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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

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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