7. NCCN Guidelines v.1.2011. – for locally advanced cervical cancer NCCN Practice Guidelines in Oncology v.1.2011 FIGO TH ERAPY 5 - y OS IA2 - IB1 IIA1 Surgery or radiotherapy 85-98 IB2 - IIA2 Surgery or Ct/ R t + surgery ~ 60-65 IIB - IVA Ct / R t 20-65 IVB Palliative C t Or S t or surgery + I ort <5

9. Overall survival rates 1Keys (GOG123), 2Rose (GOG120), 3Morris (RTOG9001), 4 Whitney (GOG85), 5 Peters SWOG8797/GOG109

11. NCIC RANDOMI ZED radiation therapy alone radiation with weekly cisplatin at a dose of 40 mg/m2/wk Pearcey et al JCO, 2002. - 253 patients - stage IB (tumor size 5 cm) to IVA

12. Conclusion Survival was not significantly different at 3 years (69% v 66%) or 5 years (62% v 58%) for chemotherapy and radiation or radiation alone Pearcey et al JCO, 2002. 12% lower death rate for the chemoradiation group

19. Kaplan - Meier curves for survival. GOG, Gynecologic Oncology Group; SWOG, Southwest Oncology Group; FU, fluorouracil; MMC, mitomycin; CDDP, cisplatin; CDBCA, carboplatin; VCR, vincristine; BLM, bleomycin; CTRT, hemoradiotherapy; O-E, observed minus expected events. J Clin Oncol 2008 ;26 :5802-5812. Difference in survival when inadequate adjuvant chemotherapy is given

20. Meta-analysis - results J CO 2008 ;26 :5802-5812 . Note: two trials with consolidation chemotherapy are excluded from analysis Survival measure HR 95 % CI P Absolute 5-year survival benefit (%) Overall DFS 0.78 0.70–0.87 0.000005 8 Locoregional DFS 0.76 0.68–0.86 0.000003 9 Metastasis free survival 0.81 0.72–0.91 0.0004 7

21. J Clin Oncol 26; 2008:5802-5812. ASCO Are we equaly effective in the treatment of different stages of the disease?

26. Is there any room for improvement ?

27. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy: An innovative, very promising treatment for women with locally advanced carcinoma of the uterine cervix - final results of prospective phase II - study Vrdoljak E, et al. Gynecol Oncol. 2006 Nov;103(2):494-9. (4)

29.  external beam radiation 2 Gy x intracavitary brachytherapy 30 Gy to point A + Ifosfamide 2 g/m 2 + Cisplatin 75 mg/m 2 x 1 Ifosfamide 2 g/m 2 , q21d x 4 x 2 Cisplatin 75 mg/m 2 , q21d x 4 Study treatment Ifosfamide 2000 mg/m 2 in 24 hr infusion + Cisplatin 75 mg/m 2 in 1 hr infusion applied during two LDR brachytherapy applications Consolidation chemotherapy with Ifosfamide 2000 mg/m 2 in 3 hr infusion (day 1-3) + Cisplatin 75 mg/m 2 in 1 hr infusion (day 1) - 4 cycles . 1 2 3 4 5 6 7 8 9 10 ....... 15 22 29 30 31 32 33 34 35 36 52 53 54 days                          x x x 2 x 1 x 1 x 1

32. To explain some important points of the study !

36. Ifosfamide shows s y nergistic action with LDR brachytherapy ! Tonkin et al., Br J Cancer 1988; 58:738-44 Days LD R=low dose-rate (5 cGy/min) Days

38. Wong LC et al. J Clin Oncol 1999 . RANDOMI ZED Radiotherapy only Concomitant chemoradiotherapy (epirubicin 60 mg/m 2 ) + adjuvant chemotherapy (epirubicin 90 mg/m 2 x 5) Chemoradiation and Adjuvant Chemotherapy in Cervical Cancer: a randomized trial - Phase III trial, 220 pts - Bulky stage I, II, III - Median FU 77 months

39. Wong LC et al. J Clin Oncol 1999 . Chemoradiation and Adjuvant Chemotherapy in Cervical Cancer: a randomized trial Cumulative survival rate of patients with cervical cancer treated by radiotherapy versus radiotherapy plus chemotherapy. P 5 .04 (log-rank test).

