Fellow GU Lecture Series, Testicular Cancer. Asit Paul, MD, PhD 02/06/2018

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1 Fellow GU Lecture Series, 2018 Testicular Cancer Asit Paul, MD, PhD 02/06/2018

2 Rare cancer worldwide, approximately 1% of all male cancers There is a large difference among ethnic/racial groups. Rates are increasing in Northern Europe and USA Most commonly diagnosed cancer among men in USA, aged years 95% of testicular tumors are germ cell tumors (GCT). GCTs also occur outside testes, such as in retroperitoneum, mediastinum & CNS (pineal/ supra-seller) (5-10%) Cure rate is 100% in stage 1 and >80% in metastatic disease

3 Incidence per /year-men ( ) Incidence is highest in Northern Europe/ Scandanivia and lowest in Asia-Africa

4 SEER DATA, USA Estimated new case in % of new cases in % % of all cancer death in % 5-year survival in % 5-year survival in % Median age at diagnosis ( ) 33 years

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6 Risk Factors for GCTs White race: X4-5 risk than black Male with Single nucleotide polymorphism in KITLG, seen in white male Crypto-orchidism: X 5-6 risk than normal counterpart Up to 10% patients have undescended testes Risks higher for both undescended & descended testes Orchioplexy reduces risk Family Hx: X2-4 risk in father, X5-9 in brother Personal hx of testicular cancer Intratubular germ cell neoplasia Testicular dysgenesis HIV Kleinfelter syndrome (mediastinal GCT)

7 Testicular Tumors: Classification Germ cell tumors (95%) Seminoma Non-seminoma: mixed subtype Embryonal cell CA, Choriocarcinoma, Yolksac tumor, teratoma (mature & immature) Non-GCTs: Sex-cord stromal tumors Secondary Lymphoma, Sarcoma Leukemic infiltration Metastatic

8 Non-seminomatous GCT Most NSGCTs contain 2 or more histologic subtypes When NSCGT contain one histology- embryonal carcinoma is the most frequent. Embryonal carcinoma is the most undifferentiated subtype and can differentiate into other NSGCT histology Choriocarcinomas contain both syncytiotrophoblasts and cytotrophoblasts Mature teratoma is histologically benign Teratoma can progress locally or transform into a somatic malignancy ( TMT) such as sarcoma, PNET, adenocarcimoma or hem-malignancies

9 Clinical Presentation Painless testicular mass Retroperitoneal LN (L>R) is the most common metastatic site Lung is the most common visceral site of metastasis Initial Work-up: USG of testes, Tumor markers, CT A/P, Chest imaging. Bone scan & brain imaging in selective cases Orchiectomy should be the initial management in all cases at presentation

10 Serum tumor markers Serum Markers Half-life Tumor subtype B-HCG h Seminoma, Non-Seminoma AFP 5-7 days Non-seminoma LDH 24 h Not specific, reflects volume B-HCG is secreted by both seminoma and non-seminoma. Elevated HCG is present in 15% of stage 1 seminoma, 50% of metastatic seminoma & 40-60% of non-seminoma Pure chorio-carcinomas have a very high HCG level AFP is never secreted by pure seminoma & choriocarcinoma Elevated AFP is present in 50-60% of non-seminoma. Elevated AFP, irrespective of histology, is considered diagnostic of non-seminoma Yolk sac tumors have high-level of AFP Embryonal carcinomas typically have rise in all 3 tumor markers

11 Isochromosome 12p or other form of 12p amplification is seen in vast majority of cancers of testicular origin, irrespective of histologic subtypes Kernek, Modern Pathology, 2004

12 Risk Non-seminoma Seminoma 5 Y PFS 5 Y OS 5 Y PFS 5Y OS Good 89% 92% 82% 86% Inter 75% 80% 67% 72% Poor 41% 48% Based on 5,202 NSGCT & 660 seminoma patients. Median FU 5 years. Post-orchiectomy markers are used for risk stratification J Clin Oncol 1997

13 Management: depends on stage, risk & disease course Inguinal Orchiectomy Surveillance, adjuvant chemotherapy or radiation for stage 1 seminoma Retroperitoneal LN dissection Chemotherapy (BEP) for advance stage, rising marker, recurrence High-dose chemotherapy with autologous stem cell transplant for refractory cancers Surveillance after treatment

