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ESTRO Educational Course Mumbai, India 2005

ESTRO Educational Course Mumbai, India 2005. Chemo/Radiation in Cervical Cancer. G. Thomas M.D. Stage LC % 5 YR S ( %) † Bulky IB 79 -87 63 -75 IIB 73 -82 62 - 68 IIIB 53 -63 28 - 48 IV 25 18 - 34

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ESTRO Educational Course Mumbai, India 2005

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  1. ESTRO Educational CourseMumbai, India 2005 Chemo/Radiation in Cervical Cancer G. Thomas M.D.

  2. Stage LC % 5 YR S ( %)† Bulky IB 79 -87 63 -75 IIB 73 -82 62 - 68 IIIB 53 -63 28 - 48 IV 25 18 - 34 † Lanciano,Weems, Mendenhall, Eifel, Perez, Thomas, Montana, Kramer, Million. Representative Results of Radical Radiation Alone By Stage

  3. Concurrent Chemotherapy/ Radiation Therapy National Cancer Institute Clinical Announcement, February 1999 “… five randomized phase III trials show an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy” “… strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer”

  4. Concurrent Chemotherapy/ Radiation Therapy “The New Standard” How strong is the evidence of benefit? What don’t we know?

  5. Ca Cervix, Selected* Stages IB/IIARH + PLND: RT Alone vs. RT + FU/Plat(Peters et al, JCO 18, ‘00) Progression Free Survival 78% P=0.005 60% Years *node,parametria,margin +ve.

  6. Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*(Keys et al, NEJM 340, ‘99) RT (Hyst)RT / Plat (Hyst) n185 183 Recurred 32% (59) 18% (33) Pelvic failure 21% 9% NED (2 year) 68% 82% * GOG #123

  7. Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*(Keys et al, NEJM 340, ‘99) 82% 68%

  8. Concurrent HU/RT vs FU/Plat/RT in Advanced (IIB-IVA) Ca Cervix(Whitney et al, JCO 17, ‘99) 57% 47%

  9. Concurrent HU/RT vs HU, 5FU,Plat/RT vs Weekly Plat/RT in Advanced (IIB-IVA) Ca Cervix(Rose et al, NEJM, ‘99) RT+Plat: 67% RT+FU,PLAT,HU RT+HU: 47%

  10. Advanced Ca Cervix: Pelvic RT + 5FU/Plat vs Pelvic & Para-aortic RT(Morris et al, NEJM, ‘99) 67% 40%

  11. Med FU: 6.6 yrs RT CT/RT n 195 194 5yr S %, 52 73 p<0.0001 5yr DFS % 43 68 p<0.0001 Pelvic recurrence 34 18 p<0.0001 Dist mets 31 18 p=0.0013 IB / IIA S % 55 79 * p<0.0001IIB / III 47 59 p=0.07 Complications %(>Gd3) 14 14 Concurrent Chemo-Radiation + RTvs Extended Field RT (RTOG 90-01)(Eifel et al, JCO: 22, 2004)

  12. LOCAL RECURRENCE RATES % AUTHORSTAGE ‘CONTROL’ CT/RT Keys IB 24 11 Peters IB/IIA 22 9 Morris IIB-IVA 35 19 Whitney IIB-IVA 30 25 Rose IIB-IVA 30 20 Ca Cervix:Concurrent Chemo/Radiation Therapy

  13. 100 80 p=0.53 e g 60 a t n e Adjusted for stage p=0.43 c 40 r e P 20 0 0.0 2.0 4.0 6.0 8.0 127 100 51 25 0 126 92 52 17 0 Time (years) Cisplatin and radiation Radiation alone RT vs Concurrent RT/Plat, Advanced Ca Cervix: Survival(Pearcey et al, JCO 20, ‘02)

  14. PFS % Control CT/RT Positive trials: (Morris, Whitney, Rose) 40- 47 57 –64 Negative trials: 53- 58 58 - 62 (Thomas ,Pearcey) Difference is in the “control arms”.RT dose, use of IC similar . But Overall TIME :Positive trials 58-64 dys Negative trials 44-59 dys Loss of LC is  1% / dy prolongation over  50 days . Comparability of Outcomes, CT/RT Advanced Cervix Trials

  15. Plat/RT vs RT in Advanced Ca Cervix(Pearcey et al, JCO 20, ‘02) % of pts Decrease in Hgb (g/l) during treatment (RT/Plat vs RT : p = 0.003)

