Testicular Cancer. Clinical Practice Guidelines in Oncology. NCCN Clinical Practice Guidelines in Oncology for Testicular Cancer NCCN

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1 502 NCCN Testicular Cancer Clinical Practice Guidelines in Oncology Robert J. Motzer, MD; Neeraj Agarwal, MD; Clair Beard, MD; Sam Bhayani, MD; Graeme B. Bolger, MD; Mark K. Buyyounouski, MD, MS; Michael A. Carducci, MD; Sam S. Chang, MD; Toni K. Choueiri, MD; Shilpa Gupta, MD; Steven L. Hancock, MD; Gary R. Hudes, MD; Eric Jonasch, MD; Timothy M. Kuzel, MD; Clayton Lau, MD; Ellis G. Levine, MD; Daniel W. Lin, MD; Kim A. Margolin, MD; M. Dr Michaelson, MD, PhD; Thomas Olencki, DO; Roberto Pili, MD; Thomas W. Ratliff, MD; Bruce G. Redman, DO; Cary N. Robertson, MD; Charles J. Ryan, MD; Joel Sheinfeld, MD; Jue Wang, MD; and Richard B. Wilder, MD Overview An estimated 8590 new cases of testicular cancer will be diagnosed in the United States in Germ cell tums (GCTs) constitute 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 uncommon tums that constitute only 2% of all human malignancies, they are the most common solid tum in men between 15 and 34 years of age. 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 histy of a GCT, positive family histy, cryptchidism, testicular dysgenesis, NCCN Clinical Practice Guidelines in Oncology f Testicular Cancer Key Wds NCCN Clinical Practice Guidelines, NCCN Guidelines, testicular cancer, germ cell tums, alpha-fetoprotein, lactate dehydrogenase, human chionic gonadotropin, cisplatin, seminoma, nonseminoma (JNCCN 2012;10: ) NCCN Categies of Evidence and Consensus Categy 1: Based upon high-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2A: Based upon lower-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Categy 3: Based upon any level of evidence, there is maj NCCN disagreement that the intervention is appropriate. All recommendations are categy 2A unless otherwise noted. Clinical trials: NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please Note The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) are a statement of consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN 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 (NCCN ) makes no representation warranties of any kind regarding their content, use, application and disclaims any responsibility f their applications use in any way. National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN. Disclosures f the NCCN Testicular Cancer Panel At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial suppt they have received from industry. Through 2008, this infmation was published in an aggregate statement in JNCCN and online. Furthering NCCN s commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member. Individual disclosures f the NCCN Testicular Cancer Panel members can be found on page 535. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at These guidelines are also available on the Internet. F the latest update, visit

2 Journal of the National Comprehensive Cancer Netwk NCCN Guidelines Testicular Cancer 503 and Klinefelter syndrome. GCTs are classified as seminoma nonseminoma. Nonseminomatous 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 β-human chionic gonadotropin (β-hcg) are critical in diagnosing GCTs, determining prognosis, and assessing treatment outcome. These should be determined NCCN Testicular Cancer Panel Members *Robert J. Motzer, MD/Chair Þ Memial Sloan-Kettering Cancer Center Neeraj Agarwal, MD Huntsman Cancer Institute at the University of Utah S Clair Beard, MD Dana-Farber/Brigham and Women s Cancer Center Sam Bhayani, MDω 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 S Mark K. Buyyounouski, MD, MS Fox Chase Cancer Center Michael A. Carducci, MD Þ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Sam S. Chang, MDω Vanderbilt-Ingram Cancer Center Toni K. Choueiri, MD Þ Dana-Farber/Brigham and Women s Cancer Center Shilpa Gupta, MD H. Lee Moffitt Cancer Center & Research Institute Steven L. Hancock, MD Þ Stanfd Cancer Institute Gary R. Hudes, MD Fox Chase Cancer Center Eric Jonasch, MD The University of Texas MD Anderson Cancer Center Timothy M. Kuzel, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Clayton Lau, MDω City of Hope Comprehensive Cancer Center Ellis G. Levine, MD Roswell Park Cancer Institute befe, during, and after treatment and throughout the follow-up period. Serum tum markers are useful f moniting all stages of nonseminomas. They are also useful in moniting metastatic seminomas, because elevated marker levels is the early sign of relapse. LDH is a less-specific marker than AFP and β-hcg. 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. When patients with a histologically pure testicular seminoma have an elevated level of AFP, it is generally assumed that an undetected focus of nonseminoma is present. 2,3 Text continues on p. 521 Daniel W. Lin, MDω University of Washington/Seattle Cancer Care Alliance Kim A. Margolin, MD Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance M. Dr Michaelson, MD, PhD Massachusetts General Hospital Cancer Center Thomas Olencki, DO The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Roberto Pili, MD Roswell Park Cancer Institute Thomas W. Ratliff, MD St. Jude Children s Research Hospital/ University of Tennessee Cancer Institute Bruce G. Redman, DO University of Michigan Comprehensive Cancer Center Cary N. Robertson, MDω Duke Cancer Institute Charles J. Ryan, MD ω UCSF Helen Diller Family Comprehensive Cancer Center Joel Sheinfeld, MDω Memial Sloan-Kettering Cancer Center Jue Wang, MD UNMC Eppeley Cancer Center at The Nebraska Medical Center * S Richard B. Wilder, MD H. Lee Moffitt Cancer Center & Research Institute NCCN Staff: Mary Dwyer, MS, and Rashmi Kumar, PhD KEY: *Writing Committee Member Subcomittee: s Principles of Radiotherapy f Pure Testicular Seminoma Specialties: Medical Oncology; ÞInternal Medicine; Hematology/Hematology Oncology; Radiotherapy/ Radiation Oncology; and ωurology

