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Keywords:

  • Antiangiogenic therapy;
  • Metronomic chemotherapy;
  • Osteosarcoma;
  • Palliative therapy

Abstract

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

Background: Metronomic chemotherapy with alkylating agents has been shown to suppress tumor angiogenesis and prevent tumor recurrence in some settings. The use of adjuvant lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) administered in a metronomic fashion has not been evaluated in dogs.

Hypothesis: Oral metronomic administration of lomustine will be well tolerated in dogs with spontaneously occurring malignant neoplasms.

Animals: Eighty-one dogs with naturally occurring primary or metastatic tumors received metronomic administration of lomustine.

Methods: Dogs were enrolled prospectively after cytological or histological diagnosis of a tumor that was unresectable, incompletely resected, refractory to chemotherapy, or metastatic. Dogs received once daily lomustine (2.84 mg/m2 PO). End points of the trial were clinical, hematologic, or biochemical evidence of toxicosis, tumor progression, or death.

Results: Starting dosage (median) was 2.84 mg/m2 PO daily and treatment duration was 98 days (median, range, 1–770 days). The drug was discontinued in 22 dogs because of toxicoses. Toxicoses occurred in 13 dogs with gastrointestinal toxicosis, 4 dogs with thrombocytopenia, 3 dogs with increased alanine transaminase, 1 dog with neutropenia, and 1 dog with progressive azotemia. Eight dogs developed some degree of azotemia during treatment. Hepatotoxicosis was observed at a median of 265 days in 11 dogs. Thrombocytopenia was identified at a median of 432 days of administration.

Conclusions and Clinical Importance: In dogs with metastatic or terminal neoplasms without renal compromise, metronomic administration of lomustine was well tolerated. This can provide a treatment strategy for dogs that do not have other standard-care treatment options, and warrants evaluation in primary therapy.

Abbreviations:
ALT

alanine transaminase

BUN

blood urea nitrogen

CR

complete response

NSAIDs

nonsteroidal anti-inflammatories

PD

progressive disease

PR

partial response

SD

stable disease

TTP

time to progression

Metronomic chemotherapy is defined as the frequent administration of small doses of drugs with no extended rest periods. Many conventional agents might have antiangiogenic effects that contribute to their efficacy.1,2 Cyclophosphamide is the most commonly studied alkylating agent to be used in this fashion with demonstrable activity inhibiting tumor angiogenesis in mice and humans.3,4 To date, published clinical studies of metronomic chemotherapy in animals have focused on cyclophosphamide. Metronomic administration of cyclophosphamide and piroxicam delayed recurrence of incompletely resected soft tissue sarcomas.5 When dogs were treated for splenic hemangiosarcoma with metronomic administration of cyclophosphamide, no statistical difference in survival was found compared with doxorubicin-based cytotoxic chemotherapy, suggesting that the 2 treatments may be equivalent in efficacy for this disease.6 There was excellent tolerability and reduced adverse events compared with traditional cytotoxic chemotherapy. In both studies, a small number of dogs developed sterile hemorrhagic cystitis secondary to chronic cyclophosphamide administration.

Lomustine was selected for the present study to avoid hemorrhagic cystitis in dogs receiving chronic therapy with cyclophosphamide, and to evaluate a commonly used alkylating agent for metronomic tumor management. No prior reports exist of using this agent in a metronomic schedule. Adverse effects associated with cytotoxic dosages of lomustine include gastrointestinal upset, myelosuppression, and hepatotoxicity.7–9 In humans, cumulative myelosuppression can occur after multiple doses of lomustine, and infrequent reports of nephrotoxicity and delayed hepatoxicity exist.10–13 Infrequent adverse events of renal toxicosis, bicavitary effusion, and unexplained fever have been documented in dogs.7,8 Clinical reports of lomustine as a single agent in animals are limited.7–9 To our knowledge, evaluation of lomustine in a metronomic protocol has not been reported in dogs. The purpose of this prospective study was to determine the tolerability of metronomic administration of lomustine in tumor-bearing dogs, to define toxicity associated with the protocol, and to document evidence of antitumor activity.

