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Advanced and Relapsed Cervix Cancer ESGO Teaching Course Yerevan Armenia September 2010

Advanced and Relapsed Cervix Cancer ESGO Teaching Course Yerevan Armenia September 2010. Nick Reed Beatson Oncology Centre GLASGOW. Relapsed Cervix Cancer. Follow up of Cervix Cancer Careful Monitoring Clinical exam Symptoms Is there any role for routine imaging?

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Advanced and Relapsed Cervix Cancer ESGO Teaching Course Yerevan Armenia September 2010

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  1. Advanced and Relapsed Cervix CancerESGO Teaching Course Yerevan Armenia September 2010 Nick Reed Beatson Oncology Centre GLASGOW

  2. Relapsed Cervix Cancer • Follow up of Cervix Cancer • Careful Monitoring • Clinical exam • Symptoms • Is there any role for routine imaging? • Imaging, CT MRI (PET) • Role of Pap smears

  3. Problems of Diagnosing Relapse • Post Radiation Effects • Difficulty in Interpretation • Need for Histological confirmation • Wait 3 months after treatment

  4. Prediction of Relapse • Traditional data indicate about 35% of patients will relapse • Stage 1B ) 10-20% • Stage 2A ) • Stage 3B ) • Stage 4A ) 60-70% • Stage 4B )

  5. Typical Symptoms of Relapse • Weight loss, Leg Oedema • Pelvic and/or thigh/buttock pain • Back ache • Bloody vaginal discharge • Supraclavicular Lymph Nodes • Cough, SOB, Haemoptysis • Chest pain

  6. Sites of metastatic disease Metastatic sites treated patients Henriksen E: Am J Obst &Gyn 1949 Metastatic sites untreated patients Henriksen E: Am J Obst & Gyn 1949

  7. Relapsed Cervix Cancer Following RT • 27% relapses in Cervix / Uterus or upper vagina • 6% Lower vagina • 43% Parametrium • 16% Distant • 8% Unknown Following RHND • 25% local recurrences at vault/upper vagina

  8. Relapsed Cervix Cancer • Triad of: • Weight Loss + Pelvic Pain + Oedema Legs • Ureteric obstruction • Back ache from Hydronephrosis

  9. Relapsed Cervix Cancer • Traditionally most deaths within 1st year • 50% of deaths within 12 months • 25% in second year • 15% during third year • Newer CCRT may delay this pattern

  10. Chemotherapy for Relapse • Predictors of Response • Site of disease following RT • Intra Field vs Outwith RT field • e.g. Para-aortics • Chest, Lung mets only • Other sites

  11. Localised Disease Surgery (Exenteration) Radiation Chemo-radiation Metastatic disease Chemotherapy Hyperthermia Chemo-radiation New Drugs Novel approaches Management of Relapse

  12. Response Rates • Response with Isolated Relapses • Response in lungs : CR 53% OR 73% • Response in pelvis : CR 0% OR 21% (Potter M : Cancer 1989) • Highlights Issues of vascular access • Hypoxia • Most studies differentiate prior RT

  13. Chemotherapy for Relapsed disease • Wasserman & Carter 1977 Review • Limited drugs available • No differences allowed for site or prior therapy • Pre Platinum era

  14. Chemotherapy for Cervix • Post 1977 • Recognition of influencing factors • Chemo naïve vs prior therapy • Previous EBRT • Advent of cisplatin • Major Impact!!

  15. Platinum • Initial data used cisplatin @ 50 mg/m2 • Given every 3 weeks • GOG 43 : 20-31% RR

  16. Ifosfamide Phase 2 studies • Coleman R 16-40% RR incl. 20% CR and median response of 26 mo • Sutton GOG : 15.7% RR • Cervellino 1995 : 50 RR% • Cis vs Cis Ifos GOG

  17. Mitolactol 28-29% Epirubicin 27% Mitomycin C 12% Vindesine 0-30% Vinorelbine 13-21% Newer Drugs Topotecan Gemcitabine Taxol 17% Irinotecan 20% Other Drugs in Cervix Cancer

  18. Combinations • Non cisplatin containing • Cisplatin containing • Bleomycin added • Vogl reported Cis/ Bleo/ Mtx

  19. C Ifx Bleo vs. C Ifx : GOG # 149 32% vs. 31% PFS and OS = Bloss (JCO 2002 15: 165-171)

  20. Relapsed Cervix Cancer • SWOG : Comparative studies • Cis 33% 17 mo • Cis + MMC 25% 7 mo • Cis+ MMC + Bleo +V 22% 6.9 mo Alberts D ; JCO 1987: 5:1791-5

  21. Relapsed Cervix Cancer • Cis + Epi > Cis + Dox, ? Why difference • BIP : 69-74% RR • GOG study # 110 • Cis 17% RR 3.2 mo PFS • Cis + Ifos 31% RR 4.6 mo PFS • Cis + Mitolactol 21% RR 3.3 mo PFS

  22. Glasgow

  23. EORTC Studies • 55802 Phase 2 VCR/Bleo/MMC/Cis (VBMP) • 55811 Phase 2 Vindesine • 55832 Phase 2 MMC/ Cis • 55835 Phase 2 Bromocriptine • 55883 Phase 2 Vinorelbine • 55842 Phase 2 Epirubicin • 55863 Phase 3 P vs BEMP

  24. EORTC VBMP : 55802 • Group A Distant mets • 26 pts • 54% RR -31% CR • Median TTP 20 wk • Median Survival 42 wk • Group B Pelvic mets • 24 pts (23 prior RT) • 25% RR - all PR • Median TTP 15 wk • Median Survival 32 wk Vermorken JB et al, Int J Gyn Cancer 2000,10: 358-65

