The University of Texas - MD Anderson Cancer Center 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 Center Houston, TX

Background Emerging consensus that HPC/SFT represent a The hemangiopericytoma/ solitary fibrous tumor (HPC/SFT) spectrum Varying cellularity Branched “staghorn” vessels Diffuse IHC +CD34 reactivity HPC and SFT are rare soft tissue tumors whose origin and classification have been debated over time. They have been initially separate entities often misdiagnosed for each other, but the latest WHO classification has considered them to be representing two ends of an overlapping spectrum of mesenchymal neoplasm, probably fibroblastic in nature. When we look at their histologies, HPC, on the left, is composed of more plump spindle cells that occur in sheet. SFT, on the right, tends to have more slender spindle cells arranged in a "patternless pattern" with admixed collagen. There is usually significant variation in cellularity. Both neoplasms can be associated with multiply branched vessels, but these are often more prominent in HPC. Both neoplasms show diffuse reactivity for CD34 on immunohistochemistry in the majority of cases. HPC SFT Emerging consensus that HPC/SFT represent a morphological continuum rather than two distinctentities1,2 1Fletcher CDM. Histopathology 48 (2006) , 3-12 2Gengler et al. Histopathology 48 (2006), 63-74

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 Size, mitotic activity, cellular atypia, pleomorphism, necrosis, and depth have been shown NOT to reliably predict the prognosis and malignant potential of HPC/SFT. There is some evidence that the location of the primary tumor may be related to outcome. In a retrospective analysis of 36 HPC patients treated at our institution from 1975-1995, tumors arising in the extremities had a significantly prolonged local recurrence-free survival than other sites. Local recurrence rates were high for meningeal and retroperitoneal sites. Overall, data regarding the long-term outcome of patients with HPC/SFT is limited. Complete surgical resection has shown 79-100% 5 yr- survival vs. 50% 5 yr survival in a small number of HPC pts with incomplete resection. Metastatic disease is associated with a shortened survival, with lung, bones, and liver being common sites. Adjuvant radiotherapy has been used to prevent recurrences, but its efficacy still remains to be better studied. Finally, the efficacy of chemotherapy in unresectable and/or metastatic setting is not well established in the current literature. In a retrospective analysis of 36 HPC patients treated at our institution, 10 were treated with either neoadjuvant or adjuvant anthracycline therapy. 1/10 experienced major radiographic response (reduction in tumor size > 50%), but chemotherapy did not seem to prolong survival in that group. 3Spitz et al. Ann of Surg Oncol; 5(4):350-355 4Espat 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 Our institution’s decision to use temozolomide and bevacizumab in our HPC/SFT patients was based on a number of regimens that were being used at the time by our neuro-oncology colleagues with a great degree of success: It was known that the combination therapy of irinotecan and bevacizumab produced overall response rates as high as 60% in our glioblastoma patients. It was also observed that the chemotherapy agent that was used with bevacizumab did not appear to make much difference; carboplatin and temozolomide seemed to work as well as irinotecan. Our first HPC/SFT patient, incidentally, had a meningeal HPC which was empirically treated with TMZ/bev by one of our neuro-oncologists, Dr. Charles Conrad. The patient had been heavily pre-treated with multiple surgical resections, XRT, chemo- and biologic therapies and was a fairly fragile patient, so temozolomide was selected in the hopes of having minimal side effects. He achieved a nice clinical and radiological response, so having been encouraged by this anecdotal experience, we over time continued to treat additional patients with advanced HPC/SFT with this regimen. 5Vredenburgh et al. J Clin Oncol 2007;25:4722-2739 6Charles 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 After obtaining permission from institutional review board (IRB), we reviewed the medical records of all patients with the diagnosis of HPC/SFT who were treated with temozolomide and bevacizumab at the M.D. Anderson Cancer Center between May 2000 and June 2007. Patients whose diagnosis was confirmed by a sarcoma pathologist were included in the study Patients seen without follow-up at our center were excluded

