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Seminoma 2012

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  • Most common testicular solid tumor.
  • Have at least 1 X & Y chromosome, implying that transformation occurs in a germ cell prior to meiotic anaphase. A: i(12p) B: normal chromosome and i(12p) Testicular GCTs are the neoplastic counterpart of primordial germ cells/gonocytes. Primordial germ cells (PGCs) are derived from the epiblast and migrate to the genital ridge as early as the 6th week of the embryonic development. PGCs are positive for OCT-4, which is thought to regulate pluripotency. Once in the genital ridge, PGCs are called gonocytes and will differentiate into oocytes (ovary) or prespermatogonia (testis). This migration is accompanied by proliferation and is controlled by the  KIT  stem-cell signaling pathway. During normal maturation of germ cells, OCT-4, PLAP, and c-KIT immunoexpression disappear. Nevertheless, the corresponding genes are later reprogrammed during oncogenesis, and these proteins are detected in germ cell neoplasms, including seminomas.[8] KIT  gene mutations are implicated in extragonadal survival of PGCs. In view of its presence in bilateral tumors, the mutation must take place in PGCs before their arrival in the gonadal ridges.[28] The initial event in the origin of seminoma is the malignant transformation of an intratubular germ cell. This process is analogous to intraepithelial or carcinoma in situ in other organs, but as gonocytes are not epithelial cells, the accurate terminology is intratubular germ cell neoplasia, unclassified (ITGCNU). Seminomas show relative overrepresentation of 12p chromosome sequences, but no consistent gain of 12p is detected in ITGCNU. These data indicate that overrepresentation of 12p is required for progression from preinvasive to invasive behavior. Candidate genes on 12p includeKRAS,CCND2, and NANOG.[29] All GCTs are aneuploid most likely because of early establishment of polyploidy. Polyploidy causes genomic instability with consequent genetic heterogeneity.
  • Hydroceles/Spermatoceles/Varicocele/Persistent processus vaginalis : transilluminate Hernia – loop of bowel – would be peristaltic Hematoma would be transilluminating and would be associated w/recent trauma Torsion would be painful US shows marginated hypoechoic vascularized mass
  • SHOULD BE COLLECTED BEFORE AND AFTER ORCHIECTOMY Half life of AFP? 5-7 days Half life of HCG? 18-36 hours Half life of PLAP? 24 hours How often is LDH found in seminoma? 80% of advanced seminoma bHCG can be mildly elevated but usually indicative of NSGCT.
  • AFP NEVER present with pure seminoma Alpha feto protein (AFP)- Never produced by Seminoma. T1/2 = 5-7 days.  in 50% of metastatic non-S GCT. Nonspecific production (Hepatocellular CA, infection, drug or alcohol induced, pancreas, stomach, lung, embryonal, teratocarcinoma, & yolk sac CA). bHCG: 'd in 10% of Seminomas overall and 50% of Choriocarcinomas. T1/2 =18-24hrs. ’ d with advanced tumors in 50% of non-S GCT & 15-20% seminomas. (antibody directed at B subunit: cross reacts with LH can lead to false positive) LDH: prognostic in advanced disease. Frequently elevated. Non-specific.
  • Images: Mediastinal and hilar, Retroperitoneal LN Abd CT- most effective to identify RP LAD, but it has limitations in thin pts. Approx. 25% of pts with (-) CT scan will still have (+) LNs. 70% of 1-2cm RP LNs contain mets. Lymphangiogram detects abnormal paraaortic LN in 15-20% of Seminoma pts with (-) CT's. Generally only get if suspect retrograde flow or if considering observation . CT vs LAG – Marks - Urol Sept 91:264-266 54 pts In all cases where CT was positive (LN>1.0cm) Lag was also positive. 22% of pts had positive LAG's in face of negative CT scans and all were due to abnormal intranodal Architecture. A paper by Dosmann argues that although upstaging may be present, there is no diff in OS in Pts staged by CT alone. Upstaging by LAG is therefore approx.=15-20% and is usefull for delineating treatment portals and enables boosts to be delivered to nodal abnormalities not seen on CT scan. MRI or CT of brain indicated based on clinical presentation. Are seminomas FDG avid? Yes Optimal use of PET for seminomas? Pts w/ residual mass after tx
  • Should sperm banking be advised? YES How long not to attempt conception after RT? 6 months
  • Scrotal violation changes drainage. Moves LN to inguinal canal. What is done during radical inguinal orchiectomy? Testis removed,spermatic cord dissected hi into abd w/ ligation of the spermatic cord at the internal ring is required for all suspected testicular tumors Most common postoperative complication? Wound hemorrhage When is retroperitoneal dissection indicated ? Controversial Who likely does not need retroperitoneal dissection? Stage I Is retroperitoneal nodal dissection considered therapeutic? Yes, even in situation of +nodes Likelihood of in-field recurrence after nodal dissection? <1% Major morbidity of retroperitoneal dissection? Ejaculatory disfunction ( damage to sympathetics)
  • Scrotal violation changes drainage. Moves LN to inguinal canal. How does scrotal violation affect local recurrence rate? 2.9% (scrotal violation) vs 0.4% (control)
  • Seminoma: (is 1/2 of all testicular GCTs; must be pure without AFP elevation) Classic (Typical): 85% of all seminomas & occurs most commonly in the fourth decade. Synctiotrophoblastic elements are noted in 10-15%, thus the frequency of bHCG production Spermatocytic: Extremely favorable prognosis. Rarely metastasizes. Occurs in men > 50. Rx with radical orchiectomy alone. Not assoc with Cis. True relation to seminoma unknown. Anaplasic: 10%. Has a  mitotic rate. Noteworthy because up to 35% of pts who die have this subtype. “ Aggressive", usually presents at a later stage, but stage for stage do the same as other histologies. Pure Seminoma histology does not change treatment except in Spermatocytic where RT is not offered Immmunoperoxidase stain positive for Placental alkaline phosphatase NonSeminoma: (usually tumor has multiple cell types – treated as Non-Seminomatous b/c more aggressive) Embryonal: Highly aggressive tumors. Assoc with  ’d AFP &/or B-HCG. Most undifferentiated. Endodermal Sinus tumor (Yolk Sac): Generally produces AFP. Pure ones frequently found in mediastinum. Teratoma: >1 germ cell layer (ecto-, meso-, endoderm). Mature, immature, and teratoma with malignant transformation. Choriocarcinoma: Ususally widely metastatic. Can present with  B-HCG. Consists of Cytotrophoblasts and Syncytiotrophoblasts. Other testicular neoplasms include Sex-cord-stromal tumors (Sertoli or Leydig cell tumors), gonadoblastoma (mixed GCT & stomal tumors), lymphomas, etc.
