Management of complications of cancer chemotherapy

Although the use of anticancer agents can be associated with severe side effects, on a practical basis complications of therapy are minimal to nonexistent. The clinician usually learns to feel more comfortable with these drugs as he or she treats more patients, to the point where treating a cancer patient with chemotherapy will become routine practice.     

Oncologic emergencies

Cancer can lead to emergencies either due to the primary disease, or as a result of therapy. Appropriate diagnosis and rapid treatment of these conditions can result in survival of the patient. Whether chemotherapy is implemented or not, the clinician may be presented with a patient in need of emergency stabilization. Common occurring emergencies are related to effects of the cancer, ranging from immune dysfunction due to marrow infiltration to brain herniation due to increased intracranial pressure from neoplasia. Often adverse effects secondary to chemotherapy can cause emergency situations such as sepsis. Prompt diagnosis and treatment may result in a favorable outcome. Addressed in this chapter are commonly occurring emergencies and specific stabilizing treatments.     

New concepts in human oncology: is it possible to use them in veterinary medicine as well?

In human oncology, novel targeted therapy focusing on monoclonal antibodies and tyrosine kinase inhibitors has become an attractive anticancer strategy. The introduction of antiangiogenetic drugs and metronomic chemotherapy has also increased the therapeutic arsenal. Chemotherapy still plays a key role in the treatment of many tumors affecting dogs and cats. However, novel anticancer strategies (including tyrosine kinase inhibitors and monoclonal antibodies, as well as antiangiogenetic treatments) are becoming relevant in veterinary medicine, too. The goal of this review is to describe new therapeutic strategies for cancer treatment in veterinary medicine, including less well-known chemotherapeutic drugs.     

Efficacy of C/B‐OPP rescue for the treatment of relapsed canine lymphoma (1998–2004)

Introduction:  MOPP chemotherapy is useful for relapsed canine lymphoma. This study evaluates the efficacy of this protocol after substitution of CCNU (lomustine) or BiCNU (carmustine) for mechlorethamine (C/B‐OPP).
Methods:  Patient signalment, response to chemotherapy, toxicity and survival data were abstracted from medical records of dogs from receiving C/B‐OPP between 1998 and 2004.
Results:  Fifty‐eight dogs received C/B‐OPP rescue chemotherapy during the study period. The median remission duration after initial chemotherapy, consisting of CHOP‐based therapy in 91% of dogs, was 133 days (range, 10 to 932 days). Thirty‐eight of fifty‐eight dogs (66%) responded to C/B‐OPP rescue after relapse (22 CR, 16 PR), for a median of 48 days (range, 2 to 359 days). Overall, C/B‐OPP extended survival by a median of 90 days (range, 2 to 426 days). Twenty‐four dogs (41%) experienced one or more episodes of Grade II or higher gastrointestinal toxicity. Forty‐one dogs (71%) experienced one or more episodes of Grade II or higher hematologic toxicity. Twelve dogs (20%) developed regenerative anemia with diarrhea consistent with gastrointestinal hemorrhage. Treatment delays due to hematologic toxicity occurred in 37 dogs (63%). There were 16 nonfatal treatment‐related episodes of sepsis requiring hospitalization. 5 dogs died due to sepsis and/or chemotherapy‐related complications.
Conclusions:  C/B‐OPP chemotherapy has activity against relapsed canine lymphoma which is similar to that of traditional MOPP rescue therapy. Moderate to severe hematologic toxicity was observed. Further work is warranted to optimize drug doses and scheduling.     

Liposome‐encapsulated chemotherapy: Current evidence for its use in companion animals

Cytotoxic drugs encapsulated into liposomes were originally designed to increase the anticancer response, while minimizing off‐target adverse effects. The first liposomal chemotherapeutic drug was approved for use in humans more than 20 years ago, and the first publication regarding its use in a canine cancer patient was published shortly thereafter. Regardless, no general application for liposomal cytotoxic drugs has been established in veterinary oncology till now. Due to the popularity of canines as experimental models for pharmacokinetic analyses and toxicity studies, multiple publications exist describing various liposomal drugs in healthy dogs. Also, some evidence for its use in veterinary cancer patients exists, especially in canine lymphoma, canine splenic hemangiosarcoma and feline soft tissue sarcoma, however, the results have not been overwhelming. Reasons for this may be related to inherent issues with the enhanced permeability and retention effect, the tumour phenomenon which liposomal drugs exploit. This effect seems very heterogeneously distributed in the tumour. Also, it is potentially not as ubiquitously occurring as once thought, and it may prove important to select patients for liposomal therapy on an individual, non‐histology‐oriented, basis. Concurrently, new developments with active‐release modified liposomes in experimental models and humans will likely be relevant for veterinary patients as well, and holds the potential to improve the therapeutic response. It, however, does not resolve the other challenges that liposomal chemotherapy faces, and more work still needs to be done to determine which veterinary patients may benefit the most from liposomal chemotherapy.     

