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

116s Central Nervous System Tumors
2004 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Relationship between overall survival and progression-free survival for
recent NCCTG glioblastoma multiforme trials. Presenting Author: Wenting
Wu, Mayo Clinic, Rochester, MN
Background: With the approval of novel agents for glioblastoma (GBM)
treatment, reliable historical outcome data for the common phase II
endpoint of progression free survival (PFS) is not available. In particular,
the association between progression and overall survival (OS) has not been
evaluated after temozolomide (TMZ) became the standard therapy for
newly diagnosed GBM. Methods: Datasets from 5 TMZ-including NCCTG
clinical trials in newly diagnosed GBM (n�325, 2005-2011, 1 phase I
only and 4 phase I and single arm phase II trials) were pooled and analyzed
to evaluate the individual level correlation between PFS and OS using
correlation coefficient, landmark analyses, and time-dependent variable
analyses. A historical control group was constructed by pooling datasets
from 12 pre-TMZ era NCCTG clinical trials in the same patient population
(n�1359, 1980-2004). Each of the 5 newer trials was compared to the
control group to estimate the treatment effect (hazard ratio) on PFS and
OS, which were analyzed to evaluate the trial level correlation between PFS
and OS using correlation coefficient and weighted linear regression.
Results: The estimated correlation coefficient between PFS and OS at
individual patient level is 0.75 (95%CI, 0.7 to 0.8). The estimated hazard
ratios of death in the landmark analysis at 4 and 6 months are 2.15
(95%CI, 1.47 to 3.15) and 2.17 (95%CI, 1.57 to 3.12), respectively, and
the estimated hazard ratio of death is 10.1 (95%CI, 6.6 to 15.4) when
progression is treated as a time-dependent variable. For trial level correlation
(against the historical control group), the estimated correlation
coefficient between HRos and HRpfs is 0.51 (95%CI, -0.67 to 0.96), with
moderate prediction: the predicted HRos is very close to the observed HRos in 4 of 5 cases, however the predicted HRos is significantly different from 1
in only 2 out of 5 cases due to small sample size in other 3 cases.
Conclusions: PFS and OS are highly associated at the individual patient
level but only moderately at the trial level, the latter possibly due to small
sample size in some of the trials. Additional validation in other trials could
support use of PFS as a primary endpoint for randomized phase II trials in
GBM.
2006 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Consolidation reduced dose whole brain radiotherapy (rdWBRT) following
methotrexate, rituximab, procarbazine, vincristine, cytarabine (R-MPV-A)
for newly diagnosed primary CNS lymphoma (PCNSL): Final results and
long-term outcome. Presenting Author: Richard Charles Curry, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: After promising early results in the pilot phase (N� 30)
reported by Shah 2007, we report on final results of a multicenter phase II
study (N�52) in newly diagnosed PCNSL combining R-MPV-A and rdW-
BRT, expanded to address long-term disease control and cognitive outcomes
in pts who actually received rdWBRT. Methods: Pts received 5 cycles
of R-MPV (MTX dose: 3.5g/m2). Those with partial response (PR) received
additional 2 cycles. Pts with a complete response (CR) after 5-7 cycles
received rdWBRT (23.4 Gy), otherwise standard WBRT was offered (45
Gy). Consolidation cytarabine was given to all pts. Primary end-point was
2-y progression-free survival (PFS) in pts receiving rdWBRT (n�30 pts in
CR required). Exploratory end-points included comprehensive neuropsychological
testing, white matter changes (WMC) analysis (Fazekas scale) and
apparent diffusion coefficient (ADC) on MRI. Results: Accrual was completed
(N�52; 22 women); median (med) age� 60 (30-79); med KPS�
70 (50-100). In total, 31 (59%) pts were assessable for the primary
endpoint (achieved a CR after induction and received rdWBRT). The 2-y
PFS for this group was 78% (95% ci: 64%- 92%); med PFS� 7.7 y; the
med OS was not reached (med follow-up� 6y); 3y-OS� 88% (ci 70-95);
5y-OS� 81% (ci 62-91). Cognitive testing showed improvement in
executive function (P � 0.01) and verbal memory (P � 0.05) following
induction chemotherapy; follow-up scores remained stable across the
various domains. Minimal WMC developed in long term survivors: 36% of
pts showed no change in Fazekas’ scores, 64% of pts developed scores 1 or
2 and no pt showed scores 3-6. The intent-to-treat (n�52) med PFS was
3.3y; med OS� 6.6 y. Differences in ADC values did not predict response
(p�0.15), PFS (p�0.41) or OS (p�0.48). Conclusions: Consolidation
rdWBRT is a highly effective and safe treatment for newly diagnosed
PCNSL. Long term follow-up showed robust PFS and OS, comparable or
superior to full dose WBRT, with excellent cognitive outcomes and no
significant WMC over time. An RTOG randomized trial has been initiated
comparing R-MPV-A with vs without rdWBRT.