42. RANDOMI ZED Cis 40 mg/m2 + Gem 125 mg/m2 weekly x 6 doses + concurrent XRT (50.4 Gy/28/x, 5 days/week) + brachy (30-35 Gy) + 2 adjuvant 21-day cycles of Gem (1,000 mg/m2 on Days 1 and 8) + Cis (50 mg/m2 on Day 1) Cis 40 mg/m2 weekly x 6 doses with concurrent XRT followed by brachy, given as in Arm A A. Dueñas-González, et al. J Clin Oncol 27:18s, 2009 Concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix: a randomized trial - phase III study , 515 pts (259 Arm A, 256 B) - bulky stage IIB to IVA - primary endpoint: PFS at 3 years

45. Peters et al. J Clin Oncol 2000 RANDOMI ZED Radiotherapy only Concomitant chemoradiotherapy+adjuvant chemotherapy (overall 4 cycles of cisplatin/5FU) SURGERY Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high risk early - stage cancer of the cervix: randomized trial - Phase III trial, 286 pts - Stages IA2,IB, IIA with high risk features

47. Peters et al., JCO 2000; 18:1606 The favorable survival seen in pts receiving a 3 rd or 4 th cycle of CT after completion of RT vs pts receiving only 1 or 2 CT - cycles ( P = 0.03) suggests that the CT was having an effect independent of the RT . Consolidation chemotherapy is active?

50. Improvements in breast cancer treatment 100 80 60 40 20 0 % Recurrence free 0 Years 2 4 6 8 10 AC + T AC CMF Nil Recurrence risk / year BIG = 1 6 ,0 % (- 33 %) AC + T = 8,3 % (-17%) AC = 10,0 % (-11%) CMF = 11,4 % (-24%) Nil = 15,0 % HR th

51. Why brachyradiochemotherapy? Beside Ifosfamide s y nergistic action with LDR brachytherapy ! Tonkin et al., Br J Cancer 1988; 58:738-44 Days XRT=low dose-rate (5 cGy/min) Days

60. Results OVERALL SURVIVAL at median FU of 58 months 83.8%!

61. Acute toxicity T oxicity grade 0 1 2 3 4 Leukopenia 44 (17%) 57 (21%) 71 (26%) 69 (25%) 29 (11%) Anemia 44 (16%) 105 (39%) 93 (35%) 24 (9%) 3 (1%) Thrombocytopenia 199 (74%) 47 (17%) 15 (6%) 8 (3%) 0 Urea, creatinine 277 (98%) 1 (0.5%) 1 (0.5%) 0 2 (1%) Diarrhea 231 (78%) 40 (13%) 19 (6%) 8 (3%) 0 Nausea 64 (21%) 115 (39%) 99 (33%) 20 (7%) 0 Vomiting 103 (35%) 82 (28%) 93 (30.5%) 19 (6%) 1 (0.5%)

62. Late toxicity Toxicity N (%) Toxicity grade R adiation proctitis 1 (1.6) 2 R adiation colitis 2 (3.2) 3, 4 R adiation cistitis 3 (4.8) 2, 3, 4 R ectovaginal fistula 2 (3.2) 4, 4 U reteral obstruction 3 (4.8) 3, 3, 4 V esicovaginal fistula 1 (1.6) 4 S ubcutaneous fibrosis 1 (1.6) 2

64. Promissing new directiones

67. Taylor A, Powelly M.E.B. Clin Oncol 2008; 20:417-425 Studies assessing the adequacy of uterus and cervix coverage by conventional field borders Study Field borders Inadequate cover of target volume Anterior Posterior 12 Mid symphysis Mid S2/3 56% GTV, 63% uterus 13 Mid symphysis Middle of rectum 53% 14 15 Mid symphysis Anterior symphysis Mid S2/3 S3 63% 6% anteriorly 24% posteriorly 16 17 Anterior symphysis Anterior symphysis Post S2/3 S2/3 20% cervix 9% anteriorly 49% posteriorly 18 Anterior symphysis S2/3 33% supine 24% prone

73. Grogan M et al. Cancer 1999; 86: 1531-1536 Patient survival according to fall in Hb level during RT

78. RANDOMI ZED same + 4-6 cycles of adjuvant chemotherapy radiation with weekly cisplatin at a dose of 40 mg/m2/wk - 400 patients - stage IB (tumor size 5 cm) to IVA PLEASE - We really have to design and run adjuvant chemotherapy trial