BALKAN MCO 2011 - E. Vrdoljak - Advanced cervical cancer - what is the gold standard

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  • 54 Mundt AJ, Roeske JC, Lujan AE, et al. Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic malignancies. Gynecol Oncol 2001; 82:456e463. 55 Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56:1354e1360. 56 Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensitymodulated whole-pelvic radiation therapy. Radiother Oncol 2003;69:201e207. 57 Brixey CJ, Roeske JC, Lujan AE, et al. Impact of intensitymodulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;54:1388e1396. 58 Lujan AE, Mundt AJ, Yamada SD, et al. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516e521.
  • 52 Greven KM, Lanciano RM, Herbert SH, et al. Analysis of complications in patients with endometrial carcinoma receiving adjuvant irradiation. Int J Radiat Oncol Biol Phys 1991;21: 919e923. 53 Yamazaki A, Shirato H, Nishioka T, et al. Reduction of late complications after irregularly shaped four-field whole pelvic radiotherapy using computed tomographic simulation compared with parallel-opposed whole pelvic radiotherapy. Jpn J Clin Oncol 2000;30:180e184.
  • BALKAN MCO 2011 - E. Vrdoljak - Advanced cervical cancer - what is the gold standard

    1. 1. <ul><li>Prof. Eduard Vrdoljak ,MD., PhD. </li></ul><ul><li>Center of Oncology and Radiotherapy </li></ul><ul><li>University Hospital Center Split </li></ul><ul><li>Eduard Vrdoljak </li></ul><ul><li>Clinical Hospital Centre Split, 2009. </li></ul>Advanced cervical cancer - what is the gold standard?
    2. 2. Estimated Cervical Cancer Incidence Worldwide in 2008 <ul><li>the most common cancer in woman of subsaharian Africa, central and south America, southeast Asia et Melanesia (78% of all cases) </li></ul><ul><li>the 2. most frequent cause of cancer death in women </li></ul><ul><li>500000 new cases and 260000 death/year – 95% in developing countries </li></ul>0 5.8 12.2 21.0 34.7 57 Age-standardised incidence rates per 100,000 GLOBOCAN 2008, International Agency for Research on Cancer Parkin DM. CA Cancer J Clin 2005;55:74-108
    3. 3. Pathology of cervical cancer <ul><li>80% squamous cell carcinomas </li></ul><ul><li>(developed cuontries – decline in incidence and mortality – result of effective screening) </li></ul><ul><li>20% adenocarcinomas </li></ul><ul><li>(incr ea sed in last t h ree years – citologyc screening methods less effective for adenoca; screening for HPV incr ea ses detection) </li></ul>Cancer Research UK website
    4. 4. Biology of cervical cancer <ul><li>Cervical carcinoma is very local disease until very late time of progression </li></ul><ul><li>Very large number of pts who are dying of cervical carcinoma are dying of uncontrolled local disease </li></ul>
    5. 5. Stage distribution <ul><li>Despite effective screening programs 2/3 of patients are diagnosed in advanced stages o f disease </li></ul>
    6. 6. Epidemiology 0 20 30 40 50 60 70 80 90 70 60 50 40 30 20 10 cervix ovary uterus vagina and vulva Incidence / 100 000 Years <ul><li>Age-adjusted standardized rate </li></ul><ul><li>Cervix 24.5 </li></ul><ul><li>Ovary 16.4 </li></ul><ul><li>Uterus 13.15 </li></ul><ul><li>Vagina and vulva 2.57 </li></ul>
    7. 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
    8. 8. NCI announcement – February 1999 . <ul><li>Based on the results of five prospective, randomized, large, multicentric studies NCI made a rare announcement proposing concurrent chemoradiotherapy with cisplatin as golden standard for the treatment of locally advanced cervical cancer . </li></ul><ul><li>30 – 50% decrease in risk of death vs. RT alone </li></ul>Morris et al., NEJM 1999; 340:1137-1143, Keys et al., NEJM 1999; 340:1154 , Peters et al., JCO 2000; 18:1606 , Whitney et al. JCO 1999;17:1339, Rose et al. NEJM 1999;240:1144
    9. 9. Overall survival rates 1Keys (GOG123), 2Rose (GOG120), 3Morris (RTOG9001), 4 Whitney (GOG85), 5 Peters SWOG8797/GOG109
