Post on 18-Nov-2020
transcript
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
De Vita F, Chest, 2002De Vita F, Chest, 2002
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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%)
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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)
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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
PTX/CDDPplus RTin EC
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)
PTX/CDDPplus RTin EC
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)