Germ Cell Cancer Edinburgh Oncology Course May 2010

1. Germ Cell Cancer Edinburgh Oncology CourseMay 2010 Dr Jeff White Consultant Medical Oncologist, The Beatson West of Scotland Cancer Centre

2. �a model for a curable neoplasm� Whilst this group of tumours do as often quoted as a model of a curable neoplasm emphasis particularly in this age group has to be given to reducing need for treatment in those who do well and thus sparing long term effects and increasing cure rates for those few that fall into a bad prognostic group. Although we talk about testicular cancer these tumours are derived from primodial germ cells and thus the term germ cell caner should be strictly speaking applied. This explains why they can occur anywhere in the body but usually in midline; sacrum, retroperitoneal, mediastinal, pineal region and in females and with a variety of different cell types. Whilst this group of tumours do as often quoted as a model of a curable neoplasm emphasis particularly in this age group has to be given to reducing need for treatment in those who do well and thus sparing long term effects and increasing cure rates for those few that fall into a bad prognostic group. Although we talk about testicular cancer these tumours are derived from primodial germ cells and thus the term germ cell caner should be strictly speaking applied. This explains why they can occur anywhere in the body but usually in midline; sacrum, retroperitoneal, mediastinal, pineal region and in females and with a variety of different cell types.

3. Indiana Beatson WOSCC

4. 2065 new patients yearly (2000) 6.9 per 100,000 population 1-2 % all male cancers, but commonest cancer in young men (http://info.cancerresearchuk.org/cancerstats/types/testis/incidence/index.htm) 58 deaths/year (2007) 2 per 1,000,000 population (http://info.cancerresearchuk.org/cancerstats/types/testis/mortality/index.htm) Globally incidence is rising (International Journal of Cancer Feb 2005) EPIDEMIOLOGY - UK More common in white compared to black populations More common in white compared to black populations

5. EPIDEMIOLOGY - SCOTLAND Incidence ranked 16th Percentage frequency of all cancers = 1.3% Number of new cases diagnosed in 2007 = 172 Number of deaths recorded in 2008 = 8 Change in incidence from 1997 to 2007 = +0.2% 1 year relative survival for patients diagnosed between 2000 and 2004 = 98.3% 5 year relative survival for patients diagnosed between�2000 and 2004 = 97.2% These figures are for all age groups This of course may simply reflect better registry data in the UK and Scotland. These figures are for all age groups This of course may simply reflect better registry data in the UK and Scotland.

6. EPIDEMIOLOGY - SCOTLAND

7. EPIDEMIOLOGY - SCOTLAND Cancer incidence rates per million years at risk in persons aged 15-24 years in Scotland, 1976-2000 Significantly commoner in 20-24 age group Significantly commoner in 20-24 age group

8. EPIDEMIOLOGY - SCOTLAND Incidence rates are increasing over time in teenagers and young adults These figures in the later part of the 20th century are higher than those quoted for the entire UK and other European regions and significantly higher than in underdeveloped countries . Stiller Cancer Treatment Review 2007; 33, 631-645. Incidence rates are increasing over time in teenagers and young adults These figures in the later part of the 20th century are higher than those quoted for the entire UK and other European regions and significantly higher than in underdeveloped countries . Stiller Cancer Treatment Review 2007; 33, 631-645.

9. AETIOLOGICAL FACTORS Clear link to cryptorchism (maldescent) up to 8 fold risk orchidopexy aged < 13 RR = 2.23 compared 5.4 > 13 Carcinoma-in-situ Histological precursor Familial risk (9.8 times general pop. risk) testicular cancer gene recently identified, pattern fits dominant gene of low penertrance Genetics Chromosome 12p, extra copies, c-KIT mutations, MSI Caucasian Contra lateral disease Mumps/orchitis? Down�s syndrome and Klienfelters Biologically the germ cell cancer occurring in young males may be slightly different from those of older men as they often lack the iso-chromosome on short arm of chromosome 12 Micro satellite instability is associated with shorter time to recurrence and platinum resistance The familial aspects of germ cell cancer are been investigated in current NCRN studies. The UK Genetics of Testicular Cancer Study Biologically the germ cell cancer occurring in young males may be slightly different from those of older men as they often lack the iso-chromosome on short arm of chromosome 12 Micro satellite instability is associated with shorter time to recurrence and platinum resistance The familial aspects of germ cell cancer are been investigated in current NCRN studies. The UK Genetics of Testicular Cancer Study

10. CLINICAL PRESENTATION

11. PRE-CHEMOTHERAPY WORK UP Audiogram PFTS Sperm storage (needs virology testing) Creatinine Clearance (Calc/EDTA) CXR CT CAP +/- CT or MRI Brain Consent needs to be tested for blood borne viruses Though < 10% of survivors ever use the semen needs to be tested for blood borne viruses Though < 10% of survivors ever use the semen

12. SEMINOMA TERATOMA (+/- SEMINOMA) Referred to as Non-Seminomatous Germ Cell Tumours (NSGCT) Malignant Teratoma Undifferentiated (MTU) Malignant Teratoma Intermediate (MTI) Malignant Teratoma Trophoblastic (MTT) Yolk sac Teratoma (TD) Other/combinations PATHOLOGY

13. PATHOLOGY

14. PATHOLOGY

15. Stage I: Limited to testis Invasion of cord/vessels has prognostic implications Stage II: Metastatic Retroperitoneal lymphadenopathy Stage III: Metastatic Retroperitoneal + surpadiaphragmatic lymphadenopathy Stage IV: Metastatic Parenchymatous

16. CONTRALATERAL TESTIS Ideally: biopsy at time of orchidectomy, with aim of diagnosing carcinoma-in-situ if carcinoma-in-situ present, discuss prophylactic RT, since at least 50% risk of developing invasive cancer in subsequent years If not done initially, consider biopsy in stage I patients on surveillance only with history of maldescent testicular atrophy, infertility, low sperm count/viability age <30 yrs

17. TUMOUR MARKERS Diagnosis Prognosis Monitoring response to therapy Monitoring remission We shall see some examples of these situations soon We shall see some examples of these situations soon

18. Alphafetoprotein (AFP) Produced from foetal yolk sac, liver, intestine Undetectable in adult life Produced by many tumour types Levels >10,000 indicate NSGCT/hepatocellular cancer Elevated in 70% teratoma patients Half life 4.5 days TUMOUR MARKERS

19. Beta human chorionic gonadotrophin (?HCG) Produced in pregnancy, gestational disorders Also produced by many cancers Associated with hyperthyroidism and gynaecomastia Levels >5,000 in males indicates GCT Produced by trophoblastic elements Elevated in 35% seminoma patients, 70% teratoma Half life < 24 hours Plasma:CSF ratio <60:1 can indicate CNS disease TUMOUR MARKERS

