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![[18F]-FDG-PET in Germ Cell Tumors following Chemotherapy:
Results of the German Multicenter Trial
n= 141
NPV
Negative
predictive value
PPV
Positive
predictive value
ACC
Accuracy
CT
95% CI
0% 51%
43; 60%
51%
43; 60%
PET
95% CI
59%
44; 72%
57%
46; 67%
57%
49; 66%
M. De Wit, ASCO 2006, abstract # 4521
Statistical plan: estimate of >70% accuracy for PET
37
Dept of Urology, GRH and KMC, Chennai.](https://image.slidesharecdn.com/testis-carcinoma-management-nsgct-210610131153/75/Testis-carcinoma-management-nsgct-37-2048.jpg)
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Similar to Testis carcinoma- management- nsgct
Testis carcinoma- management- nsgct
- 1. MANAGEMENT OF NSGCTs Deptof Urology Govt Royapettah Hospital and Kilpauk Medical College Chennai 1
- 2. Moderators: Professors: • Prof. Dr.G. Sivasankar, M.S., M.Ch., • Prof. Dr. A. Senthilvel, M.S., M.Ch., Asst Professors: • Dr. J. Sivabalan, M.S., M.Ch., • Dr. R. Bhargavi, M.S., M.Ch., • Dr. S. Raju, M.S., M.Ch., • Dr. K. Muthurathinam, M.S., M.Ch., • Dr. D. Tamilselvan, M.S., M.Ch., • Dr. K. Senthilkumar, M.S., M.Ch. Dept of Urology, GRH and KMC, Chennai. 2
- 3. Tumors of thetestis Tumorigenic hypothesis: Normal spermatocyte Totipotential germ cell Embryonal carcinoma (totipotential tumor cell) Seminoma Choriocarcimoma Yolk sac tumor Teratoma ? Extra embryonic differentiation Trophoblastic pathways Yolk sac pathways Intra embryonic differentiation 3 Dept of Urology, GRH and KMC, Chennai.
- 4. Pathological classification oftesticular cancers Teratoma Non-seminomatous germ cell tumour Teratoma Differentiated (TD) Mature teratoma Malignant teratoma intermediate (MTI) Embryonal carcinoma with teratoma (teratocarcinoma) Malignant teratoma undifferentiated (MTU) Yolk sac tumour, embryonal carcinoma Malignant teratoma trophoblastic (MTT) Yolk sac tumour; choriocarcinoma 4 Dept of Urology, GRH and KMC, Chennai.
- 5. INTRODUCTION • Cancers withhigh cure rates especially in early stages • High orchidectomy should be followed by Multimodality management which includes chemotherapy and surgery • Radiation unlike seminoma not an option • Toxicities of chemotherapy and adverse effects of RPLND should be kept in mind 5 Dept of Urology, GRH and KMC, Chennai.
- 6. 40% GCT 6 Dept ofUrology, GRH and KMC, Chennai.
- 7. TERMS • PCS • PSCS •LVI • EC • BEP 7 Dept of Urology, GRH and KMC, Chennai.
- 8. NSGCT vs SGCT SGCT NSGCT Dept of Urology, GRH and KMC, Chennai.
- 9. Tumour marker byhistological type hCG (%) AFP (%) Seminoma 7 0 Teratoma 25 38 Teratocarcinoma 57 64 Embryonal 60 70 Choriocarcinoma 100 0 Dept of Urology, GRH and KMC, Chennai.
- 10. Clinical staging • CSI is defined as disease clinically confined to the testis, • CS II indicates the presence of regional (retroperitoneal) lymph node metastasis, (A,B,C) • CS III represents non regional lymph node and/or visceral metastasis. • The AJCC and UICC staging systems were updated in 2002 and the new systems consider the presence of LVI in the primary tumor as pT2 in an otherwise organ-confined tumor. 10 Dept of Urology, GRH and KMC, Chennai.
- 11. On orchidectomy • Organ-sparingsurgery – In suspicion of a benign-lesion – In synchronous, bilateral testicular tumours – In metachronous, contralateral tumours – In a tumour in a solitary testis The tumour should be less than 30% of the testicular volume. < 2cm sized tumors 11 Dept of Urology, GRH and KMC, Chennai.
