Chemo-radiotherapy in Cancer Cervix.pptx

role of chemoradiation in the management of cervical carcinoma

1. Chemo-Radiotherapy in Ca Cx

2. Results of Radical Radiotherapy in Carcinoma Cervix STAGE LOCAL CONTROL 5 YR SURVIVAL PELVIC + DISTANT FAILURES IB(BULKY) 79-87% 63-75% 7.5% II A 73-82% 70% 13.7% II B 73-82% 62-68% 15.1% III 53-63% 28-48% 26. 9% IV 25% 18-34 % 61.1% 2

3. Types of Chemotherapy NACT Adjuvant Concurrent 3 Platinum based (Cisplatin and Carboplatin) Hydroxyurea , 5FU, Mitomycin C, Bleomycin , Vincristine etc. Newer agents Tirapazamine , Taxanes , Gemcitabine etc.

4. Aim of concurrent CTRT To improve survival by 1. Increasing local control of the primary cervical tumor . (Radio-sensitization) 2. Decreasing the rate of distant metastases . (Direct anti-tumor effect for micro-metastases and indirect effect on future metastases by preventing cervical tumor recurrence) 4

5. 5 40 patients with IIB, PA lymphadenectomy negative. F/U >5 years Toxicity : leukopenia significantly worse with HU OS : RT alone 53% vs. CRT 94% (SS)

6. 1986-1990 INCLUSION : stage IIB-IVA N= 388pts (368 eligible pts ) Randomization 5-FU+CDDP+RT HU+RT Patient no. 177 191 RT Dose: IIB with/without brachytherapy or III/IVA with brachytherapy- 81Gy III/IVA without brachytherapy- 61.2 Gy Treatment duration : 10 wks Dose of CDDP = 50 mg/ sq.m days 1 & 29, 4h before RT, 5-FU iv infused at a dose of 1,000 mg/m2/d (4,000 mg/m2 total dose, d2-5, d30-33) 3 weekly. HU= 80 mg/kg Monday –Thursday/ Tuesday- Friday (i.e. biweekly). Charles W. Whitney 6

7. OS PFS Median follow up: 8.7yrs C+F+RT RT +HU Disease progression (p=0.33) 76(43%)/177 101(53%)/191 Overall death (p=0.018) 79(45%) 108 (57%) Grade 3 or 4 Hematological Toxicity p<0.05 4% 24% Grade 3 or 4 gastrointestinal toxicity 8% 4% COMMENTS : Compares 2 CT-RT arms (no RT alone arm) Suboptimal RT dose (81 Gy) Protracted RT regime (10 wks ) No brachytherapy in few pts stage III/ IV patients 7

8. 1990 – 1997 N=389 pts INCLUSION : IIB-IVA or IB/IIA cancers with a tumor diameter =>5 cm or biopsy-proven metastasis to pelvic lymph Nodes Randomization CT+RT (5FU+CDDP) RT alone RT 85Gy to point A Pelvis EBRT + Brachy Pelvis+ paraarortic LN+ Brachy Patient no. 194 193 Treatment duration : 8 wks Doses : 85 Gy to point A Median follow up : 43 months Cisplatin dose = 75 mg/ sq.m three weekly 16 hrs after 1 st # 2 cycles. 8

9. MEDIAN FOLLOWUP 43 months PELVIC RT + CDDP+5 FU PELVIC+ PARAORTIC RT ALONE Disease free survival at 5 yrs (p<0.001) 67% 40% Overall Survival 73% 58% Distant relapse (p<0.001) 14% 33% Locoregional relapse (p<0.001) 19% 35% Comments Optimal radiotherapy doses (85 Gy) & OTT(58 Days). 70 % patients stage IB, IIA, or IIB disease. Pts with stage III or IVA disease, 5 yr DFS 58 % in the CTRT group and 38 % in the RT alone group (P=0.13). Higher doses of cisplatin(75mg/m2) used. 9

