Testicular Seminoma

Dr. John T. Lucas Jr.Wake Forest Baptist Medical

CenterDepartment of Radiation Oncology

• Epidemiology• Risk Factors• Presentation• Workup

– Labs, Imaging• Management• Histology• Anatomy• Staging, Prognosis• Tis (testicular ca in situ)• Stage 1: Rt, Chemo, Observation vs. Treatment• Stage 2A/B• Stage 2C/3• Acute and Late Effects

Outline

Epidemiology

• Most common solid tumor 15-35 yoa • Peak incidence at 25-40yo and >65yo• 1% of all men• Increasing incidence over past 40 yrs

• 2 new cases per 100,000 in 1930’s• 3.7 new cases per 100,000 in 1969-1971 • 5.4 new cases per 100,000 in 1995-1999

• 8250 new cases per year in US• Distribution:

– Scandinavia, Germany, New Zealand ancestry

• W:AA = 5:1• Does not occur before puberty• 2-3% have bilateral metachronus ca

AJR

• Cryptorchidism – 4x higher in intra abdominal testes than those in inguinal

canal– Risk in both descended and undescended testis– Risk still elevated after orchidopexy, if performed before

10yo slightly decreased risk

• Intratubular germ cell neoplasia (50% progress to Ca)• First born male• Pre/perinatal high estrogen exposure

– Testicular feminization

• Polyvinyl chloride exposure• Klinefelter’s – predisposes to mediastinal GCTs

Risk Factors

• Prior GCT in contralateral testis (5.2% over 25yrs)

• Advanced maternal age• Down’s Syndrome• HIV/AIDS• Family History• Testicular Trauma• Chromosomal abnormalities involving chromo

1 & 12

Risk Factors

• GCT's are nearly always aneuploid• i(12p) genetic material is present in >80% of

GCTs, cIS & is one of the earliest genetic events.

• Have >= X & Y indicating transformation prior to meiotic anaphase

• Candidate genes: – CDKN2A, Ras, Oct1

Genetics/Etiology

• Most commonly present as a unilateral testicular mass increasing in size– Can be painless (pain in 10%)– Associated with discomfort or swelling– Differential includes epididymitis or orchitis

• 5% w/Gynecomastia• Ultrasound initial evaluation• 20% of pts have + bilateral nodes

Presentation

• Hydrocele / Spermatocele• Orchitis / Epididimitis • Testicular Tumor• Testicular torsion, Hernia, & Hematoma

Differential Diagnosis

• AFP, beta HCG, LDH– If HCG elevated, can be

pure seminoma– AFP not elevated in

seminoma– LDH high in metastatic

disease

• CBC, BMP, Coags– Prior to patient orchiectomy

Labs

Histology Frequency

% HCG+ % AFP+ % PLAP+ Comments

Seminoma 45-50% 15-30% 0% 90%Most common, HCG

related to presence of syncytiotrophoblasts

Embryonal 3% 21% 33% >95%Seen in 50% of mixed

Yolk sac 2% 0% > 95% ?Schiller-Duvall bodies

Teratoma 5% 0 0 ?50% of mixed

Chorio-carcinoma 0.05% > 99% 0 ?

4% of mixed

Mixed (any combo of non-seminoma)

45-50% Varies Varies Varies Most common non-seminomatous GCT

PLAP- placental alkaline phosphatase

Tumor Markers

• Chest X-ray– If abnormal adenopathy, CT of chest recommended

• CT abdomen/Pelvis– Rule out nodal involvement– Regional nodes are paraaortic

• Clinical signs of bone or brain involvement warrants MRI & bone scan

Imaging

• Fertility assessment/Semen Analysis– >50% underlying fertility impairment

• Sperm Banking 30-50% Result in pregnancy

• Biopsy– Transcrotal biopsy NOT appropriate, risk of

local dissemination of tumor into scrotum or spread to local lymph nodes.

Management

Surgical Evaluation: Orchiectomy• Radical Inguinal

Orchiectomy – Scrotal violation shows

increased risk of LR 2.9% vs. 0.4%

– No difference in DMFS or OS– Capelouto et al.

