gt/05 estro educational course mumbai, india 2005 g. thomas m.d. chemo/radiation in cervical cancer
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GT/05
ESTRO Educational CourseMumbai, India 2005
ESTRO Educational CourseMumbai, India 2005
G. Thomas M.D.
Chemo/Radiation in Cervical Cancer
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Representative Results of Radical Radiation Alone By Stage
Representative Results of Radical Radiation Alone By Stage
Stage LC % 5 YR S ( %)†
Bulky IB 79 -87 63 -75
IIB 73 -82 62 - 68
IIIB 53 -63 28 - 48
IV 25 18 - 34 †
Lanciano,Weems, Mendenhall, Eifel, Perez, Thomas, Montana, Kramer, Million.
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Concurrent Chemotherapy/ Radiation Therapy
Concurrent Chemotherapy/ Radiation Therapy
National Cancer Institute Clinical Announcement, February 1999
“… five randomized phase III trials show an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy”
“… strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer”
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Concurrent Chemotherapy/ Radiation Therapy
Concurrent Chemotherapy/ Radiation Therapy
“The New Standard”
How strong is the evidence of benefit?
What don’t we know?
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Years
Progression Free Survival
Ca Cervix, Selected* Stages IB/IIARH + PLND: RT Alone vs. RT + FU/Plat
(Peters et al, JCO 18, ‘00)
Ca Cervix, Selected* Stages IB/IIARH + PLND: RT Alone vs. RT + FU/Plat
(Peters et al, JCO 18, ‘00)
78%
60%P=0.005
*node,parametria,margin +ve.
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Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*
(Keys et al, NEJM 340, ‘99)
Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*
(Keys et al, NEJM 340, ‘99)
RT (Hyst) RT / Plat (Hyst)
n 185 183
Recurred 32% (59) 18% (33)
Pelvic failure 21% 9%
NED (2 year) 68% 82%
* GOG #123
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Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*
(Keys et al, NEJM 340, ‘99)
Bulky IB Ca CervixRT (+ Hyst) vs RT + Weekly Plat (+ Hyst)*
(Keys et al, NEJM 340, ‘99)
68%
82%
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Concurrent HU/RT vs FU/Plat/RT in Advanced (IIB-IVA) Ca Cervix
(Whitney et al, JCO 17, ‘99)
Concurrent HU/RT vs FU/Plat/RT in Advanced (IIB-IVA) Ca Cervix
(Whitney et al, JCO 17, ‘99)
47%
57%
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Concurrent HU/RT vs HU, 5FU,Plat/RT vs Weekly Plat/RT in Advanced (IIB-IVA)
Ca Cervix(Rose et al, NEJM, ‘99)
Concurrent HU/RT vs HU, 5FU,Plat/RT vs Weekly Plat/RT in Advanced (IIB-IVA)
Ca Cervix(Rose et al, NEJM, ‘99)
RT+HU: 47%
RT+Plat: 67%
RT+FU,PLAT,HU
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Advanced Ca Cervix: Pelvic RT + 5FU/Plat vs Pelvic & Para-aortic RT
(Morris et al, NEJM, ‘99)
Advanced Ca Cervix: Pelvic RT + 5FU/Plat vs Pelvic & Para-aortic RT
(Morris et al, NEJM, ‘99)
67%
40%
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Med FU: 6.6 yrs RT CT/RT
n 195 194
5yr S %, 52 73 p<0.0001
5yr DFS % 43 68 p<0.0001
Pelvic recurrence 34 18 p<0.0001
Dist mets 31 18 p=0.0013
IB / IIA S % 55 79 * p<0.0001
IIB / III 47 59 p=0.07
Complications %(>Gd3) 14 14
Concurrent Chemo-Radiation + RTvs Extended Field RT (RTOG 90-01)
(Eifel et al, JCO: 22, 2004)
Concurrent Chemo-Radiation + RTvs Extended Field RT (RTOG 90-01)
(Eifel et al, JCO: 22, 2004)
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Ca Cervix:Concurrent Chemo/Radiation Therapy
Ca Cervix:Concurrent Chemo/Radiation Therapy
LOCAL RECURRENCE RATES % AUTHOR STAGE ‘CONTROL’ CT/RT
Keys IB 24 11
Peters IB/IIA 22 9
Morris IIB-IVA 35 19
Whitney IIB-IVA 30 25
Rose IIB-IVA 30 20
GT/05Cisplatin and radiation Radiation alone
Pe
r ce
nta
ge
0
20
40
60
80
100
Time (years)
0.0127126
2.010092
4.05152
6.02517
8.000
p=0.53
Adjusted for stage p=0.43
RT vs Concurrent RT/Plat, Advanced Ca Cervix: Survival
(Pearcey et al, JCO 20, ‘02)(Pearcey et al, JCO 20, ‘02)
RT vs Concurrent RT/Plat, Advanced Ca Cervix: Survival
(Pearcey et al, JCO 20, ‘02)(Pearcey et al, JCO 20, ‘02)
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PFS % Control CT/RT Positive trials:
(Morris, Whitney, Rose) 40- 47 57 –64
Negative trials: 53- 58 58 - 62
(Thomas ,Pearcey) Difference is in the “control arms”.
