow-up results
showed long-term disease-free survival in patients who progressed after Brain metastases from testicular GCTs are relatively rare and occur
high-dose chemotherapy and had not received prior paclitaxel or almost exclusively in patients with nonseminoma histology.196 The
gemcitabine.188 A phase II study of patients with treatment-resistant GCTs development of brain metastases may be more common in patients with a
found the combination of gemcitabine, oxaliplatin, and paclitaxel to be higher burden of systemic disease; lung, liver, and/or bone metastases;
effective with acceptable toxicity.184 The overall response rate was 51% high levels of serum beta-HCG (>5000 IU/L); and in those who experience
with 5% of patients achieving a complete response. A second study relapse after cisplatin-based chemotherapy. The prognosis of patients with
reported similar results.190 Additionally, high-dose single-agent oral brain metastases from testicular GCTs is poor, with >50% of patients
etoposide was shown to be effective in a phase II study involving patients dying within 1 year of diagnosis.196,197 Patients with additional adverse
who had previous treatment with cisplatin/etoposide combination prognostic factors, especially those with metachronous brain metastases,
regimens.191 have even worse outcomes.196,198,199
Pembrolizumab, a PD-1 antibody, was recently approved by the FDA for In a recent retrospective analysis, Loriot et al reported on the pattern of
the treatment of patients with unresectable or metastatic MSI-H/dMMR relapse among patients with poor-risk nonseminoma GCTs previously
solid tumors that have progressed following prior treatment and who have treated with chemotherapy.200 After a median follow-up of 4.1 years, 32%
no satisfactory alternative treatment options.192 This first-ever tissue- and were found to have radiographic evidence of brain metastases. The brain
site-agnostic indication was based on phase II clinical trials that was the only site of progression in 54% of these patients and 19%
demonstrated the efficacy of pembrolizumab in MSI-H/dMMR solid experienced progression in the brain as the first progression event.
tumors.193,194 In the first ever phase II trial investigating the efficacy of Furthermore, involvement of the brain was more common among patients
immunotherapy in testicular cancer, 12 patients with nonseminoma GCTs who were previously treated with dose-dense chemotherapy (29%)
who progressed after first-line cisplatin-based chemotherapy and at least 1 compared to BEP (12%). These data suggest that brain metastases from
testicular GCTs may occur more frequently than previously thought, often

Discussion
Testicular Cancer
as the only site of progression, and may be more likely to occur in poor-
risk patients previously treated with dose-dense chemotherapy versus
BEP. However, it is unknown whether this reduced efficacy is due to lower
cerebral drug penetrance used in the dose-dense regimen.
The optimal management of brain metastases from testicular GCTs is
controversial, with a lack of evidence from prospective trials to guide
treatment decisions.196,198 Therefore, management decisions are usually
based on institutional preferences, which may in part explain the large
variation in treatment modalities received by these patients. The NCCN
Guidelines recommend primary treatment with cisplatin-based
chemotherapy for patients with brain metastases. The addition of RT to
chemotherapy regimens can also be considered.201 Surgical resection of
metastatic brain lesions should be performed if clinically indicated and
feasible.

Discussion
Testicular Cancer
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines Version 1.2020 NCCN Guidelines Index

*Timothy Gilligan, MD/Chair † Ellis G. Levine, MD † Kanishka Sircar, MD ≠

Rahul Aggarwal, MD † ‡ Þ Bradley McGregor, MD † Daniel Vaena, MD ‡

Steven L. Hancock, MD § Þ Philip Saylor, MD †

NCCN Guidelines Version 1.2020 NCCN Guidelines Index