Presentation on theme: "Management Strategies for Stage I germ cell tumours"— Presentation transcript:
1 Management Strategies for Stage I germ cell tumours Professor Gordon J S RustinDirector of Medical OncologyMount Vernon HospitalNorthwood, MiddlesexEngland
2 Testicular Germ Cell Tumours Approximately 2000 new cases per year in UK (population )70% of seminomas and 50% of NSGCTs are diagnosed at stage I
3 Considerations in initial management Is a testicular cancer present?Are there metastatses?Is there carcinoma in situ in contralateral testis?If there are bilateral tumours is partial orchidectomy an option?
4 Initial managementWidespread malignancy refer for immediate chemotherapyNo evidence of spread inguinal orchidectomy.Biopsy of contralateral testicle should be considered if there is a high risk of carcinoma in situ eg. small testis (<12ml), and in patients < 30 years.SJ Harland. Eur Urol 1993 n= % pts had CIS in contralateral testis. Increased risk of CIS in clinically atrophic testes, but NOT in maldescent. Pts found to have CIS were younger < 30Complete post – op staging, CT chest/abdo/pelvisPost –op tumour markers if raised pre-op. Should fall according to half life – (4-6 days for AFP, 24 hours for HCG)
5 Points to consider in managing stage 1 germ cell tumours Seminomas spread predictably, firstly to the para-aortic lymph nodes and subsequently to the supra-diaphragmatic LNs and on to other metastatic sites.NSGCT spread more randomly with blood borne mets occuring earlier than with seminomaNSGCT produce AFP and/or HCG in 75% of casesSeminomas produce HCG in only 25% of casesLDH is non-specific. In our series of 494 patients who relapsed on surveillance over a 10 year period, the LDH alone did not identify any of these.
6 Management of carcinoma in situ 50% of patients with CIS will develop invasive tumours within 5 years from diagnosis.Low dose XRT (20 Gy in 10#s) to the testis eradicates CIS, relapses with lower dosesLeydig cell function increasingly impaired at doses > 17 GyLong term hormone replacement therapy may be necessary
7 Possible prognostic factors for stage 1 germ cell tumours SEMINOMASSize of tumour (J Clin Onc 2002, Warde et al)Invasion into the rete testisAgeSmall vessel invasionHistological subtype – classical vs anaplasticDNA ploidy statusMitotic countDNA S-phase %SyncitiotrophoblastsDegree of lymphocytic infiltration of primary tumourExpression of HCG and low MW keratin on immunohistochemistryTERATOMASLymphovascular invasionEmbryonal ca histology in primary tumourMIB- 1 monoclonal ab – marker of proliferative activityMitotic count
8 Options for management of stage I Seminomas Adjuvant radiotherapyAdjuvant chemotherapySurveillance
9 1980’s Management of stage I seminoma 20% will recur after orchidectomy90% relapse in para-aortic nodesTraditionally adjuvant treatment with radiotherapy to para-aortic and ipsilateral iliac nodes in a “dog leg” field. (28-30 Gy)
10 Late Morbidity from Radiotherapy Second CancersCardiac eventsPeptic ulcerationInfertility
11 Relative risks for second primary cancers (NB Relative risks for second primary cancers (NB. RR of contralateral testis ca is 35.7!)1.725Colon1.316Rectum2.2Kidney1.847Other skin5Melanoma1.042Lung1.121Prostate2.137Bladder15Pancreas1.924Stomach2.313Leukaemia1.5337All sitesRRn
13 Strategies to reduce radiotherapy morbidity Reduction of radiation field sizeMRC TE patients randomised to traditional dog-legor para-aortic radiotherapyReduction in doseMRC TE patients randomised to 30 Gray in 15 # over 3 weeks or 20 Gray in 10 # over 2 weeks
14 MRC TE10 (Fossa et al 1999)Survival at 3 years, 99% for PA vs 100% for DLRFS 96% PA vs 96.6% DLAcute toxicity ( nausea, vomiting, leukopaenia) was less frequent and less severe in PA groupWithin the first 18/12 of F/U the sperm counts were significantly higher after PA than after DL radiotherapy.CONCLUSION: Adjuvant radiotherapy confined to the paraaortic LNs is associated with decreased haematologic, GI and gonadal toxicity, but with a higher risk of pelvic recurrence compared with dog-leg radiotherapy.
15 MRC TE 18 (Jones et al 2001 & 2005) Therefore: At median follow-up of 4 years2 year relapse free survival 97.7% after 30Gy97% after 20GyBetter Quality of Life scores for acute effects in lower dose armTherefore:Standard radiotherapy for stage 1 seminoma should be:20 Gy in 10 # over 2 weeks to para-aortic stripunless previous inguino/pelvic/scrotal surgery when “dog-leg” field.
