concurrent cisplatin, paclitaxel and radiotherapy as...

PTX/CDDPplus RTin EC

Innovazioni terapeutiche in oncologiaCagliari, 23-24 giugno 2005Innovazioni terapeutiche in oncologiaCagliari, 23-24 giugno 2005

Concurrent cisplatin, paclitaxel and radiotherapy as preoperative

treatment for epidermoidesophageal cancer: a phase II study

Concurrent cisplatin, paclitaxel and radiotherapy as preoperative

treatment for epidermoidesophageal cancer: a phase II study

Fernando De VitaFernando De Vita

Oncologia MedicaDir.: Prof. G. Catalano

Seconda Università di Napoli

Oncologia MedicaDir.: Prof. G. Catalano

Seconda Università di Napoli


Ten-year OS for pts with resected ECTen-year OS for pts with resected EC

0 24 48 72 96 1200.0

.2

.4

.6

.8

1.0

Months

Cum

ulat

ive

surv

ival

R0 (n=448)

R1/R2 (n=153)

SQC

% of R0 resection by pathologic T% of R0 resection by pathologic T

10091

84

70

48

10091

84

70

48

pT1MucosaSubmucosa

pT2

pT3

pT4

pT1MucosaSubmucosa

pT2

pT3

pT4

pT1MucosaSubmucosa

pT2

pT3

pT4

pT1MucosaSubmucosa

pT2

pT3

pT4

% of node metastases by pathologic T% of node metastases by pathologic T

0 24 48 72 96 1200.0

.2

.4

.6

.8

1.0

Months

Cum

ulat

ive

surv

ival

pN0 (n=238)

pN+ (n=210)

SQC2222

50

74

79

2222

50

74

79

Stein, 2002


Three-year survivalThree-year survival

Walsh - AC

Combined (7)Walsh – SCC

UrbaNygaardLe PriseBossetApinop

OR 0.6695% CI 0.47 to 0.92P=0.016

OR 0.6695% CI 0.47 to 0.92P=0.016

Favors CTRTSFavors CTRTS Favors S aloneFavors S alone

CitationCitation 0.010.01 0.10.1 11 1010 100100

Urschel JD, Am J Surg, 2003Urschel JD, Am J Surg, 2003


Rate of CompleteResectionRate of CompleteResection

Combined (5)UrbaNygaardLe PriseLawBosset

OR 0.5395% CI 0.33 to 0.84P=0.007

OR 0.5395% CI 0.33 to 0.84P=0.007

Favors CTRTSFavors CTRTS Favors S aloneFavors S alone

CitationCitation 0.010.01 0.10.1 11 1010 100100

Urschel JD, Am J Surg, 2003Urschel JD, Am J Surg, 2003


RR of death for NCRT followed by surgery comparedwith surgery alone, measured by number of death(n)/patient-months of follow-up (N)

RR of death for NCRT followed by surgery comparedwith surgery alone, measured by number of death(n)/patient-months of follow-up (N)

0.57 [0.38, 0.85]18.552/63539/837Walsh

Test for overall effects: z=1.84 (P=.07)

Test for heterogeneity:chi-square=5.08 (P=.41)

100

14.112.411.633.69.8

Weight %RR(95% Cl fixed)

310/21192

45/709837/738

39/1039106/11070

31/612

Surgeryalonen/N

0.86 [0.74, 1.01]284/21745Total (95%Cl)

0.89 [0.58, 1.36]40/7098Urba0.92 [0.59, 1.43]39/846Nygaard0.93 [0.59, 1.47]33/946LePrise0.97 [0.74, 1.27]106/11388Bosset0.85 [0.51,1.40]27/603Apinop

Study NCRTn/N

RR(95% Cl fixed)

