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Intralesional Cisplatin Treatments in Canines with Oral Squamous Cell Carcinomas
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Jeannette M. Kelly, DVM, DACVIM and Beth A. Belding, BS
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Veterinary Cancer Care, P.C.
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2001 Vivigen Way
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Santa Fe, New Mexico, USA 87505
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Acknowledgements: ??
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Sources of funding: ??
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Objective – To determine if there was a difference in survival time for canines with oral
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squamous cell carcinoma (SCC) treated with intralesional cisplatin and canines treated
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with intralesional cisplatin combined with other chemotherapies.
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Design – Clinical study to determine the response, timeframe to response, and survival
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time for the two different treatment types.
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Animals – Seven canines were studied, all had histopathologically confirmed oral SCC.
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Procedures - All canines were treated with intralesional cisplatin (range: 7.5mg/m2 to
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20mg/m2). Three canines received additional chemotherapy including: Bleomycin
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(20U/m2), doxorubicin (range: 25mg/m2 to 30mg/m2) or lomustine (40mg tablets). The
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Mann-Whitney U test was used to determine if there was a difference in survival times.
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Results - One had a complete response after chemotherapy. Three canines had a partial
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response. One continued to have a progressive disease. One had a complete response
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followed by a recurrence. One had a partial response which became progressive again
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after treatments were halted. Mean and median times to complete response were both
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10.5 days. Mean and median times to partial response were 14.9 days and 10.5 days,
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respectively. Mean and median times to develop a progressive disease were 33.25 days
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and 35 days, respectively. Mean and median times to recurrence were both 45.5 days.
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Conclusions and Clinical Relevance - These findings suggest that intralesional cisplatin
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is potentially effective in palliative treatment of oral SCC in canines. Furthermore, there
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is no difference in survival time when treating canines with intralesional cisplatin versus
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intralesional cisplatin in combination chemotherapies.
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Keywords: Chemotherapy, Oncology – Small Animal, Oncology – General, Oncology -
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Treatment
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Introduction
Cisplatin (Cis-diamminedichloroplatinum) is one of the most potent antineoplastic
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chemotherapy drugs available1. Cisplatin has been shown to be very effective in treating
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adenocarcinomas2, 3, 4, head and neck squamous cell carcinomas2, 5, 6, 7, transitional cell
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carcinomas2, 7, 8, and osteosarcomas9, 10, 11. Intralesional (IL) chemotherapy is the
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administration of antineoplastic drugs directly into the tumor or adjacent tissues12. This
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technique of chemotherapy has shown promise because of increased antitumor activity
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within and around the tumor and decreased systemic toxicity13. However, there has been
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minimal research on the effectiveness of intralesional cisplatin in canines, Canis
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familiaris.
Squamous cell carcinoma (SCC) is the second most common oral tumor in
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canines14. SCC is highly invasive and frequently invades bone14. In older canines,
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prognosis can be dim with a median survival time of 6 months15. Surgical excision,
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radiation therapy, photodynamic therapy, and chemotherapy are the current treatment
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options for canines with SCC14. However, all treatments only provide palliative relief.
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Intravenous cisplatin has been shown to be an effective treatment in canines with
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oral squamous cell carcinomas16. Intralesional bleomycin has been shown to inhibit
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tumor cell proliferation17 and is an effective treatment for squamous cell carcinomas18, 19.
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Doxorubicin has been shown to be an effective tumor growth prohibitor20 when dealing
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with SCC21. Lomustine is an oral chemotherapy that has been used successfully in
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chemotherapy combinations22.
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The purpose of this study was designed to determine the effectiveness of
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intralesional cisplatin, and compare it to intralesional cisplatin combined with other
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chemotherapy drugs.
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Materials and Methods
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Seven canines with oral squamous cell carcinomas were treated at the Veterinary Cancer
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Care, P.C. clinic in Santa Fe, New Mexico, USA. Owners of all canines included in the
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study provided informed consent. All tumors were diagnosed histopathologically and
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graded by a standard tumor classification system devised by the World Health
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Organization23. Two of the squamous cell carcinomas (29%) were located in the tonsils,
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two (29%) were located on the right maxilla, one (14%) was on the rostral maxilla, one
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(14%) was on the right buccal mucosa, and one (14%) was submucosal oro-pharyngeal.
