Phase II study of oral docetaxel and cyclosporine in canine epithelial cancer.

The goal of the current study was to determine the efficacy of oral docetaxel in combination with cyclosporine in the treatment of canine epithelial cancer. Requirements for eligibility were histological confirmation of epithelial neoplasia, measurable disease, no chemotherapy treatment within 2 weeks, and a life expectancy of ≥ 3 months. Fifty-one dogs were enrolled. All dogs received 1.625 mg kg(-1) of docetaxel with 5 mg kg(-1) of cyclosporine (DT/CSA) by gavage. Ten dogs had progressive disease at 2 weeks, one dog died, and one dog was withdrawn from the study. Thirty-nine dogs were given a second dose of DT/CSA, three each receiving a third or fourth dose. Eight dogs had a dose reduction (1.5 mg kg(-1)) and six dogs had treatment delays primarily for gastrointestinal toxicity. The overall response rate was 16.7% (8/48 had a partial response there were no complete responses). The highest response rate was seen in dogs with oral squamous cell carcinoma (50%; 6/12).

Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours.

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.

Comparison of two questionnaires to assess gastrointestinal toxicity in dogs and cats treated with chemotherapy*.

Questionnaires completed by pet owners are widely used instruments to monitor adverse gastrointestinal (GI) effects in the owners' animals undergoing chemotherapy and for reporting toxicoses in clinical trials; however, no questionnaires have been formally evaluated. This study compares two questionnaire-based evaluations of adverse GI events: a basic, open-ended questionnaire and a detailed questionnaire modelled after the grading in the Veterinary Co-operative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE). Owners completed both questionnaires after their dog or cat received moderately emetogenic chemotherapy. Results were used to derive toxicity grades for anorexia, vomiting and diarrhoea. We evaluated 123 pairs of questionnaires. Disagreement in grade of anorexia, vomiting and diarrhoea was found in 24, 7 and 13% of paired questionnaires, respectively (κ = 0.63, 0.83 and 0.71, respectively). Although 'good' to 'very good' agreement was found, the potential for only 'fair' agreement between questionnaire methods is of concern and suggests a need to adopt a standardized form.

Phase II, open-label trial of single-agent CCNU in dogs with previously untreated histiocytic sarcoma.

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/m2 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], 14­50%) for a median of 96 days (95% CI, 55­137 days). Three dogs (1 disseminated, 2 localized) had complete responses lasting for 54­269 days and 3 dogs (2 disseminated, 1 localized) had partial responses lasting for 78­112 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.

Comparison between L-CHOP and an L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) for lymphoma in dogs.

An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.

A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high-dose vinblastine and prednisone (CVP) for treatment of dogs with high-grade, metastatic or nonresectable mast cell tumours.

Safety and efficacy of a protocol of alternating 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; 70 mg m(-2)) and vinblastine (3.5 mg m(-2)), and prednisone (1-2 mg kg(-1); CVP) in dogs with mast cell tumours (MCT) were evaluated. A total of 17 dogs had nonresectable MCTs and 35 received CVP as adjunctive treatment to locoregional control of metastatic MCTs or grade III MCTs. Neutropenia with fever occurred in 8% of dogs after treatment with vinblastine and in 2% after treatment with CCNU. Persistent elevation of serum alanine transaminase, suggestive of hepatotoxicity, occurred in 9% of the dogs. Response rate in dogs with nonresectable MCTs was 65%; five achieved a complete response (median, 141 days) and six achieved a partial response (median, 66 days). Overall median progression-free survival (PFS) time in dogs treated in the adjuvant setting was 489 days. Dogs with grade III MCTs had shorter PFS compared with dogs with metastatic grade II MCTs (190 days versus 954 days; P < 0.001). Phase III studies are needed to provide reliable information about the comparative efficacy of this protocol.

Evaluation of dexamethasone as a chemoprotectant for CCNU-induced bone marrow suppression in dogs.

In mice and people, administering corticosteroids before chemotherapy can reduce the severity of myelosuppression without reducing antitumour effects. This study investigated whether pretreatment with dexamethasone would reduce the incidence of grade 4 neutropenia in dogs receiving CCNU. Twenty-five dogs received dexamethasone [0.1 mg kg(-1) per os (PO) every 12 h] for 5 days and on the sixth day received CCNU (90 mg m(-2) PO). Historical dogs (n = 67) received CCNU alone (90 mg m(-2) PO). Forty-five percent of historical dogs had grade 4 neutropenia, while 64% of dogs pretreated with dexamethasone had grade 4 neutropenia (P = 0.16). Dexamethasone plasma levels were quantified by enzyme-linked immunosorbent assay in three healthy dogs. Peak plasma concentrations after a single oral 0.1-mg kg(-1) dose were <80 ng mL(-1), the minimum level associated with chemoprotective effects of dexamethasone in people. Pretreatment with dexamethasone did not reduce the incidence of grade 4 neutropenia in dogs receiving CCNU.

Efficacy of vinblastine for treatment of canine mast cell tumors.

