Transcript A randomized trial of neoadjuvant chemotherapy vs

Controversies in Neoadjuvant Therapy for
Esophageal / GEJ Carcinoma
Gordon Buduhan MD MSc FRCSC
Division of Thoracic Surgery
Dalhousie University
Halifax, NS
No conflicts of interest
Introduction
• Esophageal carcinoma – most rapidly increasing
tumor type in Western world
• Standard of care for resectable esophageal ca
controversial
• Majority of centers – multimodality approach
including surgery, chemotherapy, radiation
• 2 most common approaches:
1) Neoadjuvant chemo  surgery (+ post-op
chemo)
2) Neoadjuvant chemoradiation  surgery
Rationale for Neoadjuvant Therapy
• Treat micrometastatic disease
• Downstage tumor, increase probability of curative
resection
• Decrease tumor cell dissemination during resection
• Patients more likely to complete prescribed
treatment in preoperative period
Ann Surg Oncol 2011
Geographic Practice Variations
Neoadjuv ChemoRT
Neoadjuv CT
Chemo + radiation: more = better!
The argument for neoadjuvant CRT (over CT)
• Better local control
• Improved pathologic CR rate
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
The argument for neoadjuvant CRT (over CT)
• Better local control
• Improved pathologic CR rate
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
The Importance of Complete Resection
Survival rate (%)
100
P < 0.0001
log rank
80
R0
60
40
R1
20
R2
0
0
1
2
3
4
5
Time (years)
Zafirellis K, et al. Dis Esoph, 2002
Neoadjuvant chemo can increase R0
resection rate
• 2 cycles preop cis, 5FU vs. surg alone
• N=802 pts esoph SCC or ACA
• R0 (microscopically complete) resection rate
60% in chemo grp (vs. 53% surg alone,
p=0.0001)
• Significant OS improvement in chemo grp
(more on this later…)
MRC OEO2. Lancet 2002
•
Preop cis, 5FU,
concurrent XRT 35 Gy
vs. surg alone
•
N=256
 R0 resection rate 80% in
CRT grp (vs. 59% surg
alone, p=0.003)
 BUT…
Burmeister et al. Lancet Oncol 2005
Most recurrences following esophagectomy are
systemic, not locoregional
Pattern of Recurrence post Esophageal Cancer
Resection (%)
Locoregional
Hematogenous /
distant
Mixed
11
58
-
22
51
27
Fahn ATS 1994
33
61
-
Abate JACS 2010
30
60
10
Osugi
Kato
Oncol Rep 2003
Anticancer Rsrch 2005
Bottom line for local control…
• Neoadjuvant chemotx alone may improve R0 resection
rate
• Addition of preop XRT to chemo may also improve
completeness of resection, but not necessarily associated
with improved DFS / OS
• Most recurrences hematogenous  systemic treatment is
the key
The argument for neoadjuvant CRT (over CT)
• Better local control
• Improved pathologic CR rate (no residual tumor cells)
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
Fact…
• PathCR rates consistently higher with neoadjuvant
CRT (25-40%) compared to neoadjuvant CT (2-10%)
Assumption…
• Pathologic response to neoadjuvant therapy is a
reliable surrogate for clinical outcome i.e. survival
• …or is it??
Randomized Trial of Preoperative Chemoradiation
Versus Surgery Alone in Patients With Locoregional
Esophageal Carcinoma
N=100
RCT preop CRT (cis, 5FU, vinblastine;
45 Gy) vs. surg alone
•
•
28% pathCR: median OS 49.7 mo
vs.
Residual disease: median OS 12 mo
P=0.01
Urba et al. JCO 2001
N=118, neoadjuv CRT  surgery
• pathCR 32%
• No survival advantage in pathCR compared with no
path CR pts
•
SSO 57th Annual Cancer Symposium 2004
Induction Chemoradiotherapy Followed by
Esophagectomy in Patients With Carcinoma of
the Esophagus
•
54 pts
• Cisplatin, 5FU + concurrent XRT  esophagectomy
NO significant difference 3 yr
OS b/w pathCR and no
pathCR grps
(log-rank p=0.13)
Jones et al. ATS 1997
Recurrence and survival after pathologic complete
response to preoperative therapy followed by
surgery for gastric or gastrooesophageal
adenocarcinoma
•
N=60 pCR post neoadjuvant therapy GEJ / gastric adenoca
•
Recurrence @ 5 yrs lower for pCR vs non-pCR pts (27% and
51%, P=0.01)
Probability of recurrence for pts with pCR similar to non-pCR
pts with stage I or II disease