  • Seminomas originate from the germinal epithelium of seminiferous tubules The initial event in the origin of seminoma is the malignant transformation of an intratubular germ cell. This process is analogous to intraepithelial or carcinoma in situ in other organs, but as gonocytes are not epithelial cells, the accurate terminology is intratubular germ cell neoplasia, unclassified (ITGCNU).
  • IHC to diffx spermatocytic vs classic? Classic + for PLAP, spermatocytic neg for PLAP Placental Alk Phos + Seminoma Low molecular weight Keratins- Produced by non-S GCT. Seminomas don’t produce Radiation sensitivity Type A spermatogonia: presumed stem cells of spermatogenesis, considered relatively radioresistant. Possibly due to long cell cycle Type B spermatogonia: relatively radiosensitive
  • Seminiferous tubules? Finely coiled tubes w/i testis where meiosis occurs Seminiferous tubules lined with? Stem cells Other cell type within seminiferous tubules? Sertoli cells Sertoli cells? Support development of spermatogonia Tunica albuginea? Fibrous capsule that encases testis Tunica vaginalis? membrane covers albuginea derived from peritoneum Layers of testis beyond tunica vaginalis? int spermatic/cremasteric/ext spermatic fascia What is beyond external spermatic fascia? Dartos muscle and skin Rete testis? Network of seminal channels thru hilum of testis Where do efferent ducts from rete testis go?Epididymis Epididymis? Connect efferent ducts from testis to vas deferens Function of epididymis? Reservoir for sperm Physiologic ejaculation requires what steps? Bladder neck closure,seminal emission,ejaculation Which symp fibers mediate seminal emission? T12-L3 Which symp fibers mediate ejaculation? Sacral and lumbar
  • 4-8 lymphatic trunks drain hilum of the testis, and run along spermatic cord up to the internal inguinal ring Drain into retroperitoneal LNs between T11-L4, with majority between L1-L3 Then upward via thoracic duct through mediastinum and to supraclavicular fossae, and occasionally to axillary LNs
  • Serum Markers for Seminoma WNL >70% 15-30% mild elevations of hCG
  • Lymphatics- primary drainage is to the retroperitoneal lymph nodes below renal vessels; Ep ididymis drains to ipsilateral pelvic nodes Left testicular tumors drain to nodes lateral to the aorta (para-aortic) to renal vein & then PA. Right testicular tumors usually metastasize to nodes between the aorta and the inferior vena cava (interaortocaval nodes),. BOTH:  cysterna chyli  retrocural or post. mediastinal LA  L. SCV L SCV LA or pulmonary nodules may be present in the absence of RP LA. Lymphatic cross-over is at L4-5. Blood Vessels- follow similar course. Non-pulm mets (liver, bone, brain) very rare at presentation . Which laterality is associated w/  contralat spread? R-sided tumors Why are R-sided tumors assoc w/ contralat spread? Nodal drainage crosses over from R  L,but not L  R Do seminomas drain to inguinal nodes? Not unless surg disrupts lymph drainage  collaterals
  • AUC= 7 x (GFR + 25) mg
  • German Testicular Study, 2003  (1998-2001)  PMID 12644817  - "Radiotherapy with 16 Gy may fail to eradicate testicular intraepithelial neoplasia: preliminary communication of a dose-reduction trial of the German Testicular Cancer Study Group." (Classen J, Br J Cancer. 2003 Mar 24;88(6):828-31.) Prospective. Step-wise dose reduction starting at 18/9 Gy in 2 Gy steps. Results verified by biopsies Dose level 14 Gy aborted after a similar Danish trial (below) experienced a failure at 14 Gy. Cohort 16 Gy was expanded for more statistical power Interim resuls show that 16 Gy is not sufficient to control TIN (there were also viable spermatogonia present). Recommend considering different fractionation schedules. Endocrinology data not yet mature Copenhagen, 2002  (Denmark)  PMID 11896102  -- "Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis." (Petersen PM, J Clin Oncol. 2002 Mar 15;20(6):1537-43.) Prospective. Dose reduction starting at 20/10 in 2 Gy steps. Results verified by biopsies Remission in all patients at 20, 18, and 16 Gy. One relapse at 14 Gy after 20 months Toxicity: Leydig cell function - testosterone decrease for >5 years after RT. Need for androgen substitution similar at all RT dose levels Conclusion: 20/10 safe, 14/7 might result in relapse. Hormone production impaired even at 14 Gy
  • Patients who are good candidates for observation? Horseshoe kidney,IBD,prior RT,committed to f/u Stage I pts that may be appropriate for active surveillance? <3cm pure seminoma,neg postop markers/scans Warde – JCO 2002 – pooled analysis of 638 patients to identify prognostic factors for relapse in stage I seminoma managed by surveillance. 7yr FU - Patient data from four cohorts - Single and multivariate Analyses - Royal Marsden Hospital (110 pts.), Danish Testicular Cancer Study Group (258 pts.), Princess Margaret Hospital (226 pts.), Royal London Hospital (44 pts.) recommended schedule of radiographic and clinical surveillance is as follows:     Every four months for three to four years   Every 6 months for years four to seven  Every 12 months for years eight to ten 2nd Spanish Germ Cell CCG  (1999-2003)  PMID 16260698  -- "Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study." (Aparicio J, J Clin Oncol. 2005 Dec 1;23(34):8717-23.) Prospective. 314 patients. 100 with no risk factors treated with surveillance. 214 patients with risk factors (tumor >4 cm, rete testis involvement) had carboplatin x2. Median F/U 34 months 5-year DFS: surveillance 94%, chemo 96%. Relapses: surveillance 6%, chemo 3% (1% if tumor >4cm, 9% if rete testis, 6% if both). All but one in retroperitoneum. Median time to relapse 9 months (4-28 months) Conclusion: risk-adapted strategy safe and feasible 3rd Spanish Germ Cell CCG  (2004-8)  PMID 22042940  -- "Risk-Adapted Treatment in Clinical Stage I Testicular Seminoma: The Third Spanish Germ Cell Cancer Group Study." (Aparicio J, J Clin Oncol. 