Transcript Document

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
• TMH Evidence Based Guidelines
• Prospective Studies
• Molecular and Biological Studies
• Prevention
COMPARISION OF URBAN (MUMBAI#) VS RURAL (BARSHI+) IN
MAHARASHTRA
FEMALE BREAST AND GENITAL TRACT CANCERS
INCIDENCE RATE* PER
100,000
35
31.3
30
MUMBAI
23.4
25
BARSHI
17.4
20
15
10
8.3
6.8
5
1.4
3.2
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)
DOWN THE DECADES
CERVIX CANCER IN
TATA MEMORIAL HOSPITAL 1941-2000
18000
16635
16000
15080
14000
13662
12000
10000
9055
8000
6000
4679
4000
2000
2102
0
1941-50
'51-60
'61-70
'71-80
'81-90
'91-00
TATA MEMORIAL HOSPITAL CANCER REGISTRY
1985 - 2000
Down Staging of Carcinoma Cervix
70
68.5
65.8
63.3
60
54.1
1985
1989
1993
1997
2000
51.7
50
40
35.2
28.2
30
19.7
17.1
20
10
28
10 9.1
11.89.5
6.1
7.7
10.6
3.6
0
0
Stage I
Stage II
Stage III
Stage IV
TREATMENT PATTERNS IN CARCINOMA CERVIX
Sx (5%)
Comb (12%)
RT (83%)
TATA HOSPITAL CANCER REGISTRY 2000
OVERVIEW OF RESULTS
CARCINOMA CERVIX
1979 - 1994
8369 Patients
Carcinoma Cervix: 1979 - 1994
PATIENT ACCRUAL
No of Registrations
8369
Non- evaluable
1589 (19%)
Evaluable
6780 (81%)
Median FU
68 Months (57-79)
CA.CERVIX : 1979-1994 (6780 Pts)
AGE GROUP
FIGO STAGE
60
100
Youngest: 21 Yrs
Oldest :
81 Yrs
Median: 48 Yrs
< 35 Yrs: 18%
Median FU: 68 months(57-79)
60
40
35
% CASES
PERCENT
80
13
4
28
30
10
10
1
0
4
0.07
0
21-30 31-40 41-50 51-60 61-70 71-80 81-90
100
X
0
IA
IB
IIB
IIA
IIIA IIIB
GRADE
94
HISTOLOGY
80
% CASES
40
20
28
19
20
55
50
Gr I 2%
60
Gr II 28%
NK 16%
Gr III 64%
40
20
0
0
nk
in-situ
microinva SQ CA adenoca
ad-sq
undiffer
others
IVA IVB
CA. CERVIX 1979-1994
STAGE IB & IIA
Modality
Evaluable patients
SURGERY ALONE
303
PRE-OP. RT+ SURGERY
293
RADICAL IRRADIATION
356
TOTAL
952
CA. CERVIX 1979-1994
STAGE IB & IIA (952 pts)
TREATMENT MODALITY
1.2
DISEASE FREE SURVIVAL
1.1
1.0
.9
.8
PREOP+Sx(293) PTS)
% Survival
.7
Sx ALONE (303 PTS)
.6
RT ALONE (356 PTS)
.5
.4
.3
.2
.1
P = 0.24
0.0
0
24
48
72
MONTHS
96
120
144
168
CA.CERVIX : 1979 - 1994
STAGE IB & IIA (596 PTS)
SURGERY & NODES
Patient
no.
Cx + ve
Ut + ve
Vg + ve
Node
+ve
79
(26%)
SURGERY
303
