NCCN Clinical Practice Guidelines in Oncology. Testicular Cancer V Continue.

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1 Clinical in Oncology Testicular Cancer V Continue

2 TOC * Robert J. Motzer, MD/Chair Þ Memial Sloan-Kettering Cancer Center Neeraj Agarwal, MD Huntsman Cancer Institute at the University of Utah Clair Beard, MD Dana-Farber/Brigham and Women s Cancer Center Sam Bhayani, MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Graeme B. Bolger, MD University of Alabama at Birmingham Comprehensive Cancer Center Barry Boston, MD St. Jude Children s Research Hospital/University of Tennessee Cancer Institute Michael A. Carducci, MD Þ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Sam S. Chang, MD Vanderbilt-Ingram Cancer Center Toni K. Choueiri, MD Þ Dana-Farber/Brigham and Women s Cancer Center Guidelines Panel Disclosures Panel Members Robert A. Figlin, MD City of Hope Comprehensive Cancer Center Mayer Fishman, MD, PhD Þ H. Lee Moffitt Cancer Center & Research Institute Steven L. Hancock, MD Þ Stanfd Comprehensive Cancer Center Gary R. Hudes, MD Fox Chase Cancer Center Eric Jonasch, MD The University of Texas M. D. Anderson Cancer Center Timothy M. Kuzel, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Paul H. Lange, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Ellis G. Levine, MD Roswell Park Cancer Institute Kim A. Margolin, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance M. Dr Michaelson, MD, PhD Massachusetts General Hospital Cancer Center Continue Thomas Olencki, DO The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Roberto Pili, MD Roswell Park Cancer Institute Bruce G. Redman, DO University of Michigan Comprehensive Cancer Center Cary N. Robertson, MD Duke Comprehensive Cancer Center Charles J. Ryan, MD UCSF Helen Diller Family Comprehensive Cancer Center Lawrence H. Schwartz, MD ф Memial Sloan-Kettering Cancer Center Joel Sheinfeld, MD Memial Sloan-Kettering Cancer Center Jue Wang, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Medical oncology Hematology/hematology oncology Radiotherapy/Radiation oncology ф Diagnostic Radiology Supptive Care including Palliative, Pain Management, Pastal care and Oncology social wk Þ Internal medicine Urology * Writing committee member Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

3 TOC Table of Contents Panel Members Summary of Guidelines Updates Wkup, Primary Treatment and Pathologic Diagnosis (TEST-1) Seminoma: Postdiagnostic Wkup and Clinical Stage (TEST-2) Stage IA, IB (TEST-3) Stage IS (TEST-3) Stage IIA, IIB (TEST-3) Stage IIC, III (TEST-3) : Postdiagnostic Wk-up and Clinical Stage (TEST-5) Stage IA, IB, IS (TEST-6) Stage IIA, IIB (TEST-7) Postchemotherapy Management (TEST-8) Postsurgical Management (TEST-9) Stage IIC, IIIA, IIIB, IIIC, and Brain Metastases (TEST-10) Follow-up f (TEST-11) Recurrence and Second Line Therapy (TEST-12) Risk Classification (TEST-A) Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B) Second Line Subsequent Chemotherapy Regimens f Metastatic Germ Cell Tums (TEST-C) F help using these documents, please click here Staging Discussion References This manuscript is being updated to crespond with the newly updated algithm. Print the Guidelines Clinical Trials: The believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.g/clinical_trials/physician.html Categies of Evidence and Consensus: All recommendations are Categy 2A unless otherwise specified. See Categies of Evidence and Consensus These guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk makes no representations warranties of any kind, regarding their content use application and disclaims any responsibility f their application use in any way. These guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

4 TOC Summary of the Guidelines updates Summary of changes in the version of the Guidelines from the version include: Seminoma TEST-4 Residual mass, positive PET scan, salvage therapy was clarified as second line chemotherapy. Follow-up abdominal/pelvic CT interval was clarified as 4 mo post surgery, then as indicated. TEST-11 Surveillance after complete response to chemotherapy and/ RPLND and months between abdominal/pelvic CT: F 6 + years, the interval between CT scans was changed from mo to as clinically indicated. Previous footnote was modified as, CT scans apply only to patients treated with chemotherapy alone. F patients who are post RPLND, a postoperative baseline CT scan is recommended and additional CT scans as clinically indicated and moved under surveillance f clarification. TEST-12 Second line therapy f favable prognosis, high-dose chemotherapy was added as a treatment option. Second line therapy, incomplete response relapse, high-dose chemotherapy was modified by adding if not previously given to preferred. TEST-A:, post-chiectomy was added to markers f clarification f each risk status TEST-C High-dose chemotherapy regimens were added to the page. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UPDATES