3 504 Testicular Cancer Version 1:2012 WORKUP PRIMARY TREATMENT b PATHOLOGIC DIAGNOSIS Pure seminoma germ cell tumc (pure seminoma histology and AFP negative may have elevated beta-hcg) d ; Suspicious testicular mass H&P Alpha-fetoprotein (AFP) beta-hcga LDH Chemistry profile Chest x-ray Testicular ultrasound Discuss sperm banking Radical inguinal chiectomy Consider inguinal biopsy of contralateral testis if: Suspicious ultrasound f intratesticular abnmalities Cryptchid testis Marked atrophy Nonseminomatous germ cell tum (includes mixed seminoma tums and seminoma histology with elevated AFP) aquantitative analysis of beta subunit. bthough rare, when a patient presents with rapidly increasing beta-hcg, symptoms related to disseminated disease and a testicular mass, chemotherapy can be initiated immediately without waiting f a biopsy diagnosis. cmediastinal primary site seminoma should be treated by risk status used f gonadal seminomas with etoposide/cisplatin f 4 cycles bleomycin/etoposide/cisplatin f 3 cycles. dif AFP-positive, treat as nonseminoma. Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

4 NCCN Clinical Practice Guidelines in Oncology 505 Testicular Cancer Version 1:2012 PURE SEMINOMA POSTDIAGNOSTIC WORKUP e CLINICALSTAGE Stage IA, IB See Primary Treatment and Follow-Up (page 506) Abdominal/pelvic CT Chest CT if: Positive abdominal CT abnmal chest x-ray Repeat beta-hcg, LDH,AFPf Brain MRI, if clinically indicated Bone scan, if clinically indicated Discuss sperm banking Stage IS Stage IIA, IIB See Primary Treatment and Follow-Up (page 506) See Primary Treatment and Follow-Up (page 506) Stage IIC, III See Primary Treatment and Follow-Up (page 506) Stage IA, IB, IS: See Primary Treatment (page 508) Abdominal/pelvic CT ± chest imaging Repeat beta-hcg, LDH,AFPf Brain MRI, if clinically indicated Bone scan, if clinically indicated Discuss sperm banking Stage IIA, IIB: See Primary Treatment (page 508) Stage IIC, IIIA, IIIB, IIIC, and brain metastasis: See Primary Treatment (page 510) epet scan is not clinically indicated f nonseminoma. felevated values should be followed after chiectomy with repeated determination to allow precise staging. Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

5 506 PURE SEMINOMA Testicular Cancer Version 1:2012 CLINICAL STAGE Stage IA, IB PRIMARY TREATMENT Surveillance f pt1 pt2 tums (categy 1) (preferred) Single-agent carboplatin (categy 1) (AUC = 7 x 1 cycle AUC = 7 x 2 cycles) FOLLOW-UP H&P, AFP, beta-hcg, LDH: every 3-4 mo f years 1-2, every 6-12 mo f years 3-4, then annually Abdominal/pelvic CT every 6 mo f years 1-2, every 6-12 mo f year 3, then annually f years 4-5; chest x-ray as clinically indicated f years 1-5 H&P, AFP, beta-hcg, LDH: every 3 mo f years 1 every 4 mo f year 2, every 6 mo f year 3, then annually annually f years 1-3; chest x-ray as clinically indicated Abdominal/pelvic CT Recurrence, treat accding to extent of disease at relapse Recurrence, treat accding to extent of disease at relapse Stage IS RT g (categy 1) RT g,h H&P + AFP, beta-hcg, LDH: every 4 mo f years 1-2, then annually f years 3-10 Abdominal/pelvic CT annually f 3 years (f patients status post only para-atic RT); chest x-ray as clinically indicated Recurrence, treat accding to extent of disease at relapse Stage IIA, IIB RT to include para-atic and ipsilateral iliac lymph nodes to a dose of 30 to 36 Gyg Consider primary chemotherapy f selected stage IIB patients: j EP f 4 cycles BEP f 3 cycles H&P AFP, beta-hcg, LDH: every 3 mo f year 1, every 6 months f years 2-5, then annually f years 6-10 Chest x-ray every 6 months f years 1-2 Abdominal CT every 6-12 months f years 1-2, then annually f year 3 See Postchemotherapy Management and Follow-Up (page 507) Recurrence, treat accding to extent of disease at relapse Stage IIC, III Good risk i Primary chemotherapy: j EP f 4 cycles (categy 1) BEP f 3 cycles (categy 1) See Postchemotherapy Management and Follow-Up (page 507) Intermediate risk i Primary chemotherapy: j BEP f 4 cycles (categy 1) EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin g See Principles of Radiotherapy f Pure Testicular Seminoma (pages ). hsee Discussion f further infmation on the management of stage IS. isee Risk Classification f Advanced Disease (page 517). jsee Primary Chemotherapy Regimens f Germ CellTums (page 518). Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