Materials and Methods

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

Dog Selection

Dogs were eligible to receive metronomic administration of lomustine if they had a cytologically or histologically confirmed neoplasm. Additionally, dogs met one or more of the following criteria: unresectable tumor; incompletely excised tumor with microscopic residual disease; chemotherapy refractory tumor burden; or presence of gross metastasis. Because the end point of the study was evaluation of toxicosis, dogs receiving other medications, including nonsteroidal anti-inflammatories (NSAIDs), at the time of initiating lomustine were allowed. Dogs were required to have adequate bone marrow function and an expected survival of 4 weeks without treatment. Adequate marrow function was defined as a neutrophil count >3,000 cells/μL and a platelet count >100,000/μL. Dogs included in the final analysis received lomustine administered for a minimum of 1 day, and had adequate follow-up information available to assess response to treatment, tolerability, and toxicosis. Evaluations before treatment included a complete physical examination, CBC, serum biochemistry profile, urinalysis, 3-view thoracic radiographs, and, in most cases, abdominal ultrasound examination. Complete staging was not performed for all dogs. Data recorded included signalment; tumor type; anatomic site of primary tumor; macroscopic versus microscopic disease; presence or absence of nodal or distant metastasis; prior treatments received; CBC data; results of alanine transaminase (ALT), blood urea nitrogen (BUN), and creatinine; dosage of lomustine received; duration of therapy; concurrent medications; adverse drug effects; response to treatment; and date of death.

Treatment Protocol

Dogs were treated with a compounded capsule of lomustine PO once daily. A starting dosage of 60 mg/m2 body surface area was divided over 21 days (median dosage administered 2.84 mg/m2). Lomustine was reformulated into capsules by a compounding pharmacy and the dose was prepared to the nearest 0.1 mg. The total dose at the time of the first compounding was recorded. Dose reductions and delays were allowed at the discretion of the attending clinician, based on observed toxicosis. A CBC and serum chemistry were recommended within 4 weeks after starting metronomic administration of lomustine. Subsequent hematologic evaluations were recommended every 6–8 weeks. Discontinuation of the drug was recorded, when it occurred, along with adverse events observed.

Toxicosis

Evidence of lomustine-associated toxicosis was evaluated by examination of neutrophil count, platelet count, PCV, results of ALT, BUN, creatinine, and history obtained from the owners. All adverse effects were graded in accordance with standard Veterinary Cooperative Oncology Group criteria.14 Gastrointestinal toxicosis was not uniformly graded in the medical records, but owner reports were used to assess severity of toxicosis. Medications being administered concurrently with lomustine were recorded.

Response

For dogs with measurable disease, serial measurements of accessible disease were requested on dogs when possible. Tumors were evaluated with calipers or electronic evaluation of 3-view thoracic radiographs or abdominal ultrasound. Response to treatment was classified as follows: complete response (CR), 100% reduction of all gross measurable disease; partial response (PR), >50% but <100% reduction in the volume of measurable disease and no development of new lesions; stable disease (SD), <50% reduction in the volume of measurable disease and no development of new lesions; and progressive disease (PD), >25% increase in the volume of measurable disease or appearance of new lesions. Responses were required to persist for 30 days to be reported. Time to progression (TTP) was defined as the period from the beginning of chemotherapy in dogs with CR, PR, or SD until observed tumor progression.

Statistical Analysis

The effects of age, weight, sex, disease status (gross versus microscopic), presence or absence of metastatic disease, initial neutrophil count, initial platelet count, initial ALT, concurrent medications (prednisone, NSAIDs, etc.), prior treatment (surgery, chemotherapy, radiation therapy), and total cumulative dosage of lomustine were evaluated as categorical variables for association with the development of grade 2 or higher toxicosis by the Fisher's exact test. All dogs that began treatment with lomustine were included in analyses of TTP and survival. Overall response rate was defined as the number of dogs with a CR or PR divided by the number of dogs evaluable. TTP, survival, and time to development of toxicosis were calculated by the use of the Kaplan-Meier log-rank method. TTP was defined as the time from the first day of metronomic administration of lomustine until progression of disease limiting quality of life, death associated with disease, or discontinuation of lomustine because of toxicosis. Dogs lost to follow-up or alive at the conclusion of the study period were censored at that point in time to event analyses. Results were considered significant at P < .05. Statistical analysis was performed by commercially available software (SigmaStat).a

Results

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

Dog and Tumor Features

Eighty-one dogs were treated with oral metronomic administration of lomustine, 52 of which had complete hematologic and recommended biochemical data to assess toxicosis and all of which had outcome reported (Table 1).