10. INCLUSION : Bulky IB >= 4cm then extrafascial Hysterectomy after 6 wks 1992 – 1997 (369 pts ) Randomisation RT alone CDDP +RT RT 75Gy to point A 55Gy to point B Pelvis EBRT+brachy Pelvis EBRT+brachy Patient no. 186 183 RT duration : Median 50 days CISPLATIN dose = 40 mg/ sq.m weekly 10

11. Median follow up : 36 months CT+RT(CDDP) RT ALONE Progression free survival (p<0.001) 79% 63% Overall survival (p=0.008) 85% 74% Acute toxicity 35% 13% PFS CRITICS Suboptimal RT doses Trial In Pre-op setting Only Stg IB included OS 11

12. INCLUSION : IA2 -IIA ( Post radical hysterectomy + pelvic LN dissection; + ve LN,+ ve parametrium ,+ C/M) 1991 – 1996 (243 pts ) Randomisation CT+RT ( CDDP+5FU) RT alone RT Pelvis ~50Gy Para-Aortic LN ~45Gy Pelvis PA LN Pelvis PA LN Patient no. 127 116 Treatment duration : 9-10wks Median follow up : 42 months CDDP Dose = 70 mg/ sq m. 3 weekly, 2 cycles concurrent,2 post CT-RT. RT 6wks from surgery. 5-FU= 1,000mg/m2/d every 3 weeks for four cycles 12

13. Median follow up : 42 months RT alone CT+RT(CDDP+5FU) 4yr Progression free survival (p=0.003) 63% 80% Overall survival (p=0.007) 68% 83% Local+Distant failure 33% 15% PFS OS COMMENTS Post op setting Acute toxicities were almost 3 times more in CT-RT arm PFS in adenoca & adenosq . Histology better than squamous in CT-RT arm than in RT alone arm Only early stage pts NO BRACHYTHERAPY 13

14. INCLUSION : IIB-IVA 1992 – 1997(526 patients) Randomisation CT+RT (CDDP) RT + 5FU + CDDP + HU RT + HU RT Pelvis EBRT+ Brachy Pelvis EBRT+ Brachy Pelvis EBRT+ Brachy Patient no. 176 173 177 Treatment duration : 10 wks Median follow up : 35 months Total to point A - 80.8 Gy in patients with stage IIB and 81.0 Gy in patients with stage III/IVA Total dose to point B - 55.0 Gy with stage IIB 60.0 Gy stage III/IVA Cisplatin – 40 mg/ sq.m weekly, 50 mg of cisplatin per square meter on days 1 and 29 5- fluorouracil 4 g /m2givenas a 96-hour infusion on days 1 and 29 oral hydroxyurea 2 g /m2 twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea /m2twice weekly for six weeks (group 3). 14

15. CT+RT (CDDP) RT+5FU+CDDP+HU RT+HU Overall survival 88% 89% 83% Progression-free survival at 24 months 67% 64% 47% Local progression 20% 19% 30% Lung mets 4% 3% 10% PFS OS 15

16. AUTHOR ARMS RESULTS COMMENTS CRITICISMS Whitney et al. 1999 (GOG-85) IIB-IIIB N=368 RT + Cisplatin / 5FU Vs. RT+HU OS-55% Vs. 43% Better PFS and OS than HU with manageable toxicity Comparison of two CTRT regimens. No RT alone arm. Sub optimal (81Gy to pt A) protracted RT (median duration 63 days). Morris et al. 1999 (RTOG 9001) IB-IVA N=388 RT+5FU/Cisplatin Vs. RT OS-73% Vs. 52% CT had a survival advantage with decrease in both LR and distant failure. RT optimal, 89Gy to pt A, 58 days Survival benefit in IB-IIB, not in adv stage. Keys et al. 1999 (GOG-123) Bulky IB N=369 RT+Cisplatin+ SX Vs. RT+ SX OS-83% Vs. 74% Significant differences in PFS and OS favoring CTRT Suboptimal RT dose Trial for pre op regimen IB only Peters et al. 2000 IA2-IIA N=243 SX + RT+ Cisplatin/5FU Vs. SX+RT OS-80% Vs. 63% Survival favored the chemoradiotherapy arm Post op RT, no brachytherapy Early stage Rose et al. 1999 (GOG 120) IIB-III-IVA N=526 RT+Cisplatin Vs. RT+Cisplatin/5FU/HU Vs. RT+HU PFS–67% Vs. 64% Vs. 47% Superiority of concomitant CTRT regimen with cis alone was less toxic then 3 drug regimen No RT alone arm Comparison of 3 CTRT regimens Low total RT dose & protracted Rx time 16

