Testicular Cancer Germ Cell Tumors Marc Wygoda Department of Oncology

Testicular Cancer

Germ Cell Tumors Most common Solid Tumor in men 20-35 1% of cancers in males Great impact on “years of life” saved 95% arise in testis 5% are “extra-gonadal”: mediastinum, retroperitoneum, pineal body Model of a Curable Cancer even in advanced stage Model of a Cancer with Tumor Markers playing a crucial role in management

Risk Factors Age Family history Personal history Cryptorchidism (undescended testicle) Association with Infertility (mild) Klinefelter’s syndrome

Age at presentation

Symptoms Painless lump or swelling of testicle Pain or discomfort in a testicle or the scrotum Breast tenderness or growth Symptoms of advanced cancer lower back pain, abdominal pain, shortness of breath, chest pain

How is Testicular Cancer Diagnosed? Physical examination Ultrasound of Testis Blood tests / tumor markers Diagnosis is confirmed by surgically removing the testicle Needle biopsy not used (except in very specific situations) CTS of Chest, Abdomen and Pelvis No role for MRI. Mild role of PET (only in Seminoma)

DICTUM FOR ANY SOLID SCROTAL SWELLINGS All patients with a solid testicular mass should be regarded as malignant, unless proven otherwise

Radical inguinal orchiectomy Most men are still able to have children after the removal of one testicle No effect on sexual function (men with sexual problems after surgery should have their testosterone level checked) Some men may choose to have an artificial testicle implanted

Histologic Subtypes of GCT SEMINOMA (40%) Classical (32%) Anaplastic (4%) Spermatocytic (4%) NON SEMINOMA (60%) Embryonal Ca (25%) Teratoma (25%) Yolk sac Tumor Choriocarcinoma Embryonal commonly in mixed (20%) Mixed GCT: 40%

Staging Serum tumor markers (S): AFP, β-HCG, LDH

Tumor Markers AFP Half-life: 5-7 days Produced by several Non Seminoma subtypes (embryonal, teratocarcinoma, yolk sac, mixed tumors) Never produced by Seminoma or pure choriocarcinoma Falsely elevated in liver dysfunction, viral hepatitis and ETOH β-HCG Half-life: 24-36 hours Produced by syncytiotrophoblastic tissue All choriocarcinomas, 40-60% embryonal, 5-10% seminoma Falsely elevated in hypogonadism and marijuana use LDH Most useful in advanced seminoma & when other markers are not ↑ Many false positives

How is Testicular Cancer Treated? Depends on stage of cancer and type of tumor More than one treatment may be used Surgery Active surveillance Radiation therapy Chemotherapy Patients should talk with their doctor about whether treatment plan could affect sexual function and fertility before treatment begins

Seminoma Tend to remain localized or spread only to LN The disease spreads in an orderly fashion: retroperitoneal LN – (SII). Mediastinal/supraclavicular LN (SIII). Lung and then non pulmonary (brain/bone/liver) If LN <1cm repeat in 6w if normal → follow marker decline to distinguish between stage 1 and disseminated disease. Tumor marker analysis should be performed before surgery and, if elevated, 7 days after surgery to determine the half-life kinetics. Tumor markers should be monitored until normalization.

Seminoma: stage at diagnosis stage I: 70-80% Stage II (Retroperitoneal Nodes): 15-20% Stage III (Other metastases): 5%

For Right & Left Sided Testicular Tumors Lymph Nodal spread For Right & Left Sided Testicular Tumors

Testis cancer: seminoma stage I Management options Surveillance only Adjuvant Radiotherapy Adjuvant Chemotherapy

Surveillance stage 1 seminoma Relapse rate in surveillance studies:

Testicular Lymphatic Drainage

Stage I Seminoma adjuvant Radiotherapy Classical “Hockey Stick” Field

Adjuvant radiotherapy stage I seminoma 22.5-25 Gy ( ~3 weeks of treatment) Target: Paraaortic + Ipsilateral Pelvic Nodes Relapse rate: 0-2%

Hadassah experience in stage I adjuvant Radiotherapy 36 patients with stage I seminoma Post orchiectomy “hockey stick “ irradiation 22.5-24 Gy in 1.5 Gy fractions Testicular shell was always used Semen preservation was recommended to all patients

Outcome Median follow-up 98 mo No recurrences! One contralateral second primary GCT No effect of Radiotherapy on fertility

Fertility Outcome 13/36 were not interested in fertility preservation 1/36 was azoospermic prior to diagnosis 1/36 was oligospermic priot to diasgnosis 5/36 were lost to follow-up 10 pts successfully conceived w/o any intervention The oligospermic pt successfully underwent IVF treatment other pts have not yet “tested” their fertility

Stage II Seminoma - Treatment Cancer has spread to lymph nodes in the retroperitoneum, but not lymph nodes in other parts of the body Stage IIA: ≤ 2 cm: Radiotherapy Stage IIB: 2-5cm: Radiotherapy or Chemotherapy Stage IIC: >5cm: Chemotherapy Prognosis: > 95% Cure

Stage III-IV Seminoma - Treatment Chemotherapy

Stage I Non Seminoma Management Surveillance Adjuvant Chemotherapy Surgery: RPLND (Retro Peritoneal Lymph Node Dissection)

Surveillance for Markers negative stage I Non seminomas Appropriate for “low risk” patients: Compliant patient No vascular/lymphatic invasion No dominant presence of Embryonal Carcinoma Regular physical examination, CT scans, chest x-rays, and blood tests (Markers), performed every few months for the first 2 years and less often thereafter Risk of Relapse is then ~25% At relapse excellent chances of cure with chemo