303
54
(17%)
18
(5%)
PRE-OP.RT+
SURG
293
180
(62%)
27
(11%)
5
44
(1%) (15%)
483
81
(14%)
23
(4%)
Total
596
113
(19%)
CA.CERVIX 1979 - 1994
Stage IB & IIA : Sx +/-Pre-op RT (596 PATIENTS)
NODAL STATUS
1.1
DISEASE FREE SURVIVAL
1.0
.9
Node -Ve
% Survival
.8
.7
.6
Node + Ve
.5
.4
.3
.2
.1
P = 0.000
0.0
0
24
12
48
36
72
60
MONTHS
96
84
120
108
144
132
CA. CERVIX: 1979 - 1994
STAGE IB & IIA (596 PTS)
HP:DEPTH OF CERVICAL INVASION
92% ( NO TUMOR 76 PTS)
100
% DFS
80
81% ( <1/2 INVAS 174 PTS)
69% ( >1/2 INVAS 327 PTS)
60
40
20
0
0
1
2
3
4
5
6
7
Years
8
9
10
11
P = 0.001
12
CA. CERVIX: 1979 - 1994
Stage IB & IIA
POST-OP RT IN NODE +VE
100
% DFS
80
57% ( POST-OP RT :74Pts)
60
38% ( NO POST-OP RT:41Pts)
40
20
0
0
1
2
3
4
5
6
Years
7
8
9
10
11
P = 0.4 (NS)
12
Carcinoma Cervix: 1979 - 1994
STAGES IB & IIA (356 PTS)
RADICAL RADIOTHERAPY REGIMEN
RT Regimen
Evaluable
Conv. Field
46 Gy/ 23 # + 1 ICA
199
Ext. Field
50 Gy/ 32 # + 1 ICA
61
MLB after 10
Gy
40 Gy/ 20 # + 2 ICA
96
Total
356
Carcinoma Cervix: 1979 - 1994
STAGES IB & IIA (356 pts)
RADICAL RADIOTHERAPY REGIMEN
1.2
DISEASE FREE SURVIVAL
1.1
1.0
.9
% Survival
40Gy/20/28(MLB at 20/10)
.8
46Gy/23/35
.7
.6
50Gy/32/40(1.5Gy/#)
.5
.4
.3
.2
P = 0.15
.1
0.0
0
12
24
36
48
60
MONTHS
72
84
96
108
120
CA.CERVIX 1979 - 1994
STAGE IB & IIA :EXT.RT REGIMEN (356 PTS)
LATE COMPLICATIONS
Conv. 46/23#
Ext.F.50/32#
40/20#.(MLBat10Gy)
Percent
40
20
17
12
13
8
9
9
2
0
RECTAL
BLADDER
1
0
BOWEL
CA. CERVIX: 1979 -1994
Stage IB & IIA : TMH PROTOCOL
Year
Surgery
Pre-Op.RT+
Surgery
RADICAL RT
Conv. Field
RADICAL RT
Ext. Field
1979- 82
Wertheim's
40/20/4Wk
30/10/2Wk
EBRT:46/23#
Howard:34Gy
Selectron:34Gy
EBRT:50/32#
Howard:30Gy
Selectron:30Gy
1982-83
Wertheim's
40/20/4Wk
30/10/2Wk
EBRT:46/23#
Howard:30Gy
Selectron:24Gy
EBRT:46/23#
Howard:30Gy
Selectron:24Gy
1984-85
Wertheim's
40/20/4Wk
30/10/2Wk
EBRT:46/23#
Howard:30Gy
Selectron:24Gy
-
30/10/2Wk
EBRT:46/23#
Selectron:24Gy
1986-87
1988-94
Current
Wertheim's
Wertheim's
20/5#/1Wk
(Less bulky)
30/10/2Wk
(Bulky)
Wertheim’s
-
40/20# (MLB)
Selectron x 2#
30 Gy each
40/20# (MLB-20)
Selectron: 2#x30 Gy LDR
or 5# x7 Gy HDR each
-
-
-
STAGE Ib & IIa
SUMMARY