    10. 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
    11. 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
    12. 13. Meta-analysis of randomized trials with concomitant chemoradiotherapy vs radiotherapy only in the treatment of cervical cancer <ul><li>19 trials ( 1981 – 2000 . ) </li></ul><ul><li>4580 randomized pts </li></ul><ul><li>Concurrent use of : </li></ul><ul><li> - C isplatin (12 trials) </li></ul><ul><li>- 5 FU, Mitomycin, Bleomycin, Epirubicin,Vincristin (7 trials) </li></ul>Green JA et al., Lancet 2001; 358:781
    13. 14. Meta - analysis – Overall survival <ul><li>Hazard ratio 0.71 </li></ul><ul><li>29% reduction in the risk of death </li></ul><ul><li>12% absolute improvement in survival (from 40%  52%) </li></ul><ul><li>P < 0.0001 </li></ul>Green JA et al., Lancet 2001; 358:781
    14. 15. Meta-analysis – Incidence of distant metastases <ul><li>Odds ratio 0.57 </li></ul><ul><li>P < 0.0001 </li></ul><ul><li>Systemic and local effects of cytotoxic drugs </li></ul>Green JA et al., Lancet 2001; 358:781
    15. 16. Meta-analysis – PFS and local recurrence <ul><li>Absolute improvement in progression-free survival of 16%, from 47%  63% . </li></ul><ul><li>Local recurrence - Odds ratio 0.61, </li></ul><ul><li>P < 0.0001 . </li></ul>Green JA et al., Lancet 2001; 358:781
    16. 17. Meta - analysis of individual patient data from 18 randomized trials - chemoradiotherapy vs the same radiotherapy – 3452 patients <ul><li>6% absolute improvement in 5 – year survival with chemoradiotherapy (HR = 0.81, P < 0.001). </li></ul><ul><li>8% absolute improvement in disease – free survival at 5 years (HR = 0.78, P < 0.001). </li></ul><ul><li>Larger survival benefit in 2 trials in which chemotherapy was administered after chemoradiotherapy. </li></ul>J Clin Oncol 2008;26:5802-5812. ASCO
    17. 18. Meta-analysis of individual patient data from 18 randomized trials <ul><li>No evidence of a difference in the size of the benefit by RT or CT dose or scheduling was seen </li></ul><ul><li>Significant survival benefit for both group of trials used platinum - based (HR = 0.83, P = 0.017) and non - platinum based (HR = 0.77, P = 0.009). </li></ul>J Clin Oncol 200826::5802-5812.
    18. 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
    19. 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
    20. 21. J Clin Oncol 26; 2008:5802-5812. ASCO Are we equaly effective in the treatment of different stages of the disease?
    21. 22. What do we know ? <ul><li>Chemoradiotherapy is better than radiotherapy alone </li></ul><ul><li>Cisplatin is the only recognized c y to toxic drug in concurrent chemoradiotherapy for the time being </li></ul>
    22. 23. What we do not know? <ul><li>What is the best c y to toxic drug or drug combination for the treatment of cervical cancer? </li></ul><ul><li>What is the right time to ordinate the c y to toxic drug or drug combination during radiotherapy? </li></ul><ul><li>What is the right dose of radiotherapy to be given together with chemotherapy? </li></ul><ul><li>What is the role of consolidation , adjuvant chemotherapy? </li></ul>
    23. 24. What we do not know? <ul><li>Can improvements in radiation technique (conformal radiotherapy, IMRT) translate into better treatment outcomes? </li></ul><ul><li>The role of targeted therapies in advanced cervical cancer? </li></ul><ul><li>Can supportive therapy, e spe cially the treatment of anemia, impact the treatment results in advanced cervical cancer? </li></ul>
    24. 25. Conclusions <ul><li>Concomitant chemoradiation is the treatment of choice for locally advanced cervical cancer . </li></ul><ul><li>Randomized trials should be performed to define what is the best drug/drug combination and what is the best way to ordinate radiation and chemotherapy concomitantly . </li></ul>
    25. 26. Is there any room for improvement ?
