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

2008 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV)
followed by consolidation high-dose chemotherapy (HDC) and autologous
stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma
(PCNSL). Presenting Author: Antonio Marcilio Padula Omuro, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: In our previous study in newly diagnosed PCNSL, induction
chemotherapy with MTX and cytarabine followed by consolidation HDC
(carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without
radiotherapy resulted in only 50% of pts transplanted, reflecting low
efficacy of induction chemotherapy, and short intent-to-treat (ITT) median
PFS (�6m). In this phase II trial, we sought to optimize this strategy by
utilizing a more effective induction regimen (R-MPV) and a more aggressive
HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV
(MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC
with thiothepa, cyclophosphamide and busulfan was given, followed by
ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free
survival (promising: 75%, non-promising: 50%; 90% power, significance�0.05).
Follow-up included comprehensive neuropsychological evaluation.
Results: Accrual has been completed (N�32 pts, median age 57
[range 23-67], median KPS�80). Following R-MPV, 17 pts achieved a CR,
13 pts a PR and two pts progressed. A total of 25 (78%) pts were
transplanted; the reasons for not receiving transplant were progressive
disease (N�2), poor performance status/ physician’s decision (N� 2),
mobilization failure (N�1) and consent withdrawn (N� 2). One pt who
withdrew consent relapsed and received HDCASCT for salvage. Two (8%)
pts died from early complications of ASCT (Stevens-Johnson: one, sepsis:
one) and one pt experienced a fatal late colitis of unknown etiology. In the
ITT population, the median EFS and OS have not been reached after a
median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90)
and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed
neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved
response rates, allowing 78% of pts to receive HDC-ASCT. Although more
toxic, this regimen resulted in excellent disease control and survival in the
ITT population, far exceeding the efficacy of our previous transplant study.
The primary endpoint was met, warranting further investigation.
2009 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Effects of cediranib, a VEGF signaling inhibitor, in combination with
chemoradiation on tumor blood flow and survival in newly diagnosed
glioblastoma. Presenting Author: Elizabeth Robins Gerstner, Massachusetts
General Hospital, Boston, MA
Background: Anti-angiogenic therapy is hypothesized to synergize with
radiation and chemotherapy by improving tumor blood flow. We evaluated
the tolerability, efficacy and potential mechanism of action of radiation,
temozolomide, and cediranib in newly diagnosed glioblastoma patients.
Methods: Newly diagnosed glioblastoma patients were treated with radiation,
temozolomide, and cediranib followed by monthly temozolomide for 6
cycles and daily cediranib until tumor progression or toxicity as part of an
IRB-approved, Phase Ib/II clinical trial. MRI scans including measurement
of cerebral blood flow were performed at baseline, weekly during the 6
weeks of chemoradiation and then monthly. Radiographic response was
determined by RANO criteria. Results: Six patients were enrolled in the
phase Ib part of the study with cediranib 30 mg daily in combination with
temozolomide and radiation. No dose-limiting toxicities were identified.
Forty patients were enrolled in the phase II part of the study. Among the
entire cohort of 46 patients, median age was 57 (range 35-74), median
KPS was 90% (60-100), 36 patients underwent a subtotal resection and
10 underwent biopsy. 26/30 patients taking corticosteroids were able to
taper corticosteroids during chemoradiation. Off study reasons included
toxicity (14), disease progression (18), and patient preference (2). Five
patients remain on study without disease progression and 20 patients have
died. Median duration on study was 158 days. Median progression free
survival was 288 days (95%CI 240,�) and median overall survival was 786
days (95%CI 411 ,�). Best radiographic response in patients who completed
chemoradiation was CR in 2 patients, PR in 20 patients, and SD in
15 patients. Patients with increased tumor perfusion during chemoradiation
survived nearly 1 year longer (mean OS�611 days) than patients with
decreased perfusion (mean OS�269 days). Conclusions: Cediranib was
well tolerated and led to improved PFS and OS compared to historical
controls, particularly in those with improved perfusion. This combination is
being evaluated in an ongoing randomized trial (RTOG 0837).