17. NATIONAL CANCER INSTITUTE CLINICAL ANNOUNCEMENT CONCURRENT CHEMORADIATION FOR CERVICAL CANCER In 22 nd February 1999 “ Five major randomized phase III trials show that platinum based chemotherapy when given concurrently with RT prolongs survival in women with locally advanced cervical cancer stages Ib2 - IVa as well as in women with stage I / IIa found to have metastatic pelvic lymph nodes, positive parametrial disease and positive surgical margins at the time of primary surgery ” 17

18. INCLUSION : stage IB2 and IIA ( 5 cm in diameter), IIB, IIIB, IIIA, and IVA ( <5cm if LN + ve ) 1991-1996 (253 pts ) Randomisation CT(CDDP) +RT RT alone RT( pt A dose 80 – 85 Gy ) Pelvis EBRT+Brachy Pelvis EBRT+Brachy Patient no. 127 126 Median follow-up: 82 months Treatment time = 7 weeks Dose of cisplatin = 40 mg/ sq.m weekly 2h before RT. 18

19. RESULTS No significant difference in PFS (p 0.33) No significant difference in 3y & 5y O.S.(62% vs 58%) More distant recurrence in CTRT arm Acute toxicities much more in CTRT arm OS PFS Smallest of all RCTs (253 pts ; large confidence intervals) Underpowered to detect a difference of less than 15% No evaluation of para -aortic nodes More decrease in Hb in CTRT arm. Possible explanations 19

20. Compliance to chemotherapy in big 5 trials Whitney et al . A total of 161 patients (91%) randomized to CF received both drug courses. Morris et al. Of the 195 patients in the combination-therapy group, 159 (81 percent) completed at least two cycles of chemotherapy, and 133 (68 percent) completed three cycles. Keys et al. 90 percent received four or more courses of cisplatin. Peters et al. 60% pts received all 4 # of chemotherapy. Rose et al. 83% pts received 5-6 # cisplatin in arm A, 80% pts in arm B received 2# of CF, no cycles HU variable in both arm B & C. 20

21. Pitfalls of the “BIG 5” NO STANDARD RT DOSES NO STANDARD DOSES OR SCHEDULING OF CHEMOTHERAPY RESULTS IN ADVANCED STAGES(III/IV) NOT THAT ENCOURAGING HETEROGENEITY IN DATA. NO LONG TERM EFFICACY OF CTRT TOXICITY DATA ? LATE 21

22. Systematic reviews of 19 RCTs from 1981-2000 2865-3611 patients for analysis Cisplatin most common agent used Absolute benefit in OS of 12 % and in PFS of 16 % Benefits maximum in Stage I/II pts Significant benefit on both local & distant recurrence (p<0.0001) Grade 3/4 hemat . & G.I Toxicities more in CTRT arms 22

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24. COMMENTS Results better if – CT-RT used If platinum agent included Weekly CDDP as good as three weekly regimes Significant heterogeneity Acute toxicities described only in 8 studies, late in only 3. 68% patients in early stages. Results to be extrapolated with caution in advanced disease. 24

