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Keywords:

  • Clinical Trial;
  • Squamous Cell Carcinoma;
  • Taxane

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Background: The safety of IV administration of docetaxel to cats with cancer has not been reported.

Objectives: Document adverse effects of IV administration of docetaxel to cats.

Animals: Twenty-one client-owned cats with any confirmed malignancy.

Methods: Cats received up to 5 docetaxel treatments, administered IV every 3 weeks. The initial dosage was 1.0 mg/kg, and dosages were increased by increments of 0.25 mg/kg in cohorts of 3 cats. Adverse events were determined by a CBC at days 7 and 21, serum chemistry and urine specific gravity at day 21, and medical histories provided by the owners.

Results: Cats received docetaxel dosages ranging from 1.0 to 2.5 mg/kg, for a median of 2 treatments. Dose-limiting toxicoses included fever, neutropenia, and vomiting, seen in 2 of the 4 cats treated at 2.5 mg/kg. Hypersensitivity reactions were infrequent (4 of the 21 cats) and mild. The maximum tolerated dosage was 2.25 mg/kg.

Conclusions and Clinical Importance: Docetaxel can be administered IV to cats with a low incidence of adverse effects.

Abbreviations:
AE

adverse event

DLT

dose-limiting toxicosis

MTD

maximum tolerated dose

Docetaxel is a taxane cytotoxic agent that induces microtubular stability and disruption of microtubular dynamics.1 Taxane drug formulations are dissolved in inorganic solvents for IV administration, which can cause histamine release and hypersensitivity. Docetaxel is formulated with a polysorbate-80 vehicle that is considered less allergenic than the cremophor EL vehicle present in paclitaxel. Docetaxel is administered IV to humans after steroid and antihistamine premedication and is FDA approved for head and neck, non-small-cell lung, gastric, breast, and prostate cancers.2 IV administration of docetaxel results in mild hypersensitivity reactions in dogs.3 PO administration has been evaluated in both dogs and cats in order to avoid the hypersensitivity reactions; however, this requires gastric intubation under general anesthesia and coadministration of cyclosporin.4–6 The maximum tolerated dose (MTD) for PO administration to cats is 1.75 mg/kg every 3 weeks and the dose-limiting toxicosis (DLT) was gastrointestinal.4 The dose intensity of the oral regimen was 0.58 mg/kg/wk and no hypersensitivity reactions were seen with PO administration.4

The objectives of this study were to determine whether docetaxel can be safely administered IV to cats and to characterize the adverse event (AE) profiles and the MTD by cats with cancer. Although not a primary goal of phase I trials, a secondary objective was to document preliminary antitumor activity.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Cat Selection

Cats with any histologically or cytologically confirmed malignancy (measurable or microscopic disease) that had either failed standard of care treatment, declined other treatment options, or for which there was no established standard of care; were prospectively enrolled if they met the following criteria: life expectancy of at least 12 weeks; free of important underlying medical disease and a VCOG performance7 of 0 or 1, and serum bilirubin and creatinine concentrations within 1.5 times the upper limit of the reference range; albumin within 80% of lower limit of the reference range and a 3-week washout period for prior chemotherapy. Informed consent for treatment was obtained and owners agreed in principle to necropsy. The protocol was approved by the University of Wisconsin—Madison Institutional Animal Care and Use Committee.

Information Obtained

Information recorded was signalment, body weight, tumor type and method of diagnosis (histology or cytology), clinical stage, tumor measurement where possible, prior treatments, docetaxel toxicosis, clinical response to docetaxel administration, date of progression, date of death, and, where available, cause of death and results of necropsy. Pretreatment evaluation included a CBC, blood chemistry, and urinalysis. Further staging was recommended, but was not a requirement for entry into the trial.

Treatment Protocol

Clients were provided with 1 mg/kg prednisolonea to be administered to their cats PO 24 hours before administration of docetaxel.b Further premedication administered 30 minutes before docetaxel administration was diphenhydraminec (2 mg/kg IM), dexamethasone sodium phosphated (0.5 mg/kg IV), and famotidinee (0.5 mg/kg SC).

Docetaxel Administration

Docetaxel was diluted and administered IV over 1 hour via a closed system transfer device (Tevadaptorf) every 3 weeks, for up to 5 treatments until progression of disease or unacceptable toxicosis occurred, or if the client declined further treatment. Docetaxel was mixed with the diluent supplied by the manufacturer to a concentration of 10 mg/mL, which is stable for 4 weeks at room temperature or if refrigerated.8 When administered to cats, the 10 mg/mL stock solution was diluted with 0.9% NaCl to a concentration between 0.3 and 0.74 mg/mL as directed in the package insert. Administration was performed under close supervision, with evaluation of respiratory rate and demeanor every 10 minutes during the infusion. Evidence of hypersensitivity (pruritis, facial edema) triggered cessation of infusion, a decreased infusion rate, and administration of other medications if deemed necessary by the attending clinician.

