ESTRO Educational Course Mumbai, India 2005

1
ESTRO Educational CourseMumbai, India 2005
Chemo/Radiation in Cervical Cancer

• G. Thomas M.D.

2
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.
3
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
4
Concurrent Chemotherapy/ Radiation Therapy
The New Standard How strong is the evidence of
benefit? What dont we know?
5
Ca Cervix, Selected Stages IB/IIARH PLND RT
Alone vs. RT FU/Plat (Peters et al, JCO 18,
00)
Progression Free Survival
78
P0.005
60
Years
node,parametria,margin ve.
6
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 3
2 (59) 18 (33) Pelvic failure 21
9 NED (2 year) 68 82 GOG 123
7
Bulky IB Ca CervixRT ( Hyst) vs RT Weekly
Plat ( Hyst)(Keys et al, NEJM 340, 99)

82
68
8
Concurrent HU/RT vs FU/Plat/RT in Advanced
(IIB-IVA) Ca Cervix(Whitney et al, JCO 17, 99)
57
47
9
Concurrent HU/RT vs HU, 5FU,Plat/RT vs Weekly
Plat/RT in Advanced (IIB-IVA) Ca Cervix(Rose et
al, NEJM, 99)
RTPlat 67 RTFU,PLAT,HU
RTHU 47
10
Advanced Ca Cervix Pelvic RT 5FU/Plat vs
Pelvic Para-aortic RT(Morris et al, NEJM, 99)
67
40
11
Concurrent Chemo-Radiation RTvs Extended Field
RT (RTOG 90-01)(Eifel et al, JCO 22, 2004)
Med FU 6.6 yrs RT CT/RT n 195 194 5yr S ,
52 73 plt0.0001 5yr DFS 43 68
plt0.0001 Pelvic recurrence 34 18
plt0.0001 Dist mets 31 18 p0.0013 IB
/ IIA S 55 79 plt0.0001
IIB / III 47 59
p0.07 Complications (gtGd3) 14 14
12
Ca CervixConcurrent Chemo/Radiation Therapy
LOCAL RECURRENCE RATES
AUTHOR STAGE CONTROL CT/RT Keys IB 24 11 P
eters IB/IIA 22 9 Morris IIB-IVA 35
19 Whitney IIB-IVA 30 25 Rose IIB-IVA 30
20
13
RT vs Concurrent RT/Plat, Advanced Ca Cervix
Survival (Pearcey et al, JCO 20, 02)
14
Comparability of Outcomes, CT/RT Advanced
Cervix Trials
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 .
15
Plat/RT vs RT in Advanced Ca Cervix(Pearcey et
al, JCO 20, 02)
of pts
Decrease in Hgb (g/l) during treatment
(RT/Plat vs RT p 0.003)
16
Reduction in the Risk of Death from Five
Chemoradiation Clinical Trials in Cervix Cancer

17
CT/RT in Ca Cervix
Is Cisplatin a) necessary, b)
sufficient, c) optimal for
concurrent chemo/RT?
18
Phase III Study RT/Plat vs RT/FU ( PVI) in
Advanced Ca CervixLanciano et al. submitted JCO
2004
Plat
FU
ns
FUfu
19
Concurrent Mitomycin, 5-FU and RT in Advanced Ca
Cervix(Lorvidhaya et al, IJORBP 55, 2003)
RTConcAdj
RTConc
RTAdj
RT
20
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
21
Concurrent Adjuvant Epirubucin/RT, Ca Cervix
Stage I-III(Wong et al, JCO 17, 99)
22
Ca CervixConcurrent Chemo/Radiation Therapy
DISTANT METASTASES RATE AUTHOR CONTROL CT/R
T Keys 16 12 Peters 12
7 Morris 33 14 Whitney 20
17 Rose 10 3-4 Lung 2?
23
Ca Cervix Relative Risk of Death in Six
Clinical Trials of Concurrent CT/RT
Survival RR Stage Treatment Benefit
Death Control Comparison IB21 RT RTwkly
Plat 9 0.54 IB or IIA2 RT RTPlat,FU 10 0.
5 IIB-IVA3 RTHU RTPlat,FU 10 0.74 IB2-IVA4 Ex
t field RT RTPlat,FU 12 0.58 IIB-IVA5 RTHU RT
wkly Plat 18 0.61 RTPlat,FU,HU 18 0.58
IB-IVA6 RT RTwkly Plat 3 0.91
Log Weighted Average all studies 0.65 1Keys,
2Peters, 3Whitney, 4Morris, 5Rose, 6Pearcey
24
Overall Survival after ConcomitantCT/RT a
Systematic ReviewGreen et al Lancet 358, 01
25
Ca CervixConcurrent 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
26
(78 sidewall disease)
27
Indications for Concurrent CT/RTProven
Benefit
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
28
Unproven or Questionable Benefit for Concurrent
CT/RT

• 1. Post surgical adjuvant for Stage IB with
  negative nodes but high risk features (size,
  depth, CLS)
• 2. For para-aortic nodal involvement
• In Stage IIB-IVA where RT delivery is optimized
  and hemoglobin levels maintained
• For recurrent disease

29
Concurrent Chemo/Radiation in Ca Cervix

• Future Directions
• Optimize RT !
• Attempts to overcome anemia/hypoxia.

30
Chemo/Radiotherapy in Ca Cervix
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
31
Chemo/Radiotherapy in Ca Cervix
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.
32

Ca Cervix The Future
Prevention- Vaccines