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

630s Sarcoma
10000 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Predicting survival in primary resected retroperitoneal soft tissue sarcoma:
A specific nomogram built on three major sarcoma center data sets.
Presenting Author: Alessandro Gronchi, Fondazione IRCCS Istituto Nazionale
Tumori, Milano, Italy
Background: To build a specific nomogram for predicting postoperative
overall survival (OS) in primary retroperitoneal soft tissue sarcoma (RPS). A
few single institutions attempts are already available, but due to the rarity
of the disease they are based on limited number of cases with inherent
limitations. In an attempt to improve the predictive capability of such a
prognostic model we utilized series from 3 major sarcoma centers. Methods:
We included patients with primary localized RPS resected with curative
intent between 1999 and 2009 at 3 institutions (1 European and 2 North
Americans). Univariable (Kaplan Meier plots) and multivariable (Cox
model) analyses were carried out. Prognostic covariates were: Age (modeled
as continuous covariate using 3 knot restricted cubic spline transformation);
Tumor size (modeled as continuous covariate using 3 knot
restricted cubic spline transformation); Grade (I,II,III); Histological subtype
(Leiomyosarcoma, DD Liposarcoma, WD Liposarcoma, MPNST, Pleomorphic
Sa, SFT, Other); Multifocality (no,yes); Quality of surgery
(macroscopically complete, incomplete); radiation therapy (RT, done/not
done). A backward selection procedure, based on the Akaike Information
Criterion (AIC), was applied to select the Cox model covariates. The model
discriminative ability was estimated by means of bootstrap-corrected
Harrel C statistic. Results: 526 patients were identified. At a median
follow-up of 45 months (interquartile range: 22-72 months) 174 deaths
were recorded. 5-yr and 7yr OS (95% confidence interval) were 56.4%
(51.1,62.2%) and 50.1% (44.1,57.0%). The backward selection procedure
by AIC criterion lead to exclude RT from the covariates set. All other
covariates proved to be statistically significant in the final multivariable Cox
model. The Bootstrap-corrected Harrell C statistic was 0.74. Of interest,
size of the tumor and age of the patient had a bimodal contribution to the
risk of death and the combination of histological subtype and grade proved
significant. Conclusions: A new multi-institution RPS specific nomogram is
now available for prognostication in the clinic and patient selection in
clinical trials.
10002 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified
liposarcoma. Presenting Author: Mark Andrew Dickson, Memorial Sloan-
Kettering Cancer Center, New York, NY
Background: CDK4 is amplified in approximately 90% of well-differentiated/
de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6
inhibitor PD0332991 (PD) inhibits growth and induces senescence in
liposarcoma cell lines and xenografts. In a phase I trial of PD, several
patients with progressive WD/DDLS had prolonged stable disease for
several years. To determine the safety and efficacy of PD, a phase II study
was performed. Methods: Participants were patients with advanced WD/
DDLS. Eligibility criteria were age�18 years, measurable WD/DDLS
(RECIST 1.1), documented progression on at least one systemic therapy
directly before enrollment, CDK4 amplification by fluorescence in situ
hybridization and retinoblastoma protein (RB) expression by immunohistochemistry
(�1�). Pts received oral PD 200mg daily for 14 consecutive
days in 21-day cycles. The primary endpoint was progression-free survival
(PFS) at 12 weeks. Based on historical data, a promising result was defined
as a 12-week PFS of �40% and not promising as �20%. The sample size
was up to 28 evaluable patients. If 9 patients were progression free at 12
weeks, then PD would be considered to have activity in WD/DDLS. Results:
Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB�), 29 were
enrolled and 27 were evaluable for the primary endpoint. Median age was
65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%),
and the median number of prior regimens was 1 (range 1-5). PFS at 12
weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study
significantly exceeded its primary endpoint. At the data cutoff, the median
PFS was 18 weeks. Seven patients remain on study with stable disease at
18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3,
14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia
(grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions
were required in 24% of patients. Conclusions: Among patients with
WD/DDLS with CDK4 amplification and RB expression who had actively
progressing disease despite prior systemic therapy, treatment with the
CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized
phase 3 trial is planned.
