TESTICULAR CANCER Updated March 2016 by Dr. Safiya Karim (PGY-5 Medical Oncology Resident, University of Toronto)

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1 TESTICULAR CANCER Updated March 2016 by Dr. Safiya Karim (PGY-5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Aaron Hansen (Staff Medical Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 8,720 cases estimated in the US (2016) - Mortality: Highly treatable, often curable, 5 year relative survival rate = 97% RISK FACTORS - Environmental/Chemical/Infections: cryptorchidism, germ cell neoplasia in situ, hypospadias, contralateral testicular cancer, extragonadal germ cell tumor, HIV infection, - Genetic: Family history of testicular cancer, Kleinfelter s syndrome, Down syndrome, Peutz- Jeghers syndrome, Carney s complex PREVENTION & SCREENING - Prevention: Surgical correction of cryptorchidism - Screening: Nil B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Common Symptoms: painless testicular swelling/ nodule, dull ache in lower abdomen, back pain - Common Signs: o Localized: painless testicular swelling/ nodule, gynecomastia o Metastatic: neck mass, lower extremity swelling - Common Presentations: painless testicular swelling/ nodule, acute painful testes, neck mass, pulmonary mass INVESTIGATIONS - Laboratory: CBC, extended electrolytes, liver enzymes, AFP, B-HCG, LDH - Diagnostic Imaging: scrotal ultrasound, CXR +/- CT chest, CT abdo/pelvis - Diagnostic Procedures: radical inguinal orchiectomy, PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: o o Seminomas Non-seminoma! Embryonal carcinomas! Teratomas! Yolk sac tumors! Choriocarinomas - Common Metastatic Sites: Retroperitoneal lymph nodes, lungs, - Less Common Metastatic Sites: Bone, liver, brain - Relevant Molecular Biology: N/A

2 STAGING - TNM Primary tumour (T) ptx Primary tumour cannot be assessed pt0 No evidence of primary tumour (e.g. histologic scar in testis) ptis Intratubular germ cell neoplasia (carcinoma in situ) pt1 Tumour limited to the testis and epididymis without vascular/lymphatic invasion; tumour may invade into the tunica albuginea but not the tunica vaginalis pt2 Tumour limited to the testis and epididymis with vascular/lymphatic invasion, or tumour extending through the tunical albuginea with involvement of the tunica vaginalis pt3 Tumour invades the spermatic cord with or without LVI pt4 Tumour invades the scrotum with or without LVI Regional lymph nodes (N) Clinical NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass 2cm or less in greatest dimension; or multiple lymph nodes, none more than 2cm in greatest dimension N2 Metastasis with a lymph node more than 2cm but not more than 5cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2cm but not more than 5cm in greatest dimension N3 Metastasis with a lymph node mass >5cm Pathological (pn) pnx Regional lymph nodes cannot be assessed pn0 No regional lymph node metastasis pn1 Metastasis with a lymph node mass 2cm or less in greatest dimension and less than or equal to five nodes positive, none more than 2cm in greatest dimension pn2 Metastasis with a lymph node mass more than 2cm but not more than 5cm in greatest dimension; or more than five nodes positive, none more than 5cm; or evidence of extranodal extension of tumour pn3 Metastasis with a lymph node mass more than 5cm in greatest dimension Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Nonregional nodal or pulmonary metastasis M1b Distant metastasis other than to nonregional lymph nodes and lung Serum tumour markers (S) SX Marker studies not available or not performed S0 Marker study levels within normal limits S1 LDH <1.5 x ULN AND HCG <5000 IU/L AND AFP <1000 ug/l S2 LDH x ULN or hcg ,000 or AFP ,000 S3 LDH >10 x ULN or hcg > 50,000 or AFP > 10,000 Stage T N M S 0 ptis N0 M0 S0 I pt1-4 N0 M0 SX IA pt1 N0 M0 S0 IB pt2 N0 M0 S0 pt3 N0 M0 S0 pt4 N0 M0 S0 IS Any pt/tx N0 M0 S1-3 II Any pt/tx N1-3 M0 SX

