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

5512 Poster Discussion Session (Board #2), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Five years’ results of the German ARO 04-01 trial of concurrent 72 Gy
hyperfractionated accelerated radiation therapy (HART) plus once weekly
cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck
cancer. Presenting Author: Volker Budach, Department of Radiooncology
CCM/CVK, Charite University Medicine, Berlin, Germany
Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with
concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in
terms of overall survival (OS) and metastases-free survival (MFS)? Methods:
Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of �80%
stratified for sites, N-status, grading, hemoglobin and center. The HART
schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was
applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or
MMC/5-FU at 10mg/m2 day 1�36 and for both arms with 600mg/m² 5-FU
days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using
3D-conformal or IMRT-TP. 364 patients were analysed using an ITT
principle for OS, MFS, progression-free survival (PFS) and loco-regional
control (LRC). Hazard ratio (HR) calculations were adjusted for competing
risk factors. Results: Median follow-up was 48 mos. for both arms. Mean
age was 55.4 years, 83/17% were male/female and 100% stage IV patients
(UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP
cancer, respectively. The OS and MFS at 4 years for the DDP- versus
MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p�.05),
respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs.
57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute
toxicity and 9 for late morbidity showed no significant differences between
the treatment arms except for creatinine for the DDP-arm (p � 0.001)
using nonparametric analyses of variances for repeated measurements. The
overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC:
86%, respectively. Conclusions: This phase III trial first establishes level
IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4
yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of
acute and late radiation sequelae for both treatment arms. No significant
differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly
DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily
compete with other concurrent chemo- or bio-radiation schedules including
induction TPF followed by radiation.
5514 Poster Discussion Session (Board #4), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
A phase II study of temsirolimus/sorafenib in patients with radioactive
iodine (RAI)-refractory thyroid carcinoma. Presenting Author: Eric Jeffrey
Sherman, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple
targets, including RAF, VEGFR1, and VEGFR2. Published response rates
with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%.
Temsirolimus is an intravenous inhibitor of mTOR; mutations in the
PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be
associated with aggressive disease. Methods: The study was a single
institution, phase II design. Primary objective was response rate. Eligible
patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)avid,
recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable
disease; and adequate organ/marrow function. Sorafenib was given at
200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly.
38 patients were enrolled; 37 were eligible and 36 patients started
treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12.
Fourteen pts are still actively on study. Results: Of the 37 eligible pts,
demographics: female-46%; median age-64 years (30-81); histologypapillary
(23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic
(2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse
events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt):
grade 4 – colonic perforation (1 pt). Evaluation of best response: partial
(PR) (8, including 3 with anaplastic/poorly differentiated); stable disease
(SD) (21); progression (1); inevaluable (7). The partial response rate was
38% in the cohort that previously did not receive any systemic treatment.
There was no correlation of response to either BRAF (10) or RAS (5)
mutational status. Median time on treatment is 203 days (range 14-638
days) at the cutoff date. For the 21 pts with SD, the maximum percentage
shrinkage by RECIST criteria ranged from -2% to -35% (one patient with
unconfirmed PR) with a median time on treatment of 203 days (range
39-503 days). Conclusions: The combination of sorafenib and temsirolimus
shows promising results in a heavily pretreated population. This study was
approved and funded by the National Comprehensive Cancer Network
(NCCN) from general research support from Pfizer, Inc.
Head and Neck Cancer
359s
5513 Poster Discussion Session (Board #3), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Cetuximab/radiotherapy (CET�RT) versus concomitant chemoradiotherapy
(cCHT�RT) with or without induction docetaxel/cisplatin/5-fluorouracil
(TPF) in locally advanced head and neck squamous cell carcinoma
(LASCCHN): Preliminary results on toxicity of a randomized, 2x2 factorial,
phase II-III study (NCT01086826). Presenting Author: Maria Grazia Ghi,
Medical Oncology Department, Venezia, Italy
Background: The standard treatment options for LASCCHN are cCHT�RT or
CET�RT. Strategies to improve the efficacy with the integration of
induction chemotherapy are being investigated. Primary endpoints of this
study were to compare: 1) the overall survival (OS) of induction vs. no
induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT�RT vs.
