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

214s Gastrointestinal (Colorectal) Cancer
3544 General Poster Session (Board #23G), Mon, 8:00 AM-12:00 PM
Effect of bevacizumab on rate of oxaliplatin-induced thrombocytopenia and
splenomegaly. Presenting Author: Kanwal Pratap Singh Raghav, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal
injury (HSI) leading to portal hypertension. This results in splenic sequestration
of platelets and thrombocytopenia. Evidence suggests that bevacizumab
may protect against HSI, although the clinical impact of this has not
been well examined. The purpose of our study was to evaluate rate of
thrombocytopenia and splenomegaly as clinical end-points indicative of
bevacizumab mediated modulation of oxaliplatin-induced hepatic toxicity.
Methods: We performed a retrospective review of metastatic colorectal
cancer patients treated at M D Anderson Cancer Center from 1/2003 to
1/2010 with � 3 months of frontline fluoropyrimidine and oxaliplatin
(FOLFOX) with or without bevacizumab. Patients with prior liver disease,
liver surgery or absence of spleen were excluded. Splenic volumes pre,
during and post FOLFOX therapy were determined with CT scans and
correlated with platelet counts and treatment. Results: A total of 184
patients [Bev cohort: FOLFOX/Bev (n �138); Non-Bev cohort: FOLFOX
alone (n � 46)] were identified. Baseline characteristics (age, gender,
spleen size and platelet counts) were similar in both groups. Median
number of oxaliplatin cycles for each cohort was 9.00 (p � 0.9). The
median total oxaliplatin dose did not differ between the two cohorts (p �
0.9). Development of splenomegaly (volume increase � 30%) was more
common in the Non-Bev cohort (48% vs. 32%; p � 0.013). The median
time to develop splenomegaly was significantly longer in the Bev cohort
(7.6 vs. 5.5 months; p � 0.023). Splenomegaly correlated with a higher
rate of thrombocytopenia (defined as platelets � 150K) at 3 months (40%
vs. 16%, p � 0.0005) and beyond (during 3 to 6 months of treatment, p �
0.0001). Correspondingly, bevacizumab therapy was associated with lower
rates of thrombocytopenia at 3 months (24% in Bev cohort vs. 43% in
Non-Bev cohort, p � 0.006) and beyond (p � 0.003). Conclusions: In our
cohort, addition of bevacizumab to oxaliplatin chemotherapy reduces the
occurrence of splenic enlargement, which correlates with a decreased rate
of thrombocytopenia. Further studies to understand the potential hepatoprotective
mechanism of anti-VEGF therapy are needed.
3546 General Poster Session (Board #24A), Mon, 8:00 AM-12:00 PM
KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI
and bevacizumab. Presenting Author: Marta Schirripa, U.O. Oncologia
Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano
Tumori, Pisa, Italy
Background: Kinase suppressor of Ras (KSR) 1 is a scaffolding protein
regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1
could increase estrogen receptor transcriptional activity after exposure to
estrogens. Recent retrospective analyses suggested a possible role for
KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients
with mCRC. Methods: MCRC patients receiving first-line
FOLFIRI�bevacizumab prospectively enrolled in a translational research
program were selected on the basis of KRAS and BRAF mutational status
availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted
from peripheral blood by means of PCR and direct sequencing.
Taking into account the connection between estrogen pathway and KSR1,
subgroup analyses according to gender were pre-planned. Results: 287
patients were included. Main patients’ characteristics were the following:
M/F�175/112; median age�62 (range 26-79); ECOG-PS 0/1-2�240/47;
synchronous/metachronous disease�213/74; Köhne score (low/intermediate/high/data
missing)�122/129/22/14; KRAS-BRAF mutational status
(wt-wt/mut-wt/wt-mut)� 123/146/18. In the overall KRAS-BRAF wt population,
KSR1 polymorphism did not affect the outcome. The analysis
performed according to gender showed that in the KRAS-BRAF wt population
females with KSR1 rs2241906 T/- achieved a significantly better PFS
(median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos)
(HR�0.44 [95%CI 0.21-0.91], p�0.010); meanwhile males with T/showed
a worse PFS in comparison to those carrying the C/C variant
(HR�1.92 [95%CI 1.05-3.53], p�0.021). These results were significant
also in a multivariate model and a significant interaction of gender with PFS
according to KSR1 allelic variants was demonstrated (p�0.004).
Conclusions: This prospectively conceived pharmacogenetic study confims
the role of KSR1 polymorphisms in affecting the outcome of mCRC
KRAS-BRAF wt patients. In particular, these results indirectly indicate that
estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC
cells through an interaction with KSR1. Preclinical investigations to further
explore this preliminary hypothesis are ongoing.