Evaluation of an actinomycin-D-containing combination chemotherapy protocol with extended maintenance therapy for canine lymphoma

In this retrospective study, a 6-drug (prednisone, L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and actinomycin-D) chemotherapy protocol with extended maintenance for the treatment of lymphoma was evaluated for efficacy and toxicity in 39 dogs. The complete remission rate was 97%, with a median progression-free survival (PFS) of 331 d. The median overall survival (OS) was 461 d. Of the variables evaluated for prognostic significance, only immunophenotype and sex were found to be prognostic. Dogs with T-cell lymphoma had shorter PFS and OS than dogs with B-cell lymphoma. Castrated male dogs had a shorter PFS and OS than spayed female dogs. Although the majority of dogs experienced one or more episodes of chemotherapy associated toxicity, the majority of these episodes were mild and self-limiting. The results of this study warrant further investigation into the value of extended maintenance therapy and inclusion of actinomycin-D in combination chemotherapy protocols for canine lymphoma.     

A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats

A phase I clinical trial evaluating the toxicity of orally-administered imatinib mesylate was performed in 9 tumor-bearing cats. Imatinib is a small molecule, tyrosine kinase inhibitor, which selectively blocks the function of overexpressed proteins associated with various malignancies. Cats included in the study had diagnoses of fibrosarcoma, squamous cell carcinoma, and mast cell tumor, and each cat was staged using CBC and serum biochemistry; urinalysis, thoracic radiographs, and abdominal ultrasonography were performed in some cats. Most cats were treated previously by surgery, radiation therapy, chemotherapy, or some combination of these treatments. None of the cats received any concurrent chemotherapy. Six cats were treated with imatinib mesylate at 1-2 mg/kg PO q24h. Dose escalations were made to 2, 4, and 10 mg/kg PO q24h in 5 cats. Two cats started therapy at 10 mg/kg PO q24h, and 1 cat started therapy at 15 mg/kg PO q24h; all 3 cats remained at these dosages. No signs of toxicity, as evaluated by CBC and serum biochemistry, were noted in 8 of the 9 cats, and minimal gastrointestinal toxicity was observed. Due to the low frequency of adverse effects, further evaluation of imatinib is ongoing at a dosage of 10 mg/kg PO q24h.     

Whole-Body Hyperthermia

Whole-body hyperthermia is the controlled elevation of systemic temperature for therapeutic purposes. Historically, this treatment has been used for symptomatic control of many diseases. Recently, the potential therapeutic benefit of whole-body hyperthermia in the management of neoplastic disease has been investigated vigorously. The rationale for improved tumor control is based on heat-induced enhancement of the antineoplastic effects of radiation and chemotherapy. Although the complex biologic interaction of heat and radiation has been studied for many years, chemotherapy combined with hyperthermia has been studied less thoroughly. Despite a lack of adequate long-term laboratory and clinical investigation, use of whole-body hyperthermia with chemotherapy and radiotherapy is a logical and potentially powerful therapeutic strategy for neoplasia. Relevant issues regarding the application of whole-body hyperthermia with more traditional modes of therapy are being studied in preliminary clinical trials involving dogs and humans. Identification of optimal timing and sequencing of adjunctive therapy, proper cytotoxic drug application, methods to further minimize toxicity, and heat-sensitive tumor types will lead to expanded clinical use of whole-body hyperthermia. The historical development, clinical rationale, and application of whole-body hyperthermia for the control of disseminated or refractory neoplasia in humans and dogs is reviewed.     

INITIAL EVALUATION OF SAFETY OF WIDE‐FIELD IRRADIATION IN THE TREATMENT OF HEMATOPOIETIC NEOPLASIA IN THE CAT

Localized radiation therapy is well tolerated in cats with confined tumors; however, the use of wide‐field radiation therapy to treat disseminated neoplasia has not been evaluated systematically in this species. Wide‐field external beam radiation therapy, which we define as irradiation of cranial or caudal halves of the body either individually or sequentially, was undertaken as an experimental option to treat cats with either chemotherapy‐refractory or naïve hematopoietic neoplasia considered to have a poor prognosis. Fifteen cats with hematopoietic malignancies received wide‐field external beam radiation therapy between 2003 and 2006. Cats received 8 Gy delivered in 4 Gy fractions with ⁶⁰Co photons. Treatment‐related toxicity was scored according to criteria established by the Veterinary Cooperative Oncology Group. Animals without preexisting abnormalities on hemograms exhibited no or mild (Grade 1 or 2) hematopoietic toxicity. Although most cats (14 of 15) had preexisting gastrointestinal (GI) signs, these signs were stable (29%) or improved (42%) following irradiation. Worsening GI signs following irradiation occurred transiently in two cats and in association with progressive disease in two others. No pulmonary, renal, hepatic, or dermatologic toxicities were detected. In summary, wide‐field external beam radiation therapy can be administered safely to, and may provide therapeutic benefit for, cats with disseminated hematopoietic neoplasia.     