  25. EORTC55832 Phase 2 MMC/ Cis • Mitomycin C 6 mg/m2 d1 • Cisplatin 50 mg/m 2 d1 • 33pts All bar 1 had prior Sx/RT • 25 distant mets only , 8 local • OR 42% • 5 CR 9 PR duration 7.9 mo • Median Overall Survival 11.2 mo Wagenaar HC et al Eur J Cancer 37 1624-1628, 2001

  26. EORTC 55863 P vs BEMP • Cisplatin 50 mg/m2 • Bleomycin 15 mg/ m2 d2-4 • Eldisine 3 mg/ m2 d1 • Mitomycin C 8mg/m2 d1 alt cycles • Cisplatin 50 mg/m2 d1 • Q 3/52 x4 then Q 4/52 sine Bleo

  27. EORTC 55863 P vs BEMP BEMP 35% RR (CR 9%) P 20% RR (CR 6%)

  28. BEMP RR All pts 35% Eligible 42% Evaluable 54% CR 11% Med Duration 9.2 mo CISPLATIN RR All pts 20% Eligible 25% Evaluable 27% CR 7% Med Duration 7 mo BEMP vs P

  29. Future Directions Outside clinical trials the use of Cisplatin alone is still the gold standard if chemotherapy is used for palliation. The use of more aggressive regimes seems to bring additional toxicity. GOG 169 and 179 bring fresh light.

  30. GOG studies • GOG 169 • GOG 179 • GOG 204 • GOG 240

  31. Cisplatin + Taxol • Cisplatin & Paclitaxel • 47% RR (CR 14%, PR 33%) OS 9 mo Christos & Papadimitriou • GOG #169 • Cisplatin (50 mg/m2) 19.4% • Cis + Paclitaxel (135 mg/m2 /24 hr) 36.2% • Cis CR 8% PR 18% OS 8.8 mo • Cis Tax CR 20% PR 27% OS 9.7 mo Moore D, Proc ASCO 2001:20;201a

  32. Cisplatin (P) vs Cisplatin plus Paclitaxel (PP)Phase III Study in SCCUC (GOG 169) R A N D O M I Z E Patients Cisplatin 50 mg/m² Stage IV B q 3 wks x 6 Recurrent/persistent (n=134) Measurable disease PS 0-2 Cisplatin 50 mg/m² Paclitaxel 135 mg/m²/24h Paclitaxel 135 mg/24 hrs q 3 wks x 6 (n=130)

  33. Cisplatin (C) vs Cisplatin plus Paclitaxel (CP)Phase III Study in SCCUC (GOG 169) C CP n=134 n=130 p-value Response rate 19% 36% 0.002 CR rate 6% 15% < 0.05 Median PFS 2.8mo 4.8mo <0.001 Median survival 8.8mo 9.7mo ns Neutropenia (G3+4) 31% 66.6% Anemia (G3+4) 13% 27.9% Quality of life no significant difference in scores

  34. Cisplatin (C) vs Cisplatin plus Paclitaxel (CP)Phase III Study in SCCUC (GOG 169)Response rate according to previous platinum chemoradiation radiation C 2/40 ( 5%) 24/94 (26%) C+P 10/31 (32%) 37/99 (37%)

  35. GOG 169 Cis vs Cis taxol

  36. GOG 169 and QOL

  37. 179

  38. GOG 179 • Cisplatin • MVAC** • Cisplatin Topotecan • ** Stopped early because of toxicity

  39. GOG 179 Relapsed Cervix

  40. GOG 179 Relapsed CervixOverall survival Long H et al JCO 2005 : 23; 4626-33

  41. QOL in GOG

  42. GOG 204 • Cisplatin paclitaxel • Cisplatin topotecan • Cisplatin vinorelbine • Cisplatin gemcitabine • No difference

  43. Relapsed Cervix CancerNon Platinum agents • Taxol 175 mg/m2 d 1 • Topotecan 1 mg/m2 d 1-5 • 54% RR ( 1CR and 6 PR) & 23% SD • PFS 3.7 mo OS 8.6 mo Tiersten et al Gyn Onc 92,635-638: 2004 • Phase 2 RCTs , only conclusion is that no added advantage to > 1 drug

  44. GOG 240 • Cisplatin and paclitaxel • vs • Paclitaxel and topotecan • +/- Bevacizumab

  45. Newer Directions • SNAP 01 • TIP vs IP • Neo-adjuvant schedules • Carboplatin and paclitaxel • Cisplatin plus other drugs

  46. TIP • Taxol + Ifos + Cisplatin • OR 66% (CR 33%, PR 33%) • Survival in CR 13 mo+ • Survival in PR 9 mo+ • Survival in Non 6 mo Zanetta, Mangioni et al

  47. PFS and OS for SNAP 01: IP vs. TIP TIP TIP IP IP

  48. Anti-EGF Receptor Therapies EGFR expression observed in 75-100 % of CC Phase II study ZD1839 (500mg/d), no responses Inhibition of angiogenesis a/o matrixmetalloproteinases. One complete response with TNP-470, an analogue of fumagillin, was seen in phase I. Inhibition of COX-2 enhanced cytotoxicity in vitro of chemotherapy agents: potentiates tumor cell radiosensitivity in vivo EGFR Tyrosine kinase inhibitors Cetuximab (Erbitux) Alone? Or Combined with radiation? See H&N SCC data

  49. VEGFR • Avastin for relapse 2nd or 3rd line • SGO abstract 2008 • Reported 25% RR • How to integrate? • 1st line for hypoxic tumours? • Use of markers to predict, CAIX • Functional Imaging

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