    26. 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)
    27. 28. <ul><li>To investigate the efficacy and tolerability of Ifosfamide and Cisplatin in concomitant chemoirradiation of locally advanced carcinoma of the cervix uteri . </li></ul><ul><li>Open, prospective, phase II trial in patients with locally advanced cervical carcinoma (stages IB2 (bulky ,  4 cm ) - I VA ) . </li></ul>Specific aim
    28. 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
    29. 30. Specificity of the study <ul><li>This is the first time in the treatment of cervical carcinoma s that chemotherapy is exclusively applied during brachyradiotherapy applications . </li></ul><ul><li>For the first time an Ifosfamide - based chemotherapy is used in the concomitant chemoradiotherapy of cervical carcinoma . </li></ul>
    30. 31. Specificity of the study <ul><li>It is the first time in the treatment of advanced cervical carcinoma that consolidation chemotherapy based on IC protocol is used, or that proper adjuvant polichemotherapy was designed for patients treated with concomitant chemoradiotherapy </li></ul>
    31. 32. To explain some important points of the study !
    32. 33. Why Ifosfamide? <ul><li>Ifosfamide - very potent drug in the treatment of cervical cancer </li></ul><ul><li>Average response rate of 22% which is in the range of the most active drug (Cisplatin 23%) </li></ul>Sutton et al. Semin Oncol 1989; 16: 68-72. Sutton et. al. Invest New Drug 1989; 7: 341-343. Thigpen et al. Semin Oncol 1996; 6: 56-64.
    33. 34. First line combination chemotherapy with Ifosfamide and Cisplatin in the treatment of cervical carcinoma <ul><li>Chiara S et al. Tumori 1988;74:471-474 </li></ul><ul><li>Cervelino JC et al. Acta Oncol 1995;34:257-259 </li></ul><ul><li>Kühnle H et al. Cancer Chemother Pharmacol 1990;26:33-35 </li></ul>Regimen Prior RT Response (%) Ifosfamide 1.5 g/m 2 /day + Cisplatin 20 mg/day x 5 days q 4w no 15/24 (62%) Ifosfamide 2.5 g/m 2 /day + Cisplatin 20 mg/day x 5 d q 4w no 15/30 (50%) Ifosfamide 5 g/m 2 /day + Carboplatin 300 mg/m 2 x 1 day no 19/32 (59%)
    34. 35. Ifosfamide and Cisplatin in the neoadjuvant treatment of cervical carcinoma <ul><li>Response rates up to 80% </li></ul>De Jonge ETM, et al.. Int J Gynecol Cancer 1997, 7:129-42
    35. 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
    36. 37. Why consolidation chemotherapy? <ul><li>- breast cancer </li></ul><ul><li>- colon cancer </li></ul><ul><li>- lung cancer </li></ul><ul><li>- many other tumors …. </li></ul>RATIONALE – ADJUVANT (CONSOLIDATION) CHEMOTHERAPY SUCCESFULL IN: CONSOLIDATION CHEMOTHERAPY-CERVICAL CANCER EXPERIENCES
    37. 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
    38. 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).