14 Management of Seminoma

15 Pure Seminoma: Stage I (No LN or distant metastasis) 80% of seminomas are stage I. Treatment includes active surveillance, adjuvant radiation or chemotherapy. >98% can be cured regardless of type of therapy, but they differ in relapse rates 5-year relapse rate with surveillance is 15-20% NCCN recommends active surveillance as a preferred treatment after orchiectomy (category 1). NCCN has category 2A recommendations for adjuvant carboplatin (AUC 7, 1-2 cycles) or radiation (20 Gy in 10 F) 5-year relapse rate after adjuvant carboplatin is 4-9% Studies showing tumors (>4 cm) or rete testes involvement as a high-risk factors are not confirmed by subsequent studies

16 Pure seminoma Stage II: LN involvement Low-volume disease (LN 3 cm): radiation or chemotherapy LN >3 cm or multiple positive nodes Chemotherapy: EP X4 or BEP X 3 Residual LN after chemo > 3cm + normal tumor marker: PET scan 6-8 weeks after chemotherapy PET +ve: RPLND or biopsy PET ve: surveillance Rising tumor markers: 2 nd line chemotherapy

17 Pure Seminoma: Stage IIC (LN>5 cm or III visceral metastasis) IGCCCC risk stratification Good risk: BEP X3 or EP X4 Intermediate risk BEP X4 (NCCN 1) or VIP (NCCN 2A) Post-chemotherapy management

18 Management of Non-seminoma

19 Stage I Non-seminoma Options include surveillance, RPLND & BEP (X1-2) No survival advantage with adjuvant Rx. Recurrence is generally within 2-3 y of orhiectomy. Can be salvaged effectively with chemotherapy 80-85% of stage 1A are cured by orcheictomy alone. Patient with LVI are at high risk of recurrence, 45-55% vs 20-25% Primary RPLND is offered to +LVI, pt2-t4, noncompliant & predominantly embryonal carcinoma patients Chemotherapy is offered to those whose postorchiechtomy markers are not normalized

20 Non-seminoma: LN or visceral met Markers * Metastasis Treatment options Normalized LN 2 cm (N1) LN 2-5 cm (N2) RPLND or Chemotherapy** Chemotherapy* or RPLND in selected cases LN >5 cm (N3) BEP X 4 or VIP X 4 Not normalized Visceral metastasis/ Intermediate/ High risk BEP X 4 or VIP X 4 Stage II-III BEP X4 of VIP X 4 * Markers: post-orchiectomy, ** BEP X 3 or EP 4

21 Post-chemotherapy management Residual disease Seminoma LN 3 cm Surveillance Seminoma LN > 3 cm PET +ve: RPLND PET ve: Surveillance Nonseminoma LN 3 cm Surveillance Nonseminoma LN > 1 cm Tumor markers not normalized No role of PET, RPLND Salvage chemotherapy

22 Chemotherapy for GCTs Regimen Comment 1 st line BEP Preferred 1 st line for good-risk patient EP VIP/ mod TIP/VeIP For good-risk patients Bleo sparing, considered for poorrisk patients 2 nd line conventional VeIP/ TIP Growth factor support 2 nd line High-dose Paclitaxel/Ifosfomide -> Carbo/etop Palliative Gem-Ox, Gempaclitaxel, Gem-Ox-Pac, oral etop Autostem cell support Palliative Pembrolizumab MSI-H/ d-mmr patients

23 Initial chemotherapy for GCT Numerous trials have shown excellent outcomes of cisplatin-based regimens in good-risk patients with CR >90-95% 4 randomized trials showed superiority of cisplatin over carboplatin based combination regimens Indiana university and MSK studies showed equivalent outcomes of BEP X 3 & EP X4 cycles in good-risk GCT Since reduced-dose cisplatin has inferior outcome, dose reduction should be avoided. G-CSF support should be provided after an episode of FN DFS with VIP X 4 is equivalent with BEP X 4 (64% vs. 60%) in poor-risk patients. Both are NCCN I recommendations.