- 12. HIGH INGUINAL RADICAL ORCHIECTOMY 12 Dept ofUrology, GRH and KMC, Chennai.
- 13. 13 Dept of Urology,GRH and KMC, Chennai.
- 14. 14 Dept of Urology,GRH and KMC, Chennai.
- 15. GOOD 56% 15 Dept ofUrology, GRH and KMC, Chennai.
- 16. INTERMEDIATE 28% 16 Dept ofUrology, GRH and KMC, Chennai.
- 17. POOR - 16% 17 Deptof Urology, GRH and KMC, Chennai.
- 18. Stage I • Observation •Retroperitoneal lymph node dissection • Chemotherapy 18 Dept of Urology, GRH and KMC, Chennai.
- 19. Indications for observation •T1 (IA) primary tumor • Normal radiographs and physical examination • Normal serum tumor markers • Compliant patients Surveillance during the first year should include: • physical examination CXR, serum tumor markers every 1-2 months • Quarterly CT scan Frequency of visits gradually decreased afterwards 19 Dept of Urology, GRH and KMC, Chennai.
- 20. Indications for surgery •IB patients (T2,T3,T4)N0M0S0 • T1 patients who are non-compliant with abnormal radiographs tumor markers 20 Dept of Urology, GRH and KMC, Chennai.
- 21. Rationale of RPLND (1)the retroperitoneum is the most common site of occult metastatic disease and the risk of associated systemic disease is low; (2) 15% to 25% incidence of retroperitoneal teratoma (which is resistant to chemotherapy) in those with occult metastasis; (3) low risk of abdominopelvic recurrence after full, bilateral template RPLND thereby obviating the need for routine surveillance CT; (4) high cure rates after RPLND alone for patients with low-volume (pN1) retroperitoneal malignancy and teratoma (pN1-3); (5) avoidance of chemotherapy in more than 75% or more of patients if adjuvant chemotherapy is restricted to those with extensive retroperitoneal malignancy (pN2-3); (6) high salvage rate of relapses with good-risk, induction chemotherapy; and (7) low short- and long- term morbidity when a nerve-sparing RPLND is performed by experienced surgeons 21 Dept of Urology, GRH and KMC, Chennai.
- 22. Retroperitoneal lymph nodedissection • Nerve-sparing RPLND must be performed • Can be nerve dissection bilateral RPLND or modified RPLND templates • Avoids the retrograde ejaculation associated with standard bilateral RPLND • Because of long term toxicities, chemotherapy is not standard 22 Dept of Urology, GRH and KMC, Chennai.
- 23. Chemotherapy • Treatment ofchoice in stage IS • RPLND is required if new disease is demonstrated post chemotherapy • Usually two cycles of BEP 23 Dept of Urology, GRH and KMC, Chennai.
- 24. • Primary chemotherapyoffers patients the greatest chance of being relapse free with any single treatment modality • The disadvantages of primary chemotherapy are (1) it does not treat retroperitoneal teratoma and thus exposes patients to the potential for chemoresistant and/or late relapse (2) long-term surveillance CT of the retroperitoneum is required, and (3) all patients are exposed to chemotherapy and the potential risk of late toxicity (cardiovascular disease and secondary malignant neoplasms among others). 24 Dept of Urology, GRH and KMC, Chennai.
- 25. CS II A-B •? • RPLND • CHEMOTHERAPY 25 Dept of Urology, GRH and KMC, Chennai.
- 26. RPLND (1) 13% to35% of patients have pathologically negative lymph nodes and thus avoid chemotherapy; (2) approximately 30% have retroperitoneal teratoma that is resistant to chemotherapy; (3) long-term cancer-specific survival is 98% to 100% with RPLND ± adjuvant chemotherapy; (4) 10% to 52% avoid any chemotherapy and (5) ejaculatory function is preserved in 70% to 90% of patients The disadvantages of RPLND are (1) additional therapy is required in 48% or more of patients; (2) 13% to 15% have persistence of disease after RPLND and require a full induction chemotherapy regimen, and (3) high-quality RPLND may not be deliverable at all institutions 26 Dept of Urology, GRH and KMC, Chennai.
