Efficacy of Oral Lomustine in cat tumors including VAS

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Efficacy of Oral Lomustine in cat tumors including VAS

Postby guest » Fri Oct 03, 2003 7:16 pm

Hematological Toxicity and Therapeutic Efficacy of Lomustine in 20 Tumor-Bearing Cats: Critical Assessment of a Practical Dosing Regimen

Timothy M. Fan, DVM, Diplomate ACVIM (Internal Medicine, Oncology); Barbara E. Kitchell, DVM, PhD, Diplomate ACVIM (Internal Medicine, Oncology); Ravinder S. Dhaliwal, DVM, Diplomate ACVIM (Oncology); Pamela D. Jones, DVM; John G. Hintermeister, DVM; Biman C. Paria, PhD 
Journal of the American Animal Hospital Association
July 1, 2002


Hematological Toxicity and Therapeutic Efficacy of Lomustine in 20 Tumor-Bearing Cats: Critical Assessment of a Practical Dosing Regimen

Twenty cats with spontaneously arising tumors received oral lomustine at a dose range of 32 to 59 mg/m2 every 21 days. Due to biohazard concerns associated with lomustine capsule reformulation, a standardized 10-mg capsule dosage was used for all cats regardless of body weight. Severe hematological toxicity was infrequent, with the incidence of either grade III or IV neutropenia and thrombocytopenia being 4.1% and 1.0%, respectively. Cats receiving higher cumulative doses of lomustine trended toward a greater likelihood for progressive neutropenia (P=0.07). Two cats with lymphoma, two cats with fibrosarcoma, and one cat with multiple myeloma achieved a measurable partial response to lomustine therapy. Cats treated with higher dosages of lomustine trended toward statistically significant higher response rates (P=0.07).

J Am Anim Hosp Assoc 2002;38:357–363.

Timothy M. Fan, DVM, Diplomate ACVIM (Internal Medicine, Oncology); Barbara E. Kitchell, DVM, PhD, Diplomate ACVIM (Internal Medicine, Oncology); Ravinder S. Dhaliwal, DVM, Diplomate ACVIM (Oncology); Pamela D. Jones, DVM; John G. Hintermeister, DVM; Biman C. Paria, PhD 

Keywords Lomustine, Tumors, Feline, Lymphoma, Fibrosarcoma, Multiple myeloma. 

From the Department of Veterinary Medicine (Fan, Kitchell, Jones, Hintermeister, Paria), Veterinary Medical Teaching Hospital, University of Illinois,1008 West Hazelwood Drive, Urbana, Illinois 61802-4714 and the All-Care Animal Referral Center (Dhaliwal), 18440 Amistad Street, Fountain Valley, California 92708.

Address all correspondence to Dr. Fan.

Introduction

Lomustinea (CeeNU) is classified as an antitumor alkylating agent in the nitrosourea family. The nitrosoureas are highly lipid soluble, with rapid transport across the blood-brain barrier. In humans, lomustine has been shown to be effective in the treatment of refractory Hodgkin’s lymphoma and in the treatment of primary and metastatic brain tumors.1 Toxicities associated with long-term lomustine administration in humans include delayed, cumulative myelotoxicity with thrombocytopenia being more severe than leukopenia; pulmonary infiltrates, fibrosis, or both; nausea and vomiting; reversible hepatotoxicity; and nephrotoxicity.2 In the dog, lomustine has been reported to be a useful rescue agent for multicentric lymphosarcoma.3 Lomustine has also been shown to possess activity against canine mast cell tumors and cutaneous lymphosarcoma.4,5 Because of lomustine’s high lipid solubility and ability to cross the blood-brain barrier, histopathologically confirmed intracranial neoplasms in dogs have been treated with varying degrees of success.6 Toxic-ity trials in healthy beagle dogs and clinical trials in tumor-bearing dogs have shown lomustine to be a hematopoietic toxin.3,4,6,7 In addition to its myelotoxicity, lomustine has been demonstrated to induce hepatotoxicity in healthy beagle dogs8 and has been incriminated as a cause of hepatic failure in tumor-bearing dogs.9