20. Lactate dehydrogenase (LDH) Produced by skeletal muscle Produced by many tumour types 5 isoenzemes; hydroxybutyrate dehydrogenase commonly elevated in teratoma and seminoma indicator of tumour bulk Independent prognostic marker Half-life 24 hours TUMOUR MARKERS

21. TUMOUR MARKERS

22. TUMOUR MARKERS

23. STAGE I SEMINOMA Standard of care is adjuvant radiotherapy 30Gy to �dog-leg� field (Fossa, 1999) Questions:- Can the dose of radiotherapy be decreased to lessen acute toxicity without increasing relapse? As the excess risk of second malignancy after XRT is well described, is chemotherapy a valid alternative? MRC level Ib evidence; 3y survival 99-100% 2-3-fold excess relative risk MRC level Ib evidence; 3y survival 99-100% 2-3-fold excess relative risk

24. STAGE I SEMINOMA �Answers�:- Yes, decreased dose of radiotherapy to 20Gy is not associated with increased mortality and reduced albeit low GI toxicity and fatigue (MRC Trial TE18, Jones et al, 2001) Single cycle of Carboplatin AUC7 is as efficacious as radiotherapy, less acute toxicity and faster return to work (Oliver, Lancet, 2005. 366(9482): p. 293-300) What about surveillance? Subject of TRISST study TE18 Level Ib; MRC trial of 600pts Other studies have looked at 2 cycles of lower dose carboplatin Risk of relapse up to 30 % if rete testis involved and > 4 cm primary around 15 % for one factor Use of surveillance has been extensively performed by the Canadians. A recent paper for give guidance for the frequency and type of imaging to be used in follow- up according to the adjuvant strategy applied i.e. a risk adapted strategy to minimise the exposure to radiation etc. TE18 Level Ib; MRC trial of 600pts Other studies have looked at 2 cycles of lower dose carboplatin Risk of relapse up to 30 % if rete testis involved and > 4 cm primary around 15 % for one factor Use of surveillance has been extensively performed by the Canadians. A recent paper for give guidance for the frequency and type of imaging to be used in follow- up according to the adjuvant strategy applied i.e. a risk adapted strategy to minimise the exposure to radiation etc.

25. TRISST-TRIAL OF IMAGING AND SCHEDULE IN SEMINOMA TESTIS

26. STAGE I TERATOMA Confined to testis, normal markers, no metastases High and Low risk groups defined by assessment of extent of vascular/lymphatic invasion:- Reduces risk of recurrence from 45% to around 2% No level I evidence for BEP x2 but unlikely to impact on OS rates Reduces risk of recurrence from 45% to around 2% No level I evidence for BEP x2 but unlikely to impact on OS rates

27. STAGE I TERATOMA Questions:- Can the risk of second malignancy from CT scans be abrogated without increasing relapse rate in �low-risk� patients? Can the toxicity of chemotherapy (BEP) be decreased in high risk patients? Is there a more sensitive way of defining high-risk patients to avoid chemotherapy for all? RPLND?

28. STAGE I TERATOMA �Answers�:- Trial CT of scan frequency in low risk patients (TE08; 2 vs 5 scans in 2 years) CTs at 3 and 12 months only now standard of care (Rustin JCO, 2007. 25(11): p. 1310-5) BOP (substitution of etoposide by vincristine) has ? toxicity, similar progressions (Dearnaley BJC, 2005. 92(12): p. 2107-13) PET scan study in high risk patients (TE22) closed early due to a lack of ability for PET to predict relapse (Huddart JCO, 2007. 25(21): p. 3090-5) Current � 111 trial 1 BEP for high risk stage I NSGCT RCT RPLND vs BEP x 1 � surgery significantly higher RR, ? 2 year survival rate, hazard ratio for recurrence (Albers, JCO 2008 26, 2966-72) The substitution of vinc for etoposide there was no difference in relapse rate, less alopecia but more neuropathy Primary: to show that one cycle of adjuvant BEP chemotherapy results in a two year recurrence rate of less than 5% in patients with high-risk stage 1 NSGCTT. 236 patients will be recruited into this study. Etoposide does is 500 mg/m2 All patients will be given prophylactic GCSF; either pegylated G-CSF 6mg subcut on day 4 or filgrastim daily sc according to local policy. All patients will be given prophylactic antibiotics; either levofloxacin 500mg po (recommended) on days 8 to 15 or ciprofloxacin 500 mg bd on days 8 to 15. The substitution of vinc for etoposide there was no difference in relapse rate, less alopecia but more neuropathy Primary: to show that one cycle of adjuvant BEP chemotherapy results in a two year recurrence rate of less than 5% in patients with high-risk stage 1 NSGCTT. 236 patients will be recruited into this study. Etoposide does is 500 mg/m2 All patients will be given prophylactic GCSF; either pegylated G-CSF 6mg subcut on day 4 or filgrastim daily sc according to local policy. All patients will be given prophylactic antibiotics; either levofloxacin 500mg po (recommended) on days 8 to 15 or ciprofloxacin 500 mg bd on days 8 to 15.

29. ADVANCED CANCER International Germ Cell Cancer Collaborative Group (IGCCCG) classification :- based on marker levels (incl. LDH); presence/absence of visceral metastases; site of primary comprises good, intermediate and poor risk categories applies to both teratoma and seminoma Largest retrospective study based on international collaboration, 6000 patients receiving first line chemotherapy Nadir markers post orchidectomy (if performed) or @ start of chemotherapy)Largest retrospective study based on international collaboration, 6000 patients receiving first line chemotherapy Nadir markers post orchidectomy (if performed) or @ start of chemotherapy)

30. PROGNOSIS BY IGCCCG GROUP

33. BEP 5 day Note total VP16 dose 500mg/m2 = US standard; 360mg/m2 �European� dosingNote total VP16 dose 500mg/m2 = US standard; 360mg/m2 �European� dosing

34. GOOD PROGNOSIS TERATOMA BEP x 4 is standard regimen (Williams et al, NEJM 1987, 316:1435-40) and cures 96% patients in this subgroup. Questions:- How many cycles are required (i.e. reduce toxicity esp 2nd malignancy from etoposide)? Can we omit bleomycin without compromising efficacy? Can we substitute carboplatin for cisplatin (and therefore make it easier for the patient)?

35. HOW MANY CYCLES? Ref. Regimen �Winner� Einhorn 3 BE500P vs 4 BE500P N/S JCO 1989 7(3), 387-391 ? toxicity with 3 De Wit 3BE500P vs 4 BE500P N/S in OS, PFS JCO 2001 19(6), 1629-37 Toner 3 BE500P vs 4 BE360P 3 BE500P Lancet 2001 357(9258), 739-45 3 cycles may be associated with better QoL The bottom line is that 3 cycles of 3 day BE500P is the standard of care for good prognosis metatstatic disease. 3 cycles may be associated with better QoL The bottom line is that 3 cycles of 3 day BE500P is the standard of care for good prognosis metatstatic disease.

