Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer

The purpose of this study was to assess the toxicoses and antitumor activity of metronomic chlorambucil at a dosage of 4 mg m(-2) daily in dogs with naturally occurring cancer. Thirty-six dogs were enrolled in the study. The protocol was well tolerated with no grade 3 or 4 toxicoses noted. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumour, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration) for an overall remission rate of 11% (4 of 36). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. Chlorambucil given in a metronomic protocol showed antitumor activity in dogs with a variety of naturally occurring cancers.     

Retrospective comparison of three doses of metronomic chlorambucil for tolerability and efficacy in dogs with spontaneous cancer

The study hypothesis is that higher doses of metronomic (low‐dose) chlorambucil will improve outcome without significantly worsening adverse events (AE). Retrospectively, 88 dogs were screened to assess for tolerability and response to chlorambucil utilizing retrospective and prospective data sets, comparing metronomic oral daily doses 4, 6 and 8 mg m². There were 78 and 70 dogs in the tolerability and efficacy portions, respectively. The severity of gastrointestinal (GI) AE was significantly worse, and time to development of GI events was significantly shorter at 6 mg m² than at 4 mg m² (both P < 0.001). Chlorambucil was discontinued earlier in the dogs treated at the 6 mg m² doses than in the dogs treated at 4 mg m² (P = 0.015). Thrombocytopenia occurred significantly earlier at 8 mg m² than at 4 mg m² (P = 0.017). Higher doses of metronomic (low‐dose) chlorambucil did not provide improved responses and were associated with more AE.     

Comparison between symptomatic treatment and lomustine supplementation in 71 dogs with intracranial,space‐occupying lesions

Brain neoplasia is diagnosed in an increasing number of dogs. Consequently, there is a higher need for an effective treatment. Chemotherapy is considered in cases where surgery or radiation is not optional. The objective of this retrospective study was to evaluate the difference in median survival time (MST) of dogs with intracranial masses, treated symptomatically with corticosteroids and anti‐epileptic drugs, compared with the same symptomatic treatment supplemented with lomustine. The records of 71 dogs with intracranial masses were retrospectively evaluated. Fifteen dogs were treated symptomatically with corticosteroids and anti‐epileptics, and 56 dogs received additional therapy with lomustine. There was no statistically significant difference in MST between both groups, being 60 and 93 days, respectively. Age, duration of symptoms, intracranial localization of the mass and intra‐ or extra‐axial localization had no influence on survival time. However, female dogs survived significantly longer than male dogs.     

CCNU (lomustine) toxicity in dogs: a retrospective study (2002-07)

Objective To describe the incidence of haematological, renal, hepatic and gastrointestinal toxicities in tumour‐bearing dogs receiving 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU). Design The medical records of 206 dogs that were treated with CCNU at the Melbourne Veterinary Specialist Centre between February 2002 and December 2007 were retrospectively evaluated. Results Of the 206 dogs treated with CCNU, 185 met the inclusion criteria for at least one class of toxicity. CCNU was used most commonly in the treatment of lymphoma, mast cell tumour, brain tumour, histiocytic tumours and epitheliotropic lymphoma. Throughout treatment, 56.9% of dogs experienced neutropenia, 34.2% experienced anaemia and 14.2% experienced thrombocytopenia. Gastrointestinal toxicosis was detected in 37.8% of dogs, the most common sign of which was vomiting (24.3%). Potential renal toxicity and elevated alanine transaminase (ALT) concentration were reported in 12.2% and 48.8% of dogs, respectively. The incidence of hepatic failure was 1.2%. Conclusions CCNU‐associated toxicity in dogs is common, but is usually not life threatening.     

Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs

One hundred seventy-nine tumor-bearing dogs were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) between 1995 and 2001. CCNU was given as a single dose of 50-110 mg/m2 body surface area PO. Treatment interval varied, but the minimal interval between CCNU doses was 3 weeks. After treatment, 11 dogs (6.1%) developed hepatic toxicity. The median number of CCNU doses and the median total cumulative CCNU dose were significantly higher in dogs that developed hepatic toxicity (4 doses; 350 mg/m2) than in dogs without hepatic damage (3 doses; 230 mg/m2). Median duration to detection of hepatic toxicity from the last dose of CCNU was 11 weeks (range 2-49 weeks). Common biochemical abnormalities were abnormally high serum liver enzyme activities and hypoalbuminemia. Six dogs with CCNU-associated hepatic toxicity had ascites, and 3 dogs had concurrent pleural effusion. Serum concentrations of bile acids were abnormally high in 4 of 5 dogs tested. Percutaneous ultrasound-guided liver biopsies were performed in 10 dogs, and findings were nonspecific and chronic in nature. Seven dogs were euthanized because of progressive liver failure, and their median survival from diagnosis of liver disease was 9 weeks. Three dogs died of other causes and 1 dog of unknown cause. Although clinical signs resolved in 3 dogs, biochemical abnormalities and histopathologic lesions persisted 4 to 38 months from the time of diagnosis of liver disease. Our findings suggest that CCNU can cause delayed, cumulative dose-related, chronic hepatotoxicity that is irreversible and can be fatal.     

Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer

Health-related quality-of-life (HRQoL) has been studied extensively in human medicine. There is currently no standard HRQoL evaluation for veterinary oncology patients. The aim of this study was to assess the practicality, usefulness and robustness, from a pet owner and clinician perspective, of a questionnaire for the assessment of HRQoL in canine and feline cancer patients. A HRQoL assessment entitled 'Cancer Treatment Form' and two questionnaires entitled 'Owner Minitest' and 'Clinician Minitest' were designed. The first and second were completed by owners of patients presenting to a veterinary oncology referral service and the third by attending clinicians. The 'Cancer Treatment Form' was well received by owners and clinicians and provided a valuable assessment of HRQoL with 98% (82/84) of owners reporting an accurate reflection of their pet's quality-of-life. Following this, minor improvements to the form could be suggested prior to regular use in evaluation of clinical oncology patients.     

Survival analysis of dogs with advanced primary lung carcinoma treated by metronomic cyclophosphamide,piroxicam and thalidomide

Unresectable or metastatic (advanced) primary pulmonary carcinoma (PPC) represents a therapeutic challenge where surgery may be contraindicated and the therapeutic role of maximum‐tolerated dose (MTD) chemotherapy remains uncertain. This study was undertaken to explore the impact of metronomic chemotherapy (MC) in dogs with advanced PPC. Previously untreated dogs with advanced (T3 or N1 or M1) PPC, with complete staging work‐up and follow‐up data, receiving MC (comprising low‐dose cyclophosphamide, piroxicam and thalidomide), surgery, MTD chemotherapy or no oncologic treatment were eligible for inclusion. For all patients, time to progression (TTP) and survival time (ST) were evaluated. Quality‐of‐life (QoL) was only evaluated in patients receiving MC. To assess QoL, owners of dogs receiving MC were asked to complete a questionnaire before and during treatment. Ninety‐one dogs were included: 25 received MC, 36 were treated with surgery, 11 with MTD chemotherapy and 19 received no treatment. QoL was improved in dogs receiving MC. Median TTP was significantly longer in patients receiving MC (172 days) than patients undergoing surgery (87 days), receiving MTD chemotherapy (22 days), or no oncologic treatment (20 days). Median ST was similarly longer in patients receiving MC (139 days) than those undergoing surgery (92 days), MTD chemotherapy (61 days) and no oncologic treatment (60 days). In dogs with advanced PPC, MC achieved a measurable clinical benefit without significant risk or toxicity. This makes MC a potential alternative to other recognized management approaches.     

Evaluation of the oral antimitotic agent (ABT-751) in dogs with lymphoma

Background

ABT‐751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma.

Objective

Determine a maximum tolerated dose for ABT‐751, and assess long‐term tolerability and activity in canine lymphoma.

Animals

Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non‐Hodgkin's lymphoma.

Methods

Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long‐term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells.

Results

The maximum tolerated dose of ABT‐751 was 350 mg/m² PO q24h. Dose‐limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m² PO q48h. ABT‐751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs).

Conclusion

ABT‐751 was well tolerated at 350   mg/m² PO q24h for 7 days and then q48h thereafter. Activity of ABT‐751 suggested a rationale for additional studies of ABT‐751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.     

Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma

Background: Low‐dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angiogenesis and suppressing regulatory T cells (Treg) in mice and humans. The effects of metronomic chemotherapy on Treg and tumor angiogenesis in dogs has not been investigated previously. Objective: To determine whether metronomic cyclophosphamide (CYC) therapy decreases Treg or exhibits antiangiogenic activity or both in dogs with soft tissue sarcoma (STS). We hypothesized that Treg numbers would be increased in dogs with STS and that continuous dosing of CYC would decrease Treg in a dose‐dependent manner, as well as exhibit antiangiogenic activity. Animals: Eleven client‐owned dogs with grade I or II STS. Twenty‐one healthy dogs were used as controls. Methods: Prospective, open, clinical trial. Dogs with STS were enrolled in 2 dose cohorts and administered CYC at 12.5 or 15 mg/m² PO once daily for 28 days. Whole blood and tumor biopsy specimens were obtained on days 0, 14, and 28 to assess changes in T lymphocyte subsets by flow cytometry and tumor microvessel density (MVD), respectively. Results: Administration of CYC at 12.5 mg/m²/d significantly decreased the number of Treg from days 0 to 28, but there was no change in the percentage of Treg or tumor MVD. In dogs that received CYC at 15.0 mg/m²/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15 mg/m²/d should be used in further studies examining the antitumor properties of low‐dose CYC in dogs.     

Furosemide for prevention of cyclophosphamide‐associated sterile haemorrhagic cystitis in dogs receiving metronomic low‐dose oral cyclophosphamide

Sterile haemorrhagic cystitis (SHC) is a known risk of cyclophosphamide treatment. Diuresis using furosemide is effective in canines when maximally tolerated dosed cyclophosphamide is administered. This retrospective study aimed to determine whether orally administered furosemide decreased the incidence of SHC. Secondary aims were to identify predisposing factors for SHC. One‐hundred and fifteen dogs treated with metronomic cyclophosphamide were analysed retrospectively. Populations were not randomized. 25 dogs (21.7%) developed SHC. Furosemide administration significantly reduced the likelihood of SHC development (P = 0.010, where SHC was diagnosed in 30.3% of dogs administered cyclophosphamide without furosemide, and 10.2% of dogs administered cyclophosphamide with furosemide). Age, gender, breed, bodyweight, number of cyclophosphamide treatments, piroxicam use and previous or pre‐existing disease were not found to be associated with SHC development. This study demonstrates furosemide is effective in the prevention of SHC and its use may be considered when implementing metronomic cyclophosphamide therapy.     

Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study

Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m², SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m² (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.     

Use of adjuvant carboplatin for treatment of dogs with oral malignant melanoma following surgical excision

Melanoma is the most common oral malignancy in dogs. This retrospective study evaluated adjuvant carboplatin chemotherapy (with or without radiation therapy) in 17 dogs with malignant oral melanoma following surgical resection. The median dosage and number of doses of carboplatin administered to the 17 dogs was 300 mg m^?2 (range, 150–300 mg m^?2) and 4 (range, 2–11), respectively. The overall median progression‐free survival for all dogs was 259 days [95% confidence interval (CI₉₅), 119–399 days]. The first progression‐free survival event was local recurrence in seven dogs (41%) and metastases in seven dogs (41%). The median overall survival for all dogs was 440 days (CI₉₅, 247–633 days). The tumour was the cause of death in 10 dogs (59%). On the basis of this study, systemic therapy with carboplatin may be an appropriate adjunct to local treatment for canine malignant melanoma, although future prospective controlled studies are needed to compare treatment modalities for this aggressive neoplasia.     

Adjuvant anthracycline‐based vs metronomic chemotherapy vs no medical treatment for dogs with metastatic splenic hemangiosarcoma: A multi‐institutional retrospective study of the Italian Society of Veterinary Oncology