2011 Oct 31. [Epub ahead of print]) Prospective. 227 pts. 84 pts (37%) with no risk factors treated with surveillance. 44 pts (19%) had tumor > 4 cm, 25 (11%) with rete testis, 74 (33%) had both. Only the latter group (both risk factors) received treatment w/ carboplatin x 2. All others received surveillance only. Median f/u 34 mo. 16 relapses (7%) for pts on surveillance; 1 relapse (1.4%) for pts on surveillance. 3 yr DFS 88% (surveillance group), 98% (adjuvant carboplatin group). OS 100%. All relapses in retroperitoneal LNs except 1 pt w/ pelvic nodes. Median time to recurrence 14 mos; median node size 2.5 cm. All pts w/ relapse were made NED with chemotherapy. Conclusion: risk-adapted strategy is effective for stage I seminoma. For 2 risk factors: carboplatin. For 0-1 risk factors: observation. *****Close f/u required - Must have a reliable Patient. Which is more cost efficient, surveillance vs upfront RT? Upfront RT
  • Urology.  2002 Aug;60(2):324-8. Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study. OBJECTIVES: To evaluate the long-term oncologic efficacy and morbidity of carboplatin monotherapy , which was introduced at our department 11 years ago for the treatment of Stage I seminoma. Radiotherapy is the standard treatment of patients with clinical Stage I seminoma. Carboplatin has been advocated as a treatment alternative to avoid the late side effects of radiotherapy and the high recurrence rate of surveillance strategies. METHODS: From February 1990 until August 2001, 108 patients received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface on days 1 and 22) 2 weeks after high inguinal orchiectomy . To assess for myelosuppression, complete blood counts were performed at least once a week until the nadir occurred after the second treatment cycle. RESULTS: During a mean follow-up period of 59.8 months (range 6 to 134), 2 patients (1.85%) developed a recurrence (retroperitoneal tumor) within the first year . Both patients received cisplatin-based salvage chemotherapy . At last follow-up, all patients were alive without any evidence of disease. Carboplatin treatment was well tolerated by all patients and was associated with only mild gastrointestinal side effects. Leukopenia was noted in 32 patients (29.6%); 21 (19.4%) of these patients had World Health Organization (WHO) grade 1, 8 (7.4%) had grade 2, 3 (2.8%) had grade 3, and none had grade 4. No patient developed neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%); of these patients, 38 (35.2%) had WHO grade 1 , 5 (4.6%) had grade 2, 2 (1.9%) had grade 3, and 3 (2.8%) had grade 4. CONCLUSIONS: From an oncologic standpoint, two cycles of carboplatin monotherapy was highly effective and very well tolerated by all patients.
  • MRC Trial TE 18  (1995-98) 2005   PMID 15718317  -- "Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328)". (Jones WG et al.J Clin Oncol. 2005 Feb 20;23(6):1200-8.) Randomized. 625 pts. Paraaortic radiation (dogleg for patients with prior inguinal surgery). 20Gy/10 vs 30Gy/15 after orchiectomy Relapse: 30 Gy 10 relapses vs. 20 Gy 11 relapses (NS), 2-year relapse rate of 3-4%. 1 death (allocated to 20 Gy) Toxicity: At 4 weeks, 20 Gy significantly better ( moderate/severe lethargy 5% vs. 20%); at 12 weeks no difference Side effects of RT: Acute: fatigue nausea, vomiting, increased stool frequency, and rapid gastric emptying, have been described, especially in men with right-sided seminoma Myelosuppression treated skin Late: None in majority, impaired fertility, second malignancies, and possibly cardiac disease Conclusion: 20 Gy/10 sufficient, with faster return to work Severity of azospermia after 15-20 cGy? Minimal effect Severity of azospermia after 20-50 cGy? 30-50% azospermia, returns to baseline in 6-8 mo’s Severity of azospermia after 50-100 cGy? 50-80% azospermia, returns to baseline in 8-14 mo’s Severity of azospermia after 100-200 cGy? >90% azospermia, returns to baseline in 1-2 yrs Severity of azospermia after >200 cGy? Permanent azospermia
  • MRC Trial TE 10  (1989-1993) 1999   PMID 10561173  -- "Optimal planning target volume for stage I testicular seminoma: A MRC randomized trial. Medical Research Council Testicular Tumor Working Group." (Fossa SD, JCO. 1999 Apr;17(4):1146.) Randomized. 478 men with Stage I to PA or Dog-Leg. RT 30 Gy. Median F/U 4.5 years Fields: PA (sup T10/T11 ( origin of thoracic duct ), inf L5/S1 ( top of obturator foramen/internal inguinal ring ), lat inclusion of ipsilateral renal hilum usually 10-12cm width); Dog-Leg (sup T10/T11; inf mid-obturator foramen; ipsilateral inclusion of renal hilum vertically down to L5/S1, then diagonal to lateral edge of acetabulum, then vertically down to mid-obturator foramen; contralateral transverse process vertically to L5/S1, then diagonal parallel with ipsilateral and vertically down to mid-obturator foramen) - Give 2cm Margin to (+)LNs. Outcomes: No difference in 3yr overall survival between DL 97% and PA 99% 3yr pelvic RFS was 100% with DL and 98% with PA 2% Pelvic relapse risk in PA only arm PA had : less nausea and vomiting Lower azospermia (11% vs 35%) More rapid recovery of sperm count Relapse: 9 in each group (NS), but pelvic recurrences 0 DL vs. 4 PA Toxicity: Acute toxicity less frequent & less pronounced in PA arm; sperm counts significantly higher in PA arm (median time to recovery 13 months vs. 20 months if normal, 24 vs. 37 months if abnormal pre-RT) Conclusion was that you can omit DL field if patient followed regularly due to high salvage rates. MD Anderson recommend using DL for Stage I if epididymal invasion or prior inguinal scrotal surgery Where are relapses seminoma treated w/ RT? Virtually all outside of tx port
  • How to protect the testes? Scrotal shield (clam shell) Scrotal shield can decrease dose to opposite testicle to? 1-2% prescribed dose How to minimize dose to contralat testis if scrotal violation? Contralat testis retracted towards inguinal canal When is tx of ipsi hemi-scrotum definitely indicated? Massive tumor invading scrotum
