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functioning scales. Exploratory analyses included the change from baseline QoL
scores by severity of skin reactions, the change in reported symptoms from baseline
according to tumor response and treatment, and the effect of symptomatic status at
baseline on response and survival.
Results: QoL was evaluable in 627/666 pts (94%) with KRAS wild-type
tumors, 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. No
significant differences for GHS/QoL (p = 0.12) and social functioning scores
(p = 0.43) were found between the treatment arms. In pts receiving cetuximab,
themeanchangefrombaselineinGHS/QoLwas3.00inptswithoutskin
reactions compared with -1.09 and -0.51 in those with grade I and grade
II-IV early skin reactions, respectively. Social functioning score worsened in
pts with no skin reactions (mean -6.41) compared with a slight improvement
in those with grade I (mean 1.64) and grade II-IV (mean 1.48) early skin
reactions, respectively. Tumor response was higher (58% vs 40%, p = 0.0002)
and survival longer (hazard ratio 1.68, p < 0.0001) in asymptomatic versus
symptomatic pts at baseline. FOLFIRI plus cetuximab increased tumor
response in symptomatic (65% vs 52%, p = 0.0388) and asymptomatic pts at
baseline (52% vs 31%, p = 0.0034), and in pts whose tumors had responded,
maximum symptom relief from baseline occurred earlier (8 vs 16 weeks)
compared with FOLFIRI alone.
Conclusions: Adding cetuximab to FOLFIRI improved clinical outcome without
negatively impacting on QoL, improving response despite baseline symptoms
and leading to earlier symptom relief in pts whose tumors had responded.
Symptom status at baseline was demonstrated to be a useful prognostic factor
in mCRC.
Disclosure: C. Köhne: The author reports honoraria from Pfizer and Merck KGaA.
G. Folprecht: The author reports consultant/advisory roles for Merck KGaA, Roche
and BMS, honoraria from Merck KGaA, Pfizer, Roche and Novartis and research
funding from Merck KGaA. P. Rougier: The author reports, in relation to the topic
concerned, honoraria for three years from Merck KGaA for participation at scientific
boards and symposia. D. Curran: The author acted as a consultant (on statistical and
QoL analysis) for Merck KGaA. U. Sartorius: The author is an employee of Merck
KGaA. I. Griebsch: At the time of this research, the author was an employee of
Merck KGaA. E. Van Cutsem: The author has received research funding from Merck
KGaA. All other authors have declared no conflicts of interest.
562P BEVACIZUMAB BEYOND PROGRESSION: HOW TO MONITOR
TREATMENT EFFICACY? RESULTS OF A FUNCTIONAL
IMAGING STUDY IN MURINE COLORECTAL CANCER
L. Heijmen 1 , E.E.G.W. Ter Voert 2 , C.J.A. Punt 3 , L. De Geus-Oei 4 , A. Heerschap 2 ,
J. Bussink 5 , V. Zerbi 2 , W.J.G. Oyen 6 , O. Boerman 4 , H.W.M. van Laarhoven 3
1 Medical Oncology, Radboud University Medical Centre, Nijmegen,
NETHERLANDS, 2 Radiology, Radboud University Medical Centre, Nijmegen,
NETHERLANDS, 3 Department of Medical Oncology, Academic Medical Center,
Amsterdam, NETHERLANDS, 4 Nuclear Medicine, Radboud University Medical
Centre, Nijmegen, NETHERLANDS, 5 Radiation Oncology, Radboud University
Medical Centre, Nijmegen, NETHERLANDS, 6 Department of Nuclear Medicine,
Radboud University Nijmegen Medical Centre, Nijmegen, NETHERLANDS
Introduction: The BRiTE study suggested that bevacizumab beyond progression to
first line therapy is beneficial for survival in advanced stage colorectal cancer.
However, since response to bevacizumab cannot always be predicted by tumor size
measurements, we studied utility of several functional imaging modalities to assess
efficacy of bevacizumab beyond progression (BBP).
Methods: 26 BALB/c nude mice with s.c. LS174T xenografts (diameter >0.4 cm)
were treated with daily capecitabine (200 mg/kg), weekly oxaliplatin (3mg/kg) and
2x/weekly bevacizumab (5 mg/kg). Tumor volume was assessed using caliper
measurements. Tumors were considered progressive on the treatment regimen when
volume was ≥1.5 times initial volume at 2 succeeding measurements. In 13 mice
bevacizumab treatment was continued (BBP group), while the control group received
saline injections. Within 3 days after progression, imaging was performed: FDG-PET,
diffusion weighted imaging (DWI), T2*, dynamic contrast enhanced MRI
(DCE-MRI). Measurements were repeated 7 and 10 days after the first
measurements. Linear mixed models were used to assess differences between the 2
groups over time. After the last measurement, tumors were snap-frozen and
immunohistochemically examined for 9F1 (vasculature), glucose transporter 1
(GLUT-1), carbonic anhydrase IX (CAIX) and Ki67 (proliferation) expression.
Results: Tumor growth after progression was more pronounced in the control group
(p < 0.01). FDG-PET showed a trend towards higher FDG uptake in the control
group (p = 0.08). DWI, T2* and DCE-MRI parameters were not significantly
different in the 2 groups. Immunohistochemical analyses showed a trend towards
lower Ki67 expression (fraction 0.027 vs 0.041 p = 0.05) and higher CAIX fraction
(0.21 vs. 0.10 p < 0.01) in the BBP group. The relative vascular area was lower in the
BBP group (0.029 vs. 0.042 p = 0.03). Vascular density (104 vs. 127 vessels/mm 2 p=
0.16) and GLUT-1 expression (0.08 vs 0.11 p = 0.48) did not significantly differ.