• Transscrotal Orchiectomy (leaves inguinal portion of the spermatic cord left intact) – Assoc w/a 24% incidence of LR & spread to inguinal, peri-

aortic LN.

Surgical Evaluation: Orchiectomy

Histology/Seminoma subtype

• Classic: >90% of cases, +PLAP, 20-40yo, fried egg appearance

• Spermatocytic: mean 54yo, cured by orchiectomy, rarely mets, -PLAP

• Anaplastic: No longer a subtype since mitotic count is

not prognostic

SeminferousTubule filled with Abmormal cells

Normal SeminferousTubule with orderlyMaturation from the Basement membrane

Histology

Histology

Anatomy

Anatomy

Staging/Anatomy

Outside to Inside:• Skin • Tunica dartos • External spermatic fascia • Cremaster muscle • Internal spermatic fascia • Parietal layer of tunica

vaginalis • Visceral layer of tunica

vaginalis • Tunica albuginea

– Regional nodes:• Interaortocaval, para-aortic,

paracaval, preaortic, precaval, retroaortic, retrocaval

Staging/Anatomy

Staging/Anatomy

AJCC Staging

•R: testicular v. IVC below renal v. interaortocaval LNs•L: testicular v. L renal v. paraaortic LN•Both beyond renal v. cysterna chyli retrocrural or

mediastinal LAD•Inguinal surgery may redirect drainage through iliac nodes

Lymphatic Drainage

Prognosis/Treatment Paradigm

•Stage 0: RT alone

•Stage I: 98%

• Orchiectomy + inguinal/para-aortic+ipsi iliac RT

• vs. Orchiectomy + 1C AUC7 Carboplatin

• vs. Surveillance

•Stage IIA,B: 91%

• Orchiectomy + inguinal/para-aortic+ipsi iliac RT

• vs. Orchiectomy + 4C EP vs. 3C BEP

•Stage IIC, III: 75%

• 4C EP vs. 3C BEP

•Surveillance/Risk Adapted Management

• Toronto, 2005 & Spanish GCT Group studies

•RT Dose

• MRC Trial TE 18 - Jones WG et al. JCO. Feb 2011

•RT Field Size

• MRC Trial TE 10 - Fossa SD, JCO. 1999

•Stage 1 Seminoma: RT vs. Chemo

• MRC TE19/EORTC 30982 - Oliver RT et al. Lancet. 2005

•Stage 2 Seminoma

• RT: Tubingen German Trial - Classen J. JCO. 2003

• Chemo: Spanish GCT Group Garcia-Del-Muro X, JCO. 08’

Literature

Stage 0 (Carcinoma in situ of the testes)

• Testicular intraepithelial neoplasia (TIN)• 70% risk of invasive Ca at 7yrs• Chance of pt w/ h/o testicular Ca to develop 2nd testic 1 ~ 3%

• Historically well controlled w/ 20Gy/10fx• RT assoc w/25% androgen deprivation (~4%/yr)• Peterson 2008 JCO, Classen Br J Ca 2003

– De-escalation to (-) androgen decrementshowed no clear dose–response relationship

– 14Gy resulted in more relapses indicating that 20Gy is still optimal

Lancet. 1986 Mar 15;1(8481):624-5. RT treatment of carcinoma-in-situ of testis. von der Maase H, Giwercman A, Skakkebaek NE.

"Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis." (Petersen PM, J Clin Oncol. 2002 Mar 15;20(6):1537-43.)

Stage 1: Surveillance/Risk Adapted f/u•Factors predictive of relapse: (Warde 02’)

• Tumor Size (≤4 cm v >4cm, HR 2.0; 95% CI 1.3-3.2)

• Invasion of rete testis (HR 1.7; 95% CI 1.1-2.6)

•Prospective Validation

• 2nd Spanish Germ Cell Ca Group Study

• 3rd Spanish Germ Cell Ca Group Study

"Risk-adapted management for patients with clinical stage I seminoma: the 2nd Spanish GC COG study." (Aparicio J, J Clin Oncol. 2005 Dec 1;23(34):8717-23. "Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma." (Choo R, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):736-40.)"Risk-Adapted Treatment in Clinical Stage I Testicular Seminoma: The Third Spanish Germ Cell Cancer Group Study." (Aparicio J, J Clin Oncol. 2011 Oct 31.Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis. J Clin Oncol 20:4448-4452, 2002

