Dennis W. Macy

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.

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.

Current understanding of vaccination site-associated sarcomas in the cat.

E pidemiologic evidence has now been published in the United States showing a strong association between the administration of inactivated feline vaccines [feline leukaemia virus (FeLV) and rabies] and subsequent soft tissue sarcoma development at sites where these vaccines have been administered (Dubielzig et al 1993, Hendrick & Goldschmidt 1991, Hendrick et al 1992, 1994, Kass et al 1993). The prevalence of soft tissue sarcoma development at sites of vaccination has been reported as 3.6 cases/l0 000 to 1 case/l0 000 FeLV or rabies vaccines administered (Kass et al 1993, Hendrick et al 1994, Coyne et al 1997). Some believe that the prevalence may be as high as 1 /lOOO FeLV or rabies vaccines administered (Macy & Hendrick 1996). If these prevalence rates are to be applied to the 1991 United States cat population, the following projections of the number of vaccineassociated sarcomas that occurred that year can be made. In 1991, the United States’ cat population was estimated at 57 million cats (Macy & Hendrick 1996). Approximately 62% of cats see veterinarians during any given year, and 64% of the visits to veterinarians include vaccination. These data indicate that 22 million cats were vaccinated in 1991 (Macy & Hendrick 1996). Applying the vaccine-induced tumour prevalence rate of one tumour per 10 000 vaccines administered, approximately 2200 cases of vaccine-associated sarcomas occurred in 1991. Using the higher estimated vaccine-associated sarcoma prevalence of l/1000 vaccinations, a total of 22 000 vaccine-associated sarcomas occurred in 1991. Because of the relatively low

Canine osteogenic sarcoma treated by amputation and MER: An adverse effect of splenectomy on survival

Canine and human osteogenic sarcomas, like most other malignant tumors, cause or are associated with progressive impairment of host immune reactivity. Adjuvant immunotherapy with live BCG had shown increased survival in one study of canine disease. Experiments with induced fibrosarcomas in mice had suggested that some of the host immune defect might be ameliorated by splenectomy. A prospective clinical trial was conducted with several cooperating veterinary centers. Dogs with osteosarcoma apparently confined to a limb were randomized to be treated by amputation and methanol‐extracted residue of BCG (MER), or by the same modalities plus splenectomy. Randomization was discontinued relatively early in the study because of higher mortality in the splenectomy group. Animals treated by amputation and MER could be compared only with historic controls; median and one‐year survival rates did not differ significantly from those of prior series. Animals treated by amputation, splenectomy, and MER had significantly poorer survival.

Prevention and treatment of injection-site sarcomas.

There is epidemiologic evidence showing a strong association between the administration of inactivated feline vaccines (or other injectables) and subsequent development of soft tissue sarcomas at vaccine sites in cats. The prevalence of soft tissue sarcomas after vaccination varies between 1/1000 and 1/10 000. If these prevalence rates are to be applied to the 1991 United States cat population, a total of 22 000 vaccine-associated tumours occurred in 1991. Recommendations for preventing or decreasing the prevalence of injection-site sarcomas in cats are controversial, and include a change in vaccination site location, decreased use of polyvalent vaccines, use of non-adjuvanted vaccines, avoiding the use of aluminum-based adjuvants, and not overvaccinating, among others. The most important recommendation for prevention of injection-site tumours would appear to be not to overvaccinate. Kas, et al. (1993) has clearly shown that the risk of injection-site tumours increases with the number of vaccines administered. It is also clear from recently published articles by Scott et al. (1997) that the duration of immunity of many of the commercially available vaccines for cats is longer than 1 year, and an every 3 year programme should be instituted for many vaccines for infectious agents of cats. With respect to rabies vaccination, annual vaccination for rabies with a 3-year rabies product should be discouraged (malpractice?). The indiscriminate use of feline leukaemia virus vaccine should be stopped since epidemiologic

Whole body hyperthermia in dogs using a radiant heating device: Effect of surface cooling on temperature uniformity

Rectal and subcutaneous temperatures were measured during a total of 10 whole body hyperthermia treatments conducted in six dogs. During five of the treatments skin cooling, by means of initiating air flow through the radiant heating device, was necessary during the plateau phase because rectal temperature exceeded the target value. Skin cooling was not necessary in the other five treatments. Although the rectal temperatures were similar in all 10 treatments, extensive and rapid subcutaneous temperature non-uniformity, of approximately 4 degrees C, developed during treatments where skin cooling was necessary. During the treatments where skin cooling was not necessary, the subcutaneous temperature remained approximately equal to the rectal temperature. These data indicate that the environment in the radiant heating device during the plateau phase can have a profound effect on the temperature at superficial sites, which is not reflected by the temperature measured at deeper sites. The temperature at superficial sites should be measured during whole body hyperthermia to assure that the prescribed heat dose is administered to the largest percentage of body mass possible. Active skin cooling during whole body hyperthermia should be avoided if possible.