Table 1.   Characteristics of dogs receiving metronomic administration of lomustine.
 Value (n)
  1. NSAID, nonsteroidal anti-inflammatory.

Age (years) 
 Median (range)10 (2–14)
Weight (kg)
 Weight (kg) (median, range)33.9 (5.3–60.4)
Sex
 Male neutered37
 Male intact2
 Female spayed42
Breed
 Golden Retriever12
 Labrador Retriever11
 Mixed breed11
 German Shepherd, Cocker Spaniel, Malamute, Rottweiler4 each
 Shih Tzu3
 Mountain Dog, Brittany Spaniel, English Bulldog, German Shorthaired Pointer2 each
 Airdale, Bichon Frise, Giant Schnauzer, Border Collie, Boston Terrier, Doberman Pinscher, Chow Chow, Chesapeake Bay Retriever, Great Pyrenees, Greyhound, Jack Russell Terrier, Kelpie, Maltese, Bull Mastiff, Miniature Schnauzer, Pug, Standard Poodle, West Highland White Terrier, Pembroke Welsh Corgi, Rhodesian Ridgeback1 each
Previous therapy
 Surgery21
 Chemotherapy29
 Immunotherapy (melanoma vaccine)2
 Radiation therapy22
  Palliative intent15
  Curative intent7
Concurrent therapy
 NSAID29
 Prednisone7
 Tramadol6

At the start of treatment with metronomic administration of lomustine, 58 of the 81 dogs (72%) had macroscopic disease at the primary site and 51 (63%) had macroscopic metastatic disease in either regional lymph nodes (7 of 51; 14%), regional lymph nodes and another site (6 of 51; 12%), other organs (14 of 51; 27%), lungs (19 of 51; 37%), or lungs and other organs (5 of 51; 10%). Twenty-six tumor types were treated (Table 2). Two subpopulations of tumor types (osteosarcoma and hemangiosarcoma) had adequate numbers of dogs to enable statistical evaluation. Of the 18 dogs with osteosarcoma, 10 had surgery to remove the primary tumor. Seven dogs had a limb amputation, 2 dogs had a mandibulectomy, and 1 dog had a rib resection before starting lomustine. Of the 10 dogs with surgically removed osteosarcoma, 9 had visible metastasis to the lungs at time of starting metronomic administration of lomustine. Six of the remaining 8 dogs with osteosarcoma received palliative pain management with radiation therapy according to a previously published protocol, and had no metastatic disease detected at the initiation of metronomic administration of lomustine.15 Two of the remaining 8 dogs had both a primary tumor present and pulmonary metastatic disease.

Table 2.   Tumor types treated with metronomic administration of lomustine.
Osteosarcoma18
Hemangiosarcoma18
 Visceral16
 SC2
Histologically low-grade biologically high-grade fibrosarcoma, oral melanoma, high-grade sarcoma, nasal adenocarcinoma4 each
Anal sac adenocarcinoma, anaplastic sarcoma3 each
Chemodectoma, endocrine carcinoma, hepatocellular carcinoma, histiocytic sarcoma, pulmonary carcinoma, transitional cell carcinoma, thyroid carcinoma2 each
Intestinal adenocarcinoma, basosquamous carcinoma, chondrosarcoma, multiple myeloma, carcinoma of unknown origin, grade II–III mast cell tumor, poorly differentiated carcinoma, primary lung tumor, multilobular tumor of bone1 each

Treatment

Lomustine was administered in a metronomic fashion to 81 dogs at a dosage of 2.84 mg/m2 (median, range, 1.76–3.83 mg/m2) PO daily. Treatment duration was 98 days (median, range, 1–680 days). Twenty-two dogs discontinued the drug because of adverse effects after 97 days of treatment (median, range, 1–439).