No RF

>1 RF

Surveillance

2C AUC 6 Carboplatin

6% Relapse

3.3% Relapse

EP

96.2% OS

93.4% OS

EP

0-1 RF

2 RF

Surveillance

2C AUC 6 Carboplatin

7% Relapse

1.4% Relapse

EP, P or RT

98% 3yr DFS

88% 3yr DFS

EP, P, or RT100% OS

100% OS

Historical SeriesToronto Series

Stage 1: Chemotherapy• Steiner et al 2002

– 2C Carboplatin AUC 7 2% Relapse at 5 yrs

• Dieckmann et al in 2000– 1C Carboplatin AUC 7 8% RR at 4 yrs

Stage 1: Radiotherapy Dose

• MRC Trial TE 18 2005 – Randomized Prospective Phase 3

30Gy/15fx313 ptnts

20Gy/10fx312 ptnts

QOL Assessment

10% (-) Ability to do work

baseline 11 Relapses

10 RelapsesRadicalInguinal

Orchiectomy

• Moderate/Severe lethargy - NS @ 12wks• 20 Gy / 10 fx Sufficient

Treatment DFS Acute Lethargy

Acute Ability to Work

30 Gy 97 20% 46%

20 Gy 97 5% 28%

P value NS SS SS

n = 236 n = 242PA DL

Stage 1: Radiotherapy Field Size

"Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group." (Fossa SD, J Clin Oncol. 1999 Apr;17(4):1146.)

• MRC Trial TE10 – Prospective Randomized Study

30 GyDL

30 GyPA

9 relapses0 DL

9 relapses4 Pelvic PA

RadicalInguinal

Orchiectomy

100% OS

98% OS

• Sperm Count:

PA11% vs. DL35%

• Acute tox: PA<DL

ParaaorticSup: T10-11 Inf: L5-S1 Lateral: 2 cm on vertebral bodies. - If L-sided 1o, give 1-cm border on L renal hilum & SI joint.

Stage 1: Radiotherapy Field Size• Additional Field Considerations

– If prior Herniorrhaphy\Orchiopexy: consider coverage of contralateral inguinal region, as there may be altered lymphatic flow

– If Scrotal Orchiectomy\Biopsy: Inguinal and hemiscrotum must be covered

– If scrotal invasion Tx ipsi hemi-scrotum

– Blocking : If Pt desires to preserve fertility, scrotal shield blocking of contralateral testis should limit dose to <1%, but document with TLDs

• Clamshell reduces testicle dose by 2-3x

– Kidneys should be limited to at least 70% <20Gy

Stage 1: Radiotherapy vs. Chemo• MRC Trial TE19/EORTC 30982 – Prospective Randomized Study

Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005 Jul 23-29;366(9482):293-300.

1C CarboAUC7

RT 20-30GyPA or DL

5yrs RFS 94.7%

5yrs RFS 96%

RadicalInguinal

Orchiectomy

• 2nd Testicular Ca:– RT 15 vs. 2 Carbo

• RT arm: 1 death from seminoma

Stage 1: Radiotherapy vs. Chemo• Chemo

– Advantages• 1-2 C of chemo w/high disease control rates

– Disadvantages• More costly long term• Higher rate of salvage• Higher risk of secondary blood cancers

• Radiotherapy– Advantages

• 10 days to long term disease control• Long term f/u schedule more convenient

– Disadvantages• Less costly long term• Systemic relapse can be treated relatively easily w/1-2C of chemo

Adjuvant Radiation vs. Observation: A Cost analysis fo Alternate Management Schemes I Early Stage Testicular Seminoma. JCO 1996

• Stage I Surveillance– Yr 1-3: H&P, all tumor marker labs q 3-4 mo– Yr 4-7: “” q6 mo – Yr >7: “”qYr– CT A/P each visit. CXR alternate visits