Sx alone : Justified in Only Select Group of Early Stages

Pre-op Radiotherapy + Sx :No

Radiation Therapy Alone : Standard

Neoadjuvant chemo + Sx: Needs to be Investigated

Concurrent chemo-radiation: Gold Standard Rx ?
significant advantage (?20Gy/5#)
Conventional Rx
FIGO Staging Inappropriate due to large volume and grade III tumors
CARCINOMA CERVIX : 1979-1994
STAGE IIB
Modality
Radical Irradiation
Pre-op RT + Surgery
Surgery Alone
Total
Evaluable
1282
583
29
1894
Carcinoma Cervix: 1979 - 1994
STAGES IIB (1894 patients)
TREATMENT MODALITY
1.2
DISEASE FREE SURVIVAL
1.0
% Survival
.8
PREOP RT+Sx (583PTS)
.6
.4
RT ALONE (1282PTS)
.2
P = 0.23
0.0
0
24
48
72
96
MONTHS
120
144
168
192
Carcinoma Cervix: 1979 - 1994
STAGE IIB (1282PTS)
RADICAL RADIOTHERAPY REGIMEN
1.1
DISEASE FREE SURVIVAL
1.0
.9
% Survival
.8
40/20/28 (MLB AT 20)
.7
.6
50/25/35(2Gy/#MLB AT 40)
.5
50/25/35(2Gy/#)
.4
50/32/40(1.5Gy/#)
.3
.2
P = 0.000
.1
0.0
0
24
48
MONTHS
72
96
120
CA.CERVIX: 1979 - 1994
STAGE II B : EXT. R.T. REGIMEN (1282 PTS)
LATE COMPLICATIONS
Percent
20
Conv. Field
13
10
Ext.Field
MLB40, 50/25#
MLB10, 40/20#
12
9
8
8
7
6
6
3
4
3
0
Rectal
Bladder
Late Complications
Bowel
4
Carcinoma Cervix Stage IIB
Summary
• Pre-op RT : Down staging, but no Advantage
• RT Dose escalation to central disease improves
control rates
• Neo-adjuvant CT + Sx : Investigational
CA CERVIX: 1979 - 1994
STAGE IIIB (3299 PTS)
RADICAL RADIOTHERAPY REGIMEN
RT REGIMEN
EVALUABLE PTS
DAILY RADIATION
1108
THRICE WEEKLY
1018
TWICE WEEKLY
577
ONCE WEEKLY
596
TOTAL
3299
Carcinoma Cervix: 1979 - 1994
STAGE III B (3299 PTS)
RADICAL RADIOTHERAPY REGIMEN
1.2
DISEASE FREE SURVIVAL
1.1
1.0
% Survival
.9
.8
.7
.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
0.0
* P = 0.000
0
12
24
36
48
60
72
84
96
MONTHS
* Significant improvement in DFS with standard conventional RT
CA.CERVIX: 1979 - 1994
STAGE III & IV (3299 PTS)
LATE COMPLICATIONS
35
29 29
30
25
25
18
20
15
20
13 14
19
12 12 11 13
10
3 4
5
6 5
0
Rectal
Daily
Bladder
Trice/wk
Bowel
Twicw/wk
Vagina
Once/wk
Late Complications lower with standard conventional RT
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)
CA. CERVIX : 1979 - 1994
LESSONS LEARNT

OUTCOME ANALYSIS

IMPROVED COMPLIANCE AND FOLLOW–UP

ACQUISITION OF BETTER FACILITIES

GYNAE JOINT CLINIC : SINCE 1979

CLINICAL GUIDELINES

PROSPECTIVE STUDIES
Tata Memorial Hospital
Evidence Based Guidelines
Evidence Based TMH Guidelines - Feb 2003
STAGE Ib & IIa
Type III Hysterectomy
+
IB1: Radical Radiation Therapy
Pelvic Lymphadenectomy
IB2/IIA: Concomitant CT+RT
Low risk
Intermediate risk
Observation
Pelvic Radiation
High risk
Concomitant
chemo radiation
PROSPECTIVE TRIALS :
Tata Memorial Centre
Hospital Scientific
Review Committee
Clinical Research
Secretariat
DAE-
Hospital Ethics
Committee
Clinical Trials Centre
Data Monitoring
Committee
• 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
Tata Memorial Hospital
Ca. Cervix LDR Vs HDR Brachytherapy
INDCER PROTOCOL – 1996 onwards
 Ongoing Trial
 600 patients randomized till date
 Interim Analysis suggests:
ONGOING
INDCER: LDR Vs HDR (1996 Onwards)
PROTOCOL at Tata Memorial Hospital
Stage I & II
Randomized
External RT
40 Gy / 20#/ 4 Wks
External RT
40 Gy / 20#/ 4 Wks
(MLB after 20 Gy)
(MLB after 20 Gy)
+ ICA- LDR
30 Gy x 2# to point A
+ ICA - HDR
7 Gy x 5# to point A
Wk 1
    