-1-1 -2-2 11Favors treatmentFavors treatment

55 1010Favors controlFavors control

Greer SE, Surgery, 2005Greer SE, Surgery, 2005


De Vita F, Chest, 2002De Vita F, Chest, 2002


Paclitaxel activity in esophageal cancerPaclitaxel activity in esophageal cancer

Taxol control

10GY P Taxol8GY P Taxol5GY P Taxol2GY P Taxol

0.000 0.002 0.004 0.006 0.008 0.0100.0

20

40

60

80

100

Per

cent

Surv

ival

TAXOL dose (PPC)

Taxol treatment 48 hr prior to RTTaxol treatment 48 hr prior to RT

0.0000.000 0.0020.002 0.0040.004 0.0060.006 0.0080.008 0.0100.0100.00.0

2020

4040

6060

8080

100100

Per

cent

Surv

ival

TAXOL dose (PPC)

Taxol treatment 24 hr prior to RTTaxol treatment 24 hr prior to RT

Cell type

SSAA

5046

3030

Paclitaxel, 3 , 3 hourshours + C + 5+ C + 5--FUFUS + AS + A 1741Paclitaxel, 1 hour

S + AS + A 7017Paclitaxel, 3 , 3 hourshours + C + 5+ C + 5--FUFUS + AS + A 4432Paclitaxel, 24 , 24 hourshours + C+ CS + AS + AS + AS + A 5258Paclitaxel + C q 2 + C q 2 weeksweeks

4020Paclitaxel + C q 2 + C q 2 weeksweeks

Response (%)N° of patientsRegimen

STEREN A, Gynecol Oncol 1998


Prognostic value of VEGF (P)Correlation of VEGF with

0.018

<0.001

0.04

0.007

0.016

Univariate

<0.01

0.08

0.162

0.0002

MVD (P)

-

pT, N+, M+

-

pT, N+ M+

dl, M+, V+, G

Pathology

0.057IHCOgata,’03

0.001ELISAShimada, ‘01

0.046IHCShih, ‘00

0.198IHC, PCRUchida, ‘98

0.008IHC, PCRInoue, ‘97

Study VEGF analysis Multivariate

Prognostic value of VEGF in human SCC of the esophagusPrognostic value of VEGF in human SCC of the esophagus

0 5 10 15 20 25 30

Days after treatment start

Tum

orvo

lum

e (m

m3 )

0

1000

2000

3000

4000

Control

Anti- VEGF

RT

RT + Anti- VEGF

GORSKI J, Cancer Res 1999GORSKI J, Cancer Res 1999


G8G8G8 G15G15G15 G22G22G22 G29G29G29 G36G36G36

RADIOTHERAPY 46 GyRADIOTHERAPY 46 Gy

RESTAGINGRESTAGING

SURGERYSURGERY2 Cycles pPR

PD

pCR

G1G1G1

CDDP 70 mg/mq/3 sett. + TAX 175 mg/mq/3 sett.CDDP 70 mg/mq/3 sett. + TAX 175 mg/mq/3 sett.

CDDP 35 mg/mq/sett. + TAX 45 mg/mq/sett.CDDP 35 mg/mq/sett. + TAX 45 mg/mq/sett.

Plan of the StudyPlan of the Study

Off studyOff Off studystudy

Follow-upFollowFollow--upup

EndpointsEndpoints• To evaluate the activity and toxicity of the association of cisplatin and

paclitaxel administered concurrently with RT before esophagectomy

• To determine the effect of multimodality therapy on circulating VEGF levels in pts with esophageal cancer

• To evaluate the activity and toxicity of the association of cisplatin and paclitaxel administered concurrently with RT before esophagectomy

• To determine the effect of multimodality therapy on circulating VEGF levels in pts with esophageal cancer


Characteristics of patients

100ECOG PS

4291

5Distal18Middle

PRIMARY SITES

23PTS

62 (49-73)Median (range)AGE (years)

5F18M

SEXGRADING

2G1

18G2

3G3

2T4 N0 (III)11T3 N1(III)6T2 N1(IIB)4T3 N0 (IIA)

EUS STAGE


Drug DeliveryDrug Delivery

4 %4 % 4 %4 % 4 %4 %

87 %87 %

5 cycles5 cycles 4 cycles4 cycles 3 cycles3 cycles

Total No. of cyclesMedianRange

Total No. of cyclesMedianRange

132*5.1

(3 – 6)