36. BEP 3 day Note total VP16 dose 500mg/m2 = US standard; 360mg/m2 �European� dosing Efficacy is equal to 5 day regime in good prognosis disease but 3 day is associated with greater GI toxicity and tinnitus Fossa, S.D. (30941/TE20). J Clin Oncol, 2003. 21(6): p. 1107-18. Note total VP16 dose 500mg/m2 = US standard; 360mg/m2 �European� dosing Efficacy is equal to 5 day regime in good prognosis disease but 3 day is associated with greater GI toxicity and tinnitus Fossa, S.D. (30941/TE20). J Clin Oncol, 2003. 21(6): p. 1107-18.

39. OMISSION OF BLEOMYCIN? Ref. Regimen �Winner� de Wit 4 BE360P vs 4 E360P N/S JCO 1997(1)5, 1837-43 BEP? CR rate = Survival Loehrer 3 BE500P vs 3 E500P 3 BE500P JCO 1995 13(2), 470-76 Levi 4 PVB v 4 PV 4 PVB JCO 1993 1(7), 1300-05 Culine BE500P vs 4 E500P BE500P Ann Oncol 2007 18(5), 917-24 CR rate, event free & OS = deWit - CR better with BEP but no survival difference Loehrer � EP worse all outcomes Levi � more toxicity with PVB but better survival Culine � primary end point was favourable response rate, marginally inferior OS for EP, though not powered for survival analysis Despite these studies for patients with significant risk factors for pulmonary toxicity from bleomycin 4 EP is a good suitable alternative to BEP in good prognosis metastatic disease. A recent JCO paper in fact suggests that EP is a viable alternative Kondagunta . J Clin Oncol, 2004. 22(3): p. 464-7. deWit - CR better with BEP but no survival difference Loehrer � EP worse all outcomes Levi � more toxicity with PVB but better survival Culine � primary end point was favourable response rate, marginally inferior OS for EP, though not powered for survival analysis Despite these studies for patients with significant risk factors for pulmonary toxicity from bleomycin 4 EP is a good suitable alternative to BEP in good prognosis metastatic disease. A recent JCO paper in fact suggests that EP is a viable alternative Kondagunta . J Clin Oncol, 2004. 22(3): p. 464-7.

40. CARBOPLATIN? Ref. Regimen �Winner� Horwicha 4 BE360P vs 4 CE360B 4 BE360P JCO 1997 (15)5, 1844-52 Bajorina 4 E500C vs 4 E500P 4 E500P JCO, 1993. 11(4): p. 598-606 Horwichb 3 C vs 4 EP 4 EP BJC 2000. 83(12): p. 1623-9 Clemmb 4-6 C vs 4-6 PEI PEI Horwich � CR worse, more deaths and therapy failures Bajorin � relapse rate greater with EC; survival same Horwich � PFS and OS better with EP Clemm � relapse rate with C greater It was thought that for seminomas with low volume metastatic disease that single agent carboplatin my be sufficient however individual randomised trials failed to show any difference in this group in terms of DFS rates a pooled analysis showed that single agent carboplatin was inferior Bokemeyer BJC 2004; 91 (4) 683-687 Low volume seminoma relapses up 5 cm can be adequately treated with radiotherapyHorwich � CR worse, more deaths and therapy failures Bajorin � relapse rate greater with EC; survival same Horwich � PFS and OS better with EP Clemm � relapse rate with C greater It was thought that for seminomas with low volume metastatic disease that single agent carboplatin my be sufficient however individual randomised trials failed to show any difference in this group in terms of DFS rates a pooled analysis showed that single agent carboplatin was inferior Bokemeyer BJC 2004; 91 (4) 683-687 Low volume seminoma relapses up 5 cm can be adequately treated with radiotherapy

41. GOOD PROGNOSIS  Bottom line � 3 BEP is treatment of choice. 4 EP may be used in this prognostic group, but ONLY if significant concern over pulmonary function The evidence suggests that carboplatin should not be routinely used in place of cisplatin. Next questions:- Reduce to 2 BEP? Reduce bleomycin lung toxicity by changing schedule/route of administration ongoing TE03 study good prognosis metastatic germ cell cancer the current randomised Phase III study run by the NCRN Testis Clinical studies Group is TE03 comparing infusional bleomycin on day 1-3 and the standard bolus regime on day 2, 8 and 15 . The primary end-point is the radiological �evaluation on CT of potential bleomycin induced lung changes with follow �up to see if there is any difference in long term pulmonary toxicity as there is phase II data suggesting that infusional bleomycin will cause less pulmonary toxicity. � good prognosis metastatic germ cell cancer the current randomised Phase III study run by the NCRN Testis Clinical studies Group is TE03 comparing infusional bleomycin on day 1-3 and the standard bolus regime on day 2, 8 and 15 . The primary end-point is the radiological �evaluation on CT of potential bleomycin induced lung changes with follow �up to see if there is any difference in long term pulmonary toxicity as there is phase II data suggesting that infusional bleomycin will cause less pulmonary toxicity. �

42. GOOD PROGNOSIS-SEMINOMA Stage IIA/? IIB ? XRT can be used � carboplatin

43. INTERMEDIATE RISK BEP x 4 is standard regimen (Williams et al, NEJM 1987, 316:1435-40) and cures up to 70% patients. Questions therefore concern ways to increase efficacy, rather than decrease toxicity:- Add/substitute different drugs e.g. ifosfamide, Taxol? EORTC T- BEP x 4 vs BEP x 4 - suspended 4 VIP vs 4 BEP cure rates = ? toxicity with VIP (de Wit BJC �1998 78(6) 828-826) Increase dose intensity by using gCSF support NCRN Accelerated BEP with 2 weekly cycle - completed Intermediate prognosis 4 VIP vs 4 BEP �no difference in cure rates but increased toxicity with VIP de Wit BJC �1998 78(6) 828-826 Current but temporarily suspended trial run by EORTC is testing the addition of a another relatively new drug with has shown activity refractory disease The NCRN Testis Clinical Study Group are also looking at dose intensity again by trying to short the cycle length� to 2 weekly by using pegylated GCSF to accelerate the recovery of white cell count in between each cycle Intermediate prognosis 4 VIP vs 4 BEP �no difference in cure rates but increased toxicity with VIP de Wit BJC �1998 78(6) 828-826 Current but temporarily suspended trial run by EORTC is testing the addition of a another relatively new drug with has shown activity refractory disease The NCRN Testis Clinical Study Group are also looking at dose intensity again by trying to short the cycle length� to 2 weekly by using pegylated GCSF to accelerate the recovery of white cell count in between each cycle