6 NCCN Clinical Practice Guidelines in Oncology 507 Testicular Cancer Version 1:2012 PURE SEMINOMA STAGE IIB, IIC, III AFTER PRIMARY TREATMENT WITH CHEMOTHERAPY POST- CHEMOTHERAPY MANAGEMENT FOLLOW-UP Chest, abdominal, pelvic CT scan Serum tum markers No residual mass residual mass 3 cm and nmal markers Residual mass (> 3 cm) and nmal markers PET scan (approximately 6 wk postchemotherapy) Negative Positive Surveillance Surveillance Consider RPLND, if technically feasiblek Second-line chemotherapyl RT g (categy 2B) H&P + chest x-ray, AFP, beta-hcg, LDH: every 2 mo f year 1, every 3 mo f year 2, every 6 mo f year 3 and 4, then annually Abdominal/pelvic CT Post RPLND: 3-6 mo, then as clinically indicated After all other primary management as clinically indicated PET scan as clinically indicated Recurrence, See Second-Line Therapy (page 512) Progressive disease (growing mass rising markers) See Second-Line Therapy f Nonseminoma (page 512) g See Principles of Radiotherapy f Pure Testicular Seminoma (pages ). kif viable seminoma found by retroperitoneal lymph node dissection (RPLND), see page 510 (residual embryonal, yolk sac, chiocarcinoma, seminoma elements). lsee Second-Line Subsequent Chemotherapy Regimens f Metastatic Germ Cell Tums (page 519). Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

7 508 NONSEMINOMA Testicular Cancer Version 1:2012 CLINICAL STAGE Stage IA Stage IB PRIMARY TREATMENT Surveillance Nerve-sparing RPLND m,n Nerve-sparing RPLNDm,n Primary chemotherapy: j BEP f 2 cycles BEP f 1 cycle (categy 2B) Surveillance f T2 (categy 2B) only See Follow-Up f Nonseminoma (page 511) See Postsurgical Management (page 509) See Postsurgical Management (page 509) See Postchemotherapy Management (page 509) See Follow-Up f Nonseminoma (page 511) Stage IS Persistent marker elevation See Primary Treatment (page 510) Stage IIA Markers negative Nerve-sparing RPLNDm,n Primary chemotherapy j (categy 2B): EP f 4 cycles BEP f 3 cycles See Postsurgical Management (page 509) See Postchemotherapy Management (page 509) Persistent marker elevation See Primary Treatment (page 510) Stage IIB Markers negative Lymph node metastases, within lymphatic drainage sites (landing zone positive) Multifocal, symptomatic, lymph node metastases with aberrant lymphatic drainage Nerve-sparing RPLND m,n Primary chemotherapy: j EP f 4 cycles BEP f 3 cycles Primary chemotherapy: j EP f 4 cycles BEP f 3 cycles See Postsurgical Management (page 509) See Postchemotherapy Management (page 509) Persistent marker elevation See Primary Treatment (page 510) jsee Primary Chemotherapy Regimens f Germ CellTums (page 518). mretroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers. nsee Principles of Surgery (page 520). Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

8 NCCN Clinical Practice Guidelines in Oncology 509 Testicular Cancer Version 1:2012 NONSEMINOMA POSTCHEMOTHERAPY MANAGEMENT Negative markers, residual mass ( 1 cm) on CT scan Nerve-sparing bilateral RPLNDm,n Surveillance (categy 2B) Stage IB, IIA, IIB treated with primary chemotherapy See Follow-Up f Nonseminoma (page 511) Negative markers, no mass residual mass (< 1 cm) on CT scan Nerve-sparing bilateral RPLNDm,n (categy 2B) Surveillance (categy 2B) POSTSURGICAL MANAGEMENT pn0 Surveillance Stage IA, IB, IIA, IIB treated with nervesparing RPLND pn1 pn2 Surveillance (preferred) Chemotherapy: j EP f 2 cycles BEP f 2 cycles Chemotherapy (preferred): j EP f 2 cycles BEP f 2 cycles Surveillance See Follow-Up f Nonseminoma (page 511) pn3 C hemotherapy (preferred): j EP f 4 cycles BEP f 3 cycles EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin j See Primary Chemotherapy Regimens f Germ Cell Tums (page 518). mretroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers. nsee Principles of Surgery (page 520). Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

