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Small Animal World Congress 2006 - Research on Small Animal Cancers


Approach to the Cancer Patient

Author(s): Antony Moore, BVSc, MVSc, DACVIM (Oncology);Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine, Oncology); Jolle Kirpensteijn, DECVS, DACVS
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15871&O=Generic

As medical and surgical advances have become available, recognition of the human-animal bond, both by clients and veterinarians, has led to advanced care for pets. This is especially true of cancer treatment. Within the last 15 years, tremendous advances have resulted in improved response rates, disease-free intervals, and survival times. Despite these strides in veterinary cancer care, many caregivers and veterinarians are not aware that a large percentage of pets with cancer can be cured or at least rendered free of their diseases for significant periods. In most situations, pets undergoing cancer treatment experience limited or no decrease in the quality of their life. Advances in supportive care and palliative therapy have resulted in good quality of life for cancer patients while they receive treatment.

First obtain a tissue diagnosis: Each tumour is different and must be identified with a biopsy and, where appropriate, given a grade by an experienced, highly trained histopathologist.

Then determine the stage of the tumour: Once the tumour type is named, it must be staged. Stage is essentially the extent of the malignancy locally and at distant sites through the metastatic process.

Staging often carries prognostic significance and enables the veterinarian and client to make informed and rational decisions regarding the type of therapy best suited to the patient. Most staging systems are based on assessment of three major components of the malignant process:

  • The size of the primary tumour (T)
  • Lymph node metastasis (N)
  • Distant metastasis (M)

These components are further modified by the use of subscript numbers to indicate increase in tumour size, progressive involvement of regional lymph nodes, and presence or absence of distant metastasis.

To obtain this information, ancillary diagnostics are very important and sophisticated imaging techniques are often used. Although staging will vary among tumour types, in general the process begins with a thorough physical examination to identify any enlarged lymph nodes or other obvious areas of cancer spread, a complete blood count, chemistry profile, urinalysis, thoracic radiographs (right and left laterals and a ventral-dorsal view), and abdominal radiographs. In addition, ancillary diagnostics such as ultrasonography, computerized tomography, magnetic resonance imaging, or other more specialized tests may be required.

Next assess the condition of the patient: Any neoplastic process may result in a number of paraneoplastic conditions that affect the well being of the cancer patient. In addition, these pets are generally geriatric patients, which have the potential for a number of underlying conditions that may adversely affect their health and the potential success of therapy. For example, serum chemistry profiles are essential to establish the health of an animal with cancer. When complicated surgical procedures or multiple radiation therapies that require repeated or prolonged anesthesia are planned, acceptable renal and hepatic functions are vital. In addition, some chemotherapeutic agents that are metabolized or excreted by the liver or kidneys may require reduction in dosage if these organs are functionally compromised. In many instances, correcting underlying problems such as renal failure, urinary tract infections, heart disease, and metabolic disturbances may significantly improve the overall health of the patient and thus improve the potential for successful cancer care.

Finally, treat the patient: Therapies that deal with the primary tumour are still the mainstay of veterinary oncology, and surgery is the primary modality used in veterinary practice.

The results of radiotherapy have been largely based on early studies using low cumulative doses and coarse fractionation. The low total doses used in these early studies meant that long-term tumour control was rare and survival was short. The treatment schedule was determined by the difficulties of repeated anesthesia, rather than by radiobiological necessity. More recently, safe short-acting anesthetics have allowed more frequent treatments with smaller doses per fraction, and the ability to deliver higher total doses has increased as fraction size has decreased. With these advances, many of the tumours that were previously reported as non-responsive actually may prove to be well controlled by radiation therapy.

Chemotherapy for pets is a changing field, and we can expect combination chemotherapy protocols to become more available for a number of different cancers. The reader is encouraged to keep up to date with the literature, as this is a rapidly advancing field.

Results of treatment with other modalities such as biological response modifiers (immunotherapy, anti-angiogenesis) and holistic medicine approaches are becoming available.

Definitions of objective tumour remissions and responses following anticancer therapy.

Tumour Response

Tumour Size

Complete (CR)*

Disappearance of all evidence of cancer in all sites for a defined period of time (e.g., one inter-treatment interval of 3 weeks)

Partial (PR)*

Decrease in size of all tumours by 50% or greater as measured by the sum of the products of two diameters for each tumour. These diameters should be the largest tumour diameter and the diameter perpendicular to it. There should be sustained decrease in tumour size, as defined for CR, and no new tumours should arise.

