J Natl Compr Canc Netw-2012-Motzer-502-35.pdf

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02

Overview

An estimated 8590 new cases of testicular cancerwill be diagnosed in the United States in 2012. 1 Germ cell tumors (GCTs) constitute 95% of malig-nant tumors arising in the testes. These tumors alsooccur occasionally in extragonadal primary sites, butthey are still managed the same as testicular GCTs.Although GCTs are uncommon tumors that consti-tute only 2% of all human malignancies, they are themost common solid tumor in men between 15 and34 years of age. In addition, the worldwide incidenceof these tumors has more than doubled in the past40 years.

Several risk factors for GCT development have

been identified, including history of a GCT, positivefamily history, cryptorchidism, testicular dysgenesis,

NCCN

Testicular Cancer

Clinical Practice Guidelines in Oncology

Robert J. Motzer, MD; Neeraj Agarwal, MD; Clair Beard, MD;

Sam Bhayani, MD; Graeme B. Bolger, MD;

Mark K. Buyyounouski, MD, MS; Michael A. Carducci, MD;

Sam S. Chang, MD; Toni K. Choueiri, MD; Shilpa Gupta, MD;

Steven L. Hancock, MD; Gary R. Hudes, MD; Eric Jonasch, MD;

Timothy M. Kuzel, MD; Clayton Lau, MD; Ellis G. Levine, MD;

Daniel W. Lin, MD; Kim A. Margolin, MD;

M. Dror Michaelson, MD, PhD; Thomas Olencki, DO;

Roberto Pili, MD; Thomas W. Ratliff, MD;

Bruce G. Redman, DO; Cary N. Robertson, MD;

Charles J. Ryan, MD; Joel Sheinfeld, MD; Jue Wang, MD; and

Richard B. Wilder, MD

NCCN Clinical Practice Guidelines inOncology for Testicular Cancer

Key Words

NCCN Clinical Practice Guidelines, NCCN Guidelines, testicular

cancer, germ cell tumors, alpha-fetoprotein, lactate dehydro-

genase, human chorionic gonadotropin, cisplatin, seminoma,

nonseminoma (JNCCN 2012;10:502–535)

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, thereis uniform NCCN consensus that the intervention isappropriate.Category 2B: Based upon lower-level evidence, there is

NCCN consensus that the intervention is appropriate.Category 3: Based upon any level of evidence, thereis major NCCN disagreement that the intervention isappropriate.

All recommendations are category 2A unless otherwisenoted.

Clinical trials: NCCN believes that the best management forany cancer patient is in a clinical trial. Participation in clinicaltrials is especially encouraged.

Please Note

The NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®) are a statement of consensus of theauthors regarding their views of currently accepted ap-proaches to treatment. Any clinician seeking to apply orconsult the NCCN Guidelines® is expected to use indepen-dent medical judgment in the context of individual clinicalcircumstances to determine any patient’s care or treatment.

The National Comprehensive Cancer Network®

(NCCN®

)makes no representation or warranties of any kind regardingtheir content, use, or application and disclaims any respon-sibility for their applications or use in any way.

© National Comprehensive Cancer Network, Inc.2012, All rights reserved. The NCCN Guidelines and theillustrations herein may not be reproduced in any formwithout the express written permission of NCCN.

Disclosures for the NCCN Testicular Cancer Panel

At the beginning of each NCCN Guidelines panel meeting, panel

members disclosed any financial support they have received from

industry. Through 2008, this information was published in an

aggregate statement in JNCCN and online. Furthering NCCN’scommitment to public transparency, this disclosure process has

now been expanded by listing all potential conflicts of interest

respective to each individual expert panel member.

Individual disclosures for the NCCN Testicular Cancer Panel

members can be found on page 535. (The most recent version

of these guidelines and accompanying disclosures, including

levels of compensation, are available on the NCCN Web site at

www.NCCN.org.)

These guidelines are also available on the Internet. For the

latest update, visit www.NCCN.org.


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Testicular Cancer

NCCNGuidelines®

© JNCCN–Journal of the National Comprehensive Cancer Network | Volume 10 Number 4 | April 2012

503

Journal of the National Comprehensive Cancer Network

Text continues on p. 521

and Klinefelter syndrome. GCTs are classified as semi-

noma or nonseminoma. Nonseminomatous tumors of-

ten include multiple cell types, including embryonalcell carcinoma, choriocarcinoma, yolk sac tumor, and

teratoma. Teratomas are considered to be either ma-ture or immature, depending on whether adult-type

differential cell types or partial somatic differentiation,

similar to that present in the fetus, is found. Rarely,a teratoma histologically resembles a somatic cancer,

such as sarcoma or adenocarcinoma, and is then re-

ferred to as a teratoma with malignant transformation.

The serum tumor markers alpha-fetoprotein

(AFP), lactate dehydrogenase (LDH), and β-humanchorionic gonadotropin (β-HCG) are critical in di-

agnosing GCTs, determining prognosis, and assess-ing treatment outcome. These should be determined

before, during, and after treatment and throughout

the follow-up period. Serum tumor markers are use-

ful for monitoring all stages of nonseminomas. Theyare also useful in monitoring metastatic seminomas,

because elevated marker levels is the early sign ofrelapse.

LDH is a less-specific marker than AFP and

β-HCG. AFP is a serum tumor marker producedby nonseminomatous cells (embryonal carcinoma,

yolk-sac tumor) and may be seen at any stage. The

approximate half-life of AFP is 5 to 7 days. A non-

seminoma, therefore, is associated with elevated se-

rum concentrations of AFP. When patients with ahistologically “pure” testicular seminoma have an

elevated level of AFP, it is generally assumed thatan undetected focus of nonseminoma is present.2,3

NCCN Testicular Cancer Panel Members*Robert J. Motzer, MD/Chair†Þ

Memorial Sloan-Kettering Cancer Center

Neeraj Agarwal, MD‡

Huntsman Cancer Institute at the University of UtahSClair Beard, MD§

Dana-Farber/Brigham and Women’s Cancer Center

Sam Bhayani, MDω

Siteman Cancer Center at Barnes-Jewish Hospital and

Washington University School of MedicineGraeme B. Bolger, MD†

University of Alabama at Birmingham

Comprehensive Cancer CenterSMark K. Buyyounouski, MD, MS§

Fox Chase Cancer Center

Michael A. Carducci, MD†Þ

The Sidney Kimmel Comprehensive Cancer Center at

Johns Hopkins

Sam S. Chang, MDω

Vanderbilt-Ingram Cancer Center

Toni K. Choueiri, MD†Þ

Dana-Farber/Brigham and Women’s Cancer Center

Shilpa Gupta, MD†

H. Lee Moffitt Cancer Center & Research InstituteSteven L. Hancock, MD§Þ

Stanford Cancer Institute

Gary R. Hudes, MD†‡

Fox Chase Cancer Center

Eric Jonasch, MD†

The University of Texas MD Anderson Cancer Center

Timothy M. Kuzel, MD‡

Robert H. Lurie Comprehensive Cancer Center of

Northwestern University

Clayton Lau, MDω

City of Hope Comprehensive Cancer Center

Ellis G. Levine, MD†

Roswell Park Cancer Institute

Daniel W. Lin, MDω

University of Washington/Seattle Cancer Care Alliance

Kim A. Margolin, MD†‡

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

M. Dror Michaelson, MD, PhD†

Massachusetts General Hospital Cancer Center

Thomas Olencki, DO†

The Ohio State University Comprehensive Cancer Center –

James Cancer Hospital and Solove Research Institute

Roberto Pili, MD†

Roswell Park Cancer Institute

Thomas W. Ratliff, MD†

St. Jude Children’s Research Hospital/

University of Tennessee Cancer Institute

Bruce G. Redman, DO†

University of Michigan Comprehensive Cancer Center

Cary N. Robertson, MDω

Duke Cancer Institute

Charles J. Ryan, MD†ω

UCSF Helen Diller Family Comprehensive Cancer Center

Joel Sheinfeld, MDω

Memorial Sloan-Kettering Cancer Center

Jue Wang, MD†UNMC Eppeley Cancer Center at

The Nebraska Medical Center

*SRichard B. Wilder, MD§

H. Lee Moffitt Cancer Center & Research Institute

NCCN Staff: Mary Dwyer, MS, and Rashmi Kumar, PhD

KEY:

*Writing Committee Member

Subcomittee: sPrinciples of Radiotherapy for Pure Testicular

Seminoma

Specialties: †Medical Oncology; ÞInternal Medicine;

‡Hematology/Hematology Oncology; §Radiotherapy/

Radiation Oncology; and ω Urology



04

Testicular Cancer Version 1:2012

Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All

recommendations are category 2A unless otherwise indicated.

