Alain P. Théon

Radiation Therapy in the Horse

This article covers the principles and applications of radiation therapy in horses. The goal in treating tumors by irradiation is tumor control with minimum treatment complications. Various treatment techniques are available to achieve this goal. The prognosis depends on many factors such as the extent and location of the tumor, tumor type and tumor cell proliferation. Radiation therapy is a very effective treatment modality for equine tumors but logistical reasons limit its impact in equine oncology.

Survival, Neurologic Response, and Prognostic Factors in Dogs with Pituitary Masses Treated with Radiation Therapy and Untreated Dogs

BACKGROUND Pituitary masses in dogs are not uncommon tumors that can cause endocrine and neurologic signs and, if left untreated, can decrease life expectancy. HYPOTHESIS Dogs with pituitary masses that received radiation therapy (RT) have more favorable neurologic outcomes and longer survival times compared with untreated dogs. ANIMALS Nineteen dogs with a pituitary mass identified on CT or MR imaging were irradiated with 48 Gy given in 3 Gy daily-dose fractions. Twenty-seven untreated control dogs had pituitary masses. METHODS Medical records of dogs with pituitary masses were retrospectively reviewed for clinical signs, mass size, and outcome. RESULTS Median survival time was not reached in the treated group. Mean survival time in the treated group was 1,405 days (95% confidence interval [CI], 1,053-1,757 days) with 1-, 2-, and 3-year estimated survival of 93, 87, and 55%, respectively. Median survival in the nonirradiated group was 359 days (95% CI, 48-916 days), with a mean of 551 days (95% CI, 271-829 days). The 1-, 2-, and 3-year estimated survival was 45, 32, and 25%, respectively. Dogs that received RT for their pituitary tumors had significantly longer survival times than untreated dogs (P = .0039). Treated dogs with smaller tumors (based on maximal pituitary-to-brain height ratio or area of tumor to area of brain) lived longer than those with larger tumors (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE When compared with untreated dogs, RT increased survival and controlled neurologic signs in dogs with pituitary masses.

Intralesional and Topical Chemotherapy and Immunotherapy

Surgery is the mainstay of treatment for equine tumors. Conservative treatment approaches which preserve function and appearance are increasingly used in clinical practice. This article covers the principles and applications of two conservative treatment modalities including local chemotherapy and immunotherapy. The therapeutic benefit of local chemotherapy is based on the direct drug delivery to tumor tissue, i.e., topical and intratumoral administration of cytotoxic agents in slow release formulation. This treatment modality is very effective for cutaneous tumors and does not result in any permanent damage to normal tissue. Immunotherapy produces antitumor effects primarily through the action of natural host defense mechanisms against tumor cells. Although the use of immunotherapy is still under investigation there are many examples of its successful application to treatment of selected equine tumors.

CONCURRENT IRRADIATION AND INTRATUMORAL CHEMOTHERAPY WITH CISPLATIN: A PILOT STUDY IN DOGS WITH SPONTANEOUS TUMORS

PURPOSE A preliminary study was undertaken to determine whether the addition of a collagen gel in the formulation of cisplatin for intratumoral administration of cisplatin affected platinum plasma concentrations. A second study was undertaken to determine the local effects of intratumoral administration of cisplatin mixed with collagen given concurrently with irradiation. METHODS AND MATERIALS Twelve dogs with advanced stage tumors were administered a dose of 0.25 mg of cisplatin per kg of body weight intratumorally with or without collagen using a two-period crossover design. Twelve additional dogs received concurrent irradiation (48 Gy) delivered in 12 fractions over 4 weeks and intratumoral cisplatin chemotherapy given the first day of each week at a dose of 0.5 mg of cisplatin per cm3 of tissue. RESULTS The cumulative cisplatin plasma concentrations varied over time from dog to dog, but the use of collagen in the formulation significantly reduced the systemic exposure of cisplatin. For the dogs given intratumoral cisplatin and irradiation, complete responses were observed in 10 dogs. Seven dogs had local recurrence. One dog had tumor recurrence in the radiochemotherapy field and six dogs had recurrence at the margin of the radiochemotherapy field, but within the irradiation field. Normal tissue reactions were similar in the radiochemotherapy field and in the margin treated with radiation only. Cumulative effect of repeated intratumoral administration on plasma concentration of cisplatin was not observed. CONCLUSIONS These findings provide support for an extended investigation of this combined regimen. The lack of systemic toxicity associated with intratumoral administration of cisplatin mixed with collagen may allow a safe clinical evaluation of the interaction between cisplatin and radiation.