9 510 NONSEMINOMA Testicular Cancer Version 1:2012 CLINICAL STAGE PRIMARY TREATMENT POST CHEMOTHERAPY MANAGEMENT Good riski Stage IS Stage IIA, S1 Stage IIB, S1 Stage IIC Stage IIIA Primary chemotherapy: j EP f 4 cycles BEP f 3 cycles Complete response, negative markers Surveillance (categy 2B) Bilateral RPLND m,n ± nerve-sparing ( categy 2B) Intermediate riski Stage IIIB Po riski Stage IIIC Primary chemotherapy: j BEP f 4 cycles Clinical trial (preferred) Primary chemotherapy: j BEP f 4 cycles VIP f 4 cycles in selected patientsp Partial response, residual massesq with nmal AFP and beta-hcg levels Incomplete response q Surgical resection of all residual masses See Second-Line Therapy (page 512) Teratoma necrosis Residual embryonal, yolk sac, chiocarcinoma, seminoma elements Surveillance Chemotherapy f 2 cycles (EPj TIPl VIP/VeIP j l) See Follow- Up f Nonseminoma (page 511) Brain metastases o Primary chemotherapy j + RT ± surgery, if clinically indicated EP = Etoposide/cisplatin BEP = Bleomycin/etoposide/cisplatin TIP = Paclitaxel/ifosfamide/cisplatin VeIP = Vinblastine/ifosfamide/cisplatin VIP = Etoposide/ifosfamide/cisplatin isee Risk Classification fadvanced Disease (page 517). jsee Primary Chemotherapy Regimens f Germ Cell Tums (page 518). lsee Second-Line Subsequent Chemotherapy Regimens f Metastatic Germ Cell Tums (page 519). mretroperitoneal lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (categy 2B). nsee Principles of Surgery (page 520). opatients should receive adequate treatment f brain metastases, in addition to cisplatin-based chemotherapy. ppatients who may not tolerate bleomycin. qthere is limited predictive value f PET scan f residual masses. Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

10 NCCN Clinical Practice Guidelines in Oncology 511 Testicular Cancer Version 1:2012 NONSEMINOMA FOLLOW-UP FOR NONSEMINOMA Table 1 Follow-Up f Stage IA, IB on Surveillance Only Table 2 Follow-Up After Complete Response to Chemotherapy and RPLND Year 1 Months between H&P, markers, chest x-ray 1-2 Months between abdominal CT 3-4 Year Months between H&P, markers, chest x-ray (categy 2B f chest x-ray frequency) Months between abdominal/pelvic CT As clinically indicated Table 3 Follow-Up After RPLND Only Year Months between H&P, markers, chest x-ray (categy 2B f chest x-ray frequency) Months between abdominal/pelvic CT Recurrence, See Second-Line Therapy (page 512) Baseline As indicated As indicated 4 6 As indicated As indicated As indicated Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

11 512 NONSEMINOMA Testicular Cancer Version 1:2012 RECURRENCE r Pri chemotherapy Favable prognosis: s Low markers Low volume Complete response on first-line therapy Testis primary SECOND-LINE THERAPY Chemotherapyl Conventional dose therapy (VeIP TIP) High-dose chemotherapy Incomplete response relapse Complete response Chemotherapyl High-dose chemotherapy (preferred if not previously given) Clinical trial Surgical salvage should be considered if solitary site Best supptive care Relapse Follow-up Persistent disease Relapse Palliative chemotherapyl RT Unfavable prognosis: s Incomplete response High markers High volume Extratesticular primary Late relapse Chemotherapyl Clinical trial (preferred) Conventional dose therapy (VeIP TIP) High-dose chemotherapy (categy 2B) Surgical salvage should be considered if solitary site Best supptive care Persistent disease Relapse No pri chemotherapy Treat as per risk status on page 510 VeIP = Vinblastine/ifosfamide/cisplatin TIP = Paclitaxel/ifosfamide/cisplatin l See Second-Line Subsequent Chemotherapy Regimens f Germ Cell Tums (page 519). r It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease. s Examples of systems used to estimate prognosis are: 1) Lch A, Beyer J, Bascoul-Mollevi C, et al. Prognostic facts in patients with metastatic germ cell tums who experienced treatment failure with cisplatin-based first-line chemotherapy. International Prognostic Facts Study Group. J Clin Oncol 2010;28: ) 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: ) Motzer RJ, Geller NL, Tan CC, et al. Salvage chemotherapy f patients with germ cell tums. The Memial Sloan-Kettering Cancer Center experience ( ). Cancer 1991;67: Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

12 NCCN Clinical Practice Guidelines in Oncology 513 Testicular Cancer Version 1:2012 PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA General Principles Modern radiotherapy involves smaller fields and lower doses than were used in the past. References are provided to suppt current recommended management. Risk-adapted management using tum size > 4 cm and rete testis invasion f stage I seminoma is discouraged. This is based on a validation study in 2010, which revealed that tum size > 4 cm and rete testis invasion were not predicts of relapse. 1,2 Linear accelerats with > 6 MV photons should be used when possible. The mean dose (Dmean) and dose delivered to 50% of the volume (D50%) of the kidneys, liver, and bowel are lower with CT-based anteroposteri-posteroanteri (AP-PA) 3-dimensional confmal radiation therapy (3D-CRT) than intensity-modulated radiation therapy (IMRT). 3 As a result, the risk of second cancers arising in the kidneys, liver, bowel may be lower with 3D-CRT than IMRT, and IMRT is not recommended. 4 Timing of radiotherapy: Radiotherapy should start within 7 weeks after chiectomy. Patients should be treated 5 days per week. Patients who miss a fraction should be treated to the same total dose and with the same fraction size, extending the overall treatment time slightly. Antiemetic medication significantly improves nausea. See NCCN Clinical Practice Guidelines (NCCN Guidelines) in Oncology f Antiemesis (available in this issue and online at Antiemetic prophylaxis is encouraged at least 2 hours befe each treatment, and some cases may require me frequent dosing. Preparation f Radiotherapy Adiscussion of semen analysis and sperm banking befe chiectomy is recommended in patients who wish to preserve fertility. sperm banking is desired, it should be perfmed befe imaging and the delivery of adjuvant therapy. 5,6 If Treatment Planning Principles A noncontrast CT simulation should be perfmed with the patient supine, arms at his sides, in the treatment position. Immobilization with a cast may be used to improve the reproducibility of patient setup. All patients, with the exception of those who have undergone bilateral chiectomy, should be treated with a scrotal shield. The legs should be separated by a rolled towel of approximately the same diameter as the scrotal shield and its stand. Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