25. Aims to evaluate the role of concurrent cisplatin + RT in the treatment of cervical cancer 8 RCTs Significant benefit in CTRT arms – R.R of death 0.74 (translates into Absolute reduction in risk of death by 11% ) Six studies show improvement in local and distant control 25

26. Update includes 24 trials 4921 patients available for analysis CTRT improves OS & PFS, whether or not cisplatin was used with absolute benefits of 10% and 13% respectively. Concurrent scheduling better, results with weekly scheduling comparable. Benefit for both local & distant failures Acute toxicities more ,late toxicities not reported Green Meta-analysis UPDATE 2005 26

27. The need for IPD analysis What regimen? Which drug? What dose? Combination? Is there a benefit? Any subgroup? Should we forget about the chemotherapy induced toxicities ? 27

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30. Subgroup analysis Effect of CTRT did not differ in groups of women defined by age, histology, tumor grade and pelvic lymph node involvement NO evidence of a difference in the size of the effect of CTRT when trials were grouped according to type of CT, planned RT dose, duration of RT, or cycle length or dose intensity of cisplatin 30

31. Stage wise benefit The HRs obtained for each stage translate to 5-year OS benefits for women with Stages IB to IIA  10% Stages IIB  7% Stages III to IVB  3% 31

32. GI toxicities There was a significant increase in serious gastrointestinal toxicity for the groups of trials using platinum -based chemoradiation ( p=0.000002) chemoradiation plus additional chemotherapy (p=0.001) additional radiotherapy on the control arm (p=0.000002). This increase was not observed for the group of trials using non-platinum based chemoradiation (p=0.465), where the event rate was low (~2%) on both arms Hematological toxicities Serious hematological toxicity increased by approximately 2 to 10 - fold in individual trials However, for the group of trials that used HU on the control arm, a high level of serious hematological toxicity was evident on both arms, slightly greater on the control arm (OR= 0.74, 95% CI 0.53 – 1.03, p=0.075 ). 32

33. update includes 24trials (21 published, 3 unpublished) and 4921 patients 2009 Chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 10% and 13% respectively. Effect was greater in trials including a high proportion of stage I and II patients. Significant benefit for local recurrence and a suggestion of a benefit for distant recurrence. Acute haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. five-year survival rates of 50% to 80% for FIGO stage IIB and 25%to 50%for Stage III 33

34. Randomized Concurrent chemoradiation (weekly cisplatin 40 mg/m2, six #) Concurrent chemoradiation (triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) To compare compliance, toxicity, and outcome of weekly and triweekly cisplatin 104 patients Stage IIB–IVA 34

35. Median follow up : months Weekly cisplatin Triweekly cisplatin Overall survival ( p=0.03) 66.5% 88.7% Compliance NS 86.3% 92.5% Gr 3-4 neutropenia) ( p=0.03) 22.6% 39.2% 35

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37. Early stage cervical cancer (stages IA2, IB1 or IIA) with risk factors such as LN mets , LVSI, depth invasion >10mm , microscopic parametrial invasion, non-squamous histology and positive surgical margins. safety of platinum-based adjuvant chemotherapy after radical hysterectomy, radiotherapy, or both. Three trials were included. Two trials enrolling 325 participants, of whom 297 (91%) were assessed. Radiotherapy and chemotherapy with radiotherapy alone in adjuvant setting. 37

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39. CONSOLIDATION CHEMOTHERAPY 2002-2004 N= 515 pts arm A (cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly conc with RT, then two adjuvant 21-day cycles of cisplatin, 50 mg/m2 on day 1, plus gemcitabine, 1,000 mg/m2 on days 1 and 8) arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A ). Both drugs were administered 1 to 2 hours before XRT 39

40. Median follow up : 36 months CTRT alone CTRT+ consolidation chemotherapy 3yr Progression free survival (p=0.023) 65% 74.4% Locoregional failure rate 16.4% 11.2% Arm A had more grade 3 or 4 nonhematologic toxicities, including vomiting and diarrhea, than arm B ( P .002). 40