Stable disease (SD)

Decrease of <50% or an increase of <25% in the sum of the products of the diameters as measured for PR.

Progressive disease (PD)

Increase of 25% or more in the sum of the products of tumour diameters or the appearance of a new tumour.

*CR + PR = Objective response rate.

The best therapeutic approach for the veterinary cancer patient is yet to be devised. It is clear that a combination of surgery, radiation therapy, chemotherapy and biologic response modifiers, in addition to supportive care for the relief of pain and nutritional status, will give the best outcomes. The lecture presented here will outline strategic approaches to a pet with cancer.



Canine Lymphoma

Author(s): Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine, Oncology)
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15721&O=Generic

It is important that the client be given all the options and that the best option be used first. As a general rule, combination chemotherapy is superior to single-agent therapy. Each time an effective drug is added to the COP protocol, the remission duration increases; however, so do the cost and the potential for toxicity. It is also important that clients realize that a second or third remission is possible with appropriate therapy but that these subsequent remissions are more difficult to attain and that their duration is generally half the duration of the previous remission.

The treatment options below are tiered according to risk of toxicity, cost, and efficacy. First-level protocols provide a low risk of toxicity at low cost but have low efficacy; as the level rises, so do efficacy, cost, and risk of toxicity.

First Level: For clients who cannot afford or will not accept a combination chemotherapy protocol due to the risks of toxicity, a protocol using prednisone alone (40 mg/m2 PO daily for 7 days then every other day) or in combination with chlorambucil (6 to 8 mg/m2 PO every other day) may provide palliation with few risks of side effects. A CBC should be collected every 2 to 3 weeks to make sure that myelosuppression is not occurring.

Second Level: The COP protocol is a relatively inexpensive chemotherapy protocol with a low risk of toxicity. Dogs tolerate the treatments, and veterinarians find the protocol very manageable. CBCs should be taken 1 week after each dose of cyclophosphamide to ensure that myelosuppression (if it occurs) is not severe and that doses do not need to be adjusted.

Doxorubicin administered every 3 weeks for five to eight treatments at a dosage of 30 mg/m2 (1 mg/kg for small dogs) is the most effective single chemotherapeutic agent. This treatment regimen results in a relatively high remission rate with relatively few serious life-threatening toxicities (<5%). With the advent of generic doxorubicin, the cost is reasonable for most clients. Because the drug is given every 3 weeks, this treatment approach is less time intensive than most chemotherapeutic protocols. A second remission seems more likely if with doxorubicin is used as first-line therapy and COP is used after relapse than if COP is used first. Overall remission time for the two-protocol treatment approach is similar to that of the COPA protocol.

Third Level: The most effective chemotherapy protocols use a five-drug combination of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and prednisone. Similar remission rates and survival times have been obtained for the protocols that include these drugs. Although these protocols require more intense client-veterinarian communication and monitoring for toxicity, the overall level of satisfaction for owners, pets, and veterinarians is high. Most oncologists recommend discontinuous protocols such as VELCAP-S or the Wisconsin protocol; however, some clients will not restart chemotherapy when first remission is over.

For dogs with T-cell lymphoma, protocols that rely heavily on alkylating agents, such as Tufts VELCAP-SC, should be used.


Table 47-10. Wisconsin protocol.

Vincristine is administered at 0.5 to 0.7 mg/m2 IV. L-asparaginase is given at 400 IU/kg IM. The dose for cyclophosphamide* is 200 mg/m2 IV. Doxorubicin is administered at 30 mg/m2 IV. The dose for prednisone is 2.0 mg/kg PO, week 1; 1.5 mg/kg PO, week 2; 1.0 mg/kg PO, week 3; and 0.5 mg/kg PO, week 4.

Week Vincristine L-asparaginase Cyclophosphamide* Doxorubicin Prednisone
1 x x     x
2   x x   x
3 x       x
4       x x
5          
6 x        
7     x    
8 x        
9       x  
11 x        
13     x    
15 x        
17          
19 x        
21     x    
23 x        
25       x  

From week 25, repeat weeks 11 to 17, but every 3 weeks. After week 49, treatments given every 4 weeks.