13 514 Testicular Cancer Version 1:2012 PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA Stage I Dose: F stages IA, IB, and IS, a total dose of 20.0 Gy (midplane) in 10 daily 2.0-Gy fractions is recommended f the minity of patients who prefer adjuvant treatment realizing that there is a high likelihood of salvage should a relapse occur during surveillance. Para-atic (PA) strip fields - field arrangement: In patients with no histy of pelvic scrotal surgery, para-atic strip irradiation may be delivered with opposed AP-PA fields. The weights of the fields may be equal. Recent nodal mapping studies suggest that fields should target the retroperitoneal lymph nodes but not necessarily the ipsilateral renal hilar nodes (see lateral bders). Superi and inferi bders: bders may be determined by bony anatomy. - The superi bder should be placed at the bottom of vertebral body T11. - The inferi bder should be placed at the inferi bder of vertebral body L5. Lateral bders: - Conventionally, PA strip fields are approximately 10 cm wide, encompassing the tips of the transverse processes of the para-atic vertebrae. - The location of the kidneys within the PA strip fields varies from patient to patient. F patients whose kidneys are relatively medial, small renal blocks may be added at the level of T12. The right and left kidney D50% should be 8 Gy (i.e., no me than 50% of each kidney can receive 8 Gy higher). If only one kidney is present, the kidney D15% should be 20 Gy (i.e., no me than 15% of the volume of the kidney can receive 20 Gy higher). An alternative 3D-CRT planning technique is to base the lateral bders on vascular structures on a treatment planning CT scan without contrast. The ata and inferi vena cava may be contoured on the CT scan; one should allow a 1.2- to 1.9-cm margin on the ata and inferi vena cava to include the para-atic, paracaval, interatocaval, and preatic nodes in the clinical target volume. The planning target volume is then established by unifmly expanding the clinical target volume by 0.5 cm in all directions to account f treatment setup errs. A unifm 0.7-cm margin should be provided on the planning target volume to the block edge to take beam penumbra into account (Figure 1, see page 516) ,12 Special Considerations Ipsilateral pelvic surgery (e.g., inguinal hernirhaphy chiopexy) may alter the lymphatic drainage of the testis. As a result, irradiation of the ipsilateral iliac and inguinal lymph nodes, including the surgical scar from pri surgery, has been advocated even in stage I patients. Given the large volume of tissue that would be irradiated and the resulting increased risks of late effects, other management approaches are recommended f these patients. 12, , ,15 9 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

14 NCCN Clinical Practice Guidelines in Oncology 515 Testicular Cancer Version 1:2012 PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA Stage IIA-B F clinical stage IIA-B patients, treatment is delivered in 2 consecutive AP-PA phases (modified dog-leg fields and cone down). There is no break between the 2 phases. Modified dog-leg fields: Dose: the initial phase consists of treatment of modified dog-leg fields to 20.0 Gy (midplane) in 10 daily 2.0-Gy fractions Gy in 15 daily 1.7-Gy fractions. 18 Target: the fields should include the retroperitoneal and proximal ipsilateral iliac lymph nodes. Modified dog-leg fields as described by Classen et al. 19 are preferred. - Care should be taken to ensure coverage of the ipsilateral common, external, and proximal internal iliac lymph nodes down to the top of the acetabulum. -The fields can be set up using bony landmarks by contouring the vascular structures, as f stage I. The superi bder should be placed at the bottom of vertebral body T The inferi bder should be placed at the top of the acetabulum. 19 The medial bder f the lower aspect of the modified dog-leg fields extends from the tip of the contralateral transverse process of the fifth lumbar vertebra toward the medial bder of the ipsilateral obturat famen. The lateral bder f the lower aspect of the modified dog-leg fields is defined by a line from the tip of the ipsilateral transverse process of the fifth lumbar vertebra to the superolateral bder of the ipsilateral acetabulum. Preferably, one should contour the ata and inferi vena cava from the bottom of the T11 vertebra inferily and ipsilateral iliac arteries and veins down to the top of the acetabulum. One should provide a 1.2- to 1.9-cm margin on these vascular structures f the clinical target volume. 11,15 The planning target volume is then established by unifmly expanding the clinical target volume by 0.5 cm in all directions to account f treatment setup errs. 16 A unifm 0.7-cm margin should be provided on the planning target volume to the block edge to take beam penumbra into account (Figure 2, see page 516). 3 It is not necessary to include the ipsilateral inguinal nodes the inguinal scar in the AP-PA fields unless the patient has a histy of ipsilateral pelvic surgery (e.g., inguinal hernirhaphy chiopexy). 12 Cone Down: Dose: the second phase (cone down) of the radiotherapy consists of daily 2-Gy fractions to a cumulative total dose of approximately 30 Gy f stage IIA and 36 Gy f stage IIB. 19 Target: the nodal mass (gross tum volume) must be contoured. A unifm, 2-cm margin from the gross tum volume to block edge should be provided f the AP-PA cone down fields (Figure 3, see page 516). Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