41. 1998-2007 n= 880 pts Randomized Concurrent chemoradiation 1 #NACT f/b Concurrent chemoradiation 2# Consolidation chemotherapy every 3 wkly Paclitaxel at a dose of 135 mg/m 2 on day 1 followed by 75 mg/m 2 of cisplatin administered over 4 h on day 2 41

42. Median follow up : 60 months CTRT alone CTRT+ consolidation chemotherapy 5yr Progression free survival 62.9% 74.7% Overall survival 60.4% 71.4% 42

43. Toxicities 43

44. NACT: RATIONAL Tumor size reduction may facilitate local therapy: radiotherapy or surgery Possible transformation of inoperable tumor in radically resectable one Treatment of micrometastatic disease Response to NACT has been identified as an important prognostic factor Benedetti-Panici E J Cancer 1998, Buda JCO 2005 NACT: DISADVANTAGES Delay in curative treatment (20-30% of patients who don’t respond to NACT), The development of radioresistant cellular clones Crossresistance with radiotherapy. 44

45. Two comparisons : (1) neoadjuvant chemotherapy followed by radical radiotherapy compared to the same radiotherapy alone (2)neoadjuvant chemotherapy followed by surgery compared to radical radiotherapy alone . 1975-2000 data from 18 trials and 2074 patients . Trials using chemotherapy cycle lengths shorter than 14 days (HR = 0.83, 95% CI = 0.69 to 1.00, p = 0.046) or cisplatin dose intensities greater than 25 mg/m2 per week (HR = 0.91, 95% CI = 0.78 to 1.05, p = 0.20) tended to show an advantage for neoadjuvant chemotherapy on survival. In contrast, trials using cycle lengths longer than 14 days (HR = 1.25, 95% CI = 1.07 to 1.46, p = 0.005) or cisplatin dose intensities lower than 25 mg/m2 per week (HR = 1.35, 95% CI = 1.11 to 1.14, p = 0.002) tended to show a detrimental effect of neoadjuvant chemotherapy on survival. 45

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47. Role of neoadjuvant chemotherapy followed by surgery versus surgery alone is still unclear . Six trials, 1072 pts 47

48. Conclusions: PFS was significantly improved (HR = 0.76, 95%CI = 0.62 to 0.94, p = 0.01) No OS benefit was observed. Although the OR for local recurrence is in favour of neoadjuvant chemotherapy (OR = 0.76, 95% CI = 0.49 to 1.17, p = 0.21)the result was not statistically significant and there was evidence of substantial heterogeneity . Rates of resection not favorable (OR = 1.55, 95%CI = 0.96 to 2.50, p = 0.07) a significant benefit of neoadjuvant chemotherapy for decreasing adverse pathological findings. the results tend towards a benefit of neoadjuvant chemotherapy, the results are inconsistent both by outcome and by trial. 48

49. Newer approaches 49

50. SOME “TARGETED THERAPY” BEVACIZUMAB OTHERS CELECOXIB CETUXIMAB SOREFINIB ERLOTINIB 50

51. Summary: Concurrent chemoradiation is standard of care in lacally advanced cervical cancers. Conc Cisplatin –equivalent results as compared multiagent chemotherapy. weekly cisplatin has equivalent results as triweekly. Adjuvant chemoradiation post hysterectomy is indicated in patients with high risk features , like parametrial involvement, positive CM, LN involvement. Role of consolidation chemotherapy is experimental , though initial data suggest better PFS & OS with adjuvant chemotherapy. Role of Neoadjuvant chemotherapy in early stage cervical cancers is doubtful , as it does improve adverse pathological findings, tends to favor PFS, but no survival benefit. 51

52. Thank you 52

53. Cisplatinum Reacts with cellular DNA to form interstrand and intrastrand crosslinks that impair DNA replication & RNA transcription DNA breaks ( intrastrand adducts is the dominant lesion) 53