5 TOC WORKUP PRIMARY TREATMENT PATHOLOGIC DIAGNOSIS Suspicious testicular mass H&P Alpha-fetoprotein (AFP) beta-hcga LDH Chemistry profile Chest x-ray Optional: Testicular ultrasound Discuss sperm banking Radical inguinal chiectomy Consider open inguinal biopsy of contralateral testis if: Suspicious ultrasound f intratesticular abnmalities Cryptchid testis Marked atrophy Seminoma (AFP negative; may have elevated beta-hcg) tous germ cell tum b See Postdiagnostic Wkup and Clinical Stage (TEST-2) See Postdiagnostic Wkup and Clinical Stage (TEST-5) aquantitative analysis of beta subunit. bthis includes seminoma histology with elevated AFP. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-1

6 Seminoma TOC PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUP CLINICAL STAGE Seminomac (AFP negative d; may have elevated beta-hcg) Abdominal/pelvic CT Chest CT if: Positive abdominal CT abnmal chest x-ray Repeat beta-hcg, LDH, AFP e (if elevated preoperatively) Brain MRI, if clinically indicated Bone scan, if clinically indicated Discuss sperm banking Stage IA, IB Stage IS Stage IIA, IIB Stage IIC, III See Primary Treatment and Follow-up (TEST-3) See Primary Treatment and Follow-up (TEST-3) See Primary Treatment and Follow-up (TEST-3) See Primary Treatment and Follow-up (TEST-3) cmediastinal seminoma should be treated as good risk nonseminomatous germ cell tum with etoposide/cisplatin f 4 cycles bleomycin/etoposide/cisplatin f 3 cycles. dif positive, treat as nonseminoma. eelevated values should be followed with repeated determination to allow precise staging. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-2

7 Seminoma TOC CLINICAL STAGE Stage IA, IB Stage IS Stage IIA, IIB Stage IIC, III Good risk f Intermediate risk f PRIMARY TREATMENT Surveillance if: (categy 1) Hseshoe pelvic kidney Inflammaty bowel disease Pri RT Consider surveillance if: (categy 2B) T1 T2 histology in selected patients committed to long-term follow-up Single agent carboplatin (categy 1) (AUC=7 x 1 cycle AUC=7 x 2 cycles) RT: Infradiaphragmatic (20-30 Gy) to include para-atic ± ipsilateral iliac nodes (categy 1) RT: Infradiaphragmatic (25-30 Gy) to include para-atic ± ipsilateral iliac nodes RT: Infradiaphragmatic (35-40 Gy) to include para-atic and ipsilateral iliac nodes Consider primary chemotherapy: g EP f 4 cycles f selected stage IIB patients Primary chemotherapy: g EP f 4 cycles (categy 1) BEP f 3 cycles (categy 1) Primary chemotherapy: g BEP f 4 cycles (categy 1) f See Risk Classification (TEST-A). gsee Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B). FOLLOW-UP H&P, AFP, beta-hcg, LDH: every 3-4 mo f years 1-3, every 6 mo f years 4-7, then annually Abdominal/pelvic CT at each visit, chest x-ray at alternative visits (up to 10 y) H&P + chest x-ray, AFP, beta-hcg, LDH: every 3-4 mo f year 1, every 6 mo f year 2, then annually Pelvic CT annually f 3 years (f patients status post only para-atic RT) H&P + chest x-ray, AFP, beta-hcg, LDH: every 3-4 mo f years 1-3, every 6 mo f year 4, then annually Abdominal CT at month 4 of year 1 See Post Chemotherapy Management and Follow-up (TEST-4) See Post Chemotherapy Management and Follow-up (TEST-4) Recurrence, treat accding to extent of disease at relapse Recurrence, treat accding to extent of disease at relapse Recurrence, treat accding to extent of disease at relapse EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-3

8 Seminoma TOC STAGE IIB, IIC, III AFTER PRIMARY TREATMENT WITH CHEMOTHERAPY Chest, abdominal, pelvic CT scan Serum tum markers No residual mass and nmal markers h Residual mass and nmal markers h Progressive disease (growing mass rising markers) h PET scan (preferred) PET scan not feasible Negative Positive Residual mass (nodes > 3 cm on CT) Residual mass (nodes 3 cm on CT) POST CHEMOTHERAPY MANAGEMENT Surveillance Surveillance Consider surgery with biopsy Biopsy and second line chemotherapyi RT (categy 2B) Surveillance Surgery (categy 2B) RT (categy 2B) Surveillance FOLLOW-UP H&P + chest x-ray, AFP, beta-hcg, LDH: every 2 mo f year 1 every 3 mo f year 2, every 4 mo f year 3, every 6 mo f year 4, then annually Abdominal/pelvic CT 4 mo post surgery, then as indicated PET scan as clinically indicated See Second line Therapy f nonseminoma (TEST-12) Recurrence, See Second line Therapy (TEST-12) h F persistent elevated beta-hcg which is not rising, repeat serial markers, testosterone suppression test and consider a PET scan i See Second Line Subsequent Chemotherapy Regimens f Metastatic Germ Cell Tums (TEST-C). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-4

