Pharmacokinetic and phase I evaluation of carboplatin in dogs.

Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD50) or a 5% incidence of severe toxicity (SEV5). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD50 and SEV5 for the first treatment course were 340 and 278 mg/M2, respectively. MOD50 and SEV5 values for the first plus second treatment courses were 327 and 231 mg/M2, respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541/microL and 62,600/microL, respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T1/2), area-under-the-curve and total body clearance (CLb) were not dose dependent. Volume of distribution (VDss) significantly increased with dose only between 100 and 150 mg/M2, not between 150 and 300 mg/M2. Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity.

Quantitative estimation of the thermal dose-modifying factor for cis-diamminedichloroplatinum (CDDP) in tumour-bearing dogs.

A statistical method for estimating clinical toxicity was used to determine a theoretical isoeffect dose-modifying factor for dogs with disseminated or refractory neoplasia treated with cis-diammine dichloroplatinum (II) plus whole-body hyperthermia or CDDP alone. CDDP was administered every 3 weeks with vigorous saline hydration to 54 dogs (CDDP alone n = 21, CDDP/WBH n = 33) that were eligible for entry into this non-randomized study. CDDP was administered during the plateau phase of WBH in dogs receiving combined therapy. Acute toxicity included myelosuppression (CDDP n = 7; CDDP/WBH n = 5), nephrotoxicity (CDDP n = 1, CDDP/WBH n = 1) and respiratory distress (CDDP/WBH n = 2). Eight dogs experienced chronic renal dysfunction as a result of CDDP (n = 2) or CDDP/WBH (n = 6). A theoretical thermal dose-modifying factor was determined for both acute and cumulative toxicity by comparing the maximum tolerated dose of each treatment group. The maximum tolerated dose (MTD) of CDDP +/- WBH was defined as that dose producing a 50% incidence of moderate acute toxicity or acute plus mild chronic toxicity as estimated from logistic regression analysis of the toxicity data. The MTD (+/- .standard error) of CDDP/WBH for acute toxicity only was 54.6 (4.3) mg/M2 and for CDDP alone the MTD was 73.6 (40) mg/M2. Thus, the isoeffect dose-modifying factor for acute toxicity was 1.35 (0.12). The MTD (SE) of CDDP/WBH for cumulative toxicity (acute plus chronic toxicity) was 46.4 (2.7) mg/M2 and for CDDP alone waas 70.0 (2.9) mg/M2. The isoeffect dose-modifying factor for total cumulative toxicity was 1.5 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between quantitative tumor scintigraphy and time to metastasis in dogs with osteosarcoma.

Parameters that predict tumor aggressiveness or response to therapy are potentially useful in selecting the most appropriate treatment. In theory, the biologic aggressiveness of an untreated bone tumor may be reflected in bone scan parameters. The purpose of this study was to assess the usefulness of bone scintigraphy as a predictive indicator of subsequent metastasis in 25 dogs with primary osteosarcoma. Dogs received radiotherapy and/or intra-arterial cisplatin prior to limb-sparing surgery. Quantitative bone scintigraphy of the tumor was performed prior to treatment (25 dogs) and following treatment but prior to limb-sparing surgery (22 dogs). All dogs developed metastasis at a median time of 202 days (range, 41-444 days) after initiation of treatment. A statistically significant relationship was identified between time to metastasis and: (1) the radiographic tumor area, (2) the pretreatment ratio of mean counts per pixel in tumor-to-adjacent nontumor bone (T/NTT), and (3) the pre:post-treatment T/NTT. Larger tumor area and high pretreatment tumor activity were associated with earlier metastasis. Tumors characterized by greater decreases in scintigraphic uptake after treatment were associated with earlier metastasis. These data suggest that osteosarcomas with high pretreatment mean counts per pixel signify aggressive tumors subject to early metastasis.

Phase I evaluation of doxorubicin and whole-body hyperthermia in dogs with lymphoma.