WORKUP PRIMARY

TREATMENTb

PATHOLOGIC

DIAGNOSIS

a

bQuantitative analysis of beta subunit.

Though rare, when a patient presents with rapidly increasing beta-HCG, symptoms related to disseminated disease and a testicular mass, chemotherapycan be initiated immediately without waiting for a biopsy diagnosis.

c

d

Mediastinal primary site seminoma should be treated by risk status used for gonadal seminomas with etoposide/cisplatin for 4 cycles or bleomycin/etoposide/cisplatin for 3 cycles.

If AFP-positive, treat as nonseminoma.

Suspicious

testicular

mass

Nonseminomatous germ cell tumor

(includes mixed seminoma tumors and

seminoma histology with elevated AFP)

•

•

•

Discuss sperm bankingRadical inguinal orchiectomy

Consider inguinal biopsy of contralateral testis if:

Suspicious ultrasound for

intratesticular

abnormalitiesCryptorchid testisMarked atrophy

•

•

•

•

•

•

H&P

Alpha-fetoprotein (AFP)beta-hCG

Chemistry profileChest x-ray

a

LDH

• Testicular ultrasound

Pure seminoma germ cell tumor

(pure seminoma histology and AFP

negative may have elevated beta-HCG)

c

d;



NCCN Clinical Practice Guidelines in Oncology


505


Version1.2012, 01-17-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be

reproduced in any form without the express written permission of NCCN®.

CLINICAL STAGE

•

•

•

•

•

•

Abdominal/pelvic CTChest CT if:

Positive abdominal CT or abnormal

chest x-rayRepeat beta-HCG, LDH,AFPBrain MRI, if clinically indicatedBone scan, if clinically indicatedDiscuss sperm banking

f

Stage

IA, IB

Stage

IIA, IIB

Stage

IIC, III

See Primary Treatment and Follow-Up(page 506)

See Primary Treatment and Follow-Up(page 506)

See Primary Treatment and Follow-Up

(page 506)

e

f PET scan is not clinically indicated for nonseminoma.

Elevated values should be followed after orchiectomy with repeated determination to allow precise staging.

Stage

ISSee Primary Treatment and Follow-Up(page 506)

POSTDIAGNOSTIC WORKUPe

•

•

•

•

•

Abdominal/pelvic CTRepeat beta-HCG, LDH,AFPBrain MRI, if clinically indicatedBone scan, if clinically indicatedDiscuss sperm banking

± chest imagingf

Stage IA, IB, IS:See Primary Treatment (page 508)

Stage IIA, IIB:See Treatment (page 508)Primary

Stage IIC, IIIA, IIIB, IIIC,and brain metastasis:See Treatment (page 510)Primary

PURE SEMINOMA



06




CLINICAL

STAGE

Stage

IA, IB

FOLLOW-UPPRIMARY

TREATMENT

Surveillance for pT1 or pT2 tumors

Single-agent carboplatin

(AUC = 7 x 1 cycle or AUC = 7 x 2

cycles)

(category 1) (preferred)

(category 1)

RT (category 1)g

•

•

H&P, AFP, beta-HCG, LDH:

every mo for years ,every 6-12 mo for years , then annually Abdominal/pelvic CT every 6 mo for years 1-2,

every 6-12 mo for year 3, then annually for years

4-5; chest x-ray as clinically indicated for years 1-5

3-4 1-23-4 Recurrence, treataccording to extent of

disease at relapse

Recurrence, treat

according to extent of disease at relapse

gSee Principles of Radiotherapy for Pure Testicular Seminoma (pages 513-516).

See Discussion for further information on the management of stage IS.

See Risk Classification for Advanced Disease (page 517).

See Primary Chemotherapy Regimens for Germ Cell Tumors (page 518).

h

i

j

Stage

ISRTg,h

or

or

•

•

H&P, AFP, beta-HCG, LDH:

every mo for years

every 4 mo for year 2,

hen annually Abdominal/pelvic CT

3 1

every 6 mo for year 3, tannually for years 1-3;

chest x-ray as clinically indicated

H&P + AFP, beta-HCG, LDH:

every 4 mo for years 1-2, then annually for

years 3-10 Abdominal/pelvic CT annually for 3 years (for

patients status post only para-aortic RT);

chest x-ray as clinically indicated

Recurrence, treat

according to extent of

disease at relapse

Stage

IIA, IIB

RT to include para-aortic and

ipsilateral iliac lymph nodes to a dose

of 30 to 36 Gy

Consider p

EP for 4 cycles or

g

j

rimary chemotherapy for

selected stage IIB patients:

BEP for 3 cycles

H&P

Chest x-ray every 6 months for years 1-2 Abdominal CT every 6-12 months for years

1-2, then annually for year 3

AFP, beta-HCG, LDH:

every 3 mo for year 1, every 6 months for

years 2-5, then annually for years 6-10Recurrence, treat

according to extent of

disease at relapse

See Postchemotherapy Management

and Follow-Up (page 507)

Stage

IIC, III

Primary chemotherapy:EP for 4 cycles (category 1)or BEP for 3 cycles (category 1)

j

Good risk i

Intermediate

risk i

Primary chemotherapy: j

BEP for 4 cycles (category 1)

See Postchemotherapy Management

and Follow-Up (page 507)

or

EP = Etoposide/cisplatinBEP = Bleomycin/etoposide/cisplatin

PURE SEMINOMAPURE SEMINOMA





507




FOLLOW-UP

H&P + chest x-ray

every 2 mo for

for

then annually Abdominal/pelvic CT

Post RPLND:

3-6 mo, then as

clinically indicated After all other

primarymanagement as

clinically indicatedPET scan as clinically

indicated

,

AFP, beta-HCG, LDH:

year 1,

every 3 mo year 2,

every 6 mo for year 3

and 4,

Recurrence,SeeSecond-LineTherapy(page 512)

Progressive disease

(growing mass or

rising markers)

See Second-Line Therapy for Nonseminoma (page 512)

Chest,abdominal, pelvic

CT scanSerum tumor

markers

No residual massor residual mass

3 cm and

normal markers

Residualmass

(> 3 cm)

and

normal

markers

Surveillance

Consider RPLND, if

technically feasibleor Second-line

chemotherapyor RT (category 2B)

k

l

g

PET scan

(approximately

6 wk post-

chemotherapy)

Positive

Negative Surveillance

STAGE IIB, IIC, III AFTER PRIMARY

TREATMENT WITH CHEMOTHERAPY

POST-

CHEMOTHERAPY

MANAGEMENT

gSee Principles of Radiotherapy for Pure Testicular Seminoma (pages 513-516).

If viable seminoma found by retroperitoneal lymph node dissection (RPLND), see page 510 (residual embryonal, yolk sac, choriocar cinoma, or seminomaelements).

See Second-Line or Subsequent Chemotherapy Regimens for Metastatic Germ Cell Tumors (page 519).

k

l

PURE SEMINOMAPURE SEMINOMA



08




CLINICAL STAGE

Stage IA

Surveillance

or

Nerve-sparing RPLNDm,n

Stage IB

Nerve-sparing RPLND

or

Primary chemotherapy:

BEP for 2 cycles or

BEP for 1 cycle (category 2B)

or

Surveillance for T2

(category 2B)

m,n

j

only See Follow-Up for

Nonseminoma (page 511)

See Follow-Up for Nonseminoma (page 511)

Stage IS

Persistent

marker

elevation

See PostchemotherapyManagement (page 509)

See PostsurgicalManagement (page 509)


j

m

n

See Primary Chemotherapy Regimens for Germ Cell Tumors (page 518).

Retroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers.

See Principles of Surgery (page 520).