3 IIA Any pt/tx N1 M0 S0 Any pt/tx N1 M0 S1 IIB Any pt/tx N2 M0 S0 Any pt/tx N2 M0 S1 IIC Any pt/tx N3 M0 S0 Any pt/tx N3 M0 S1 III Any pt/tx Any N M1 SX IIIA Any pt/tx Any N M1a S0 Any pt/tx Any N S1 IIIB Any pt/tx N1-3 M0 S2 Any pt/tx Any N M1a S2 IIIC Any pt/tx N1-3 M0 S3 Any pt/tx Any N M1a S3 Any pt/tx Any N M1b Any S - IGCCC Risk Classification for advanced disease Classification Nonseminoma Seminoma Good risk Gonadal or retroperitoneal primary tumour No nonpulmonary visceral metastasis Good tumour markers (AFP <1000ug/L and hcg <5000 IU/L and LDH <1.5 x N) Any primary site No nonpulmonary visceral metastasis Normal AFP, any hcg, any Intermediate risk Poor risk Gonadal or retroperitoneal primary tumour No nonpulmonary visceral metastasis Intermediate tumour markers (AFP < ,000 ug/l or hcg < IU/L or LDH < x N) Mediastinal primary tumour or Nonpulmonary visceral metastasis or Poor tumour markers (AFP >10,000 ug/l or hcg >50,000 IU/L or LDH >10 x N) LDH Any primary site Nonpulmonary visceral metastasis Normal AFP, any hcg, any LDH N/A C) TREATMENT Early Stage Disease: Stage I Seminoma: - Bottom Line General Approach: orchiectomy followed by surveillance or chemotherapy (1-2 cycles of carboplatin) - Prognosis: cure rate approaches 100% regardless of whether any post orchiectomy adjuvant therapy is given, 10-yr recurrence rate = 15-20% Stage II Seminoma: - Bottom Line General Approach: Stage IIa: orchiectomy followed by RT or chemotherapy (BEP x 3 cycles) Stage IIb/c: orchiectomy followed by chemotherapy (BEP x 3 cycles) - Prognosis: 5 year disease free survival of >90% for stage IIa and non-bulky stage IIb disease Important Phase III Clinical Trials:

4 Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial (ISRCTN ) Jones, WG et al. J Clin Oncol Feb 20; 23(6): Regimen 20 Gy/ 10 fractions vs. 30 Gy/ 15 fractions Mechanism of N/A Primary Endpoint Relapse free rate Secondary endpts: morbidity and quality of life Inclusion/Exclusion Stage 1 seminoma following orchiectomy pt4 tumors excluded Size (N) 625 patients Results 2 year relapse free rate: 97.7% (30 Gy) vs 97 % (20 Gy) Quality of Life: trend towards higher rates of nausea and vomiting in the 30 Gy group, higher rates of moderate to severe lethargy and inability to work in the 30 Gy group Toxicity Nausea/ vomiting, leucopenia, thrombocytopenia Conclusion 20 Gy/ 10 fractions is unlikely to produce relapse rates higher than 3% and provides reduction in morbidity Other Comments Higher risk of second malignancies Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC study (ISRCTN ) Oliver, RT et al. J Clin Oncol Mar 10; 29(8): Regimen RT (30 Gy/15 or 20 Gy/10) vs. carboplatin AUC 7 x 1 dose Non-inferiority design Mechanism of Carboplatin causes the intra- and inter-strand cross-linkage of DNA molecules within the cell. This modifies the DNA structure and inhibits DNA synthesis. Primary Endpoint Relapse free rates Inclusion/Exclusion Stage 1 seminoma post orchiectomy Size (N) 1477 patients Results 5 year Relapse free rate: 94.7% (carboplatin) vs 96.0% (RT), HR 1.25, p=0.37 Risk of contralateral germ-cell tumor: significantly decreased with carboplatin vs RT, HR 0.22, p=0.03 Toxicity Not reported Conclusion Carboplatin x 1 dose (AUC 7) is non-inferior to adjuvant RT and reduces the risk of contralateral germ-cell tumors Other Comments Stage I non-seminoma: - Bottom Line General Approach: radical orchiectomy followed by surveillance - At some centers retroperitoneal lymph node dissection (RPLND) or chemotherapy (BEP x 1 or 2 cycles is done but this is not routine - Prognosis: Disease free survival of ~99%. 70% cure rate with orchiectomy alone; 30% relapse rate