24 Overall survival Hinton, Cancer, 2002

25 T: 240 mg/m2 X 2 d, I: 6 g/m2 X 5 d + mesna, P: 100 mg/m2 X 5 d G-CSF, Q 3 W CR rate 68%, 3 y PFS 72% & OS 91%, GIII-IV toxicity: 18% Feldman, J Clin Oncol 2016

26 Salvage therapy after relapse 70-80% patients with mgct can have durable response after 1 st line chemotherapy Patients with incomplete response to 1 st line chemotherapy have suboptimal response to 2 nd line conventional dose chemotherapy 2 nd line TIP chemotherapy has 70% RR in IGCCCG good risk group (Kondagunta, JCO, 2005) At MSKCC, patients with at least 1 poor-risk factor treated with HDCT/SCT (TI-CE) had 5 Y DFS 47% & OS 52% (Feldman, JCO, 2010) Updated data from Indiana University showed patients treated with HDCT/SCT with CE has 2 y OS of 82%, 58% & 43%, for IGCCCG good, intermediate & poor risk category (Adra, JCO, 2017)

27 2 nd line CD chemotherapy Rashdan & Einhorn, JOP, 2016

28 46 patients, Testes primary Non-seminoma 89% All patients had CR or PR with negative marker >6 m to 1 st line chemo Prior BEP 74% IGCCCG good risk at dx 4 cycles of TIP 63% durable CR at 69 m median FU 2 y PFS 65% Kondagunta, JCO, 2005

29 Prospective Phase I/II trial at MSKCC Progressive GCT, after at least 1 cycle of cisplatin based chemotherapy 1 poor prognostic feature: Extragonadal primary,, PD after prior salvage CDCT, IR or relapse <6 m after 1 st line, 2 cycles of TI (CD), 14 days apart, followed by 3 cycles of CE with autosct, days apart CR 50%, PR-neg 8%, PR 45% 5 y DFS 47%, OS 52% Mediastinal primary PFS 24%, OS 29% Feldman, J Clin Oncol 2010

30 mgct who relapsed after 1 CD chemo (n=364) 1 st Cycle: Carbo/etop X 3 d -> autosct, after 3 days. 2 nd cycle: After recovery of neutrophil & platelet counts. Oral etoposide daily for 21 days, q 4 W X 3 J Clin Oncol 2017

31 Lorch, J Clin Oncol 2011

32 J Clin Oncol 2010 Pagliaro, J Clin Oncol 2016

33 Who should receive salvage HDCT/ autosct? Initial salvage to all patients (Indiana Univ) Poor risk features (Extra-gonadal primary, progressive dz after CDCT, incomplete response or relapse <6 m of 1 st line (MSKCC) IGCCCG poor risk at relapse 3 rd line setting

34 Pagliaro, J Clin Oncol 2016

35 NCT Standard-Dose Combination Chemotherapy or High- Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors (TIGER) Arm A: Standard TIP X 4 cycles Arm B: TI-CE X 5 cycles TI X 2, q 14 d -> CE (D1-3) SC (D5) X3, q21d

36 Salvage chemo for relapse after HDCT Rashdan & Einhorn, JOP, 2015

37 Special situations Cisplatin-refractory: Progression during or within 4 weeks of cisplatin-based chemotherapy. Should be referred for HDCT Late-relapse: Relapse >2 y of initial Rx. Late relapse in seminoma should be treated same as early relapse. NSGCT should be treated with surgery with or without salvage chemotherapy Elevated tumor markers after initial Rx: Alternative explanation of low-level elevated markers after chemotherapy (such as AFP <25 ng/ml) should be looked for. Rising tumor markers should raise the concern for relapse. LDH alone should never be used as a marker of relapse. Mediastinal NSGCT: Rare entity with worse outcome. Predominantly contain yolk-sac components. 5 y survival is 40-45%. Generally classified as poor-risk category and should be treated with regimens for poor risk disease, such as VIP, TIP or HDCT, followed by resection.

38 Testicular cancer is the most frequent solid tumor in the year age group. Rate of testicular cancer is rising The survival of patients with early stage disease is close to 100% About 70-80% patients with mgct can achieve durable response with cisplatin based regimen. Conventional dose 2 nd - line chemotherapy can provide durable response in 70% of patients who recur after 1 st line chemotherapy HD-chemotherapy with stem cell support can salvage high-risk refractory patients with durable response Ongoing phase III, international TIGER trial is comparing standard dose vs HDCT in relapsed GCT patients (NCT )

39 Survivorship & life issues Fertility issues Hypogonadism Secondary cancers, including leukemia Hearing issues from cisplatin Lung function from cisplatin and bleomycin Cardiovascular effects from radiation & chemotherapy