A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas.

Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41 degrees C, 60 min). Tumor expression of feline IL-12 and IFN-gamma was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 10(11) plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-gamma mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-gamma mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 10(10) pfu/tumor as dose-limiting toxicities were noted at the 4 x 10(10) pfu dose.

Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.

Thermal dose is related to duration of local control in canine sarcomas treated with thermoradiotherapy.

PURPOSE: To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. EXPERIMENTAL DESIGN: 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2-5 CEM43 degrees CT90) or high (20-50 CEM43 degrees CT90) thermal dose in combination with radiotherapy. Most dogs (90%) received four to six hyperthermia treatments over 5 weeks. RESULTS: In the primary analysis, median (95% confidence interval) duration of local control in the low-dose group was 1.2 (0.7-2.1) years versus 1.9 (1.4-3.2) years in the high-dose group (log-rank P = 0.28). The probability (95% confidence interval) of tumor control at 1 year in the low-dose versus high-dose groups was 0.57 (0.43-0.70) versus 0.74 (0.62-0.86), respectively. Using multivariable procedure, thermal dose group (P = 0.023), total duration of heating (P = 0.008), tumor volume (P = 0.041), and tumor grade (P = 0.027) were significantly related to duration of local tumor control. When correcting for volume, grade, and duration of heating, dogs in the low-dose group were 2.3 times as likely to experience local failure. CONCLUSIONS: Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription.

Total skin electron therapy technique for the canine patient.

Cutaneous epitheliotropic T-cell lymphoma in canine patients is a radiation sensitive tumor but total skin electron therapy is used only rarely. Our purpose was to evaluate dose distribution from a total skin electron therapy technique using 6MeV electron beams. The treatment was comprised of 12 fields, with the dog in lateral recumbency in a stride position at an extended distance from the source. Uniformity, flatness and symmetry were determined for each beam. The composite percent depth dose profile for all beams was measured in solid water phantoms and skin dose was determined on a canine cadaver using thermoluminescent dosimeters. The resulting d(max) of the composite beams was 1mm and dose variation over the skin was 6.8%, with the extremities having the most uneven dose distribution. Dimensions of the fields were adequate to obtain an effective treatment profile for the entire thickness of canine epidermis and the technique was feasible for clinical application. Individual tailoring of the protocol to deal with hot and cold spots may be necessary and set up will likely involve a significant time commitment for the therapy team.

Chemotherapy followed by abdominal cavity irradiation for feline lymphoblastic lymphoma.

Combination chemotherapy is standard care for feline lymphoma, although clinically relevant improvements in remission duration are unlikely to result from manipulations of chemotherapy agents alone. Lymphopoietic tissues generally are sensitive to radiation, and support for chemoradiotherapy as a treatment for lymphoma is found in both humans and dogs. The goal of this prospective pilot study was to determine the normal tissue tolerance to 15 Gy total abdomen fractionated radiation therapy following induction chemotherapy in cats with lymphoblastic lymphoma. Eight cats with lymphoblastic gastrointestinal or multicentric lymphoma confined to the abdominal cavity were treated with a 6-week combination chemotherapy protocol followed 2 weeks later by whole-abdomen radiation therapy consisting of 10 daily fractions of 1.5 Gy. Treatment was well tolerated; renal insufficiency documented in one cat at the start of radiation therapy progressed to stable chronic renal failure. One cat not in complete remission at the time of radiation therapy relapsed 2 weeks later, one cat with multicentric lymphoma relapsed with hepatic large granular lymphoma, and one cat was euthanatized 3 weeks following completion of radiation therapy for other reasons; no evidence of lymphoma or radiation toxicoses was identified on post mortem evaluation. The remaining five cats remain in remission at least 266 days after starting therapy; median remission duration has not been reached (range, > 266 to > 1332 days). Results of this study suggest that 15 Gy total abdomen fractionated radiation therapy after induction chemotherapy is tolerated satisfactorily. This protocol is suitable for further testing to quantify efficacy.

Effect of wetness level on the suitability of wet gauze as a substitute for Superflab as a bolus material for use with 6 mv photons.

