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Improving therapeutic ratio in Cervical Cancer

Improving therapeutic ratio in Cervical Cancer. Tata Memorial Centre Experience. ESTRO INTERNATIONAL SYMPOSIUM ESTRO / TMH – EBM 2005. OVERVIEW OF CARCINOMA CERVIX At Tata Memorial Centre. Carcinoma Cervix : The Indian Scenario Retrospective Overview of Results 1979 -1994

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Improving therapeutic ratio in Cervical Cancer

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  1. Improving therapeutic ratio in Cervical Cancer Tata Memorial Centre Experience ESTRO INTERNATIONAL SYMPOSIUM ESTRO / TMH – EBM 2005

  2. OVERVIEW OF CARCINOMA CERVIX At Tata Memorial Centre • Carcinoma Cervix : The Indian Scenario • Retrospective Overview of Results 1979 -1994 • TMH Evidence Based Guidelines • Prospective Studies • Molecular and Biological Studies • Prevention

  3. COMPARISION OF URBAN (MUMBAI#) VS RURAL (BARSHI+) IN MAHARASHTRA FEMALE BREAST AND GENITAL TRACT CANCERS 35 31.3 30 MUMBAI 23.4 BARSHI 25 17.4 20 INCIDENCE RATE* PER 100,000 15 8.3 10 6.8 3.2 5 1.4 0.2 0 BREAST CERVIX UTERI OVARY CORPUS UTERI SITES * AGE STANDARDISED TO WORLD POPULATION SOURCE : # BOMBAY CANCER REGISTRY REPORT FOR THE YEAR 2000 + CANCER INCIDENCE IN FIVE CONTINENTS VOL. VII, IARC (1997)

  4. 18000 16635 16000 15080 14000 13662 12000 10000 9055 8000 6000 4679 4000 2102 2000 0 1941-50 '51-60 '61-70 '71-80 '81-90 '91-00 DOWN THE DECADESCERVIX CANCER IN TATA MEMORIAL HOSPITAL 1941-2000

  5. TATA MEMORIAL HOSPITAL CANCER REGISTRY 1985 - 2000 Down Staging of Carcinoma Cervix 70 68.5 65.8 63.3 1985 60 1989 54.1 51.7 1993 1997 50 2000 40 35.2 28.2 28 30 19.7 20 17.1 11.8 10.6 9.5 10 9.1 7.7 10 6.1 3.6 0 0 Stage I Stage II Stage III Stage IV

  6. TREATMENT PATTERNS IN CARCINOMA CERVIX Sx (5%) Comb (12%) RT (83%) TATA HOSPITAL CANCER REGISTRY 2000

  7. OVERVIEW OF RESULTSCARCINOMA CERVIX1979 - 1994 8369 Patients

  8. Carcinoma Cervix: 1979 - 1994PATIENT ACCRUAL No of Registrations 8369 Non- evaluable 1589 (19%) Evaluable 6780 (81%) Median FU 68 Months (57-79)

  9. GRADE 100 94 HISTOLOGY 80 2% Gr II 28% Gr I 60 NK 16% % CASES 64% Gr III 40 IIB 0 IA IB IIIB IVB X IIA IIIA IVA 20 0 adenoca others microinva undiffer nk ad-sq 0 in-situ SQ CA CA.CERVIX : 1979-1994 (6780 Pts) AGE GROUP FIGO STAGE 100 55 Youngest: 21 Yrs Oldest : 81 Yrs Median: 48 Yrs < 35 Yrs: 18% Median FU: 68 months(57-79) 80 60 % CASES 28 PERCENT 40 35 28 10 19 20 13 4 4 1 0.07 0 21-30 31-40 41-50 51-60 61-70 71-80 81-90

  10. Evaluable patients Modality SURGERY ALONE 303 PRE-OP. RT+ SURGERY 293 RADICAL IRRADIATION 356 TOTAL 952 CA. CERVIX 1979-1994STAGE IB & IIA