- 27. CT The arguments infavor of induction chemotherapy are (1) 60% to 78% of patients achieve a complete response and avoid PCS; (2) treatment can be delivered at community-based institutions, and (3) cancer-specific survival is 96% to 100%. The disadvantages of chemotherapy are (1) all patients are exposed to the risk of long-term toxicity of chemotherapy and (2) those who do not undergo post- chemotherapy RPNLD are at risk of relapse with chemorefractory GCT. 27 Dept of Urology, GRH and KMC, Chennai.
- 28. stage II (lowtumor burden) • Nerve sparing bilateral RPLND is the treatment of choice • Less than 3 cm nodes • Not multifocal • No suprahilar, retrocrural or contralateral nodes • No history of back pain • Normal or declining markers post orchidectomy • For cases not satisfying the above criteria, initial chemotherapy is the treatment of choice 28 Dept of Urology, GRH and KMC, Chennai.
- 29. stage II (lowtumor burden) post RPLND • Surveillance: • Compliant patients • Less than six involved nodes • None greater than 2 cm (pN1) • Adjuvant chemotherapy: • pN2/N3 • Extra nodal extension • Non-compliantpatients • Usually two cycles of BEP • Standard treatment at relapse : 3-4 cycles of BEP 29 Dept of Urology, GRH and KMC, Chennai.
- 30. Stage II (hightumor burden) and stage III • Usually cisplatin - based chemotherapy followed by nerve-sparing RPLND is the treatment of choice • Surgery often essential to achieve a disease free state • Management based on an international consensus for germ cell tumor risk stratification – Site of primary – Tumor markers – Visceral metastasis 30 Dept of Urology, GRH and KMC, Chennai.
- 31. Good – prognosisNSGCTs • EP4 or BEP3 is the standard • Complete response rate ranges form 88-95% • Various trials have proved the efficacy and toxicity of various regimens • Cumulative dose per cycle of treatment is cisplatin 100mg/m2 and etoposide 500mg/m2 31 Dept of Urology, GRH and KMC, Chennai.
- 32. Intermediate and poor– risk NSGCTs • BEP4 is the treatment of choice • Also various other regimens used • VIP with hematopoietic growth factor • High-dose carboplatin based chemotherapy • A slow serum marker decline after two cycles is associated with shorter progression-free and overall survival rates 32 Dept of Urology, GRH and KMC, Chennai.
- 33. Management of residualdisease • Aim: resection of all residual disease and normalization of tumor markers • Done by standard or nerve sparing RPLND • Template RPLND not useful • Stage III disease without retroperitoneal involvement – RPLND not needed 33 Dept of Urology, GRH and KMC, Chennai.
- 34. Management of residualdisease Histology of residual disease post chemotherapy: • Necrosis-45% • Teratoma-40% • Viable GCT-15% • PET scans not useful post chemotherapy-high false negative rate 34 Dept of Urology, GRH and KMC, Chennai.
- 35. Limitations of FDGPET - ≤ 2 weeks after chemotherapy, tumor- and treatment specific - Limited resolution in lesions <5mm (possible positivity of extremely active lesions 5- 10mm) - Mature teratoma, negative result expected False negative 35 Dept of Urology, GRH and KMC, Chennai.
- 36. FDG PET andthe „teratoma dilemma“ Residual tumors Resection PET Fibrosis/ necrosis 40% No Negative Mature teratoma 40% Yes Negative* Viable tumor 20% Yes Positive *Differences in the kinetic rate constants of FDG uptake between mature teratoma and necrosis/fibrosis, based on kinetic modeling (n=6). Sugawara Y et al , Radiology 1999;211:249-56 Dept of Urology, GRH and KMC, Chennai.
- 37. [18F]-FDG-PET in GermCell Tumors following Chemotherapy: Results of the German Multicenter Trial n= 141 NPV Negative predictive value PPV Positive predictive value ACC Accuracy CT 95% CI 0% 51% 43; 60% 51% 43; 60% PET 95% CI 59% 44; 72% 57% 46; 67% 57% 49; 66% M. De Wit, ASCO 2006, abstract # 4521 Statistical plan: estimate of >70% accuracy for PET 37 Dept of Urology, GRH and KMC, Chennai.