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All trials were run between April 2003 and March 2008.
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Before each chemotherapy treatment, all canines were evaluated with a physical
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examination, CBC, and blood serum biochemical analysis. Urinalysis and additional
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testing was performed on a case by case basis, based on the canine’s clinical status.
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Tumor response to treatment was assessed before each new chemotherapy treatment or
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during weekly or bimonthly check ups. Tumor responses to chemotherapy were graded
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as complete response (no visually detectable tumor), partial response (>50% reduction in
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tumor size), stable disease (no change in tumor size), and progressive disease (>50%
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increase in tumor size) 16. Survival time was based on number of days from start of
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chemotherapy to date of death. The Mann-Whitney U test t-test was performed to
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compare the survival times of canines on IL cisplatin only and canines on IL cisplatin and
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other chemotherapies.
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Chemotherapy was given weekly or every other week, depending on the severity
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of the carcinoma, for 4-6 total treatments. Intralesional cisplatin was given at doses
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ranging from 7.5mg/m2 to 20mg/m2 (average: 10.68mg/m2, median: 10mg/m2). Cisplatin
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was always used in conjunction with purified sesame seed oil. Bleomycin was given
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subcutaneously to one canine at a dosage of 20U/m2. Doxorubicin was given in doses
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ranging from 25mg/m2 to 30mg/m2 (average: 26.2mg/m2, median: 25mg/m2),
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intravenously. Lomustine was given to one canine in 40mg tablet form.
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All IL injections were done with the canines under general anesthesia. Isoflurane
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was used as an induction agents, as well as propfol or equal parts ketamine and diazepam
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were used as a pre-anesthetic or general anesthetic.
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During injection, the sesame oil and cisplatin were mixed back and forth in two
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syringes, keeping the mixture in a suspension. The mixture was injected into the tumor,
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the region of the tumor, or the surgical site of tumor excision. Attempts were made to
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keep the injections within 3cm wide and deep. If the tumor was too ulcerated or friable,
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the injections were done in nearby healthy tissue, as it has been shown that injection into
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surrounding tissue is equally as efficient as IL injections12. Once the injection was
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finished, the area was massaged to help disperse the chemotherapeutics throughout the
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tumor, and to minimize leakage. For ease of injection, several of the tumors were
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injected from outside of the skin and into the oral cavity. Safety gear for all treatments
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included goggles, gloves, and mask.
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Canines 1-4 received cisplatin intralesional injections only. Canine 5 received
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cisplatin and doxorubicin. Canine 6 received cisplatin and lomustine. Canine 7 received
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cisplatin, bleomycin, and doxorubicin.
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For the seven canines tested, 44 individual treatments were given. Thirty
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treatments were IL cisplatin, seven were subcutaneous bleomycin, six were intravenous
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doxorubicin, and one was lomustine tablets.
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Thirty three (75%) received dexamethasone injections with strength ranging from
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4mg-10mg IV, SQ, or IL. Twenty one of the treatments (47%) received sodium chloride
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0.9% SQ fluids ranging from 100ml to 1000ml depending on each canine’s hydration.
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Other supportive drugs include diazepam (25%), buprenorphine (20%), cefazolin (18%),
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triamcinolone acetonide (18%), carprofen (16%), depomedrol (16%), enrofloxacin
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(16%), metocloperamide (14%), butorphenol (9%), atropine (5%), clavamox (5%),
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clindamycin (5%), famotidine (5%), fentanyl patches (5%), metronidazole (5%),
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ampicillin (2%), cephalexin (2%), diphenhydramine (2%), metacam (2%), and piroxicam
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(2%).
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Results
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Based on visual examination of the tumor site, the degree of response to
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treatments was categorized as complete response, partial response, stable disease, and
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progressive disease. The following is data on all seven canines given intralesional
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cisplatin with or without other chemotherapy drugs. Canine 1 had a complete response
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by day 7. Canine 2 continued to have a progressive disease by day 14, which was never
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helped by intralesional cisplatin chemotherapy. Canine 3 had a partial response by day 7,
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a complete response by day 14, and a recurrence by day 49. Canine 4 had a partial
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response by day 4, which became a progressive disease by day 49, another partial
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response by day 70, and once again a progressive disease by day 91. Canine 5 received a
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combination of chemotherapies and had a partial response by day 7, which was stable and
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unchanging beyond day 14. Canine 6 also received multiple chemotherapy drugs, and
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had a partial response by day 14 which was stable and unchanging beyond day 63.