  11. 1.2 DISEASE FREE SURVIVAL 1.1 1.0 .9 .8 PREOP+Sx(293) PTS) .7 Sx ALONE (303 PTS) .6 RT ALONE (356 PTS) % Survival .5 .4 .3 .2 .1 P = 0.24 0.0 0 24 48 72 96 120 144 168 MONTHS CA. CERVIX 1979-1994STAGE IB & IIA (952 pts) TREATMENT MODALITY

  12. CA.CERVIX : 1979 - 1994STAGE IB & IIA (596 PTS)SURGERY & NODES Patient Cx + ve Ut + ve Vg + ve Node no. + ve SURGERY 303 303 54 18 79 (17%) (5%) (26%) PRE-OP.RT+ 293 180 27 5 44 SURG (62%) (11%) (1%) (15%) 81 23 113 Total 596 483 (14%) (4%) (19%)

  13. 1.1 DISEASE FREE SURVIVAL 1.0 .9 Node -Ve .8 .7 .6 % Survival Node + Ve .5 .4 .3 .2 .1 0.0 0 24 48 72 96 120 144 12 36 60 84 108 132 MONTHS CA.CERVIX 1979 - 1994Stage IB & IIA : Sx +/-Pre-op RT (596 PATIENTS)NODAL STATUS P = 0.000

  14. CA. CERVIX: 1979 - 1994STAGE IB & IIA (596 PTS)HP:DEPTH OF CERVICAL INVASION 92% ( NO TUMOR 76 PTS) 100 80 81% ( <1/2 INVAS 174 PTS) 69% ( >1/2 INVAS 327 PTS) 60 % DFS 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years P = 0.001

  15. CA. CERVIX: 1979 - 1994Stage IB & IIAPOST-OP RT IN NODE +VE 100 80 57% ( POST-OP RT :74Pts) 60 % DFS 38% ( NO POST-OP RT:41Pts) 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years P = 0.4 (NS)

  16. RT Regimen Evaluable Conv. Field 199 46 Gy/ 23 # + 1 ICA Ext. Field 61 50 Gy/ 32 # + 1 ICA MLB after 10 Gy 96 40 Gy/ 20 # + 2 ICA Total 356 Carcinoma Cervix: 1979 - 1994STAGES IB & IIA (356 PTS)RADICAL RADIOTHERAPY REGIMEN

  17. 1.2 DISEASE FREE SURVIVAL 1.1 1.0 .9 40Gy/20/28(MLB at 20/10) .8 46Gy/23/35 .7 % Survival .6 50Gy/32/40(1.5Gy/#) .5 .4 .3 .2 P = 0.15 .1 0.0 0 12 24 36 48 60 72 84 96 108 120 MONTHS Carcinoma Cervix: 1979 - 1994STAGES IB & IIA (356 pts)RADICAL RADIOTHERAPY REGIMEN

  18. CA.CERVIX 1979 - 1994STAGE IB & IIA :EXT.RT REGIMEN (356 PTS)LATE COMPLICATIONS Conv. 46/23# Ext.F.50/32# 40/20#.(MLBat10Gy) 40 Percent 20 17 13 12 9 9 8 2 1 0 0 RECTAL BLADDER BOWEL

  19. CA. CERVIX: 1979 -1994Stage IB & IIA : TMHPROTOCOL CurrentWertheim’s 40/20# (MLB-20) - Selectron: 2#x30 Gy LDR - or 5# x7 Gy HDR each

  20. STAGE Ib & IIa SUMMARY • Sx alone : Justified in Only Select Group of Early Stages • Pre-op Radiotherapy + Sx :No significant advantage (?20Gy/5#) • Radiation Therapy Alone : Standard Conventional Rx • Neoadjuvant chemo + Sx: Needs to be Investigated • Concurrent chemo-radiation: Gold Standard Rx ? FIGO Staging Inappropriate due to large volume and grade III tumors