Calcitriol (1,25‐dihydroxycholecalciferol) enhances mast cell tumour chemotherapy and receptor tyrosine kinase inhibitor activity in vitro and has single‐agent activity against spontaneously occurring canine mast cell tumours*

Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single‐agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two‐ to six‐fold lower when the drugs were used in combination than when used individually. High‐dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.     

Combretastatin A4‐phosphate and its potential in veterinary oncology: a review

For many years, research on anticancer therapy has focussed almost exclusively on targeting cancer cells directly, to selectively kill them or restrict their growth. But limited advances in this strategy have led researchers to shift their attention to other potential targets. Active research is now on‐going on targeting tumour stroma. Vascular disrupting agents (VDAs) appear a promising class of anticancer drugs that are currently under investigation as a sole or combined therapy in human cancer patients. This article will briefly touch on the history and biology of combretastatin A4‐phosphate (CA4P) as a typical example of VDAs and will concentrate on the side effects that can be expected when used in veterinary patients. Particularly, the pathogenesis of these side effects and how they may be prevented and/or treated will be discussed. The purpose of this article is to illustrate the potentials of CA4P as anticancer therapy in veterinary oncology patients.     

Coagulation abnormalities associated with neoplasia

Subclinical abnormalities in hemostasis occur commonly in small animal patients with cancer, but the incidence of clinical thrombosis or hemorrhage is unknown. Malignancy can lead to abnormalities in both primary and secondary hemostasis, which in turn can lead to either thrombotic or hemorrhagic tendencies. These coagulation abnormalities can be associated with the tumor itself, with anticancer chemotherapy, or with secondary organ dysfunction. Thrombocytopenia and DIC are probably the most common defects associated with clinical bleeding in small animal patients.     

A Prospective Study of Radiation Therapy for the Treatment of Grade 2 Mast Cell Tumors in 32 Dogs

Surgery, chemotherapy, and irradiation have been used singly or in combination to treat dogs with cutaneous grade-2 mast cell tumors (MCT). However, optimal treatment has not been established. At The Animal Medical Center, 32 dogs with grade 2, stage 0 MCT received cobalt radiation treatment to a dose of 54 Gy; 94% had a disease-free interval of 1 year. The 2–,3–,4–, and 5–year disease-free intervals were 86%. Survival rates were 100% for 1 year and 96% for 2 to 5 years, with only 1 death caused by MCT. Primary site was not a prognostic factor for survival in this study. Minimal toxicity was observed and was limited to acute cutaneous reactions. Late-term reactions to radiation therapy were mild and considered acceptable in all cases. No deaths occurred due to treatment, and no dog was eliminated from the study because of radiation therapy toxicity. Radiation therapy appears to be an effective treatment for dogs with grade 2, stage 0 MCT.     

Phase I clinical trial evaluating STI571 in tumor bearing cats

Introduction: STI571 (Gleevec, imatinib mesylate) is a receptor tyrosine kinase inhibitor with selectivity for Bcr‐Abl, platelet‐derived growth factor (PDGF), stem cell factor (SCF), and c‐Kit. Side effects with use in humans include vomiting, diarrhea, nausea, myalgia, edema, and cutaneous reactions. Renal and hepatic toxicity have also been reported. In dogs, there is significant hepatic toxicity at sub‐clinical doses. The purpose of this prospective study was to determine the toxicity level and potential treatment protocol in tumor bearing cats. Methods: A phase I clinical trial was performed in client owned cats using an escalating dose of STI571 in tumor bearing cats. Cats included in the study had a histologic diagnosis of fibrosarcoma or other tumors and were staged with CBC, biochemical profile, thoracic radiographs, and abdominal ultrasound. None of the cats received concurrent chemotherapy, but those previously treated with surgery, radiation therapy, or chemotherapy, were not excluded. The initial starting dose was 5 mg/cat PO SID and was gradually increased to 10 and 20 mg/cat PO SID at a 2–6 week interval depending on laboratory work and disease progression. A repeat physical examination, CBC, and biochemical profile, were performed every 2 weeks for 2 rechecks, then every 4 weeks. Results: Six cats were enrolled in the study. Four cats had oral squamous cell carcinoma, and two cats had cutaneous fibrosarcoma. One cat demonstrated leukocytosis, increased liver enzymes, and signs of acute renal failure two weeks after initiating therapy (5 mg PO SID). No dose escalation was made in this cat. Five cats endured dose escalations of 10 mg PO SID in two cats and 20 mg PO SID in three cats and were treated for 2–4 months. None of these cats experienced any signs of toxicity as measured by CBC and biochemical profile. Conclusions: Only one cat experienced toxicity that may have been associated with low dose administration of STI571. As most cats tolerated the drug without an adverse effect, further evaluation of STI571 in a phase II clinical trial is warranted.     