  16. Reduction in the Risk of Death from Five Chemoradiation Clinical Trials in Cervix Cancer

  17. Is Cisplatin a)necessary, b) sufficient, c) optimal for concurrent chemo/RT? CT/RT in Ca Cervix

  18. Phase III Study :RT/Plat vs RT/FU ( PVI) in Advanced Ca CervixLanciano et al. submitted JCO 2004 Plat FU ns FUfu

  19. Concurrent Mitomycin, 5-FU and RT in Advanced Ca Cervix(Lorvidhaya et al, IJORBP 55, 2003) RT+Conc+Adj RT+Conc RT+Adj RT

  20. RT CT/RT  CT Number 110 110 RELAPSE % Pelvic (any) 24 15 p = 0.99 Distant (any) 24 8 p = 0.012 Total 33 21 Concurrent and Adjuvant Epirubicin/ Radiation Therapy, Ca Cervix Stage I-III(Wong et al, JCO 17, ‘99)

  21. Concurrent & Adjuvant Epirubucin/RT, Ca Cervix Stage I-III(Wong et al, JCO 17, ‘99)

  22. DISTANT METASTASES RATE: AUTHOR ‘CONTROL’ CT/RT Keys 16 12 Peters 12 7 Morris 33 14 Whitney* 20 17 Rose* 10 3-4 * Lung 2 Ca Cervix:Concurrent Chemo/Radiation Therapy

  23. Survival RR StageTreatment Benefit Death Control Comparison IB21 RT RT+wkly Plat 9% 0.54 IB or IIA2 RT RT+Plat,FU 10% 0.5 IIB-IVA3 RT+HU RT+Plat,FU 10% 0.74 IB2-IVA4 Ext field RT RT+Plat,FU 12% 0.58 IIB-IVA5 RT+HU RT+wkly Plat 18% 0.61 RT+Plat,FU,HU 18% 0.58 IB-IVA6 RT RT+wkly Plat 3% 0.91 Log Weighted Average all studies0.65 1Keys, 2Peters, 3Whitney, 4Morris, 5Rose, 6Pearcey Ca Cervix: Relative Risk of Death in Six Clinical Trials of Concurrent CT/RT

  24. Overall Survival after ConcomitantCT/RT: a Systematic ReviewGreen et al Lancet 358, 01

  25. ACUTE TOXICITY %, Grade 3/4: 1ST AUTHORCHEMOHAEMGIGUOTHER Rose Plat 19 7 3 6 Keys Plat 21 14 2 8 Pearcey Plat 5 13 2 12 Whitney Plat/FU 7 8 1 0 Morris Plat/FU 37 17 1 8 Peters Plat/FU 39 44 - 8 Ca Cervix:Concurrent Chemo/Radiation Therapy

  26. (78% sidewall disease)

  27. Indications for Concurrent CT/RTProven Benefit 1. As post surgical adjuvant for IB/IIA node, parametrial, margin positive 2. As definitive treatment (without routine Sx) in Stage IB2 3. As definitive treatment for Stage IIB-IVA

  28. Unproven or Questionable Benefit for Concurrent CT/RT • 1. Post surgical adjuvant for Stage IB with negative nodes but high risk features (size, depth, CLS) • 2. For para-aortic nodal involvement • In Stage IIB-IVA where RT delivery is optimized and hemoglobin levels maintained • For recurrent disease

  29. Future Directions: • Optimize RT ! • Attempts to overcome anemia/hypoxia. Concurrent Chemo/Radiation in Ca Cervix

  30. 3. Determine if benefits of CT/RT accrue to only some subsets of patients: Define subgroups likely to have therapeutic gain by characteristics defined by, e.g. a. ‘conventional’ staging b. functional imaging (MRI, PET) c. molecular markers d. Gene assays e. DNA/Plat adduct assays f. Dynamic oxygenation status Chemo/Radiotherapy in Ca Cervix

  31. 4. Identify ‘better’ agents to  pelvic control tailored to specific molecular characteristics: - Tirapazamine - Taxanes, Gemcitabene - antiangiogenics - exploit molecular targets that block proliferation /invasion or sensitize tumours (Cox-2) or target activated oncogenes(e.g.RAS) 5. Explore adjuvant as well as concurrent schedules to  distant metastases. 6. Define existing acute and late toxicities and choose strategies to minimize them. Chemo/Radiotherapy in Ca Cervix

  32. Ca Cervix: The Future Prevention- Vaccines

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