• Post RT for Stage I – Yr 1: H&P, all tumor marker labs, & CXR q3-4mo – Yr 2: q6 mo – Yr>2: Annually– Pelvic CT annually for 3yrs for PA-only RT

• PET/CT can predict viable tumor if postchemo residual disease

Seminoma Stage 1- Management

• Accounts for ~15% of patients with seminoma are Stage II

• Tx Options:– Orchiectomy + inguinal/para-aortic+ipsi iliac RT– vs. Orchiectomy + 4C EP vs. 3C BEP

• Historically tx’d w/XRT w/ RFS of 85-94% & CSS 91-100%– Bulky (>5cm) LNs have poor 5yr DFS: 65% w/RT alone w/5 yr OS

77%– Lifetime risk of DM ~ 50% w/bulky LN

Stage 2A/B: Tx Options

• No more Prophylactic Mediastinal RT as assoc w/survivaldecrement

• Most common relapse site: •If RT: SCV fossa or mediastinum•If Chemo: Retroperitoneum• Platinum based chemo is able to salvage >80%

of relapses

Stage 2A/B: RT Alone

66 ptnts - Stage2a30Gy PA21 ptnts - Stage2b36Gy PA

6yrs RFS 95%

5yrs RFS 89%

RadicalInguinal

Orchiectomy

• Classen JCO 2003 – Prospective Randomized Study

• 31% of patients had protocol violations related to staging• All but 5 were treated w/limited volume high hockey sticks• If 2-5cm LA @ L4 or lower, consider tx bilat pelvis.

Stage 2A/B: Chemo Alone• Spanish GC Ca Group, 2008 – Prospective NonRandomized

Study

60 ptnts - 4C PE

12 ptnts -3C BEP

5yrs PFS 100%

5yrs PFS 87%

72 PatientsRadicalInguinalOrchiectomy

100% RR83% CR17% PR

Stage IIA 5yr PFS 100%Stage IIB 5yr PFS 87%

Stage II 5yr OS 95%

• Nodes > 5 cm• Only 300-400 pts annually in US• If nodes are greater than 10 cm recurrence rate is >40%

• Tx: – RT alone has RR & difficulty avoiding liver & kidney >30% so chemo is 1st choice– RT indications= Consolidative tx for residual mass >3cm, 2 mo following Chemo – review

PET– Primary RT be used for IIC dz when doesn’t overlap most of 1kidney/too much liver– Most fail distant and not local

• Chemotherapy regimens include– Good Prognosis:

• 4 cycles EP – Etoposide 100 mg/m2, Cisplatin 20 mg/m2 (d1-5 q3 wks)• 3 cycles BEP – Add Bleomycin 30 units wkly (d1,8,15)

– Poor Prognosis:• X cycles BOMP-EPI

– BOMP: (Bleo 30mg, Vinc2 mg, MTX 300mg/m2 & Cis 100mg/m2 (BOMP), – Alt after a 14d interval w/EPI: Etop 120mg/m2 d1-4, Ifos 1.3g/m2 d1–4 & Cis 25mg/m2 d1–4 (EPI). – BOMP admin 21 days after the EPI. Bleomycin admin qwk for 12 weeks. for poor prognosis GCTs

– 80% of pts will have residual mass at 1 month

Stage 2C/3 Seminoma

Germà-Lluch JR, Garcia del Muro X, Tabernero JM, Sánchez M, Aparicio J, Alba E, Barnadas A. BOMP/EPI intensive alternating chemotherapy for IGCCC poor-prognosis germ-cell tumors: the Spanish GCT Group experience (GG). Ann Oncol. 1999 Mar;10(3):289-93. PubMed PMID: 10355572.