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Canine 7 received multiple chemotherapies and had a partial response by day 7.
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The overall statistics show that one (14%) canine had a complete response after
chemotherapy: on IL cisplatin only. Three (43%) canines had a partial response: all were
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on combination chemotherapies. One (14%) canine continued to have a progressive
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disease: on IL cisplatin. One (14%) canine had a complete response followed by a
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recurrence: on IL cisplatin. One (14%) canine had a partial response which became
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progressive again after treatments were halted: on IL cisplatin.
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Furthermore, mean and median times to complete response were both 10.5 days.
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Mean and median times to partial response were 14.9 days and 10.5 days, respectively.
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Mean and median times to develop a progressive disease were 33.25 days and 35 days,
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respectively. Mean and median times to recurrence were both 45.4 days.
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All seven canines had blood work checked before each treatment. Noted side
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effects included lymphopenia in three canines (43%), neutropenia in three canines (43%),
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leukocytosis in two canines (29%), lymphoid hyperplasia in two canines (29%),
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thrombocytopenia in two canines (29%), azotemia in one feline (14%), erythrocytosis in
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one canine (14%), and hypercalcemia in one canine (14%). In addition, six (86%) had
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decreased appetites, five (71%) had face and neck swelling, three (43%) had extreme
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lethargy, three (43%) developed abscesses, three (43%) developed defects at the site of
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injection with bone exposure, three (43%) had difficulty swallowing, two (29%) had
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diarrhea, two (29%) developed difficulty breathing, two (29%) developed enlarged lymph
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nodes, two (29%) suffered loose teeth, two (29%) developed tissue necrosis, one (14%)
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had a tissue reaction to the chemotherapy, one (14%) had liver failure, one (14%) had
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cellulitis, one (14%) developed sepsis, and one (14%) suffered from nose bleeds.
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Average survival times ± standard deviation for all canines was 172 days ± 153
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days (N=7). Mean survival time for canines on IL cisplatin only was 164 days ± 208
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days (N=4). Mean survival time for canines on IL cisplatin combined with other
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chemotherapy drugs was 184 days ± 69 days (N=3). The Mann-Whitney U test showed
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that there was no significant difference in survival time on IL cisplatin alone or IL
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cisplatin combined with other chemotherapies (U=9.0, p=0.144).
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Discussion
The findings of this study suggest that intralesional cisplatin, whether or not it is
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combined with other chemotherapeutics, may provide palliation for canines with oral
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squamous cell carcinomas. In the past, as well as in the current study, cisplatin,
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bleomycin, lomustine and doxorubicin have been shown to be effective chemotherapeutic
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agents. However, there is no statistical difference in the survival time of canines with
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oral SCC on IL cisplatin or IL cisplatin in combination chemotherapies.
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In this study, only one of the canines given intralesional chemotherapy did not
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respond to the treatment. The other six canines did have a positive initial response to the
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IL chemotherapy treatments. In fact, one of the canines had a complete response with no
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recurrences. On average, complete responses were seen within the first two weeks from
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the start of chemotherapy. In this study, IL cisplatin combined with other
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chemotherapies developed a partial response, allowing owners more time with their pets.
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Recurrences typically happened after the IL chemotherapy treatments had ended. Even
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so, recurrence, on average, did not happen for a month and a half. In instances where
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recurrence had happened, it can be postulated that the chemotherapeutic did not
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adequately diffuse into the tissue12.
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While side effects to the IL cisplatin were minimal, effects of the cancer were
more pressing; including severe face and neck welling, infections, abscesses and defects
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with bone exposure. With the aid of intralesional cisplatin, our test subjects had an
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average lifespan of 172 days, or 5.7 months. When treating oral canine SCC, palliation is
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the only option available, and cisplatin was very effective in increasing quality of life in
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these canines.
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