Surgical resection of the primary tumor in a variety of tumor types occurred in 21 dogs, and adjuvant chemotherapy was administered to 29 dogs. Fifteen dogs received prior palliative radiation therapy for gross disease (day 0, 7, 21 protocol) to a total of 24 Gy, with 1 dog repeating the protocol for a total of 48 Gy. These dogs had hemangiosarcoma (n = 4), oral melanoma (n = 2), thyroid carcinoma (n = 2), osteosarcoma (n = 2), histologically low-grade, biologically high-grade oral fibrosarcoma (n = 2), anaplastic sarcoma (n = 2), and chondrosarcoma (n = 1). Before treatment with metronomic administration of lomustine, 7 dogs had been treated with full-course radiation therapy to 54 Gy (median, range, 50–57 Gy) for nasal carcinoma (n = 2), anal sac adenocarcinoma (n = 1), basosquamous cell carcinoma (n = 1), multilobular tumor of bone (n = 1), soft tissue sarcoma (n = 1), and anaplastic sarcoma (n = 1). Six dogs with osteosarcoma received palliative radiation therapy consisting of 2 consecutive daily doses of 8 Gy to the region of the tumor. Chemotherapy administered included doxorubicin (n = 16), carboplatin (n=10), cytotoxic dosage (60 mg/m2) lomustine (n=3), doxorubicin and cyclophosphamide (n = 2), mitoxantrone (n = 1), melphalan (n = 1), and azathioprine (n = 1). Two dogs also received the Onceptb melanoma vaccine before starting metronomic administration of lomustine, and 1 dog discontinued metronomic administration of lomustine to receive the melanoma vaccine when it became available. Fifty-one dogs received concurrent medications with metronomic administration of lomustine. Drugs included NSAIDs (n = 29), prednisone (n = 7), tramadol (n = 6), gabapentin (n = 2), amlodipine (n = 2), butorphanol (n = 1), doxycycline (n = 1), levothyroxine (n = 1), pamidronate (n = 1), and vitamin C (n = 1). NSAIDs used included carprofen (n = 13), firocoxib (n = 6), meloxicam (n = 5), piroxicam (n = 3), and deracoxib (n = 2).

Hematologic and Biochemical Toxicosis

Fifty-two dogs had CBC and serum chemistries available for evaluation of hematologic or organ toxicosis. One dog receiving lomustine had grade 1 neutropenia after receiving the medication for 46 days. Neutropenia persisted 45 days after initial identification, and lomustine was discontinued. Thrombocytopenia developed in 12 dogs (20%) at a median of 432 days (range, 19–436 days). Of the 12 instances of thrombocytopenia after lomustine, 9 were grade 1, 2 were grade 3, and 1 was grade 4. Two dogs began metronomic administration of lomustine while thrombocytopenic. One dog with multiple myeloma had grade 1 thrombocytopenia (146,000/μL) at the start of therapy. The platelet count continued to decrease while on medication (63,000/μL after 51 days of administration) and the dog expired 2 days later of its disease. The 2nd dog with SC hemangiosarcoma had grade 2 thrombocytopenia (104,000/μL) at the start of therapy, which resolved at the 1 month recheck CBC (427,000/μL). The dog with grade 4 thrombocytopenia (14,000/μL) was clinically bleeding, which was attributed to the hemangiosarcoma.

Eight dogs (15%) with a normal PCV at initiation of therapy developed anemia during lomustine administration after 148 days (median, range, 32–220 days) of administration. Of these 8, 6 remained anemic or were anemic terminally. Of these 6, all became anemic in the last month of their lives. Seven of the 8 dogs experienced a grade 1 anemia, and 1 a grade 2 anemia. Eight dogs (15%) were anemic at initiation of metronomic administration of lomustine (5 grade 1, 2 grade 2, and 1 grade 3). Four of these dogs remained persistently anemic throughout treatment. Of the persistently anemic dogs, 1 dog had multiple myeloma and 3 dogs had hemangiosarcoma with macroscopic disease.

Eight dogs (15%) developed azotemia during lomustine administration after 116 days (median, range, 20–390 days). Seven of 8 were grade 1 events. One dog was azotemic at therapy initiation and the BUN and creatinine doubled within 20 days of administration, prompting discontinuation of the lomustine. Progressive renal toxicosis and death were attributed to lomustine in this dog. This dog was receiving enalapril concurrently, but not an NSAID.

Eleven dogs (21%) experienced increase in ALT above 1.5 times the upper limit of normal after a median treatment duration of 265 days (range, 19–413 days). Therapy was discontinued for 3 dogs solely because of ALT elevation. No dog experienced clinical signs suggestive of hepatic failure.

