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

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3589 General Poster Session (Board #33B), Mon, 8:00 AM-12:00 PM<br />

Examining the effects <strong>of</strong> metformin on survival outcome in stage II/III<br />

colorectal cancer patients with diabetes mellitus. Presenting Author: Guek<br />

Eng Lee, Department <strong>of</strong> Medical Oncology, National Cancer Centre,<br />

Singapore<br />

Background: Insulin resistance and deregulation <strong>of</strong> the insulin-like growth<br />

factor (IGF) axis is implicated in colonic carcinogenesis. Metformin inhibits<br />

hepatic gluconeogenesis and increases insulin sensitivity. It induces AMPK<br />

activation, thus inhibiting mTOR and downstream survival and proliferation<br />

pathways. We evaluated the effects <strong>of</strong> metformin on survival outcomes <strong>of</strong><br />

patients with stage 2 and 3 colorectal cancer (CRC). Methods: Among 1455<br />

patients with stage II or III colorectal cancer, we identified 344 patients<br />

with both CRC and diabetes mellitus. 219 diabetic patients received<br />

metformin and 125 diabetic patients were not receiving metformin.<br />

Patient’s demographics, clinical and histopathologic characteristics, overall<br />

survival, time to recurrence and relapse-free survival were evaluated.<br />

Molecular analysis for AMPK, and mTOR pathway on archival tissue is<br />

ongoing. Results: After a median follow-up <strong>of</strong> 78 months (6.5 years), there<br />

was no difference in survival outcomes between diabetic and non-diabetic<br />

patients. Among diabetic patients, there were 99 relapses and 90 deaths.<br />

Metformin use was associated with improved overall survival (HR 0.23;<br />

95%CI: 0.15-0.35 p�0.01), time to recurrence (HR 0.63; 95%CI:<br />

0.41-0.96) and relapse-free survival (HR 0.47; 95%CI:0.33-0.67,p�0.01).<br />

In multivariate analysis, after adjustment for T stage, N stage and patients’<br />

age, metformin use remained associated with improved overall survival (HR<br />

0.18, p�0.01); time to recurrence (HR 0.55; p�0.04) and relapse-free<br />

survival (HR 0.44, p�0.01). Results <strong>of</strong> molecular correlative studies<br />

performed on archival tissue will be presented at the meeting. Conclusions:<br />

Among patients with diabetes and colorectal cancer, use <strong>of</strong> metformin is<br />

associated with improved survival outcomes in both univariate and multivariate<br />

analysis lending support to the hypothesis that it may have anti-cancer<br />

activity.<br />

3591 General Poster Session (Board #33D), Mon, 8:00 AM-12:00 PM<br />

First-line chemotherapy plus cetuximab in patients grouped according to<br />

prognostic risk factors: Analysis <strong>of</strong> the CRYSTAL and OPUS studies.<br />

Presenting Author: Gunnar Folprecht, University Hospital Carl Gustav<br />

Carus, Dresden, Germany<br />

Background: Analysis <strong>of</strong> randomized trials has shown that mCRC patients<br />

(pts) can be divided into prognostic risk groups according to baseline<br />

clinical parameters including ECOG performance status, white blood cell<br />

count (WBC), alkaline phosphatase (ALP) and number <strong>of</strong> metastatic (met)<br />

sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect <strong>of</strong> adding<br />

cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these<br />

groups <strong>of</strong> KRAS wild-type mCRC pts was investigated in the CRYSTAL and<br />