2005 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Bayesian adaptive randomized trial design for patients with recurrent
glioblastoma. Presenting Author: Brian Michael Alexander, Dana-Farber
Cancer Institute/Brigham and Women’s Cancer Center, Boston, MA
Background: Bayesian-based trial design has the ability to utilize accumulating
data in real time to alter the course of the trial, thereby enabling
dynamic allocation to experimental arms and earlier dropping of ineffective
arms. This flexibility results in a potentially more efficient trial framework
by increasing the probability of enrollment to arms that show evidence of
efficacy. In this study we considered a hypothetical scenario in which
patients who have been previously treated on several separate experimental
protocols at the Dana-Farber/Harvard Cancer Center and the University of
California, Los Angeles were instead enrolled in a single multi-arm protocol
utilizing a Bayesian adaptively randomized trial design. The purpose was to
determine whether similar scientific results could have been accomplished
more efficiently. Methods: We generated an adaptive randomization procedure
that was retrospectively applied to primary patient data from four
separate phase II clinical trials in patients with recurrent glioblastoma. We
then compared AR to more conventional trial designs using realistic
hypothetical scenarios consistent with survival data reported in the literature.
Our primary endpoint is the number of patients needed to achieve a
desired statistical power. Results: If our phase II trials had been a single
multi-arm AR trial, bevacizumab would have been identified as an
efficacious therapy, and 30 fewer patients would have been needed
compared to a multi-arm balanced randomized (BR) design. More generally,
Bayesian AR trial design for patients with glioblastoma would result in
trials with fewer overall patients with no loss in statistical power, and in
more patients randomized to effective treatment arms. For a trial with a
control arm, two ineffective arms and one effective arm with hazard ratio
0.6, a median of 47 patients would be randomized to the effective arm
compared with 35 in a BR design. Conclusions: Given the desire for control
arms in phase II trials, an increasing number of experimental therapeutics
for patients with glioblastoma, and a relatively short time for events,
Bayesian adaptive designs are attractive for clinical trials in glioblastoma.
2007 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Elderly patients with primary CNS lymphoma: Results from the G-PCNSL-
SG-1 trial. Presenting Author: Patrick Roth, University Hospital Zurich,
Zurich, Switzerland
Background: Age is the most important therapy-independent prognostic
factor in patients with primary central nervous system lymphoma (PCNSL).
Here we aimed at providing an analysis of the impact of higher age on
response to therapy, toxicity, and survival in the largest PCNSL trial ever
performed to date. Methods: Response to therapy, toxicity and survival of
PCNSL patients enrolled in the G-PCNSL-SG-1 trial evaluating the role of
radiotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy
were monitored. Subjects aged 70 or more were compared to younger
patients. Results: Of all eligible patients (n�526), 126 (24%) were aged
70 or more. In the per protocol population, 66 of 318 patients (21%) were
at least 70 years old. Among the eligible patients, the rate of complete and
partial responses (CR�PR) to HD-MTX-based chemotherapy was 44% in
the elderly compared to 57% in the younger patients (p�0.016). A higher
rate of grade III/IV leukopenia was observed in the elderly (34% versus
21%, p�0.007). Also, death on therapy was more frequent (18% versus
11%; p�0.027) in these patients. In contrast, there was no other major
age-dependent toxicity. Survival analyses revealed shorter progression-free
survival (PFS) (4.0 versus 7.7 months, p�0.014) and overall survival (OS)
(12.5 versus 26.2 months, p�0.001) in the elderly population. The PFS of
CR patients was 35.0 months in younger patients compared to 16.1 in the
elderly (p�0.024). Salvage therapy was used less commonly in elderly
patients. When salvage WBRT was applied in patients who had failed on
HD-MTX-based chemotherapy, there was no association between age and
survival (p�0.633). Conclusions: Elderly PCNSL patients have a lower
response rate and higher mortality on HD-MTX-based chemotherapy. Their
PFS is shorter and they receive less salvage therapy which may contribute
to the poor prognosis.
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