TESTICULAR CANCER

Dr Christoph OingThe Christie NHS Foundation TrustManchester, UK

The “most fascinating” cancer entity.

CONFLICT OF INTEREST DISCLOSURE Dr Christoph Oing

Personal financial interests• Honoraria speaker activity: Medac (2018), IPSEN (2017)Institutional financial interests• NoneNon-financial interests / Leadership role medical societies non-remunerated• Chairman “Junge DGHO” of the German Society of Hematology and Oncology

(DGHO)• ESMO YOC memberOther• Travel and conference attendance: IPSEN (2017)

PATHOPHYSIOLOGY

RISK CLASSIFICATION

TREATMENT

CASE DISCUSSION

TESTICULAR CANCERAgenda

EPIDEMIOLOGY & CLINICAL

PRESENTATION

TESTICULAR CANCERSigns and Symptoms

• Scrotal mass / swelling 74% Other NPL, Hydrocele, Spermatocele

• Scrotal pain 30% Inflammation, Torsion• Gynecomastia 10% Drugs, Liver disease• Infertility 5% Primary infertility• Organ-specific <5% Other medical conditions

(Jaundice, Dyspnea, neurol. Disorder, Fractures)

Signs & Symptoms Differential diagnosis

Most common solid malignancy among adolescents and men aged ≤ 40 years

Onset after puberty onset >75 years: spermatocytic tumours separate entity

TESTICULAR CANCER Age Distribution

TESTICULAR CANCERGeographical incidence

Established Risk Factors Relative risk Contralateral testicular cancer 24.8 - 27.6 Cryptorchidism / Maldescensus testis 3.5 - 17.1

Early orchidopexia important to decrease risk Positive family history 2.5 - 12.3

Highest risk if father or brother affected

Potential Risk Factors Relative risk Infertility 1.6 - 10.0 Atrophic testis <12mL 2.7 - 12.7 HIV 2.0 - 57.0

TESTICULAR CANCERRisk Factors

PATHOGENESIS

TESTICULAR CANCERHistopathology

WHO classification 2016

TESTICULAR CANCERHistology

YS

Bremmer et al., Der Pathologe 2014

GCNIS Pure Seminoma Mixed NSGCT

YS

CC

EC

EC

Courtesy of Dr Pedro Oliveira, The Christie NHS Foundation Trust. Histopathology Dept

TESTICULAR CANCERSubtype evolvement

Seminoma

Embryonal carcinoma

Choriocarcinoma

Yolk sac tumour

Teratoma

Embryonic Extra-embryonic

GCNIS

Non-seminoma40% 60%

Diffe

rent

iatio

n

Sensitivity

TESTICULAR CANCEROrigin of GCTs

Mediastinal

Retroperitoneal

Testicular

Cerebral / hypothalamic area

3 - 5%

95 - 97%

ORIGIN AND PROGNOSIS

0 12 24 360.0

0.2

0.4

0.6

0.8

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med NS (N=228)retrop NS (N=226)

p < 0.001

Months

Prop

ortio

n su

rviv

ing

Bokemeyer et al., J Clin Oncol 2002

DIAGNOSTIC WORK-UP

Primary prevention

• No established primary prevention strategy

Secondary prevention

• Monthly self-examination recommended for every man

• Ultrasound of testes in brothers of patients and infertile men

TESTICULAR CANCERScreening

EXTRAGONADAL GCC

No testicular primary detectable

1-5 % of all GCCs

Arise from primordial germ cells on their developmental journey from the endodermal

layer to the genital ridge localised in the midline of the body

Histologically identical to testicular GCCs

Mediastinum Retroperitoneum Pituitary/hypothalamic region / CNS

10% of all retroperitoneal masses are extragonadal GCCs

Mediastinal GCCs have a dismal prognosis and often harbor TP53mut

STAGING & RISK ASSESSMENT

TNM / UICC STAGING

M1a med./cerv. LN or lung

M1b extr. pulm.

N1 < 2 cm(max. 5 LN)

N2 2 – 5 cmor > 5 LN

N3 > 5cm

T1 no vascular invasion

T2 vascular invasion

T3 invades sperm cord

T4 invades scrotum

Description of disease spread

RADIOLOGIC STAGING

Contrast-enhanced CT-scan of chest and abdomen

NO ROLE for 18F-FDG-PET imaging

Sensitivity and specificity not higher than for conventional CT-scan

MRI CNS only if brain mets suspected or choriocarcinoma with multiple

lung metastases and highly elevated HCG levels

Bone scan only if bone metastases suspected

STAGE DISTRIBUTIONAt Primary Diagnosis

Stage I 60% 80%

Stage II 20% 15%

Stage III 20% 5%

SGCTNSGCT

Horwich & Huddart, Lancet 2006

THE S-FACTORTumor marker elevation

LDH [IU/L] HCG [IU/L] AFP [ng/mL]