Wk 1
   

Wk 2
    
Wk 2
   

Wk3
   

Wk3
   

Wk4
    
Wk4
   

Wk5

Wk5
   


INDCER: LDR Vs HDR (1996 Onwards)
PROTOCOL At Tata Memorial Hospital
Stage III
Randomized
External RT
External RT
50 Gy / 25#/ 5 Wks
50 Gy / 25#/ 5 Wks
(MLB after 40 Gy)
(MLB after 40 Gy)
+ ICA- LDR
+ ICA - HDR
30 Gy x 1# to point A
7 Gy x 3# to point A
Wk 1
    
Wk 1
   

Wk 2
    
Wk 2
   

Wk3
   

Wk3
   

Wk4
    
Wk4
   

Wk5
   

Wk5
   

Tata Memorial Hospital
Ca. Cervix LDR Vs HDR (INDCER PROTOCOL – 1996 onwards)
IInd Interim Analysis of 352 patients : Jan. 2004
1.2
STAGE I & II
STAGE III
% Survival
1.0
75% AT 3 YRS
.6
.4
.2
0.0
0
70 % AT 3 YRS
78% AT 3 YRS
.8
65 % AT 3 YRS
HDR (120 pts)
LDR (148 pts)
12
24
36
MONTHS
HDR (37 pts)
HDR (37 pts)
LDR (47 pts)
LDR (47 pts)
P = 0.70
48
60
720
12
24
P = 0.70
36
48
60
72
MONTHS
- No significant difference in outcome
-No significant difference in the toxicities
ONGOING
640 pts accrued
Randomized Trials comparing LDR & HDR Brachytherapy
HDR
Author
LDR
No of
pts
Stag
5 yr surv
(%)
Local
control
(%)
No of
pts
42
59
11
I
II
III
83
75
37
….
….
….
28
121
88
I
II
III
89
76
52
…
…
…
143
II-III
60
92
106
IIB-III
56
72
Teshima
(1993)
32
80
147
I
II
III
66
61
47
87
87
67
28
61
82
I
II
III
89
78
45
100
87
54
Patel
(1994)
35
90
111
I
II
III
78
64
43
91
76
71
39
93
114
I
II
III
73
62
50
92
79
76
157
I-III
74 (3yr
DFS)
74
(3 yrs)
195
I-III
70 (3yr
DFS)
70
(3 yrs)
Rotte
(1978)
Shigemat
(1983)
TMH
(2004)
Stage 5 yr surv
(%)
Local
control
(%)
Randomized Trials of HDR Vs LDR
Moderate & Severe Late Complications
HDR
Author
No of
Pts
Stage
Rotte
(1978)
112
Shigemats
(1983)
LDR
Bladder
No of
Pts
Stage
(%)
Rectal
(%)
Bladder
(%)
Rectal
(%)
I/III
1
3
121
I/III
3
11
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
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
DAE- CTC-TMH Study: Sept. 2003
Carcinoma Cervix Stage Ib2 - IIb
49 patients recruited till Nov. 2004
365 patients
Neoadjuvant chemotherapy
(3 courses Taxol + Carboplatin based)
Followed by Surgery +/- RT
365 patients
Concomitant chemotherapy
weekly Cisplatin and
radiotherapy
• Absolute Benefit in DFS: 10%
• Accrual Period: Aug 2003 - 2006 (3 yrs)
• Power of detection: 80% (alpha error: 0.05)
ONGOING
Tata Memorial Hospital
Ca. Cervix IIIB Study August 2003 Onwards
Carcinoma Cervix Stage IIIB
400 patients
Radical Radiotherapy Ext RT+ICA
50 Gy(MLB at 40)/5wks + LDR/HDR
LDR: 30Gy or HDR: 7Gyx3#
400 patients
Concomitant chemotherapy
weekly Cisplatin and
Radiotherapy
• Absolute Benefit in DFS: 10%
• Accrual Period: Aug 2003 - 2006 (3 yrs)
• Power of detection: 80% (alpha error: 0.05)
ONGOING