44. POOR RISK BEP remains standard regimen (Williams et al, NEJM 1987, 316:1435-40) but 50 % patients will not be cured Questions therefore concern ways to increase efficacy, not decrease toxicity:- Add/substitute different drugs e.g. ifosfamide, Taxol? Increase dose intensity by intensive induction/sequencing? Increase dose of cisplatin? Myeloablative chemotherapy with stem cell support These represent a challenging group of patient requiring multi-disciplinary team working. It is an area where answers are need and when ever possible patients should be entered into clinical trials Appropriate surgical management of residual retroperitoneal and other sites of disease is required. �Evidence for improved outcomes for poor prognosis patient over the years through involvement of clinical trial protocols and also there is a volume effect in outcomes are worse in situations entering < �5 patients per clinical trial protocol. Collette, L J Natl Cancer Inst, 1999. 91(10): p. 839-46. These represent a challenging group of patient requiring multi-disciplinary team working. It is an area where answers are need and when ever possible patients should be entered into clinical trials Appropriate surgical management of residual retroperitoneal and other sites of disease is required. �Evidence for improved outcomes for poor prognosis patient over the years through involvement of clinical trial protocols and also there is a volume effect in outcomes are worse in situations entering < �5 patients per clinical trial protocol. Collette, L J Natl Cancer Inst, 1999. 91(10): p. 839-46.

45. POOR RISK IMPROVING OUTCOMES

46. POOR RISK BEP remains standard regimen (Williams et al, NEJM 1987, 316:1435-40) but 50 % patients will not be cured. Ongoing high dose studies include:- NCRN TE 23 CBOP-BEP vs BEP x 4 � completed 2009, results Summer 2010 NCRN Accelerated BEP with 2 weekly cycle - completed The NCRN Testis Clinical Study Group have completed a randomised phase II of C-BOP-BEP with BEP over half the patients have been recruited but accrual to the study is slower than expected. CBOP-BEP consists of 6 weeks of induction therapy including cisplatin, carboplatin , vincristine and etoposide and a modified BEP with 15 IU Bleomycin per week though the entire 16 weeks CBOP-BEP it has yielded impressive 5 year survival rate in this tricky group of patients in both single institution and multi- centre phase II trials Accelerated BEP study is also suitable for the poor prognosis group. But I personally have concerns for those with bulky disease with this approach The NCRN Testis Clinical Study Group have completed a randomised phase II of C-BOP-BEP with BEP over half the patients have been recruited but accrual to the study is slower than expected. CBOP-BEP consists of 6 weeks of induction therapy including cisplatin, carboplatin , vincristine and etoposide and a modified BEP with 15 IU Bleomycin per week though the entire 16 weeks CBOP-BEP it has yielded impressive 5 year survival rate in this tricky group of patients in both single institution and multi- centre phase II trials Accelerated BEP study is also suitable for the poor prognosis group. But I personally have concerns for those with bulky disease with this approach

47. POOR RISK - BEATSON WOSCC RECENT EXPERIENCE We have recently reviewed our experience in Glasgow of this group of patients in 2005 - 2007 and found we are seeing more than expected frequency of these poor prognosis groups compares to more favourable stages 45 % of poor prognosis entered a clinical trial. We have recently reviewed our experience in Glasgow of this group of patients in 2005 - 2007 and found we are seeing more than expected frequency of these poor prognosis groups compares to more favourable stages 45 % of poor prognosis entered a clinical trial.

48. BEP ALTERNATIVES? deWit � toxicity Nichols � VIP more myelotoxic Kaye � 3 BEP+1EP; BOP/VIP more toxic and despite G-CSF no improvement in survival C-BOP-BEP in single centre the impressive 87.6% 5 year survival was reproduced in Fossa�s multi-centre phase II deWit � toxicity Nichols � VIP more myelotoxic Kaye � 3 BEP+1EP; BOP/VIP more toxic and despite G-CSF no improvement in survival C-BOP-BEP in single centre the impressive 87.6% 5 year survival was reproduced in Fossa�s multi-centre phase II

49. HIGH(er) DOSE? Ref. Regimen Result Nichols BEP vs BEP(40mg/m2x5) more toxicity JCO 19919(7)1163 Chevreaua 3-4 VE+B vs 2 VE+B + PEC more toxicity Euro Urol 1993;23:213-7 Droza 3/4 PVBE vs 2 x PVBE + HD HD more toxicity Eur Urol 2007 51(3), 739-46 not superior Motzera 4 BEP vs 2 BEP + 2HD HD more toxicity JCO 2007 25(3), 247-56 not superior Picoa 4 BEP vs 1 VIP + 3 VIP [HD] + PBSCT no difference in OS Nichols � doubling cisplatin increased toxicity only Chevreau � increased toxicity, no improvement in survival Bottom line is in these poor prognosis patients as yet no method of dose intensification such as high dose chemotherapy or the use of growth factors nor the introduction of new drugs to date has increased survival end-points over BEP x 4 alone. The literature regarding high dose chemotherapy is extremely complex due to the heterogeneity of patients entering the studies HD is used as front line treatment for poor prognosis disease, and consolidation treatment, salvage treatment on first and subsequent relapse and for refractory disease. Motzer study JCO 2007 25 247-256 � BEP vs BEP plus HD no difference in survival outcomes, but sub-group analysis if Markers failed to normalise with an acceptable T1/2 those with HD did better than standard therapy. The addition of paclitaxel to combination conditioning regimes can lead to increased response rate and survival rates Hartmann, J.T., JCO, 2007. 25(36): p. 5742-7 Studies now looking at sequential c.f. single HD procedures seem to better tolerated Lorch, A JCO 2007. 25(19): p. 2778-84. As yet no RCT have shown a definite benefit but what seems important is establishing prognostic markers for survival after HD. Nichols � doubling cisplatin increased toxicity only Chevreau � increased toxicity, no improvement in survival Bottom line is in these poor prognosis patients as yet no method of dose intensification such as high dose chemotherapy or the use of growth factors nor the introduction of new drugs to date has increased survival end-points over BEP x 4 alone. The literature regarding high dose chemotherapy is extremely complex due to the heterogeneity of patients entering the studies HD is used as front line treatment for poor prognosis disease, and consolidation treatment, salvage treatment on first and subsequent relapse and for refractory disease. Motzer study JCO 2007 25 247-256 � BEP vs BEP plus HD no difference in survival outcomes, but sub-group analysis if Markers failed to normalise with an acceptable T1/2 those with HD did better than standard therapy. The addition of paclitaxel to combination conditioning regimes can lead to increased response rate and survival rates Hartmann, J.T., JCO, 2007. 25(36): p. 5742-7 Studies now looking at sequential c.f. single HD procedures seem to better tolerated Lorch, A JCO 2007. 25(19): p. 2778-84. As yet no RCT have shown a definite benefit but what seems important is establishing prognostic markers for survival after HD.