PRIMARY TREATMENT

See Primary Treatment (page 510)

Stage IIA

Markers negative

Persistent marker

elevation

Nerve-sparing RPLND

or

Primary chemotherapy (category 2B):

EP for 4 cycles or BEP for 3 cycles

m,n

j


See PostchemotherapyManagement (page 509)


Stage IIB

Markers negative

Persistent marker

elevation

Lymph node metastases,

within lymphatic drainage

sites (landing zone positive)

Multifocal, symptomatic, or

lymph node metastases with

aberrant lymphatic drainage



j

Nerve-sparing RPLND

or



m,n

j

SeePostchemotherapyManagement(page 509)



NONSEMINOMA





509




Negative markers,

residual mass ( 1 cm)on CT scan

≥

Nerve-sparing bilateral RPLNDor

Surveillance(category 2B)

m,n

Negative markers, no

mass or residual mass

(< 1 cm) on CT scan

Nerve-sparing bilateral RPLND

(category 2B)or Surveillance

(category 2B)

m,n

POSTCHEMOTHERAPY MANAGEMENT

Stage IB, IIA, IIB

treated with primary

chemotherapy


jSee Primary Chemotherapy Regimens for Germ Cell Tumors (page 518).m

nRetroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers.


POSTSURGICAL MANAGEMENT

pN0

pN1

Surveillance (preferred)or Chemotherapy:

EP for 2 cycles

or BEP for 2 cycles

j

Surveillance

pN2

Chemotherapy (preferred):

EP for 2 cycles or BEP for 2 cyclesor

j

Surveillance

pN3C (preferred)hemotherapy :

EP for 4 cyclesor BEP for 3 cycles

j


Stage IA, IB, IIA, IIB

treated with nerve-

sparing RPLND

EP = Etoposide/cisplatinBEP = Bleomycin/etoposide/cisplatin

NONSEMINOMA



10




CLINICAL

STAGE

Intermediate

risk

Stage IIIB

i

Poor risk

Stage IIIC

i

Good riskStage IS

Stage IIA,

Stage IIB, S1

Stage IICStage IIIA

i

S1

Primary

chemotherapy: j

EP for 4 cyclesor BEP for 3 cycles

Primary

chemotherapy: j

BEP for 4 cycles

Clinical trial

(preferred)or

BEP for 4 cyclesor VIP for 4 cycles in

selected patients

Primary

chemotherapy: j

p

Complete

response,

negative

markers

Partial response,

residual masses

with normal AFP

and beta-HCG

levels

q

Incomplete

responseq

Surgical

resection of

all residual

masses

Surveillance (category 2B)or Bilateral RPLND category 2B)m,n ± nerve-sparing (

Teratoma or

necrosis

Residual

embryonal, yolk

sac,

choriocarcinoma, or

seminoma elements

Chemotherapy

for 2 cycles(EP or TIP or

VIP /VeIP )

j

j

l

l

See Second-LineTherapy (page 512)

See Follow-Up for Nonseminoma(page 511)

Surveillance

Primary chemotherapy + RT

± surgery, if clinically indicated

j

i

j

l

m

n

o

See Risk Classification for Advanced Disease (page 517).See Primary Chemotherapy Regimens for Germ Cell Tumors (page 518).

See Second-Line or Subsequent Chemotherapy Regimens for Metastatic Germ Cell Tumors (page 519).

Retroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (category 2B).


Patients should receive adequate treatment for brain metastases, in addition to cisplatin-based chemotherapy.

Patients who may not tolerate bleomycin.

There is limited predictive value for PET scan for residual masses.

p

q

PRIMARY TREATMENT POST

CHEMOTHERAPY

MANAGEMENT

Brain

metastaseso

EP = Etoposide/cisplatinBEP = Bleomycin/etoposide/cisplatinTIP = Paclitaxel/ifosfamide/cisplatinVeIP = Vinblastine/ifosfamide/cisplatinVIP = Etoposide/ifosfamide/cisplatin

NONSEMINOMA





511




FOLLOW-UP FOR NONSEMINOMA

Follow-Up for Stage IA, IB on Surveillance Only

Year

1

2

3

4

5

6+

Months between H&P,

markers, chest x-ray

1-2

2

3

4

6

12

Months between

abdominal CT

3-4

4-6

6-12

6-12

12

12-24

Recurrence, See Second-Line

Therapy (page 512)

Table 1 Follow-Up After Complete Response to Chemotherapy and

RPLND

Year

1

2

3

4

5

6+

Months between H&P,


(category 2B for

chest x-ray frequency)

2-3

2-3

3-6

6

6-12

12

Months betweenabdominal/pelvic CT

6

6-12

12

12

12

As clinically

indicated

Table 2

Follow-Up After RPLND Only

Months between H&P,


(category 2B for

chest x-ray frequency)

2-3

2-3

3-6

6

6-12

12

Months between

abdominal/pelvic CT

Baseline

As indicated

As indicated

As indicated

As indicated

As indicated

Table 3

Year

1

2

3

4

5

6+

NONSEMINOMA



12




• ChemotherapyConventional

dose therapy

(VeIP or TIP)

or High-dose

chemotherapy

l

Favorable

prognosis:Low markersLow volumeComplete response

on first-line therapyTestis primary

s

•

•

•

•

Unfavorable prognosis:Incomplete responseHigh markersHigh volumeExtratesticular primaryLate relapse

s

•

•

•

•

•

Incomplete

response or

relapse

Complete

responseFollow-up

Relapse

lSee Second-Line or Subsequent Chemotherapy Regimens for Germ Cell Tumors (page 519).

r It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.

No prior chemotherapy

Prior chemotherapy

Treat as per risk status on page 510

•

•

•

Chemotherapy

Best supportive care

l

High-dose

chemotherapy

(preferred if not

previously given) or Clinical trial

Surgical salvage should be

considered if solitary site

•

•

•

Chemotherapy

High-dose chemotherapy (category 2B)Surgical salvage should be considered if

solitary siteBest supportive care

l

Clinical trial (preferred)or Conventional dose therapy (VeIP or TIP)

or

Palliative

chemotherapyor RT

l

RECURRENCEr SECOND-LINE THERAPY

sExamples of systems used to estimate prognosis are:1) Lorch A, Beyer J, Bascoul-Mollevi C, et al. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure withcisplatin-based first-line chemotherapy. International Prognostic Factors Study Group. J Clin Oncol 2010;28:4906-4911.2) Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med2007;357:340-348.3) Motzer RJ, Geller NL, Tan CC, et al. Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer 1991;67:1305-1310.

Persistentdisease

or

Relapse

Persistent disease

or Relapse

VeIP = Vinblastine/ifosfamide/cisplatinTIP = Paclitaxel/ifosfamide/cisplatin

NONSEMINOMA





513




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.Risk-adapted management using tumor size > 4 cm and rete testis invasion for stage I seminoma is discouraged. This is based on a

validation study in 2010, which revealed that tumor size > 4 cm and rete testis invasion were not predictors of relapse.Linear accelerators with > 6 MV photons should be used when possible.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) 3-dimensional conformal radiation therapy (3D-CRT) than intensity-modulated radiation

therapy (IMRT). 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.Timing of radiotherapy:

Radiotherapy should start within 7 weeks after orchiectomy.Patients should be treated 5 days per week.Patients who miss a fraction should be treated to the same total dose and with the same fraction size, extending the overall

treatment time slightly. Antiemetic medication significantly improves nausea.

1,2

3

4

See NCCN Clinical Practice Guidelines (NCCN Guidelines) in Oncology for

Antiemesis (available in this issue and online at www.NCCN.org). Antiemetic prophylaxis is encouraged at least 2 hours before

each treatment, and some cases may require more frequent dosing.

A discussion of semen analysis and sperm banking before orchiectomy is recommended in patients who wish to preserve fertility. If

sperm banking is desired, it should be performed before imaging and the delivery of adjuvant therapy.

Preparation for Radiotherapy•

5,6

Treatment Planning Principles• A noncontrast 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.

The legs should be separated by a rolled towel of approximately the same diameter as the scrotal shield and its stand.



16




Figure 2Figure 1 Figure 3

PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

References

1. Chung P, Warde P. Stage I seminoma: adjuvant treatment is effective but is it necessary? J Natl Cancer Inst 2011;103:194-196.