Dose escalation was performed in a standard 3 × 3 cohort design.9 The starting dose of docetaxel for the 1st cohort of 3 cats was 1.0 mg/kg based on the prior treatment of 2 cats with this dose at the authors' institution. The dose escalation per cohort was by 0.25 mg/kg. AEs were graded according to VCOG-CTCAE v1.07. Any AE deemed to be severe or life threatening (any grade 4 AE) or that had an important impact on quality of life (grade 3 AE) resulted in cohort expansion to 6 cats. If 2 such DLTs occurred in any 1 cohort, the preceding, lower cohort was considered to be the MTD. If only 1 such intoxication occurred in that expanded cohort, then the trial would continue with dose escalation. Cats were treated with concomitant medications for anorexia, pain, or perceived nausea on a case-by-case basis as determined by the attending clinician.

A CBC was performed at day 7 after each administration of chemotherapy either at the VMTH or the patient's local veterinary office. A further CBC, serum chemistry, and urine specific gravity was performed on the day of each subsequent docetaxel treatment.

Response

Where measurable disease was present, tumor size was determined by caliper measurement or radiographs according to the Response Evaluation Criteria in Solid Tumors guidelines in which the size was measured as the sum of the longest diameters of the lesions.10 Thoracic radiographs were recommended but not mandatory for cats with microscopic disease at the 3rd and 5th treatments to evaluate for progression of disease. Best overall response and biological observed response were assessed; best overall response was defined as any cats with either a CR or PR at any time point and a biological observed response was defined as cats with any clinical benefit (ie, CR or PR at any time, or SD for at least 6 weeks).

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Cat Characteristics

Twenty-one cats with cancer were treated with docetaxel from May 2008 to December 2010. There were 12 females and 9 males; all were neutered. Breeds included 15 domestic short hair, 4 domestic long hair, 1 Persian, and 1 Maine Coon. The median age was 11 (range, 3–15 years). The median body weight was 4.8 kg (range, 2.9–8.3 kg). Histologic diagnoses were available for 18 cats; however, 3 cytologic diagnoses were accepted in 3 instances. Tumor types included carcinoma (oral squamous cell carcinomas in 9 cats, mammary gland carcinoma in 4 cats, nasal carcinoma in 2 cats, and 1 each of pulmonary carcinoma, ceruminous gland adenocarcinoma, and periocular carcinoma) and sarcoma (1 each of oral spindle cell sarcoma, auricular sarcoma, ilial wing sarcoma). Previous therapy before entry into the study included surgical excision by the referring veterinarian in 5 cats. At the time of the 1st treatment, 20 of the 21 cats had measurable disease; 1 had no evidence of disease but had previously incompletely excised mammary carcinoma. Furthermore, 5 cats had metastasis to local lymph nodes, lung, or both.

A total of 47 doses were administered, ranging from 1.0 to 2.5 mg/kg. Eight cats received only 1 dose of docetaxel, 6 received 2 doses, 4 received 3 doses, 1 received 1 dose, and 2 received 5 doses. The median number of doses was 2. One cat received 1 dose of 1.5 mg/kg and was erroneously escalated to receive 2 further doses of 1.75 mg/kg, but was counted in both cohorts. The only cohort expansion was for the highest dose of 2.5 mg/kg; the trial was halted after the 4th cat at this dose.

Hematologic Toxicoses

Hematologic AEs were seen in 4 of 42 doses (10%, Table 1), with only 3 episodes of grade 3 or 4 toxicosis, 2 of which were seen in a cat receiving the 2nd dose of 2.5 mg/kg. The only grade 4 neutropenia and the only fever documented, occurred in different cats both receiving 2.5 mg/kg, at day 4 after treatment. The cat with fever at day 4 did not have a CBC performed on that day, but the neutrophil count was within reference range on day 7.

Table 1.   Hematologic and gastrointestinal adverse event scores according to VCOG-CTCAE.7
Number of CatsDose (mg/kg)Total Number of DosesHematologic or Gastrointestinal Adverse Events
Grade 0Grade 1Grade 2Grade 3Grade 4
31.088 (8)0 (0)0 (0)0 (0)0 (0)
31.2577 (5)0 (1)0 (1)0 (0)0 (0)
31.554 (4)0 (1)0 (0)1 (0)0 (0)
31.7576 (3)1 (3)0 (1)0 (0)0 (0)
32.033 (0)0 (2)0 (1)0 (0)0 (0)
32.2577 (3)0 (0)0 (4)0 (0)0 (0)
42.5108 (6)1 (1)0 (1)0 (2)1 (0)

Gastrointestinal Toxicoses

Gastrointestinal AEs were identified following 18 of 42 doses (45%, see Table 1). The most frequent gastrointestinal toxicosis was anorexia. Sixteen of these episodes were grade 1 or 2; only 2 episodes were grade 3, both of which were seen in cats receiving the 2.5 mg/kg dose. Vomiting occurred in 3 of 4 cats treated at 2.5 mg/kg between days 2 and 6 after treatment, which was treated with antinausea medications (metoclopramide,g maropitanth) for subsequent treatments. No modification was made to the overall treatment protocol. Vomiting and neutropenia were determined to be DLTs.

