Abstract: Peripheral T cell lymphoma (PTCL) has a poor prognosis. Overexpression of vascular endothelial growth factor (VEGF) might contribute to the poor prognosis of PTCL and could be the target of novel therapy. The efficacy and safety of recombinant human endostatin (Endostar) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (ECHOP) have been explored in 15 PTCL patients. The objective response rate was 80%, with 53.3% patients having achieved complete response (CR) rate. The CR rate was 100% (3/3) in angioimmunoblastic T cell lymphoma (AITL) patients compared to only 36.4% (4/11) in PTCL not otherwise specified (PTCL-NOS) patients. With a median follow-up of 69 months, the 5-year progression-free survival and overall survival (OS) were 53% and 60%, respectively. The 5-year OS was 100% in AITL but was only 45% in PTCL-NOS. Seven out of 11 patients showed overexpression of VEGFR2 in their tumor vessels and had a better efficacy than those with low expression of VEGFR2. Grade 3 or 4 neutropenia is the most common toxicity observed. ECHOP was safe and might display potential benefit in AITL patients.


Keywords: peripheral T cell lymphoma, recombinant human endostatin, VEGFR2, safety, efficacy, prognosis 


INTRODUCTION

Peripheral T cell lymphomas (PTCL) are highly heterogeneous diseases with several distinct and provisional entities. Of these, PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) that is ALK positive or ALK negative are the most common aggressive PTCL subtypes. PTCL accounts for 10%–15% of non-Hodgkin’s lymphoma (NHL) and the prevalence varies geographically. The incidence of PTCL is higher in East Asia than in Western countries.1,2

The optimal treatment for patients with aggressive PTCL remains uncertain. CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen is still the first-line treatment choice. The prognosis of PTCL is poor and the 5-year overall survival is approximately 38.5%.3 Incorporating novel targeted agents into the therapeutic regimens are encouraged to improve the outcome of patients with PTCL.

Angiogenesis plays an important role in tumor development and progression. The vascular endothelial growth factor (VEGF) is one of the most potent inducers of angiogenesis by stimulating endothelial cell proliferation.4 VEGF and its receptors are frequently expressed in NHL and strongly expressed in PTCLs, especially in AITL.5,6 Higher levels of VEGF expression also have been reported to be associated with resistance to chemotherapy and poor prognosis.7,8 Integrating anti-angiogenesis therapy with CHOP regimen may improve the survival of PTCL patients.

Endostatin, a fragment of collagen XVIII, is an endogenous inhibitor of angiogenesis. It suppresses angiogenesis through multiple pathways: by suppressing cell cycle control and anti-apoptosis genes expression,9 by blocking pro-angiogenic gene expression controlled by c-Jun N terminal kinase,10 by inhibiting the signaling pathways of Ras and Raf kinases and decreasing ERK-1 and p38 activity,11 and by blocking the VEGF downstream targets by direct interaction with vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial cells.12,13 It was also identified that endostatin could inhibit tumor endothelial cell proliferation and tumor growth.14 A phase III study has shown that recombinant human endostatin (Endostar) in combination with NP (vinorelbine plus cisplatin) regimen significantly improved the response rate and the median time to tumor progression compared with NP alone in advanced non-small-cell lung cancer patients.15 Recombinant human endostatin has been approved by the China Food and Drug Administration for advanced lung cancer. Studies have also revealed the synergistic effects of recombinant human endostatin when combined with chemotherapy for advanced breast cancer, gastric cancer, colorectal cancer and metastatic melanoma.16–20 However, clinical evaluation of recombinant human endostatin for PTCL has not been reported.

The purpose of this study was to determine the efficacy and safety of recombinant human endostatin in combination with CHOP regimen (ECHOP) for PTCL patients (ClinicalTrials.gov; Identifier: NCT00974324). The study and the study protocol were approved by the institutional review board of Fudan University Shanghai Cancer Center.