9 TOC PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUP CLINICAL STAGE j Stage IA, IB, IS: See Primary Treatment (TEST-6) tous germ cell tum b Abdominal/pelvic CT Chest CT if: Abnmal abdominal CT Abnmal chest x-ray Repeat beta-hcg, LDH, AFPe Brain MRI, if clinically indicated Bone scan, if clinically indicated Discuss sperm banking Stage IIA, IIB: See Primary Treatment (TEST-7) Stage IIC, IIIA, IIIB, IIIC, and brain metastasis: See Primary Treatment (TEST-10) bthis includes seminoma histology with elevated AFP. e Elevated values should be followed with repeated determination to allow precise staging. jtreatment may be initiated pri to histology f patients with rising markers and a deteriating clinical situation. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-5

10 TOC CLINICAL STAGE PRIMARY TREATMENT Stage IA Stage IB Surveillance (in compliant patients) Open nerve-sparing RPLND k Open nerve-sparing RPLNDk Primary chemotherapy: BEP f 2 cycles (categy 2B) Surveillance (only if T2, compliant patients [categy 2B]) g See Follow-up f (TEST-11) See Postsurgical Management (TEST-9) See Postsurgical Management (TEST-9) See Postchemotherapy Management (TEST-8) See Follow-up f (TEST-11) Stage IS Persistent marker elevation Primary chemotherapy: g EP f 4 cycles BEP f 3 cycles See Postchemotherapy Management (TEST-8) The EP and BEP chemotherapy regimens have shown survival advantage in randomized clinical trials and may be considered as categy 1 compared with other chemotherapy regimens. EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin gsee Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B). kretroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (categy 2B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-6

11 TOC CLINICAL STAGE PRIMARY TREATMENT Open nerve-sparing RPLNDk See Postsurgical Management (TEST-9) Markers negative Stage IIA Primary chemotherapy (categy 2B): EP f 4 cycles BEP f 3 cycles g See Postchemotherapy Management (TEST-8) Persistent marker elevation Primary chemotherapy: g EP f 4 cycles BEP f 3 cycles See Postchemotherapy Management (TEST-8) Stage IIB Markers negative Lymph node metastases, within lymphatic drainage sites (landing zone positive) Multifocal symptomatic lymph node metastases with aberrant lymphatic drainage Open nerve-sparing RPLNDk Primary chemotherapy: EP f 4 cycles BEP f 3 cycles Primary chemotherapy: g EP f 4 cycles BEP f 3 cycles g See Postsurgical Management (TEST-9) See Postchemotherapy Management (TEST-8) Persistent marker elevation Primary chemotherapy: g EP f 4 cycles BEP f 3 cycles The EP and BEP chemotherapy regimens have shown survival advantage in randomized clinical trials and may be considered as categy 1 compared with other chemotherapy regimens. EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin g See Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B). k Retroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (categy 2B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-7

12 TOC POSTCHEMOTHERAPY MANAGEMENT Negative markers, residual mass Open nerve-sparing RPLNDk Surveillance (categy 2B) Stage IB, IS, IIA, IIB treated with primary chemotherapy Negative markers, Nmal CT scan, no mass Open nerve-sparing RPLNDk (categy 2B) Surveillance (categy 2B) See Follow-up f (TEST-11) k Retroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (categy 2B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-8

13 TOC POSTSURGICAL MANAGEMENT pn0 Surveillance Stage IA, IB, IIA, IIB treated with open nerve-sparing RPLND pn1 pn2 Compliant Noncompliant Compliant Surveillance (preferred) Chemotherapy: g EP f 2 cycles BEP f 2 cycles g Chemotherapy: EP f 2 cycles BEP f 2 cycles Surveillance Chemotherapy (preferred): g EP f 2 cycles BEP f 2 cycles See Follow-up f (TEST-11) Noncompliant g Chemotherapy: EP f 2 cycles BEP f 2 cycles pn3 Chemotherapy: g EP f 4 cycles BEP f 3 cycles (preferred) EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin g See Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-9

14 TOC CLINICAL STAGE PRIMARY TREATMENT Good riskf Stage IIC Stage IIIA Primary chemotherapy: g EP f 4 cycles BEP f 3 cycles Complete response, negative markers Surveillance (categy 2B) Open nerve-sparing RPLND k (categy 2B) Intermediate riskf Stage IIIB Po riskf Stage IIIC Primary chemotherapy: g BEP f 4 cycles Clinical trial (preferred) Primary chemotherapy: g BEP f 4 cycles VIP f 4 cycles in selected patients m Partial response, residual massesn with nmal AFP and beta-hcg levels Incomplete response n Surgical resection of all residual masses See Second Line Therapy (TEST-12) Teratoma necrosis Residual embryonal, yolk sac, chiocarcinoma, seminoma elements Surveillance Chemotherapy f 2 cycles (EPg TIPi VIP g/veip i) See Follow-up f (TEST-11) Brain metastases l Primary chemotherapy g + RT ± surgery, if clinically indicated The EP and BEP chemotherapy regimens have shown survival advantage in randomized clinical trials and may be considered as categy 1 compared with other chemotherapy regimens. EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin TIP = Paclitaxel/ifosfamide/cisplatin VeIP = Vinblastine/ifosfamide/cisplatin VIP = Etoposide/ifosfamide/cisplatin fsee Risk Classification (TEST-A). gsee Primary Chemotherapy Regimens f Germ Cell Tums (TEST-B). isee Second Line Subsequent Chemotherapy Regimens f Metastatic Germ Cell Tums (TEST-C). kretroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (categy 2B). lpatients should receive adequate treatment f brain metastases, in addition to cisplatin-based chemotherapy. m Patients who may not tolerate bleomycin. nthere is limited predictive value f PET scan f residual masses. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-10