Conclusion: Bevacizumab after progression had significant effects on tumor
microenvironment. FDG-PET may be a sensitive functional imaging technique to
assess the effects of bevacizumab.
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
563P SKIN RASH AND OUTCOME IN COLORECTAL CANCER (CRC)
PATIENTS TREATED WITH ANTI-EGFR MONOCLONAL
ANTIBODIES
F. Petrelli 1 , K.F. Borgonovo 2 , M. Cabiddu 3 , M. Ghilardi 4 , M. Cremonesi 3 ,
F. Maspero 3 , S. Barni 3
1 UO Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY,
2 Medical Oncology Division, A.O. Treviglio-Caravaggio, Treviglio, ITALY, 3 Medical
Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY,
4 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY
Introduction: The most common toxicity associated with anti-EGFR monoclonal
antibodies (MoAbs) is an acneiform rash, that occurs in nearly all patients. One
of the more interesting and useful clinical observations regarding EGFR-targeted
therapy has been the association of clinical benefit with development of skin
rash. We have performed a systematic review and a pooled analysis of the
predictive value of skin rash for patients with advanced CRC treated with
cetuximab (C) and panitumumab (P) in prospective clinical trials or in
retrospective case series.
Materials and methods: We searched PubMed and ASCO Meetings for
publications reporting the correlation of skin rash with survival and/or response
rate. The lower limit date for the search was February 11,2012 with no upper
limit. The primary outcome was overall survival as a function of severity of
cutaneous toxicity in patients treated with C or P (OS). Secondary endpoints were
the predictive role of skin rash for progression free survival/time to progression
and response rate (ORR).
Results: Fourteen publications (for a total of 3,833 patients) were included in this
meta-analysis. All included studies enrolled patients with advanced disease. For the
primary endpoint (OS) 11 trials had available data; the occurrence of skin rash was
significantly associated with reduced risk of death in patients treated with C or P
(HR 0.51, P < 0.00001). For the association of risk of progression with skin rash (data
available from 5 trials) the HR was significant too (HR 0.58, P < 0.00001). According
to response rate analysis (15 trials available) skin rash was a significant predictor of
activity with a RR of 2.23 (P < 0.00001) for patients with toxicity compared to
patients with no or low-grade toxicity. ORR was 35% compared with 13% for
high-grade compared to low-grade skin toxicity arms. The results appear similar for
C and P trials for all the endpoints.
Conclusion: Skin rash represents an early predictive biomarker of response, however
the prognostic value of this event is presently unknown.
Disclosure: All authors have declared no conflicts of interest.
564P QUALITY-ADJUSTED SURVIVAL IN PATIENTS WITH
WILD-TYPE (WT) KRAS METASTATIC COLORECTAL CANCER
(MCRC) RECEIVING FIRST-LINE THERAPY WITH
PANITUMUMAB PLUS FOLFOX VERSUS FOLFOX ALONE
J. Wang 1 , Z. Zhao 2 , B. Barber 2 , J. Zhang 1 , B. Sherrill 3 , S. Braun 4 , R. Sidhu 5 ,
M. Gallagher 2 , J. Douillard 6
1 Biostatistics, RTI Health Solutions, Research Triangle Park, NC, UNITED
STATES OF AMERICA, 2 Global Health Economics, Amgen Inc., Thousand
Oaks, CA, UNITED STATES OF AMERICA, 3 Biometrics, RTI Health Solutions,
Research Triangle Park, NC, UNITED STATES OF AMERICA, 4 Amgen (Europe)
GmbH, Zug, SWITZERLAND, 5 Department of Clinical Research, Amgen Inc.,
Thousand Oaks, CA, UNITED STATES OF AMERICA, 6 Medical Oncology, Centre
René Gauducheau (ICO) Institut de Cancerologie de l’Ouest, St Herblain,
FRANCE
Background: Panitumumab plus FOLFOX significantly improved progression-free
survival (PFS) in patients with WT KRAS mCRC. The objective of this analysis was
to use the quality-adjusted time without symptoms of disease or toxicity of treatment
(Q-TWiST) method to compare quality-adjusted survival between the treatment
arms.
Methods: Patients with mCRC were randomized to panitumumab plus FOLFOX or
FOLFOX alone in a phase III clinical trial. For each treatment arm, the area under
the survival curve, which was estimated using the Weibull distribution, was
partitioned into health states: toxicity (TOX), time without symptoms of disease
progression or toxicity (TWiST, i.e., PFS minus TOX), and relapse period (REL, i.e.,
overall survival (OS) minus PFS); and adjusted using utility weights derived from
patient-reported EuroQoL 5-dimensions measures. The null hypothesis of no
difference between treatment groups was tested based on the normal approximation
with standard errors calculated by the bootstrap method. Sensitivity analyses were
performed using the standard Q-TWiST approach with means restricted to median
OS.
Results: Of 1,183 patients who were randomly assigned, 1,096 patients (93%) had
available tumor KRAS status, of which 656 patients (60%) had WT KRAS tumors
(panitumumab plus FOLFOX, n = 325; FOLFOX alone, n = 331) and were included
in this analysis. Compared to patients treated with FOLFOX alone, the panitumumab
plus FOLFOX group had significantly longer quality-adjusted PFS (8.5 versus 7.2
months, respectively; 1.3 additional quality-adjusted months; p = 0.02) and
quality-adjusted OS (22.4 versus 18.6 months; 3.8 additional quality-adjusted
ix192 | Abstracts Volume 23 | Supplement 9 | September 2012