Little information exists regarding the safe and efficacious use of lomustine in tumor-bearing cats. One preliminary study concluded that a single oral dose of lomustine may be safely administered to cats at a dosage of 60 mg/m2 body surface area, although chronic toxicity data has yet to be published.10 Lomustine is commercially available in 10-, 40-, and 100-mg capsules. In order to minimize biohazard concerns associated with reformulation of these capsules, the authors elected to treat all cats, regardless of body size, with a standard 10-mg capsule dosage. Realizing that a uniform 10-mg dosage would produce a wide therapeutic dose range and could result in differences in hematological toxicity and therapeutic efficacy, the authors undertook this retrospective study to evaluate the utility of this simple dosing method in tumor-bearing, client-owned cats. The purpose of this study was to document the antitumor activity and frequency of hematopoietic toxicity of lomustine in cats with various malignant tumors.

Materials and Methods

Tumor-Bearing Cats

All tumor-bearing cats entered into the protocol were treated and evaluated at the University of Illinois’ Veterinary Cancer Care Clinic (n=14) or All-Care Animal Referral Center (n=6) between December 20, 1997 and December 20, 2000. In 19 cases, there was a definitive cytopathological or histopathological diagnosis of malignant neoplasia. In the remaining cat, a distinct, contrast-enhancing intracranial mass was identified on computed tomography (CT), but a cytopathological or histopathological diagnosis of this mass was not obtained.

Treatment

To be included in the study, all 20 cats had to have received at least one 10-mg dosage of lomustine, in conjunction with a complete blood count (CBC) and physical examination before and after lomustine administration. All 20 cats were dosed with a commercially available 10-mg capsule,a regardless of body weight. Lomustine was given orally, and cats were monitored for an hour after administration to ensure that the drug was not regurgitated or vomited. A total of 97 doses of lomustine were administered to the entire study population. The cumulative numbers of lomustine doses per cat were as follows: one dose (n=4), three doses (n=8), four doses (n=1), seven doses (n=1), eight doses (n=2), 10 doses (n=3), and 12 doses (n=1). The lowest and highest calculated dose intensities evaluated in this trial were, respectively, 32 and 59 mg/m2 body surface area every 21 days. A total of six cats received adjunctive therapy in addition to oral lomustine, with five cats receiving anti-inflammatory doses of prednisone and one cat receiving piroxicam. Only four cats were treated with lomustine as a first-line agent; the remaining 16 cats received lomustine as a salvage chemotherapeutic agent after multiple failed treatment modalities, including chemotherapy, radiation therapy, surgery, or a combination of the above, with evidence of progressive disease.

Follow-Up

All cats were evaluated by physical examination and CBC at an average of 15 days after lomustine administration (median, 14 days; range, 3 to 50 days). Information pertaining to the effects of lomustine administration, including clinical signs of drug-induced toxicoses and clinical signs associated with neoplastic disease progression, were obtained from owners and attending clinicians. Lomustine therapy was continued in all cats until definitive progressive disease or until the cat’s quality of life diminished to an unacceptable level, as determined by the owner or the attending veterinarian.

Grouping of Subjects

In 10 cats (Group A), a direct means of assessing tumor response was possible. In Group A, the dimensions of neoplastic tissue or the measurement of paraneoplastic hypergammaglobulinemia were recorded prior to the induction of lomustine therapy and then again upon each follow-up examination. In the remaining 10 cats (Group B), response to lomustine therapy could not be directly evaluated. Reasons for classification in Group B included treatment of microscopic disease following surgical reduction (n=7) and financially restrictive imaging procedures (i.e., CT or magnetic resonance imaging [MRI]) required to assess response to therapy (n=3).

Hematological Toxicity Grading

All cats were evaluated with a CBC on an average of 15 days after lomustine administration. Hematological toxicity was graded according to the guidelines established by the World Health Organization [Table 1].

Response Evaluation

For cats in Group A, complete or partial remission and remission duration were measured in days. Duration of remission was defined as the time from the tumor achieving maximal reduction in size until progression in size. A complete remission (CR) was defined as the complete disappearance of clinically detectable disease. A partial remission (PR) was defined as _50% decrease in overall tumor size and no evidence of new tumor. Stable disease (SD) was defined as <50% decrease or <50% increase in overall tumor size, without development of new tumor. Progressive disease (PD) was defined as an unequivocal increase of at least 50% in overall tumor size, or the appearance of new tumor. Response to lomustine therapy for Group B cats was determined by the following subjective methodology. Cats with microscopic disease or requiring special imaging procedures that failed to show evidence of clinical disease progression upon physical examination were categorized as being nonevaluable (NE). If physical examination findings or clinical signs supported disease progression, or if quality-of-life scores assessed by the attending clinician or owner were considered diminished, cats were categorized as having PD.