15 TOC FOLLOW-UP FOR NONSEMINOMA Surveillance f Stage IA, IB Surveillance After Complete Response to Chemotherapy and/ RPLND Year 1 Months between visits, markers, chest x-ray 1-2 Months between abdominal/pelvic CT 2-3 Year Months between visits, markers, chest x-ray (categy 2B f chest x-ray frequency) Months between abdominal/pelvic CT* As clinically indicated *CT scans apply only to patients treated with chemotherapy alone. F patients who are post RPLND, a postoperative baseline CT scan is recommended and additional CT scans as clinically indicated. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Recurrence, See Salvage Therapy (TEST-12) Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-11

16 TOC RECURRENCE SECOND LINE THERAPY Pri chemotherapy Favable prognosis: Low markers Low volume Complete response on first-line therapy Testis primary Chemotherapy Conventional dose therapy (VeIP TIP) High-dose chemotherapy i Incomplete response relapse Complete response Chemotherapy High-dose chemotherapy (preferred if not previously given) Clinical trial Surgical salvage should be considered if solitary site Best supptive care Relapse Follow-up i Palliative chemotherapy RT i Unfavable prognosis: Incomplete response High markers High volume Extratesticular primary Late relapse i Chemotherapy Clinical trial (preferred) Conventional dose therapy (VeIP TIP) High-dose chemotherapy (categy 2B) Surgical salvage should be considered if solitary site Best supptive care No pri chemotherapy Treat as per risk status on TEST-10 VeIP = Vinblastine/ifosfamide/cisplatin TIP = Paclitaxel/ifosfamide/cisplatin i See Second Line Subsequent Chemotherapy Regimens f Germ Cell Tums (TEST-C). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-12

17 TOC RISK CLASSIFICATION 1 Risk Status Seminoma Good Risk Intermediate Risk Po Risk Testicular retroperitoneal primary tum and No nonpulmonary visceral metastases and Post-chiectomy markers- all of: AFP < 1,000 ng/ml hcg < 5,000 iu/l LDH < 1.5 x upper limit of nmal Testicular retroperitoneal primary tum and No nonpulmonary visceral metastases and Post-chiectomy markers- any of: AFP 1,000-10,000 ng/ml hcg 5,000-50,000 iu/l LDH x upper limit of nmal Mediastinal primary tum Nonpulmonary visceral metastases Post-chiectomy markers- any of: AFP > 10,000 ng/ml hcg > 50,000 iu/l LDH > 10 x upper limit of nmal Any primary site and No nonpulmonary visceral metastases and Nmal AFP Any HCG Any LDH Any primary site and Nonpulmonary visceral metastases and Nmal AFP Any HCG Any LDH No patients classified as po prognosis Source: Figure 4 from the International Germ Cell Cancer Collabative Group: International Germ Cell Consensus Classification: A Prognostic Fact-Based Staging System f Metastatic Germ Cell Cancers. J Clin Oncol. 15(2);1997: Reprinted with permission of the American Society of Clinical Oncology. 1 Markers used f risk classification are post-chiectomy. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-A

18 TOC PRIMARY CHEMOTHERAPY REGIMENS FOR GERM CELL TUMORS EP Etoposide 100 mg/m2 IV on Days 1-5 Cisplatin 20 mg/m2 IV on Days 1-5 Repeat every 21 days1 BEP Etoposide 100 mg/m2 IV on Days 1-5 Cisplatin 20 mg/m2 IV on Days 1-5 Bleomycin 30 units IV weekly on Days 1, 8, and 15* Repeat every 21 days2 VIP Etoposide 75 mg/m2 IV on Days 1-5 Mesna 120 mg/m2 slow IV push befe ifosfamide on Day 1, then Mesna 1200 mg/m2 IV continuous infusion on Days 1-5 Ifosfamide 1200 mg/m2 on Days 1-5 Cisplatin 20 mg/m2 IV on Days 1-5 Repeat every 21 days3 *Some Institutions administer bleomycin on a 2, 9, 16 schedule. 1Xiao H, Mazumdar M, Bajin DF, et al. Long-term follow-up of patients with good-risk germ cell tums treated with etoposide and cisplatin. J Clin Oncol 1997;15(7): Saxman SB, Finch D, Gonin R & Einhn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favable-prognosis germ-cell tums: The Indiana University Experience. J Clin Oncol 1998;16(2): Nichols CR, Catalano PJ, Crawfd ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin ifosfamide in treatment of advanced disseminated germ cell tums: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 1998;16: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-B