2. Chung P. Prognostic factors for relapse in stage I seminoma: a validation study [abstract]. J Clin Oncol 2010;28:Abstract 4535.

3. 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.

4. 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.

5. 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.

6. 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.

7. Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and

contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011;29:957-962.8. Mead GM, Fossa SD, Oliver RT, et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst2011;103:241-249.

9. Garmezy B, Pagliaro LC. Choosing treatment for stage I seminoma: who should get what? Oncology (Williston Park) 2009;23:753, 759.

10. 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;17:1146-1154.

11. Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhancedmagnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;74:844-851.

12. McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology2010;254:31-46.

13. 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 Oncol2005;44:142-148.

14. 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 trialof the German testicular cancer study group (GTCSG). Br J Cancer 2004;90:2305-2311.

15. Shih HA, Harisinghani M, Zietman AL, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvicnodal irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63:1262-1269.

16. Boujelbene N, Cosinschi A, Khanfir K, et al. Pure seminoma: a review and update. Radiat Oncol 2011;6:90.

17. 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 Oncol2005;23:1200-1208.

18. Choo R, Sandler H, Warde P, et al. Survey of radiation oncologists: practice patterns of the management of stage I seminoma of testis in Canada and aselected group in the United States. Can J Urol 2002;9:1479-1485.

19. Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. JClin Oncol 2003;21:1101-1106.

20. Paly J, Efstathiou J, Hedgire S, et al. Mapping patterns of nodal metastases in seminoma: rethinking the para-aortic field [abstract]. Int J Radiat Oncol BiolPhys 2011;81:Abstract 88.





517




Risk Status Nonseminoma Seminoma

Good Risk Any primary site

and

No nonpulmonary visceral metastases

and

Normal AFP

Any HCG

Any LDH

Intermediate Risk Any primary site

and

Nonpulmonary visceral metastasesand

Normal AFP

Any HCG

Any LDH

Poor Risk No patients classified as poor prognosis

Source: Figure 4 from the International Germ Cell Cancer Collaborative Group. International Germ CellConsensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers.J Clin Oncol 1997;15:594-603. Reprinted with permission of the American Society of Clinical Oncology.

1Markers used for risk classification are postorchiectomy.

Testicular or retroperitoneal primary tumor

and

No nonpulmonary visceral metastases

and

- all of:

AFP < 1,000 ng/mL

HCG < 5,000 IU/L

LDH < 1.5 x upper limit of normal

Postorchiectomy markers

Testicular or retroperitoneal primary tumor

and

No nonpulmonary visceral metastasesand

- any of:

AFP 1,000-10,000 ng/mL

HCG 5,000-50,000 IU/L

LDH 1.5-10 x upper limit of normal


Mediastinal primary tumor

or

Nonpulmonary visceral metastases

or

- any of :

AFP > 10,000 ng/mL

HCG > 50,000 IU/LLDH > 10 x upper limit of normal


(postorchiectomy)1

RISK CLASSIFICATION FOR ADVANCED DISEASE



18




PRIMARY CHEMOTHERAPY REGIMENS FOR GERM CELL TUMORS

1

2

3

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 Oncol1997;15:2553-2558.

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 infavorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol 1998;16:702-706.

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 BStudy. J Clin Oncol 1998;16:1287-1293.

EPEtoposide, 100 mg/m IV on days 1-5Cisplatin, 20 mg/m IV on days 1- 5Repeat every 21 days

BEPEtoposide, 100 mg/m IV on days 1- 5Cisplatin, 20 mg/m IV on days 1- 5Bleomycin, 30 units IV weekly on days 1, 8, and 15 or daysRepeat every 21 days

VIPEtoposide, 75 mg/m IV on days 1-5Mesna, 120 mg/m slow IV push before ifosfamide on day 1, thenMesna,1200 mg/m IV continuous infusion on days 1-5Ifosfamide, 1200 mg/m on days 1-5Cisplatin, 20 mg/m IV on days 1-5Repeat every 21 days

2

2

2

2

2

2

2

2

2

1

2

3

2, 9, 16





519




SECOND-LINE OR SUBSEQUENT CHEMOTHERAPY REGIMENS FOR

METASTATIC GERM CELL TUMORS

VeIPVinblastine, 0.11 mg/kg IV push on days 1-2Mesna, 400 mg/m IV every 8 h on days 1-5Ifosfamide, 1200 mg/m IV on days 1-5Cisplatin, 20 mg/m IV on days 1-5Repeat every 21 days

TIPPaclitaxel, 250 mg/m IV on day 1Ifosfamide, 1500 mg/m IV on days 2-5Mesna, 500 mg/m IV before ifosfamide, and then 4 and

8 h after each ifosfamide dose on days 2-5Cisplatin, 25 mg/m IV on days 2-5Repeat every 21 days

2

2

2

2

2

2

2

1

2

Conventional-dose chemotherapy regimens High-dose chemotherapy regimens

Carboplatin, 700 mg/m (body surface area) IVEtoposide, 750 mg/m IV Administer 5, 4, and 3 days before peripheral blood stem cell

infusion for 2 cycles

Paclitaxel, 200 mg/m IV over 24 h on day 1

Ifosfamide, 2000 mg/m over 4 h with mesna protection on days 2-4Repeat every 14 days for 2 cycles followed byCarboplatin, AUC 7-8 IV over 60 min days 1-3Etoposide, 400 mg/m IV days 1-3 Administer with peripheral blood stem cell support at 14- to 21-day

intervals for 3 cycles

2

2

2

2

2

3

4

1

2

3

4

Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. AnnIntern Med 1988;109:540-546.

Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsedtesticular germ cell tumors. J Clin Oncol 2005;23:6549-6555.

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.

Kondagunta GV, Bacik J, Sheinfeld J, et al. Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ celltumors. J Clin Oncol 2007;25:85-90.

Palliative chemotherapy regimens*

GemOx

Paclitaxel/gemcitabine

Gemcitabine/oxaliplatin/paclitaxel

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.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.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;50:893-894.

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. 2007;25:513-516.Mulherin B, Brames M, Einhorn L. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose

chemotherapy with tandem transplants [abstract]. J Clin Oncol 2011;29:Abstract 4562.

Bokemeyer C, Oechsle K, Honecker F, et al. 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.

J Clin Oncol

Gemcitabine/oxaliplatinGemcitabine/paclitaxelGemcitabine/paclitaxel/oxaliplatin

*Please see references for dosing.below



20




PRINCIPLES OF SURGERY

•

•

•

•

•

•

RPLND is the standard approach to the surgical management of nonseminoma germ cell tumor (NSGCT) in both primary and

postchemotherapy setting.

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.

Referral to high-volume centers should be considered for surgical resection of postchemotherapy.

Completeness of resection is an independent and consistent predictive variable of clinical outcome. In postchemotherapy RPLND,

surgical margins should not be compromised in an attempt to preserve ejaculation. Additional procedures and resection of adjacent

structures may be required.

Postchemotherapy RPLND is indicated in patients with metastatic NSGCT with a residual retroperitoneal mass after systemic

chemotherapy and normalized postchemotherapy serum tumor markers.

A full bilateral template RPLND should be performed in all patients undergoing RPLND in the postchemotherapy setting, with the

boundaries of dissection being the renal hilar vessels (superiorly), ureters (laterally), and the common iliac arteries (inferiorly).

• 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 (aorta, IVC) and minimizes the risk of an in-field recurrence.

massesPostchemotherapy setting

NONSEMINOMA




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521

Text continued from p. 503

An elevated serum concentration of β-HCG, whichhas a half-life of approximately 1 to 3 days, may alsobe present with seminomatous and nonseminoma-tous tumors. The elevations of β-HCG must be in-

terpreted with caution, because hypogonadism andmarijuana use may cause benign serum elevations ofβ-HCG.

Nonseminoma is the more clinically aggressivetumor. When both seminoma and elements of a non-seminoma are present, management follows that fora nonseminoma. Therefore, the diagnosis of a semi-noma is restricted to pure seminoma histology and anormal serum concentration of AFP.

More than 90% of patients diagnosed withGCTs are cured, including 70% to 80% with ad-

vanced tumors who are treated with chemotherapy.A delay in diagnosis correlates with a higher stageat presentation. Standard therapy has been estab-lished at essentially all stages of management andmust be closely followed to ensure the potential forcure.

