Phase II, Open-Label Trial of Single-Agent CCNU in Dogs with Previously Untreated Histiocytic Sarcoma

Abstract

Background: Histiocytic sarcoma (HS) is an aggressive neoplasm in dogs, and in most instances, the disease is localized, but not amenable to surgical removal, or is disseminated. Affected patients usually die within 6 months. There have been no prospective studies to determine efficacy of single-agent chemotherapy in dogs with HS.Hypothesis: Single-agent CCNU [1-(2-chloroethyl)3-cyclohexyl-1-nitrosourea; lomustine] has antitumor activity against HS in dogs.Animals: Twenty-one dogs with histologically confirmed, nonresectable localized or disseminated HS. Methods:Prospective, open-label phase II clinical trial in which dogs with previously untreated HS were uniformly treated with CCNU as a single oral dosage of 90 mg/m 2 every 4 weeks. The primary outcome measure was reduction in tumor size. Results: Fourteen dogs with disseminated HS and 7 with localized HS were enrolled between 1999 and 2008. Overall response rate was 29% (95% confidence interval [CI], 14-50%) for a median of 96 days (95% CI, 55-137 days). Three dogs (1 disseminated, 2 localized) had complete responses lasting for 54-269 days and 3 dogs (2 disseminated, 1 localized) had partial responses lasting for 78-112 days.Conclusions and Clinical Importance: CCNU, when used as a single agent, has activity against HS in dogs. Evaluation of CCNU postoperatively for dogs with resectable localized HS and as part of combination therapy for tumors that are nonresectable or disseminated should be considered.

Mediastinal histiocytic sarcoma with abdominal metastasis in a Somali cat

“…Surgical treatment alone has poor reported success in canine HS with survival times less than six months postoperatively (Rassnick and others 2010). With the poor prognosis along with the impossibility of achieving complete resection, surgery alone was not considered to be the most appropriate therapy in this case.…”

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…For example, the patient with PHS was euthanized over 8 months after EGT and a single application of CCNU due to progression of clinical signs, namely dispnoa and exercise intolerance. According to the literature, median survival time for dogs with PHS, treated with full CCNU chemotherapy (four consecutive applications every 3 weeks), is 96-106 days (Fulmer & Maudlin, 2007;Rassnick et al, 2010;Skropuski et al, 2007). In this patient, CCNU therapy was discontinued after one application due to pronounced hepatotoxicity, therefore probably exerting only negligible therapeutic effect.…”

Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models

“…Dogs with HS (hereafter referred to as HS dogs) exhibit generally poor treatment outcomes because of the tumor's aggressive biological behavior, including its high cell proliferation, multidrug resistance, and metastatic potential (Yamazaki et al, 2013(Yamazaki et al, , 2014. Lomustine (CCNU) or doxorubicin have been commonly used as antitumor agents for HS dogs (Rassnick et al, 2010); however, the therapeutic benefit on the disseminated and hemophagocytic HS is insufficient because of resistance to these drugs (Klahn et al, 2011;Rassnick et al, 2010). It is suggested that overexpression of the inhibitor of apoptosis protein (IAP) and P-glycoprotein (P-gp) is able to induce multidrug resistance in breast cancer cells and its chemoresistant cells (Liu et al, 2007.…”

“…Canine histiocytic sarcoma (HS) is malignant tumor that originates from dendritic cells or macrophages, and can be classified into three categories, including localized, disseminated and hemophagocytic HS (Rassnick et al, 2010). Localized HS commonly occurs in bones, joints, skin, and lungs.…”