19 TOC SECOND LINE OR SUBSEQUENT CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS Conventional dose chemotherapy regimens VeIP Vinblastine 0.11 mg/kg IV Push on Days 1-2 Mesna 400 mg/m2 IV every 8 hours on Days 1-5 Ifosfamide 1200 mg/m2 IV on Days 1-5 Cisplatin 20 mg/m2 IV on Days 1-5 Repeat every 21 days1 TIP Paclitaxel 250 mg/m2 IV on Day 1 Ifosfamide 1500 mg/m2 IV on Days 2-5 Mesna 500 mg/m2 IV befe ifosfamide, and then 4 and 8 hours after each ifosfamide dose on Days 2-5 Cisplatin 25 mg/m2 IV on Days 2-5 Repeat every 21 days2 High-dose chemotherapy regimens Carboplatin 700 mg/m 2 (Body Surface Area) IV Etoposide 750 mg/m2 IV Administer 5, 4, and 3 days befe peripheral blood stem cell infusion f 2 cycles6 2 Paclitaxel 200 IV over 24 hours Ifosfamide 2000 mg/m2 over 4 hours with mesna protection Repeat every 14 days f 2 cycles followed by Carboplatin AUC 7-8 IV over 60 minutes Days 1-3 Etoposide 400 mg/m2 IV Days 1-3 Administer with peripheral blood stem cell suppt at day intervals f 3 cycles7 Palliative chemotherapy regimen GEMOX Gemcitabine 1000 mg/m2 IV on Days 1 and 8 followed by Oxaliplatin 130 mg/m2 IV on Day 1 Repeat every 21 days3,4 2 Gemcitabine 1250 mg/m IV on Days 1 and 8 followed by Oxaliplatin 130 mg/m2 IV on Day 1 Repeat every 21 days5 See Chemotherapy References (TEST-C 2 of 2) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-C 1 of 2

20 TOC SECOND LINE OR SUBSEQUENT CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS CHEMOTHERAPY REFERENCES 1Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine etoposide. Ann Intern Med 1988;109(7): Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy f patients with relapsed testicular germ cell tums. J Clin Oncol 2005;23(27): Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refracty germ cell tums: a phase II study. Ann Oncol 2004;15(3): Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated refracty germ cell cancer: A study of the German Study Group. J Clin Oncol 2004; 22(1): De Gigi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refracty nonseminomatous germ cell tum. Eur Urol 2006;50(5): Einhn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue f metastatic germ-cell tums. N Engl J Med 2007;357(4): Kondagunta GV, Bacik J, Sheinfeld J, et al. Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tums. J Clin Oncol 2007;25(1): Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. TEST-C 2 of 2

21 TOC Staging Table 1 AJCC Staging of Testis Tums Primary Tum (pt) The extent of primary tum is usually classified after radical chiectomy, and f this reason, a pathologic stage is assigned. N2 N3 Metastasis with a lymph node mass, me than 2 cm but not me than 5 cm in greatest dimension; multiple lymph nodes, any one mass greater than 2 cm but not me than 5 cm in greatest dimension Metastasis with a lymph node mass me than 5 cm in greatest dimension *ptx pt0 ptis pt1 pt2 pt3 pt4 Primary tum cannot be assessed No evidence of primary tum (e.g. histologic scar in testis) Intratubular germ-cell neoplasia (carcinoma in situ) Tum limited to the testis and epididymis without vascular/lymphatic invasion; tum may invade into the tunica albuginea but not the tunica vaginalis Tum limited to the testis and epididymis with vascular/lymphatic invasion, tum extending through the tunica albuginea with involvement of the tunica vaginalis Tum invades the spermatic cd with without vascular/lymphatic invasion Tum invades the scrotum with without vascular/lymphatic invasion *Note: Except f ptis and pt4, extent of primary tum is classified by radical chiectomy. TX may be used f other categies in the absence of radical chiectomy. Regional Lymph Nodes (N) NX N0 N1 Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis with a lymph node mass 2 cm less in greatest dimension; multiple lymph nodes, none me than 2 cm in greatest dimension Pathologic (pn) pnx Regional lymph nodes cannot be assessed pn0 No regional lymph node metastasis Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional nodal pulmonary metastasis M1b Distant metastasis other than to non-regional lymph nodes and lungs Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. pn1 pn2 pn3 Continued... Metastasis with a lymph node mass, 2 cm less in greatest dimension and less than equal to 5 nodes positive, none me than 2 cm in greatest dimension Metastasis with a lymph node mass me than 2 cm but not me than 5 cm in greatest dimension; me than 5 nodes positive, none me than 5 cm; evidence of extranodal extension of tum Metastasis with a lymph node mass me than 5 cm in greatest dimension ST-1