Despite the availability of commercial tissue equivalent bolus material, wet gauze has an application in radiation therapy to provide superior conformance to irregular contours. Wet gauze bolus has the potential to reduce air gaps between the bolus and surface, which could decrease surface dose if sufficiently large to disrupt electronic equilibrium. Wet gauze bolus is often fabricated and wetness judged qualitatively. We assessed the effect of specific gauze wetness levels, quantified in terms of physical density, at various field sizes with respect to their effectiveness as bolus material compared with Superflab. For large fields, > 7 x 7 cm2 in this study, wet gauze sponges with a physical density of 1.02 g/cm3 performed essentially identical to Superflab; at a smaller field size the wet gauze was slightly less effective, likely due to the heterogeneity of the gauze-water matrix. Gauze that was wetter, with a physical density of 1.2 g/cm3, or less wet, with a physical density of 0.75 g/cm3 was not as effective either due to enhanced photon absorption in the wetter sponges, or less effective establishment of electronic equilibrium in the less wet sponges. The presence of an air gap under Superflab led to reduced surface dose, especially for small fields and large air gaps. Thus, if Superflab use leads to poor contact with the skin, wet gauze having a physical density of 1.02 g/cm3 can be used as a substitute. Judging the water content of wet gauze subjectively is not acceptable as over- or under wetness can lead to decreased effectiveness of the bolus material.

Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation.

Our objective was to further characterize the late normal tissue complications developing after definitive irradiation of pelvic region tumors in dogs, and to search for prognostic factors. The medical records of dogs receiving definitive irradiation of the pelvic region between 1987 and 2005 were reviewed. The following criteria were established for inclusion: total dose > or =45 Gy, a portion of colon in the primary field, and a minimum of 6 months follow-up. Fifty-one dogs were identified. Prognostic factors evaluated included multiple descriptors of the patient, tumor and radiation treatment. One or more late complications were documented in 20 of 51 patients (39%). Complications were necrotic drainage/ulceration in the skin and subcutaneous tissues within the radiation field (n=7), chronic colitis (n=4), strictures (n=4), osteopenia (n=2), and one each rectal perforation, urinary bladder thickening, iliosacral osteosarcoma, pelvic limb edema, and perianal pain. Two prognostic factors were identified. There was an increase in complications in dogs with perineal tumors compared with other pelvic region sites (P = 0.04), and also in dogs with larger radiation fields (P = 0.04). The finding of an association of tumor site to complications may be a spurious finding and the association between field size and complications is not unexpected although absolute difference in field size between dogs with and without complications was small. There was no association between development of complications and survival. Based on the observed complication rate, consideration can be given to reducing dose per fraction in dogs receiving definitive pelvic region irradiation to <3 Gy.

Use of photon fields with noncoincident isocenters to improve homogeneity of dose distribution.

To compare changes in dose distribution in irregularly shaped volumes treated using fields with noncoincident isocenters compared with fields with coincident isocenters. The hypothesis was that use of fields with noncoincident isocenters would result in improved homogeneity of dose distribution. We chose to test the hypothesis in canine nasal tumors because of the increased dorsoventral thickness of the caudal compared with the rostral nasal cavity. Computed tomography images from eight dogs with nasal tumors were selected. A tissue-contouring program was used to outline contours, including the mandible as a normal tissue structure and the planning target volume (PTV), divided into a rostral and caudal volume. A traditional computerized treatment plan consisting of two parallel-opposed fields was constructed for each dog. A second treatment plan using a third caudally located field having a different isocenter was constructed for comparison. Dose-volume histograms were generated and compared for each contoured structure in both plans. In all dogs the use of noncoincident fields resulted in increased dose to the ethmoid region through the caudal field. Minimum dose in the caudal tumor PTV increased as well. At the same time, dose delivered to the mandible, prone to develop significant side effects, was lower in all dogs with the use of noncoincident fields, as it was possible to reduce the dose delivered from the ventral field. Use of photon fields with noncoincident isocenters can improve the dose distribution in irregularly shaped volumes in comparison with fields with coincident isocenters. Improved tumor dose distribution was achieved with the addition of a smaller field having a different isocenter.