Adjuvant Chemotherapy for High Risk stage I NSGCT Definition of High Risk Stage I NSGCT: Lympho-vascular invasion, or Embryonal Carcinoma Predominance (≥ 45%) Natural History: ~ 50% recurrence rate Moul et al: Cancer Res 54:1, 1994 30

RR is 45-50% in VI positive tumors No VI (n=199) VI (n=192) 23 publications (1979-2001; 2587 cases) repeatedly confirm overwhelming importance of VI RR is 45-50% in VI positive tumors Vergouwe et al JCO 2003 31

Hadassah Adjuvant Chemotherapy PEB x2 Protocol Entry: Feb. 1993 → June 2011 Eligibility: High Risk Stage I NSGCT Normal Chest-Abdomen-Pelvis CTS AFP and ΒHCG normal, or return to normal according to ½ lives after Orchiectomy Number of pts: 31 Age: 15-53 ( median 25 ) Sperm Banking recommended to all pts 32

Results Median Follow-Up: 9.4yrs (range: 0.5-19 yrs) # of Relapses: 1 (3%) (Retroperitoneal mass 3months after PEB Completion in a pt with pure EC without LVI → RPLND: Growing Mature Teratoma) DFS: 97% OS: 100% 3/31 Controlateral Testicular Cancer: Stage I Embryonal Ca after 3 yrs → NED Stage IIB Seminoma after 7yrs → XRT → NED Stage I Mixed GCT (Teratoma + Seminoma) after 19m → NED No other Secondary Malignancy seen 33

Fertility 11/31 pts have not attempted to father children 16/20 pts known to have desired it, were able to impregnate their wives, and to father 34 healthy children (1-4), without need to use their banked sperm. Overall Fertility Ratio: 80% (85%?) 34

Retroperitoneal Lymph node dissection Morbidity of from disruption of the sympathetic nerves Morbidity is increased after XRT or chemo because of a desmoplastic reaction -also morbidities: atalectasis, penumonitis, ileus, lymphocele, pancreatitis f/u post RPLND:F/u exam, CXR and markers every 2 months for 1 year, and every 4 months for 1 year and then annually (relapse beyond 2 years is rare) Major morbidity is ejaculatory dysfunction Modified nerve sparing RPLND preserves function in > 90% Identify the sympathetic nerves Dissection is limited to below the level of the IMA on the ipsilateral side only

36

37

German Randomized Trial in all stage I NSGCT Risk Grouping by T Stage 38

German Randomized Trial in all stage I NSGCT Recurrence Free Survival 39

Stage II to IV Non Seminoma Chemotherapy Important role for Surgery to resect post chemo residual mass

Advanced Testicular Cancer: Risk Group Classification Based on tumor location, tumor spread, and serum marker levels 3 groups for both seminoma and non-seminoma Good risk Intermediate risk Poor risk Patients with poor-risk cancer still have about a 50% chance of successful treatment

Non seminoma seminoma Good risk Intermediate risk Poor risk AFP<1000 60% of non seminoma HCG<5000 Any HCG 90% of seminoma LDH<1.5 *ULN Any LDH Non-pulmonary mets absent Gonadal/retroperitoneal primary Any primary site AFP 1000 – 10000 Non-pulmonary visceral mets present Intermediate risk HCG 5000 – 50000 13%-28% of non seminoma LDH 1.5 – 10 * ULN 10% of seminoma Non-pulmonary / visceral mets absent Gonadal/retroperitoneal Mediastinal primary: Visceral mets presents( bone liver brain AFP>10000 HCG > 50000 LDH>10*ULN Never Poor risk 16%-26% of non semin.

PFS and OS according to risk 5y PFS (%) 5y OS (%) prognosis seminoma Non seminoma good 82 89 90 92-94 intermediate 67 75 72 80-83 poor 41 71

Cancer Treatment: Chemotherapy Classical Protocol: PEB Platinum (Cisplatinum) Etoposide (VP-16) Bleomycin Common Side effects may include fatigue, infection, nausea and vomiting, alopecia. Rare side effects: hearing loss, skin marks, numbness and tingling, lung damage, kidney damage, cardiovascular disease, and secondary cancers Nowadays very little severe long term side effects

Highly Curable Cancer even in Advanced Stage Before chemo After chemo

Lung mets before and after Chemo

Metastatic Seminoma Chemotherapy PEB x 3

Post Chemo RPLND Pathological findings 40-45% teratoma 40-45% Necrosis 10-20% viable Tumor

PROGNOSIS Seminoma Nonseminoma Stage I 99% 95% to 99% Stage II 95% 90% Stage III 80% to 85% 70% to 80%

Post treatment Follow up Regular physical examinations and/or medical tests may be required to monitor for the following long-term effects Effect of bleomycin on lungs Effect of chemotherapy on kidneys, blood vessels and lipids profile Effect of cisplatin on nerves, hearing, and the brain Secondary cancers Fertility problems Testosterone levels Fear of recurrence is common: psychological support

Relapse of Testicular Cancer Still Curable 2nd line Chemotherapy High Dose Chemo with Stem Cell Rescue Post chemo Surgery

Conclusions Imperial Surgery Turkey/Persia 15th century Bibliotheque Nationale, Paris 52

Testicular Germ Cell tumors Model of highly curable cancel Stage I pts have a long term cure rate close to 100% Low to intermediate burden metastatic pts cure rate: ~90% Very advanced pts are infrequent: cure rate ~50-60% Pts can still be cured after relapse

Five-Year Survival Progress Against Testicular Cancer Source: National Cancer Institute

תודה רבה !