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Combination therapy with temozolomide and bevacizumab in the treatment of hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT): an updated analysis. Park MS , Lazar AJ, Trent JC, Conrad CA, Ludwig JA, Wang W, Boonsirikamchai P, Choi H, Patel SR, Benjamin RS, Araujo DM - PowerPoint PPT PresentationTRANSCRIPT
Combination therapy with temozolomide and bevacizumab in the treatment of
hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT): an updated
analysis
Park MS, Lazar AJ, Trent JC, Conrad CA, Ludwig JA, Wang W, Boonsirikamchai P, Choi H, Patel SR, Benjamin RS, Araujo DM
The University of Texas - MD Anderson Cancer CenterHouston, TX
Background
Emerging consensus that HPC/SFT represent a
morphological continuum rather than two distinctentities1,2
The hemangiopericytoma/ solitary fibrous tumor (HPC/SFT) spectrum
•Varying cellularity•Branched “staghorn” vessels•Diffuse IHC +CD34 reactivity
1Fletcher CDM. Histopathology 48 (2006) , 3-122Gengler et al. Histopathology 48 (2006), 63-74
HPC SFT
Background
Malignant potential of HPC/SFT is difficult to predict at the time of diagnosis
Limited data regarding the long-term outcome of HPC/SFT in the advanced setting3,4
3Spitz et al. Ann of Surg Oncol; 5(4):350-3554Espat et al. Cancer 2002;95:1746–51
Background Rationale for temozolomide & bevacizumab:
Activity in Glioblastomas5,6
Irinotecan and bevacizumab (RR 57-60%) Carboplatin and bevacizumab Temozolomide and bevacizumab
Our institution’s anecdotal experience in a single patient with meningeal HPC/SFT Previously heavily treated with multiple surgeries, XRT,
chemo- and biologic therapies with no prior response
5Vredenburgh et al. J Clin Oncol 2007;25:4722-27396Charles A. Conrad, personal communication
Methods Retrospective review of all HPC/SFT
patients treated with temozolomide and bevacizumab at MD Anderson Cancer Center IRB-approved protocol Study period: May 2005 – June 2007 All diagnoses confirmed by a sarcoma
pathologist All had follow-up scans available
Methods Radiologic response: Choi criteria7
7Choi et al. J Clin Oncol 2007;25:1753-1759
Statistical analysis for progression-free survial: Kaplan-Meier method
Results: Patient Characteristics 14 HPC/SFT patients treated with temozolomide &
bevacizumab at MD Anderson Cancer Center, 05/2005-06/2007
Gender (M/F): 9/5 Median age: 59 (range 44-75)
Reason for starting treatment: Symptomatic disease: 7 Neoadjuvant treatment: 4 Disease progression: 8
Local disease recurrence/progression: 3 Development of metastatic disease: 5
Results: Patient Characteristics
TumorPrior
Systemic RxMetastatic
DiseasePrior XRT
Primary Tumor Location
SFT Y Y N Lung/Pleura
HPC Y Y Y Meninges
HPC Y Y Y Meninges
SFT Y N N Lung/Pleura
HPC Y N Y Meninges
SFT N Y N Lung/Pleura
HPC N Y Y Gluteal Soft Tissue
HPC N Y N Meninges
HPC N Y N Abdominal wall
HPC N N N Pelvis
HPC N N N Pelvis
HPC N N Y Meninges
HPC N N Y Meninges
SFT N N Y Bladder
Prior surgery: 10 (median = 1.5, range 0-6) Prior XRT: 7 Prior chemotherapy: 5
Results: Prior Systemic Therapy History
*Received regimen after R0 resection as adjuvant therapy
TumorMetastatic Disease Prior Regimen(s)
Duration of Rx
(months)Best
Response Reason for Stopping Therapy
HPC Y endostatin 7 PD Disease Progression, Toxicities
paclitaxel 8 SD Disease Progression
gemcitabine 8 SD Disease Progression
HPC Y celecoxib* 14 SD* Disease Recurrence
imatinib 2 PD Disease Progression
paclitaxel* 6 SD* Physician Decision
gemcitabine/ docetaxel 3 SD Disease Progression
SFT Y gemcitabine/ docetaxel 2 PD Disease Progression
HPC N imatinib 5 SD Disease Progression
imatinib/ thalidomide 1 PD Disease Progression
imatinib/ thalidomide/ etoposide 1 SD Toxicities, Patient Intolerance
