Annual Meeting Proceedings Part 1 - American Society of Clinical ...

3589 General Poster Session (Board #33B), Mon, 8:00 AM-12:00 PM
Examining the effects of metformin on survival outcome in stage II/III
colorectal cancer patients with diabetes mellitus. Presenting Author: Guek
Eng Lee, Department of Medical Oncology, National Cancer Centre,
Singapore
Background: Insulin resistance and deregulation of the insulin-like growth
factor (IGF) axis is implicated in colonic carcinogenesis. Metformin inhibits
hepatic gluconeogenesis and increases insulin sensitivity. It induces AMPK
activation, thus inhibiting mTOR and downstream survival and proliferation
pathways. We evaluated the effects of metformin on survival outcomes of
patients with stage 2 and 3 colorectal cancer (CRC). Methods: Among 1455
patients with stage II or III colorectal cancer, we identified 344 patients
with both CRC and diabetes mellitus. 219 diabetic patients received
metformin and 125 diabetic patients were not receiving metformin.
Patient’s demographics, clinical and histopathologic characteristics, overall
survival, time to recurrence and relapse-free survival were evaluated.
Molecular analysis for AMPK, and mTOR pathway on archival tissue is
ongoing. Results: After a median follow-up of 78 months (6.5 years), there
was no difference in survival outcomes between diabetic and non-diabetic
patients. Among diabetic patients, there were 99 relapses and 90 deaths.
Metformin use was associated with improved overall survival (HR 0.23;
95%CI: 0.15-0.35 p�0.01), time to recurrence (HR 0.63; 95%CI:
0.41-0.96) and relapse-free survival (HR 0.47; 95%CI:0.33-0.67,p�0.01).
In multivariate analysis, after adjustment for T stage, N stage and patients’
age, metformin use remained associated with improved overall survival (HR
0.18, p�0.01); time to recurrence (HR 0.55; p�0.04) and relapse-free
survival (HR 0.44, p�0.01). Results of molecular correlative studies
performed on archival tissue will be presented at the meeting. Conclusions:
Among patients with diabetes and colorectal cancer, use of metformin is
associated with improved survival outcomes in both univariate and multivariate
analysis lending support to the hypothesis that it may have anti-cancer
activity.
3591 General Poster Session (Board #33D), Mon, 8:00 AM-12:00 PM
First-line chemotherapy plus cetuximab in patients grouped according to
prognostic risk factors: Analysis of the CRYSTAL and OPUS studies.
Presenting Author: Gunnar Folprecht, University Hospital Carl Gustav
Carus, Dresden, Germany
Background: Analysis of randomized trials has shown that mCRC patients
(pts) can be divided into prognostic risk groups according to baseline
clinical parameters including ECOG performance status, white blood cell
count (WBC), alkaline phosphatase (ALP) and number of metastatic (met)
sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect of adding
cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these
groups of KRAS wild-type mCRC pts was investigated in the CRYSTAL and
OPUS studies. Methods: Pt risk groups were: low-risk (LRG� ECOG 0/1, 1
met site) intermediate-risk (IRG� ECOG �1, �1 met site, ALP �300 U/L
or, ECOG�1, low WBC, 1 met site) and high-risk (HRG� ECOG�1, �1 met
site, ALP�300 U/L or ECOG�1, high WBC, or ECOG�1, low WBC and �2
met sites). Exploratory analyses comprised estimates of effects using Cox‘s
proportional hazards model for OS on individual pt data and comparison of
treatment arms by log-rank test. Results: Data are shown in the table. In the
pooled analyses, in both treatment arms OS was longest in LRG pts and
shortest in HRG pts. Adding cetuximab to CT led to marked improvements
in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157,
p�0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p�0.033), while
improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p�0.287)
were observed only after prolonged follow up. Data were similar in the
separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms
the concept of prognostic risk groups for OS according to baseline clinical
parameters in pts with KRAS wt mCRC. Benefit from the addition of
cetuximab to first-line CT in terms of OS appears to be more pronounced in
the IRG and HRG.
CT CT � cetuximab
Study/risk group N Median OS, mo (95% CI) N Median OS, mo (95% CI)
Pooled
LRG 164 25.7 (21.9–28.7) 173 27.0 (24.8–29.5)
IRG 213 16.4 (14.9–20.0) 166 22.2 (19.5–25.7)
HRG 59 12.6 (9.2–14.4) 46 17.7 (13.1–19.3)
CRYSTAL
LRG 127 26.1 (21.2–29.9) 132 28.2 (24.9–31.5)
IRG 172 16.6 (14.8–20.4) 141 23.5 (20.0–29.6)
HRG 43 12.8 (9.2–14.6) 31 16.7 (8.3–19.0)
OPUS
LRG 37 23.9 (19.5–n.e.) 41 26.0 (22.9–n.e.)
