GERM-CELL TUMOURS. ESMO Preceptorship on Adolescents and Young Adults with cancer Lugano, May 2018

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1 ESMO Preceptorship on Adolescents and Young Adults with cancer Lugano, May 2018 GERM-CELL TUMOURS Giannis Mountzios MSc, PhD Medical Oncology University of Athens School of Medicine Athens, Greece

2 Germ-cell tumors (GCTs) 1% of cancer in males The most frequent tumors among men between years of age Median age: for non-seminomatous, for seminomatous Annual incidence: 4-11/ men Increasing incidence in the last 50 years 95% cure rates, especially in stage I Seer database, 2014

3 Embryogenesis of Germ Cell Tumors

4 Risk factors Intra-Tubular Germ Cell Neoplasia (ITGCN) Crypsorchy History of testicular cancer or extragonadal GCT Family history HIV (+) individuals Testicular microlithiasis Insensitivity to androgens Genetic syndromes with gonadal dysplasia (Kleinefelter syndrome) Embryonal exposure to steroids Nationality and Ethnicity Dietary-environmental factors (?)

5 Clinical Presentation Usually a painless, gradually enlarging testicular mass Pain in 10-20% of cases (can be misdiagnosed as orcheo-epididymitis) Gynecomasty (β-hcg secreting tumors) Symptoms due to metastasis (back-pain, Fatigue, cough, dyspnoea..) Unusual presentations

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7 Diagnosis: Often delayed! AYA tend to consider themselves as unaffected by serious disease, such as cancer Professionals and patients may underestimate symptoms that should be stimulating investigation (e.g. severe fatigue, headache, enlarged lymph nodes, weight loss etc) Demanding education or work-place obligations may lead AYA to neglect health issues Reluctant to report symptoms or signs related to reproductive system, and may longer be a parent to 7 25/05/2018 advocate for them (e.g amenorrhea, testicular mass)

8 Clinical presentation

9 CT thorax

10 HISTOPATHOLOGIC FINDINGS Choriocarcinoma (9,5Χ6,5Χ4,5/81g)

11 HISTOPATHOLOGIC FINDINGS IHC staining for β-hcg

12 HISTOLOGICAL EXAMINATION OF THE TESTICULAR MASS Typical testicular seminoma

13 Non seminomatous GCTs (NSGCTs) Variety of morphological and histological features with common origin from the stem germ cells that differentiate to various embryonal or extra-embryonal elements during ontogenesis This finding explains the significant overlap between different histologies and the frequent discovery of mixed NSGCTs in the same patient, as in our case

14 Embryonal carcinoma Neoplastic transformation during the fetal phase of blastocele production of α-fp. Most frequent in the 2 nd and 3 rd decade of life Often located in extragonadal places (ie mediastinum) harboring worse prognosis compared to gonadal counterparts Potential for distal metastasis. Less radiosensitive than seminoma but very sensitive to chemotherapy

15 Yolk sac tumors Neoplastic transformation of the germ cell of the endodermal duct in the phase of blastomeride α-fp production. Pure form: Infants and children up to 2 years, bearing excellent prognosis Mixed form: as a component of a mixed NSGCT, bearing a worse prognosis α-fp very useful for disease staging, monitoring of response to treatment and early detection of recurrence

16 : Choriocarcinoma Neoplastic transformation in the stage of syncytiotrophoblasts of the chorionic villi Production of β-hcg (gynecomasty testicular atrophia, azoospermia) Most frequent in young men years of age Potential to invade vessels and promote angiogenesis Early hematogenous metastases (lungs, hemoptysis) Aggressive biological behavior but very chemosensitive β-hcg very useful for disease staging, monitoring of response to treatment and early detection of recurrence

17 Teratoma Neoplastic transformation of germ-cells that have been differentiated to the level of embryonal elements Production of both β- hcg and α-fp. Possible co-existence of tissues originating from all three embryonal layers ( ectoderm, mesoderm,endoderm (ie cartilage,neuronal tissue, epithelia) Possible co-existence with other NSGCTs, (ie embryonal carcinoma)

18 Clinical staging- Tests

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20 Surgery Surgical removal of the testicle with inguinal access Placement of testicular prosthesis One procedure Less psychological burden for the patient Better esthetic result But: Increased possibility for infections Biopsy of the contralateral testicle: Small testicle (<12 ml) History of cryptorchy Poor spermatogenesis

21 Management: Stage I Seminoma

22 Prognostic factors in stage I Seminoma General risk of relapse without treatment: 15% Invasion to rete testis or tumor size > 4 cm increase the risk for relapse When both factors are present, the risk for relapse increases to 30% Newer studies emphasize on tumor size but also suggest lympho-vascular infiltration as potential contributor

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25 NSGCTs stage I Treatment options: Chemotherapy (BEP) Active surveillance Retroperitoneal Lymph node dissection (RPLND)

26 Prognostic factors in stage I NSGCTs General risk of relapse without treatment: 30% Presence of lymphovascular infiltration (LVI) increases risk of relapse to 50% High percentile of embryonal carcinoma (>50%) increases risk of LVI Low risk group has a recurrence probability of 10-15%, whereas high risk group has a probability of 50%...