132*5.1

(3 – 6)

13 % Stop CT13 % Stop CT

*Cycles delaied and/or modified :6*Cycles delaied and/or modified :6


G3G4

Toxicity of CTRT according toWHO gradeToxicity of CTRT according toWHO grade

13 %13 %

4 %4 % 4 %4 % 4 %4 % 4 %4 % 4 %4 %

17 %17 %

9 %9 %9 %9 %

13 %13 %

Neutropenia

Neutropenia

Fatig

ue

Fatig

ue

Esophagitis

Esophagitis

Stomatiti

s

Stomatiti

s

Nausea/

Vomiting

Nausea/

Vomiting

Thrombo

topenia

Thrombo

topenia

Diarrhea

Diarrhea

Anemia

Anemia

cycy


Results

Chemoradiation resultsChemoradiation results

(9)2PD7

14No. of pts

(30)SD(61)OR(%)Response

EUS results: activity of CTRT according to EUS AreaEUS results: activity of CTRT according to EUS AreaEUS Area post-CTRT

Post-MAX (cm2)EUS Area pre-CTRT

Pre-MAX (cm2)

0.5 – 8.01.41 *3 wks

0 – 3.1Range 1.3 – 110.91 **Median 3.786 wksBasal

* p < 0.001 vs pre-CTRT** p = ns vs 3 wks post-CTRT* p < 0.001 vs pre-CTRT** p = ns vs 3 wks post-CTRT


Surgery results

CDDP / PTX + RTCDDP / PTX + RT

23 PTS23 PTS

RESTAGINGRESTAGING

PD2 pts

SECOND LINE CT

CR + PR + SD

21 pts

SURGERY

Pts1Local only

15

Local + distantDistant mts only

Site of initial failureR0 resection17/21 (81%)

R1 resection4/21 (19%)

Path CR9/21 (43%)


Correlation between EUS staging andpathologic complete response

noT1 N0T2 N1

yesT0 N0T2 N1

noT1 N0T3 N0

yesT0 N0T2 N1

noT2 N1T2 N1

noT1 N1T3 N1

noT2 N1T3 N1

noT2 N0T3 N0

Path CREUS Stage

T3 N1

T3 N1

Pre – CTRT

T3 N1

T2 N1

Post – CTRT

nono


0.40.4

OS and DFSOS and DFS

1.01.0

00

OS

prob

abili

ty e

stim

ate

OS

prob

abili

ty e

stim

ate

66 1212 1818 2424 3030 3636

39 %39 %49 %49 %

All ptsAll pts

Path PRPath PR

0.00.0

0.20.2

1.01.0

00

DFS

prob

abili

ty e

stim

ate

DFS

prob

abili

ty e

stim

ate

66 1212 1818 2424 3030 3636

35 %35 %39 %39 %

72 %72 %Path CRPath CR

All ptsAll pts

Path PRPath PR

81 %81 %Path CRPath CR

OSOS DFSDFS

p < 0.035p < 0.035p < 0.021p < 0.021

med FUP = 30 momed OS = 21 momed FUP = 30 momed OS = 21 mo

med FUP = 30 momed DFS = 13 momed FUP = 30 momed DFS = 13 mo

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8 0.80.8

0.60.6

Time (mo)Time (mo) Time (mo)Time (mo)


MULTIVARIATE ANALYSIS RELATED TO OS(Cox’s Hazard Model)MULTIVARIATE ANALYSIS RELATED TO OS(Cox’s Hazard Model)

pHAZARDRATE

STANDARDERROR

PROGNOSTICFACTOR

0.002523.17541.1919Response0.09805.75261.1222Weight loss0.41890.99990.0002WBC0.29160.69010.3589Hb0.22114.02541.1904Grading0.07610.16381.0932Nodal0.09480.29610.7615Tumor0.91951.07730.7374PS0.110010.30451.5563Sex0.40861.17550.0615Age