Pattern of local / regional (LR) vs distant recurrence
comparable (43% LR vs 57% distant) between pCR and nonpCR grps
↑ incidence CNS first recurrences in pCR patients (36 vs 4%,
P=0.01)
•
•
•
Fields et al. Br J Cancer 104, 1840-1847 (7 June 2011)
Is it really a CR? …depends how hard you look for it!
N=18 pts with pathCR H/E stain
post neoadjuv CRT
IHC CK staining – 7/18 +
• 3 of 7 had microscopic residual
disease not detected on H/E
• 3/7 CK+ had systemic relapse
•
Chadha et al. Int J Oncol 2008
Bottom line for pathCR…
• Some correlation between pathCR and ↑survival, but not
consistently reported
• pathCR may not be optimal surrogate outcome
• Need to look for it
The argument for neoadjuvant CRT (over CT)
• Better local control
• Improved pathologic CR rate
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
Harmful effects of radiation!
Increased pulmonary complications with
neoadjuvant chemoradiation + esophagectomy
Avendano et al. ATS 2002
•
preop CRT: longer duration mechanical ventilation c/w preop
chemo only (mean 187 vs. 10 hrs)
Abou-Jawde et al.
•
45 Gy: 22% median ↓ DLCO; 17% postop resp complications
Lee et al.
•
Chest 2005
Int J Rad Oncol Biol Phys 2003
Median 45 Gy: 18% major pulm complications
Increased mortality with neoadjuvant
chemoradiation + esophagectomy
Bossett et al. RCT neoadjuv CRT vs surg alone
•
NEJM 1997
12% periop mortality in CRT grp (vs. 4% surg alone, p=0.012); no diff
OS b/w grps
Urschel –meta-analysis RCTs preop CRT vs surg Am J Surg 2003
•
preop CRT: trend toward ↑operative (p=0.07) and all-cause
mortality (p=0.05) c/w surg alone
Urschel –meta-analysis RCTs preop CT vs surg Am J Surg 2002
•
Preop CT: no difference operative (p=0.76) or treatment
mortality (p=0.22)
Increased mortality with neoadjuvant
chemoradiation + esophagectomy
FFCD 9901 (France)
•
RCT 195 pts Stage 1, 2 esophageal SCC / adenoca:
surg alone vs. CRT 5-FU 800 mg/m2/day D1-4, cisplatin
75 mg/m2 D1/2 x 2 cycles, 45 Gy concurrent rad
- median OS 32 mo CRT arm vs. 44 mo surg arm
p=0.66
- 30 day mortality 7.3% CRT arm vs. 1.1% surg p=0.05
J Clin Oncol 28:15s, 2010
BUT…
• Many other RCTs* have shown no increase in post-
op mortality post neoadjuvant CRT
*Tepper JCO 2008
Van der Gaast ASCO 2010
Burmeister Lancet Oncol 2005
The argument for neoadjuvant CRT (over CT)
• Better local control
• Improved pathologic CR rate
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
Neoadjuvant chemotherapy
Intergroup 0113
MRC OEO2
# pts
440
802
Chemo regimen
Cis 100 mg/m2, 5FU
1000 mg/m2 x 3 cycles
preop, x 2 cycles postop
Cis 80 mg/m2, 5FU
1000 mg/m2 x 2 cycles
preop
Duration chemo
12 wks
6 wks
% completed chemo
71
90
Median time (days)
randomization - OR
93
63
% pts in chemo arm
that did not have
surgery
20
6.5
MRC OEO2 trial – long term F/U
•
Median F/U 6 yrs
•
Recurrences reduced by 18% (P = 0.003)
•
Mortality reduced by 16% (P = 0.03)
•
5 yr OS 23% with neoadjuvant chemotherapy
vs. 17% with surgery alone
•
Survival advantage in favor of neoadjuvant
chemotherapy - consistent in both pts with
ACA (5-yr OS 24% vs 17%) and SCC (23% vs
18%)
Meta-analysis neoadjuvant chemo vs.
surgery in esophageal ca
• Overall surv benefit (HR 0.90, 95% CI 0.81-1.0; p=0.05)
• 2 yr absolute surv benefit 7% (over surg alone)
Gebski et al. Lancet Oncol 2007
MAGIC trial
•
Gastric / GEJ adenoca,
n=503
•
3 cycles ECF pre-op, 3
cycles post-op vs. surg only
•
5 yr survival 36% chemo grp
(vs. 23% in surg grp)
p=0.009
•
Only 26% GEJ / esoph ca
BUT no heterogeneity
treatment effect based on
tumor location
•
91% pts completed preop
chemo, 50% completed
postop chemo
FNLCC ACCORD07-FFCD 9703 trial
•
N=224 adenoca (75% GEJ)
•
Surgery alone vs. preop chemo cis, 5FU
x 2-3 cycles preop  surg  1-4 cycles
postop if pLN+ or response to preop tx
•
Median F/U 6 yrs
•
R0 resection rate 87% chemo arm (vs.
74% surg arm, p=0.04)
•
5 yr OS 38% chemo grp (vs. 24% surg,
p=0.021)
J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20
Suppl), 2007: 4510
Neoadjuvant Chemo
MRC OEO2