Clinical Presentation

A painless solid testicular mass is pathognomonicfor testicular tumor. More often, patients present

with testicular discomfort or swelling suggestive ofepididymitis or orchitis. A trial of antibiotics may begiven in this circumstance, but persistent tenderness,swelling, or any palpable abnormality warrants fur-ther evaluation.

Diagnosis and Workup

If an intratesticular mass is identified, completeblood count, creatinine, electrolytes, and liver en-zymes should be obtained. Further evaluation in-cludes measurement of serum tumor markers anda chest radiograph. Testicular ultrasound serves to

confirm the presence of a testicular mass and to ex-plore the contralateral testis; it is sensitive and hasan important role in determining whether a mass isintra- or extratesticular.4

Serum tumor markers are critical in assignmentof prognosis and also management during treat-ment. Serum tumor markers are prognostic factorsand contribute to diagnosis and staging.5 Markersare assessed before orchiectomy and repeated afterorchiectomy. Elevated values of β-HCG, LDH, orAFP should be followed up with repeated tests to

allow precise staging.

Biopsy may also be considered if a suspicious in-tratesticular abnormality, such as a hypoechoic massor macrocalcification, is identified on ultrasound. Incontrast, if microcalcifications without any other ab-

normality can be observed, testicular biopsy is notnecessary.

In patients of reproductive age, sperm bankingmust be discussed.6,7 It must be discussed with thepatients before undergoing any therapeutic inter-vention that may compromise fertility, includingsurgery, radiation therapy, and chemotherapy.8–10 Ifsperm banking is desired, it may be performed eitherbefore or after orchiectomy, but certainly before sub-sequent therapy.

Inguinal orchiectomy is considered the prima-

ry treatment for most patients who present with asuspicious testicular mass.11 An open inguinal bi-opsy of the contralateral testis is not routinely per-formed, but can be considered when a cryptorchidtestis or marked atrophy is present.12 The extent ofprimary tumor is classified after orchiectomy, andtherefore pathological (p) stage is assigned to theprimary tumor (T).

Further management is dictated by histology, adiagnosis of pure seminoma or nonseminoma (in-cludes mixed seminoma tumors and seminoma his-

tology with elevated AFP), and the stage. Althoughrare, when a patient presents with rapidly increas-ing β-HCG, symptoms related to disseminated dis-ease, and a testicular mass, chemotherapy can beinitiated immediately without waiting for a biopsydiagnosis.

Risk Classification for Advanced Disease

In 1997, the International Germ Cell Cancer Con-sensus Group (IGCCCG) defined a prognostic

factor–based classification system based on identi-fication of some clinically independent prognosticfeatures, such as extent of disease and levels of serumtumor markers postorchiectomy. Postorchiectomymarkers are used to classify the patient according tothe IGCCCG risk classification. This classificationcategorizes patients with pure seminoma and non-seminoma GCT into good-, intermediate-, or poor-risk groups.13

Stage and risk classification are assigned accord-ing to the American Joint Committee on Cancer

(AJCC) and IGCCCG classification.




Testicular Cancer


22

Pure Seminoma

If a GCT is found, an abdominopelvic CT scan isperformed. Abdominopelvic CT scanning is usedto assess the retroperitoneal nodes.14 A chest CT isindicated if the abdominopelvic CT shows retroperi-toneal adenopathy or the chest radiograph shows ab-normal results. A chest CT scan is a sensitive way toevaluate the thorax and mediastinal nodes.15

The panel members recommend a brain MRI orbone scan only if metastases to these organs is suspected.

Elevated values of β-HCG, LDH, or AFPshould be followed up with repeated tests. Serumconcentrations of β-HCG and LDH may be el-evated in patients with seminoma. An elevatedAFP level indicates nonseminoma, and patientsshould be managed accordingly. Initial manage-ment of pure seminoma involves a radical inguinalorchiectomy. Orchiectomy is both diagnostic andtherapeutic. Patients with seminoma arising froman extragonadal site, such as the mediastinum, aretreated with standard chemotherapy regimens ac-cording to risk status.

Pure Seminoma Stages IA and IB

Primary Treatment for Pure Seminoma Stages IA

and IB: For patients with stages IA and IB pure sem-

inoma, the standard treatment options after initialorchiectomy include surveillance, radiotherapy, orchemotherapy with 1 or 2 cycles of carboplatin. Thedisease-specific survival for stage I disease is 99%, ir-respective of the management strategy used.16 Sever-al prospective nonrandomized studies of surveillancehave been conducted.17–20 The relapse rate seen inthese studies is 15% to 20% at 5 years, and mostof the relapses are first detected in infradiaphrag-matic lymph nodes.18–20 Some studies report tumorsize greater than 4 cm and rete testis invasion as risk

factors for relapse.19,21,22

However, a validation studyby Chung et al.23,24 showed that tumor size greaterthan 4 cm and rete testis invasion were not predic-tors of relapse. Therefore, the panel members dis-courage risk-adapted management based on tumorsize greater than 4 cm and rete testis invasion forstage I pure seminoma. Surveillance is listed as thepreferred option (category 1) for patients with pT1and pT2 disease.

If surveillance is not applicable, alternatives areeither adjuvant carboplatin or adjuvant radiothera-

py, as described later. Each approach has distinct ad-

vantages and disadvantages. The physicians shoulddiscuss these with the patients and their families andpick the best approach on a case-by-case basis.

Oliver et al.25 reported on the results of a trial

that randomized 1477 patients with stage I testicularcancer to undergo either radiotherapy or one injec-tion of carboplatin. In the study, carboplatin (areaunder the cure [AUC] × 7) was administered intra-venously. The dose was calculated by the formula 7 ×

(glomerular filtration rate [GFR, mL/min] + 25 mg).With a median follow-up of 4 years, the relapse-freesurvival rates were similar for both groups.25 Late re-lapses and secondary GCTs can occur beyond 5 and10 years. Therefore, the investigators continued tofollow these patients. The updated results reported

noninferiority of single-dose carboplatin versus ra-diation therapy.26 In an intent-to-treat analysis,the relapse-free rates at 5 years were 94.7% for thecarboplatin arm and 96% for the radiotherapy arm(hazard ratio, 1.25; P = .37). Two cases of contralat-eral GCTs were seen in the carboplatin arm versus15 in the radiation therapy arm, with hazard ratio of0.22; the contralateral GCT-free rates at 5 years are99.8% and 98.8%, respectively. The authors con-cluded that a single dose of carboplatin is less toxicand as effective in preventing disease recurrence

as adjuvant radiotherapy in men with stage I pureseminoma after orchiectomy.26 Two courses of adju-vant carboplatin have also been reported to reducethe relapse rate.27 The panel recommends either 1or 2 cycles of carboplatin AUC × 7 as a category 1recommendation for patients with stages IA and IBpure seminoma.

If radiation therapy is delivered, the panel rec-ommends a total dose of 20 Gy (midplane) in 10 dai-ly 2.0-Gy fractions,28 given to an infradiaphragmaticarea, including para-aortic lymph nodes; in special

circumstances, this area may include the ipsilateralilioinguinal nodes.29–32 Patients for whom radiationtherapy is generally not given include those at high-er risk for morbidity from radiation therapy, such asthose with a history of pelvic surgery. Prophylaxisto the mediastinum is not provided, because relapserarely occurs at this site. For patients with stages IAand IB pure seminoma, adjuvant radiation therapyto include the para-aortic nodes is also a category1 recommendation, although active surveillance ispreferred (see Principles of Radiotherapy for Pure

Testicular Seminoma, pages 513–516).