Hypersensitivity

Four cats had a total of 5 episodes of acute hypersensitivity associated with docetaxel infusion. One cat (2 mg/kg) had grade 2 urticaria associated with the only dose received. Two cats that received 2.25 mg/kg had reactions characterized by grade 2 auricular flushing or pruritis at the first of 2 treatments. One cat that received 2.5 mg/kg had grade 2 auricular edema during both infusions received. These AEs were treated by discontinuing the infusion followed by restarting at a lower infusion rate once the AEs abated. If they did not appear to improve within 5–10 minutes of halting the infusion, a further dose of 2 mg/kg diphenhydramine (IM) was administered. No signs of respiratory distress were detected in any cats.

MTD

The MTD for IV docetaxel in cats given every 3 weeks was 2.25 mg/kg, equivalent to 0.75 mg/kg/wk dose intensity.

Responses

The biologically observed response rate was 50%, with 10 of 20 cats with measurable disease achieving SD (n = 9) or PR (n = 1). One cat treated with 1.5 mg/kg docetaxel with a 6.0 × 4.0 cm ilial wing sarcoma achieved a partial response to 5.0 × 3.2 cm as measured by calipers for 9 weeks before developing progression. One cat died because of a presumed anesthetic complication during management of an esophageal feeding tube when at their local veterinary office before the 2nd treatment and response could not be evaluated. Seventeen cats had tumor progression by the 2nd (n = 7), 3rd (n = 6), or 4th (n = 4) scheduled treatment and discontinued therapy. One cat with an incompletely resected mammary carcinoma developed recurrence at the time of the 5th scheduled treatment. Two cats received all 5 scheduled treatments and maintained stable disease for a recurrent auricular sarcoma (1.0 mg/kg) and an oral squamous cell carcinoma (2.5 mg/kg), for 14 months and 14 weeks, respectively. Nine cats maintained stable disease for a median of 6 weeks (range, 6 weeks–14 months). Of 9 cats with SCC, 6 achieved stable disease for a median of 6 weeks, although only 2 of these were durable (9 and 14 + weeks).

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Docetaxel has been previously described for PO administration in cats.4 In our study, docetaxel administered IV was apparently safe in this low number of cats. Hypersensitivity reactions were uncommon and mild, and the major AEs seen were hematologic and gastrointestinal.

IV administration of docetaxel to humans results in a higher peak plasma concentration and mean AUC than when administered PO with cyclosporine.11 Whether this is true in cats is unknown. In this study, a higher dose intensity (0.75 mg/kg/wk IV) was achieved when compared with PO administration (0.58 mg/kg/wk PO), but plasma concentrations of docetaxel were not measured.

In humans, PO administration of docetaxel is more convenient, cost-effective, and less invasive for patients than is IV administration.12 In contrast, PO administration of docetaxel in cats is performed under general anesthetic via gastric intubation and is therefore less convenient, more costly, and poses a greater potential for chemotherapy exposure to staff from emesis, leakage, or aerosolization. IV administration can be performed in an awake cat, and can be performed via a closed system transfer device, reducing the potential for staff exposure.

One of the major concerns regarding IV administration of taxane agents has been the risk of hypersensitivity. Taxane drugs typically require excipients for solubilization, many of which are allergens. Humans are premedicated to reduce the risk of developing hypersensitivity reactions and a generalized fluid retention syndrome.13 In this study, hypersensitivity reactions were only seen above a dosage of 2.0 mg/kg, of which only 25% of administrations resulted in a reaction. These reactions manifested as mild pruritis and facial edema. No respiratory difficulty or generalized fluid retention was identified.

The DLTs identified in this study were gastrointestinal (vomiting) and hematologic (neutropenia), and all but 1 DLT occurred in the highest dose cohort (2.5 mg/kg) resulting in the MTD to be established at 2.25 mg/kg. One cat developed a grade 4 neutropenia at day 4, and another developed a fever at day 4 (but no CBC performed at that time), suggesting that the nadir in cats can occur as early as day 4. Many cats at lower doses experienced low-grade anorexia; however, most of these cats had oral tumors, which would likely have contributed to the frequency of this AE.