  21. CARCINOMA CERVIX : 1979-1994STAGE IIB Modality Evaluable Radical Irradiation 1282 Pre-op RT + Surgery 583 Surgery Alone 29 Total 1894

  22. 1.2 DISEASE FREE SURVIVAL 1.0 .8 PREOP RT+Sx (583PTS) .6 % Survival .4 RT ALONE (1282PTS) .2 P = 0.23 0.0 0 24 48 72 96 120 144 168 192 MONTHS Carcinoma Cervix: 1979 - 1994STAGES IIB (1894 patients)TREATMENT MODALITY

  23. 1.1 DISEASE FREE SURVIVAL 1.0 .9 .8 40/20/28 (MLB AT 20) .7 .6 50/25/35(2Gy/#MLB AT 40) % Survival .5 50/25/35(2Gy/#) .4 50/32/40(1.5Gy/#) .3 .2 .1 0.0 0 24 48 72 96 120 MONTHS Carcinoma Cervix: 1979 - 1994STAGE IIB (1282PTS)RADICAL RADIOTHERAPY REGIMEN P = 0.000

  24. CA.CERVIX: 1979 - 1994STAGE II B : EXT. R.T. REGIMEN (1282 PTS) LATE COMPLICATIONS Conv. Field Ext.Field MLB40, 50/25# MLB10, 40/20# 20 13 12 Percent 9 8 8 10 7 6 6 4 3 3 4 0 Rectal Bladder Bowel Late Complications

  25. Carcinoma Cervix Stage IIBSummary • Pre-op RT : Down staging, but no Advantage • RT Dose escalation to central disease improves control rates • Neo-adjuvant CT + Sx : Investigational

  26. CA CERVIX: 1979 - 1994STAGE IIIB (3299 PTS)RADICAL RADIOTHERAPY REGIMEN RT REGIMEN EVALUABLE PTS DAILY RADIATION 1108 THRICE WEEKLY 1018 TWICE WEEKLY 577 ONCE WEEKLY 596 TOTAL 3299

  27. Carcinoma Cervix: 1979 - 1994STAGE III B (3299 PTS)RADICAL RADIOTHERAPY REGIMEN 1.2 DISEASE FREE SURVIVAL 1.1 1.0 .9 .8 .7 % Survival .6 50/25/35(2Gy/#) 1108 pts .5 45/15/35(thrice weekly)1018 pts .4 40/10/35(twiceweekly) 577 pts .3 37.8/7/42(once weekly) 596 pts .2 .1 * P = 0.000 0.0 0 12 24 36 48 60 72 84 96 MONTHS * Significant improvement in DFS with standard conventional RT

  28. CA.CERVIX: 1979 - 1994STAGE III & IV (3299 PTS) LATE COMPLICATIONS Late Complications lower with standard conventional RT

  29. Carcinoma Cervix Stage IIIB /IV Summary • No survival difference noted with various fractionation schemes studied • Higher complications with hypofractionation schemes • Palliation Achieved for Advanced Stages(III/IV)

  30. CA. CERVIX : 1979 - 1994LESSONS LEARNT • OUTCOME ANALYSIS • IMPROVED COMPLIANCE AND FOLLOW–UP • ACQUISITION OF BETTER FACILITIES • GYNAE JOINT CLINIC : SINCE 1979 • CLINICAL GUIDELINES • PROSPECTIVE STUDIES

  31. Tata Memorial HospitalEvidence Based Guidelines

  32. Evidence Based TMH Guidelines - Feb 2003 STAGE Ib & IIa Type III Hysterectomy + Pelvic Lymphadenectomy IB1: Radical Radiation Therapy IB2/IIA: Concomitant CT+RT Low risk Intermediate risk High risk Concomitant chemo radiation Observation Pelvic Radiation

  33. PROSPECTIVE TRIALS : Tata Memorial Centre

  34. Hospital Scientific Review Committee Clinical Research Secretariat Hospital Ethics Committee DAE- Clinical Trials Centre Data Monitoring Committee

