Chemotherapy for Testicular Cancer

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1 Chemotherapy for Testicular Cancer Jeremy Cetnar, MD Assistant Professor of Medicine Genitourinary Oncology and Experimental Therapeutics Program University of Wisconsin Comprehensive Cancer Center University of Wisconsin Carbone Cancer Center

2 Outline Epidemiology Staging Treatments Chemotherapy Stage I Adjuvant Recurrent disease

3 Epidemiology 90% of germ cell tumors (GCTs) arise in testis GCTs are the most common solid tumors in men age15-35 In 2009, 8400 new cases, 380 deaths ACS, cancer facts 2009 Highest incidence in Germany, Scandinavia, and Switzerland Lowest incidence in Africa and Asia Risk Factors Race: caucasians >>>blacks Age: bimodal: 20-30s and >50s Cryptorchidism 4-40x higher compared to normal Risk persists despite orchiopexy Kleinfelter syndrome Family History: up to 6x greater risk, greatest for siblings Infertility Contralateral GCT

4 Histology NSCGT Seminoma

5 Seminoma Most frequently present in those 35 to 45 years old On IHC, + PLAP, C-kit (CD117), VASA, NANOG, and OCT4 Rarely produces HCG (from syncytiotrophoblasts) Does not influence prognosis NEVER PRODUCE AFP* Nazeer T, Oncol Rep, 1998; 2 cases of pure seminoma producing AFP Have a greater propensity to met to bone compared to NSGCT 80% present with stage 1 disease

6 Nonseminomatous GCTs Typically present in the 20s Four most common types Embryonal carcinoma Choriocarcinoma Yolk Sac tumor Teratoma Most tumors are mixed with a combination of types including seminoma Note: Any element of a non-seminoma makes the tumor a NSGCT

7 NSGCT Embryonal: Most common component of mixed NSGCT AFP and HCG are commonly elevated Poorly defined histologically Areas of necrosis and hemorrhage frequently seen Choriocarcinoma: Consists of both syncytiotrophoblast and cytotrophoblasts Results in very high HCG levels (>100K) Spreads hematogenously Results in bleeding Mets to brain and lung commonly

8 NSGCT Teratoma Derived from ectoderm, endoderm, and mesoderm Able to differentiate Mature teratoma contains adult type differentiated tissue Immature teratoma contain partial somatic differentiation Teratoma with malignant transformation resembles a non-gct somatic cancer (ie; sarcoma, carcinoma, leukemia) Yolk Sac Tumor Demonstrates extraembryonic yolk sac differentiation Most common germ cell tumor in children Makes AFP Most common mediastinal NSGCT Ten different histologic subtypes

9 Pathogenesis 100% of GCTs show an increased copy of 12p Genes associated with 12p CCND2 oncogene GLUT3 glucose transporter GAPDH and TP11 glycolytic enzymes NANOG, DPPA3, and GDF3 self renewal and pluripotency Carcinoma in situ (ITGCN) is the precursor for GCTs Median time of 5 years until progression invasive ca.

10 Anatomy Initial route of metastasis is lymphatic drainage to the retroperitoneal lymph nodes Right testicular tumor drains into interaortocaval inferior to the renal vessels Right testicular a/v from aorta and IVC Left testicular tumor drains into the para-aortic nodes inferior to the left renal vessels Left testicular a/v from left renal artery and left vein

11 Staging CT of the chest, abdomen, and pelvis Tumor markers AFP: ½ life of 5-7 days HCG: ½ life of 30 hours LDH

12 Clinical staging General rules Stage 1: Tumor confined to the testis Stage 2: Tumor confined to the testis and retroperitoneum Stage 3: Metastatic

13 TNM Staging

14 Germ Cell Tumor Risk Classification

15 Advanced GCTs IGCCCG risk % of population 5-year survival (%) Good Intermediate Poor J Clin Onc, 1997

16 Stage 1 Seminoma Radiation Stage 1 Seminoma Observation Chemotherapy

17 Treatment: Stage 1 Seminoma Risk factors for relapse >4cm and rete testis invasion 0 = 8%, 1 = 10-15%, 2 = 25% Median time to relapse: months 30% of relapses occur after 2 years 5% of relapses occur after 5 year 1. Radiation 2500 cgy Relapse rate of 3-5% after radiation Typically in the posterior mediastinum or suplaclavicular area 2. Observation

18 Treatment: Stage 1 Seminoma cont. 1. Radiation 2. Observation 3. Chemotherapy: Single dose of carboplatin 1477 patients randomized to XRT or carboplatin After four years relapse rate of 95% for chemo vs. 96% for XRT Two cycles of carboplatin 3.3% relapse Criticisms Still need regular imaging of the retroperitoneum Carboplatin inferior to cisplatin Long term consequences of 1-2 cycles of carbo unknown

19 Stage 1 NSGCT RPLND Stage 1 NS Observation Chemotherapy

20 Treatment: Stage 1 NSGCT 1. RPLND Both diagnostic AND therapeutic Most consistent long term morbidity is retrograde ejaculation If lymph nodes are positive then what? If pn % chance of recurrence If pn2-3 50% chance of micrometastatic disease 2 cycles of Etoposide/Cisplatin

21 RPLND Modified bilateral retroperitoneal lymph node dissection Devita, 2008

22 Treatment: Stage 1 NSGCT 1. RPLND 2. Observation Why? Retrograde ejaculation after RPLND Most would not have needed RPLND Ability of cisplatin chemotherapy to cure systemic disease >50% chance of recurrence if > pt2 (+/- embryonal) If pt1 = 15% chance of recurrence <10% of relapses occur more than 2 years after diagnosis (compared with 30% in seminoma) Sites of relapse: retroperitoneum (2/3) markers or lungs (1/3)