- 38. PET in postchemotherapy non-seminomaresiduals • False positives due to inflammation • False negatives due to teratoma or small lesions • High PPV in poor prognosis or relapsed patients after high dose-chemotherapy • Strict timing of PET after chemotherapy is key 38 Dept of Urology, GRH and KMC, Chennai.
- 39. 39 Dept of Urology,GRH and KMC, Chennai.
- 40. PET in postchemotherapy non-seminomaresiduals Conclusion • Resection of postchemotherapy NSGCT residuals continues to be mandatory. • In poor prognosis and relapse-patients after HD-chemotherapy, PET might be helpful for decision making. – Further prospective trials are needed to explore this indication of PET. 40 Dept of Urology, GRH and KMC, Chennai.
- 41. Management of residualdisease Surveillance : • Good-risk patients • Residual disease <1cm • Infrequent or rare relapses RPLND: • Residual disease >1 cm • Poor risk patients • High frequency of teratoma and viable GCT • Templates leave behind disease in 7-32% 41 Dept of Urology, GRH and KMC, Chennai.
- 42. Relapse and refractorydisease • 20-30% - relapse or refractory to standard treatment • Salvage chemotherapy is the treatment of choice • Response to salvage chemotherapy is better with • Testis primary • Initial CR to BEP • 35-40 % 3-year survival rate 42 Dept of Urology, GRH and KMC, Chennai.
- 43. Salvage therapy • Conventionaldose salvage therapy • VeIP Regimen • TIP Regimen • High dose salvage therapy • Carboplatin and etoposide with or without cyclophosphamide • Europe : high dose chemotherapy not first salvage • USA: used as first salvage • High dose chemotherapy (TI-CE) is the treatment of choice after failure of first salvage (second salvage) and for late relapses 43 Dept of Urology, GRH and KMC, Chennai.
- 44. 44 Dept of Urology,GRH and KMC, Chennai.
- 45. Role for surgeryafter salvage chemotherapy • If viable NSGCT persists after salvage chemotherapy, additional standard chemotherapy offers no survival benefit • most of them are not surgical candidates • Some are given better results with “desperation” surgeries – DESPERATE RPLND 45 Dept of Urology, GRH and KMC, Chennai.
- 46. Management of EGGCT •SURGICAL EXCISION – sacrococcygeal tumors, mediastinal • RADIOTHERAPY – pineal • CHEMOTHERAPY-retroperitoneal, mediastinal 46 Dept of Urology, GRH and KMC, Chennai.
- 47. Newer agents • Gemcitabineplus paclitaxel with or without oxaliplatin • Flavopiridol plus FOLFOX • Inhibitor of cdk 4/6 • Oral etoposide – only palliative role 47 Dept of Urology, GRH and KMC, Chennai.
- 48. Retroperitoneal lymph node resection 48 Deptof Urology, GRH and KMC, Chennai.
- 49. Retroperitoneal lymph noderesection • Critical staging information • Performed with curative intent • Bilateral RPLND is the standard • Mortality <1% • Dissection of precaval, retrocaval, paracaval, interaortocaval, retroaortic, preaortic, Para - aortic and common-iliac lymph nodes 49 Dept of Urology, GRH and KMC, Chennai.
- 50. 50 Dept of Urology,GRH and KMC, Chennai.
- 51. Types of RPLND: •Bilateral infrahilar • Suprahilar • Nerve –dissection bilateral • Modified RPLND templates 51 Dept of Urology, GRH and KMC, Chennai.
- 52. RPLND types (Infrahilar dissection) • Rationale: – The incidence of supra hilar metastasis in low stage NSGCT is very rare – Infra hilar dissection diminishes morbidity and reduces mortality below 1% • Complications: – loss of antegrade ejaculation 52 Dept of Urology, GRH and KMC, Chennai.
- 53. Bilateral infrahilar • Standardagainst which the therapeutic alternatives are tested • Ipsilateral gonadal vein and surrounding fibro adipose tissue from its insertion to the deep ring must be completely excised 53 Dept of Urology, GRH and KMC, Chennai.