Results

The study included 20 cats, most being domestic shorthairs (n=18), with a mean weight of 3.8 kg (range, 2.4 to 5.4 kg) and mean age of 10.5 years (range, 3 to 19 years). Six cats had lymphoma, five had fibrosarcoma, and three had visceral mast cell disease. Tumors diagnosed in the remaining six cats included multiple myeloma (n=1), cutaneous melanoma (n=1), nasal carcinoma (n=1), hepatocellular carcinoma (n=1), nephroblastoma (n=1), and intracranial mass (n=1). Four cats were treated primarily with lomustine, while the remaining 16 cats failed prior treatment modalities. These modalities included surgery alone (n=1); surgery with adjunctive chemotherapy other than lomustine (n=3); surgery with adjunctive chemotherapy other than lomustine and radiation therapy (n=3); adjunctive chemotherapy other than lomustine (n=6); and adjunctive chemotherapy other than lomustine and radiation therapy (n=3).

Dosage and Toxicological Effects

All 20 cats were given a standard 10-mg lomustine capsule, resulting in a variable dose intensity range of 32 to 59 mg/m2 (mean, 42.9 mg/m2; median, 42 mg/m2) every 21 days. Out of the total of 97 doses of lomustine administered, three episodes of grade IV neutropenia, one episode of grade III neutropenia, and one episode of grade III thrombocytopenia were recorded. The incidence rates of grade III and IV neutropenia and thrombocytopenia were 4.1% and 1.0%, respectively. One cat with concurrent feline leukemia virus (FeLV) infection and advanced neoplastic bone marrow involvement, experienced an episode of grade IV neutropenia (0 cells/µL); this cat was euthanized for complications secondary to myelosuppression and sepsis. All other cats manifesting with grade III or IV neutropenia or thrombocytopenia recovered uneventfully from their hematological toxicity within 7 to 14 days without the administration of exogenous granulocyte colony-stimulating factors (Neupogenb).

To determine if the incidence of hematological toxicity was correlated with dose intensity, the study population was divided into two cohorts. Group 1 included cats treated at the lower 50% of dose intensity (32 to 45 mg/m2), and Group 2 consisted of cats in the upper 50% of dose intensity (45 to 59 mg/m2). The incidence of either grade III or IV neutropenia with respect to varying dose intensities established by Groups 1 and 2 was not significant when analyzed by linear regression (P=0.22). Similarly, the frequency of either grade III or IV thrombocytopenia analyzed against Groups 1 and 2 failed to reveal any statistically significant differences by linear regression (P=0.67). When the incidence of either grade III or IV neutropenia or thrombocytopenia was compared with the achievement of a therapeutic response by one-way analysis of variance (ANOVA) (P=0.45, P=0.18, respectively), no significant differences were identified. Prior drug therapy did not have a statistically significant effect on the likelihood of developing grade III or IV neutropenia or thrombocytopenia as analyzed by one-way ANOVA (P=0.16, P=0.89, respectively).

The potential for cumulative myelotoxicity from long-term serial lomustine administration was evaluated. Total cumulative dose of lomustine compared to the likelihood for progressive thrombocytopenia was not significant by Spearman’s rank correlation coefficient (P=0.42). However, a trend toward significant progressive neutropenia, as analyzed by Spearman’s rank correlation coefficient (P=0.07), was detected when cases were evaluated with regard to cumulative dose of lomustine.