15 516 Testicular Cancer Version 1:2012 PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA Figure 2 Figure 1 Figure 3 References 1. Chung P, Warde P. Stage I seminoma: adjuvant treatment is effective but is it necessary? J Natl Cancer Inst 2011;103: Chung P. Prognostic facts f relapse in stage I seminoma: a validation study [abstract]. J Clin Oncol 2010;28:Abstract Zilli T, Boudreau C, Doucet R, et al. Bone marrow-sparing intensity-modulated radiation therapy f stage I seminoma. Acta Oncol 2011;50: Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56: Ragni G, Somigliana E, Restelli L, et al. Sperm banking and rate of assisted reproduction treatment: insights from a 15-year cryopreservation program f male cancer patients. Cancer 2003;97: Saito K, Suzuki K, Iwasaki A, et al. Sperm cryopreservation befe cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005;104: Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy f stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC study (ISRCTN ). J Clin Oncol 2011;29: Mead GM, Fossa SD, Oliver RT, et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst 2011;103: Garmezy B, Pagliaro LC. Choosing treatment f stage I seminoma: who should get what? Oncology (Williston Park) 2009;23:753, Fossa SD, Hwich A, Russell JM, et al. Optimal planning target volume f stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tum Wking Group. J Clin Oncol 1999;17: Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography f radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;74: McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tums: anatomic classification, characterization, and staging. Radiology 2010;254: Bruns F, Bremer M, MeyerA, et al. Adjuvant radiotherapy in stage I seminoma: is there a role f further reduction of treatment volume? Acta Oncol 2005;44: Classen J, Schmidberger H, Meisner C, et al. Para-atic irradiation f stage I testicular seminoma: results of a prospective study in 675 patients. A trial of the German testicular cancer study group (GTCSG). Br J Cancer 2004;90: Shih HA, Harisinghani M, Zietman AL, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume f pelvic nodal irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63: Boujelbene N, Cosinschi A, Khanfir K, et al. Pure seminoma: a review and update. Radiat Oncol 2011;6: Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a rept on Medical Research Council Trial TE18, European Organisation f the Research and Treatment of Cancer Trial (ISRCTN ). J Clin Oncol 2005;23: Choo R, Sandler H, Warde P, et al. Survey of radiation oncologists: practice patterns of the management of stage I seminoma of testis in Canada and a selected group in the United States. Can J Urol 2002;9: Classen J, Schmidberger H, Meisner C, et al. Radiotherapy f stages IIA/B testicular seminoma: final rept of a prospective multicenter clinical trial. J Clin Oncol 2003;21: Paly J, Efstathiou J, Hedgire S, et al. Mapping patterns of nodal metastases in seminoma: rethinking the para-atic field [abstract]. Int J Radiat Oncol Biol Phys 2011;81:Abstract 88. Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

16 NCCN Clinical Practice Guidelines in Oncology 517 Testicular Cancer Version 1:2012 RISK CLASSIFICATION FOR ADVANCED DISEASE (postchiectomy) 1 Risk Status Nonseminoma Seminoma Good Risk Testicular retroperitoneal primary tum and No nonpulmonary visceral metastases and Postchiectomy markers - all of: AFP < 1,000 ng/ml HCG < 5,000 IU/L LDH < 1.5 x upper limit of nmal Any primary site and No nonpulmonary visceral metastases and NmalAFP Any HCG Any LDH Intermediate Risk Testicular retroperitoneal primary tum and No nonpulmonary visceral metastases and Postchiectomy markers - any of: AFP1,000-10,000 ng/ml HCG 5,000-50,000 IU/L LDH x upper limit of nmal Any primary site and Nonpulmonary visceral metastases and NmalAFP Any HCG Any LDH Po Risk Mediastinal primary tum Nonpulmonary visceral metastases Postchiectomy markers - any of : AFP > 10,000 ng/ml HCG > 50,000 IU/L LDH > 10 x upper limit of nmal No patients classified as po prognosis Source: Figure 4 from the International Germ Cell Cancer Collabative Group. International Germ Cell Consensus Classification: aprognostic fact-based staging system f metastatic germ cell cancers. J Clin Oncol 1997;15: Reprinted with permission of theamerican Society of Clinical Oncology. 1 Markers used f risk classification are postchiectomy. Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