OPUS studies. Methods: Pt risk groups were: low-risk (LRG� ECOG 0/1, 1<br />

met site) intermediate-risk (IRG� ECOG �1, �1 met site, ALP �300 U/L<br />

or, ECOG�1, low WBC, 1 met site) and high-risk (HRG� ECOG�1, �1 met<br />

site, ALP�300 U/L or ECOG�1, high WBC, or ECOG�1, low WBC and �2<br />

met sites). Exploratory analyses comprised estimates <strong>of</strong> effects using Cox‘s<br />

proportional hazards model for OS on individual pt data and comparison <strong>of</strong><br />

treatment arms by log-rank test. Results: Data are shown in the table. In the<br />

pooled analyses, in both treatment arms OS was longest in LRG pts and<br />

shortest in HRG pts. Adding cetuximab to CT led to marked improvements<br />

in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157,<br />

p�0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p�0.033), while<br />

improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p�0.287)<br />

were observed only after prolonged follow up. Data were similar in the<br />

separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms<br />

the concept <strong>of</strong> prognostic risk groups for OS according to baseline clinical<br />

parameters in pts with KRAS wt mCRC. Benefit from the addition <strong>of</strong><br />

cetuximab to first-line CT in terms <strong>of</strong> OS appears to be more pronounced in<br />

the IRG and HRG.<br />

CT CT � cetuximab<br />

Study/risk group N Median OS, mo (95% CI) N Median OS, mo (95% CI)<br />

Pooled<br />

LRG 164 25.7 (21.9–28.7) 173 27.0 (24.8–29.5)<br />

IRG 213 16.4 (14.9–20.0) 166 22.2 (19.5–25.7)<br />

HRG 59 12.6 (9.2–14.4) 46 17.7 (13.1–19.3)<br />

CRYSTAL<br />

LRG 127 26.1 (21.2–29.9) 132 28.2 (24.9–31.5)<br />

IRG 172 16.6 (14.8–20.4) 141 23.5 (20.0–29.6)<br />

HRG 43 12.8 (9.2–14.6) 31 16.7 (8.3–19.0)<br />

OPUS<br />

LRG 37 23.9 (19.5–n.e.) 41 26.0 (22.9–n.e.)<br />

IRG 41 16.2 (12.0–21.6) 25 18.4 (11.0–19.8)<br />

HRG 16 11.8 (4.8–18.5) 15 19.9 (13.1–30.4)<br />

Abbreviation: n.e., not estimable.<br />

Gastrointestinal (Colorectal) Cancer<br />

225s<br />

3590 General Poster Session (Board #33C), Mon, 8:00 AM-12:00 PM<br />

U.S. patients receiving resin 90Y microspheres for unresectable colorectal<br />

liver metastases: A multicenter study <strong>of</strong> 506 patients. Presenting Author:<br />

Andrew S. Kennedy, Cancer Centers <strong>of</strong> North Carolina, Cary, NC<br />

Background: Implantation <strong>of</strong> radioactive microspheres via the hepatic artery<br />

with Yttrium-90 ( 90Y) is termed “radioembolization, (RE)”. Resin microspheres<br />

were FDA cleared for use in colorectal liver metastases (mCRC) in<br />

2002. Rapid worldwide acceptance <strong>of</strong> this therapy has resulted in greater<br />

than 30,000 procedures conducted in the past 10 years. This investigatorinitiated<br />

study focuses on RE treatment outcomes in US-only patients since<br />

2002. Methods: A retrospective multi-institutional study was designed to<br />

analyze the outcome <strong>of</strong> consecutively treated mCRC patients undergoing<br />

RE by experienced treatment centers in the USA using resin 90Y microspheres.<br />

IRB approval was obtained by each center with independent data<br />

collection and analyses. Primary endpoints: CTC 3.0ae toxicity, RECIST<br />

response and survival; baseline treatment parameters, prior chemotherapy,<br />

and liver directed therapies. Results: 506 patients at 10 institutions (193<br />

M, 313 F) received 770 RE treatments; median age � 60.4 years (20.8 –<br />

91.9 years); median number <strong>of</strong> RE treatments per patient � 1.0 (1-5<br />

treatments). Active extrahepatic disease was present at first RE in 34.8%<br />

<strong>of</strong> patients. The majority (90%) <strong>of</strong> patients received prior chemotherapy,<br />

with 30.6% also having undergone prior hepatic surgery/ablative procedures.<br />