Gastrointestinal Toxicosis

Thirteen dogs (25%) developed some gastrointestinal toxicosis, including 4 dogs with vomiting, 7 with anorexia, 1 with nausea, and 2 with diarrhea. In 13 dogs, therapy was discontinued because of gastrointestinal effects at 20 days (median, range, 1–439 days). One dog had weight loss because of anorexia, and 2 dogs were reportedly lethargic while receiving lomustine. Two dogs that had gastrointestinal toxicosis also had ALT elevations and therapy was discontinued. Therapy was discontinued in 1 dog because of azotemia and mild anorexia. All were grade 1 (13 episodes) or 2 (5 episodes) adverse events.

Five dogs received doxorubicin concurrently with metronomic administration of lomustine, and 2 of these dogs experienced gastrointestinal adverse effects (anorexia and vomiting, respectively). Two dogs received palliative radiation therapy for osteosarcoma concurrent with lomustine and experienced no adverse effects.

Treatment Delays and Dose Reductions

No treatment delays were recorded in any dogs. Two dogs had dosing decreased to every other day and both were below 15 kg in body weight at 11 and 8.6 kg. One dog with pulmonary carcinoma experienced increased ALT, and was decreased to every other day dosing. The dog subsequently had PD, and therapy was discontinued. The other dog had osteosarcoma and experienced grade 1 anorexia, and subsequently the dosing frequency was reduced.

Response

Sixty-four dogs could be evaluated for objective tumor response at recheck visits to the primary study institution. Four (6%) PR were observed. Nineteen of the 64 dogs (30%) achieved SD for a biological response rate of 36% (cumulative proportion of dogs experiencing stable or improved disease). Median duration of SD was 137 days (range, 46–290 days). Only dogs with macroscopic disease were considered in the category of SD. Responses were measured with radiographic imaging of primary and metastatic lesions and direct visualization of primary tumors. Tumor types experiencing a PR included histiocytic sarcoma with resolution of metastases in the lungs, hepatocellular carcinoma with decreased tumor size on ultrasound examination of the liver, and 2 anaplastic sarcomas, 1 with regression of the primary tumor in the mouth as well as diminished metastases to the lungs, and another with diminishing metastases to the lungs. None of these dogs were receiving prednisone or other cytotoxic therapy concurrently. Each of these dogs demonstrated response within the first 30 days of therapy, leaving open the possibility of a direct cytotoxic effect of the metronomic administration for some individuals. The median survival of dogs with primary, nonmetastatic osteosarcoma that received palliative radiation and metronomic administration of lomustine therapy was 237 days (range, 74–417 days). Dogs that had metastatic osteosarcoma at the time of starting lomustine had a median survival of 74 days (range, 38–165 days). Thirteen of 18 dogs with hemangiosarcoma had macroscopic disease present at the primary site. Nine of these dogs also had metastatic disease present when lomustine was initiated. Location of primary tumors included 5 in the right atrium/auricle, 6 in the spleen, 1 in the bladder, 2 in SC tissue, and 4 in the spleen and SC tissue, concurrently. Two dogs had distant metastasis to the lungs, a visceral organ, or both. Dogs with macroscopic primary and metastatic hemangiosarcoma had a median survival of 120 days (range, 19–307 days) (Fig 1). There was no statistical difference between survival of dogs with localized hemangiosarcoma and metastatic hemangiosarcoma.

image

Figure 1.  Kaplan-Meier survival curve for 18 dogs with hemangiosarcoma treated with metronomic administration of lomustine. Closed circle represents censored dog.

Download figure to PowerPoint

Discussion

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

Based on this prospective tolerability trial, a daily dosage of 2.84 mg/m2 of lomustine is well tolerated for short-term treatment in tumor-bearing dogs. Overall, mild hematologic, gastrointestinal, and moderate biochemical negative effects were observed with 13% of dogs developing the more severe adverse event of azotemia. The dogs in this series had uniformly poor prognoses with significant comorbidities because of advanced-stage disease and inadequate control of local disease. Because the diseases were so advanced, it is difficult to identify which toxicoses were directly caused by the therapy, and which by the diseases. The low cost, tolerability, and ease of administration of this protocol make it worth evaluating further in efficacy trials for less heavily treated dogs in earlier stage disease.