- 54. RPLND types (Suprahilar dissection) • Initial method: – Bilateral suprahilar dissections – All the nodal tissue between both ureters down to the bifurcation of the common iliac arteries are dissected • Complications – Pancreatic injury - infection – Renovascular complications • Current role of supra hilar dissection is reserved for residual mass after cytoreductive chemo for advanced NSGCT 54 Dept of Urology, GRH and KMC, Chennai.
- 55. Bilateral dissection -boundaries • Ureters laterally • Superiorly the inferior border of the superior mesenteric artery extended bilaterally at a level 1 to 2 cm above the renal arteries • Inferiorly to the midpoint of the ipsilateral external iliac artery and to the bifurcation of the contralateral common iliac artery including the aortic bifurcation 55 Dept of Urology, GRH and KMC, Chennai.
- 56. Suprahilar • Supra-hilar metastasis rarein low stage NSGCT • Reserved for residual hilar or suprahilar masses following chemotherapy • Higher complication rates • Chylous ascites 56 Dept of Urology, GRH and KMC, Chennai.
- 57. Modified RPLND templates •Limiting dissection in areas thought to be at reduced risk for metastatic spread • Based on surgical mapping studies • Do not identify specific nerve fibers resection of all interaortocaval and ipsilateral nodes 57 Dept of Urology, GRH and KMC, Chennai.
- 58. • Reduces traumato hypo gastric plexus and contralateral post ganglionic sympathetic fibers • Emerging data: underestimation of disease (3-23%) 58 Dept of Urology, GRH and KMC, Chennai.
- 59. 59 Dept of Urology,GRH and KMC, Chennai.
- 60. “Split & roll”technique 60 Dept of Urology, GRH and KMC, Chennai.
- 61. Nerve –dissection bilateral •Prospectively identifies and preserves both sympathetic chains, post ganglionic fibers and hypo gastric plexus • Anterograde ejaculation preserved in over 95% 61 Dept of Urology, GRH and KMC, Chennai.
- 62. Nerve-Sparing Techniques -requisites 1) In depth understanding of retroperitoneal anatomy 2) Ability to recognise variations in anatomy 3) Excellent exposure of the retroperitoneum 4) Meticulous application of “split and roll “ technique 62 Dept of Urology, GRH and KMC, Chennai.
- 63. Prospective Nerve-Sparing Technique •Appropriate candidates – Clinical stage I & low-volume stage II NSGCT – Selected subset of patients in post chemo RPLND 63 Dept of Urology, GRH and KMC, Chennai.
- 64. Prospective Nerve-Sparing Technique •The emphasis is in identification and preservation of relevant sympathetic nerves – (1) The sympathetic chains bilaterally – (2) The postganglionic sympathetic nerves arising from the sympathetic chains – (3) The hypogastric plexus (anastomosing network of nerve fibers anterior to the lower aorta) 64 Dept of Urology, GRH and KMC, Chennai.
- 65. Complications • Retrograde Ejaculation •Infertility • Prolonged ileus • Hemorrhage • Ureteral injury • Injury to major viscera • Lymphocele • Wound infection • Atelectasis • Pulmonary embolism • Bowel obstruction • Wound dehiscence 65 Dept of Urology, GRH and KMC, Chennai.
- 66. • Ante gradeejaculation requires: – Closure of bladder neck – Seminal emission – Ejaculation • Sympathetic fibers : T12-L3 • Parasympathetic fibers : S2,3,4 66 Dept of Urology, GRH and KMC, Chennai.
- 67. When Primary RPLND? • EAU • Alternative to Chemotherapy or Surveillance in – markers • Not willing to undergo primary Chemotherapy • NCCN • In CS IIa/b choice of treatment depends on marker levels, • And extension of abnormal radiographic findings in CS IIb (landing zone) • IGCCCG • In – markers and lymph nodes 1 -2 cm (CS IIa) as alternative to Surveillance 67 Dept of Urology, GRH and KMC, Chennai.