54. Radio- sensitisation Enhanced formation of toxic platinum intermediates in presence of radiation induced free radicals. Capacity to scavenge free electrons formed by interaction of RT with DNA which may repair DNA damage Synergistic effect because of cell cycle disruption RT induced increase in cellular uptake of cisplatin. Inhibition of repair of RT-induced DNA lesions. ENHANCED EFFECT SEEN ONLY IF GIVEN 2-4h BEFORE FRACTION OF RT 54

55. Mechanisms of chemotherapy induced radiosensitization DRUGS MECHANISM OF RADIOSENSITIZATION TAXANES CELLULAR ARREST IN G2-M PHASE OF CELL-CYCLE INDUCES APOPTOSIS REOXYGENATION OF TUMOUR CELLS ANTIMETABOLITES DISRUPTION OF RNA FUNCTION INHIBITS THYMIDYLATE SYNTHETASE DIRECT INCORPORATION OF DRUG INTO DNA MITOMYCIN C TARGETS HYPOXIC CELLS Hydroxyurea HU induces cell asynchrony at the radiation sensitive G1/S interface and inhibits the repair of sublethal radiation-induced cellular damage. 55

56. IPD Meta-analysis Compared wit h primary RT , t he use of chemoradiat ion result ed in: A reduct ion in t he risk of deat h (hazard rat io [HR] 0. 69, 95% CI 0. 61-0. 77), which t ranslat ed int o a 10 percent absolut e improv ement in surv iv al. T he surv iv al benef it associat ed wit h chemoradiat ion signif icant ly decreased wit h increasing st age. For women wit h st age I B t o I I A, I I B, and I I I t o I VA cerv ical cancer, t he f iv e-year surv iv al benef it was 10, 7, and 3 percent , respect iv ely (p = 0. 017). A reduct ion in t he risk of recurrence (HR 0. 66, 95% CI 0. 59-0. 73), which t ranslat ed int o a 13 percent absolut e improv ement in progression f ree surv iv al. T here was no associat ion between st age and disease f ree surv iv al report ed. A reduct ion in t he risk of local recurrence (odds rat io [OR] 0. 59, 95% CI 0. 50-0. 69) and a t rend t owards a reduct ion in dist ant met ast ases (OR 0. 81, 95% CI 0. 65-1. 01). T his reduct ion was seen in t rials using bot h plat inum -based and non-plat inum based regimens. Higher rat es of serious (grade 3/ 4) adv erse ev ent s including gast roint est inal t oxicit y

57. Che mothe ra py re gime n weekly cisplat in (40 mg/m ) during RT Single agent cisplat in administ ered wit h RT achiev es similar out comes t o cisplat in plus 5-FU and has a bet t er t oxicit y prof ile Pa ti e nts wi th pote nti a l contra i ndi ca ti ons to ci s pl a ti n – weekly carboplat in dosed at area under t he curv e (AUC) 2 Chemoradiot herapy f or Cerv ical Cancer Met a-analysis Collaborat ion (CCCMAC). Reducing uncert aint ies about t he ef f ect s of chemoradiot herapy f or cerv ical cancer: indiv idual pat ient dat a met a-analysis. Cochrane Dat abase Syst Rev 2010; :CD008285

58. Importa nce of time to compl e ti on of che mora di a ti on For all women undergoing chemoradiat ion, t reatment should be complet ed wit hin eight weeks. I n one series of 113 women wit h st age I B t o I I I B disease, wit h a median f ollow -up of 26 mont hs , t ime t o complet ion of brachyt herapy >56 days was associat ed wit h a higher rat e of disease progression wit hin t he pelv is (26 v ersus 9 percent Song S, Rudra S, Hasselle MD, et al. T he ef f ect of t reatment t ime in locally adv anced cerv ical cancer in t he era of concurrent chemoradiot herapy . Cancer 2013; 119: 325