16 Can chemotherapy replace radiotherapy for stage 1 seminoma Can chemotherapy replace radiotherapy for stage 1 seminoma ? TE19 / EORTC 30982Randomised comparison of single agent carboplatin AUC 7 with radiotherapy in adjuvant treatment of stage 1 seminoma following orchidectomy.carboplatinn= Gy/15#sRadiotherapy20Gy/10#s
17 TE 19 Radiotherapy vs carboplatin : Relapse Free Rate RFR at 2 years at 3 yearsR96.7% (95%, 98%)95.9% (94%, 97%)C97.7% (96%, 99%)94.8% (93%, 96%)Absolute differenceR - C =-1.0% (-2.5%, 0.5%)1.1% (-1.0%, 3.2%)HR based CI for differenceR – C =0.9% (-0.5%, 3.0%)1.1% (-0.6%, 3.7%)
19 Late Morbidity from Chemotherapy InfertilitySecond TumoursCardiovascular damage
20 Prognostic Factors for seminomas on surveillance ( Warde et al 2002) 121 of 638 patients relapsed at a median follow up of 7 years (Relapse free survival 82%)On multivariate analysis:Tumour size <4cm vs >4cm, hazard ratio 2 Invasion of the rete testis, hazard ratio 1.75 year recurrence rateBoth risk factors 32%Single risk factor 16%No risk factors 12%
21 Post orchidectomy surveillance vs carboplatin for stage 1 seminoma – Spanish germ cell cancer cooperative group; Ann oncol 2003N = 20360 pts with tumour >4cm or lymphovascular invasion given 2 x carboplatin143 pts with no risk factors put on surveillance5 yr DFS 83.5% in surveillance pts and 96.6% in carbo grp. All salvaged with 3 or 4 cycles of BEP5 year OS 96.7%. Cause specific survival 100%
22 Conclusion on management of stage 1 seminomas Almost 100 % of patients with stage 1 seminoma are cured regardless of approach chosen as post orchidectomy therapy.Adjuvant radiotherapy or chemotherapy are both as effective at reducing relapse rates.However with a relapse rate of 15-20%, and a 5 year survival of 97.7%, surveillance may be considered an alternative “treatment” option.Identification of prognostic factors for relapse on surveillance will allow clinicians to recommend the most appropriate therapy for individual patients.Current recommendations – tumours <4cm and absence of rete testis invasion – RR 12% - surveillance. Tumours >4cm and presence of rete testis invasion – RR 35% offer adjuvant therapy
25 Surveillance programme MVH - NSGCTs Month123456789101112182436OPDXCXRMarkersxxCT Chest/ abdo/ pelvisMarkers currently HCG, AFP and LDHFollow up for 10 years
26 Advantages of Surveillance for Low risk NSGCT >80% avoid any chemotherapy or RPLND>80% avoid risk of 2nd tumours>80% avoid risk of cardiovascular damage>80% avoid risk of infertility
27 Disadvantages of surveillance for NSGCT More frequent clinic visits and blood testsGreater diagnostic radiation (10 body CT scans induces 1% 2nd tumours)Anxiety of follow -upConcern about non-attendance
28 MRC TE08 trial of surveillance intensities Currently a wide variation in the intensity of surveillance programs between hospitalsConcern about high levels of radiation produced by CT scansAlternative methods need to be found to determine relapse during surveillanceFrequency of CT scans needs to be kept to a minimum
29 Histologically confirmed Study DesignHistologically confirmedStage I NSGCTRandomise5 CT scansChest and abdomen CT at 3 monthsChest and abdomen CT at 6 monthsChest and abdomen CT at 9 monthsChest and abdomen CT at 12 monthsChest and abdomen CT at 24 months2 CT scans3:2 randomisation in favour of 2 CT arm
30 Lack of value of chest CT scans in surveillance of Stage I NSGCT 168 patients 42 (25%) relapsed8/42 (19%) intrathoracic relapseAll 8 had abnormal CXR at relapse7/8 also had elevated AFP and or HCG(Harvey et al Annals Oncol 13: , 2002)11
31 183 stage 1 GCT on surveillance: Initial Presenting Factors among 52 relapses (Francis et al EJC 2000)Symptoms Tumour MarkersRadiology (total/no. NSGCT/no. seminoma)4/3/124/21/33/2/13/3/015/8/73/3/018/12/6
32 Adjuvant BEP chemotherapy for high risk NSGCT (Cullen et al 1996) 2 courses Bleomycin 30,000 units day 2, 8, 15, Etoposide 120 mg/m2 days 1-2, Cisplatin 50 mg/m2 day 1&2Reduces risk of relapse to <3%
33 MRC Trial TE22: Study of FDG PET in the prediction of relapse in patients with high risk stage 1 NSGCT108 patients registered by78/96 (81%) PET scans negative, 77/78 chose surveillanceExpected relapse free rate for high risk ~60% at 2 yearsAnticipated relapse free rate for PET –ve patients ~90% at 2 years (90%CI >80%)Interim analysis 12 month relapse free rate in 77 PET –ve patients 65% (90% CI 53-74%) at 2 years at best 70%Trial closed