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523

Follow-Up After Primary Treatment for Pure Sem-

inoma Stages IA and IB: For follow-up, the differ-ent risk of recurrence associated with each treatmentmodality is important to distinguish (surveillance vs.

adjuvant therapy). An analysis of more than 5000patients with stage I seminoma from various trialsshowed that, independent of the treatment modal-ity, the risk of recurrence is highest in the first 2 yearsand decreases after that.33

Follow-up during surveillance includes a historyand physical, with measurement of postorchiectomyserum tumor markers (AFP, β-HCG, and LDH), per-formed every 3 to 4 months for 1 to 2 years, every 6 to12 months for years 3 to 4, and annually thereafter.34, 35

Controversy exists regarding how many imaging

studies must be performed in patients on active sur-veillance. The panel recommends abdominal/pelvicCT every 6 months for years 1 to 2, every 6 to 12months for year 3, and then annually for years 4 to5. The most common site of relapse in patients man-aged with surveillance or adjuvant chemotherapy isthe retroperitoneal nodes. Chest radiographs may beobtained as clinically indicated for years 1 to 5. Theclinical trial TRISST (MRC TE24/Trial of Imagingand Schedule in Seminoma Testis) in the UnitedKingdom is currently studying whether a reduced

CT schedule or MRI could be used as a safe and ef-fective alternative to standard CT-based surveillancein the management of stage I seminoma.36

The risk of recurrence 5 years after adjuvanttreatment is less than 0.3% annually.33 Follow-up ofpatients treated with carboplatin includes a historyand physical, with measurement of post orchiectomyserum tumor markers (AFP, β-HCG, and LDH) per-formed every 3 months the first year, every 4 monthsthe second year, every 6 months the third year, andannually thereafter.

The panel recommends abdominal/pelvic CTannually for the first 3 years after radiotherapy orcarboplatin. In a recently published meta-analysis of2466 patients, Mead et al.16 reported that recurrencerarely occurred after more than 3 years from treat-ment with either radiotherapy or carboplatin. Re-lapse occurred after 3 years only in 4 of the 2466 pa-tients (0.2%).16 They recommend that CT scans ofthe pelvis and chest can be omitted in these patientsas part of routine follow-up. The panel recommendsthat chest radiographs be obtained only as clinically

indicated.

Follow-up of patients treated with radiotherapyincludes a history and physical, with measurementof postorchiectomy serum tumor markers (AFP,β-HCG, and LDH). Follow-up should be performed

every 4 months for 1 to 2 years, and then annuallyfor 3 to 10 years.33 Para-aortic radiation therapy isrecommended when patients with stage I seminomaare irradiated (see pages 513–516). Patients treatedwith para-aortic radiation therapy have a slightlyhigher rate of pelvic relapse than those treated with‘‘dog-leg’’ radiograph.30,33,37,38 Some NCCN Mem-ber Institutions obtain a CT scan of the pelvis onlyevery 6 months for 3 years after para-aortic radio-therapy.33 Others obtain CT scans of the pelvis andabdomen annually for 3 years.30 The panel’s con-

sensus recommendation is for abdominal and pelvicCT scans annually for 3 years in patients treatedwith para-aortic radiotherapy. Chest radiographsshould be obtained only when clinically indicated.Recurrences are treated according to the stage atrelapse.16

Pure Seminoma Stage IS

Primary Treatment for Pure Seminoma Stage IS: According to the AJCC definition, stage IS requirespersistent elevation of serum tumor markers (LDH,AFP, and β-HCG) after orchiectomy. Stage IS isuncommon and patients are generally treated withradiation to an infradiaphragmatic area, includingpara-aortic lymph nodes with or without radiationto the ipsilateral ilioinguinal nodes.30–32

Follow-Up After Primary Radiation Treatment for

Pure Seminoma Stage IS: Follow-up recommenda-tions by the panel for patients with stage IS treatedwith adjuvant radiation therapy are similar to thosefor patients with stages IA and IB treated with adju-vant radiation therapy. Recurrences are treated ac-cording to the stage at relapse.

Pure Seminoma Stages IIA and IIB

Primary Treatment for Pure Seminoma Stages IIA

and IIB: Stage IIA is defined as metastatic disease tolymph nodes, with a lymph node mass measuring lessthan 2 cm in diameter in greatest dimension on CTscan, whereas stage IIB is disease measuring 2 to 5 cmin maximum diameter.

Radiotherapy has been the mainstay of treat-ment in patients with stage IIA and IIB semino-ma.39–41 The standard radiation field compared with

stage I is extended from the para-aortic region to




Testicular Cancer


24

include an ipsilateral iliac field. The relapse rates aremoderate (5%–6% for stage IIA) and overall sur-vival is almost 100%.39,41,42

For patients with stage IIA or IIB seminoma, the

panel recommends radiation therapy to an infradia-phragmatic area, including para-aortic and ipsilateraliliac lymph nodes in 2 anteroposterior–posteroanteriorphases. The initial phase consists of radiation tomodified dog-leg fields at a dose of 20 Gy (midplane)in 10 daily 2.0-Gy fractions29 or 25.5 Gy in 15 daily1.7-Gy fractions.43 The panel prefers modified ‘dog-leg’ fields as described by Classen et al.39 For detailson field arrangement, see pages 513–516. The sec-ond phase (cone down) of radiotherapy consists ofdaily 2.0-Gy fractions to a cumulative total dose of

approximately 30 Gy for stage IIA and 36 Gy forstage IIB.39 As with the management of stage I dis-ease, prophylactic mediastinal radiation therapy isnot indicated for stage II disease.44

For selected patients with stage IIB seminoma,such as those with adenopathy measuring more than3 cm,45 chemotherapy with 4 courses of etoposide andcisplatin (EP) or 3 cycles of bleomycin, etoposide, andcisplatin (BEP) is an alternative to radiotherapy.42,46

Follow-Up for Stages IIA and IIB Pure Semino-

ma After Primary Treatment: The recommended

follow-up schedules for patients with stage IIA/Bseminoma after radiation therapy include a historyand physical, with measurement of postorchiectomyserum tumor markers (AFP, β-HCG, and LDH) per-formed every 3 months for year 1, every 6 months foryears 2 to 5, and then annually for years 6 to 10.

Chest radiograph is recommended every 6months for the first 2 years. An abdominal CT scanis recommended every 6 months in years 1 to 2 andannually in year 3 after radiotherapy. In patients whohave undergone retroperitoneal lymph node dissec-tion (RPLND), it is recommended between 3 to 6months postsurgery and then as clinically indicated.39

The follow-up of patients with stage IIB semi-noma after chemotherapy is similar to follow-up af-ter chemotherapy for patients with stages IIC and IIIseminoma, as discussed in Follow-Up for Pure Semi-noma Stages IIB, IIC, and III After Chemotherapyon page 525.

Pure Seminoma Stages IIC and III

Primary Treatment for Pure Seminoma Stages

IIC and III: Patients with stage IIC or III disease

are those considered at either good or intermediate

risk. All stage IIC and stage III seminoma is consid-ered good-risk disease, except for stage III diseasewith nonpulmonary visceral metastases (e.g., bone,liver, brain), which is considered intermediate-risk.

Standard chemotherapy is used for both groups ofpatients. However, for patients with good risk, 3cycles of BEP47–49 or 4 cycles of EP50–52 are recom-mended. In contrast, more intensive chemotherapy(i.e., 4 cycles of BEP) is recommended for those withintermediate-risk disease.53,54 All of these chemo-therapy options are category 1 recommendations ac-cording to the panel.Postchemotherapy Management of Pure Seminoma

Stages IIB, IIC, and III: After initial chemothera-py, patients with stage IIB, IIC, and III disease are

evaluated with serum tumor markers and a CT scanof the chest abdomen and pelvis. Patients are thenclassified according to the presence or absence of aresidual mass and the status of serum tumor markers.Patients with normal markers and either no residualmass or residual mass of 3 cm or less need no furthertreatment. They should undergo surveillance, as dis-cussed in Follow-Up for Pure Seminoma Stages IIB,IIC, and III After Chemotherapy, on page 525.

In cases of residual tumor larger than 3 cm andmarker levels that are normal, a PET scan is recom-

mended to assess whether residual viable tumor ispresent.55 A PET scan has high positive and negativepredictive values with regard to the question of re-maining disease in patients with residual masses afterchemotherapy.56 To reduce the incidence of false-positive results, the PET scan is typically performedat least 6 weeks after completion of chemotherapy. Notably, granulomatous disease, such as sarcoid, isa source of false-positive results. The panel recom-mends a PET scan in patients with seminoma, a re-sidual mass larger than 3 cm, and normal levels of

markers, approximately 6 weeks after chemotherapyto determine whether to continue with surveillanceor resume treatment.55,57–61

If the PET scan is negative, no further treatmentis needed; however, the patient should undergofollow-up,62,63 as discussed in the next section onFollow-Up for Pure Seminoma Stages IIB, IIC, andIII After Chemotherapy.