Treatment options for dogs with metastatic (stage III) splenic hemangiosarcoma are limited. A doxorubicin‐based chemotherapy regimen is commonly administered; however, there are no published data to support this practice. The aim of this study was to investigate the impact of maximum‐tolerated‐dose chemotherapy (MTD), metronomic chemotherapy (MC) and no adjuvant treatment on outcome in dogs with stage III splenic hemangiosarcoma undergoing splenectomy. Medical records of dogs with stage III splenic hemangiosarcoma that underwent splenectomy followed by MTD chemotherapy, MC or no adjuvant treatment were retrieved. Time to progression (TTP), survival time (ST) and toxicity were evaluated. One hundred three dogs were identified: 23 received adjuvant MTD, 38 MC and 42 were not medically treated. Overall median TTP and ST were 50 (95% confidence interval [CI], 39‐61) and 55 days (95% CI, 43‐66), respectively. Dogs treated with adjuvant MTD had a significantly longer TTP and ST compared with dogs receiving MC (median TTP, 134 vs 52 days, P = .025; median ST, 140 vs 58 days, P = .023, respectively). Dogs treated by splenectomy only had the shortest median TTP (28 days) and ST (40 days). However, treatment‐related adverse events (AEs) were significantly more frequent in the MTD group (P = .017). The outcome for dogs with metastatic splenic hemangiosarcoma is poor. While MTD showed greater efficacy compared to MC, toxicity was higher in this group. Treatment‐related AEs need to be carefully balanced against this modest survival prolongation when offering adjuvant MTD to dogs with advanced stage hemangiosarcoma.     

Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats

The objective of the study was to retrospectively evaluate the short‐term safety of intrathecal administration of cytosine arabinoside alone or in combination with methotrexate in dogs and cats. One hundred and twelve dogs and eight cats admitted between September 2008 and December 2013, diagnosed with suspected inflammatory (meningoencephalomyelitis of unknown aetiology) or neoplastic disease affecting brain or spinal cord and treated with an intrathecal administration of cytosine arabinoside alone or in combination with methotrexate were included in the study. Recorded information regarding possible adverse events during administration while recovering from anaesthesia and during hospitalization period were evaluated. The results showed that one patient developed generalized tonic‐clonic seizure activity after administration of cytosine arabinoside and methotrexate during recovery from anaesthesia, however responded to intravenous administration of diazepam. On the base of our results we can conclude that intrathecal administration of cytosine arabinoside alone or in combination with methotrexate is a safe procedure in dogs and cats.     

Canine hemangiosarcoma treated with standard chemotherapy and minocycline

Standard treatments for canine hemangiosarcoma include surgery and chemotherapy with doxorubicin, but in spite of treatment most dogs with this disease die within 6 months of diagnosis. Tumor growth and metastasis are angiogenesis dependent. Antiangiogenic drugs such as minocycline may provide therapeutic benefits in cancer patients. The purpose of this prospective study was to evaluate the efficacy of chemotherapy with doxorubicin and minocycline, an antiangiogenic agent, in dogs with hemangiosarcoma. Eighteen dogs with histologically confirmed hemangiosarcoma of any stage were treated with doxorubicin, cyclophosphamide, and minocycline. Complete staging was performed before and during the treatment period to assess remission status and response to therapy. No statistically significant difference was found in survival between the dogs treated with chemotherapy and minocycline, and historical controls consisting of dogs that received chemotherapy alone. Postmortem examination revealed widespread metastasis, suggesting that minocycline is ineffective as a single antiangiogenic agent in canine hemangiosarcoma.     

Phase I lead‐in and subsequent randomized trial assessing safety and modulation of regulatory T cell numbers following a maximally tolerated dose doxorubicin and metronomic dose cyclophosphamide combination chemotherapy protocol in tumour‐bearing dogs

Maximally tolerated dose (MTD) and metronomic dose chemotherapeutic approaches alter the immune system and the angiogenic process in different yet potentially complementary ways. A combination of MTD doxorubicin (MTD‐DOX) and metronomic cyclophosphamide (mCTX) protocol was evaluated for safety and effect on circulating regulatory T (Treg) cells. We found that mCTX can be safely administered with MTD‐DOX in tumour‐bearing dogs. Both combination DOX/mCTX and single‐agent DOX resulted in significant depletions of circulating lymphocytes throughout the chemotherapy cycle without apparent selectivity for Tregs. The indiscriminant lymphocyte depletions were similar between dogs randomized to receive DOX and dogs randomized to receive DOX/mCTX, suggesting this effect is because of DOX alone. These findings may have implications as to the therapeutic benefit (or lack thereof) of concurrent combination MTD and metronomic protocols. Future investigations are required to determine the effects and indeed the efficacy of concurrent versus sequential applications of MTD and metronomic chemotherapy protocols.