Tata Memorial Hospital
Ca. Cervix IIIB Study August ‘03 Onwards
Total No of patients randomized till Sept. 2004 = 144 pts
RT alone
CT + RT
Pts Accrued
71
73
Rx Completed
57
55
1 (Disease)
1(CT)
7
4
2
Nil
1(Lung+Lt. SCN)
4
Nil
1
1(Pelvic)
1 (LT. SCN)
Died
Recurrences
Progressive
Local
Nodal
Distant
INTENSITY MODULATED RADIATION THERAPY (IMRT)
IN CERVICAL CANCERS :
IMRT
IMRT
CONVENTIONAL
Potential for : Reduction in toxicities
: Dose Escalation
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
INTENSITY MODULATED RADIATION THERAPY (IMRT)
IN CERVICAL CANCERS
Carcinoma Cervix Stage IIB
100 patients
100 patients
Conventional External RT
IMRT Pelvis
+ ICA – HDR (7 Gy x 5#)
+ ICA – HDR (7 Gy x 5#)
with Concomitant Chemoradiation
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
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
PELVIC RT
CONVENTIONAL / IMRT +CT
+HDR – ICA (3-5#)
PET –ve & Imaging +ve
MRI
PELVIS
PET & Imaging +ve
EXTENDED FIELD RT /
IMRT + CT
+HDR – ICA (3-5#)
POST RT FDG PET SCANNING
06 months
12 months
18 months
24 months
Jan 2005
Expression pattern of different biological markers in
Carcinoma of Uterine Cervix
Number of patients
b Actin
1 2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
29 30 31 32 33 34 35 36 37
Met
14-3-3 s
RR2
hTERT
Bax
p15
p16
p27
Cyclin D1
K-19
Survivin
HIF 1 A
HIF B
CA-9 N
VEGF A
• Currently 16 molecular markers being evaluated
Bandopadhyay et al.
Delineation of Prognostic Biomarkers of
Progression of Cervical Cancer
ACTREC/TMH:TMC
Aim:
To undertake a micro-array based approach to
delineate gene expression patterns and to
identify molecular markers for:
•
prognosis
•
staging
•
prediction of response to radiotherapy
PI: Chandan Kumar
SUMMARY
• Since decades: Significant Downstaging
• Refinements in Treatment Protocols
• TMH Guidelines
• Prospective Trials : Further impact on Outcome
• Molecular Studies : Impact on Clinical Practice
• Early Detection: Health Education and Screening
• Prevention
TATA MEMORIAL CENTRE
Pathology
Dr. R. Chinoy
Dr. N. Jambekar
Dr. K. Deodhar
Dr. S. V Kane
Dr. S. Desai .
Dr. R. Kelkar
Ms. Dulhan Ajit
Cervix Working Group
Dr. KA Dinshaw
Gyneac Surgery
Dr. H.B.Tongaonkar
Dr. R. Kerkar
Dr. A. Maheshwari
Radiation Onco.
Dr. S.K.Shrivastava
DR KA Dinshaw
Dr S (Ghosh) Laskar
Dr. U. Mahantshetty
Dr. R. Engineer
Medical Onco.
Dr. P. Parikh
Dr. S. Gupta
Radio-Diagnosis
Dr. M. Thakur
Prev. Onco.
Dr. S. Shastri
Dr. S. Patil
Dr. G. Mishra
Nursing Staff &
Field Social Workers
Lab. Medicine
Dr. D. Bandopadhyay
ACTREC
Dr. S. Zingde
Dr. S. Chiplunkar
Dr. R. Mukhopadhyay
Dr. T. Teni
Dr. C. Sinha