- 68. Primary NS-RPLND • AdvantagesRPLND – True pathological stage • Imaging 25% suprastaging /10% underestimation – If PS I : Follow-up (spare Chemotherapy) – If PS II: Follow-up or reduced Chemotherapy ( 2 vs 3 cycle ) – If Teratoma in the primary (?) • Disadvantages – Morbidity (perioperative / retrograde ejaculation) – Loco-regional treatment 68 Dept of Urology, GRH and KMC, Chennai.
- 69. Goals Primary NS-RPLND • As a Staging procedure – Very low morbidity !! • As a Curative procedure – No adjuvant chemotherapy – Less cycles than primary chemotherapy • As a Loco-regional procedure – Systemic relapse – Relapse outside landing zone 69 Dept of Urology, GRH and KMC, Chennai.
- 70. A standard establishedin 1987… • Phase III trial: 4 BEP vs 4 PVB (n=261) • BEP > PVB: – Poor prognosis NSGCT: DFS: 77% vs 61% (p<0.05) and OS (p<0.05) – Better tolerance (neurotoxicity) 4 BEP= standard 70 Dept of Urology, GRH and KMC, Chennai.
- 71. 4 BEP arenot 5, 6, or 7… • Giving additional cycles: – Did not demonstrate any improvement in outcome – Increases the risk of: • severe paresthesia, • auditive toxicity, • neutropenic fever, • and fertility troubles 71 Dept of Urology, GRH and KMC, Chennai.
- 72. 4 BEP vs4 VIP VIP: Etoposide,Ifosfamide,Cisplatin Nichols,J Clin Oncol 1998, 16: 1287-93 Hinton,Cancer 2003, 97: 1869-75 n= 304 Intermediate/poorrisk IGCCCG Poor prognosis (n=181) OS: 57% vs 62% 72 Dept of Urology, GRH and KMC, Chennai.
- 73. 73 Dept of Urology,GRH and KMC, Chennai.
- 74. 74 Dept of Urology,GRH and KMC, Chennai.
- 75. 75 Dept of Urology,GRH and KMC, Chennai.
- 76. Toxicities of chemotherapy •Nausea & vomiting • Nephrotoxicity • Myelosuppression • Peripheral neuropathy • Auditory toxicity • Pulmonary toxicity • Sarcoidosis 76 Dept of Urology, GRH and KMC, Chennai.
- 77. Vascular toxicity andmetabolic syndrome • The most significant delayed toxicity of BEP chemotherapy • Risk of cardiac events 2-7 fold • Reynaud's phenomenon • Altered lipoprotein • Hypercholestrolemia • Weight gain • Hypertension • Erectile dysfunction • Acute vascular events 77 Dept of Urology, GRH and KMC, Chennai.
- 78. Hypogonadism & infertility •Can be due to RT or chemotherapy • Chemotherapy affects germinal epithelium directly • Paternity – 62% at 15 years of surveillance • Cis-platin main offender • Cryopreservation of semen should offered to all patients (RT or chemotherapy or RPLND) 78 Dept of Urology, GRH and KMC, Chennai.
- 79. Second malignancies • Secondprimary GCT in contralateral testis – 2% • Etoposide - secondary leukemia – 6% patients receiving cumulative doses of 3000mg/m2 – 2-4 years latency • Solid tumors with RT and radiation exposure due to CT and PET scans (cum dose of 100 mSv) 79 Dept of Urology, GRH and KMC, Chennai.
- 80. Follow-up • Aim isto: – find out early and late relapses – Identify and manage treatment related side effects – Identify second malignancies • Frequency varies between institutions • Yearly visits after 5 years • Investigation during follow-up visit includes : 80 Dept of Urology, GRH and KMC, Chennai.
- 81. 81 Dept of Urology,GRH and KMC, Chennai.
- 82. Summary • Chemotherapy andRPLND cornerstones for the management of NSGCTs • Very high cure rates possible in these patients who are very young in the productive period • Follow up is essential not only to identify relapses but also for complications arising out of therapy in these long term survivors • Sperm banking is a very good option prior to treatment 82 Dept of Urology, GRH and KMC, Chennai.
- 83. 83 Dept of Urology,GRH and KMC, Chennai.
- 84. 84 Dept of Urology,GRH and KMC, Chennai.