  • (Oliver et al) MRC TE19 1447 Stage I seminoma patients randomized: 904 patients received XRT Para-aortic (87%) or dogleg (13%) field XRT 20Gy/10fx or 30Gy/15fx 573 patients received 1 cycle of carboplatin: 4 year follow up Relapse free rate at 3years 95.9% rad vs. 94.8% carbo Relapse sites RT: 9% PA, 28% Pelvic Carboplatin: 74% PA, 0% Pelvic Physician recorded toxicity during treatment Patient recorded diary of symptoms for 12 weeks Carboplatin pts took less time off from work (-) in 2 nd testicular Ca thought to be due to tx of contralateral Tis 2008 Update Fewer rate of new GCTs with Chemo (2pt on chemo vs. 15pt on RT) Late toxicity of chemotherapy not yet known
  • (Oliver et al) MRC TE19 1447 Stage I seminoma patients randomized: 904 patients received XRT Para-aortic (87%) or dogleg (13%) field XRT 20Gy/10fx or 30Gy/15fx 573 patients received 1 cycle of carboplatin: 4 year follow up Relapse free rate at 3years 95.9% rad vs. 94.8% carbo Relapse sites RT: 9% PA, 28% Pelvic Carboplatin: 74% PA, 0% Pelvic Physician recorded toxicity during treatment Patient recorded diary of symptoms for 12 weeks Carboplatin pts took less time off from work (-) in 2 nd testicular Ca thought to be due to tx of contralateral Tis 2008 Update Fewer rate of new GCTs with Chemo (2pt on chemo vs. 15pt on RT) Late toxicity of chemotherapy not yet known
  • Study that got rid of mediastinal RT for stage I seminoma? Princess Margaret Study (Red Journal 1982) Relapse rate in mediastinum for Princess Margaret? <1%
  • Radiotherapy for stages IIA/B testicular seminoma: final report of a Phase 2: prospective multicenter clinical trial 94pts. 66 Stage IIA, 21 Stage IIB Reduced Portals RT to PA and ipsilateral iliac LN (Low PA) Dose stage IIA 30Gy and Stage IIB 36Gy F/U 5.8yrs Conclusion: RT for Stage IIA-B seminoma, with reduced portals, yields excellent tumor control and no late toxicity
  • Bleomycin, etoposide, cisplatin Phase 2 : Prospective, non-randomized. 72 pts (18-Stage IIA, 54-Stage IIB). Treatment with 4 cycles of cisplatin + etoposide or 3 cycles of BEP (bleomycin, etoposide, cisplatin). 83% achieved CR 17% PR 5yr PFS 100% and 87% for Stage IIa and IIB respectively 5yr OS 95% Conclusion: Chemotherapy is highly effective and well-tolerated treatment for Stage IIA and IIB - - Alternative that could avoid some of serious late effects associated with RT
  • Do orchiectomy in cases of advanced disease? Yes, b/c likelihood of residual disease in testis When to do orchiectomy in case of advanced disease? Generally pre-chemotherapy (b/c testis privileged) Tx mediastinal seminoma w/45-50 Gy to mediastinum Most common sitea of relapse after RT for stage II- Supraclav fossa and mediastinum Supraclav/mediastinal relapse after RT -<10% Site of relapse if single agent carboplatin for stage II- Retroperitoneum Primary RT be used for IIC dz when doesn’t overlap most of 1kidney/too much liver Is primary RT first line option for IIC dz? No, combination chemo is first line Relapse rate for primary RT if nodal dz >10 cm? >40% Role for adjuvant RT for dz tx’d w/ primary chemo- Consolidative tx for residual dz Rate of residual dz after primary chemo for stage II/III - 80% at 1 month Most residual dz after 1 month- Most tends to regress over subsequent months What pts w/ residual mass is observation sufficient <3cm Tx for pts w/ residual mass >3cm = consolidative surg or RT Likelihood of residual dz if >3cm residual mass? 30-50% Characteristics of residual mass that  likelihood of dz there? Well defined on CT Which masses should not be resected-Ill defined mass (even if >3cm b/c risk of injury) Role of PET in evaluating residual masses- High specificity , good sensitivity in German series BOMP/EPI intensive alternating chemotherapy for IGCCC poor-prognosis germ-cell tumors: the Spanish Germ-Cell Cancer Group experience (GG) BACKGROUND: Patients with poor-prognosis germ-cell tumors according to the IGCCC have a poor long-term survival. This study evaluates the efficacy and toxicity of the intensive alternating chemotherapy regimen BOMP/EPI in these patients. PATIENTS AND METHODS: Patients with IGCCC poor-prognosis germ-cell tumors treated at 13 centres were studied. Treatment consisted of bleomycin 30 mg, vincristine 2 mg, methotrexate 300 mg/m2 and cisplatin 100 mg/m2 (BOMP), alternating after a 14-day interval with etoposide 120 mg/m2 day 1-4, ifosfamide 1.3 g/m2 day 1-4 and cisplatin 25 mg/m2 day 1-4 (EPI). BOMP was administered 21 days after the EPI. Bleomycin was administered weekly per 12 weeks. RESULTS: Thirty-eight patients were treated. The median number of cycles administered was 7 (1-10 cycles). Eighteen patients achieved complete responses with chemotherapy alone (12 had necrosis and 2 mature teratoma at postchemotherapy resection), and four achieved complete responses with chemotherapy and surgical resection of viable cancer. Thus, an overall favorable response was achieved in 22 patients (60%). Four additional patients had marker-negative non-resected residual masses. Eleven patients were considered treatment failures, including one who died early and another who succumbed to granulocytopenic sepsis and renal failure. Hematologic toxicity was the most common, with 26 patients (70%) having grade 4 granulocytopenia. After a median follow-up of 41 months, the actuarial two-year overall survival and progression-free survival were 64% and 58%, respectively. CONCLUSION: BOMP/EPI is active in poor-prognosis germ-cell tumors according to the IGCCC criteria. The results obtained compare favorably with those expected with conventional chemotherapy, and justify further studies.
  • XRT- pericardits, mycardial fibrosis, conduction defects, valv decfts, well documented from hodgkins and breast cacncer.