Methods Radiologic response: Choi criteria7 Radiologic response to therapy was determined by applying the Choi criteria, which, unlike the commonly used RECIST, takes account of the changes that occur in tumor density as well as size. Unlike the RECIST, the Choi criteria defines PR as either a decrease of 10% or more in size OR a decrease of 15% of more in tumor density, measured in HU. Likewise, PD is defined as an increase of 10% or more in size without corresponding decrease in density. The Choi criteria has been shown to be a sensitive and specific method for assessing response to therapy in GIST, and its clinical utility in other soft tissue sarcomas is currently being validated in a prospective manner in the ongoing Perifosene trial. Statistical analysis for progression-free survial: Kaplan-Meier method 7Choi et al. J Clin Oncol 2007;25:1753-1759

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 We identified a total of 14 patients with HPC/SFT who began treatment with TMZ/BEV at MDACC between the time period of May 2005 and June 2007. There were 9 men and 5 women. The median patient age was 59 years with a range of 44 to 75 years. The main reasons for starting treatment were: Symptomatic disease: 7 Neoadjuvant treatment: Disease recurrence/ progression: 8, with 5 with new Development of metastatic disease.

Results: Patient Characteristics Tumor Prior Systemic Rx Metastatic Disease XRT Primary Tumor Location SFT Y N Lung/Pleura HPC Meninges Gluteal Soft Tissue Abdominal wall Pelvis Bladder This table shows that that the majority of patients have received prior treatment, be it surgery, with 10 patients, XRT with 7 patients, systemic Rx, with 5 patients, or a combination. 7 patients had metastatic disease at the time of initiation of treatment. The most common site of primary disease was the meninges. No patients had extremities as their primary disease. Prior surgery: 10 (median = 1.5, range 0-6) Prior XRT: 7 Prior chemotherapy: 5

Results: Prior Systemic Therapy History Tumor Metastatic 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 celecoxib* 14 SD* Disease Recurrence imatinib 2 paclitaxel* 6 Physician Decision gemcitabine/ docetaxel 3 SFT N 5 imatinib/ thalidomide 1 imatinib/ thalidomide/ etoposide Toxicities, Patient Intolerance imatinib/ thalidomide/ hydrea imatinib/ hydrea 2.5 doxorubicin/ dacarbazine Toxicities For the 5 patients who had received prior systemic therapy, their history of past regimens, duration of therapy, as well as their best responses on their past regimens (according to Choi criteria) are listed on this table. Patients received a number of different types of regimens. It’s important to note that although in many instances patients achieved stable disease and often improvement in their symptoms on their prior therapies, in no instances did they achieve PR. The most common reason for switching therapy was disease progression. *Received regimen after R0 resection as adjuvant therapy

Results: Treatment Regimen All patients treated with: D1 D7 D15 D21 D28 Temozolomide 150 mg/m2 Temozolomide 150 mg/m2 D8 D22 Bevacizumab 5mg/kg Bevacizumab 5mg/kg All patients were treated with: Dose-Dense Temozolomide 150mg/m2 orally D1-7, D15-21 Bevacizumab 5mg/kg IV D8, D22 Treatment repeated at 28-day cycle. In 3 patients, Temozolomide dosage was reduced to 75-125mg/m2, and/or duration was shortened to days 1-5 and 15-19, when neutropenia and/or thrombocytopenia developed. 1 patient received G-SCF growth factor support. Median no. of cycles of therapy administered was 7.5, with 1 patients still undergoing therapy at the time of analysis Median no. of cycles of therapy administered: 7.5 (2.5-20.5) 1 patient still undergoing therapy at the time of analysis