  35. FIGO Stage I-III : LDR Vs HDR Brachytherapy: 1996 • FIGO Stage Ib / IIb : Neoadjuvant CT + Sx Vs CT + RT : 2003 • FIGO Stage IIIb : Chemoradiation Vs Radiation Alone : 2003 • FIGO Stage IIb : 3D Conformal Vs Intensity Modulated RT:2004 • Locally Adv. Disease : Evaluation of PET / CT-PET: 2004 • Molecular Studies : DBT Multicentric Study :2004 • : TMH 2002 • : ACTREC 2005 • EIS : SCTMIST / TMC : 2004 • Preventive Oncology : Mumbai / Barshi / Chiplun: 1994

  36. Tata Memorial Hospital Ca. CervixLDR Vs HDR Brachytherapy INDCER PROTOCOL – 1996 onwards • Ongoing Trial • 600 patients randomized till date • Interim Analysis suggests: ONGOING

  37. INDCER: LDR Vs HDR (1996 Onwards) PROTOCOL at Tata Memorial Hospital Stage I & II Randomized External RT 40 Gy / 20#/ 4 Wks (MLB after 20 Gy) + ICA- LDR 30 Gy x 2# to point A External RT 40 Gy / 20#/ 4 Wks (MLB after 20 Gy) + ICA - HDR 7 Gy x 5# to point A Wk 1      Wk 2      Wk3      Wk4      Wk5   Wk 1      Wk 2      Wk3      Wk4      Wk5     

  38. INDCER:LDR Vs HDR (1996 Onwards) PROTOCOL At Tata Memorial Hospital Stage III Randomized External RT 50 Gy / 25#/ 5 Wks (MLB after 40 Gy) + ICA- LDR 30 Gy x 1# to point A External RT 50 Gy / 25#/ 5 Wks (MLB after 40 Gy) + ICA - HDR 7 Gy x 3# to point A Wk 1      Wk 2      Wk3      Wk4      Wk5      Wk 1      Wk 2      Wk3      Wk4      Wk5     

  39. HDR (37 pts) HDR (37 pts) HDR (120 pts) LDR (47 pts) LDR (47 pts) LDR (148 pts) Tata Memorial Hospital Ca. CervixLDR Vs HDR (INDCER PROTOCOL – 1996 onwards) IInd Interim Analysis of 352 patients : Jan. 2004 1.2 STAGE I & II STAGE III 1.0 70 % AT 3 YRS 78% AT 3 YRS .8 % Survival 75% AT 3 YRS 65 % AT 3 YRS .6 .4 .2 P = 0.70 P = 0.70 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 MONTHS MONTHS ONGOING 640 pts accrued • - No significant difference in outcome • No significant difference in the toxicities

  40. HDR LDR Randomized Trials comparing LDR & HDR Brachytherapy Author No of pts Stag 5 yr surv (%) Local control (%) No of pts Stage 5 yr surv (%) Local control (%) 42 59 11 I II III 83 75 37 …. …. …. 28 121 88 I II III 89 76 52 … … … Rotte (1978) 143 II-III 60 92 106 IIB-III 56 72 Shigemat (1983) 32 80 147 I II III 66 61 47 87 87 67 28 61 82 I II III 89 78 45 100 87 54 Teshima (1993) 35 90 111 I II III 78 64 43 91 76 71 39 93 114 I II III 73 62 50 92 79 76 Patel (1994) 157 I-III 74 (3yr DFS) 74 (3 yrs) 195 I-III 70 (3yr DFS) 70 (3 yrs) TMH (2004)

  41. HDR LDR Author No of Pts Stage Bladder (%) Rectal (%) No of Pts Stage Bladder (%) Rectal (%) Rotte (1978) 112 I/III 1 3 121 I/III 3 11 Shigemats (1983) 143 IIB/III 2 36 106 IIB/III 7 25 Teshima (1993) 32 80 147 I II III 6 0 4 3 5 4 28 61 82 I II III 0 0 0 4 5 1 Patel (1994) 235 I/III 3.7 0.4 246 I/III 3.8 2.4 TMH (2004) 157 I-III 5.0 4.5 195 I-III 5.2 7.9 Randomized Trials of HDR Vs LDR Moderate & Severe Late Complications