  • Zagars G, et al (2004) JCO 22(4) 641-8. N=453 stage I and II seminoma MD Anderson 1949-1999 Mean F/U was 13.3 years Observed vs. expected mortality for those receiving XRT. Multiple field designs All patient (453) received Dog Leg 31 (6.8 %) received whole abdominal XRT 71 (15.7 %) received prophylactic mediastinal XRT (PMI) 127 (28 %)received > 25 Gy Fig 1. 453 patients survival rates. Age and race adjusted surgival curves are shown. No difference in standard mortality ratio in the first 15 years. PMI was only factor that was found to have significant impact on mortality. 1st- the decrease in survival vs. expected 2nd- impact of PMI which was routinely done before 1971 regardless of stage. Finally, table of increased cardiac deaths Standardized Mortality Ratio (SMR) for first 15yrs 1.30 Beyond 15yrs SMR increased to 1.85 Cardiac SMR elevated only after 15yrs Cancer specific SMR only elevated after 15yrs 11 men died from seminoma relapse, 38 men died from excess nonseminoma mortality Increased cardiac and cancer mortality was significant after 15 yrs (P< .01) Elevated mortality seen regardless of PMI after 15 years recommendations: Surveillance for Stage I If XRT dose reduction from 25Gy/15fx to 20Gy/10Fx Field borders: Top of T10 questionable. T12 to bottom of L5 ?2 cycles of Carboplatin Men sucessfully treated with orchietomy and XRT have increased mortality as a result of causes other than their orignial tumor. XRT- pericardits, mycardial fibrosis, conduction defects, valv decfts, well documented from hodgkins and breast cacncer. Fig 2. Actuarial survival curves – only differed w/respect to whether or not PMI was delivered.
  • Types of 2ndry Malignancy: ALL, AML, melanoma, NHL, GI, sarcoma, renal, bladder Travis et al. 2005 40,576 testicular cancer survivors in 14 population registries in Europe and North America If dx by 35 years of age, cumulative risk of solid cancer 40yrs later 36% Seminoma 31% Nonseminoma 23% General Population Significant increase of cancers of the pleura and esophagus. Also GI, renal, stomach, bladder, and pancreas Increased relative risk of solid cancers for RT (RR=2.0), chemo alone (RR=1.8) and both (RR=2.9)
  • Types of 2ndry Malignancy: ALL, AML, melanoma, NHL, GI, sarcoma, renal, bladder Travis et al. 2005 40,576 testicular cancer survivors in 14 population registries in Europe and North America If dx by 35 years of age, cumulative risk of solid cancer 40yrs later 36% Seminoma 31% Nonseminoma 23% General Population Significant increase of cancers of the pleura and esophagus. Also GI, renal, stomach, bladder, and pancreas Increased relative risk of solid cancers for RT (RR=2.0), chemo alone (RR=1.8) and both (RR=2.9)
  • Still not perfectly clear if or how to treat seminoma Risk of Heart Attack if treated surgery alone vs. if given chemo
  • Still not perfectly clear if or how to treat seminoma Risk of Heart Attack if treated surgery alone vs. if given chemo
  • Salvage very effective
  • Transcript

    • 1. Testicular Seminoma Dr. John T. Lucas Jr. Wake Forest Baptist Medical Center Department of Radiation Oncology
    • 2.
      • Epidemiology
      • Risk Factors
      • Presentation
      • Workup
        • Labs, Imaging
      • Management
      • Histology
      • Anatomy
      • Staging, Prognosis
      • Tis (testicular ca in situ)
      • Stage 1: Rt, Chemo, Observation vs. Treatment
      • Stage 2A/B
      • Stage 2C/3
      • Acute and Late Effects
      Outline
    • 3. Epidemiology
      • Most common solid tumor 15-35 yoa
      • Peak incidence at 25-40yo and >65yo
      • 1% of all men
      • Increasing incidence over past 40 yrs
          • 2 new cases per 100,000 in 1930’s
          • 3.7 new cases per 100,000 in 1969-1971
          • 5.4 new cases per 100,000 in 1995-1999
      • 8250 new cases per year in US
      • Distribution:
        • Scandinavia, Germany, New Zealand ancestry
      • W:AA = 5:1
      • Does not occur before puberty
      • 2-3% have bilateral metachronus ca
      AJR
    • 4.
      • Cryptorchidism
        • 4x higher in intra abdominal testes than those in inguinal canal
        • Risk in both descended and undescended testis
        • Risk still elevated after orchidopexy, if performed before 10yo slightly decreased risk
      • Intratubular germ cell neoplasia (50% progress to Ca)
      • First born male
      • Pre/perinatal high estrogen exposure
        • Testicular feminization
      • Polyvinyl chloride exposure
      • Klinefelter’s – predisposes to mediastinal GCTs
      Risk Factors
    • 5.
      • Prior GCT in contralateral testis (5.2% over 25yrs)
      • Advanced maternal age
      • Down’s Syndrome
      • HIV/AIDS
      • Family History
      • Testicular Trauma
      • Chromosomal abnormalities involving chromo 1 & 12
      Risk Factors
    • 6.
      • GCT's are nearly always aneuploid
      • i(12p) genetic material is present in >80% of GCTs, cIS & is one of the earliest genetic events.
      • Have >= X & Y indicating transformation
      • prior to meiotic anaphase
      • Candidate genes:
        • CDKN2A, Ras, Oct1
      Genetics/Etiology
    • 7.
      • Most commonly present as a unilateral testicular mass increasing in size
        • Can be painless (pain in 10%)
        • Associated with discomfort or swelling
        • Differential includes epididymitis or orchitis
      • 5% w/Gynecomastia
      • Ultrasound initial evaluation
      • 20% of pts have + bilateral nodes
      Presentation
    • 8.
      • Hydrocele / Spermatocele
      • Orchitis / Epididimitis
      • Testicular Tumor
      • Testicular torsion, Hernia, & Hematoma
      Differential Diagnosis
    • 9.