51. RESECTION OF RESIDUAL MASSES

52. RESECTION OF RESIDUAL MASSES applies to all significant lesions in pts. treated for metastatic teratoma 30-40% will have mature teratoma 30-40% will have necrosis 10-20% will have viable cancer complete excision is the aim in all cases majority of pts. are cured; those at highest risk of relapse have >10% viable cancer in resected lesions, initial intermediate or poor IGCCCG group and incomplete excision Predictive model for PFS and OS (Fizazi, K JCO; 2001 19:2647-57) 30% discordant histology between RPLND and lung lesions, but high concordance with bilateral lung lesions

53. RESECTION OF RESIDUAL MASSES Standard approach for most (all > 2 cm) teratoma residual masses; individualised approach for seminoma patients Open issues: RPLND as primary therapy for high risk stage 1 and stage II? Reduction of surgical morbidity? Who needs chemotherapy post surgery? What is optimal post-operative chemotherapy ? Avoid surgery in selected patients? (e.g. by use of PET scanning) Recent paper Oldenburg JCO 2003 33% residual masses <2cm have tumour tissue (differentiated teratoma or viable cancer) Chemo therapy is not indicated for good and probably intermediate risk group defined by clear resection margin< 10 % viable cells and initial IGCCC good prognosis group Fizazi, K Ann Oncol, 2008. 19(2): p. 259-64. USA nerve spring retroperitoneal lymph node dissection is used as treatment for high risk stage 1 disease and low volume stage 2 disease but retrograde ejaculation is seen in 6-8 % cases In Seminoma residual masses > 3 cm hot on FDG PET are predictive of residual viable Tumour De Santis, M.. JCO 2004. 22(6): p. 1034-9. Recent paper Oldenburg JCO 2003 33% residual masses <2cm have tumour tissue (differentiated teratoma or viable cancer) Chemo therapy is not indicated for good and probably intermediate risk group defined by clear resection margin< 10 % viable cells and initial IGCCC good prognosis group Fizazi, K Ann Oncol, 2008. 19(2): p. 259-64. USA nerve spring retroperitoneal lymph node dissection is used as treatment for high risk stage 1 disease and low volume stage 2 disease but retrograde ejaculation is seen in 6-8 % cases In Seminoma residual masses > 3 cm hot on FDG PET are predictive of residual viable Tumour De Santis, M.. JCO 2004. 22(6): p. 1034-9.

54. DETECTION OF RESIDUAL MASSES

55. DETECTION OF RESIDUAL MASSES PET not predictive of the nature of residual masses post chemotherapy in stage IIc/ III disease (JC0 2008 26:5930-35)

56. RELAPSED DISEASE Overall 10-20% of advanced disease patients do require treatment for relapse/recurrence 10 - 50% of these are still curable Platinum resistance is associated with poor outcome and few long term survivors management often requires repeat surgery with/without further chemotherapy late relapses can be most difficult Specialist centre referral is essential No adequately powered randomised trials of second-line/salvage therapies have been performed Salvage drugs standard newer cytotoxics oxaliplatin, gemcitabine - biological drugs have not seen much promise yet unlike in common tumour types and certain other rare cancers Around 90 germ cell patients have been treated with biological agents to date some minor tomour marker responses are seen Investigation of PARP inhibitors may well be indicated on the basis of cell lie activity Despite the expression of c-Kit in seminomas little significant clinical activity is seen There are 1-2 case reports of bevacuzimab in refractory germ cell cancerSalvage drugs standard newer cytotoxics oxaliplatin, gemcitabine - biological drugs have not seen much promise yet unlike in common tumour types and certain other rare cancers Around 90 germ cell patients have been treated with biological agents to date some minor tomour marker responses are seen Investigation of PARP inhibitors may well be indicated on the basis of cell lie activity Despite the expression of c-Kit in seminomas little significant clinical activity is seen There are 1-2 case reports of bevacuzimab in refractory germ cell cancer

57. IGCCCG-2 prognostic score

58. PFS and OS estimates for all patients according to IGCCCG-2 prognostic score

59. RELAPSED DISEASE Phase II of �TIP� (taxol, ifosfamide, cisplatin) in first relapse at MSKCC (Kondagunta G, JCO 2005; 6549-55) Long term progression free rate 78% �MRC TIP� less dose intense & results less impressive (Mead , G et al. BJC 2005; 93:178-184) Phase II of GEM TIP in the near future High dose as initial salvage - single randomised trial (n=280) (Pico JL; Ann Oncol 200516: 1152-9,) 4 VeIP vs 3 VeIP + 1 CEC + PBSCT No differences in survival; higher death rate for HDC Phase II date suggesting event free survival rates 23 - 40% Matched pair analysis suggests 10 % improved EFS and OS Benefit of drugs over platinum and etoposide is controversial Multi-cycle HD seems better tolerated Largest retrospective series (n=184) from Indiana event free survival = 63% (Einhorn, L NEJM 2007;3577:340-348)

60. RANDOMIZED PHASE III TRIAL OF INITIAL SALVAGE CHEMOTHERAPY FOR PATIENTS WITH GERM CELL TUMORS (TIGER) Increasingly high dose is seen as the only potential cure for those patients with poor risk factors @ relapse These are relatively rare in number and an international collaborative approach across a variety of germ cell research groups to try to answer this question Increasingly high dose is seen as the only potential cure for those patients with poor risk factors @ relapse These are relatively rare in number and an international collaborative approach across a variety of germ cell research groups to try to answer this question

61. Special Issues Brain Mets Extra-gonadal primary sites Brain metastases consideration for multi-modality treatment but remember Lance Armstrong 3 situations - brain met at presentation do reasonably well 45 % 5 year survival - Isolated brain met as sanctuary site 39% 5 year survival - Brain mets as part of systemic progression 2 % 5 year survival Extra-gonadal primaries sites- approach same generally though primary medisatinal NSGCT tend to do very badly compared to other sites and automatically fall in to IGCCCG poor group Brain metastases consideration for multi-modality treatment but remember Lance Armstrong 3 situations - brain met at presentation do reasonably well 45 % 5 year survival - Isolated brain met as sanctuary site 39% 5 year survival - Brain mets as part of systemic progression 2 % 5 year survival Extra-gonadal primaries sites- approach same generally though primary medisatinal NSGCT tend to do very badly compared to other sites and automatically fall in to IGCCCG poor group