22 TOC Serum Tum Markers (S) SX Marker studies not available not perfmed SO Marker study levels within nmal limits S1 LDH < 1.5 x N AND hcg (miu/ml) < 5000 AND AFP (ng/ml) < 1000 S2 LDH1.5-10xNOR hcg (miu/ml) ,000 OR AFP (ng/ml) ,000 S3 LDH > 10 x N OR hcg (miu/ml) > 50,000 OR AFP (ng/ml) > 10,000 *N indicates the upper limit of nmal f the LDH assay. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New Yk. (F me infmation, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer-Verlag New Yk, Inc., on behalf of the AJCC. Stage Grouping Stage 0 ptis N0 M0 S0 Stage I pt1-4 N0 M0 SX Stage IA pt1 N0 M0 S0 Stage IB pt2 N0 M0 S0 PT3 N0 M0 S0 PT4 N0 M0 S0 Stage IS Any pt/tx N0 M0 S1-3 Stage II Any pt/tx N1-3 M0 SX Stage IIA Any pt/tx N1 M0 S0 Any pt/tx N1 M0 S1 Stage IIB Any pt/tx N2 M0 S0 Any pt/tx N2 M0 S1 Stage IIC Any pt/tx N3 M0 S0 Any pt/tx N3 M0 S1 Stage III Any pt/tx Any N M1 SX Stage IIIA Any pt/tx Any N M1a S0 Any pt/tx Any N M1a S1 Stage IIIB Any pt/tx N1-3 M0 S2 Any pt/tx Any N M1a S2 Stage IIIC Any pt/tx N1-3 M0 S3 Any pt/tx Any N M1a S3 Any pt/tx Any N M1b Any S Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ST-2

23 TOC Discussion Categies of Evidence and Consensus Categy 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is unifm consensus. Categy 2A: The recommendation is based on lower-level evidence and there is unifm consensus. Categy 2B: The recommendation is based on lower-level evidence and there is nonunifm consensus (but no maj disagreement). Categy 3: The recommendation is based on any level of evidence but reflects maj disagreement. All recommendations are categy 2A unless otherwise noted. Overview This manuscript is being updated to crespond with the newly updated algithm. Last updated 11/21/08 An estimated 8,090 new cases of testicular cancer will be diagnosed in the United States in Germ cell tums (GCTs) comprise 95% of malignant tums arising in the testes. These tums also occur occasionally in extragonadal primary sites, but they are still managed the same as testicular GCTs. Although GCTs are relatively uncommon tums that comprise only 2% of all human malignancies, they constitute the most common solid tum in men between the ages of 15 and 34 years. In addition, the wldwide incidence of these tums has me than doubled in the past 40 years. Several risk facts f GCT development have been identified, including pri histy of a GCT, positive family histy, cryptchidism, testicular dysgenesis, and Klinefelter s syndrome. GCTs are classified as seminoma nonseminoma. tous tums often include multiple cell types, including embryonal cell carcinoma, chiocarcinoma, yolk sac tum, and teratoma. Teratomas are considered to be either mature immature depending on whether adult-type differential cell types partial somatic differentiation, similar to that present in the fetus, is found. Rarely, a teratoma histologically resembles a somatic cancer, such as sarcoma adenocarcinoma, and is then referred to as a teratoma with malignant transfmation. The serum tum markers alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chionic gonadotropin (hcg) are critical in diagnosing the presence of tums, determining prognosis, and assessing treatment outcome. These should be determined befe, during, and after treatment and throughout the follow-up period. AFP is a serum tum marker produced by nonseminomatous cells (embryonal carcinoma, yolk-sac tum) and may be seen at any stage. The approximate half-life of AFP is 5 to 7 days. A nonseminoma, therefe, is associated with elevated serum concentrations of AFP. An elevated serum concentration of hcg, which has a half-life of approximately 1 3 days, may also be present with seminomatous and nonseminomatous tums. Seminomas are occasionally associated with an elevated serum concentration of hcg but not an elevated concentration of AFP. is the me clinically aggressive tum. When both a seminoma and elements of a nonseminoma are present, management follows that f a nonseminoma. Therefe, the diagnosis of a seminoma is restricted to pure seminoma histology and a nmal serum concentration of AFP. Me than 90% of patients diagnosed with GCTs are cured, including 70% to 80% of patients with advanced tums who are treated with chemotherapy. A delay in diagnosis crelates with a higher stage at presentation. Standard therapy has been established at essentially all stages of management and must be closely followed to ensure the potential f cure. Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-1