23 Treatment: Stage 1 NSGCT 1. RPLND 2. Observation 3. Chemotherapy 2 cycles of BEP 5% relapsed and 1% death rate 1 cycle of CVB for LVI patients No difference in relapse rate compared to observation 2 cycles of CVB for LVI+ patients Reduced recurrence rate by >90% ¼ of patients had grade ¾ obstipation or infection

24 Treatment 1: Stage 1 NSCGT What should you do if the markers do not normalize or plateau after orchiectomy?

25 Treatment: Stage 2 GCTs Remember the clinical staging: 2A: <2cm 2B: >2cm but less than 5cm 2C: >5cm Seminoma 2A and 2B XRT NSGCT Same dosage of radiation for stage 1 but in a dog leg distribution Relapse <10% 2A RPLND If pn1: 15-20% chance of relapse observation If pn2-3: 50% of micrometastatic disease 2 of EP

26 Treatment: Stage 2 GCTs For NSGCT stage 2B and 2C and seminoma 2C Treat as advanced disease (chemotherapy) Idenitification for relapse: Stage 1 NSGCT: Observation: PE, tumor markers, and CXR monthly, and CT every 3 months during year #1 PE, tumor markers, CXR every other month and CT every four months during year #2 PE, tumor markers, and CXR every three months and CT every 6 months for years 3-5 Beyond 5 years yearly markers, CXR, and PE If undergoing XRT no need for abdominal CT If undergoing RPLND no need for abdominal CT

27 Treatment of advanced disease Unresectable stage 2 NSGCT/Seminoma Includes extensive or bulky retroperitoneal, supradiaphragmatic nodal or visceral mets Advanced disease Good risk: 3 cycles of BEP Bleomycin 30 units (D 1,8,15) Cisplatin 20mg (D1-5) Etoposide 100mg/m2 (D1-5) 21 day cycle Need G-CSF If wanting to avoid bleomycin: 4 cycles of EP Etoposide 100mg (D1-5) Cisplatin 20mg (D1-5)

28 Treatment: Int/Poor risk GCTs 4 cycles of BEP is the standard If wanting to avoid bleomycin toxicity may use 4 VIP Equivalent efficacy but increased hematologic toxicity Etoposide 75mg (D1-5) Ifosphamide 1.2grams (D1-5) Cisplatin 20mg (D1-5)

29 High dose chemotherapy Does high dose chemotherapy for intermediate/poor as initial treatment improve survival? JCO, 2007, Motzer R 219 patients with I/P risk GCT randomized to either 4 cycles of BEP 2 cycles of BEP followed by high dose carbo, etoposide, cytoxan

30 Post chemotherapy treatment If a residual mass remains following chemotherapy for NSGCT RESECT!!! PET scan not reliable Biggest concern is viable carcinoma or teratoma Teratoma is relatively chemotherapy insensitive and may grow or transform therefore it must be resected In the retroperitoneum: necrosis 45-50%, teratoma 35-40%, viable 10-15% Predictors of viable mass: presence of teratoma in the original tumor, pre-op tumor markers, and size of mass post-chemo If viable tumor is present then 2 cycles of EP are indicated If necrosis or teratoma no further therapy indicated If residual mass in lung or mediastinum resect, more likely to be residual tumor or teratoma

31 Post-chemotherapy seminoma Unlike NSGCT, PET scan is helpful in identifying if viable tumor is present in a residual mass If residual mass is <3cm then observe If residual mass is >3cm then PET If positive then higher risk for viable tumor Unlike NSGCT, teratoma is unlikely in the residual mass Unlike NSGCT, RPLND following chemotherapy is more difficult due to desmoplastic reaction and obliteration of tissue planes

32 Relapsed disease 20-30% will relapse following initial chemotx. Most relapses occur within 2 years Standard salvage regimens include VeIP x 4 (Vinblastine, ifosfamide, and cisplatin) OR TIP x 4 (paclitaxel, ifosfamide, and cisplatin) Devita, 2008

33 Relapsed disease Defining relapse Primary refractory: progression either during or within four weeks of finishing initial chemotherapy Poor prognosis with <10% 3yr survival with conventional dose salvage regimens Treatment is typically high dose chemotherapy with stem cell rescue If relapsing mediastinal NSGCT then also a poor prognosis and should consider HD chemotherapy Late relapse: > 2 years from initial chemotherapy Typically slow growing and chemo resistant For NSGCT surgical resection +/- chemo is critical For seminoma, tend to behave like early relapsing Treat with chemotherapy since teratomas are rare

34 HD chemo for refractory disease GCTs are chemosensitive, could more chemo be better? As first line treatment in poor risk GCTs compared to standard BEP Motzer R, JCO, patients with either Intermediate or poor risk Randomized to either 4 BEP or 2 BEP followed by 2 HDSCR HD= carbo, etop, and cytoxan No difference in OS

35 High dose chemotherapy As first line therapy for salvage treatment Pico JL, Annals of Oncology, patients with complete or partial response to first line cisplatin based chemotherapy Randomized to either VeIP or EIP x 4 or VeIP or EIP x 3 then carbo, etoposide and cytoxan x 1 No difference in 3yr survival 7% death rate with HD chemo compared to 3% with standard

36 High dose chemotherapy What is the role of high dose chemo with stem cell rescue? Primary refractory Relapse after standard VeIP or TIP Relapsing mediastinal NSGCT? The University of Indiana Experience Retrospective study 184 patients who received HD chemotherapy Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease Einhorn, NEJM, 2007

37 Einhorn LH et al. N Engl J Med 2007;357:

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39 Boards Growing teratoma syndrome

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