imatinib/ thalidomide/ hydrea 7 SD Disease Progression
imatinib/ hydrea 2.5 SD Disease Progression
SFT N gemcitabine/ docetaxel 1 PD Disease Progression
doxorubicin/ dacarbazine 3 SD Toxicities
Results: Treatment Regimen
Median no. of cycles of therapy administered: 7.5 (2.5-20.5) 1 patient still undergoing therapy at the time of
analysis
All patients treated with:
Results: Response Rate
Best Response rate: 11/14 (79%) (PR) (≥10% ↓ size, ≥15% ↓ HU) SD: 2/14 (14%); PD 1/14 (7%) (≥10% ↑ size without 15% ↓ HU)
* History of prior systemic therapy; + patient with ongoing therapy
TumorBest Response
(Choi)
Best Response (RECIST)
No. of Cycles to Reach Best
ResponseTotal No. of
CyclesReason(s) for Stopping Therapy
HPC PR ↓Size ↓HU SD 2 4 Toxicities
SFT PR ↓Size ↓HU SD 2 13+ N/A
HPC* PR ↓Size ↓HU SD 3 10 Disease Progression
SFT PR ↓Size ↓HU SD 4 20.5 Patient Preference
HPC PR ↓Size PR 2 7 Toxicities
HPC PR ↓Size SD 2 8 Patient Preference
HPC* PR ↓Size SD 2 2.5 Toxicities
HPC* PR ↓HU SD 2 4.5 Disease Progression
HPC PR ↓HU SD 2 8 Disease Progression
SFT* PR ↓HU SD 2 8.5 Disease Progression
SFT* PR ↓HU SD 4 8 Patient Preference
HPC SD - SD 2 6 Disease Progression
HPC SD - SD 2 2.5 Death
HPC PD - SD 2 3.5 Disease Progression
Results: Patient Example 1
PR (↓ SIZE)
15.8 mm75.3 HU
After 8 cyclesPre-Treatment
33.8 mm107.8 HU
After 2 cycles
23.7 mm101.3 HU
Results: Patient Example 2
Pre-Treatment
13.6 mm37.5 HU
18.0 mm52 HU
After 2 Cycles
14.4 mm115 HU
16.4 mm140.1 HU
PR(↓ HU)
Results: Progression Free Survival
Median PFS: 8.6 months
Historical HPC/SFT Cohort – Comparison of Response Rates
Best Response rate (Choi) : 1/5 (20%) (PR) (≥10% ↓ size, ≥15% ↓ HU) SD: 3/5 (60%); PD 1/5 (20%) (≥10% ↑ size without 15% ↓ HU)
TumorMet.Dz Regimen
Best Response (Choi)
Best Response (RECIST)
No. of Cycles to
Reach Best
Response
Duration of
Therapy (Mo.)
Reason(s) for Stopping Therapy
HPC YDoxorubicin/
Ifosfamide PR ↓Size ↓HU SD 4 6Disease Progression
HPC YDoxorobicin/
Ifosfamide SD - SD 2 6 Side effects
SFT YDoxorobicin/
Ifosfamide SD - SD 2 5Disease Progression
HPC* Y Ifosfamide SD - SD 2 6Disease Progression
HPC YGemcitabine/
Taxotere PD - PD 2 2Disease Progression
* History of prior systemic therapy with doxorubicin and cisplatin.
Historical HPC/SFT Cohort – Comparison of Progression-Free Survivals
Median PFS (TMZ/BV): 8.6 months
Median PFS (Others): 6.1 months
Results: Major Treatment Toxicities Hematologic Toxicities
Neutropenia (Grade 3): 1 Thrombocytopenia (Grade 3): 2
Infectious Toxicities Fungal pneumonia (Grade 2): 1
Metabolic Toxicities Renal Insufficiency (Grade 2): 1
1 case of mortality during treatment Renal failure, DIC, hypotension, cardiac arrest Death secondary to disease & performance status
IHC analysis of tumor specimens for angiogenesis & cell growth biomarkers
No strong correlation between levels of IHC expression and clinical outcomes were found in this limited set
Tumor
IHC
Best Response
No. of Cycles of Therapy Received PFS (mo.)VEGF PDGF-A PDGFR-A PDGF-B PDGFR-B
SFT - +/- + ++ +/- PR 8 18.5
HPC + PR 4 18.5+
HPC +++ +++ ++ +++ ++ PR 8 10
HPC ++ + ++ ++ ++ PR 7 7.7
HPC + - PD 3.5 4
5 patients had tissue specimens readily available for IHC analysis
Conclusions• Hemangiopericytoma/ malignant solitary fibrous tumor
(HPC/SFT) are a rare spectrum of tumors with no known effective medical therapy in the advanced setting.
• In our retrospective series, combination therapy with temozolomide and bevacizumab has demonstrated clinical benefit in a majority of patients with a low rate of major toxicities.
• These findings advocate a role for a larger, prospective phase II study to further investigate the biological mechanism and efficacy of temozolomide and bevacizumab in HPC/SFT.