62. Late Relapse Increasingly recognised problem Defined < 2 years post treatment 1-6 % of cases Commonest site RPLN Often marker negative, if present usually AFP Histology glandular patter and yolk sac TD in primary is associated with relapse Predictive factor on multivariate analysis differentiated teratoma in excised specimen (van As NJ, et al. Br J Cancer. 2008 Jun 17;98(12):1894-902.) Consider transformation into somatic malignancy Treatment excision or salvage chemotherapy (TIP) � surgery 50% PFS (Kondagunta GV, et al. J Clin Oncol. 2005 Sep 20;23(27):6549-55). Controversial as to whether symptomatic vs asymptomatic cases have an adverse effect on survival outcomes; potentially difficult to justify the radiation exposure for low event rate George DW, Foster RS, Hromas RA, Robertson KA, Vance GH, Ulbright TM, et al. Update on late relapse of germ cell tumor: a clinical and molecular analysis. J Clin Oncol. 2003 Jan 1;21(1):113-22. Oldenburg J, Alfsen GC, Waehre H, Fossa SD. Late recurrences of germ cell malignancies: a population-based experience over three decades. Br J Cancer. 2006 Mar 27;94(6):820-7. Sharp DS, Carver BS, Eggener SE, Kondagunta GV, Motzer RJ, Bosl GJ, et al. Clinical outcome and predictors of survival in late relapse of germ cell tumor. J Clin Oncol. 2008 Dec 1;26(34):5524-9. Potential candidates for indefinite follow up until more accurate predictive factors are available are relapse after first line chemo, extra-gonadal sites, residual unresectable masses. Controversial as to whether symptomatic vs asymptomatic cases have an adverse effect on survival outcomes; potentially difficult to justify the radiation exposure for low event rate George DW, Foster RS, Hromas RA, Robertson KA, Vance GH, Ulbright TM, et al. Update on late relapse of germ cell tumor: a clinical and molecular analysis. J Clin Oncol. 2003 Jan 1;21(1):113-22. Oldenburg J, Alfsen GC, Waehre H, Fossa SD. Late recurrences of germ cell malignancies: a population-based experience over three decades. Br J Cancer. 2006 Mar 27;94(6):820-7. Sharp DS, Carver BS, Eggener SE, Kondagunta GV, Motzer RJ, Bosl GJ, et al. Clinical outcome and predictors of survival in late relapse of germ cell tumor. J Clin Oncol. 2008 Dec 1;26(34):5524-9. Potential candidates for indefinite follow up until more accurate predictive factors are available are relapse after first line chemo, extra-gonadal sites, residual unresectable masses.

63. Chemo is not all bad! Reduced risk second new testis cancer with adjuvant carboplatin cf XRT (Oliver RT, et al. Lancet. 2005 Jul 23-29;366(9482):293-300)

64. LATE EFFECTS The interpretation of the latent effects of chemotherapy needs to be viewed with knowledge of the changes in the management of the disease The interpretation of the latent effects of chemotherapy needs to be viewed with knowledge of the changes in the management of the disease

65. LATE EFFECTS Acute effects Nausea/ vomiting Mucositis/diarrhoea Myelosuppression Nephropathy Neuropathy Pulmonary toxicity Alopecia Skin toxicity Thrombo-embolic events Chronic effects Nephropathy Neuropathy Pulmonary toxicity Raynaud�s ? risk of CV disease In/sub-fertility Low androgens Retrograde ejaculation Second malignancy A high LDH and BSA > 1.9 m2 has recently been showed to be associated with an increased risk of thrombotic events in germ cell cancer patients treated with cisplatin Piketty, A.C. BC 2005. 93(8): p. 909-14. Raynauds is reported in up to 25% (Fossa, S JOC 2003 (21):1107-1118) For many of these their incidence increase with higher cumulative doses so are seen more frequently in intermediate and poor prognosis patients Studies suggest between 2 (Huddart, R.A., et al. J Clin Oncol, 2003. 21(8): p. 1513-23) to 7 (Meinardi, M.TJ Clin Oncol, 2000. 18(8): p. 1725-32) fold increase in the risk of cardio-vascular events We are currently designed studies to look more closely at this problem including using inflammatory markers such as CRP as an early marker of cardiovascular disease in the patients by 5 years 80 % regain fertility However persistent low sperm production is associated with high FSH �10-30% persistent sensory neuropathy 20% otoxicity its development is related to polymorphism of the gene GST-P1 A high LDH and BSA > 1.9 m2 has recently been showed to be associated with an increased risk of thrombotic events in germ cell cancer patients treated with cisplatin Piketty, A.C. BC 2005. 93(8): p. 909-14. Raynauds is reported in up to 25% (Fossa, S JOC 2003 (21):1107-1118) For many of these their incidence increase with higher cumulative doses so are seen more frequently in intermediate and poor prognosis patients Studies suggest between 2 (Huddart, R.A., et al. J Clin Oncol, 2003. 21(8): p. 1513-23) to 7 (Meinardi, M.TJ Clin Oncol, 2000. 18(8): p. 1725-32) fold increase in the risk of cardio-vascular events We are currently designed studies to look more closely at this problem including using inflammatory markers such as CRP as an early marker of cardiovascular disease in the patients by 5 years 80 % regain fertility However persistent low sperm production is associated with high FSH �10-30% persistent sensory neuropathy 20% otoxicity its development is related to polymorphism of the gene GST-P1