Response

Of the 10 cats in Group A with measurable disease [Table 2], response rates were as follows: CR (n=0), PR (n=5), SD (n=3), and PD (n=2). The overall response rate (CR or PR) for this subgroup of cats was therefore 50% (5/10). The five responding cats consisted of two cats with lymphoma, two cats with fibrosarcoma, and one cat with multiple myeloma. In Group A, the five responding cats had a median remission duration of 65 days (range, 14 to 107 days). Three of the responding cats (one each with lymphoma, multiple myeloma, and fibrosarcoma) received adjunctive therapy in the form of daily antiinflammatory prednisone. These same three responding cats remained on lomustine and prednisone until death, with a median survival time of 72 days (range, 30 to 178 days). The remaining two responders were switched to other chemotherapeutic agents following disease progression and were censored from the calculation of survival time for this group. The overall median survival time of Group A cats (i.e., responders and nonresponders) was 120 days (range, 31 to 178 days).

Of the seven cats in Group B with microscopic disease [Table 3], four cats received single-agent lomustine until death or euthanasia, and two cats received lomustine and prednisone until death. The median survival time of these six cats was 153 days (range, 60 to 308 days). The remaining cat was switched to alternative chemotherapeutic agents following disease progression and was censored from median survival time calculation. Three cats in Group B had neoplastic disease initially identified with either CT or MRI [Table 3]. All three cats had a subjective response to lomustine therapy based upon physical examination findings and amelioration of clinical signs that included epi-staxis, nasal discharge, facial deformity, and neurological deficits. Two of these cats received exclusively single-agent lomustine therapy, while the third cat received lomustine and piroxicam. Two of the three cats remain alive. Although these three cats clinically appeared to benefit from lomustine therapy, an accurate and objective response to lomustine therapy could not be evaluated due to the financially restrictive costs of serial CT or MRI procedures.

The documented measurable response rate of all 20 cats evaluated in this study was a conservative 25% (5/20). Response to therapy for Group A and Group B cats analyzed against tumor type (round cell, carcinoma, or sarcoma) by one-way ANOVA (P=0.34) or prior drug therapy by Mann-Whitney rank sum test (P=0.70) was not significant. When the study population was divided into two groups based upon dose intensity, cats treated in the upper 50% of the dose intensity range (Group 2) trended toward statistically significant higher response rates by one-way ANOVA (P=0.07) when compared to cats treated in the lower 50% of the dose intensity range (Group 1).

Discussion

The primary purposes of this study were to evaluate the potential for hematological toxicity and to assess therapeutic efficacy associated with oral lomustine administration in client-owned, tumor-bearing cats. Due to the potential biohazards associated with lomustine capsule reformulation, the authors chose to study the utility of giving a commercially available, 10-mg capsule dosage regardless of individual body weight. Because of the wide dose intensity range consequently seen in this study (32 to 59 mg/m2 every 21 days), the results must be analyzed cautiously with the understanding that a more stringent dosing regimen based exclusively on a mg/m2 body weight or kg body weight may be expected to produce different outcomes.

In humans, the most common and serious toxicity of lomustine is myelosuppression. Maximum myelosuppression occurs 4 to 6 weeks after drug administration and appears to be dose dependent. Dose intensity appears to play an important role in the onset of toxicity in humans.11 Toxicities associated with long-term lomustine administration in humans include a delayed, cumulative myelosuppression, with thrombocytopenia being more severe than leukopenia.2

Single-dose hematological toxicity for lomustine has been evaluated in healthy beagle dogs. Beagle dogs receiving 5 mg/kg body weight of lomustine suffered either grade III or IV neutropenia, with hematological recovery 20 days after drug administration.7 Beagle dogs receiving doses of 10 to 30 mg/kg body weight of lomustine experienced grade IV neutropenia, lymphopenia, and thrombocytopenia, and subsequent death from sepsis, intractable bleeding, or gastrointestinal toxicity.7 Myelotoxicity in the form of either grade III or IV neutropenia has been reported with oral lomustine administration in dogs with multicentric lymphosarcoma, mast cell tumors, and intracranial neoplasms.3,4,6 Despite the observation of either grade III or IV neutropenia following single dosage of 90 mg/m2, severe thrombocytopenia or cumulative myelosuppression was not reported in these clinical studies.3,4

Myelotoxicity can be a common adverse side effect of many chemotherapeutic agents. In some clinical trials, the hematological toxicities associated with lomustine therapy may be attributed to its use at high-dose intensities and from its non-cell cycle-specific cytotoxicity. In this study, oral lomustine administered at a dose intensity range of 32 to 59 mg/m2 every 21 days produced minimal hematological toxicities. Out of 97 doses of lomustine, the incidence rates of either grade III or IV neutropenia or thrombocytopenia were 4.1% and 1.0%, respectively. Only one fatal myelotoxic event was documented. For this one fatality, lomustine cytotoxicity likely contributed to the grade IV neutropenia recorded. However, ascribing the observed fatal myelotoxic event to lomustine must be tempered by the fact that this individual cat was FeLV positive and had neoplastic invasion of the bone marrow.

