1. GT/05 ESTRO Educational Course Mumbai, India 2005 G. Thomas M.D. Chemo/Radiation in Cervical Cancer

2. GT/05 Representative Results of Radical Radiation Alone By Stage Stage LC % 5 YR S ( %) † Bulky IB79 -8763 -75 IIB73 -8262 - 68 IIIB53 -6328 - 48 IV 25 18 - 34 † Lanciano,Weems, Mendenhall, Eifel, Perez, Thomas, Montana, Kramer, Million.

3. GT/05 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. GT/05 Concurrent Chemotherapy/ Radiation Therapy “The New Standard” How strong is the evidence of benefit? What don’t we know?

5. GT/05 Years Progression Free Survival Ca Cervix, Selected* Stages IB/IIA RH + PLND: RT Alone vs. RT + FU/Plat (Peters et al, JCO 18, ‘00) 78% 60% P=0.005 *node,parametria,margin +ve.

6. GT/05 Bulky IB Ca Cervix RT (+ Hyst) vs RT + Weekly Plat (+ Hyst)* (Keys et al, NEJM 340, ‘99) RT (Hyst)RT / Plat (Hyst) n185183 Recurred32% (59) 18% (33) Pelvic failure21% 9% NED (2 year)68%82% * GOG #123

7. GT/05 Bulky IB Ca Cervix RT (+ Hyst) vs RT + Weekly Plat (+ Hyst)* (Keys et al, NEJM 340, ‘99) 68% 82%

8. GT/05 Concurrent HU/RT vs FU/Plat/RT in Advanced (IIB-IVA) Ca Cervix (Whitney et al, JCO 17, ‘99) 47% 57%

9. GT/05 Concurrent HU/RT vs HU, 5FU,Plat/RT vs Weekly Plat/RT in Advanced (IIB-IVA) Ca Cervix (Rose et al, NEJM, ‘99) RT+HU: 47% RT+Plat: 67% RT+FU,PLAT,HU

10. GT/05 Advanced Ca Cervix: Pelvic RT + 5FU/Plat vs Pelvic & Para-aortic RT (Morris et al, NEJM, ‘99) 67% 40%

11. GT/05 Med FU: 6.6 yrs RTCT/RT n195194 5yr S %, 5273 p<0.0001 5yr DFS %43 68 p<0.0001 Pelvic recurrence 3418 p<0.0001 Dist mets31 18 p=0.0013 IB / IIA S %5579 * p<0.0001 IIB / III 47 59 p=0.07 Complications %(>Gd3)14 14 Concurrent Chemo-Radiation + RT vs Extended Field RT (RTOG 90-01 ) (Eifel et al, JCO: 22, 2004)

12. GT/05 Ca Cervix: Concurrent Chemo/Radiation Therapy LOCAL RECURRENCE RATES % AUTHORSTAGE‘CONTROL’CT/RT KeysIB2411 PetersIB/IIA22 9 MorrisIIB-IVA35 19 WhitneyIIB-IVA3025 RoseIIB-IVA30 20

13. GT/05 (Pearcey et al, JCO 20, ‘02) RT vs Concurrent RT/Plat, Advanced Ca Cervix: Survival (Pearcey et al, JCO 20, ‘02)

14. GT/05 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. GT/05 Plat/RT vs RT in Advanced Ca Cervix (Pearcey et al, JCO 20, ‘02) Decrease in Hgb (g/l) during treatment (RT/Plat vs RT : p = 0.003) % of pts

16. GT/05 Reduction in the Risk of Death from Five Chemoradiation Clinical Trials in Cervix Cancer

17. GT/05 CT/RT in Ca Cervix Is Cisplatin a) necessary, b) sufficient, c) optimal for concurrent chemo/RT?

18. GT/05 Phase III Study :RT/Plat vs RT/FU ( PVI) in Advanced Ca Cervix Lanciano et al. submitted JCO 2004 FUfu FU Plat ns

19. GT/05 Concurrent Mitomycin, 5-FU and RT in Advanced Ca Cervix (Lorvidhaya et al, IJORBP 55, 2003) RT RT+Adj RT+Conc+Adj RT+Conc

20. GT/05 Concurrent and Adjuvant Epirubicin/ Radiation Therapy, Ca Cervix Stage I-III (Wong et al, JCO 17, ‘99) RTCT/RT  CT Number110110 RELAPSE % Pelvic (any) 24 15p = 0.99 Distant (any) 24 8p = 0.012 Total 33 21

21. GT/05 Concurrent & Adjuvant Epirubucin/RT, Ca Cervix Stage I-III (Wong et al, JCO 17, ‘99)

22. GT/05 Ca Cervix: Concurrent Chemo/Radiation Therapy DISTANT METASTASES RATE: AUTHOR‘CONTROL’CT/RT Keys16 12 Peters12 7 Morris33 14 Whitney*20 17 Rose*10 3-4 * Lung 2 

23. GT/05 SurvivalRR Stage Treatment Benefit Death Control Comparison IB2 1 RTRT+wkly Plat 9%0.54 IB or IIA 2 RTRT+Plat,FU10%0.5 IIB-IVA 3 RT+HURT+Plat,FU10%0.74 IB2-IVA 4 Ext field RTRT+Plat,FU12%0.58 IIB-IVA 5 RT+HURT+wkly Plat18%0.61 RT+Plat,FU,HU18%0.58 IB-IVA 6 RTRT+wkly Plat 3%0.91 Log Weighted Average all studies0.65 1 Keys, 2 Peters, 3 Whitney, 4 Morris, 5 Rose, 6 Pearcey Ca Cervix: Relative Risk of Death in Six Clinical Trials of Concurrent CT/RT

24. GT/05 Overall Survival after Concomitant CT/RT: a Systematic Review Green et al Lancet 358, 01

25. GT/05 Ca Cervix: Concurrent Chemo/Radiation Therapy ACUTE TOXICITY %, Grade 3/4: 1ST AUTHORCHEMOHAEMGIGUOTHER RosePlat 19 7 3 6 KeysPlat 2114 2 8 PearceyPlat 513 2 12 WhitneyPlat/FU 7 8 1 0 MorrisPlat/FU 3717 1 8 PetersPlat/FU 3944 - 8

26. GT/05 (78% sidewall disease)

27. GT/05 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 Indications for Concurrent CT/RT Proven Benefit

28. GT/05 1.Post surgical adjuvant for Stage IB with negative nodes but high risk features (size, depth, CLS) 2.For para-aortic nodal involvement 3.In Stage IIB-IVA where RT delivery is optimized and hemoglobin levels maintained 4.For recurrent disease Unproven or Questionable Benefit for Concurrent CT/RT

29. GT/05 Future Directions: 1.Optimize RT ! 2.Attempts to overcome anemia/hypoxia. Concurrent Chemo/Radiation in Ca Cervix

30. GT/05 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. GT/05 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. GT/05 Ca Cervix: The Future Prevention- Vaccines