      • AFP, beta HCG, LDH
        • If  HCG elevated, can be pure seminoma
        • AFP not elevated in seminoma
        • LDH high in metastatic disease
      • CBC, BMP, Coags
        • Prior to patient orchiectomy
      Labs
    • 10. PLAP- placental alkaline phosphatase Tumor Markers Histology Frequency % HCG+ % AFP+ % PLAP+ Comments Seminoma 45-50% 15-30% 0% 90% Most common, HCG related to presence of syncytiotrophoblasts Embryonal 3% 21% 33% >95% Seen in 50% of mixed Yolk sac 2% 0% > 95% ? Schiller-Duvall bodies Teratoma 5% 0 0 ? 50% of mixed Chorio-carcinoma 0.05% > 99% 0 ? 4% of mixed Mixed (any combo of non-seminoma) 45-50% Varies Varies Varies Most common non-seminomatous GCT
    • 11.
      • Chest X-ray
        • If abnormal adenopathy, CT of chest recommended
      • CT abdomen/Pelvis
        • Rule out nodal involvement
        • Regional nodes are paraaortic
      • Clinical signs of bone or brain involvement warrants MRI & bone scan
      Imaging
    • 12.
      • Fertility assessment/Semen Analysis
        • >50% underlying fertility impairment
      • Sperm Banking  30-50% Result in pregnancy
      • Biopsy
        • Transcrotal biopsy NOT appropriate, risk of local dissemination of tumor into scrotum or spread to local lymph nodes.
      Management
    • 13. Surgical Evaluation: Orchiectomy
      • Radical Inguinal Orchiectomy
        • Scrotal violation shows increased risk of LR 2.9% vs. 0.4%
        • No difference in DMFS or OS
        • Capelouto et al.
    • 14.
      • Transscrotal Orchiectomy
        • (leaves inguinal portion of the spermatic cord left intact)
        • Assoc w/a 24% incidence of LR & spread to inguinal , peri-aortic LN.
      Surgical Evaluation: Orchiectomy
    • 15. Histology/Seminoma subtype
      • Classic: >90% of cases, +PLAP, 20-40yo,
      • fried egg appearance
      • Spermatocytic: mean 54yo, cured by
      • orchiectomy, rarely mets, -PLAP
      • Anaplastic: No longer a subtype since mitotic count is
      • not prognostic
    • 16. Normal Seminferous Tubule with orderly Maturation from the Basement membrane Histology Seminferous Tubule filled with Abmormal cells
    • 17. Histology + PLAP
    • 18. Anatomy
    • 19. Anatomy
    • 20. Staging/Anatomy
      • Outside to Inside:
      • Skin
      • Tunica dartos
      • External spermatic fascia
      • Cremaster muscle
      • Internal spermatic fascia
      • Parietal layer of tunica vaginalis
      • Visceral layer of tunica vaginalis
      • Tunica albuginea
    • 21.
        • Regional nodes:
          • Interaortocaval, para-aortic, paracaval, preaortic, precaval, retroaortic, retrocaval
      Staging/Anatomy
    • 22. Staging/Anatomy
    • 23. AJCC Staging
    • 24.
      • R: testicular v.  IVC below renal v.  interaortocaval LNs
      • L: testicular v.  L renal v.  paraaortic LN
      • Both beyond renal v.  cysterna chyli  retrocrural or mediastinal LAD
      • Inguinal surgery may redirect drainage through iliac nodes
      Lymphatic Drainage
    • 25. Prognosis/Treatment Paradigm
      • Stage 0: RT alone
      • Stage I: 98%
        • Orchiectomy + inguinal/para-aortic+ipsi iliac RT
        • vs. Orchiectomy + 1C AUC7 Carboplatin
        • vs. Surveillance
      • Stage IIA,B: 91%
        • Orchiectomy + inguinal/para-aortic+ipsi iliac RT
        • vs. Orchiectomy + 4C EP vs. 3C BEP
      • Stage IIC, III: 75%
        • 4C EP vs. 3C BEP
    • 26.
      • Surveillance/Risk Adapted Management
        • Toronto, 2005 & Spanish GCT Group studies
      • RT Dose
        • MRC Trial TE 18 - Jones WG et al. JCO. Feb 2011
      • RT Field Size
        • MRC Trial TE 10 - Fossa SD, JCO. 1999
      • Stage 1 Seminoma: RT vs. Chemo
        • MRC TE19/EORTC 30982 - Oliver RT et al. Lancet. 2005
      • Stage 2 Seminoma
        • RT: Tubingen German Trial - Classen J. JCO. 2003
        • Chemo: Spanish GCT Group Garcia-Del-Muro X, JCO. 08’
      Literature
    • 27. Stage 0 (Carcinoma in situ of the testes)
      • Testicular intraepithelial neoplasia (TIN)
      • 70% risk of invasive Ca at 7yrs
      • Chance of pt w/ h/o testicular Ca to develop 2nd testic 1  ~ 3%
      • Historically well controlled w/ 20Gy/10fx
      • RT assoc w/25% androgen deprivation (~4%/yr)
      • Peterson 2008 JCO, Classen Br J Ca 2003
        • De-escalation to (-)
        • androgen decrement
        • showed no clear dose–
        • response relationship
        • 14Gy resulted in more
        • relapses indicating that
        • 20Gy is still optimal
      Lancet. 1986 Mar 15;1(8481):624-5. RT treatment of carcinoma-in-situ of testis. von der Maase H, Giwercman A, Skakkebaek NE. "Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis." (Petersen PM, J Clin Oncol. 2002 Mar 15;20(6):1537-43.)