MAGIC

FFCD

Neoadjuvant chemoradiation
Meta-analysis neoadjuvant chemorad vs.
surgery in esophageal ca
Overall survival benefit (HR 0.81; 95%CI 0.7-0.93, p=0.002)
2 yr absolute survival benefit 13% (over surg alone)
Gebski et al. Lancet Oncol 2007
Flaws in + neoadjuvant CRT trials
Walsh
Tepper CALGB 9781
• Single institution, n=113
• Underpowered!!
• Surgery alone grp –
• Only 56 pts (target
poor survival (6% 3 yr
OS)
accrual 475)
• Staging issues: done
after completion CRT,
used CXR, UGI, U/S
NEJM 1996
JCO 2008
Effect of preoperative concurrent
chemoradiotherapy on survival of patients with
resectable esophageal or esophagogastric
junction cancer: Results from a multicenter
randomized phase III study.
A. van der Gaast, P. van Hagen, M. Hulshof, M.I. van Berge
Henegouwen, G.A. Nieuwenhuijzen, J.T. Plukker, J.J.
Bonenkamp, E.W. Steyerberg, H.W. Tilanus.
CROSS study group
Chemoradiotherapy treatment regimen
• Chemoradiotherapy regimen:
• Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29
• Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
• Surgery within 6 weeks after completion of chemoradiotherapy
CROSS study
188 pts surg arm
175 pts CRT arm
Median F/U 32 mo
Overall survival
3 yr OS 59% CRT (vs 48% surg alone)
p=0.011
CRTx
Surgery
HR 0.67 95% CI (.49 - .91) P=0.012
HR 0.67 95% CI (0.49 - 0.91)
No’s at risk
Surgery alone
188
131
71
44
22
1
CRT + surgery
175
144
85
55
30
2
CROSS study
HR’s (95% CI) for death according to baseline
variables
Overall
0.67 (0.49 – 0.91)
N0
0.49 (0.27 – 0.90)
N1
0.72 (0.50 – 1.04)
Male
0.62 (0.44 – 0.87)
Female
0.92 (0.45 – 1.89)
AC
0.82 (0.58 – 1.16)
SCC
0.34 (0.17 – 0.68)
WHO 0
0.67 (0.49 – 0.94)
WHO 1
0.67 (0.32 – 1.41)
0.0
0.5
Favors preoperative CRT
1.0
1.5
2.0
Favors surgery alone
CROSS study
CROSS – interesting, but questions…
• Subgroup analysis – no significant survival benefit for
adenoca (74% of pts!)…
• Low radiation dose – is it the drugs?
Carboplatin-Paclitaxel as Neoadjuvant
Therapy for Esophageal Ca
Keresztes et al. JTCVS 2003
• Carbo AUC 6, Taxol 200 mg/m2 q3wk x 2 cycles  surgery
• 26 pts – 100% completion full course
- 12% grade III/IV leucopenia
-95% improvement dysphagia w/in 1 wk
-61% major clinical response, 11% pathCR
-3 yr OS 64% for resected patients
D’Addario et al. Onkol 2002
• Carbo AUC 3, Taxol 75 mg/m2 days 1, 8, 15 q4wks x 2  surgery
• 19 pts -15.2% grade III/IV leucopenia, 3.2% grade III/IV
thrombocytopenia
- 83% overall RR, 17% pathCR
- 70% RR adenoca, 87% RR SCC esophagus
- median F/U 19 mo – 11/19 pts alive
Neoadjuvant Chemo RCTs
MRC OEO2