17 518 Testicular Cancer Version 1:2012 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 days 2, 9, 16 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 days Xiao 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: 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: 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: Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

18 NCCN Clinical Practice Guidelines in Oncology 519 Testicular Cancer Version 1:2012 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 h 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 h 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 cycles3 Paclitaxel, 200 mg/m2 IV over 24 h on day 1 Ifosfamide, 2000 mg/m2 over 4 h with mesna protection on days 2-4 Repeat every 14 days f 2 cycles followed by Carboplatin,AUC 7-8 IV over 60 min days 1-3 Etoposide, 400 mg/m2 IV days 1-3 Administer with peripheral blood stem cell suppt at 14- to 21-day intervals f 3 cycles4 Palliative chemotherapy regimens* Gemcitabine/oxaliplatin Gemcitabine/paclitaxel Gemcitabine/paclitaxel/oxaliplatin *Please see references below f dosing. GemOx 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: 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 Testicular Cancer Study Group. J Clin Oncol 2004;22: 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: Paclitaxel/gemcitabine Einhn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy f germ cell tums after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 2007;25: Mulherin B, Brames M, Einhn L. Long-term survival with paclitaxel and gemcitabine f germ cell tums after progression following high-dose chemotherapy with tandem transplants [abstract]. J Clin Oncol 2011;29:Abstract Gemcitabine/oxaliplatin/paclitaxel Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatinrefracty multiply relapsed germ-cell tums: a study of the German Testicular Cancer Study Group. Ann Oncol 2008;19: Loehrer 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: Kondagunta GV, Bacik J, DonadioA, 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: Einhn LH, Williams SD, ChamnessA, et al. High-dose chemotherapy and stem-cell rescue f metastatic germ-cell tums. N Engl J Med 2007;357: 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: Version1.2012, National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

19 520 NONSEMINOMA Testicular Cancer Version 1:2012 PRINCIPLES OF SURGERY RPLND is the standard approach to the surgical management of nonseminoma germ cell tum (NSGCT) in both primary and postchemotherapy setting. Atemplate dissection a nerve-sparing approach to minimize the risk of ejaculaty disders should be considered in patients undergoing primary RPLND f stage I nonseminoma. The split and roll technique in which lumbar vessels are identified and sequentially ligated allows resection of all lymphatic tissue around and behind the great vessels (ata, IVC) and minimizes the risk of an in-field recurrence. Postchemotherapy setting Referral to high-volume centers should be considered f surgical resection of masses postchemotherapy. Completeness of resection is an independent and consistent predictive variable of clinical outcome. In postchemotherapy RPLND, surgical margins should not be compromised in an attempt to preserve ejaculation. Additional procedures and resection of adjacent structures may be required. Postchemotherapy RPLND is indicated in patients with metastatic NSGCT with a residual retroperitoneal mass after systemic chemotherapy and nmalized postchemotherapy serum tum markers. Afull bilateral template RPLND should be perfmed in all patients undergoing RPLND in the postchemotherapy setting, with the boundaries of dissection being the renal hilar vessels (superily), ureters (laterally), and the common iliac arteries (inferily). Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

20 NCCN Clinical Practice Guidelines in Oncology 521 Text continued from p. 503 An elevated serum concentration of β-hcg, which has a half-life of approximately 1 to 3 days, may also be present with seminomatous and nonseminomatous tums. The elevations of β-hcg must be interpreted with caution, because hypogonadism and marijuana use may cause benign serum elevations of β-hcg. Nonseminoma is the me clinically aggressive tum. When both 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% 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. 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. Diagnosis and Wkup If an intratesticular mass is identified, complete blood count, creatinine, electrolytes, and liver enzymes should be obtained. Further evaluation includes measurement of serum tum markers and a chest radiograph. Testicular ultrasound serves to confirm the presence of a testicular mass and to exple the contralateral testis; it is sensitive and has an imptant role in determining whether a mass is intra- extratesticular. 4 Serum tum markers are critical in assignment of prognosis and also management during treatment. Serum tum markers are prognostic facts and contribute to diagnosis and staging. 5 Markers are assessed befe chiectomy and repeated after chiectomy. Elevated values of β-hcg, LDH, AFP should be followed up with repeated tests to allow precise staging. Testicular Cancer Biopsy may also be considered if a suspicious intratesticular abnmality, such as a hypoechoic mass macrocalcification, is identified on ultrasound. In contrast, if microcalcifications without any other abnmality can be observed, testicular biopsy is not necessary. In patients of reproductive age, sperm banking must be discussed. 6,7 It must be discussed with the patients befe undergoing any therapeutic intervention that may compromise fertility, including surgery, radiation therapy, and chemotherapy If sperm banking is desired, it may be perfmed either befe after chiectomy, but certainly befe subsequent therapy. Inguinal chiectomy is considered the primary treatment f most patients who present with a suspicious testicular mass. 11 An open inguinal biopsy of the contralateral testis is not routinely perfmed, but can be considered when a cryptchid testis marked atrophy is present. 12 The extent of primary tum is classified after chiectomy, and therefe pathological (p) stage is assigned to the primary tum (T). Further management is dictated by histology, a diagnosis of pure seminoma nonseminoma (includes mixed seminoma tums and seminoma histology with elevated AFP), and the stage. Although rare, when a patient presents with rapidly increasing β-hcg, symptoms related to disseminated disease, and a testicular mass, chemotherapy can be initiated immediately without waiting f a biopsy diagnosis. Risk Classification f Advanced Disease In 1997, the International Germ Cell Cancer Consensus Group (IGCCCG) defined a prognostic fact based classification system based on identification of some clinically independent prognostic features, such as extent of disease and levels of serum tum markers postchiectomy. Postchiectomy markers are used to classify the patient accding to the IGCCCG risk classification. This classification categizes patients with pure seminoma and nonseminoma GCT into good-, intermediate-, porisk groups. 13 Stage and risk classification are assigned accding to the American Joint Committee on Cancer (AJCC) and IGCCCG classification.