3545 General Poster Session (Board #23H), Mon, 8:00 AM-12:00 PM
Comparative effectiveness of sphincter-sparing surgery (SSS) versus abdomino-perineal
resection (APR) in rectal cancer: Patient-reported outcomes
(PROs) from NSABP R-04. Presenting Author: Patricia A. Ganz,
University of California, Los Angeles Jonsson Comprehensive Cancer
Center, Los Angeles, CA
Background: R-04 is a trial of pre-surgical RT and either capecitabine or
5-FU with or without oxaliplatin in patients (Pts) with resectable rectal
cancer. PROs were measured before treatment, post-RT, and 1 yr post-op.
We compare PROs at 1 yr by type of surgery with hypothesis that APR Pts
would have worse quality of life (QOL). Methods: Pts completed the FACT-C
and EORTC-CR38 at all times. Baseline and 1 yr were compared within
groups (SSS and APR) with paired t-test, and between groups at 1 yr, with
adjustment for covariates of age, gender, clinical stage, baseline score, and
surgery intent in a general linear model. These secondary/exploratory
hypotheses were significant if p � 0.05. Results: 1,608Pts were randomized
and 1405 completed baseline QOL form after consent, prior to
treatment. 1,003 completed QOL form 1 yr post-op: 6 were ineligible, 10
did not have surgery, leaving 987 Pts. 615 had SSS and 372 had APR.
66.6% were male, 61.5% stage II, and almost all had post-surgical
adjuvant chemotherapy. SSS Pts were significantly younger (60.3% vs.
53.5% � 59 yr, p�0.04). FACT-C total and subscale scores were not
significantly different by surgery type at 1 yr, with only minimal decline
from baseline in both groups. For SSS Pts, EORTC-CR38 scores significantly
worsened for body image, sexual function, sexual enjoyment (all p
�0.0001), while future perspective improved (p�0.0001) at 1 yr from
baseline. All symptom subscales except weight loss and micturition showed
worsened symptoms (GI tract, chemo side effects, defecation problems,
sexual problems) all p � 0.0001 at 1 yr from baseline. Compared to APR
Pts, SSS had less severe functional problems and symptoms, especially in
sexual enjoyment, weight loss, GI symptoms, and body image, all significant.
Conclusions: Contrary to prediction, there were no significant differences
in FACT-C scores for SSS vs. APR. Symptoms and functional
problems were detected by the EORTC-CR38, reflecting expected differences.
The largest differences between the surgical treatments were for GI
symptoms and body image. Information from these PROs may be useful in
counseling Pts anticipating surgery for rectal cancer.
3547 General Poster Session (Board #24B), Mon, 8:00 AM-12:00 PM
First European phase II trial of intravenous (iv) cetuximab (Cet) and hepatic
artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin in patients
with unresectable liver metastases from wt KRAS colorectal cancer (CRC)
after systemic therapy failure (OPTILIV, NCT00852228). Presenting
Author: Francis Levi, Medical Oncology Department, INSERM U776, Paul
Brousse Hospital, Villejuif, France
Background: HAI of chronomodulated (Chrono) irinotecan (I), 5-Fluorouracil
(F) and oxaliplatin (O), or flat O combined with iv F-leucovorin allowed
secondary metastases resections and prolonged survival in patients (pts)
with CRC liver metastases despite prior chemotherapy failure (Bouchahda,
Cancer 2009; Goere, Ann Surg 2010). Purpose: To prospectively evaluate
safety and efficacy of combining iv Cet with HAI of IFO in pts with CRC liver
metastases. Methods: This Phase II trial involved previously treated pts with
unresectable CRC liver metastases. Pts received iv Cet (500 mg/m²) and
Chrono or conventional HAI of I (180 mg/m²), F (2800 mg/m²), and O (85
mg/m²) q2 weeks. Liver metastases were resected if adequately downstaged.
Results: Planned accrual of 60 pts was reached on 01/24/2012. 3
pts were not treated, 9 are ongoing. 48 consecutive treated pts (18F, 30 M;
aged 32-76 years) are fully assessed and monitored. They had PS 0-1
(98%), bilobar liver lesions (69%), a median of 8 metastases (1-50; largest
diameter, 57 mm – 15-172). Prior chemotherapy involved one (43%), or
two or three (57%) lines. A median of 5 protocol courses (1-13) was given.
Main grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain
(15%), fatigue (15%), nausea (15%), diarrhea (13%) and sensory neuropathy
(4%). Objective response rate was 44% [30-58], with 6% radiological
complete responses. Disease control rate was 85%. Secondary liver surgery
was performed in 15 pts (31.3%).One pt with 25 metastases (1-6 cm) in all
liver segments had pathologic complete response in 24 lesions removed
through three-stage hepatectomy. She currently has an off treatment
disease-free survival of 17� months.With a follow up of 4 to 47 months,
median progression-free survival is 14.2 months [9.7-18.8], 1- and 2-year
survival rates are 92.8% and 59.2% respectively. Conclusions: OPTILIV
offers a safe and unusually effective treatment option for patients with CRC
liver metastases after failure of systemic chemotherapy within a coordinated
medico-surgical strategy.
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