35 Comparison of costs per life saved for managing stage 1 germ cell tumours (Francis et al EJC 2000) Surveillance RPLND Adjuvant chemotherapy£ £ £5851
36 Management of Stage 1 Testicualr Germ Cell tumours Many surgeons do orchidectomies,Only a few oncologists should specialise in managing GCT patientsPatients should be made aware of the different management optionsDeciding which option depends upon histology, prognosis, geography, personality, reliability, bias of the doctor, but most importantly the patient
37 Life insurance for patients treated for germ cell tumours Time withoutTime to standardExtra/£1000 yr3-4Extra year 5-6Seminoma stage11 year4 years£5Non-seminoma stage 16 years£10Stage 2 A/B2-3 years9 yearsStage 2 B, stage 33 years£15Stage 4, intermediate and poor risk3-4 years£20Temporary loading usually lasts 3-6 yearsProvided by Graham JonesUnderwriting Development Product Management & Development - ProtectionDirect line: (internal: 5736)
38 Factors for ResearchPrognostic factors to more accurately define those requiring treatment : eg. Compare by comparative genomic hybridization and expression micoarray analysis relapses versus non relapsesReduce diagnostic radiation by comparing MRI with CT scansTo better understand factors increasing incidence of germ cell tumoursTo better understand relationship of 12p isochromosome and Kit with germ cell tumours
39 STROMAL TUMOURS OF THE TESTIS Leydig, Sertoli cell, Granulosa cell or combined tumours3% of testis tumours, 10% bilateralDerive from cells making hormonesMean age 36 years10% metastasise – cannot currently be predicted from histopathology of the primary tumourtestosterone, oestradiol and androstenedione are markers (AFP and hCG are not)Resistant to conventional chemotherapy and radiotherapy.
40 .SURVIVAL FOLLOWING RPLND FOR STROMAL TUMOURS OF THE TESTIS ACCORDING TO PATHOLOGICAL STAGE.0.000.250.500.751.00.0255075100Time (months)SurvivalStage IStage II
43 Curr opin oncol 2004 n= 394 stage I seminomas, 301 stage I NSGCTs, post orchidectomy % relapse rate – 17% seminomas, 29% NSGCTs.Median time to relapse 13 months for seminomas with 49% relapsing in first year, 5 months for NSGCT, 80% relapsing in first year.54% of NSGCTs with vascular invasion relapsed and 38% of the seminomas32% of NSGCTs with embryonal ca relapsed.90% of relapses detected as routine examination, remaining 10% at patients initiative – treated appropriately with surgery/chemo/radiation10 deaths in F/u, not related to GCTOs 98.6%, cause specific survival 100%
48 Surveillance programme MVH - seminomas Month1234567891012182436OPDXCXRMarkersCT abdo/ pelvisCXR & markers performed at each clinic visit. Year 2 OPD every 2/12, Year 3 every 3/12, year 4 every 4/12, years 5 and 6 every 6/12. Yearly thereafter to 10 years. Lifetime follow-up if had XRT.
49 Management of stage I NSGCT Relapse rate after orchidectomy alone – 25%Vascular or lymphatic invasion relapse rate – 40%Surveillance – low risk patients (85% cure rate surgery alone)2 x BEP – in high risk patients with vascular or lymphatic invasion reduces relapse rate to 1%Prophylactic RPLNDJ Urol 2000 – group of high risk stage I teratomas, relapse risk 35-40% - RPLND reduced relapse risk to 23%. Comparable group given BEP x 2 – risk of relapse 3-4%. Good risk patients on surveillance with a 15-20% risk of relapse -RPLND reduces relapse risk to 5%
51 Management of Stage IIA and B seminoma Radiotherapy 30Gy in 15 fractions
52 Stage II NSGCTOngoing debate ?PRLND alone vs neoadjuvant chemo followed by surgery. German trial n=187. No difference in OS but in suregery alone group, significantly higher loss of ejaculationOldenberg et al n=87, stage II NSGCT undergoing RPLND All patients had masses < 2cm on imaging. Viable tumour found in 33% (26% mature teratoma, 7% malignant tumour), 67% fibrosis/necrosis.No clinical/serological parameters were predictive of histopath findings. CONCLUSION: RPLND recommended for all patients with masses < 2cm because of high rate of viable tumour found
53 Testicular germ cell tumours – Professor Rustin – MVH Cancer Centre
54 Testicular germ cell tumours Professor Rustin – MVH Cancer Centre
59 1-1.5% of male neoplasmsMost common tumour in men aged yrs.Incidence has doubled in last 20 yearsOne of the few solid tumours which is completely curable even after it has metastasized with an overall survival of 90%70% of seminomas and 50% of NSGCTs are diagnosed at stage I