CET�RT. Methods: Patients (pts) with unresectable LASCCHN, stage
III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1:
cCHT�RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET�RTX; Arm B1:
3 cycles of TPF followed by the same cCHT�RT; Arm B2: 3 cycles of TPF
followed by CET�RT. A total of 204 deaths over 420 pts ( including the
101 randomized in the phase II part of the study comparing cCHT�RT with
or w/o induction TPF) were required to detect a HR of death of 0.675
(A1�A2 vs. B1�B2; 2-sided a�0.05; b�0.20) and a 10% difference in
G3-4 in-field mucosal toxicity (A1�B1 vs. A2�B2). Results: By February
2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were
male; median age was 60y; PS: 0�77.8% and 1�22.2%. Disease stage
was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%),
oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21
months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary
endpoint) and compliance to cCHT�RT vs CET�RT are shown in the table.
Conclusions: No advantage for CET�RT over cCHT�RT was observed
regarding G3-4 in-field toxicities and feasibility. Pts are still being
followed-up to assess OS.
cCHT�RTX CET�RTX p
In-field mucositis G3-4 29.4% 23% 0.15
In-field skin reaction G3-4 11.1% 13.7% 0.43
RT median dose, Gy (range) 66 (18-70.2) 70 (35-70.4) �0.01
RT median duration, weeks (range) 7.2 (0.6-13.3) 8.4 (1-12.7) �0.01
RT interruption > 3days 32.8% 38.7% 0.28
Pts receiving 2 CHT cy or 7 weekly CET 91.3% 78.2% �0.01
RT modification due to acute toxicity 18.5% 27.7% 0.08
5515 Poster Discussion Session (Board #5), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Expression of p16, ERCC1, and EGFR amplification as predictors of
responsiveness of locally advanced squamous cell carcinomas of head and
neck (SCCHN) to cisplatin, radiotherapy, and erlotinib: A phase II randomized
trial. Presenting Author: Melissa Austin, University of Washington,
Seattle, WA
Background: This study evaluated the expression of p16 and ERCC1 and
EGFR amplification as predictive and prognostic factors in a recently
completed phase II randomized trial comparing cisplatin (100 mg/m2 on d
1, 22, 43) with radiotherapy (70Gy) �/- erlotinib (150 mg/d during
radiotherapy) in locally advanced SCCHN. p16 (HPV surrogate) is a known
prognostic factor in oropharyngeal SCCHN, and high ERCC1 expression has
been correlated with resistance to cisplatin. EGFR gene copy number may
be prognostic in SCCHN and alter response to erlotinib. Methods: Pretreatment
formalin-fixed, paraffin-embedded tumor tissue was available for
84/204 patients. EGFR copy number was assessed using Vysis LSI DNA
probes, and immunohistochemistry was performed on Leica Bond III
machines using Lab Vision ERCC-1 (8F1) and CINtec p16 antibodies. All
assays were performed in accordance with manufacturer instructions; all
studies were reviewed by a single Pathologist (MA) who was blinded to
patient outcome. Logistic regression and Cox regression models fit a
treatment arm by marker interaction and tested selected linear contrasts.
Results: Efficacy analysis showed no difference in complete response rate
(CRR) and progression-free survival (PFS) between treatment arms. However,
PFS in both arms was better than historical comparisons, with only 46
events over a median follow-up of 23 months. Positivity in p16 was
associated with greater CRR (OR 3.5, p�0.03) and longer PFS (HR�0.38;
p� 0.07). The CRR effect was greater for the erlotinib arm (OR 8.1,
p�0.01) than for Arm A (OR 1.5, p�0.56). The ERCC1 (�) rate was 46%
(39/84).ERCC1 expression above the median was not associated with
worse CRR (OR 0.69; p�0.46) or PFS (HR 0.99; p�0.98). Only 4 tumors
showed EGFR amplification precluding further analysis. Conclusions: p16(�)
tumors had a better outcome, similar to other recent trials, and erlotinib
seemed to increase the CRR among p16(�) tumors. ERCC1 expression did
not predict chemoradioresistance in this study. EGFR amplification was too
rare in the tested population to assess predictive or prognostic value.
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