Because a positive PET scan is a strong indicatorof residual active tumor, resection should be consid-ered. Therefore, if technically feasible, RPLND may

be considered (category 2A). The other option, if re-




Testicular Cancer


26

diograph, and an abdominal CT scan. The frequencyof these tests is outlined in Follow-Up for Nonsemi-noma, page 511.

Nonseminoma Stage IB

Primary Treatment of Nonseminoma Stage IB: Af-ter orchiectomy, either nerve-sparing RPLND or ad-juvant chemotherapy is an option to reduce the riskof relapse in patients with stage IB disease.

Several studies using 2 cycles of BEP as primarytreatment for patients with stage I nonseminomahave reported relapse-free survival in more than95% of patients,76,82,86–90 leading the panel to con-sider this approach a category 2A recommendation.Late consequences of cisplatin-based chemotherapyhave been reported based on long-term follow-up

of patients.91–96 A trial by Albers et al.97 randomizedpatients with stage I disease after orchiectomy to un-dergo unilateral RPLND (n = 191) or one adjuvantcourse of BEP (n = 191). After a median follow-upof 4.7 years, 2 relapses were reported in the group ofpatients treated with one course of adjuvant BEP andin 13 patients with relapse in the arm treated withRPLND (P = .0011). This study indicates that onecourse of BEP is active, and could be an option inpatients unable to tolerate the toxicity of treatment.The comparator arm in this trial (unilateral RPLND)

is not the standard treatment approach. Therefore,although the results of this study are promising, thisapproach merits further investigation comparing 1cycle of BEP versus 2 cycles with longer follow-up.The panel considers 1 cycle of BEP a category 2Boption as primary therapy.

Surveillance alone may be offered to selectedpatients with T2 disease (category 2B). Vascularinvasion is a significant predictor of relapse whenorchiectomy is followed by surveillance alone.11 Surveillance is generally not recommended for T2

disease with vascular invasion because of the 50%chance of relapse. Exceptions are made accordingto individual circumstances. When surveillance isopted in selected patients with T2 disease, both thepatient and physician must be compliant with fol-low-up recommendations.

Management of Nonseminoma Stage IB After

Primary Treatment: The adjuvant treatment af-ter primary nerve-sparing RPLND for patients withIB disease is similar to that described for stage IAin Management of Nonseminoma Stage IA After

RPLND, page 525.

Management after primary chemotherapy in pa-tients with normal values of serum tumor markersmay be nerve-sparing RPLND or surveillance. Thepanel considers nerve-sparing bilateral RPLND a

category 2A recommendation for patients with re-sidual mass of 1 cm or greater and a category 2B rec-ommendation if the residual mass is smaller than 1cm. Surveillance is category 2B for both populations.In the current guidelines, the long-term follow-uptests for patients electing surveillance include serummarker assessment, chest radiograph, and abdominalCT scan. The frequency of these tests is outlined inFollow-Up for Nonseminoma, on page 511.

Nonseminoma Stage IS

Patients with stage IS disease exhibit a persistentelevation of serum tumor markers postorchiectomybut no radiographic evidence of disease. The el-evated levels of AFP and β-HCG after orchiectomymust be interpreted with caution, because these maybe from causes other than disseminated nonsemi-noma, such as hepatobiliary disease, marijuana use,and hypogonadism.Primary Treatment of Nonseminoma Stage IS: Thepanel consensus recommendation is that these pa-tients be treated with standard chemotherapy witheither 4 cycles of EP or 3 cycles of BEP. Either regi-men is preferable to initial RPLND, because thesepatients nearly always have disseminated disease.98,99

Management of Stage IS Nonseminoma Postpri-

mary Treatment: The management of patients withstage IS nonseminoma after primary treatment withchemotherapy is similar to the management schemaoutlined for patients with good-risk nonseminoma,including stages IIB, IIC, and IIIA, described in thefollowing sections.

Nonseminoma Stage IIA

Primary Treatment of Nonseminoma Stage IIA: Treatment for patients with stage IIA nonseminomadepends on postorchiectomy serum tumor markerlevels.

For patients with stage IIA disease and normalpostorchiectomy levels of AFP and β-HCG, thepanel considers either primary RPLND (category2A) or chemotherapy (category 2B) as treatmentoptions.100–104 The chemotherapy regimens include4 cycles of EP or 3 cycles of BEP. Chemotherapy isconsidered particularly appropriate if the patient has

multifocal disease.




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For patients with persistently elevated AFP orβ-HCG levels, the panel recommends inductionchemotherapy, based on data from 2 retrospectivestudies of patients with low-stage nonseminoma

treated with RPLND.105,106 The presence of elevatedpostorchiectomy AFP or β-HCG levels was associ-ated with a high risk of relapse.105,106

Management after primary chemotherapy andRPLND is discussed in the following sections.

Management After Primary Treatment of Nonsem-

inoma Stage IIA: After primary chemotherapy, sub-sequent management depends on marker levels andthe residual mass on CT scan. Therefore, patientsmust undergo a CT scan before treatment is decided.Lesions smaller than 1 cm on CT scan may represent

false-positives and must be interpreted with cau-tion. The options listed by the panel for managingpatients with stage IIA disease after primary chemo-therapy include nerve-sparing bilateral RPLND orsurveillance.

The panel considers nerve-sparing bilateralRPLND a category 2A recommendation for patientswith a residual mass of 1 cm or greater, and a category2B recommendation if the residual mass is less than1 cm. A bilateral RPLND involves removal of lym-phatic tissue between both ureters, spanning from

the diaphragmatic crus to the bifurcation of the com-mon iliac arteries. The rationale for this extendedregion of dissection is the greater likelihood of bilat-eral disease with greater tumor burden.107 Referral tohigh-volume centers must be considered for RPLNDpostchemotherapy. Surveillance, however, is a cat-egory 2B recommendation for both populations.

After primary nerve-sparing RPLND, treatmentoptions include either surveillance or chemotherapy.The treatment choice depends on the number ofpositive lymph nodes identified. For example, be-

cause RPLND is likely a curative procedure in pa-tients with pathologic stage N0 (pN0), surveillanceis the only option listed for this group. Surveillanceand chemotherapy are options for patients with pN1and pN2 disease. RPLND is a curative procedure in60% to 90% of patients with pN1 disease,106,108,109 and therefore the panel prefers surveillance overchemotherapy for these patients. The risk of re-lapse in patients with pN2 through pN3 disease isgreater than 50%.106,108,110 With 2 cycles of adjuvantcisplatin-based chemotherapy, the risk of relapse af-

ter RPLND is generally less than 1%.106,111,112

The

panel prefers 2 cycles of adjuvant chemotherapy forpN2 disease, and full-course chemotherapy (not sur-veillance) is recommended for pN3 disease. Recom-mended adjuvant chemotherapy regimens for pN1

and pN2 disease consists of 2 cycles of either BEP orEP,113 resulting in a relapse-free survival rate of nearly100%. For pN3, the panel recommends a longer che-motherapy course consisting of either 4 cycles of EPor 3 cycles of BEP.

If patients with stage IIA disease have persistentmarker elevation (i.e., stage IIA, S1), the primarytreatment is chemotherapy as described later forgood-risk nonseminoma.

Nonseminoma Stage IIB

Primary Treatment of Nonseminoma Stage IIB:

Treatment for patients with stage IIB nonsemino-ma depends also on both postorchiectomy tumormarker levels and radiographic findings. When tu-mor markers are negative, the CT findings deter-mine the proper course of treatment. If abnormalradiographic findings are limited to sites within thelymphatic drainage in the retroperitoneum (i.e., thelanding zone), 2 management options are available.One option is to perform nerve-sparing RPLND andconsider adjuvant treatment as described for patientswith stage IIA disease. The second option is to treat

with primary chemotherapy involving either 4 cyclesof EP or 3 cycles of BEP, followed by nerve-sparingRPLND or surveillance.