    • 28. Stage 1: Surveillance/Risk Adapted f/u
      • Factors predictive of relapse: (Warde 02’)
        • Tumor Size (≤4 cm v >4cm , HR 2.0; 95% CI 1.3-3.2)
        • Invasion of rete testis (HR 1.7; 95% CI 1.1-2.6)
      • Prospective Validation
        • 2 nd Spanish Germ Cell Ca Group Study
        • 3 rd Spanish Germ Cell Ca Group Study
      "Risk-adapted management for patients with clinical stage I seminoma: the 2 nd Spanish GC COG study." (Aparicio J, J Clin Oncol. 2005 Dec 1;23(34):8717-23. "Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma." (Choo R, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):736-40.) "Risk-Adapted Treatment in Clinical Stage I Testicular Seminoma: The Third Spanish Germ Cell Cancer Group Study." (Aparicio J, J Clin Oncol. 2011 Oct 31. Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis. J Clin Oncol 20:4448-4452, 2002 Historical Series Toronto Series No RF >1 RF Surveillance 2C AUC 6 Carboplatin 6% Relapse 3.3% Relapse EP 96.2% OS 93.4% OS EP 0-1 RF 2 RF Surveillance 2C AUC 6 Carboplatin 7% Relapse 1.4% Relapse EP, P or RT 98% 3yr DFS 88% 3yr DFS EP, P, or RT 100% OS 100% OS
    • 29. Stage 1: Chemotherapy
      • Steiner et al 2002
        • 2C Carboplatin AUC 7  2% Relapse at 5 yrs
      • Dieckmann et al in 2000
        • 1C Carboplatin AUC 7  8% RR at 4 yrs
    • 30. Stage 1: Radiotherapy Dose
      • MRC Trial TE 18 2005 – Randomized Prospective Phase 3
      • Moderate/Severe lethargy - NS @ 12wks
      • 20 Gy / 10 fx Sufficient
      30Gy/15fx 313 ptnts 20Gy/10fx 312 ptnts QOL Assessment 10% (-) Ability to do work baseline 11 Relapses 10 Relapses Radical Inguinal Orchiectomy SS SS NS P value 28% 5% 97 20 Gy 46% 20% 97 30 Gy Acute Ability to Work Acute Lethargy DFS Treatment
    • 31. n = 236 n = 242 PA DL Stage 1: Radiotherapy Field Size "Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group." (Fossa SD, J Clin Oncol. 1999 Apr;17(4):1146.)
      • MRC Trial TE10 – Prospective Randomized Study
      30 Gy DL 30 Gy PA 9 relapses 0 DL 9 relapses 4 Pelvic PA Radical Inguinal Orchiectomy 100% OS 98% OS
      • Sperm Count:
      • PA11% vs. DL35%
      • Acute tox:
      • PA<DL
      Paraaortic Sup: T10-11 Inf: L5-S1 Lateral: 2 cm on vertebral bodies. - If L-sided 1o, give 1-cm border on L renal hilum & SI joint.
    • 32. Stage 1: Radiotherapy Field Size
      • Additional Field Considerations
        • If prior HerniorrhaphyOrchiopexy: consider coverage of contralateral inguinal region, as there may be altered lymphatic flow
        • If Scrotal OrchiectomyBiopsy: Inguinal and hemiscrotum must be covered
        • If scrotal invasion  Tx ipsi hemi-scrotum
        • Blocking : If Pt desires to preserve fertility, scrotal shield blocking of contralateral testis should limit dose to <1%, but document with TLDs
          • Clamshell reduces testicle dose by 2-3x
        • Kidneys should be limited to at least 70% <20Gy
    • 33. Stage 1: Radiotherapy vs. Chemo
      • MRC Trial TE19/EORTC 30982 – Prospective Randomized Study
      Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005 Jul 23-29;366(9482):293-300.
      • 2 nd Testicular Ca:
        • RT 15 vs. 2 Carbo
      • RT arm: 1 death from seminoma
      1C Carbo AUC7 RT 20-30Gy PA or DL 5yrs RFS 94.7% 5yrs RFS 96% Radical Inguinal Orchiectomy
    • 34. Stage 1: Radiotherapy vs. Chemo
      • Chemo
        • Advantages
          • 1-2 C of chemo w/high disease control rates
        • Disadvantages
          • More costly long term
          • Higher rate of salvage
          • Higher risk of secondary blood cancers
      • Radiotherapy
        • Advantages
          • 10 days to long term disease control
          • Long term f/u schedule more convenient
        • Disadvantages
          • Less costly long term
          • Systemic relapse can be treated relatively easily w/1-2C of chemo
      Adjuvant Radiation vs. Observation: A Cost analysis fo Alternate Management Schemes I Early Stage Testicular Seminoma. JCO 1996
    • 35.
      • Stage I Surveillance
        • Yr 1-3: H&P, all tumor marker labs q 3-4 mo
        • Yr 4-7: “” q6 mo
        • Yr >7: “”qYr
        • CT A/P each visit. CXR alternate visits
      • Post RT for Stage I
        • Yr 1: H&P, all tumor marker labs, & CXR q3-4mo
        • Yr 2: q6 mo
        • Yr>2: Annually
        • Pelvic CT annually for 3yrs for PA-only RT
      • PET/CT can predict viable tumor if postchemo residual disease
      Seminoma Stage 1- Management
    • 36.
      • Accounts for ~15% of patients with seminoma are Stage II
      • Tx Options:
        • Orchiectomy + inguinal/para-aortic+ipsi iliac RT
        • vs. Orchiectomy + 4C EP vs. 3C BEP
      • Historically tx’d w/XRT w/ RFS of 85-94% & CSS 91-100%
        • Bulky (>5cm) LNs have poor 5yr DFS: 65% w/RT alone w/5 yr OS 77%
        • Lifetime risk of DM ~ 50% w/bulky LN
      Stage 2A/B: Tx Options
      • No more Prophylactic Mediastinal RT as assoc w/survival
      • decrement
      • Most common relapse site:
          • If RT: SCV fossa or mediastinum
          • If Chemo: Retroperitoneum
          • Platinum based chemo is able to salvage >80%
          • of relapses
    • 37. Stage 2A/B: RT Alone
      • Classen JCO 2003
        • – Prospective Randomized Study
      • 31% of patients had protocol violations related to staging
      • All but 5 were treated w/limited volume high hockey sticks
      • If 2-5cm LA @ L4 or lower, consider tx bilat pelvis.
      66 ptnts - Stage2a 30Gy PA 21 ptnts - Stage2b 36Gy PA 6yrs RFS 95% 5yrs RFS 89% Radical Inguinal Orchiectomy
    • 38.
      • Stage IIA 5yr PFS 100%
      • Stage IIB 5yr PFS 87%
      • Stage II 5yr OS 95%
      Stage 2A/B: Chemo Alone
      • Spanish GC Ca Group, 2008 – Prospective Non Randomized Study
      60 ptnts - 4C PE 12 ptnts -3C BEP 5yrs PFS 100% 5yrs PFS 87% 72 Patients Radical Inguinal Orchiectomy 100% RR 83% CR 17% PR
    • 39.