BACKGROUND: The optimal dosage and clinical efficacy of vinblastine (VBL) for treatment of mast cell tumors (MCTs) in dogs has not been established. HYPOTHESIS: Single-agent VBL has antitumor activity against MCTs in dogs. ANIMALS: Fifty-one dogs with nonresectable grade II or III cutaneous MCTs. METHODS: Prospective, open clinical trial. Dogs were systematically allocated (by hospital record number) to receive IV treatment with VBL at a dosage of 2.0 mg/m2 (weekly for 4 treatments then biweekly for 4 treatments; VBL 2.0) or treatment with VBL at a dosage of 3.5 mg/m2 (biweekly for 5 treatments; VBL 3.5). The primary outcome measure was reduction in tumor size. RESULTS: Twenty-five dogs were allocated to the VBL 2.0 group and 26 were allocated to the VBL 3.5 group. In the VBL 2.0 group, 3 (12%) had a partial response (PR) for a median of 77 days (range, 48-229 days). Overall response rate in the VBL 3.5 group was 27%. One dog (4%) had a complete response for 63 days and 6 dogs (23%) had a PR for a median of 28 days (range, 28-78 days). Toxicoses were uncommon in the VBL 2.0 group. Twelve (46%) dogs in the VBL 3.5 group had < 500 neutrophils/microL 7 days after treatment; 2 dogs with neutropenia developed concurrent fevers. CONCLUSIONS AND CLINICAL IMPORTANCE: VBL, when used as a single-agent, has activity against MCTs in dogs although the response rate is lower than those reported for VBL-containing combination protocols. Further, findings suggest VBL at a dosage of 3.5 mg/m2 should be considered for use in future phase II/III trials.

Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs.

BACKGROUND: Pleotropic-glycoprotein (P-gp)-mediated resistance is the usual cause of relapse in dogs with lymphoma. 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) are alkylating agents that are not affected by P-gp and lack cross-resistance to each other. A combination protocol offers the advantage of improved summation dose and synergistic activity. HYPOTHESIS: A combination of CCNU and DTIC that is well tolerated can be used to treat dogs with lymphoma that developed resistance or failed to respond to previously administered chemotherapy. ANIMALS: Fifty-seven dogs with lymphoma that were resistant to treatment with standard chemotherapy (L-CHOP; L-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone). METHODS: Prospective phase I and II trials were performed. CCNU was given PO immediately before a 5-h IV infusion of DTIC. Concurrent antiemetics and prophylactic antibiotics were used. Treatments were administered every 4 weeks. RESULTS: Based on the results of 8 dogs in the phase I study, CCNU at 40 mg/m(2) PO combined with DTIC at 600 mg/m(2) IV was used to treat 57 dogs with resistant lymphoma. Thirteen (23%) dogs had a complete response (CR) for a median of 83 days and 7 (12%) had a partial response for a median of 25 days. The median L-CHOP CR duration of the dogs that did not respond to CCNU-DTIC was significantly longer than that of the dogs that did achieve remission with CCNU-DTIC (225 days versus 92 days, P= .02). The principal toxic event was neutropenia; the median neutrophil count 7 days after treatment was 1,275 cells/microL. Increases in alanine transaminase activity, possibly associated with hepatotoxicity, were detected in 7 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A combination of CCNU and DTIC can be an effective option to rescue dogs with resistant lymphoma.

The relationship of the intrauterine device, actinomycosis infection, and bowel abscesses.

PIP: A case study of the injurious effect of an IUD as a contributing factor to the development of an actinomycotic infection in the female genitalia and associated abdominal viscera is reviewed. A 38-year-old white woman presented with a 2-month history of pelvic cramps, menorrhagia, and "weakness." She also complained of occasional night sweats, a 6-pound weight loss, vaginal discharge, and a low-grade fever for 6 weeks prior to admission. The patient had no significant medical history except for a calcified pelvic mass (fibroid uterus); she had had a Dalkon Shield IUD in place for several years. The patient was admitted to the hospital gynecological service for removal of the IUD, dilatation and curettage, and probable hysterectomy. Cultures were taken of the IUD and the curettings. The mass involving the rectosigmoid as well as the enlarged fibroid uterus were confirmed on pelvic examinations. The histologic diagnosis of modern squamous metaplasia was made on microscopic examination. Fungal colonies in the detritus were noted on the IUD and curettings. The pelvic mass that was palpable on examination and associated with the fibroid uterus was found to be an abscess in juxtaposition to the sigmoid colon. The operative procedure included lysis of multiple adhesions, a subtotal hysterectomy and bilateral salpingo-oophorectomy, omentectomy with a transverse colon resection leaving a proximal colostomy and a distal mucous fistula. Microscopic examination of the abscesses was diagnostic for actinomycosis. Intravenous penicillin and clindamycin were used for treatment of the actinomycosis and bacteroids that were cultured from the abscesses. The IUD, colonic abscess, fallopian tubes, uterus, transverse colon and ovaries had microscopic evidence of actinomycotic infection. Review of the world literature reveals that the papers of Barth and Tietze are the 1st to indict the IUD as an etiologic factor for actinomycosis of the female genital organs.^ieng