66. Mortality Statistics We know from cohort studies, case series from single institutions and from large single regional, national and multinational combined cancer registries, that testicular cancer patients have increased mortality compared to the normal population. The causes are of death included second malignancies and non-malignant causes such as cardiovascular and GI disease. A variety of second cancer and other disease have documented increased incidence in testicular cancer patients. Also some of the risk factors for these conditions are seen with increased frequency or �clustering� in our patients. Generally the data in these studies is generated by comparing the mortality or incidence in the cancer survivor to that of usually aged matched local populations, to generate standardised mortality or incidence rates respectively. Fossa 2004 There did not appear to be decrease in the elevated SMR in the latter of the 3 chronological periods study 1990-1997 for second cancers, which is a concern as it may have been anticipated that by this point that reductions in the size of radiotherapy fields and standard platinum based therapy may have reduced the second malignancy rate associated with older treatments. Robinson et al In a similar study in SE England and looked at the SMR according to the period of diagnosis, histological type. Since 1960s for all period since diagnosis the SMRs have decreased but now largest excess mortality seen in the early years from diagnosis. Fossa 2007 This large multinational registry study looked at the SMR for non-cancer deaths in survivors of testicular cancer. The overall SMR was increased with a 6 % increase in mortality compared to the general population. SMRs were statistically significantly increased for infections, digestive disease and for men diagnosed < 35 years of age the SMR for circulatory disease was 1.23 (95% CI 1.09-1.39). Generally the SMRs for NSCGT were higher than for seminoma patients, 3.07 vs 1.82 Zagars[5] In this more restrictive, yet relatively large, study of stage I and II seminomas treated with surgery and XRT at a single institution with radiotherapy alone the SMR rate was not significantly raised in the first 15 years of FU. Overall and beyond 15 years of follow up the SMR for second cancers and cardiac disease were also significantly elevated. The increased mortality appeared in patients who did and not received mediastinal XRT, thought the latter group were the only one to demonstrate this before 15 years of follow up. A striking feature in this Texan paper was the median age of death for cardiac cause was 62 and for cancer was 59, these are bad even for the West of Scotland ! We know from cohort studies, case series from single institutions and from large single regional, national and multinational combined cancer registries, that testicular cancer patients have increased mortality compared to the normal population. The causes are of death included second malignancies and non-malignant causes such as cardiovascular and GI disease. A variety of second cancer and other disease have documented increased incidence in testicular cancer patients. Also some of the risk factors for these conditions are seen with increased frequency or �clustering� in our patients. Generally the data in these studies is generated by comparing the mortality or incidence in the cancer survivor to that of usually aged matched local populations, to generate standardised mortality or incidence rates respectively. Fossa 2004 There did not appear to be decrease in the elevated SMR in the latter of the 3 chronological periods study 1990-1997 for second cancers, which is a concern as it may have been anticipated that by this point that reductions in the size of radiotherapy fields and standard platinum based therapy may have reduced the second malignancy rate associated with older treatments. Robinson et al In a similar study in SE England and looked at the SMR according to the period of diagnosis, histological type. Since 1960s for all period since diagnosis the SMRs have decreased but now largest excess mortality seen in the early years from diagnosis. Fossa 2007 This large multinational registry study looked at the SMR for non-cancer deaths in survivors of testicular cancer. The overall SMR was increased with a 6 % increase in mortality compared to the general population. SMRs were statistically significantly increased for infections, digestive disease and for men diagnosed < 35 years of age the SMR for circulatory disease was 1.23 (95% CI 1.09-1.39). Generally the SMRs for NSCGT were higher than for seminoma patients, 3.07 vs 1.82 Zagars[5] In this more restrictive, yet relatively large, study of stage I and II seminomas treated with surgery and XRT at a single institution with radiotherapy alone the SMR rate was not significantly raised in the first 15 years of FU. Overall and beyond 15 years of follow up the SMR for second cancers and cardiac disease were also significantly elevated. The increased mortality appeared in patients who did and not received mediastinal XRT, thought the latter group were the only one to demonstrate this before 15 years of follow up. A striking feature in this Texan paper was the median age of death for cardiac cause was 62 and for cancer was 59, these are bad even for the West of Scotland !

67. Incidence Statistics Robinson et al showed increased incidence rates for a variety of cancers which were seen with different increased frequencies with the time elapsed since diagnosis including for: � For seminomas, there was a significant excess of cancers of the colon, soft tissue and bladder in the long term, of pancreatic cancer in both the medium and long term For NSGCT, significant excesses were found in the long term for cancers of the stomach, rectum and pancreas Richardi study showed there was no reduction in the elevated SIR with era of treatment and generally all SIR increased with increasing length of follow up. � Latent One of the more recent publications regarding late effects is a comprehensive study from Holland published in 2007 in JCO 25: 4370-4378, it is called the LATENT � Latent Adverse Treatment Effects in Netherlands Testicular cancer survivors � 2, 707 5-year survivors identified from Dutch cancer registries divided into 3 group. chemo, infra-diaphragmatic XRT and surgery alone, patients were treated between 1965- 1995 There is comparison of the incidence of second malignancies and cardiovascular disease according to age, sex, and calendar specific rates of the general population. After median FU of 17.6 years of 90 % Dutch testis cancer patients. 270 had developed second malignancy and 357 developed CV disease MI, angina, CCF. By 20 years cumulative incidence 4 % case second neoplasm and CV disease in chemo treated group and 1.5% in XRT group compared to surgery, this equates to a 1.8 fold increase in either major toxicity for those treated with infra-diaphragmatic XRT and 1.9 for chemotherapy compared to surgery alone. For comparison smoking increases the risk of either second major complication by 1.7 fold Infra-diaphragmatic XRT < 35Gy did not increase the CV risk compared to surgery alone, but was associated with 2.6 fold risk of second cancer. Chemotherapy increased the risk of second cancer by 2.1 and increased risk of CV by 1.7 disease compared to surgically treated patients. For patients treated with both modalities cumulative incidence of second cancer or cardio-vascular was 26.7 %. � Robinson et al showed increased incidence rates for a variety of cancers which were seen with different increased frequencies with the time elapsed since diagnosis including for: � For seminomas, there was a significant excess of cancers of the colon, soft tissue and bladder in the long term, of pancreatic cancer in both the medium and long term For NSGCT, significant excesses were found in the long term for cancers of the stomach, rectum and pancreas Richardi study showed there was no reduction in the elevated SIR with era of treatment and generally all SIR increased with increasing length of follow up. � Latent One of the more recent publications regarding late effects is a comprehensive study from Holland published in 2007 in JCO 25: 4370-4378, it is called the LATENT � Latent Adverse Treatment Effects in Netherlands Testicular cancer survivors � 2, 707 5-year survivors identified from Dutch cancer registries divided into 3 group. chemo, infra-diaphragmatic XRT and surgery alone, patients were treated between 1965- 1995 There is comparison of the incidence of second malignancies and cardiovascular disease according to age, sex, and calendar specific rates of the general population. After median FU of 17.6 years of 90 % Dutch testis cancer patients. 270 had developed second malignancy and 357 developed CV disease MI, angina, CCF. By 20 years cumulative incidence 4 % case second neoplasm and CV disease in chemo treated group and 1.5% in XRT group compared to surgery, this equates to a 1.8 fold increase in either major toxicity for those treated with infra-diaphragmatic XRT and 1.9 for chemotherapy compared to surgery alone. For comparison smoking increases the risk of either second major complication by 1.7 fold Infra-diaphragmatic XRT < 35Gy did not increase the CV risk compared to surgery alone, but was associated with 2.6 fold risk of second cancer. Chemotherapy increased the risk of second cancer by 2.1 and increased risk of CV by 1.7 disease compared to surgically treated patients. For patients treated with both modalities cumulative incidence of second cancer or cardio-vascular was 26.7 %. �

68. Increased Cardio-vascular disease Meinardi This Dutch was a case control single centre study of stage one patients managed by surgery alone with those receiving chemotherapy with at least 10 years of follow-up. PVB was the commonest regime used. The latency between treatment and cardiac event was 9-16 years. All cases with had an event had at least on cardiac risk factor and 97% of chemotherapy treated patients had at least one factor. Those risk factors with significant difference frequency compared to stage I patients are shown in the table. There was no difference in smoking history, FH of CV disease between these two groups. 33 % of the chemotherapy patients had diastolic dysfunction on echocardiogram which is a predictor early myocardial dysfunction. In a large Dutch study [18] where cardiac events were defined as MI, CCF. The SIR for MI was significantly increased for NSGCT survivors aged of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors > 55 years. Median time to MI was 14 years Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk BEP was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1)., but the median follow up in this sub set was shorter than the median time to MI. Smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. � The authors conclude that NSCGT survivors have slight increased MI risk at young age. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is important in survivors of testis cancer. Meinardi This Dutch was a case control single centre study of stage one patients managed by surgery alone with those receiving chemotherapy with at least 10 years of follow-up. PVB was the commonest regime used. The latency between treatment and cardiac event was 9-16 years. All cases with had an event had at least on cardiac risk factor and 97% of chemotherapy treated patients had at least one factor. Those risk factors with significant difference frequency compared to stage I patients are shown in the table. There was no difference in smoking history, FH of CV disease between these two groups. 33 % of the chemotherapy patients had diastolic dysfunction on echocardiogram which is a predictor early myocardial dysfunction. In a large Dutch study [18] where cardiac events were defined as MI, CCF. The SIR for MI was significantly increased for NSGCT survivors aged of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors > 55 years. Median time to MI was 14 years Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk BEP was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1)., but the median follow up in this sub set was shorter than the median time to MI. Smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. � The authors conclude that NSCGT survivors have slight increased MI risk at young age. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is important in survivors of testis cancer.

69. Leukaemia incidence This slide summaries some of the increased rates of leukaemia seen in germ cell patients, generally the SIR is 2-7 fold that of the various control populations. Of concern in the study by Richardi the SIR increased to 37.9 (95% CI: 18.9-67.8) among NSCGT patients diagnosed since 1990 Howard These the SIRs are highest in the first 5 years post treatment, but remain elevated at over 15 years. By 30 years the cumulative rate of leukaemia was 0.23%. There was no statistically significant difference in the excess absolute or relative risk for those treated initially with chemotherapy and radiotherapy. Travis {Travis, 2000 #288} study was registry based with those developing leukaemia were aged matched for controls within the registry. A variety of different alkylating agents and XRT schedules were seen I have concentrated on the data for more modern germ cell cancer strategies. The median latency was 5 years and they estimated that for 10 000 men treated and followed for 15 years with; standard dose of radiotherapy (25Gy) to abdomen may lead to an excess of 9 leukaemia cases Cisplatin dose 650 mg may lead to 16 excess leukaemia cases �So although the excess relative risks are high the excess absolute risk is small, the benefits if treatment still out weigh this risk. This slide summaries some of the increased rates of leukaemia seen in germ cell patients, generally the SIR is 2-7 fold that of the various control populations. Of concern in the study by Richardi the SIR increased to 37.9 (95% CI: 18.9-67.8) among NSCGT patients diagnosed since 1990 Howard These the SIRs are highest in the first 5 years post treatment, but remain elevated at over 15 years. By 30 years the cumulative rate of leukaemia was 0.23%. There was no statistically significant difference in the excess absolute or relative risk for those treated initially with chemotherapy and radiotherapy. Travis {Travis, 2000 #288} study was registry based with those developing leukaemia were aged matched for controls within the registry. A variety of different alkylating agents and XRT schedules were seen I have concentrated on the data for more modern germ cell cancer strategies. The median latency was 5 years and they estimated that for 10 000 men treated and followed for 15 years with; standard dose of radiotherapy (25Gy) to abdomen may lead to an excess of 9 leukaemia cases Cisplatin dose 650 mg may lead to 16 excess leukaemia cases �So although the excess relative risks are high the excess absolute risk is small, the benefits if treatment still out weigh this risk.

70. Androgens Encourage healthy lifestyle Awareness of increased risk of cardiovascular disease Psychological � usually not a problem and not related to treatment modality (Mykletun, A JCO, 2005. 23(13): p. 3061-8) LATE EFFECTS Testicular cancer through Lance Armstrong�s Livestrong Foundation has led the way with survivorship issues not been applied to other cancers. Up to 20% will have low androgens even at Dx, this is asscoaited with worse QOL, sexual function and adverse health outcomes androgen supplementation is to be studies in the TRYMS study (? ACRONYM) with QOL and fat mass indices as end points It is important to spot and support those who don�t seem to be coping well and thus the MDT approach we have with the TYA CNS as we don�t have a germ cell specific CNS. Mykletun, A JCO, 2005. 23(13): p. 3061-8. QOL in 1400 survivors of testicular cancer showed no significant difference compared to matched controls and wasn�t dependent on treatment modality however those experiencing test cancer related stress and reported more side effect were likely to have reduced QOL scores. � In follow up we looked at our lack of communication of normal results and somewhat surprisingly most are well adjusted and don�t feel the need for individual communication of normal results. Testicular cancer through Lance Armstrong�s Livestrong Foundation has led the way with survivorship issues not been applied to other cancers. Up to 20% will have low androgens even at Dx, this is asscoaited with worse QOL, sexual function and adverse health outcomes androgen supplementation is to be studies in the TRYMS study (? ACRONYM) with QOL and fat mass indices as end points It is important to spot and support those who don�t seem to be coping well and thus the MDT approach we have with the TYA CNS as we don�t have a germ cell specific CNS. Mykletun, A JCO, 2005. 23(13): p. 3061-8. QOL in 1400 survivors of testicular cancer showed no significant difference compared to matched controls and wasn�t dependent on treatment modality however those experiencing test cancer related stress and reported more side effect were likely to have reduced QOL scores. � In follow up we looked at our lack of communication of normal results and somewhat surprisingly most are well adjusted and don�t feel the need for individual communication of normal results.

71. CONCLUSIONS Maximise survival rates whilst minimising toxicities if at all possible BEP remains standard primary treatment option for all patients with metastatic GCT although schedule/cycles may differ according to risk Alternatives to BEP need to be evaluated in clinical trials Still need better treatments for poor risk patients and relapsed disease

72. Resources/Websites It's Not About the Bike: My Journey Back to Life - Lance Armstrong Every second Counts - Lance Armstrong www.laf.org Lance Armstrong Foundation www.cancerresearchuk.org www.cancerbacup.org.uk www.orchid-cancer.org.uk www.icr.ac.uk/everyman/index.html���� � ww..tc-cancer.com � �www.tcrc.acor.org������� � www.nlm.nih.gov/medlineplus/testicularcancer.html�������� www.royalmarsden.org/patientinfo/booklets/testicular_cancer/testicular.asp����