The low incidence of hematological toxicity reported in this study suggests that the dose range of 32 to 59 mg/m2 every 21 days, albeit safe and efficacious against certain feline neoplasms, falls short of the maximally tolerated dose (MTD) of lomustine in cats. A prospective dose escalation study with lomustine is warranted to determine if therapeutic response rates, disease-free intervals, and survival times can be increased without causing unacceptable hematological, biochemical, or idiosyncratic toxicities.

Cumulative myelotoxicity has been reported to be a hematological side effect in humans following chronic lomustine therapy.2 In contrast to what has been documented in humans treated long term with lomustine, this study failed to identify any statistical correlation between increasing cumulative doses of lomustine and onset of progressive and refractory thrombocytopenias. The failure to identify progressive thrombocytopenia as a consequence of long-term lomustine administration may be explained by the limited number of cats in this study population that survived for any significant amount of time following treatment as well as the mild dose intensity utilized. Interestingly, a correlation between cumulative lomustine therapy and progressive neutropenia trending toward statistical significance was identified in this study. The clinical importance of this finding should be viewed with caution. Although there was a trend for cats to become more neutropenic with higher cumulative doses of lomustine, the actual incidence of grade III or IV neutropenia that necessitated treatment delays or dose de-escalation was not increased with higher cumulative doses of lomustine. Progressive neutropenia identified in this study may have been partially attributed to the use of lomustine as a rescue chemotherapeutic agent in a majority (15/20) of the treated cats. The prior use of multiagent, dose-intense protocols in conjunction with the non-cell cycle-specific cytotoxicity of lomustine may have resulted in bone-marrow hematopoietic stem-cell depletion.

In humans, lomustine is effective against and licensed for the treatment of round cell neoplasms such as refractory Hodgkin’s lymphoma. Furthermore, because lomustine is highly lipid soluble, it crosses the blood-brain barrier and is useful for the treatment of primary and metastatic brain tumors. Lomustine’s antitumor activity appears to be similar in dogs. Round cell tumors including relapsing multicentric lymphosarcoma, cutaneous lymphosarcoma, and mast cell tumors have been successfully treated with lomustine.3-5 In addition, lomustine has been used in dogs with primary brain tumors.6

In the authors’ study, 10 out of 20 cats were cytopathologically or histopathologically diagnosed with one of three round cell tumors, which included lymphosarcoma (n=6), visceral mastocytosis (n=3), and multiple myeloma (n=1). Interestingly, three of the five cats with macroscopic disease achieving a PR had round cell tumors. Although achievement of a response proved not to be statistically significant when evaluated with regard to tumor type, this finding is likely a type II statistical error due to the small number of cats in this study achieving a therapeutic response. Given lomustine’s documented efficacy in the treatment of Hodgkin’s lymphoma in humans and relapsing multicentric and cutaneous lymphoma in dogs, a phase II clinical trial evaluating the use of single-agent lomustine for the treatment of feline lymphomas would be justified. The remaining two cats with macroscopic disease in this study that achieved a partial response to therapy had fibrosarcomas (oral and vaccine-associated).

The documented response rate for lomustine in this study was 25% (5/20). Based on the fact that only quantifiable responses from Group A cats (i.e., the cats with macroscopic disease) were used to calculate the response rate for the entire study population, this response rate of 25% may be conservative. Three of the Group A cats (one each with lymphoma, multiple myeloma, and fibrosarcoma) achieving a partial response were treated not only with lomustine, but also with daily anti-inflammatory doses of prednisone. All three cats responding to lomustine and prednisone therapy had previously failed multiagent chemotherapy protocols that contained prednisone. Therefore, the observed response in these three cats was attributed to the antitumor activity of lomustine, as opposed to the antiinflammatory or cytotoxic properties of prednisone.