24 TOC Clinical Presentation A painless solid testicular mass is pathognomonic f testicular tum. Me often, patients present with testicular discomft swelling suggestive of epididymitis chitis. A trial of antibiotics may be given in this circumstance, but persistent tenderness, swelling, any palpable abnmality warrants further evaluation using testicular ultrasound. Although testicular ultrasound is optional if the diagnosis is obvious from the physical examination, it is perfmed in most instances to define the lesion. If an intratesticular mass is identified, further evaluation includes measurement of the serum concentrations of alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and beta-human chionic gonadotropin (beta-hcg) and a chest radiograph. Elevated values of beta-hcg, LDH, AFP should be followed up with repeated tests to allow precise staging. Inguinal chiectomy is considered the primary treatment f most patients who present with a suspicious testicular mass. 2 If a GCT is found, an abdominopelvic computed tomographic (CT) scan is perfmed. Serum concentrations of hcg and LDH may be elevated in patients with seminoma. An elevated AFP level indicates nonseminoma, and the patient should be managed accdingly. A chest CT may be indicated if the abdominopelvic CT shows retroperitoneal adenopathy the chest radiograph shows abnmal results. An open inguinal biopsy of the contralateral testis is not routinely perfmed, but can be considered when a cryptchid testis marked atrophy is present. 3 Biopsy may also be considered if a suspicious intratesticular abnmality, such as a hypoechoic mass macrocalcifications, is identified on ultrasound. In contrast, if microcalcifications without any other abnmality can be observed, testicular biopsy is not necessary. These studies, and others as clinically indicated, determine the clinical stage and direct patient management. If clinical signs of metastases are present, magnetic resonance imaging (MRI) of the brain and bone scanning are indicated. Further management is dictated by histology, a diagnosis of seminoma nonseminoma, and stage (ST-1). Patients should consider sperm banking befe undergoing any therapeutic intervention that may compromise fertility, including radiation therapy, surgery, and chemotherapy. Seminoma The risk classification f seminoma is defined in TEST-A. Stages IA and IB Patients with disease in stages IA and IB are treated with radiation (20 30 Gy) to the infradiaphragmatic area, including para-atic lymph nodes with without radiation to the ipsilateral ileoinguinal nodes. 4 Prophylaxis to the mediastinum is not provided, because relapse rarely occurs at this site. A single dose of carboplatin has also been investigated as an alternative to radiation therapy. Oliver et al 5 repted on the results of a trial that randomized 1477 patients with stage 1 testicular cancer to undergo either radiotherapy one injection of carboplatin. In the study, carboplatin was administered at a dose of AUC X 7 (AUC=area under the dose-time concentration curve). The doses were given intravenously and calculated by a fmula based on the AUC estimate of drug disappearance from the body. The dose was calculated by the fmula 7 X (glomerular filtration rate [GFR, ml/min] + 25) mg. With a median follow-up of 4 years, the relapse-free survivals f both groups were similar. Because late relapses and secondary germ cell tums can occur beyond 5 and 10 years, the auths continued follow-up of these patients. The updated follow-up results of 1,148 patients were repted at the 2008 ASCO Annual Meeting. 6 In an intent-to-treat analysis, the relapse free rates at 5 years were 94.7% f the carboplatin arm and 96% f the radiotherapy arm (hazard ratio, 1.25; P =.37), There was a significant difference in the rate of new germ cell tums (2 on carboplatin versus 15 on radiation therapy), giving a hazard ratio (HR) of 0.22 (95% CI 0.05, 0.95 p=0.03). The Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-2