10001 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
How well do we communicate risk? An evaluation of AJCC version 6 and 7
staging systems for soft tissue sarcomas. Presenting Author: Robert G.
Maki, Department of Medicine, Memorial Sloan-Kettering Cancer Center,
Present address: Departments of Medicine, Pediatrics, and Orthopaedics,
Mount Sinai School of Medicine, New York, NY
Background: Cancer staging systems allow physicians to communicate risks
of a particular clinical situation with one another and with patients. Few
data have been presented to support the update of a commonly employed
staging system for soft tissue sarcoma (STS). We examined American Joint
Committee on Cancer (AJCC) versions 6 (2002) and 7 (2010) staging
systems for patients with primary STS using a single institution clinically
annotated prospective database. Methods: Subsets of the prospectively
collected Memorial Sloan-Kettering Cancer Center STS database of 8647
patients from 1982 to 2010 were examined with respect to criteria of the
AJCC versions 6 and 7 staging systems. Results: Tumor size does not appear
to be adequately addressed in version 6 or 7. Relapse-free survival was
statistically worse for increasing size of primary STS �5, 5-10, 10-15, and
�15 cm; in comparison, overall survival decreased over three size categories
(�5, 5-10, �10 cm). Tumor depth, a statistically significant factor in
patient outcomes that is included in version 6, is functionally omitted in
version 7. Patients with node involvement without other metastases fare
statistically worse than patients with large, high grade tumors without nodal
metastasis, as shown previously. Version 6 and 7 criteria do not address
effects of primary anatomic site and histology, even for tumors with same
FNCLCC grade. Sarcoma subtypes defined after publication of FNCLCC
criteria are difficult to incorporate into existing guidelines. Conclusions:
Improved prognostication of STS outcomes is better achieved by staging
according to anatomic primary site, depth, and a larger number of size
categories. Histology-specific nomograms improve prognostic accuracy,
such as those for liposarcoma, GIST, or rhabdomyosarcoma. Staging
accuracy increases at the cost of portability and simplicity. The increasing
difficulties with use of a single STS staging system highlight the potential
benefit of newer techniques, such as patient-specific nomograms or
Bayesian networks. Staging systems will require significant modifications
to incorporate increasingly sophisticated molecular diagnostics.
10003 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
A phase II multicenter study of the IGF-1 receptor antibody cixutumumab
(A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with
refractory IGF-1R positive (�) and negative (-) bone and soft tissue
sarcomas (STS). Presenting Author: Gary K. Schwartz, Memorial Sloan-
Kettering Cancer Center, New York, NY
Background: Preclinical studies demonstrate synergistic anti-tumor activity
by inhibiting mTOR and IGF-1R. This study evaluated the safety and
efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (�) STS
(Arm A), IGF-1R (�) bone (Arm B), and IGF-1R (-) bone and STS (Arm C).
Methods: An optimal Simon 2 stage design was used for each arm. The
primary end-point was progression free survival (PFS) at 12 weeks. Based
on historical data, a 40% PFS rate was considered promising and a 20%
PFS non-promising (type I/ II error, 0.05/0.10). �5 PFSs at 12 weeks were
required in the first 19 and �16 PFSs were required in a total of 54 pts to
consider each arm positive. Key eligibility: measurable disease (RECIST
1.1), age �18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25
mg) were administered IV weekly. Pre and post treatment tumor biopsies
and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers
participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R
by immunohistochemistry (IHC; 54% �) and 171 were treated: mean age
47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities
�10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT)
analysis, each arm of the study achieved its primary 12 week PFS end-point
(�16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm
C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1),
(0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in
weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0,
17.9), respectively, and for chondro (n�18), Ewing’s (n�24), and osteo
(n�23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0),
respectively. Westerns on 32 matched pair tumor biopsies indicate
inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts
(Arm C), 5 were IGF-1R (�) by western. Plasma biomarkers did not
correlate with PFS. Conclusions: A12 and TEM met its primary end-point of
improved PFS in pts with metastatic sarcoma. This effect was independent
of IGF-1R status by IHC. These results support further clinical development
of this combination in bone and STS.
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