Response to lomustine therapy in Group B cats could not be accurately evaluated, due either to the treatment of microscopic disease or the need for serial CT or MRI to determine response. Two cats received adjunctive anti-inflammatory prednisone, and one cat received adjunctive piroxicam in addition to lomustine therapy. The two cats receiving adjunctive antiinflammatory prednisone had previously failed multimodality therapies that included prednisone. Despite the inability to document response in Group B cats, some cats from this group experienced long survival times and dramatic improvement in their clinical signs following lomustine therapy. One Group B cat, treated with single-agent lomustine for an intracranial mass, had complete resolution of neurological deficits and was still alive at the time of this writing, 420 days after starting therapy. Another Group B cat, with nasal carcinoma treated with lomustine and piroxicam, experienced resolution of facial deformity and epistaxis and had an ongoing survival time of 385 days.

Although achievement of a therapeutic response was not significant when evaluated with regard to tumor type (i.e., round cell, carcinoma, and sarcoma), a trend toward significance was detected when therapeutic response was compared to dose intensity. Group 2 cats treated with higher dose intensity (45 to 59 mg/m2) trended toward having a greater chance of achieving a therapeutic response when compared to Group 1 cats treated with lesser dose intensity (32 to 45 mg/m2). The statistical trend for a higher response rate at higher dose intensities, in conjunction with the extremely low incidence for documented myelotoxicity, supports the treatment of cats at the higher dose intensity used in this study. The authors speculate that using a higher dose would maximize the chance for therapeutic response while not increasing the risk for hematological toxicity. However, dose optimization in cats needs to be further investigated.

Hepatotoxicity is a serious but rarely reported adverse effect of lomustine therapy in humans and dogs.2,8,9 Hepatotoxicity was not clinically manifested by any of the cats included in this retrospective study; however, postmortem histopathology of the liver was not performed in any of the treated cats enrolled in this study. Failure to identify hepatotoxicity in these cats may have been due to a number of factors, including sporadic biochemical profile evaluation, short survival times, and an inadequate population size to document this potentially rare toxicity.

Conclusion

The incidence of hematological toxicity and response rates seen in this retrospective study must be interpreted with caution, because several dose intensities, varying numbers of treatments, and only a small number of cats were evaluated. However, the conservatively calculated response rate of 25% is promising. Coupled with the cost-effective aspect of this drug in veterinary medicine and the low adverse effect rate reported in this study, the authors’ findings suggest that the use of lomustine is both practical and tolerable. There is certainly ease and practicality in dosing all cats, regardless of body weight, with a standardized 10-mg dosage. However, the findings summarized in this report forced the authors to conclude that this dosing method is not optimal. The authors have discontinued the 10-mg per cat dosing as a standard in their clinic. In the future, the authors plan to determine the MTD of lomustine using reformulated capsules, as well as to initiate specific phase II clinical trials evaluating lomustine’s efficacy against a variety of feline malignancies.

 

a CeeNU; Bristol-Myers Squibb Co., Princeton, NJ

b Neupogen; Amgen, Thousand Oaks, CA

 

References

1. Rosenblum ML, Reynolds AF, Smith KA. Chloroethyl-cyclohexyl-nitrosourea (CCNU) in the treatment of malignant brain tumors. J Neurosurg 1973;39:306-314.

2. Weiss RB, Issell BF. The nitrosoureas: carmustine (BCNU) and lomustine (CCNU). Cancer Treat Rev 1982;9(4):313-330.

3. Moore AS, London CA, Wood CA, et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J Vet Intern Med 1999;13:395-398.

4. Rassnick KM, Moore AS, Williams LE, et al. Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med 1999;13:601-605.

5. Graham JC, Myer RK. Pilot study on the use of lomustine (CCNU) for the treatment of cutaneous lymphoma in dogs. In: Proceedings, 17th Ann ACVIM Forum, 1999:273.

6. Fulton LM, Steinberg SH. Preliminary study of lomustine in the treatment of intracranial masses in dogs following localization by imaging techniques. Sem Vet Med Surg (Sm Anim) 1990;5:241-245.

7. Abb J, Netzel B, Rodt HV, Thierfelder S. Autologous bone marrow grafts in dogs treated with lethal doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Cancer Res 1978;38(7):2157-2159.