S0 normal and < 5 and < 10

S1 < 1.5x ULN and < 5.000 and < 1.000

S2 1.5 – 10x ULN or 5.000 – 50.000 or 1.000-10.000

S3 > 10x ULN or > 50.000 or > 10.000

Prior to orchiectomy Day 5-6 post-surgery Half-life HCG 2-3 days

AFP 4-7 days During chemotherapy - prior every cycle

- don‘t take markers right after chemo

TESTICULAR CANCERRisk assessment stage IIC / III

Prognosis 5-year OS Seminoma Non-seminoma

Good 90% Any primary location No non-pulmonary visceral

metastases Any marker level

Testis or primary extragonadal retroperitoneal tumor

No non-pulmonary visceral metastases Low markers AFP < 1,000 ng/ml HCG < 5,000 IU/l LDH < 1.5 x normal level

Intermediate 75%

Any primary location Presence of non-pulmonary

visceral metastases (liver, CNS, bone, intestinum)

Any marker level

Testis or primary extragonadal retroperitoneal tumor

No presence of non-pulmonary visceral metastases

Intermediate markers AFP 1,000-10,000 ng/ml HCG 5,000-50,000 IU/l LDH 1.5-10 x normal level

Poor 50% Does not exist

Primary mediastinal GCT with or without testis Primary retroperitoneal tumor Presence of non-pulmonary visceral

metastases (liver, CNS, bone intestinum) High markers AFP < 10,000 ng/ml HCG > 50,000 IU/l LDH > 10 x normal level

IGCCCG, J Clin Oncol 1997

90%

10%

56%

28%

16%

TESTICULAR CANCER… as times are changing

More recent retrospective series reported improved outcomes forall three risk groups

OS about 10-15% higher in contemporary intermediate and poorprognosis cohorts Fankhauser et al. Ann Oncol 2018 Seidel et al. Eur J Cancer 2018

TREATMENTSTAGE I

Seminoma(pT1-4 N0 M0)

CarboplatinAUC7 x1

Active Surveillance

RT para-aorticregion 20 Gy

• 80% overtreatment• Relapse risk

3-9%

• Recommended forall CS I SGCT

• Relapse risk10-15%

• SMN?

TESTICULAR CANCERStage I Seminoma

TESTICULAR CANCERStage I Seminoma

Active surveillance Radiation Carboplatin AUC 7 x1

Overall cure rate > 99% > 99% > 99%Relapse rate 15% 4-5% 5%Abdominal imagingrequired in FU Yes No Yes

% pts. unnecessarilyexposed to treatment 0% 85% 85%

TESTICULAR CANCERStage I Non-seminoma

Non-Seminoma(pT1-4 N0 M0)

BEP (1 cycle)

Active Surveillance

RPLND• Only expert centers• In-field relapses

• Relapse riskLVI neg 15-20%LVI pos 40-50%

• Recommendedfor LVI pos

• Relapse risk5%

TESTICULAR CANCERRisk factor stage I non-seminoma

MRC Prospective Surveillance Study 1984 - 1987

Relapse-free Rate by vascular invasion

Months from orchidectomy

168144120967248240

Rel

apse

-fre

e ra

te

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Read et al., JCO 1992; 10:1762-8

TESTICULAR CANCERStage I Non-seminoma

Active surveillance RPLND BEP x 1 for LVI+Overall cure rate > 99% > 99% > 99%

Relapse rate15% low risk50% high risk

30% unselected10-15% 3-5%

Abdominal imagingrequired in FU Yes No Yes

% pts. unnecessarilyexposed totreatment

0%70%

85% low risk50% high risk

70%85% low risk50% high risk

TREATMENTADVANCED DISEASE

TESTICULAR CANCERCisplatin – a Story of Success

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 6 12 18 24 30 36 42 48 54 60 66

months

Prob. of survival

OS Bleo/Vinblastin

OS PVB

OS BEP

Samuels Cancer Treat Rev 1976, Williams NEJM 1987, Sonneveld Cancer 2000

TESTICULAR CANCERAdvanced Stages IIC / III

IGCCCG Risk Group 5 yr OS Treatment EBM Level

“good prognosis” 90 % 3 x BEP ( I B)SGCT & NSGCT [*alternatively 4 x EP] ( II A)“intermediate prognosis” 80 % 4 x BEP ( IV)SGCT & NSGCT [*alternatively 4 x VIP] ( I B)“poor prognosis” 50 % 4 x BEP ( I B)only NSGCT [*alternatively 4 x VIP] ( I B)

*only if Bleomycine not allowedOldenburg J et al., ESMO CPG Testicular Cancer, Ann Oncol 2015