Chemotherapy and radiotherapy for treatment of cutaneous lymphoma in a ground cuscus (Phalanger gymnotis)

A 15-year-old female ground cuscus (Phalanger gymnotis) was presented with an isolated ulcerated, nonhealing lesion on the lateral thorax. Histopathology and immunohistochemistry were diagnostic for cutaneous T-cell lymphoma with incomplete excision. Oral chemotherapy with CCNU (lomustine) resulted in clinical remission that lasted 255 days, with no appreciable toxicity. Tumor recurrence was treated with radiation therapy, which resulted in 120 additional days of clinical remission. Subsequently, the tumor developed at a distant site and the cuscus was humanely euthanized. A slight decrease in appetite early in disease progression was the only adverse effect noted throughout the treatment period. Oral, minimally invasive chemotherapy, and adjunct radiation therapy were viable treatment options for this ground cuscus and should be considered for treatment of neoplasia in other nontraditional species.     

Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder

Invasive transitional cell carcinoma (TCC) of the urinary bladder responds poorly to medical therapy. Combining platinum chemotherapy with a cyclooxygenase (cox) inhibitor has shown promise against canine TCC, where the disease closely mimics the human condition. A phase II clinical trial of carboplatin combined with the cox inhibitor, piroxicam, was performed in 31 dogs with naturally occurring, histopathologically confirmed, measurable TCC. Complete tumour staging was performed before and at 6‐week intervals during therapy. Tumour responses in 29 dogs included 11 partial remissions, 13 stable disease and five progressive disease. Two of the 31 dogs were withdrawn prior to the re‐staging of the tumour. Gastrointestinal toxicity was observed in 23 dogs. Hematologic toxicity was noted in 11 dogs. The median survival was 161 days from first carboplatin treatment to death. In conclusion, carboplatin/piroxicam induced remission in 40% of dogs providing evidence that a cox inhibitor enhances the antitumour activity of carboplatin. The frequent toxicity and limited survival, however, do not support the use of this specific protocol against TCC.     

P‐Glycoprotein Mediated Drug Interactions in Animals and Humans with Cancer

Drug–drug interactions can cause unanticipated patient morbidity and mortality. The consequences of drug–drug interactions can be especially severe when anticancer drugs are involved because of their narrow therapeutic index. Veterinary clinicians have traditionally been taught that drug–drug interactions result from alterations in drug metabolism, renal excretion or protein binding. More recently, drug–drug interactions resulting from inhibition of P‐glycoprotein‐mediated drug transport have been identified in both human and veterinary patients. Many drugs commonly used in veterinary patients are capable of inhibiting P‐glycoprotein function and thereby causing an interaction that results in severe chemotherapeutic drug toxicity. The intent of this review is to describe the mechanism and clinical implications of drug–drug interactions involving P‐glycoprotein and anticancer drugs. Equipped with this information, veterinarians can prevent serious drug–drug interactions by selecting alternate drugs or adjusting the dose of interacting drugs.     

天然免疫调节药物在肿瘤辅助治疗中的研究进展

寻求肿瘤治疗或肿瘤辅助治疗的药物一直以来是医学科技工作者致力的热门研究领域,但长期以来,以手术和放化疗为主的侵入性治疗仍是肿瘤治疗的主要方式,但放化疗对免疫系统的破坏在很大程度上影响了肿瘤治疗的效果。中医治疗以整体调节机体主动免疫、低毒副作用成为目前肿瘤放化疗辅助治疗的研究热点。作者从中药升白免疫调节复方和复方中单味药活性成分的免疫功效研究进展方面,对近年肿瘤辅助治疗的天然免疫调节药物进行了综述。     

The use of IV lipid emulsion for lipophilic drug toxicities

IV lipid emulsion (ILE) therapy is emerging as a potential antidote for lipophilic drug toxicities in both human and veterinary medicine. ILE has already gained acceptance in human medicine as a treatment of local anesthetic systemic toxicity, but its mechanism of action, safety margins, and standardized dosing information remains undetermined at this time. Experimental and anecdotal use of ILE in the human and veterinary literature, theorized mechanisms of action, current dosing recommendations, potential adverse effects, and indications for use in human and veterinary emergency medicine are reviewed herein.