Testicular CancerProf. Dr. Jörg BeyerPhysician-in-ChiefDepartment of Oncology, University Hospital Berne, Switzerland

Mail: joerg.beyer@insel.ch

The menue:

• Epidemiology & Staging• Ongoing discussions & risk-adapated treatment• Focus on early stage disease• Little on advanced/poor risk disease• Little on relapsed or refractory disease• Some emphasis on survivorship care• Full presentation via the ESO webpage

Testis cancer in Europe 2012Incidence Mortality

All pts. treated inDenmark between

1984 - 2007

Mortensen Eur Urol 2014Daugaard J Clin Oncol 2014Kier Eur Urol 2016

Take home message

Germ-cell cancer is the most frequent cancerin men age 20-40 years. About 3% are primaryextragonadal.

+ H & P, physical examination including testes+ Testicular ultrasound+ Tumormarker AFP, HCG and LDH (no PLAP)+ CT thorax and abdomen+/- CT/MRI brain (only if pulmonary metastases present)

- No PET CT scans !!

Initial Staging

• Tumor size, rete testis involvement• Seminoma vs Non-seminoma or mixed tumors• In non-seminoma: is there teratoma present• Evidence of lymphovascular invasion

Take home message

About 70% of patients present as clinical stage I.

Vascular invasion - must be stated in the pathology report- needs an experienced pathologist- is helped by anti CD 31 immunohistology- must be obvious in the section

Slide at the courtesy of Prof. Loy, Berlin

Cancer Medcine 2014, doi: 10.1002/cam4.324

Case No 1: 33 years

• Testicular cancer• Orchiectomy => pure seminoma• Size 4 cm, no infiltration rete testis or vascular invasion• AFP und HCG normal• LDH prior orchiektomy 480 U/L• LDH post orchiektomy normal• CT thorax & abdomen w/o LN metastases

Stadium Inur im Hoden

Stadium II

N1 = abd. Lk. < 2 cmN2 = abd. Lk. 2-5 cmN3 = abd. Lk. > 5 cm

Stadium III

M1a = med. / cerv. Lk. oder pulmonale Met.M1b = extr. pulm. Met.

Stadieneinteilungnach UICC

Stage accordingto the UICC

classification

Case No 1: 33 years

• Testicular cancer• Orchiectomy => pure seminoma• Size 4 cm, no infiltration rete testis or vascular invasion• AFP und HCG normal• LDH prior orchiektomy 480 U/L• LDH post orchiektomy normal• CT thorax & abdomen w/o LN metastases

Seminoma Stage I => Which treatment ?

Abbildung 2: Strahlenfeld Seminom im Stadium I

Radiation treatment Seminoma Stage I

Dose 20 Gy

Pro: long experiencelow relapse rate

Con: acute & late toxicitiessecondary tumors

Abbildung 2: Strahlenfeld Seminom im Stadium I

Upd

ate

ASC

O 2

008

Lancet 2005; 366:293-300

AUC 7cave: avoid

undertreatment, no capping

Ann

Onc

ol M

arch

201

3

• Safe• Relapse rate of 15-20% in seminoma• Almost all relapses can be salvaged by BEP x 3• Overall survival close to 100%• Only those who need treatment get treated• Avoids adjuvant treatment in 80-85% of patients

all patients with metastatic seminoma (stage II & III) should receive first-line chemotherapy

with three rarely four cycles of BEP*

* four cycles BEP in patients with bulky or extrapulmonary disease

3 Zyklen BEPevery 21 days

No Bleomycin

• Age > 50 years• Packyears > 20 years• DLco < 60% of normal• Restrictive lung disease (e.g. COPD)• Poor renal function GFR < 80 ml/min

3 Zyklen BEP (4 Zyklen EP)every 21 days

PET - CT

Only in Seminomawith residual tumorpost chemotherapy

Summary Current Treatment Strategies in Seminoma

Histologie !

• Ca. 80% of patients present as stage I

"Active Surveillance“ the new standard, alternatively one cycle adjuvantCarboplatin AUC 7. Adjuvant radiation no longer recommended.

• Ca. 20% of patients present with metastastic disease

Standard treatment with three (rarely four) cycles BEP

Careful with bleomycin in poor pulmonary & renal function & older age

No residual tumor resection after chemotherapy !

