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.