The dogs in this study included a variety of sizes and breeds and equally represented male and female dogs. No subset of dogs was more likely to be negatively affected by this protocol. A possible exception to this is the observation that 5 of the dogs that developed renal compromise were small to medium breed dogs. Although this was a relatively rare event, careful monitoring of renal function in small to medium breed dogs receiving metronomic administration of lomustine may be warranted.

The dogs in this study had a wide variety of tumors, including both sarcomas and carcinomas, treated with combinations of surgery, radiation, and chemotherapy with curative and palliative intents. Further, these dogs were at a variety of stages, from locally microscopic disease to widely metastatic at the time of diagnosis. The authors' original intention was to treat dogs with hemangiosarcoma with this protocol. The tolerability study was expanded to include dogs with many tumor types because of the lack or exhaustion of standard treatment options. Markers of angiogenesis have been shown to be prognostic for metastasis or survival in canine mammary tumors, lymphoma, mast cell tumors, and hemangiosarcoma, making dogs with these and perhaps other tumors appealing candidates for metronomic chemotherapy.16–24 Evaluating the efficacy of antiangiogenic therapy in specific tumor types will require reliable surrogate markers of angiogenesis, and controlled clinical trials in dogs of similar stages.4

There were several limitations in the present study. First, the study lacked evaluation of surrogate markers for antiangiogenic activity. A 2nd prospective trial is currently recruiting cases to evaluate the effect of metronomic administration of lomustine on circulating endothelial precursor cells. Second, the study did not attempt to identify an optimal biological dosage. The dosage was selected based on expected toxicosis, but was not altered during the course of the study. Finally, many of these dogs were managed by their primary care veterinarians. Many of these dogs did not receive the recommended hematologic and biochemical monitoring. This resulted in 29 of the dogs not being evaluable for objective evidence of toxicosis. However, follow-up information was available on outcome for all 81 dogs.

In this population, metronomic administration of lomustine was well tolerated after treatment with many chemotherapy drugs and in combination with medications frequently used in end-stage oncology dogs. The dogs in this study were treated with a variety of protocols containing anthracyclines, carboplatin, alkylating agents, and an antimetabolite. No prior drug exposure appeared to increase the risk of negative effects from metronomic administration of lomustine. Metronomic administration of lomustine was well tolerated in dogs receiving steroids and NSAIDs, narcotics, antimicrobials, antihypertensives, and pamidronate. Of the 5 dogs that received metronomic administration of lomustine in conjunction with doxorubicin chemotherapy, 2 experienced mild gastrointestinal effects, but hematologic consequences were not identified. No evidence of negative interactions with standard palliative drug therapies was identified.

Of the negative effects observed, myelosupression, specifically thrombocytopenia, may be the most likely consequence of long-term administration of metronomic administration of lomustine. This is not surprising, as myelosuppression is a well-described adverse event associated with cytotoxic lomustine therapy. Lomustine DNA damage preferentially affects very early hematopoietic precursors, leading to cumulative-dose suppression of the marrow.11 The median time to onset of thrombocytopenia suggests that dogs could receive metronomic administration of lomustine for up to 12 months with minimal concern for drug-induced thrombocytopenia. Dogs included in this study had a variety of neoplastic diseases, which may have led to thrombocytopenia as a comorbid or paraneoplastic phenomenon. Most dogs in the study received other chemotherapy agents before the metronomic administration of lomustine, which may have altered the onset of thrombocytopenia for some dogs. Dogs should be selected to receive this medication if their predicted survival is <1 year and they have an adequate platelet count at the beginning of therapy.

The anemia identified in this population of dogs is of questionable significance. Of the 8 dogs that developed anemia while receiving metronomic administration of lomustine, 2 returned to a normal hematocrit while still on protocol. Of the 6 who remained anemic, all were in the final month of their lives. These observations suggest that disease, rather than therapy, was the primary cause of the observed anemia in these cases.

Although renal toxicosis with chloroethyl nitrosoureas is uncommon, its incidence is highest in human patients receiving prolonged cytotoxic therapy.25–27 Thickening of the glomerular basement membranes and tubular atrophy have been observed in humans with lomustine-induced renal toxicosis.25–27 Renal dysfunction develops months to years after cessation of chemotherapy.26 Fifteen percent of the dogs in our study population developed or had progressive azotemia. Of this group of dogs, only 1 was receiving concurrent NSAID therapy. Two of the dogs had underlying protein losing nephropathy. The renal disease could have been paraneoplastic in any of these dogs. However, the lack of CRs in the dogs treated with this protocol would not be expected to alleviate such a paraneoplastic condition. It is unclear whether lomustine contributed to the renal disease in any of these dogs. The pattern did not match that of the documented human toxicosis. However, in future uses, careful evaluation of renal function is warranted.