• Acute nausea, vomiting, diarrhea• If PMI field then pericardits, mycardial fibrosis, conduction

defects, valve deficits are possible• Chemo side effects

– BEP causes immediate azospermia, >50% recover sperm count– Infertility– 50% subfertile on presentation

Seminoma Tx Acute Effects

• Late small bowel obstruction, chronic diarrhea, PUD (<2% w/<35 Gy)

• Cardiac dz (Valve defects, CAD)• Fertility, 2nd malignancyAzospermia – Severity: (After RT

30% able to have children)• - after 1.5-2 cGy Minimal• - after 2-5 cGy 30-50% azospermia, baseline in 6-8

mo’s• - after 5-10 cGy 50-80% azospermia, baseline in 8-14

mo’s• - after 10-20 cGy >90% azospermia, baseline in 1-2 yrs• - after >20 cGy Permanent azospermia

Seminoma Radiotherapy Late Effects

Seminoma Radiotherapy Late Effects

•Cardiac Death following Prophylactic Mediastinal Irradiation (PMI)

2nd malignancy in 29K ptnts tx’d for Testicular Ca (JNCI 1997) 15 yrs: ~ 8% (1/2 outside RT field) - NCI 25yrs: ~ 16% (testicular Ca) vs 9% (controls) 30yrs: ~ 23% (testicular Ca) vs 14% (controls)@40 yrs: ~ 36% (Seminoma) (Travis et al. 05’)

Testicular Radiotherapy 2nd Ca

2nd malignancy in 29K ptnts tx’d for Testicular Ca (JNCI 1997)

Increased RR of solid cancers for: RT (RR=2.0) Chemo alone (RR=1.8) Both (RR=2.9)

Increased RR of blood cancers for: RT (RR=4.27) Chemo alone (RR=16.24)

Both (RR=3.61)

Testicular Radiotherapy 2nd Ca

Seminoma: Tx Recommendations

Chemo

20/10 RT

5 yr RFS 79%, 10yr 58%

Androgen supplementation

Stage 0

5 yr RFS 100%

2C CarboAUC7

RT 20GyPA

5yrs RFS 98%

5yrs RFS 96%

Stage 1Radical

InguinalOrchiectomy

Post RT for Stage I (if post Chemo then yr1-3 q4mo)

Yr 1: H&P, all tumor markers & CXR q3-4mo Yr 2: q6 mo Yr>2: AnnuallyPelvic CT annually for 3yrs for PA-only RTSurveillance 5yrs RFS 93%0-1 RF Yr 1-3: H&P, tumor marker labs q 3-4 mo

Yr 4-7: “” q6 mo Yr >7: “”qYrCT A/P each visit. CXR alternate visits

Stage2a20Gy DL or PA30Gy Gross DzStage2b20Gy DL or PA36Gy Gross Dz

6yrs RFS 95%

5yrs RFS 89%

RadicalInguinal

Orchiectomy

4C PE or 3C BEP 6yrs RFS 89-95%100% RR83% CR17% PR PET Consider

Stage 2A/B

RadicalInguinal

Orchiectomy

Stage 2C/3 4C PE or 3C BEP 6yrs RFS 89-95%100% RR83% CR17% PR PET Consider

RT Salvage should be considered for

all Stage 2/3 Seminoma:

30Gy to all PET+ Gross Disease

**Remember Spermatocytic can be treated w/Orchiectomy alone

• MRC/EORTC: Phase 3 - Radiation Therapy Compared With Chemotherapy in Treating Patients With Stage I Testicular Cancer

• Arm I: Patients receive a single dose of carboplatin IV.

• Arm II: Patients undergo radiotherapy once daily, 5 days a week. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.

• PROJECTED ACCRUAL: Completed Accrual at 800 patients

Seminoma: Current Trials

End

Observation• Advantages

– For Stage I post orchiectomy recurrence 12%-30%

– We can save >70% of individuals from a toxic therapy

– Cause specific survival ~ 100% at 5 years

Toronto 2005

• Choo et al.• Prospective, single arm.• 88 stage I patients managed by

radical inguinal orchiectomy alone• 20% rete testis invasion, 45%

>4cm• FU 12.1 year median

• Outcome• RFS 5-yrs 83%, 10-yrs 80%, 15-yrs 80%• Relapse site: 88% (15/17) below diaphragm• Salvage: 14/17 RT, 3/17 chemo-RT

– 1 had second relapse, further salvaged by chemo

• All 17 remained disease free after salvage• Conclusion: Surveillance is a safe alternative