BEP; Cisplatin, Etoposide, Bleomycine

EP; Cisplatin, Etoposide

VIP; Cisplatin, Etoposide, Ifosfamide

TESTICULAR CANCERImproving „poor risk“ outcomes

IGCCCG poor prognosis GCC

> 1 criterion: PMNSGCT CNS Metastases Liver Metastases Bone Metastases

None of the criteria

1 cycle standard doseBEP or VIP

Adequate marker declineNO adequate tumor

marker decline

3 more cycles of BEP or VIP

Recommendation:High-dose chemotherapy with 3 x HD-VIP + autolog. PBSCTAlsdorf, Oing et al., Exp Opin Pharmacother 2019

TESTICULAR CANCERResidual seminoma

Advanced SEM

Chemotherapy

Residues < 3cm Residues ≥ 3cm

Follow-up 18F-FDG-PET-CT

PET - PET +

W W Surgery RTxOing et al., Nuclear Oncology, 1st Ed., 2014

TESTICULAR CANCERResidual non-seminoma

Advanced NSEM

Chemotherapy

Residues < 1cm Residues ≥ 1cm

Follow-up Surgery

50-60%necrosis

30%Teratoma

10-20%Vital GCT

TESTICULAR CANCERThe teratoma issues

Growing teratoma syndrome

Teratomas completelytreatment resistant

Only surgery curative Secondary malignant

transformation withdismal prognosis Courtesy of Dr Pedro Oliveira, The Christie NHS Foundation Trust.

Histopathology Dept

TREATMENT@1ST RELAPSE

TESTICULAR CANCERTiming of relapse

Ko et al., J Clin Oncol 2016

Most relapses occur duringthe first 2 yrs after EOT

Most relapses detecteddue to symptoms

< 5% of relapses duringthird year or later

Late relapses confer dismal prognosis

Surgical approachespreferred for late relapsesif technically feasible

TESTICULAR CANCERIPFSG Score – Prognosis @1st relapse

Internsational Prognostic Factors Study Group, J Clin Oncol 2010

RISK FACTORS AT RELAPSE

Extragonadal Primary Non-seminoma No CR / PR after 1st-line Relapse within 12mos Extrapulmonary Mets High AFP / HCG 2nd or further Relapse

SALVAGE TREATMENTSalvage Chemotherapy – dose matters…

Lorch et al., J Clin Oncol 2011

Cure rates 30-50% with conventional-dose chemo TIP VIP PVbl

TESTICULAR CANCERTIGER Phase III trial

REFRACTORY DISEASELimited Treatment Options

Most active agents

Gemcitabine (oral Etoposide) Oxaliplatin (Temozolomide) Paclitaxel (Irinotecan)

ORR Mono 10-15% Doublet 30-35% Triplet 50%

R/R GERM CELL CANCERSNovel targeted therapies

Many agents investigated TKI (Sunitinib, Pazopanib, Imatinib)

mTORi (Everolimus)

Immune-Checkpoint-Inhibitors (Pembro, Tremelimumab/Durvalumab)

Anitbody-Drug-Conjugates (Brentuximab-vedotin)

No relevant activity in unselected phase II trials!

SURVIVORSHIP CARE

SURVIVORSHIP CAREA Field of Growing Importance

Cancer Registry of Norway, pers. communication

LONG-TERM TOXICITYSide Effects of GCC Treatment

Kier et al., JAMA Oncol 2016

Secondary Neoplasms Leukemia Lung, Bladder,

Sarcoma Pancreas, Stomach

Cardiovascular Events Metabolic Syndrome Neurotoxixcity Pneumonitis, Fibrosis Chronic Kidney Failure Fatigue Hypogonadism / Infertility

TAKE HOME MESSAGE

Most common solid malignancy among men aged ≤ 40 years Extraordinary cure rates >90% over all stages GCNIS as malignant precursor Pure seminoma (SGCT) vs Non-seminoma (NSGCT) AFP and HCG as prognostic and predictive biomarkers

Active surveillance after orchiectomy preferred in CS I seminoma Active surveillance also for CS I non-seminoma

Alternatively 1x BEP in high-risk patients (LVI+) SGCT CS IIA: Radiotherapy 30-36Gy preferred over chemo NSGCT CS IIA/B: Chemo preferred over RPLND

Localised Disease Stages

TAKE HOME MESSAGE

Advanced stages CS IIC-III: IGCCCG risk-stratification Good risk: 3x BEP or 4x EP OS >90% Intermediate/poor risk: 4x BEP or 4x VIP OS 60-90% Consider high-dose VIP + autoSCT for selected cases

NSGCT residues > 1cm have to be surgically removed Salvage treatment still curative

4x TIP, VIP, VeIP conventional options Higher cure rates with HD-Carbo/Eto TIGER trial

Secondary tumors, metabolic syndrome, peripheral neuropathy, renal impairment and infertility important survivorship issues

Advanced Disease & Relapse

EMUC 2019… if you haven‘t been to Vienna!