Both options of primary chemotherapy or pri-mary RPLND are comparable options in terms ofoutcome, but side effects and toxicity are different.101 The reported relapse-free survival with either ap-proach is close to 98%.108,113–118

If metastatic disease (based on radiographicfindings) is not confined to the lymphatic drainage(i.e., multifocal lymph node metastases outside the

lymphatic drainage sites), chemotherapy is recom-mended with either 4 cycles of EP or 3 cycles of BEP,followed by nerve-sparing RPLND or surveillance.

For patients with stage IIB disease with persis-tent marker elevation (stage IIB, S1), the primarytreatment is chemotherapy as described for good-risknonseminoma, including stages IS, IIC, and IIIA inlater sections. Initial RPLND is not recommended inthis situation.

Management After Primary Treatment of Nonsem-

inoma Stage IIB: The management of patients with

stage IIB nonseminoma after primary treatment with




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either nerve-sparing bilateral RPLND or chemother-apy is similar to the management scheme outlinedearlier for patients with stage IIA nonseminoma af-ter primary treatment.

Advanced Metastatic Nonseminoma

The preferred primary chemotherapy regimensfor patients with advanced disease depends on theIGCCCG risk classification.13 This classificationcategorizes patients as good-, intermediate-, or poor-risk.13 Also, patients with an extragonadal primarysite, whether retroperitoneal or mediastinal, aretreated with initial chemotherapy.Primary Treatment of Good-Risk Nonseminoma: Based on the IGCCCG good-risk classification, thisgroup includes patients with stages IS; IIA and IIB

(with persistent marker elevation); IIC; and IIIAdisease. Treatment for good-risk GCTs were designedto decrease toxicity while maintaining maximal effi-cacy. Randomized clinical trials showed that this canbe achieved through either substituting etoposide forvinblastine,119,120 or eliminating or reducing the doseof bleomycin.119,121 Currently, 2 regimens are recom-mended by the panel: 4 cycles of EP51 or 3 cycles ofBEP47,49,122,123 (both category 2A). Either regimen iswell tolerated and cures approximately 90% of pa-tients with good risk.124

Primary Treatment of Intermediate-Risk (StageIIIB) Nonseminoma: For patients with intermediaterisk (stage IIIB), the cure rate is approximately 70%with standard therapy using 4 cycles of BEP,125,126 andthis is a category 2A recommendation by the panel.Primary Treatment of Poor-Risk (Stage IIIC) Non-

seminoma: Between 20% and 30% of all patients withpoor-risk, (stage IIIC) metastatic GCTs are not curedwith conventional cisplatin therapy, and fewer thanone-half experience a durable complete response with4 cycles of BEP, and therefore the panel lists treatment

in a clinical trial as the preferred option.124

The standard chemotherapy regimen for poor-

risk patients is 4 cycles of BEP. The regimen contain-ing etoposide, ifosfamide, and cisplatin (VIP) wascompared with BEP and found to be more toxic thanBEP but equally as effective. Therefore, 4 cycles ofVIP may be used for patients who may not toleratebleomycin.127 Postchemotherapy Management for Good-,

Intermediate-, and Poor-Risk Nonseminoma: Atthe conclusion of induction chemotherapy, CT scans

of the abdomen and pelvis are indicated, along with

serum tumor marker assays. PET scans for residualdisease have limited predictive value. The frequencyof these tests is outlined in Follow-Up for Nonsemi-noma, on page 511.

If a complete response to chemotherapy is foundthrough radiographic imaging and the tumor markersare negative, the panel lists 2 management options:surveillance (category 2B) or bilateral RPLND usingnerve-sparing technique, if possible (category 2B).63

If a residual mass is found and the serum tumormarkers (AFP and β-HCG) have normalized, thenall sites of residual disease are resected.128–130 If onlynecrotic debris or mature teratoma is encountered,no further therapy is necessary and patients must beput under surveillance. If embryonal, yolk sac, cho-

riocarcinoma, or seminoma elements are found inthe residual mass, 2 cycles of conventionally dosedchemotherapy (EP, VelP, or TIP) are administered.

After patients are rendered disease-free, stan-dard surveillance is initiated. The frequency of thesefollow-up tests is outlined in Follow-Up for Nonsem-inoma, on page 511.

Patients who experience an incomplete responseto first-line therapy are treated with second-linetherapy (see following section). The panel prefersthat patients with recurrent nonseminoma be treat-

ed at centers with expertise in the management ofthis disease.

Second-Line Therapy for Metastatic GCTs

Patients who do not experience a durable completeresponse to first-line therapy or those who experi-ence a recurrence can be divided into those with afavorable or unfavorable prognosis based on prognos-tic factors. Prognostic factors can be used in decidingwhether a patient is a candidate for conventional-

dose therapy or high-dose therapy with stem cellsupport as a second-line option. To determine theprognosis at initial diagnosis, the IGCCCG classifi-cation is used. However, for patients with progressiveor relapsed disease after first-line treatment, severalprognostic models have been reported.131–133

Favorable prognostic factors for conventional-dose second-line chemotherapy include a testicularprimary site, prior complete response to first-linetherapy, low levels of postorchiectomy serum tu-mor markers, and low-volume disease.131 Standard

second-line therapy includes conventional-dose




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chemotherapy or high-dose chemotherapy. Theconventional-dose regimen includes cisplatin andifosfamide combined with either vinblastine or pa-clitaxel.134 In patients who experience an incom-

plete response or disease relapse after second-lineconventional-dose chemotherapy, the preferredthird-line option would be high-dose chemothera-py135,136 or chemotherapy in the context of a clinicaltrial.

Unfavorable prognostic features include incom-plete response to first-line treatment, high levels ofserum markers, high-volume disease, and presence ofan extratesticular primary tumor. Patients with a tes-ticular primary site and rising postorchiectomy serumtumor markers during first-line therapy are usually

considered for high-dose programs. Chemotherapyoptions for patients with poor prognostic features in-clude chemotherapy in the context of a clinical trial,conventional-dose second-line therapy (with VeIPor TIP), or high-dose chemotherapy (category 2B).Alternatively, patients may undergo best supportivecare or salvage surgery if feasible.

The high-dose regimens include high-dose car-boplatin plus etoposide followed by autologous stemcell transplant132,137 or paclitaxel plus ifosfamide fol-lowed by high-dose carboplatin plus etoposide with

stem cell support (see Second-Line or SubsequentChemotherapy Regimens for Metastatic Germ CellTumors, page 519).138

For patients who do not experience complete re-sponse to second-line, high-dose therapy, the diseaseis nearly always incurable; the only exception is therare patient with elevated serum tumor markers anda solitary site of metastasis (usually retroperitoneal)that undergoes surgical resection.139 Other optionsare participation in a clinical trial or best supportivecare.

Palliative TherapyAll patients with either persistent or recurrent dis-ease should be considered for palliative chemothera-py or radiation therapy.

Palliative chemotherapy options for patientswith intensively pretreated, cisplatin-resistant, or re-fractory GCTs are combinations of gemcitabine andpaclitaxel and/or oxaliplatin.140–145

The recommendation for gemcitabine and oxali-platin is based on data from phase II studies140–142 thatinvestigated the efficacy and toxicity of gemcitabine

and oxaliplatin in patients with relapsed or cisplatin-

refractory GCTs. The results showed that the oxali-platin and gemcitabine combination is safe for pa-tients with cisplatin-refractory testicular GCTs, andmay offer a chance of long-term survival.140–142

Gemcitabine and paclitaxel is another op-tion that has shown promising results in a phase IIstudy,144 and long-term follow-up results with thiscombination show long disease-free survival in rarepatients who experienced progression after high-dosechemotherapy and had not received prior paclitaxelor gemcitabine.145

Furthermore, a phase II study of patients withtreatment-refractory GCTs found the combinationof gemcitabine, oxaliplatin, and paclitaxel to be ef-fective, with acceptable toxicity.143

Therefore, for palliative therapy, the panel rec-ommends gemcitabine with oxaliplatin140–142; gem-citabine with paclitaxel144,145; or gemcitabine withoxaliplatin and paclitaxel143 (all are category 2Arecommendations).

Treatment of Brain Metastases

The prognosis of patients with brain metastasis ispoor.146 Primary chemotherapy (using a cisplatin-based regimen) with radiotherapy is indicated for

patients in whom brain metastases are detected.147,148

If clinically indicated and feasible, surgical resectionof the metastasis should also be performed.

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