27 NSGCT st.1: Prognostic factors Meta-analysis including 23 publications ( ), 2587 pts 566 pts (22%) relapsed during surveillance 193 pts had positive retroperitoneal LNs during RPLND Prognostic factors Odds Ratios Vascular invasion 5.2 (95% CI, ) Embryonal carcinoma 2.9 (95% CI, ) High pathologic stage (G 2 -G 3 ) 2.6 (95% CI, ) Size of primary tumor (>3cm) 1.5 (95% CI, ) Older age (>30 years) 1.6 (95% CI, ) Vergouwe et al. JCO 2003

28 7 out of 10 patients will never relapse regardless of treatment and those who will relapse will be cured in >90% of cases NSGCT st.1: Active surveillance 1 st author Year N m F/U Relapse (%) Disease-free post-relapse(%) Freedman (27) 67/70 (96) Colls (28) 67/70 (97) Read (27) 95/100 (95) Gels (27) 41/42 (98) Sogani (26) 24/27 (89) Francis (28) 49/52 (92) Daugaard (29) 86/86 (100) Oliver NR 71 (30) 65/71 (92) Ernst (29) 57/57 (100)

29 NSGCT st.1: Active surveillance 1 st author Year N mttr (months) Relapse 2 years Relapse in LNs retroperitoneal Other relapse Only markers Gels % 88% 34% 0% Sogani % 74% 30% 7% Francis % 48% 27% 27% Sharir % 71% 46% 8% Roeleveld % 83% 17% 4% Maroto et al. Ann Oncol 2005 PROs: Avoidance of unnecessary toxicity from chemotherapy High cure rates even after relapse CONs: Intensive follow-up protocol/requires adherence Increased psychological stress

30 NSGCT st.i: Chemotherapy 1 st author Year N m F/U (months) Regimen Relapses (%) Klepp BEP x 1 7 (2) Cullen BEP x 2 2 (2) Bohlen PVB/BEP x2 1 (2) Oliver BEP, BOP 6 (4) Dearnaley BOP x 2 2 (2) Amato BEC x 2 1 (1) Pectasides BEC 90 x 2 0 Bamias BEP x 2 1 (0.7) Klepp BEP x 3 1 (3) Cure rates: 97%

31 Meta-analysis including 873 chemo-treated pts / 23 relapses Overall estimated recurrence rate: 3.8% Estimated recurrence rate after: 1 cycle : 7.2% 2 cycles : 3.9% 3 cycles : 3.9% of platinum-based chemotherapy

32 RETROPERITONEAL LYMPH NODE DISSECTION: CHALLENGES Demanding surgical skills Long learning curve for surgeons Risk of retrograde ejaculation Requires large-volume reference centers Mainly used in USA, tends to be abandoned in Europe Hedgepeth & Wood. ASCO Educational Book 2010

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34 NSGCT: follow-up Surveillance Chemo / RPLND NCCN ESMO NCCN ESMO 1 st y 2 nd y 3 rd y 4 th y 5 th y 6-10 th y Exam/Markers CT abdomen Exam/Markers Chest X-rays CT abdomen 6 12 Exam/Markers CT abdom/pelvis Exam/Markers x Chest X-rays CT abdomen 12

35 Management of Advanced Stages

36 BEP in low risk patients BEP Χ 3 equally effective 3-days BEP non-inferior to 5-days BEP EP x 4 non-inferior to BEP x 3 Cisplatin can NOT be substituted by carboplatin Total cisplatin dose has to be at least 100 mg/m2 for each cycle

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38 BEP: Room for improvement? Reduced duration (3-day regimen) Greater efficacy (addition or substitution with taxanes, ifosfamide or Vinca alkaloids) Reduce long-term toxicity Interstitial lung fibrosis Raynaud s syndrome Preservation of fertility Leucemia

39 BEP in intermediate- and high-risk patients Standard of care : BEP x 4 Other cytotoxics Ifosfamide Taxanes Gemcitabine High-dose chemotherapy with autologous stemcell transplantation (HDCT-ASCT)

40 Efforts to improve outcomes in poor-prognosis patients Dose intensifications (ie CDDP) Implementation of intercalating regimens Addition of Ifosfamide or Paclitaxel in first line (TIP regimen) Megatherapy with ACST

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42 Risk-adapted strategies

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46 What about chemo-refractory disease?

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48 Prognostic markers in salvage treatment

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51 Excellent outcomes but still room for improvement