Residual tumors after chemotherapy „rare“ indication for PET-CT scans

Case No 2: 36 years

• Testicular cancer• Orchiectomy, mixed NSGCT, 80% EC.• Size 4 cm, no vascular invasion • CT thorax and abdomen w/o metastases• AFP 1.480 U/L, HCG 10 U/L prior orchiectomy

Case No 2: 36 years

• Testicular cancer• Orchiectomy, Mixed NSGCT, 80% EC.• Size 4 cm, no vascular invasion • CT thorax and abdomen w/o metastases• AFP 1.480 U/L, HCG 10 U/L prior orchiectomy• AFP 560 U/L, HCG normal post orchiectomy

Case No 2: 36 years

• Testicular cancer• Orchiectomy, Mixed NSGCT, 80% EC.• Size 4 cm, no vascular invasion • CT thorax and abdomen w/o metastases• AFP 1.480 U/L, HCG 10 U/L prior orchiectomy• AFP 560 U/L, HCG normal post orchiectomy• AFP 140 U/L, HCG normal after 2 weeks• AFP 64 U/L, HCG normal after 3 weeks• AFP normal, HCG normal after 35 days

Case No 2: 36 years

• Testicular cancer• Orchiectomy, mixed NSGCT, 80% EC.• Size 4 cm, no vascular invasion • CT thorax and abdomen w/o metastases• AFP 1.480 U/L, HCG 10 U/L prior orchiectomy• Normalization of tumor markers post orchiectomy

Non-Seminoma CS I => Which treatment ?

Stadium Inur im Hoden

Stadium II

N1 = abd. Lk. < 2 cmN2 = abd. Lk. 2-5 cmN3 = abd. Lk. > 5 cm

Stadium III

M1a = med. / cerv. Lk. oder pulmonale Met.M1b = extr. pulm. Met.

Stadieneinteilungnach UICC

Stage accordingto the UICC

classification

Eur U

rol 2

015

14%Relapses

48%Relapses

1 cycle1 cycle

• Safe• Relapse rate of 15-50% in non-seminoma• Almost all relapses can be salvaged by BEP x 3 (-4)• Overall survival close to 100%• Only those who need treatment get treated• Avoids adjuvant treatment in 80-85% of patients

Summary Current Strategies inNon-Seminoma

• Ca. 60% of patients present as clinical stage I

"Surveillance“ in "low risk" patients without vascular invasion in theprimary tumor, one cycle adjuvant BEP in "high risk" patients withevidence of vascular invasion in the primary tumor

Case No 3: 36 years

• Lumberjack• Increasing shortness of breath at work• Went to the A & E of his local hospital• Pleural mass and multiple pulmonary metastases

Case No 3: 36 years

• Increasing shortness of breath at work• Pleural mass and multiple pulmonary metastases

• Admitted to pulmonary service of the local hospital• Thoracic CT scan and bronchoscopy• Undifferentiated cancer compatible with NSCLC

Case No 3: 36 years

• Increasing shortness of breath at work• Pleural mass and multiple pulmonary metastases

• Admitted to pulmonary service of the local hospital• Thoracic CT scan and bronchoscopy• Undifferentiated cancer compatible with NSCLC

• Carboplatin, gemcitabine & bevacizumab• Staging PET CT scan after first cycle

Case No 3: 36 years

• Increasing shortness of breath at work• Pleural mass and multiple pulmonary metastases

• Admitted to pulmonary service of the local hospital• Thoracic CT scan and bronchoscopy• Undifferentiated cancer compatible with NSCLC

• Carboplatin, gemcitabine & bevacizumab• Staging PET CT scan after first cycle

• AFP 138.000 ng/ml, LDH 834 U/l, HCG normal

Overall Survival> 90 %

Overall Survival~ 78 %

Overall Survival~ 45 %

Case No 3: 36 years

• Patient with extensive disease germ-cell cancer

• High risk of first-line failure & treatment related death

- poor performance status- poor pulmonary & renal function- high risk of sepsis and multiorgan failure- high incidence of cns metastases- fatal bleeding from ruptured metastases- fatal pulmonary embolism

Influence of center experience on "failure-free survival" in poor prognosis germ-cell tumor

< 5 Pat.

> 19 Pat. 10-19 Pat.

5-9 Pat.

p < 0.018

EORTC/MRC trial

Impact of Center Expertise on Surivalin Patients with "poor prognosis" Germ-cell Cancer

Collette et. al J Natl. Cancer Inst. 1999

All patients with metastastic Non-Seminoma shouldreceive first-line chemo with three to four cycles BEP

No dose reduction or treatment delay for uncomplicated cytopenias.No routine G-CSF or other growth factors. In patients with dyspnoeor pneumonia check for bleomycin toxicity, before continuation with BEP

Standard first-line treatment regimens

days

days

days

R

PEB

RPEB PEB PEB

PEIPEI PEI PEI

Randomized trials using upfront HDCT

„Intergroup trial“ USAStarted 1997Published 2007

No benefit from upfront HDCT

„EORTC GU“ EuropeStarted 1999Published 2011

No benefit from upfront HDCT

n=219, JCO 2007, Motzer et al.

n=131, Ann Oncol 2011, Daugaard et al.