Gastrointestinal toxicosis was the most frequent reason for discontinuing therapy. This tended to be noticed early in the course of therapy. In all cases, discontinuing the drug caused resolution of the clinical signs.

Hepatotoxicosis in dogs is a well-documented adverse effect of lomustine administration at cytotoxic dosages.7–9 The rate of significant hepatotoxicosis is between 6 and 29%.7,8 It is notable that no dog in this series demonstrated clinical or biochemical signs of hepatic failure. The 21% of dogs in this study that developed increases in serum ALT is consistent with earlier reports of potential hepatotoxicosis. However, only 3 dogs required discontinuation of therapy because of ALT elevation, and in no dog were there clinical signs referable to the liver. The authors continue to recommend periodic evaluation of a serum biochemistry panel to screen for this toxicosis. Gastrointestinal toxicosis was generally mild. Of the 25% of dogs with episodes of gastrointestinal distress, all were low-grade adverse events.

As the intended target of this protocol is angiogenesis, major tumor responses were not anticipated before the study. Of 64 evaluable dogs, 6% experienced a PR to the protocol, possibly because of direct cytotoxicity, and 30% SD. Recently, the concept of a biological response to antiangiogenic therapy has been advanced as a reasonable endpoint, including SD.28–30 Given that endothelial precursor cells, not tumor cells, are the direct target of metronomic chemotherapy, arresting disease progression is a reasonable goal of the treatment. Unfortunately, resources were not present to measure levels of circulating endothelial precursor cells for this study. As such, an overall biological response of 36% in this advanced stage population of dogs may be promising for future therapeutic trials. It must be considered that a partial explanation of the observation of SD was a by-product of the tumors reaching a plateau phase of growth. However, the tumors that remained stable were not particularly large for the population of dogs studied, most of which progressed over time. Only a randomized trial could support any potential significance of the findings here.

A tantalizing subgroup of dogs in this study was the 6 dogs with primary, nonmetastatic osteosarcoma that received palliative radiation therapy, followed by metronomic administration of lomustine. The observed median survival of approximately 8 months is almost twice as long as reported with the palliative radiation therapy protocol alone used in this institution.15 The small number of dogs in our population precludes comparison to other published treatment protocols, so an ongoing trial is being conducted to evaluate this treatment approach. The median survival time of dogs with stage 3 osteosarcoma was similar to that previously reported in the literature.31

Although the original intent of this protocol was to treat dogs with hemangiosarcoma, no particular survival benefit over previously published data was apparent. Median survival was similar for dogs with metastatic and residual local disease. Further evaluation may be warranted for use of this protocol as a maintenance therapy after standard surgery and chemotherapy.

The advantages of metronomic administration of chemotherapy regimens include reduced toxicoses, potentially reduced costs, and convenient drug administration for clients. A problem with metronomic regimens is the empiricism associated with determining the optimum biologic dose. The dosage for this trial was selected by dividing the low end of the accepted dosage range (60–90 mg/m2) into daily aliquots. The absence of an objective marker of antiangiogenic activity of the protocol prevents a clear conclusion about the efficacy of target inhibition, but trials at this institution are beginning to assess this. Historically, the objective of treating metastatic malignancies has been primarily palliative. The major aim of chemotherapy in such dogs is to manage clinical signs, prevent serious complications, and increase survival without diminishing quality of life, making a metronomic protocol ideal. Establishing which tumors are most responsive, optimizing an administration schedule, and developing clear response criteria is paramount to rational development. It will also be necessary to define the role of metronomic protocols in primary therapy, in combination therapy, and as palliative therapy.

Footnotes

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

a Systat Software, Point Richmond, CA

b Merial, Duluth, GA

Acknowledgments

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

This work was not supported by a grant. The authors acknowledge Dr Wayne Hause of Associated Veterinary Specialists and the University of Missouri for contribution of cases. We also acknowledge Betsy Wheeler and Tammie Grabill for their role in client education and support, and Diamondback Drugs for their assistance.

References

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