  42. Critical Review of Randomized Trials Chemo-radiation in Carcinoma Cervix • Heterogenous patient data • Suboptimal Radiotherapy Schedules Used • Non-uniform use of chemotherapeutic drugs and Sequencing • QOL issues : Unknown • Cost effectiveness ? • Needs to be tested optimally in our setting

  43. DAE- CTC-TMH Study: Sept. 2003 Carcinoma Cervix Stage Ib2 - IIb 49 patients recruited till Nov. 2004 365 patients 365 patients Neoadjuvant chemotherapy Concomitant chemotherapy (3 courses Taxol + Carboplatin based) weekly Cisplatin and Followed by Surgery +/- RT radiotherapy • Absolute Benefit in DFS: 10% • Accrual Period: Aug 2003 - 2006 (3 yrs) • Power of detection: 80% (alpha error: 0.05) ONGOING

  44. Tata Memorial Hospital Ca. Cervix IIIB Study August 2003 Onwards Carcinoma Cervix Stage IIIB 400 patients 400 patients Concomitant chemotherapy Radical Radiotherapy Ext RT+ICA weekly Cisplatin and 50 Gy(MLB at 40)/5wks + LDR/HDR Radiotherapy LDR: 30Gy or HDR: 7Gyx3# • Absolute Benefit in DFS: 10% • Accrual Period: Aug 2003 - 2006 (3 yrs) • Power of detection: 80% (alpha error: 0.05) ONGOING

  45. Tata Memorial Hospital Ca. Cervix IIIB Study August ‘03 Onwards Total No of patients randomized till Sept. 2004 = 144 pts

  46. IMRT CONVENTIONAL IMRT INTENSITY MODULATED RADIATION THERAPY (IMRT) IN CERVICAL CANCERS : Potential for : Reduction in toxicities : Dose Escalation

  47. IMRT PILOT STUDY Oct ‘02-March ‘04 • Total No of patients treated : 11 • FIGO Stage: IIB (6 pts) and IIIB (5 pts) • Protocol:Concomitant Chemo-Radiation - IMRT Pelvis: 60Gy/30#/6-7 weeks - ICA-LDR (30 Gy to Pt ‘A’) or HDR (7 Gy x 3#) • Follow-up:6 - 24 months: All loco-regionally controlled • Toxicities:No Grade III acute toxicities seen One patient: Grade II Radiation Proctitis at 16months

  48. INTENSITY MODULATED RADIATION THERAPY (IMRT) IN CERVICAL CANCERS Carcinoma Cervix Stage IIB 100 patients Conventional External RT + ICA – HDR (7 Gy x 5#) with Concomitant Chemoradiation 100 patients IMRT Pelvis + ICA – HDR (7 Gy x 5#) with Concomitant Chemoradiation • Reduction in Acute and Late RT toxicity’s by:15-25% • Accrual Period: Dec 2004 - 2007 (3 yrs) • Power of detection: 80% (alpha error: 0.05) Dec. 2004

  49. EVALUATION OF PET IN ADVANCED (FIGO IIB /IIIB) CARCINOMA CERVIX - AN OBSERVATIONAL STUDY: 100 Patients Para Aortic Nodal Staging (CT Scan / USG Abdomen) FDG PET SCANNING PET & Imaging -ve PET –ve & Imaging +ve PET & Imaging +ve PET+ve & Imaging -ve MRI PELVIS PELVIC RT CONVENTIONAL / IMRT +CT +HDR – ICA (3-5#) EXTENDED FIELD RT / IMRT + CT +HDR – ICA (3-5#) POST RT FDG PET SCANNING 06 months 12 months 18 months 24 months Jan 2005

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