Serum VEGF levels according totreatment (box-whisker diagram)Serum VEGF levels according totreatment (box-whisker diagram)

0

200

400

600

800

1000

1200

1400

1600

1800

1332.91332.9

1008.21008.2

461.4461.4

Seru

mVE

GF

leve

ls(p

g/m

l)Se

rum

VEG

F le

vels

(pg/

ml)

sVEGFafter CTRT

sVEGFafter CTRT

sVEGFafter surgery

sVEGFafter surgery

sVEGFbefore CTRT

sVEGFbefore CTRT

**

****

p < 0.0001 vs controls* p < 0.085 vs sVEGF before CTRT** p < 0.003 vs sVEGF after surgery

p < 0.0001 vs controls* p < 0.085 vs sVEGF before CTRT** p < 0.003 vs sVEGF after surgery

Mean values in 50 Healthy subjectsMean values in 50 Healthy subjects


ConclusionsConclusions

• The current study supports the feasibility of incorporating paclitaxel into preoperative regimens for pts with EC

• The efficacy of this regimen compares favorably with our previously reported data

• VEGF serum levels are raised in the serum of EC pts, but preoperative CTRT has littleeffect on the angiogenic profile of tumor

• The current study supports the feasibility of incorporating paclitaxel into preoperative regimens for pts with EC

• The efficacy of this regimen compares favorably with our previously reported data

• VEGF serum levels are raised in the serum of EC pts, but preoperative CTRT has littleeffect on the angiogenic profile of tumor


0.15

1.86

0.14

1.68

0.12

1.65

Oxaliplatin

0.13

1.55

0.08

1.74

0.14

1.79

Carboplatin

0.310.230.09CT followed by cetuximab(Cl at IC50)

1.491.621.64Cetuximab followed by CT(Cl at IC50)

0.270.300.08CT followed by ZD6474(Cl at IC50)

1.711.571.92ZD6474 followed by CT(Cl at IC50)

0.290.260.11CT followed by gefitinib(Cl at IC50)

1.681.471.85Gefitinib followed by CT(Cl at IC50)

Sequence Cisplatin Docetaxel Paclitaxel

Effects on KYSE30 cancer cell growth of the combinantof EGFR inhibitors and cytotoxic drugsEffects on KYSE30 cancer cell growth of the combinantof EGFR inhibitors and cytotoxic drugs

De Vita F, Annals of Oncology 2005De Vita F, Annals of Oncology 2005

Future directionsFuture directions


Effect of neoadjuvant CTRT on microvesseldensity in the primary tumourEffect of neoadjuvant CTRT on microvesseldensity in the primary tumour

0

1

2

3

4

5

6

7

8

9

Surgery Neoadjuvant CPR

Mea

nm

icro

vess

elco

untp

er h

.p.f.

Mea

nm

icro

vess

elco

untp

er h

.p.f.

Mc Donnell CO, Br J Surg, 2003 Mc Donnell CO, Br J Surg, 2003


OSOS

TitoloTitolo

DFSDFS

0.00.0

00

Surv

ival

pro

babi

lity

estim

ate

Surv

ival

pro

babi

lity

estim

ate

2020 4040 6060 00

DFS

prob

abili

ty e

stim

ate

DFS

prob

abili

ty e

stim

ate

2020 4040 6060

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0 1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Time (mos)Time (mos) Time (mos)Time (mos)


TitoloTitolo

OSOS DFSDFS

00

Surv

ival

pro

babi

lity

estim

ate

Surv

ival

pro

babi

lity

estim

ate

2020 4040 6060 00

DFS

prob

abili

ty e

stim

ate

DFS

prob

abili

ty e

stim

ate

2020 4040 6060

Landmark = 3 mosLandmark = 3 mos Landmark = 3 mosLandmark = 3 mos

69 %69 %

27 %27 %

69 %69 %

28 %28 %

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0 1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Time (mos)Time (mos) Time (mos)Time (mos)

concurrent cisplatin, paclitaxel and radiotherapy as...

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