Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas

Abstract

Purpose: Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response.

Methods and materials: Patients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans.

Results: The 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence.

Conclusions: The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response.

Conflict of interest statement

CONFLICT OF INTEREST NOTIFICATION

Rakesh K. Jain

Advisory Role: SynDevRx, Millennium Pharmaceuticals, MorphoSys AG, Regeneron Pharmaceuticals, Genzyme, Dyax, AstraZeneca

Stock Ownership: SynDevRx

Honoraria: Genzyme, Alnylam

Research Funding: AstraZeneca, Dyax

David G. Kirsch

Advisory Role: Lumicell Diagnostics

Stock Ownership: Lumicell Diagnostics

All other authors reported no conflict of interest.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Schema for clinical trial and perfusion CT scan parameters. Patients prior to surgical resection received an initial dose of BV followed two weeks later by a 6-week course of BV combined with RT. Surgical resection (Surgery) of the tumor was then performed 6–7 weeks after completion of neoadjuvant treatment. Intra-operative electron RT (IOERT) or post-operative RT (post-op RT) was delivered when indicated. Blood sample, tumor biopsy, and perfusion CT scans were obtained where indicated.

Figure 2

Perfusion CT scans. (A) Perfusion CT scans from patient #2. Axial CT scan images and post-processing images of blood volume (BlV) and permeability surface area (PS) of an ankle synovial sarcoma before and after one dose of BV. (B) Perfusion CT scan median values of blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface area (PS) are shown normalized to pre-treatment values. Bars represent standard deviation, *p

Figure 3

Proliferation, apoptosis, and microvessel density. (A) Median number of proliferating cells as measured by immunohistochemistry for proliferation cell nuclear antigen (PCNA) before treatment, after BV and after BV plus RT. (B) Median number of apoptotic cells as measured by TUNEL staining. (C) Median microvessel density following staining for CD31. (D) Representative images of tumor sections for PCNA immunohistochemistry (IHC), TUNEL immunofluorescence (IF), or CD31 IHC. Bars represent standard deviation, *p

Figure 4

Local and distant recurrence-free survival. (A) LR-free survival. Distant recurrence-free survival for all patients (B) or stratified by tumor location (C).

Figure 5

Gene expression microarrays. (A) Unsupervised hierarchical clustering of pre-treatment tumor samples. Histologic subtype and pathologic necrosis following treatment is given for each sample. (B) Supervised hierarchical clustering based on 24 genes which were found to distinguish good responders (>80% necrosis) from poor responders (