Central Nervous System Tumors
117s
2008b Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with
anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase
III study. Presenting Author: J. Gregory Cairncross, University of Calgary,
Calgary, AB, Canada
Background: Anaplastic oligodendrogliomas, pure (AO) and mixed (AOA),
are chemosensitive tumors, especially if co-deleted for chromosomes 1p
and 19q, but whether addition of CT to RT prolongs overall survival (OS), is
unknown. Methods: In the RTOG 9402 Phase III trial, patients (pts) with
AO/AOA were randomly assigned to PCV [procarbazine, CCNU (lomustine)
and vincristine] followed by immediate RT vs. immediate RT alone. Early
analysis showed no OS benefit for the PCV�RT group but combined therapy
was associated with a longer progression-free survival (PFS). It also showed
that the finding of 1p/19q co-deletion was associated with a longer OS
independent of treatment. The current analysis has a median follow up of
11.3 years (yrs). Results: Two hundred ninety-one patients were randomized,
148 to PCV�RT and 143 to RT. PCV�RT was associated with longer
PFS [2.5 vs. 1.7 yrs, hazard ratio (HR) 0.68, 95% confidence interval (CI)
(0.53, 0.88), P � 0.003] and the 1p/19q co-deletion with a longer Median
Survival Time (MST) [8.7 vs. 2.7 yrs, HR 0.41, 95% CI (0.30, 0.55), P �
0.001]. For the entire cohort, there was no difference in MST by treatment
[4.6 yrs for PCV�RT vs. 4.7 yrs for RT, HR 0.79, 95% CI (0.60, 1.04), P �
0.1]. However, patients with 1p/19q co-deleted tumors lived much longer
after PCV�RT (n � 59) than after RT (n � 67) [14.7 vs. 7.3 yrs, HR 0.59,
95% CI (0.37, 0.95), P � 0.03]. There was no difference in MST by
treatment in pts without the 1p/19q co-deletion [n�137; 2.6 vs. 2.7 yrs,
HR 0.85, 95% CI (0.58, 1.23), P � 0.39]. Re-operation rates upon
progression were similar between treatment arms in co-deleted pts (43%,
PCV�RT vs. 54%, RT) but salvage CT rates were higher in the RT arm [57%
vs. 81% (P � 0.04)]. Conclusions: PCV followed by immediate RT was a
highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In
this setting, 1p/19q co-deletion was both prognostic and predictive, and
the early PFS benefit in co-deleted cases was a harbinger of their longer OS.
[This work was supported by RTOG grants U10 CA21661 and U10
CA32115, NCCTG grant U10 CA25224, ECOG grants CA17145 and
CA21115, SWOG grant CA32102, and CCOP grant U10 CA37422 from
the National Cancer Institute (NCI)]
2010 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Effect of antiangiogenic therapy on tumor-associated macrophages in
recurrent glioblastoma. Presenting Author: Christine Lu-Emerson, Massachusetts
General Hospital, Boston, MA
Background: Antiangiogenic therapy is associated with increased radiographic
responses in glioblastoma (GBM), but tumors invariably recur.
Tumor associated macrophages (TAMs) have been proposed as a mechanism
of resistance to anti-angiogenic therapy in preclinical models. To
examine the role of TAMs in recurrent GBM, we analyzed autopsy
specimens from patients with or without history of antiangiogenic therapy.
Methods: We compared autopsy brain specimens from 17 recurrent GBM
patients who received anti-angiogenic treatment and chemoradiation
(AAT�) to 7 patients who received chemotherapy and/or radiotherapy
without anti-angiogenic therapy, or no treatment (AAT-). TAMs were
morphologically and phenotypically identified with flow cytometry and
immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163
markers. All specimens were obtained from the Department of Pathology at
Massachusetts General Hospital and clinical information gained through
review of the patients’ records. Results: Using flow cytometry, we observed
an increase in CD11b�CD14� cells in the AAT� patients compared to
AAT- patients. Using IHC analysis, we observed a significant increase in
CD68� macrophages in the tumor bulk (p�0.01) and infiltrative areas
(p�0.05) in AAT� versus AAT- patients. We also observed a significant
increase in CD11b� myeloid cells in the tumor bulk (p�0.01) and a
significant increase in CD163� cells in the infiltrative areas (p�0.05) in
the AAT� group. Finally, we noted a trend toward an increase in CD163�
cells in the tumor bulk (p�0.087) in the AAT� versus the AAT- patients.
Conclusions: Patients with recurrent GBM after antiangiogenic therapy
showed a significant increase in CD68� TAMs and in CD11b� cells in the
tumor bulk. Additionally, antiangiogenic treatment induced an increase in
CD68� and CD163� TAMs in the infiltrative region. These data indicate
that TAMs may participate in escape from antiangiogenic therapy and may
represent a future therapeutic target in recurrent GBM.
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