25 TOC auths conclude that a single dose of carboplatin is less toxic and just as effective in preventing disease recurrence as adjuvant radiotherapy in men with stage I seminoma after chiectomy, The panel now recommends single dose of carboplatin (categy 1) as an alternative to radiation therapy f patients with stages IA and IB disease. Between 15% and 20% of patients with seminoma, experience relapse during surveillance if they do not undergo adjuvant radiation therapy after chiectomy. 7 The median time to relapse is approximately 12 months, but relapses can occur me than 5 years after chiectomy. Because both radiation and chemotherapy can potentially lead to late mbidity, surveillance f stage I seminoma is an option f management of stage I seminoma (categy 1). In particular, observation may be offered to selected patients with T1 T2 disease (categy 2B) who are committed to long-term follow-up. Relapse occurring after observation essentially represents a prolongation in the lead time of treatment. Therefe, these patients are treated accding to the stage at relapse. Patients f whom radiation therapy is generally not given include those with patients at higher risk f mbidity from radiation therapy. These patients include those with stages IA and IB with a hseshoe pelvic kidney, with inflammaty bowel disease, and who underwent pri radiation therapy. Follow up includes a histy and physical, with measurement of serum tum markers, perfmed every 3 to 4 months f the first year, and 6 months f the second year and annually thereafter. Me intense follow-up is recommended f patients not undergoing radiation therapy - a histy and physical, with measurement of serum tum markers, should be perfmed every 3 to 4 months f the first 3 years, and 6 months f the next 3 years and annually thereafter. Annual pelvic CT is recommended f 3 years f patients who underwent para-atic RT, whereas an abdominal/pelvic CT scan is recommended at each visit and chest x-ray at alternate visit f up to 10 years f those treated with a single dose of carboplatin those under surveillance. Stage 1S Patients with stage IS are treated with radiation (25-30 Gy) to the infradiaphragmatic area, including para-atic lymph nodes with without radiation to the ipsilateral ileo inguinal nodes. 4 Follow-up recommendations are similar to that of patients with stages 1A and 1B. If advanced, disseminated disease is suspected, than full course chemotherapy is administered accding to guidelines f good risk GCT. Stages IIA and IIB Stage IIA is defined as disease measuring less than 2 cm in diameter on CT scan, and stage IIB as disease measuring 2 to 5 cm in maximum diameter. F patients with stage IIA IIB disease, 35 to 40 Gy is administered to the infradiaphragmatic area, including para-atic and ipsilateral iliac lymph nodes. As in the management of stage I disease, prophylactic mediastinal radiation therapy is not indicated. 8 Surveillance is not an option f patients with stage IIA IIB disease with relative contraindications f radiation. Instead, 4 courses of etoposide and cisplatin (EP) are recommended. Follow-up f patients with stage IIA IIB disease includes a histy and physical, with measurement of serum tum markers, should be perfmed every 3 to 4 months f the first 3 years, and 6 months f the fourth year and annually thereafter. Abdominal CT is recommended after 4 months during the first year. Stages IIC and III Patients with stage IIC III disease are those considered at good intermediate risk. All stage IIC and stage III disease is considered good risk except f stage III disease with non-pulmonary visceral Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-3

26 TOC metastases, which is considered intermediate risk. Standard chemotherapy is used f both groups of patients, but f patients with good risk, either 4 cycles of EP are recommended 3 cycles of bleomycin, etoposide, and cisplatin (BEP). In contrast, 4 cycles of BEP are recommended f those with intermediate risk disease. These options are all considered categy 1 recommendations After initial chemotherapy, patients with stage IIC and III are evaluated with serum tum markers and a CT scan of the chest abdomen and pelvis. Patients are then classified accding to the presence absence of a residual mass and the status of serum tum markers. Patients with no residual mass and nmal markers need no further treatment and undergo surveillance. In patients with a residual mass with nmal markers, a positron emission tomography (PET) scan is recommended to assess f residual viable tum. 13 To reduce the incidence of false-positive results, the PET scan is typically perfmed no less then 6 weeks after completion of chemotherapy. Notably, granulomatous disease, such as sarcoid, is a frequent source of false-positive results. If the PET scan is negative, no further treatment is needed however, the patient should be observed closely f recurrence. If it is positive, then biopsy should be considered followed by surgical excision (categy 2B), salvage therapy. Alternatively, the patient can be treated with radiation therapy (categy 2B). F patients who cannot undergo a PET scan, post-chemotherapy management is based on CT scan findings. Controversy exists regarding optimal management when the residual mass is greater than 3 cm, because approximately 25% of these patients have a viable seminoma previously unrecognized nonseminoma. 14 Options include surgery (categy 2B), radiation therapy (categy 2B), and observation. 8 If surgery is selected, the procedure consists of resection of the residual mass multiple biopsies. A full bilateral modified retroperitoneal lymph node dissection (RPLND) is not perfmed because of its technical difficulty in patients with seminoma and because of extensive fibrosis, which may be associated with severe mbidity. 15 If the residual mass is 3 cm less, patients should undergo observation, which is detailed in TEST-4. Recurrent disease is initially treated accding to the stage at recurrence. Salvage therapy is recommended f patients with rising markers a growing mass detected on CT scan. Salvage therapy f seminoma and nonseminoma is similar and is discussed further in section on nonseminomas. Patients with seminoma arising from an extragonadal site, such as the mediastinum, are treated with standard chemotherapy regimens accding to risk status. Approximately 90% of patients with advanced seminoma are cured with cisplatin-containing chemotherapy. 16 The risk classification f nonseminoma is defined in TEST-A. Stage-dependent treatment options after inguinal chiectomy include observation, chemotherapy, and RPLND. Although the timing of the RPLND may vary, most patients with nonseminoma will undergo an RPLND f either diagnostic therapeutic purposes at some point during treatment. The maj mbidity associated with bilateral dissection is retrograde ejaculation, resulting in infertility. Nerve-dissection techniques preserve antegrade ejaculation in 90% of cases. 17 Template dissections, which avoid the contralateral sympathetic chain, postganglionic sympathetic fibers, and hypogastric plexus, preserve ejaculation in approximately 80% of patients. In general, an open nerve-sparing RPLND rather than a laparoscopic RPLND is recommended f therapeutic purposes. F example, a concern exists that a laparoscopic RPLND may result in false-negative results caused by inadequate sampling, and no published repts focus Version , 08/28/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-4