MAGIC
Neoadjuvant Chemorad RCTs
✗
Walsh
Tepper CALGB

½
FFCD

CROSS

Need a head-to-head comparison!
Neoadjuv CT
Neoadjuv CRT
p
No. of pts
58
64
-
Postop
mortality (%)
0
6
0.12
% postop
complications
33
48
0.09
Recurrence
rate
33
28
0.43
%PathCR
3
11
0.02
% 5 yr DFS
21
31
0.68
Retrospective single institution cohort
RCT neoadjuvant chemoradiation vs.
chemo for esophageal ca
• Stahl et al. J Clin Onc 2009
• N=119, adenoca distal esophagus, GEJ
• Randomized to
a) Induction chemo: 2.5 cycles cis, 5FU, leucovorin
b) Induction chemorad: 2 cycles a) + 30 Gy +
concurrent cis, etoposide
RCT neoadjuvant chemoradiation vs. chemo
…inconclusive
•
No difference b/w grps: R0 resection rate
•
CRT grp - significant increase:
•
•
pathCR (15.6 vs. 2%)
Non-significant trend toward improved survival CRT grp
(3 yr OS 47.4 vs. 27.7%, p=0.07)
•
CRT: 3-fold increase post-op mortality
(10.2 vs. 3.8%, p=0.26)
BUT -underpowered, closed early, non-standard chemo used
Stahl et al. J Clin Onc 2009
Summary
• Better local control
• Improved pathologic CR rate
• No added morbidity / mortality with addition of XRT
• Improved survival – evidence from RCTs
• there is currently no conclusive evidence that
neoadjuv CRT superior to neoadjuv CT for resectable
esophageal / GEJ ca
• optimal multimodality tx for locally advanced esoph
ca unknown…
• a proper RCT is needed to answer this question!
Current feasibility trial in Halifax
Eligibility:
-age <75
-cT2-3Nx, T1N1,
M0 esophageal /
GEJ adenoca or
SCC
->20 cm from
incisors, <2 cm
cardia (EGD,
CT/PET)
-ECOG 0-2
-no previous ca
last 5 yrs, no
major
comorbidities
R
A
N
D
O
Neoadjuvant
chemoradiation
-5 cycles carboplatin
50 mg / m2 IV &
paclitaxel AUC=2;
days 1, 8, 15, 22, 29
Z
E
U
-45- 50.4 Gy in 25-28
fractions of 1.8 Gy /
fraction, 5 fractions /
wk
R
RESTAGING CT / PET
– if no mets, resectable
M
I
S
Neoadjuvant
chemotherapy
-6 cycles carboplatin
75 mg / m2 IV &
paclitaxel AUC=3;
days 1, 8, 15 q4wks x 2
G
E
R
Y
Feasibility trial - status
• Local grant funded
• Health Canada approved Aug 3, 2011
CANADA PROTOCOL RECORD 147937-7
• Trial registered
Clinicaltrials.gov Identifier: NCT01404156
• Plan to begin patient enrollment Oct-Nov 2011
pending final REB approval
• Study “introduced” NCIC GI oncology grp 2011 Spring
mtg…formal proposal 2012
• Stay tuned!
More = better??