COMPUTED TOMOGRAPHIC APPEARANCE OF EQUINE SINONASAL NEOPLASIA

The computed tomography (CT) features of tumors involving the nasal cavity and/or paranasal sinuses of 15 horses were reviewed. The 15 tumors included five neuroendocrine tumors/neuroblastomas, two undifferentiated carcinomas, two myxosarcomas, and one each of nasal adenocarcinoma, hemangiosarcoma, chondroblastic osteosarcoma, anaplastic sarcoma, myxoma, and ossifying fibroma. All tumors except the ossifying fibroma were iso- or hypoattenuating relative to masseter muscle. Thirteen of the fifteen tumors exhibited moderate or marked osteolysis of adjacent cortical bone and 14/15 were characterized by destructive changes of the nasal turbinates, nasal septum, and/or infraorbital canal. Ten horses had moderate or marked involvement of the cribriform plate and six had clear intracranial extension of the mass. CT features were compared to radiographic findings for 10 horses. A mass was observed in 10/10 radiographic studies and mass within the caudal maxillary sinus (7/8) and rostral maxillary sinus (6/7) was identified correctly in most horses. The radiographs were least sensitive for identifying masses within the sphenopalatine sinus (0/5), cranium (0/4), and retrobulbar space (1/7) compared to CT. The radiographs also underestimated potential features of malignancy, such as severity of osteolysis or osseous production. While radiographs are a useful screening tool for identification of sinonasal masses, CT provides greater information regarding mass extent, features of malignancy, and important prognostic indicators.

Analysis of the equine tumor suppressor gene p53 in the normal horse and in eight cutaneous squamous cell carcinomas

Wild type equine p53 was amplified between exons 2 and 9 by the polymerase chain reaction using primers designed from conserved regions in other species. An 828 base pair region, corresponding to codons 25-313 of human p53, was sequenced in both directions. Human and equine amino acid sequences were 87% homologous in this region and 96% homologous in conserved domains II-V. Of eight equine cutaneous or mucocutaneous squamous cell carcinomas directly sequenced from exons 5-8, two had p53 point mutations resulting in single amino acid substitutions.

Sequential low-dose rate half-body irradiation and chemotherapy for the treatment of canine multicentric lymphoma.

BACKGROUND Sequential half-body irradiation (HBI) combined with chemotherapy is feasible in treating canine lymphoma, but prolonged interradiation intervals may affect efficacy. A 2-week interradiation interval is possible in most dogs receiving low-dose rate irradiation (LDRI) protocols at 6 Gy dose levels. HYPOTHESIS LDRI incorporated into a cyclophosphamide, doxorubicin, vincritine, and prednisone (CHOP)-based chemotherapy protocol is effective for the treatment of lymphoma in dogs. ANIMALS Thirty-eight client-owned animals diagnosed with multicentric lymphoma. METHODS Retrospective study evaluating the efficacy and prognostic factors for the treatment of canine lymphoma with sequential HBI and chemotherapy. RESULTS The median 1st remission was 410 days (95% confidence interval [CI] 241-803 days). The 1-, 2-, and 3-year 1st remission rates were 54, 42, and 31%. The median overall survival was 684 days (95% CI 334-1,223 days). The 1-, 2-, and 3-year survival rates were 66, 47, and 44%. CONCLUSIONS AND CLINICAL RELEVANCE Results of this study suggest that treatment intensification by a 2-week interradiation treatment interval coupled with interradiation chemotherapy is an effective treatment for dogs with lymphoma.