IRG 41 16.2 (12.0–21.6) 25 18.4 (11.0–19.8)
HRG 16 11.8 (4.8–18.5) 15 19.9 (13.1–30.4)
Abbreviation: n.e., not estimable.
Gastrointestinal (Colorectal) Cancer
225s
3590 General Poster Session (Board #33C), Mon, 8:00 AM-12:00 PM
U.S. patients receiving resin 90Y microspheres for unresectable colorectal
liver metastases: A multicenter study of 506 patients. Presenting Author:
Andrew S. Kennedy, Cancer Centers of North Carolina, Cary, NC
Background: Implantation of radioactive microspheres via the hepatic artery
with Yttrium-90 ( 90Y) is termed “radioembolization, (RE)”. Resin microspheres
were FDA cleared for use in colorectal liver metastases (mCRC) in
2002. Rapid worldwide acceptance of this therapy has resulted in greater
than 30,000 procedures conducted in the past 10 years. This investigatorinitiated
study focuses on RE treatment outcomes in US-only patients since
2002. Methods: A retrospective multi-institutional study was designed to
analyze the outcome of consecutively treated mCRC patients undergoing
RE by experienced treatment centers in the USA using resin 90Y microspheres.
IRB approval was obtained by each center with independent data
collection and analyses. Primary endpoints: CTC 3.0ae toxicity, RECIST
response and survival; baseline treatment parameters, prior chemotherapy,
and liver directed therapies. Results: 506 patients at 10 institutions (193
M, 313 F) received 770 RE treatments; median age � 60.4 years (20.8 –
91.9 years); median number of RE treatments per patient � 1.0 (1-5
treatments). Active extrahepatic disease was present at first RE in 34.8%
of patients. The majority (90%) of patients received prior chemotherapy,
with 30.6% also having undergone prior hepatic surgery/ablative procedures.
Median follow up after RE � 8.4 mo. (0.4 – 67.6 mo.) with median
survival � 10.1 mo. (95% CI 9.1 – 12.0). For first RE treatment, median
tumor volume was 146.0 mL (2.8 – 3228.0 mL). Median radiation activity
delivered � 1.18 GBq (0.12 – 2.29 GBq), lung shunt median � 4.8 % (.02
– 45%). Total grade 1-3 events were 32% GI, 44% fatigue and 1% liver
failure. Only 2.4% of all treatments required an overnight stay postprocedure.
Conclusions: The modern USA experience of 90Y therapy for
unresectable, heavily pretreated mCRC liver metastases is encouraging
with a median survival of 10.1 months after first RE procedure. Toxicity was
mild and of short duration in most patients. RECIST response is being
analyzed currently as are data of additional patients.
3592 General Poster Session (Board #33E), Mon, 8:00 AM-12:00 PM
A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus
infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously
untreated metastatic colorectal cancer (mCRC). Presenting Author: Yong Sang
Hong, Department of Oncology, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, South Korea
Background: We designed a phase I study to determine maximum tolerated dose
(MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts).
Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3
groups according to the number of defective allele (DA), designated 0 (*1/*1), 1
(*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of
irinotecan was escalated (table) in combination with fixed dose of sLV5FU2.
Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1.
Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA
group. The MTD was estimated as 300 mg/m2 /2-week for the 1 DA group with 2
DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT
in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio
of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups,
respectively (P�0.017). Of the 43 pts, five pts showed AUClast, SN38 that
exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5).
The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete
responses and 23 partial responses. Median progression-free and overall survival
was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7),
respectively. Grade 3 or 4 toxicity during all treatment cycles included
neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%;
0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient.
Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2
DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are
feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of
irinotecan was 330, 270, 150 mg/m2 /2-week for pts with 0, 1, 2 DA based on
pharmacokinetic analysis.
Level and dose
Number of patients
Group of irinotecan Treated DLT occurred
DLTs
0DA 1 240 * 4 0
2 270 3 0
3 300 6 0
4 330 6 1 Gr 4 neutropenia
1DA 1 240 * 3 0
2 270 14 0
3 300 3 2 Gr 4 neutropenia,
Gr 3 febrile neutropenia
2DA -1 150 * 4 0
0 180 - -
* Starting dose of irinotecan for each dose level (mg/m2 ).
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