Transcript The 12th Charles G. Moertel Lecture Adjuvant Therapy of

A randomized phase III study of gemcitabine
in combination with radiation therapy versus
gemcitabine alone in patients with localized
unresectable pancreatic cancer: E4201
P. J. Loehrer Sr., M. Powell, H. Cardenes,
L.Wagner, J. Brell, R. Ramanathan,
C. Crane, S. Alberts, A. B. Benson
On behalf of
The Eastern Cooperative Oncology Group
Background:
Radiation in Pancreatic Cancer
• In locally advanced pancreatic cancer,
radiation plus FU has been standard therapy
(GITSG: Moertel,1981)
• Trials in the US and Europe have questioned
the role of radiation in pancreatic cancer:
– ECOG: 5-FU vs. 5-FU plus XRT
(Klaassen,1985)
– ESPAC (Neoptolemos JP,2001)
Background:
Gemcitabine plus Radiation
• Gemcitabine in pancreatic cancer
– Superior to 5-FU (Burris, 1997)
– Potent radiation sensitizer in vitro (Lawrence, 1996).
• Numerous phase I/II trials with once or twice
weekly gemcitabine plus radiation
– Phase I trial (Fox Chase, Michigan, Indiana): 50.4 Gy
plus GEM (DLT- 600 mg/m2) (McGinn, ASCO 1997).
– Phase II trial (HOG): Six PR/28 pts (21%), MST 7.9
mos and 31% one year survival (Moore, ASCO 2004)
E4201: Schema
Stratify:
• PS (0 vs 1)
• Weight loss
( >10% vs <10%)
R
A
N
D
O
M
I
Z
E
ARM A: INDUCTION
GEMCITABINE 1000mg/M2
Once weekly x 6 weeks
ARM B: INDUCTION
GEMCITABINE 600 mg/M2
Once weekly x 6 weeks
CONCURRENT RT 180 cGy/day
5 days week x 6 weeks
Total dose 50.40 Gy
1 week rest
ARM A: CONSOLIDATION
GEMCITABINE 1000mg/M2
Once weekly x 3 weeks
Followed by 1 week rest x 5 cycles
1 cycle = 4 weeks
4 weeks rest
ARM B: CONSOLIDATION
GEMCITABINE 1000mg/M2
Once weekly x 3 weeks
Followed by 1 week rest x 5 cycles
1 cycle = 4 weeks
Radiation Therapy
• 3D-conformal Therapy
• PTV1: 3960 cGy
–
–
–
GTV (primary + gross nodal disease) +
2-3 cm margin
Immediately adjacent lymph node
regions + 1.5 cm margin
Adjust margins to accommodate
normal tissue tolerance requirements
– PTV2: 5040 cGy
•
GTV + 1.5-2 cm margin
• Treatment dose-volume were
centrally reviewed
(submitted within 3 days)
Endpoints
• Primary:
– Overall Survival
• Secondary:
– Response Rates
– Progression Free Survival
– Quality of Life (not presented today)
Inclusion Criteria
• Histological confirmation of adenocarcinoma
or adenosquamous carcinoma of the
pancreas
• Loco-regionally advanced disease
• Unresectable disease without evidence of
metastasis
• No prior therapy
• Measurable or evaluable disease
• Adequate hematological, renal and hepatic
functions
• ECOG performance status of 0 or 1
Statistics
• Primary Endpoint: Overall Survival
– 88% Power to detect a 50% difference in median
survival (8 months vs. 12 months)
– Two-sided log-rank test (alpha = 0.05)
– Accrual goal: 316 patients
• Activated April 2003; terminated December 2005
– Reason: “poor accrual” (i.e. <10 entries per month)
– Final accrual was 74 patients
– All patients have expired
• Data updated May, 2008
Patient Population
No. eligible patients
Ineligible (metastases)
Total evaluable for survival
Total evaluable for toxicity
GEM
38
1
GEM/XRT
36
2
37
35
34
34
Patient characteristics
GEM alone
(n=37)
GEM plus XRT
(n=34)
Median Age (yrs.)