RT dose, use of IC similar .But Overall TIME :Positive trials 58-64 dys Negative trials 44-59 dys
Loss of LC is 1% / dy prolongation over 50 days .
Comparability of Outcomes, CT/RT Advanced Cervix TrialsComparability of Outcomes,
CT/RT Advanced Cervix Trials
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Plat/RT vs RT in Advanced Ca Cervix(Pearcey et al, JCO 20, ‘02)
Plat/RT vs RT in Advanced Ca Cervix(Pearcey et al, JCO 20, ‘02)
0
5
10
15
20
25
30
35
RT alone RT/ Plat
0 to -2.9
-3 to 5.9
-6 to 8.9
-9 to -11.9
-12 to -14.9
< -14.9
Decrease in Hgb (g/l) during treatment (RT/Plat vs RT : p = 0.003)
%
of
pts
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Reduction in the Risk of Death from Five Chemoradiation Clinical Trials in
Cervix Cancer
Reduction in the Risk of Death from Five Chemoradiation Clinical Trials in
Cervix Cancer
-0.3-0.2-0.1
00.10.20.30.40.50.60.70.8
Risk Reduction with 90% C.I.Line 4
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CT/RT in Ca CervixCT/RT in Ca Cervix
Is Cisplatin a) necessary,
b) sufficient,
c) optimal
for concurrent chemo/RT?
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Phase III Study :RT/Plat vs RT/FU ( PVI) in Advanced Ca Cervix
Lanciano et al. submitted JCO 2004
Phase III Study :RT/Plat vs RT/FU ( PVI) in Advanced Ca Cervix
Lanciano et al. submitted JCO 2004
By Treatment GroupP
ropo
rtion
Pro
gres
sion
-Fre
e
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months on Study0 12 24 36
Rx Group PF Failed Total Cisplatin 92 67 159
PF Failed Total
PVI 5-FU 81 76 157
FUfuFU
Plat
ns
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Concurrent Mitomycin, 5-FU and RT in Advanced Ca Cervix
(Lorvidhaya et al, IJORBP 55, 2003)
Concurrent Mitomycin, 5-FU and RT in Advanced Ca Cervix
(Lorvidhaya et al, IJORBP 55, 2003)
RTRT+Adj
RT+Conc+Adj
RT+Conc
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Concurrent and Adjuvant Epirubicin/ Radiation Therapy, Ca Cervix Stage I-III
(Wong et al, JCO 17, ‘99)
Concurrent and Adjuvant Epirubicin/ Radiation Therapy, Ca Cervix Stage I-III
(Wong et al, JCO 17, ‘99)
RT CT/RT CT
Number 110 110
RELAPSE %
Pelvic (any) 24 15 p = 0.99
Distant (any) 24 8 p = 0.012
Total 33 21
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Concurrent & Adjuvant Epirubucin/RT, Ca Cervix Stage I-III
(Wong et al, JCO 17, ‘99)
Concurrent & Adjuvant Epirubucin/RT, Ca Cervix Stage I-III
(Wong et al, JCO 17, ‘99)
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Ca Cervix:Concurrent Chemo/Radiation Therapy
Ca Cervix:Concurrent Chemo/Radiation Therapy
DISTANT METASTASES RATE:
AUTHOR ‘CONTROL’ CT/RT
Keys 16 12
Peters 12 7
Morris 33 14
Whitney* 20 17
Rose* 10 3-4
* Lung 2
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Survival RRStage Treatment Benefit Death
Control ComparisonIB21 RT RT+wkly Plat 9% 0.54IB or IIA2 RT RT+Plat,FU 10% 0.5IIB-IVA3 RT+HU RT+Plat,FU 10% 0.74IB2-IVA4 Ext field RT RT+Plat,FU 12% 0.58IIB-IVA5 RT+HU RT+wkly Plat 18% 0.61