As expected from a phase I study where the majority of dosages are below the MTD, the response rate was low and not durable. The 1 measurable response was seen in a cat receiving a 1.5 mg/kg dose with a sarcoma of the right ilial wing; progression was noted at 9 weeks. Stable disease was seen in 6 of 9 (66%) of cats with oral SCC; however, most of these were not durable and in our opinion more likely a reflection of the behavior of these bony tumors rather than a sign of activity of chemotherapy. Two cats with oral SCC, however, did develop more durable responses, one of which maintains stable disease at that time of manuscript preparation (14 weeks).

The gold standard for determining response to treatment of cats with SCC has not been defined, although measuring bony lesions with calipers is likely a poor reflection of the biologic response to chemotherapy. Alternate methods of evaluation that should be considered for a phase II study include computed tomography and bone resorption markers such as C telopeptide.14,15

Docetaxel in humans is most commonly administered in a 3-weekly IV schedule; however, weekly administration is becoming more common because it causes less severe hematologic toxicoses and has similar efficacy for non-small-cell lung cancer.16 In this study, administration was evaluated in a 3 weekly fashion. Unfortunately, a CBC was evaluated at day 7, but not day 14, so it is not clear whether or not dose intensification to biweekly administration could be performed. However, hematologic AEs occurred within 7 days in this study, suggesting that more frequent administration should be evaluated in a future phase I study and that evaluation of a CBC sooner than day 7 may be prudent.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

a Millipred, 5 mg tab, Laser Pharmaceuticals LLC, Greenville, SC

b Taxotere, 20 mg vial/0.5 mL (before dilution), Sanofi-Aventis US LLC, Bridgewater, NJ

c Diphenhydramine, 50 mg/mL, Baxter Healthcare Corp, Deerfield, IL

d Dexamethasone sodium phosphate, 4 mg/mL, APP Pharmaceuticals LLC, Schaumburg, IL

e Pepcid, 10 mg/mL, Baxter Healthcare Corp

f Tevadaptor, B Braun Medical Inc, Bethlehem, PA

g Reglan, 5 mg/mL, Baxter Healthcare Corp

h Cerenia, 10 mg/mL, Pfizer Animal Health, New York, NY

Acknowledgment

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

This work was supported by the UW-Madison School of Veterinary Medicine Animal Cancer Tumor fund.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References
  • 1
    Bissery MC, Nohynek G, Sanderink GJ, et al. Docetaxel (Taxotere): A review of preclinical and clinical experience. Part I: Preclinical experience. Anticancer Drugs 1995;6:339355, 363–338.
  • 2
    National Cancer Institute. Cancer drug information: FDA approval for Docetaxel 2011, January 18, 2011. Available at: http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel. Accessed April 10, 2011.
  • 3
    Simon D, Schoenrock D, Baumgartner W, et al. Postoperative adjuvant treatment of invasive malignant mammary gland tumors in dogs with doxorubicin and docetaxel. J Vet Intern Med 2006;20:11841190.
  • 4
    McEntee MC, Rassnick KM, Bailey DB, et al. Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats. J Vet Intern Med 2006;20:13701375.
  • 5
    McEntee M, Silverman JA, Rassnick K, et al. Enhanced bioavailability of oral docetaxel by co-administration of cyclosporin A in dogs and rats. Vet Comp Oncol 2003;1:105112.
  • 6
    McEntee MC, Rassnick KM, Lewis LD, et al. Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing dogs. Am J Vet Res 2006;67:10571062.
  • 7
    Veterinary Co-operative Oncology Group - Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol 2004;2:195–213.
  • 8
    Thiesen J, Kramer I. Physico-chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers. Pharm World Sci 1999;21:137141.
  • 9
    Vail DM. Cancer clinical trials: Development and implementation. Vet Clin North Am Small Anim Pract 2007;37:10331057, v.
  • 10
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205216.
  • 11
    Malingre MM, Richel DJ, Beijnen JH, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 2001;19:11601166.
  • 12
    Koolen SL, Beijnen JH, Schellens JH. Intravenous-to-oral switch in anticancer chemotherapy: A focus on docetaxel and paclitaxel. Clin Pharmacol Ther 2010;87:126129.
  • 13
    Baker J, Ajani J, Scotte F, et al. Docetaxel-related side effects and their management. Eur J Oncol Nurs 2009;13:4959.
  • 14
    Gendler A, Lewis JR, Reetz JA, et al. Computed tomographic features of oral squamous cell carcinoma in cats: 18 cases (2002–2008). J Am Vet Med Assoc 2010;236:319325.
  • 15
    Wypij JM, Fan TM, Fredrickson RL, et al. In vivo and in vitro efficacy of zoledronate for treating oral squamous cell carcinoma in cats. J Vet Intern Med 2008;22:158163.
  • 16
    Schuette W, Nagel S, Blankenburg T, et al. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol 2005;23:83898395.