Fizazi et al. Lancet 2014

Do resect all residual lesions > 1 cm afterchemotherapy in non-seminoma !

• may contain vital cancer (more frequent than in seminoma)• may contain teratoma (does not exist in seminoma)

PET scans are useless in non-seminoma !Do not resect resdiual lesions in seminoma !

Pre BEP x 3 Post BEP x 3

Summary Current Strategies inNon-Seminoma

Histologie !

• Ca. 60% of patients present as clinical stage I

"Surveillance“ in "low risk" patients without vascular invasion in theprimary tumor, one cycle adjuvant BEP in "high risk" patients withevidence of vascular invasion in the primary tumor

• Ca. 40% of patients present with metastatic disease

Standard chemotherapy three to four cycles PEB according to risk.Resection of all residual tumor post chemotherapy. No role for PET-CTscans

Prognostic factors in relapsed/refractory GCC

Histologie !

poor good• Primary Tumor mediastinal gonadal

• Histology non-seminoma seminoma

• Respone 1° Line no CR/NED/PRm- CR/NED

• Response duration short long

• Marker Level high low

• Metastatic location brain, bone, liver lymphnodes or lung

• Salvage attempt second or subsequent first-salvage

OhneRisikofaktoren

Patienten mitProgress oder Rezidivnach Chemotherapie

KonventionelldosierteTherapie

MitRisikofaktoren

Hoch dosisierteTherapie

Indication for salvage surgery?

- Progression mature teratoma- late relapse > 2 years- resectable relapse after HDCT

Risk factors

- extragonadal primary tumor- no CR / PRm- after first-line- early relapse- extrapulmonary metastases- high AFP or HCG levels- any second or subsequentrelapse

Strategy for first-salvagePatients

with relapse or progressionafter chemotherapy

Withoutrisk factors

Withrisk factors

Conventionaldose treatment

Highdose treatment

Travis/Fosså JNCI 2005

Second solid non-germ cell cancer

Diagnosis at 20y at age 70: 40% vs. 20%

No of solidtumors

RR (95%CI)

Radiotherapy alone 892 2.0 (1.9-2.2)Chemotherapy alone 35 1.8 (1.3-2.5)

Radioth. + Chemoth. 25 2.9 (1.9-4.2)

Modern radiotherapy:Reduced dose & field

Metabolic syndrome in will develop in 20-30 % of testicular cancer survivors

de H

aas

et a

l,Ann

Onc

ol 2

013

• Details on histology & intial stage

• Details on treatment delivered (drugs, schedules, modalities)

• Recommendation for a follow-up schedule (10 years)

• Risk of relapse only in the first 2-3 years

• Identify main individual long-term toxicities that might occur

• Give life-style recommendations

• Identify possible additional resources (e.g. support groups)

• Identify the person in charge for follow-up including contactinformation!

Basi

cs o

f a s

urvi

vors

hip

plan

Summary testicular cancer

Histologie !

• Get exact histological information

• Get exact staging information

• Follow the correct management algorithmus meticulously

• High cure rates even in metastatic tumor stages

• Manage patients only in interdisciplinary teams specificallydedicated to the management of testicular cancers !

German/Swiss/Austrian Grouphttp://www.hodenkrebs.de

Get experts involved

Foliennummer 1Foliennummer 2Foliennummer 3Foliennummer 4Foliennummer 5Foliennummer 6Foliennummer 7Foliennummer 8Foliennummer 9Foliennummer 10Foliennummer 11Foliennummer 12Foliennummer 13Foliennummer 14Foliennummer 15Foliennummer 16Foliennummer 17Foliennummer 18Foliennummer 19Foliennummer 20Foliennummer 21Foliennummer 22Foliennummer 23Foliennummer 24Foliennummer 25Foliennummer 26Foliennummer 27Foliennummer 28Foliennummer 29Foliennummer 30Foliennummer 31Foliennummer 32Foliennummer 33Foliennummer 34Foliennummer 35Foliennummer 36Foliennummer 37Foliennummer 38Foliennummer 39Foliennummer 40Foliennummer 41Foliennummer 42Foliennummer 43Foliennummer 44Foliennummer 45Foliennummer 46Foliennummer 47Foliennummer 48Foliennummer 49Foliennummer 50Foliennummer 51Foliennummer 52Foliennummer 53Foliennummer 54Foliennummer 55Foliennummer 56Foliennummer 57Foliennummer 58Foliennummer 59Foliennummer 60Foliennummer 61