Fifteen previously untreated dogs with histologically confirmed, high-grade multicentric lymphoma were entered into a phase I study to evaluate combined doxorubicin and whole-body hyperthermia (DOX/WBH). Groups of three, four, and eight dogs were treated with whole-body hyperthermia and concurrent doxorubicin at 12 mg/m2, 24 mg/m2 and 30 mg/m2, respectively, after one doxorubicin induction dose at 30 mg/m2. Plateau temperature (42 +/- 0.1 degree C) was maintained for 90 minutes using a radiant heating device. A total of five DOX/WBH treatments per dog were planned, and these were given every 21 days. Treatment-related toxicity was not seen in the 12-mg/m2 doxorubicin dose group. Tumor progression prohibited administration of more than three DOX/WBH treatments to any dog in the 12-mg/m2 group. Premature ventricular contractions developed after the fifth treatment in one of the four dogs treated with 24 mg/m2 of doxorubicin. Two dogs (25%) in the 30-mg/m2 dose group had treatment-related toxicity. One dog experienced acute serious myelosuppression 1 week after the third treatment. This dog received all planned DOX/WBH treatments. Asymptomatic cardiac toxicosis consisting of decreased ejection fraction and fractional shortening developed in the second dog. This dog received only two DOX/WBH treatments. The three dogs treated at 12 mg/m2 had partial responses of short duration (60-83 days). Four dogs treated at 24 mg/m2 had complete responses for 150, 164, 186, and 200 days. Eight dogs treated at 30 mg/m2 had complete responses with a mean and median duration of 241 and 190 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase III evaluation of doxorubicin and whole-body hyperthermia in dogs with lymphoma.

Sixty-one dogs with histologically confirmed, untreated, high-grade lymphoma were evaluated and treated with doxorubicin (DOX, 30 mg/m2) alone. Forty-seven dogs (77%) achieved a complete response. Forty-six of the 47 dogs were randomized to receive five additional treatments with doxorubicin +/- whole-body hyperthermia (WBH). Median disease-free survival for the group treated with DOX alone (n = 22) was 189 days and for the DOX plus WBH (n = 24) was 239 days (p = 0.17). After the analysis was adjusted for stratification variables (i.e. institution, weight, stage), the effect of heat on disease-free survival remained statistically insignificant (p = 0.10), but suggested a tendency towards increased disease-free survival in hyperthermic dogs. Intact male dogs had significantly shorter disease-free survival than neutered males and neutered females (178 days vs 266 days, respectively; p = 0.013). No intact females were treated. Body weight, when evaluated as a continuous variable, was found to be a negative prognostic factor (p = 0.036). Tumour volume, stage and institution were not significant. Clinical incidence of cardiac dysfunction was not increased in dogs receiving DOX and WBH; however, post-mortem histological analysis of cardiac tissue suggested that the combined therapy of DOX and WBH was associated with greater myocyte degeneration (p = 0.012) and a tendency for increased cardiac fibrosis (p = 0.08). We concluded that continued refinement of DOX-WBH protocols is warranted, and may ultimately result in significant therapeutic improvement.

Treatment of canine appendicular osteosarcoma using cobalt 60 radiation and intraarterial cisplatin.

Twelve dogs with appendicular osteosarcoma were treated with 24-40 Gy of cobalt 60 radiation and two doses of intraarterial cisplatin. Improvement in limb function occurred in four dogs, and three dogs, which had only mild initial lameness, had no worsening of their lameness post-treatment. In nine dogs in which local control was evaluable, eight had local failure, with the median (95% CI) duration of local control being 5.9 (4.6, 6.7) months. Two dogs had metastatic disease before therapy, and an additional nine dogs had metastatic disease at a median time of 6.4 months. Pathologic fracture was present in four dogs; two fractures occurred before treatment and two were documented at the time of tumor recurrence. Median (95% CI) survival time for all 12 dogs was 4.9 (3.4, 6.8) months. Excluding the two dogs with preexisting metastatic disease, median survival time was 6.7 months. Three dogs survived longer than 1 year. This mode of therapy was well tolerated and may be considered an alternative to amputation or limb-sparing surgical procedures in selected dogs with appendicular osteosarcoma.

Analysis of survival in a retrospective study of 86 dogs with brain tumors.