Results: Response Rate Tumor Best Response (Choi) Best Response (RECIST) No. of Cycles to Reach Best Response Total No. of Cycles Reason(s) for Stopping Therapy HPC PR ↓Size ↓HU SD 2 4 Toxicities SFT 13+ N/A HPC* 3 10 Disease Progression 20.5 Patient Preference 7 8 2.5 4.5 SFT* 8.5 - 6 -  Death PD 3.5 Our patient’s best response rates are summarized in this table, where we can see that 11 of 14 patients achieved PR after starting TMZ/bev therapy. PR was seen both as decrease in size, or in density. Best response assessment using conventional RECIST criteria, 1 patient had a RECIST PR. It’s interesting to note that response to therapy was seen very early in therapy: majority of patients received their best response after only 2 cycles, with longest being 4. Major reasons for stopping therapy consisted of: disease progression, toxicities, which will be discussed later, or decision by patient or physician to try a period of treatment break after achieving SD for a period of time. * History of prior systemic therapy; + patient with ongoing therapy Best Response rate: 11/14 (79%) (PR) (≥10% ↓ size, ≥15% ↓ HU) SD: 2/14 (14%); PD 1/14 (7%) (≥10% ↑ size without 15% ↓ HU)

Results: Patient Example 1 Pre-Treatment 33.8 mm 107.8 HU After 2 cycles 23.7 mm 101.3 HU 15.8 mm 75.3 HU After 8 cycles Here is one example of a patient, a 64 year old female with hemangiopericytoma of the R gluteal region whose primary site had undergone resection and adjuvant radiation, but developed unresectable liver metastasis 1.5 years later. After 2 cycles of starting therapy, her liver lesion decreased in size by 30%, thus achieving partial response. PR (↓ SIZE)

Results: Patient Example 2 13.6 mm 37.5 HU 18.0 mm 52 HU After 2 Cycles 14.4 mm 115 HU PR (↓ HU) Pre-Treatment This is an example of another patient, a 72 year old female with solitary fibrous tumor of the pleura who developed unresectable recurrent disease after 2 surgeries. Her disease progressed after 2 cycles with gemcitabine and docetaxel, at which time her therapy was switched to TMZ and BV. After 2 cycles of therapy, there was a greater than two-thirds reduction in her tumor radiodensity, thus achieving partial response. 16.4 mm 140.1 HU

Results: Progression Free Survival Median PFS: 8.6 months At the time of analysis, 10 out of 14 patients had disease progression. Median Progression-free survival period for the entire group was 8.87 months. Median follow-up period for the group was 20 months.

Historical HPC/SFT Cohort – Comparison of Response Rates Tumor Met. 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 Y Doxorubicin/ Ifosfamide PR ↓Size ↓HU SD 4 6 Disease Progression Doxorobicin/ - 2 Side effects SFT 5 HPC* -  Gemcitabine/ Taxotere PD All had metastatic disease. 4 of 5 had received prior therapy, combination of surgery, XRT of prior systemic therapy – 1 of 5 had prior systemic Rx. * History of prior systemic therapy with doxorubicin and cisplatin. 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)

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 Overall, major toxicities were low and treatment compliance was high. Most of the major toxicities were those related to TMZ rather than bevacizumab. We did not encounter any side effects that led us to holding bevacizumab therapy. 1 case of mortality occurred during treatment. The patient was a 48 yo female with HPC of the skull base who had recurrent disease despite 3 surgeries and radiation. She underwent 5 cycles of therapy, then presented with renal failure, DIC and hypotension and expired after 1 day after presentation. It was felt that her death was mostly due to her overall performance status and her disease, rather than being directly related to treatment.

No. of Cycles of Therapy Received IHC analysis of tumor specimens for angiogenesis & cell growth biomarkers 5 patients had tissue specimens readily available for IHC analysis 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 4 18.5+ +++ 10 7 7.7 -  PD 3.5 All had metastatic disease. 4 of 5 had received prior therapy, combination of surgery, XRT of prior systemic therapy – 1 of 5 had prior systemic Rx. No strong correlation between levels of IHC expression and clinical outcomes were found in this limited set

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.