RT+Plat,FU,HU 18% 0.58IB-IVA6 RT RT+wkly Plat 3% 0.91 Log Weighted Average all studies 0.651Keys, 2Peters, 3Whitney, 4Morris, 5Rose, 6Pearcey
Ca Cervix: Relative Risk of Death in Six Clinical Trials of Concurrent CT/RT
Ca Cervix: Relative Risk of Death in Six Clinical Trials of Concurrent CT/RT
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Overall Survival after ConcomitantCT/RT: a Systematic Review
Green et al Lancet 358, 01
Overall Survival after ConcomitantCT/RT: a Systematic Review
Green et al Lancet 358, 01
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Ca Cervix:Concurrent Chemo/Radiation Therapy
Ca Cervix:Concurrent Chemo/Radiation Therapy
ACUTE TOXICITY %, Grade 3/4:
1ST AUTHOR CHEMO HAEM GI GU OTHER
Rose Plat 19 7 3 6
Keys Plat 21 14 2 8
Pearcey Plat 5 13 2 12
Whitney Plat/FU 7 8 1 0
Morris Plat/FU 37 17 1 8
Peters Plat/FU 39 44 - 8
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(78% sidewall disease)
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1. As post surgical adjuvant for IB/IIA node,
parametrial, margin positive
2. As definitive treatment (without routine Sx) in
Stage IB2
3. As definitive treatment for Stage IIB-IVA
Indications for Concurrent CT/RTProven Benefit
Indications for Concurrent CT/RTProven Benefit
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1. Post surgical adjuvant for Stage IB with negative
nodes but high risk features (size, depth, CLS)
2. For para-aortic nodal involvement
3. In Stage IIB-IVA where RT delivery is optimized
and hemoglobin levels maintained
4. For recurrent disease
Unproven or Questionable Benefit for Concurrent CT/RT
Unproven or Questionable Benefit for Concurrent CT/RT
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Future Directions:
1. Optimize RT !
2. Attempts to overcome anemia/hypoxia.
Concurrent Chemo/Radiation in Ca Cervix
Concurrent Chemo/Radiation in Ca Cervix
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3. Determine if benefits of CT/RT accrue to only some subsets of patients:
Define subgroups likely to have therapeutic gain by characteristics defined by, e.g.
a. ‘conventional’ staging
b. functional imaging (MRI, PET)
c. molecular markers
d. Gene assays
e. DNA/Plat adduct assays
f. Dynamic oxygenation status
Chemo/Radiotherapy in Ca CervixChemo/Radiotherapy in Ca Cervix
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4. Identify ‘better’ agents to pelvic control tailored to specific molecular characteristics:
-Tirapazamine
-Taxanes, Gemcitabene
-antiangiogenics
- exploit molecular targets that block proliferation /invasion or sensitize tumours (Cox-2) or target
activated oncogenes(e.g.RAS)
5. Explore adjuvant as well as concurrent schedules to distant metastases.
6. Define existing acute and late toxicities and choose strategies to minimize them.
Chemo/Radiotherapy in Ca CervixChemo/Radiotherapy in Ca Cervix
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Ca Cervix: The Future
Ca Cervix: The Future
Prevention- Vaccines
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