A retrospective study of 86 dogs with brain tumors was undertaken. Sixty-nine dogs had histologic confirmation of tumor type, whereas the remaining 17 dogs had CT evidence of a brain tumor. All dogs had neurologic abnormalities. Seven dogs received no treatment, 38 dogs received only symptomatic treatment, and 41 dogs received some form of definitive treatment, in addition to medical management. Types of definitive treatment included surgery, cobalt-60 radiation, whole-body hyperthermia, 125I implants, and chemotherapy, alone or in combination. The factor that was most associated with survival duration was mode of therapy. Those dogs who were treated with cobalt-60 radiation, with or without other combinations of therapy, lived significantly longer than dogs who received surgery (+/- 125I implants), or dogs who received symptomatic treatment (P = 0.01 and P less than 0.001, respectively). After statistic adjustment for treatment, multiplicity of brain involvement (solitary vs. multiple) provided prognostic information with respect to survival (P = 0.001), with dogs who had a solitary site of involvement having a better prognosis. After further adjustment, initial neurologic dysfunction (mild/moderate vs. severe) showed significance as prognostic variable (P = 0.005). Both the mild and moderate groups had a more favorable prognosis compared with dogs who had severe initial neurologic impairment. The median survival time for the 86 dogs was 1.0 month (range: 1 day-42.4 mo). Median survival times of dogs receiving: 1) no therapy or only symptomatic therapy, 2) surgery (+/- 125I), or 3) cobalt-60 radiation (+/- hyperthermia, +/- surgery) were 0.2, 0.9, and 4.9 months, respectively.

Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma.

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.

Radiotherapy prior to cortical allograft limb sparing in dogs with osteosarcoma: a dose response assay.

Twenty-one dogs with spontaneously occurring appendicular osteosarcoma were given preoperative radiation therapy prior to a limb sparing procedure using a cortical allograft. Radiation doses were randomly assigned, ranged from 36-52 Gy in 4 Gy intervals, and were given in 10 equally-sized fractions on a M, W, F schedule. Seventeen of the 21 dogs underwent the limb sparing procedure approximately 3 weeks after completion of radiation therapy. Local tumor recurrence was documented in 4 of 17 dogs at mean and median times of 5.5 and 5.8 months, respectively, after initiation of radiation therapy. Three of 4 recurrences were in anatomic regions with sparse adjacent soft tissue which precluded wide excision. Complications were significant. Fixation device failure occurred in 9 of 17 dogs and was associated with host bone necrosis, muscle thinning and fibrosis of vessels and nerves in irradiated normal tissue. Incidence of host bone necrosis was directly related to radiation dose (Kendall's statistic, p = 0.005). Metastasis occurred in all 21 dogs. Mean and median times to metastasis in these dogs were 5.1 and 4.0 months, respectively, after initiation of radiation therapy. Local tumor control rates and survival times were higher in dogs developing allograft infection suggesting that infection acted as an immunostimulant. All local failures occurred in dogs that did not develop allograft infection and median survival times for uninfected versus infected dogs were 5 and 11 months, respectively (logrank test, p = 0.029). Increased tumor radiopacity following radiation therapy was significantly related to survival. Median survival in dogs whose tumors were characterized by decreased, unchanged or increased opacity after radiation therapy were 3.5 and 14 months, respectively (logrank test, p = 0.014). Based on the results of our study, radiation therapy can not be recommended as part of limb sparing treatments for patients with osteosarcoma at doses and dose per fraction values similar to those used herein.

Unexpected toxicity associated with use of body surface area for dosing melphalan in the dog.

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m2 of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, less than 1500/mm3; and/or thrombocytopenia, less than 80,000/mm3), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively. It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

Cholelithiasis in a cat.

A 4-year-old cat was examined because of anorexia and lethargy. The cat became icteric within 3 days of admission. Values for aspartate transaminase, alanine transaminase, total bilirubin, alkaline phosphatase, and cholesterol were higher than normal. Radiography revealed hepatomegaly, with loss of detail in the cranioventral portion of the abdomen. Further diagnostic procedures were not permitted, and the cat was euthanatized. At necropsy, cholecystitis, cholangitis, and numerous choleliths were found. Cholelithiasis is a rare cause of obstructive jaundice in the cat.