      • Nodes > 5 cm
      • Only 300-400 pts annually in US
      • If nodes are greater than 10 cm recurrence rate is >40%
      • Tx:
        • RT alone has RR & difficulty avoiding liver & kidney >30% so chemo is 1st choice
        • RT indications= Consolidative tx for residual mass >3cm, 2 mo following Chemo – review PET
        • Primary RT be used for IIC dz when doesn’t overlap most of 1kidney/too much liver
        • Most fail distant and not local
      • Chemotherapy regimens include
        • Good Prognosis:
          • 4 cycles EP – Etoposide 100 mg/m2, Cisplatin 20 mg/m2 (d1-5 q3 wks)
          • 3 cycles BEP – Add Bleomycin 30 units wkly (d1,8,15)
        • Poor Prognosis:
          • X cycles BOMP-EPI
            • BOMP: (Bleo 30mg, Vinc2 mg, MTX 300mg/m2 & Cis 100mg/m2 (BOMP),
            • Alt after a 14d interval w/EPI: Etop 120mg/m2 d1-4, Ifos 1.3g/m2 d1–4 & Cis 25mg/m2 d1–4 (EPI).
            • BOMP admin 21 days after the EPI. Bleomycin admin qwk for 12 weeks. for poor prognosis GCTs
        • 80% of pts will have residual mass at 1 month
      Stage 2C/3 Seminoma Germà-Lluch JR, Garcia del Muro X, Tabernero JM, Sánchez M, Aparicio J, Alba E, Barnadas A. BOMP/EPI intensive alternating chemotherapy for IGCCC poor-prognosis germ-cell tumors: the Spanish GCT Group experience (GG). Ann Oncol. 1999 Mar;10(3):289-93. PubMed PMID: 10355572.
    • 40.
      • Acute nausea, vomiting, diarrhea
      • If PMI field then pericardits, mycardial fibrosis, conduction defects, valve deficits are possible
      • Chemo side effects
        • BEP causes immediate azospermia, >50% recover sperm count
        • Infertility
        • 50% subfertile on presentation
      Seminoma Tx Acute Effects
    • 41.
      • Late small bowel obstruction, chronic diarrhea, PUD (<2% w/<35 Gy)
      • Cardiac dz (Valve defects, CAD)
      • Fertility, 2nd malignancyAzospermia – Severity: (After RT 30% able to have children)
      • - after 1.5-2 cGy Minimal
      • - after 2-5 cGy 30-50% azospermia, baseline in 6-8 mo’s
      • - after 5-10 cGy 50-80% azospermia, baseline in 8-14 mo’s
      • - after 10-20 cGy >90% azospermia, baseline in 1-2 yrs
      • - after >20 cGy Permanent azospermia
      Seminoma Radiotherapy Late Effects
    • 42. Seminoma Radiotherapy Late Effects
      • Cardiac Death following Prophylactic Mediastinal Irradiation (PMI)
    • 43. 2nd malignancy in 29K ptnts tx’d for Testicular Ca (JNCI 1997) 15 yrs: ~ 8% (1/2 outside RT field) - NCI 25yrs: ~ 16% (testicular Ca) vs 9% (controls) 30yrs: ~ 23% (testicular Ca) vs 14% (controls) @40 yrs: ~ 36% (Seminoma) (Travis et al. 05’) Testicular Radiotherapy 2 nd Ca
    • 44. 2nd malignancy in 29K ptnts tx’d for Testicular Ca (JNCI 1997) Increased RR of solid cancers for: RT (RR=2.0) Chemo alone (RR=1.8) Both (RR=2.9) Increased RR of blood cancers for: RT (RR=4.27) Chemo alone (RR=16.24) Both (RR=3.61) Testicular Radiotherapy 2 nd Ca
    • 45. Seminoma: Tx Recommendations Chemo 20/10 RT 5 yr RFS 79%, 10yr 58% Androgen supplementation Stage 0 5 yr RFS 100% 2C Carbo AUC7 RT 20Gy PA 5yrs RFS 98% 5yrs RFS 96% Stage 1 Radical Inguinal Orchiectomy
      • Post RT for Stage I (if post Chemo then yr1-3 q4mo)
        • Yr 1: H&P, all tumor markers & CXR q3-4mo
        • Yr 2: q6 mo
        • Yr>2: Annually
        • Pelvic CT annually for 3yrs for PA-only RT
      Surveillance 5yrs RFS 93% 0-1 RF
        • Yr 1-3: H&P, tumor marker labs q 3-4 mo
        • Yr 4-7: “” q6 mo
        • Yr >7: “”qYr
        • CT A/P each visit. CXR alternate visits
      Stage2a 20Gy DL or PA  30Gy Gross Dz Stage2b 20Gy DL or PA  36Gy Gross Dz 6yrs RFS 95% 5yrs RFS 89% Radical Inguinal Orchiectomy 4C PE or 3C BEP 6yrs RFS 89-95% 100% RR 83% CR 17% PR PET  Consider Stage 2A/B Radical Inguinal Orchiectomy Stage 2C/3 4C PE or 3C BEP 6yrs RFS 89-95% 100% RR 83% CR 17% PR PET  Consider RT Salvage should be considered for all Stage 2/3 Seminoma: 30Gy to all PET+ Gross Disease **Remember Spermatocytic can be treated w/Orchiectomy alone
    • 46.
      • MRC/EORTC: Phase 3 - Radiation Therapy Compared With Chemotherapy in Treating Patients With Stage I Testicular Cancer
      • Arm I: Patients receive a single dose of carboplatin IV.
      • Arm II: Patients undergo radiotherapy once daily, 5 days a week. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.
      • PROJECTED ACCRUAL: Completed Accrual at 800 patients
      Seminoma: Current Trials
    • 47. End
    • 48. Observation
      • Advantages
        • For Stage I post orchiectomy recurrence 12%-30%
        • We can save >70% of individuals from a toxic therapy
        • Cause specific survival ~ 100% at 5 years
    • 49. Toronto 2005
      • Choo et al.
      • Prospective, single arm.
      • 88 stage I patients managed by radical inguinal orchiectomy alone
      • 20% rete testis invasion, 45% >4cm
      • FU 12.1 year median
    • 50.
      • Outcome
      • RFS 5-yrs 83%, 10-yrs 80%, 15-yrs 80%
      • Relapse site: 88% (15/17) below diaphragm
      • Salvage: 14/17 RT, 3/17 chemo-RT
        • 1 had second relapse, further salvaged by chemo
      • All 17 remained disease free after salvage
      • Conclusion: Surveillance is a safe alternative
    • 51.