    39. 40. <ul><li>Pts who received epirubicin and radiation therapy showed a significantly longer disease-free </li></ul><ul><li>(P = 0 .03) and cumulative survival (P = 0 .04) . </li></ul><ul><li>Pts who received radiation alone had significantly more distant metastasis than those who received chemoradiation (P = 0 .012) . </li></ul><ul><li>No difference in long-term local tumor control (P= 0 .99) . </li></ul><ul><li>Wong LC et al. J Clin Oncol 1999 . </li></ul>
    40. 41. <ul><li>Epirubicin not considered optimal chemotherapy . </li></ul><ul><li>Lack of comparative arm of only concurrent chemoradiotherapy without adjuvant chemotherapy . </li></ul><ul><li>Wong LC et al. J Clin Oncol 1999 </li></ul>
    41. 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
    42. 43. <ul><li>Pts in Arm A showed a statistically significant improvement (p = 0.029) in PFS at 3 years (74% vs. 65%) </li></ul><ul><li>Overall survival (log-rank p = 0.0224) and time to progressive disease (log-rank p = 0.0008) were also significantly improved </li></ul><ul><li>Significantly more pts in Arm A experienced grade 3/4 toxicities (86.5%), compared to pts in Arm B (46.3%; Fisher's p < 0.001) </li></ul>A. Dueñas-González, et al. J Clin Oncol 27:18s, 2009
    43. 44. <ul><li>concurrent Gem + Cis and XRT followed by brachy and adjuvant Gem plus Cis significantly improved outcomes in pts with LACC </li></ul><ul><li>increased but acceptable toxicity, compared to the current standard of care </li></ul>A. Dueñas-González, et al. J Clin Oncol 27:18s, 2009
    44. 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
    45. 46. <ul><li>Radiotherapy arm </li></ul><ul><li>OS (4-year): 71% </li></ul><ul><li>PFS (4-year): 63% </li></ul><ul><li>Distant relapse: 16% </li></ul><ul><li>Local recurrence: 22% </li></ul><ul><li>Chemoradiotherapy arm </li></ul><ul><li>OS (4-year): 81% </li></ul><ul><li>PFS (4-year): 80% </li></ul><ul><li>Distant relapse: 10% </li></ul><ul><li>Local recurrence: 9% </li></ul><ul><li>Toxicity increased but self limited and manageable </li></ul>P<0.007 or better for OS and PFS Hazard ratio for PFS of RT alone vs CT + RT: 2.01 (p = 0.003) Hazard ratio for OS of RT alone vs CT + RT: 1.96 (p = 0.007) (median FU – 42 months)
    46. 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?
    47. 48. Bad chemotherapy is making the difference! <ul><li>Concurrent use of monochemotherapy with cisplatin (12 trials) and 5 FU, Mitomycin, Bleomycin, Epirubicin, Vincristin (7 trials) </li></ul><ul><li>Hazard ratio 0.71 </li></ul><ul><li>29% reduction in the risk o f d eath </li></ul><ul><li>12% absolute improvement in survival (from 40%  52%) </li></ul><ul><li>P < 0.0001 </li></ul>Green JA et al., Lancet 2001; 358:781
    48. 49. What will happen with appropriate chemotherapy regimen? <ul><li>Monotherapy with cisplatin – RR: 23% </li></ul><ul><li>Ifosfamide + Cisplatin – RR: 65% </li></ul><ul><li>Ifosfamide + Cisplatin (NA) – RR: 80% </li></ul>
    49. 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
    50. 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
    51. 52. Why brachyradiochemotherapy? <ul><li>It is logical that the effect of chemotherapy will be greater when chemotherapy will be applied during brachytherapy insertions . </li></ul><ul><li>The reason : when applied during external radiotherapy, chemotherapy is combined with only 2 Gy of irradiation. </li></ul><ul><li>In contrast, when ordinated with brachyradiotherapy, chemotherapy is combined with a dose of irradiation of up to 30 Gy. </li></ul>
    52. 53. Why brachyradiochemotherapy? <ul><li>Potentialy we can end up with less side effects of the combined treatment due to fact that brahiradiotherapy is much more concentrated way of treatment – less healthy tissue in the field of irradiation. </li></ul>
    53. 54. Conclusion <ul><li>Right chemotherapy (Ifosfamide s y nergistic action with low - dose rate brachyradiotherapy), applied at the right time (during the application of the highest dose of radiotherapy - 30 Gy in 30 hr) and followed by consolidation chemotherapy with Ifosfamide and Cisplatin . </li></ul><ul><li>Possible win n ing combination in the treatment of advanced cervical cancer ! </li></ul>