Median follow up after RE � 8.4 mo. (0.4 – 67.6 mo.) with median<br />

survival � 10.1 mo. (95% CI 9.1 – 12.0). For first RE treatment, median<br />

tumor volume was 146.0 mL (2.8 – 3228.0 mL). Median radiation activity<br />

delivered � 1.18 GBq (0.12 – 2.29 GBq), lung shunt median � 4.8 % (.02<br />

– 45%). Total grade 1-3 events were 32% GI, 44% fatigue and 1% liver<br />

failure. Only 2.4% <strong>of</strong> all treatments required an overnight stay postprocedure.<br />

Conclusions: The modern USA experience <strong>of</strong> 90Y therapy for<br />

unresectable, heavily pretreated mCRC liver metastases is encouraging<br />

with a median survival <strong>of</strong> 10.1 months after first RE procedure. Toxicity was<br />

mild and <strong>of</strong> short duration in most patients. RECIST response is being<br />

analyzed currently as are data <strong>of</strong> additional patients.<br />

3592 General Poster Session (Board #33E), Mon, 8:00 AM-12:00 PM<br />

A UGT1A1 *28 and *6 genotype-directed phase I study <strong>of</strong> irinotecan plus<br />

infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously<br />

untreated metastatic colorectal cancer (mCRC). Presenting Author: Yong Sang<br />

Hong, Department <strong>of</strong> Oncology, Asan Medical Center, University <strong>of</strong> Ulsan<br />

College <strong>of</strong> Medicine, Seoul, South Korea<br />

Background: We designed a phase I study to determine maximum tolerated dose<br />

(MTD) <strong>of</strong> irinotecan when combined with sLV5FU2 in mCRC patients (pts).<br />

Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3<br />

groups according to the number <strong>of</strong> defective allele (DA), designated 0 (*1/*1), 1<br />

(*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose <strong>of</strong><br />

irinotecan was escalated (table) in combination with fixed dose <strong>of</strong> sLV5FU2.<br />

Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1.<br />

Results: A total <strong>of</strong> 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA<br />

group. The MTD was estimated as 300 mg/m2 /2-week for the 1 DA group with 2<br />

DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT<br />

in the level 4 (table). The mean relative extents <strong>of</strong> glucuronidation, AUClast ratio<br />

<strong>of</strong> SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups,<br />

respectively (P�0.017). Of the 43 pts, five pts showed AUClast, SN38 that<br />

exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5).<br />

The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete<br />

responses and 23 partial responses. Median progression-free and overall survival<br />

was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7),<br />

respectively. Grade 3 or 4 toxicity during all treatment cycles included<br />

neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%;<br />

0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient.<br />

Conclusions: Dose-normalized exposure <strong>of</strong> SN38 was significantly higher in the 2<br />

DA UGT1A1 group. Higher doses <strong>of</strong> irinotecan based on UGT1A1 genotyping are<br />

feasible when combined with sLV5FU2 in mCRC pts. The recommended dose <strong>of</strong><br />

irinotecan was 330, 270, 150 mg/m2 /2-week for pts with 0, 1, 2 DA based on<br />

pharmacokinetic analysis.<br />

Level and dose<br />

Number <strong>of</strong> patients<br />

Group <strong>of</strong> irinotecan Treated DLT occurred<br />

DLTs<br />

0DA 1 240 * 4 0<br />

2 270 3 0<br />

3 300 6 0<br />

4 330 6 1 Gr 4 neutropenia<br />

1DA 1 240 * 3 0<br />

2 270 14 0<br />

3 300 3 2 Gr 4 neutropenia,<br />

Gr 3 febrile neutropenia<br />

2DA -1 150 * 4 0<br />

0 180 - -<br />

* Starting dose <strong>of</strong> irinotecan for each dose level (mg/m2 ).<br />

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