8. Henry MC, Davis RD, Schein PS. Hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs: the use of serial percutaneous liver biopsies. Toxicol Appl Pharmacol 1973;25:410-417.

9. Kristal O, Rassnick KM, Gliatto J, et al. Hepatotoxicity associated with CCNU chemotherapy in dogs. In: 19th Ann Vet Cancer Soc Conf, 1999:15.

10. Rassnick KM, Northrup NC, Kristal O, et al. Phase I/II evaluation of CCNU (lomustine) in tumor bearing cats: preliminary report. In: 19th Ann Vet Cancer Soc Conf, 1999:65.

11. Koller CA, Gorski CC, Benjamin RS, Legha SS, Papadopoulos NE, Plager C. A phase I trial of weekly lomustine in patients with advanced cancer. Cancer 1994;73(1):236-239.
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cats with lymphosarcoma

Postby guest » Thu Jan 22, 2004 6:33 pm

Therapy for Australian cats with lymphosarcoma.
Aust Vet J 79[12]:808-17 2001 Dec
Malik R, Gabor LJ, Foster SF, McCorkell BE, Canfield PJ
OBJECTIVE: To determine the response of Australian cats with lymphosarcoma to chemotherapy and/or surgery in relation to patient and tumour characteristics, haematological and serum biochemical values and retroviral status. DESIGN: Prospective study of 61 client-owned cats with naturally-occurring lymphosarcoma subjected to multi-agent chemotherapy and/or surgery. PROCEDURE: An accepted chemotherapy protocol utilising l-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate and prednisolone was modified and used to treat 60 cats with lymphosarcoma. Clinical findings were recorded before and during therapy. As far as practical, cases were followed to death, euthanasia or apparent cure. Owner satisfaction with the results of chemotherapy was determined using a questionnaire sent after the completion of chemotherapy. RESULTS: One cat, with lymphosarcoma limited to a single mandibular lymph node, was treated using surgery alone and was cured. The other 60 cats were treated using multi-agent chemotherapy, although seven cats with localised intestinal, ocular and subcutaneous lesions had these lesions partially (2 intestinal lesions) or completely (2 eyes, 2 intestinal lesions and a cluster of regional lymph nodes) resected prior to starting chemotherapy. The median survival time for these 60 cats was 116 days. Of the 60 cats, 48 rapidly went into complete remission following the administration of 1-asparaginase, vincristine and prednisolone (complete remission rate 80%) and these cats had a median survival of 187 days. Three cats were censored from further analysis as their long-term survival data were uninterpretable because they died of causes unrelated to lymphosarcoma or were prematurely lost to follow-up. Twenty cats were classed as 'long-term survivors' based on survival time in excess of one year and at least 14 were 'cured' based on the absence of physical evidence of lymphosarcoma 2-years after initiating treatment. In other words, of the 48 cats that reached complete remission, in excess of 29% were 'cured'. Despite detailed analysis, few meaningful prognostic indicators based on patient or tumour characteristics were identified, although long-term survivors were more likely to be less than 4-years (P= 0.04) and to have tumours of the T-cell phenotype (P= 0.06). Excluding the one FeLV ELISA-positive cat with mediastinal LSA, 7 of 9 cats less than 4 years-of-age were long-term survivors (median survival time >1271 days). There was a strong association between achieving complete remission and long-term survival (P = 0.003). On the basis of 27 replies to a questionnaire, owners were generally very satisfied with the response to chemotherapy, irrespective of the survival time of the individual patient. Eighty five percent of owners expressed complete satisfaction with their decision to pursue chemotherapy and 70% believed their cat's health status improved during the first 2-weeks of treatment. Importantly, 78% of owners considered that chemotherapy required a very substantial time commitment on their part. CONCLUSIONS: It was possible to cure approximately one quarter of cats with lymphosarcoma using sequential multi-agent chemotherapy and/or surgery. FeLV-negative cats younger than 4 years (typically with mediastinal lymphosarcoma) had a particularly favourable prognosis. The decision to embark on chemotherapy should be based on the results of induction chemotherapy with l-asparaginase, vincristine and prednisolone, as the response to this was a good predictor of long-term survival. Cats surviving the first 16 weeks of chemotherapy generally enjoyed robust remissions (in excess of 1 year) or were cured of their malignancy.
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