    54. 55. Inclusion criteria <ul><ul><ul><li>Histologically confirmed squamous , adeno or adenosquamous cell carcinoma of the cervix uteri FIGO - stage IB2 (bulky) - I VA . </li></ul></ul></ul><ul><ul><ul><li>All females with childbearing potential must have had negative pregnancy test within 3 days prior to enrollment into the study. </li></ul></ul></ul><ul><ul><ul><li>Age 18 - 7 5 years, inclusive. </li></ul></ul></ul><ul><ul><ul><li>ECOG performance status  1. </li></ul></ul></ul><ul><ul><ul><li>Life expectancy  6 months. </li></ul></ul></ul><ul><ul><ul><li>Adequate hematological, renal and hepatic functions obtained not more than 7 days prior to enrollment. </li></ul></ul></ul><ul><ul><ul><li>Patients’ informed consent must have been obtained. </li></ul></ul></ul>
    55. 56. Exclusion criteria <ul><ul><ul><li>Pts must not have received any prior antineoplastic therapy . </li></ul></ul></ul><ul><ul><ul><li>Past or current history of neoplasm other than the cervical carcinoma or skin cancer . </li></ul></ul></ul><ul><ul><ul><li>Significant history of cardiac disease . </li></ul></ul></ul><ul><ul><ul><li>Significant history of mental disease . </li></ul></ul></ul>
    56. 57. Primary endpoints <ul><li>1. Objective response </li></ul><ul><li>2. Pathologically determined response </li></ul><ul><li>3. Safety of the treatment </li></ul>Secondary endpoints <ul><li>Progression - free Survival </li></ul><ul><li>Overall Survival </li></ul><ul><li>Qu a lity of Life </li></ul>
    57. 58. Patients’ profile <ul><li>N= 62 , Median of age: 52.3 years (34-77) </li></ul>ECOG status 0 55 88% 1 6 10% 2 1 2% FIGO stage IB2 12 19% IIA 12 19% IIB 27 44% IIIA 0 0 IIIB 10 16% IVA 1 2% Tm grade 1 9 14% 2 45 73% 3 8 13%
    58. 59. Results <ul><li>Average radiotherapy duration: 44.6 days </li></ul><ul><li>Average chemotherapy interval: 24.4 days </li></ul><ul><li>Radiotherapy dose at point A 85 Gy: 100% </li></ul><ul><li>100% complete response rate - clinical, radiological and pathological </li></ul><ul><li>Median FU of 58 months </li></ul>
    59. 60. Results OVERALL SURVIVAL at median FU of 58 months 83.8%!
    60. 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%)
    61. 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
    62. 63. Conclusions <ul><li>The 100% complete response rate observed in this study is the highest response rate reported up to now in the same patient population (usual response rate is about 80%). </li></ul><ul><li>The 83.8% 5 - year survival rate is one of the best reported up to now. </li></ul><ul><li>The toxicity of the whole treatment is acceptable and qu a lity of life preserved . </li></ul>
    63. 64. Promissing new directiones
    64. 65. Radiotherapy optimalisation - important treatment parameter <ul><li>Radiotherapy for cervical carcinoma consists of </li></ul><ul><ul><li>external radiotherapy (2 Gy fractions, 25 x , together 50 Gy to the pelvis) . </li></ul></ul><ul><ul><li>brachiradiotherapy (two insertions with up to 30 Gy per insertion, together up to 60 Gy to the tumor ) . </li></ul></ul><ul><li>With every day o f prolongation of radiotherapy above 50 days – lost of 1% in local control </li></ul>Grinsky T, et al. Int J Radiat Oncol Biol Phys 1993;27:1051–6 Perez CA, et al. Int J Radiat Oncol Biol Phys 1995;32:1275–88
    65. 66. <ul><li>Potential for improving outcomes in cervical cancer. </li></ul><ul><li>Accurate target volume definition is essential in order to maximise normal tissue sparing while minimising the risk of a geographical miss. </li></ul><ul><li>This reduction in toxicity provides the option of dose escalation , particularly with simultaneous integrated boost intensity-modulated radiotherapy. </li></ul>Conformal and Intensity-modulated Radiotherapy for Cervical Cancer Taylor A, Powelly M.E.B. Clin Oncol 2008; 20:417-425
    66. 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
    67. 68. Intensity - modulated Radiotherapy (IMRT) <ul><li>Acute toxicity of the 40 pts treated with IMRT was compared retrospectively with the 35 pts treated with conventional radiotherapy. Grade 2 gastrointestinal symptoms were reduced from 91 to 60% and grade 2 genitourinary morbidity reduced from 20 to 10% with IMRT. After further follow-up, late gastrointestinal toxicity was reduced from 50 to 11%. </li></ul>Mundt AJ et al. Gynecol Oncol 2001;82:456e463 .