5 Stage II non-seminoma: - Bottom Line General Approach: radical orchiectomy followed by RPLND +/- chemotherapy If Stage IIb/c radical orchiectomy followed by chemo (BEP x 3) (with resection of residual masses) or RPLND (followed by BEP x 3 if active malignanct in resection) Prognosis: 95% cure rate - Important Phase III Clinical Trials: Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group Albers, P et al. J Clin Oncol Jun 20; 26(18): Regimen Retroperitoneal lymph node dissection (RPLND) vs BEP x 1 cycle post orchiectomy (bleomycin 30mg d1,8,15, etoposide 100mg/m2 day 1-5), cisplatin 20mg/m2 day 1-5) Mechanism of Primary Endpoint Rate of recurrence Inclusion/Exclusion Stage 1 non-seminoma post orchiectomy Excluded if LN > 10mm in transverse diameter Size (N) 382 patients Results 2 year difference in recurrence free rate: 7.59% in favor of chemotherapy Toxicity Grade 3 hematologic toxicities seen in 37.4% of patients receiving 1 cycle of BEP Neutropenic fever in only 4 patients receiving 1 cycle of BEP Conclusion 1 cycle of BEP is superior to RPLND in patients with stage 1 nonseminoma post orchiectomy Other Comments A significant number of patients on the RPLND arm received 2 BEP. This trial has been criticized for the poor quality of surgery in the RPLND arm. Hence this trial should be very interpreted cautiously. ADVANCED DISEASE

6 - Bottom Line General Approach: Treatment determined on basis of prognosis (good, intermediate, poor risk) o Good risk disease: BEP x 3 or EP x 4 (if bleomycin contraindicated) o Intermediate/ poor risk disease: BEP x 4 or VIP x 4 (if bleomycin contraindicated) - Prognosis: o Good risk: > 95% cause specific survival o Intermediate risk: ~75-80% cause specific survival o Poor risk: 50-60% cause specific survival - Important Phase III Clinical Trials: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide Williams, SD et al. NEJM Jun 4; 316(23): Regimen Cisplatin+ etoposide+ bleomycin (BEP) vs cisplatin + vinblastine + bleomycin (PVB) Mechanism of Vinblastine produces significant neuromuscular toxicity Use of etoposide would prevent development of neuromuscular toxicity Primary Endpoint Disease free survival Inclusion/Exclusion Men with disseminated germ cell tumors Size (N) 244 patients Results DFS: 83% (BEP) vs. 74% (PVB) p = not significant In patients with high tumor volume: 77% vs 61% DFS OS: Increased in patients on etoposide Fewer parasthesias, abdominal cramps and myalgias with etoposide Toxicity Similar rates of myelosuppresive effects and pulmonary toxicity Conclusion BEP is superior to PVB due to diminished neuromuscular toxicity and increased efficacy in patients with high tumor volume Other Comments Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council De Wit, R et al. J Clin Oncol Mar 15; 19(6): Regimen BEP x 4 cycles vs BEP x 3 cycles and 5 day vs. 3 day regimen (2x2 factorial trial) Mechanism of Primary Endpoint 2 year PFS Inclusion/Exclusion Good prognosis germ cell tumors post orchiectomy Size (N) 812 patients Results 2 year PFS: 90.4% (3 cycles) vs. 89.4% (4 cycles) 88.8% (5 day regimen) vs. 89.7% (3 day regimen) Quality of Life: Better maintained with 3 cycle vs 4 cycle regimen; no difference between 5 day vs 3 day regimen Toxicity Similar rates of hematologic and non-hematologic toxicites Conclusion 3 cycles of BEP is sufficient therapy in good prognosis germ cell tumors and administration of chemotherapy over 3 days has no