Localized thermo-cisplatin therapy: a pilot study in spontaneous canine and feline tumours

Local hyperthermia combined with intralesional cisplatin chemotherapy is a logical and potentially effective therapeutic approach for localized cancers. A trial using outbred animals with spontaneously occurring tumours was initiated to evaluate the toxicity and efficacy of this approach. Treatment consisted of injection of a colloidal suspension of cisplatin into the tumour prior to hyperthermia once a week for 4 weeks. Immediately after intratumoral injection of a mixture of cisplatin and collagen, thermotherapy was given. The goal temperature was 42 +/- 1 degrees C for 30 min. Ten animals (nine dogs and one cat) with soft tissue neoplasms were treated with one to four hyperthermia and cisplatin sessions for a total of 30 treatment sessions. Complete responses occurred in 4/10 cases (one carcinoma, two sarcomas, one melanoma). One dog with haemangiopericytoma had partial response. The lack of systemic toxicity and the minimal local normal tissue reactions indicate that the treatments were well tolerated. These data provide preliminary evidence that a combination of local hyperthermia and intratumoral cisplatin chemotherapy is a safe and effective method for the treatment of selected localized neoplasms.

In Situ Analysis of Cellular Proliferation in Canine, Feline and Equine Tumors by Immunohistochemistry: A Comparison of Bromodeoxyuridine, Proliferating Cell Nuclear Antigen, and Interchromatin-Associated Antigen Immunostaining Techniques

Cell proliferation in canine, feline, and equine tumors was evaluated using immunohistochemical detection of in vitro 5–bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA), and interchromatin-associated antigen (p105). Ten tumors in each species were analyzed. The tumor proliferative fraction (PF) was defined as the percentage of labeled nuclei for 5,000 tumor nuclei counted. Immunoreactivity was observed with all techniques in all species. A good correlation was observed between the proliferative fractions measured with the BrdU (PFBrdU) and PCNA (PFPCNA) techniques (r s = 0.523, P = 0.0026). There was no correlation between the PFs measured with the BrdU (PFBrdU) and p105 (PFP105) techniques. Using the median values obtained from the different approaches as cutoff points to define slowly and rapidly proliferating tumors, there was an 80% agreement (P = 0.009) between PFBrdU and PFPCNA and no agreement between PFBrdU and PFP105 The results of this study indicate that both BrdU and PCNA labeling methods can be used reliably for identifying proliferating cells in animal tumors. In addition, PCNA could be used to replace the BrdU method to assess tumor proliferative fraction because it does not require pretreatment of tissues.

Tissue distribution of transdermal toremifene

Abstract Purpose: Toremifene is an orally administered triphenylethylene derivative with antiestrogenic activity that is primarily used in the treatment of patients with metastatic breast cancer. The purpose of this study was to evaluate the therapeutic advantage of local (transdermal) administration of toremifene in several animal models. Local (subcutaneous and skin) versus systemic concentrations of toremifene were evaluated serially following transdermal application of the drug. With high local concentrations and minimal distribution to other organs via the circulation, topical toremifene may deliver maximal therapeutic effects to local tissue while avoiding the side effects seen with systemic therapy. Methods: Three animal models (nude mice, baboons, and a horse) were used to examine topically administered toremifene for kinetic measurements. Results: In nude mice implanted subcutaneously with MDA-MB-231 human breast tumors, topical toremifene (2.5 mg/day×5 days) produced greater than 50-fold higher tumor concentrations compared with intraperitoneal (i.p.) administration (1.0 mg/day×5 days). Systemic distribution in plasma, uterus, and liver was lower following topical than following i.p. administration. In nude mice inoculated subcutaneously with estrogen receptor-positive (ER+) MCF-7 human breast cancer cells, topical toremifene and 4-hydroxytoremifene (4-OH) prevented tumor growth in the presence of estradiol. In four nontumor-bearing baboons that were given transdermal toremifene, relatively high distribution of drug was noted in normal breast tissue and fat, compared with undetectable serum concentrations. Finally, a new topical formulation of toremifene (a gel preparation for human use, Orion-Farmos, Finland) achieved high local tumor toremifene concentrations in a horse melanoma, with minimal systemic distribution. Conclusions: Transdermal toremifene can achieve high local tissue concentrations with minimal systemic distribution.