21 522 NCCN Clinical Practice Guidelines in Oncology Testicular Cancer Pure Seminoma If a GCT is found, an abdominopelvic CT scan is perfmed. Abdominopelvic CT scanning is used to assess the retroperitoneal nodes. 14 A chest CT is indicated if the abdominopelvic CT shows retroperitoneal adenopathy the chest radiograph shows abnmal results. A chest CT scan is a sensitive way to evaluate the thax and mediastinal nodes. 15 The panel members recommend a brain MRI bone scan only if metastases to these gans is suspected. Elevated values of β-hcg, LDH, AFP should be followed up with repeated tests. Serum concentrations of β-hcg and LDH may be elevated in patients with seminoma. An elevated AFP level indicates nonseminoma, and patients should be managed accdingly. Initial management of pure seminoma involves a radical inguinal chiectomy. Orchiectomy is both diagnostic and therapeutic. Patients with seminoma arising from an extragonadal site, such as the mediastinum, are treated with standard chemotherapy regimens accding to risk status. Pure Seminoma Stages IA and IB Primary Treatment f Pure Seminoma Stages IA and IB: F patients with stages IA and IB pure seminoma, the standard treatment options after initial chiectomy include surveillance, radiotherapy, chemotherapy with 1 2 cycles of carboplatin. The disease-specific survival f stage I disease is 99%, irrespective of the management strategy used. 16 Several prospective nonrandomized studies of surveillance have been conducted The relapse rate seen in these studies is 15% to 20% at 5 years, and most of the relapses are first detected in infradiaphragmatic lymph nodes Some studies rept tum size greater than 4 cm and rete testis invasion as risk facts f relapse. 19,21,22 However, a validation study by Chung et al. 23,24 showed that tum size greater than 4 cm and rete testis invasion were not predicts of relapse. Therefe, the panel members discourage risk-adapted management based on tum size greater than 4 cm and rete testis invasion f stage I pure seminoma. Surveillance is listed as the preferred option (categy 1) f patients with pt1 and pt2 disease. If surveillance is not applicable, alternatives are either adjuvant carboplatin adjuvant radiotherapy, as described later. Each approach has distinct advantages and disadvantages. The physicians should discuss these with the patients and their families and pick the best approach on a case-by-case basis. Oliver et al. 25 repted on the results of a trial that randomized 1477 patients with stage I testicular cancer to undergo either radiotherapy one injection of carboplatin. In the study, carboplatin (area under the cure [AUC] 7) was administered intravenously. The dose was calculated by the fmula 7 (glomerular filtration rate [GFR, ml/min] + 25 mg). With a median follow-up of 4 years, the relapse-free survival rates were similar f both groups. 25 Late relapses and secondary GCTs can occur beyond 5 and 10 years. Therefe, the investigats continued to follow these patients. The updated results repted noninferiity of single-dose carboplatin versus radiation therapy. 26 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). Two cases of contralateral GCTs were seen in the carboplatin arm versus 15 in the radiation therapy arm, with hazard ratio of 0.22; the contralateral GCT-free rates at 5 years are 99.8% and 98.8%, respectively. The auths concluded that a single dose of carboplatin is less toxic and as effective in preventing disease recurrence as adjuvant radiotherapy in men with stage I pure seminoma after chiectomy. 26 Two courses of adjuvant carboplatin have also been repted to reduce the relapse rate. 27 The panel recommends either 1 2 cycles of carboplatin AUC 7 as a categy 1 recommendation f patients with stages IA and IB pure seminoma. If radiation therapy is delivered, the panel recommends a total dose of 20 Gy (midplane) in 10 daily 2.0-Gy fractions, 28 given to an infradiaphragmatic area, including para-atic lymph nodes; in special circumstances, this area may include the ipsilateral ilioinguinal nodes Patients f whom radiation therapy is generally not given include those at higher risk f mbidity from radiation therapy, such as those with a histy of pelvic surgery. Prophylaxis to the mediastinum is not provided, because relapse rarely occurs at this site. F patients with stages IA and IB pure seminoma, adjuvant radiation therapy to include the para-atic nodes is also a categy 1 recommendation, although active surveillance is preferred (see Principles of Radiotherapy f Pure Testicular Seminoma, pages ).