68.7
65.7
% Female
51%
44%
PS = 1
76%
82%
>10% Weight Loss
43%
47%
Grade 3/4 Toxicities
GEM alone GEM plus XRT p value*
(n=35)
(n=34)
Neutropenia
3%
12%
ns
Thrombocytopenia
6%
21%
ns
Hemorrhage
0%
3%
ns
Gastrointestinal
14%
38%
0.03
Fatigue
6%
32%
0.006
Overall Grade 3/4
82%
93%
ns
Two grade 5 toxicities: Cardiac (GEM) and ARDS (GEM/XRT)
* Two sided Fisher’s exact test
Response
Partial Resp.
GEM alone
5%
GEM plus XRT
6%
Stable Disease
35%
68%
Progression
Inevaluable*
16%
46%
6%
21%
* Clinical “progression’ without confirmation scans
or scans performed outside of scheduled times
GEM
Overall Survival
p-value = 0.034
two-sided, stratified Log rank
HR = 0.574 (95% CI- 0.342, 0.963)
GEM plus XRT
GEM
GEM: Median Survival 9.2 Months (95% CI [7.8, 11.4])
-----------------------
GEM + Radiation: Median Survival 11.0 Months (95% CI [8.4, 15.5]) -----------------------
Survival
6 mos 12 mos 18 mos 24 mos
GEM alone
76%
32%
11%
4%
GEM plus XRT 74%
50%
29%
12%
Progression-Free Survival
p-value = 0.50
two-sided, stratified Log rank
HR= 0.821 (95%CI- 0.463,1.463)
GEM plus XRT
GEM
GEM: Median PFS 6.7 Months (95% CI [4.6, 8.7])
-----------------------
GEM + Radiation: Median PFS 6.0 Months (95% CI [5.6, 8.4])
-----------------------
Sites of Relapse
Local
GEM alone
41%
GEM plus XRT
23%
Distant
14%
23%
Local and Distant
Not documented*
5%
41%
9%
44%
* Clinical “progression’ without confirmation scans
or scans performed outside of scheduled times
Progression-Free Survival in
Pancreatic cancer: Problems
• Definition of PFS: “The shorter of:
– The time from registration to progression.
– The time from registration to death from any
cause without documentation of progression”
• Difficulty measuring objective response
• Surrogate markers of progression (e.g.
pain, anorexia, performance status)
“Explanations” for poor accrual
• Competing trials in metastatic disease
include locally advanced disease
• Dosages of gemcitabine not equal
• “Unethical” not to use radiation therapy
• “Unethical” to use radiation therapy
E4201: Limitations
•
•
•
•
•
Survival only modestly prolonged
Response Rate and PFS not different
Toxicity: Treatment or disease related?
Single study
Small sample size
Conclusions
• Gemcitabine plus radiation therapy has
superior survival compared to gemcitabine
alone (11.0 mos vs. 9.2 mos; p=0.034)
• Similar PFS and overall response rates
• Toxicity is very common, but manageable
in both arms (QOL to be reported later)
• Locally advanced and stage IV pancreatic
cancers should be treated as separate
entities
Final Personal Comments
• Clinical significance:
– Some: an affirmation for radiation
– Others: an underpowered trial
• If combined modality therapy is considered
for locally advanced pancreatic cancer,
gemcitabine is more attractive than 5-FU
• It remains a sobering reality that in nearly
three decades of research, the true impact of
radiation therapy in pancreatic cancer is still
controversial
Acknowledgments
• The patients who participated in this
study
• Those investigators and nurses within
ECOG and the CTSU who continue to
work hard for their patients and to seek
knowledge on their behalf
My Comments
• Small trial
• Response rates are superior with CTRT if we count
those with stable disease (74% vs 40%)
• Dose of concomitant Gem (600 mg/m2) is rather high
with no significant excessive Gr 3,4 toxicity
• Mandatory use of 3D conformal RT is maybe a
reason
• These data are different from the French trial using
PF/RT-Gem vs Gem alone (B. Chauffert; ASCO 2006 )