    68. 69. IMRT <ul><li>The use of concomitant chemotherapy increases the likelihood of developing clinically significant myelotoxicity. </li></ul><ul><li>IMRT significantly reduced the volume of irradiated bone marrow compared with conventional radiotherapy. This translated into clinical benefit, with grade 2 white cell toxicity reduced from 60 to 31% (P = 0.08). </li></ul><ul><li>This offers the potential for the addition of novel systemic therapies to be used either in conjunction with radiotherapy or in the adjuvant setting. </li></ul>Mundt AJ et al. Gynecol Oncol 2001;82:456e463
    69. 70. Conformal and Intensity - modulated Radiotherapy for Cervical Cancer <ul><li>In order to be used routinely for cervical cancer, there needs to be evidence that the theoretical dosimetric advantage for three - dimensional radiotherapy techniques translates into significant clinical benefit to justify the increased workload involved in volume definition, treatment planning and delivery. </li></ul>
    70. 71. Anemia in cervical cancer <ul><li>Important prognostic factor! </li></ul><ul><li>Potential therapeutic target? </li></ul>
    71. 72. Grogan M et al. Cancer 1999; 86: 1531-1536 <ul><li>S ignificant reduction in both pelvic and distant recurrence (P < 0.0001 and P < 0.0006, respectively) in patients whose AWNH level during RT was >/= 120 g/L compared with < 120 g/L . </li></ul>Patient survival by hemoglobin (Hgb) level at presentation. Influence of baseline Hb value on survival of patients with advanced cervical cancer
    72. 73. Grogan M et al. Cancer 1999; 86: 1531-1536 Patient survival according to fall in Hb level during RT
    73. 74. <ul><li>Conclusions </li></ul><ul><li>AWNH is highly predictive of outcome for patients treated with RT for carcinoma of the cervix. </li></ul><ul><li>Blood transfusion appears to overcome the negative prognostic effects of low presenting Hgb levels and AWNH levels. </li></ul>Grogan M et al. Cancer 1999; 86: 1531-1536
    74. 75. Does raising hemoglobin >120 g/dL lead to improved outcomes when patients are treated with chemoradiation? <ul><ul><ul><ul><ul><li>Thomas G et al.Gynecol Oncol 2008 </li></ul></ul></ul></ul></ul>RANDOMI ZED 52 received CT/RT (Cisplatin weekly) 57 received CT/RT+/-R-HUEPO (40,000 units s.c. weekly). R-HUEPO was stopped if HGB > 14.0 g/dL - Phase III trial - Eligibility criteria: - stage IIB-IVA cervical cancer - HGB < 14.0 g/dL
    75. 76. Does raising hemoglobin >120 g/dL lead to improved outcomes when patients are treated with chemoradiation? <ul><li>Endpoints: PFS, OS and local control </li></ul><ul><ul><li>- The study closed prematurely due to potential concerns for thromboembolic event (TE) with R-HUEPO </li></ul></ul><ul><ul><li>- TE occurred in 4/52 receiving CT/RT and 11/57 with CT/RT+R-HUEPO </li></ul></ul><ul><ul><li>- Median follow-up was 37 months </li></ul></ul><ul><ul><ul><ul><ul><li>Thomas G et al.Gynecol Oncol 2008 </li></ul></ul></ul></ul></ul>
    76. 77. Novel therapeutic agents for cervical cancer <ul><li>Targeted therapies against EGFR and VEGF </li></ul><ul><li>signalling pathways : </li></ul><ul><li>1. Blocking monoclonal antibodies </li></ul><ul><li>C etuximab, M atuzumab, P anitumumab - against extracellular domain of the EGFR1 </li></ul><ul><li>B evacizumab - against VEGF - A </li></ul><ul><li>2. Tyrosine - kinase inhibitors </li></ul><ul><li>G efitinib, E rlotinib - EGFR1 tyrosine - kinase inhibitors </li></ul><ul><li>Lapatinib - dual, EGFR1 and EGFR2 tyrosine - kinase inhibitor </li></ul><ul><li>Sorafenib, P azopanib - VEGFR tyrosine - kinase inhibitors </li></ul>J.M.del Campo et al. Gynecol Oncol 110 (2008) S72-S76
    77. 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

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