7 Other Comments detrimental effect Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. Nichols, CR et al. J Clin Oncol Apr; 16(4): Regimen Bleomycin, Etoposide and Cisplatin (BEP) x 4 cycles vs Etoposide, Ifosfomide and Cisplatin (VIP) x 4 cycles Mechanism of Primary Endpoint Overall survival Inclusion/Exclusion Poor and intermediate risk germ cell tumors post orchiectomy Size (N) 304 patients Results 2 year OS: BEP 71% vs VIP 74% Overall complete remission rate: BEP 31% vs VIP 37% Failure free at 2 years: BEP 60% vs VIP 64% Toxicity Higher rates of grade 3+ hematologic and genitourinary toxicity with VIP Conclusion 4 cycles of VIP produce similar response rates and survival to 4 cycles of BEP with increased toxicity. Other Comments Patients intolerant or not candidates for bleomycin are treated with VIP Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors Motzer RJ et al. J Clin Oncol Jan 20; 25(3): Regimen 4 cycles of bleomycin, etoposide and cisplatin (BEP) vs. 2 cycles of BEP + high dose chemotherapy containing carboplatin followed by hematopoetic stem cell rescue (BEP + HDCT) Mechanism of High-dose chemotherapy (HDCT) was studied in single-arm phase II trials as first-line therapy for patients with poor-prognostic features The relative tolerability and improvement in relapse-free survival and overall survival (OS) compared with historical controls treated with conventional-dose programs suggested that this was a promising approach Primary Endpoint Durable CR at 1 year Inclusion/Exclusion Poor and intermediate risk germ cell tumors post orchiectomy Size (N) 219 patients Results 1 year durable CR: BEP 52% vs BEP + HDCT 48%, p=0.53 Median time to treatment failure: BEP: 11.3 months vs BEP + HDCT 23.2 months, p=0.4 Toxicity Higher rates of grade 3+ neurologic, GI and hepatobiliary toxicity in BEP + HDCT arm Conclusion The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome

8 Other Comments Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P =.02 and P =.03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P =.03) MANAGEMENT OF RESIDUAL MASSES FOLLOWING CHEMOTHERAPY Residual disease in seminomas: Residual masses are often fibrotic but may contain residual seminoma 3 main options: o observation with no additional treatment or biopsy unless mass is growing o o observation of masses <3cm and PET scan for masses > 3cm PET scan 2 months after completion of chemotherapy. If PET negative, no further scans. If PET positive, consider surgical resection or if tumor has responded but still above 3 cm then consider observation 5 Residual disease in non-seminomas: > 1cm: o Most often contain residual tumor or teratoma o Standard of care is to resect all residual masses however there are no randomized trials to validate this approach <=1cm: o Area of controversy o Observe vs RPLND o If RPLND shows fibrosis, necrosis or mature teratoma " no further therapy o If RPLND positive for viable cancer, observation vs. chemotherapy (usually EP) x 2 cycles D) REFERENCES 1. Beard, CJ and Oh, WK. Treatment of stage II seminoma. In Kantoff, PW and Ross, ME (Eds): UpToDate. Retrieved from 2. Gilligan, TD and Kantoff, PW. Initial risk stratified treatment for advanced testicular germ cell tumors. In Oh, WK and Ross, ME (Eds). UpToDate. Retrieved from 3. PDQ Adult Treatment Editorial Board. Testicular Cancer Treatment (PDQ ): Health Professional Version Feb 17. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); Available from: 4. Oh, WK. Overview of the treatment of testicular germ cell tumors. In Kantoff, PW and Ross, ME (Eds): UpToDate. Retrieved from 5. De Santis et al fluoro-deoxy-d-glucose Positron Emission Tomography Is a Reliable Predictor for Viable Tumor in Postchemotherapy Seminoma: An Update of the Prospective Multicentric SEMPET Trial. J Clin Oncol. 2004; 22(6):

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