Fourth Level: The addition of radiation therapy or, if available, autologous bone marrow support to allow chemotherapy dose intensification represents the best possible treatment option for a dog with lymphoma. The potential for long-term remission and possibly cure is much higher than with other protocols. Dogs with T-cell lymphoma may not benefit to the same extent as those dogs with B-cell lymphoma. Although risks of toxicity are higher, the addition of radiation or chemotherapy dose intensification has not negatively affected the quality of life for treated dogs.

High-dose chemotherapy with hematopoietic stem cell support or bone marrow transplantation (BMT) has become an important component of therapy for lymphoma and other malignancies in humans. Although combination chemotherapy results in a complete remission rate of 75% or greater in dogs, relapses frequently occur after a median of 10 to 12 months. It appears that autologous BMT allows dogs to receive intensified doses of myelosuppressive chemotherapy without increased toxicity and that this intensification improves remission duration and overall survival.

In a reported protocol reported by AS Moore and A Fermberger based on VELCAP-S, dogs in CR at week 8 were treated with filgrastim (G-CSF) followed by bone marrow collection. A high dose of cyclophosphamide was given with mesna followed by prophylactic antibiotics, and bone marrow was administered intravenously. Three dosage levels of cyclophosphamide were used: 300 mg/m2 (3 dogs), 400 mg/m2 (12 dogs), and 500 mg/m2 (13 dogs). Toxicity was acceptable, with only one dog requiring hospitalization after transplant for complications that resolved in 24 hours. Remission duration was not significantly different for dogs receiving 300 mg/m2 or 400 mg/m2. For dogs receiving 500 mg/m2, the median remission was 12.4 months, significantly longer than for dogs receiving 400 mg/m2, with 6 of 13 dogs still in remission between 6 and 33 months after starting chemotherapy and 1-year survival of 57.1%. Using autologous bone marrow to support chemotherapy dose intensification allows dogs to receive 2.5 times the standard dose of cyclophosphamide without any increase in clinical toxicity. This dose intensification results in significant prolongation of remission.

Supportive and Nutritional Treatment for Canine Lymphoma

The induction death rate decreased markedly for the VELCAP-SC protocol compared with previous protocols, despite an increase in the percentage of dogs needing a dose reduction of at least one chemotherapy drug (toxicity) and despite a higher proportion of substage b dogs undergoing therapy. We attribute the difference in death rate to careful staging that required the owners' commitment to therapy, as well as strict use of hospitalized induction for any animal that was in substage b.

We suggest that any dog that has signs compatible with substage b (particularly anorexia and other GI signs) be admitted for intravenous fluid therapy (maintenance x 1.5), broad-spectrum antibiotics (cefazolin sodium or enrofloxacin), and GI prophylaxis (metoclopramide and bland diet). This supportive care should be continued for at least 4 days after induction and preferably for a week. Dogs can be discharged to the owner as soon as they are self-supporting. Antibiotics and prophylactic metoclopramide are continued for the first 3 weeks of the protocol.

In addition, in one study, administration of trimethoprim/sulfadiazine (Tribrissen®) to dogs for 14 days, starting on the day of treatment with doxorubicin, markedly reduced the likelihood of GI toxicity (vomiting or diarrhea), hospitalization, and lower quality-of-life (Karnofsky) score. The effect was most marked in dogs with lymphoma and may be due to reduced bacterial translocation in damaged intestinal epithelial layers.

Nutrition is an important part of supportive care for any dog with cancer, particularly for dogs with a systemic disease like lymphoma. Lactate and insulin concentrations in untreated dogs with lymphoma are higher than in dogs without lymphoma and do not improve when dogs enter chemotherapy-induced remission.

Nutrition may also play a role in prolonging remission and survival. Polyunsaturated n-3 fatty acids have been shown to inhibit the growth and metastasis of tumors. In one study, 32 dogs with lymphoma were randomized to receive a diet supplemented with polyunsaturated n-3 fatty acids (menhaden fish oil and arginine) or an otherwise identical diet supplemented with soybean oil.14 Diets were fed from the start of doxorubicin chemotherapy and continued after remission was attained. Dogs fed the diet supplemented with n-3 fatty acids had higher serum levels of n-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid) and lower plasma lactate responses to carbohydrate testing. Increased serum levels of docosahexaenoic acid were associated with longer remission and survival times for dogs with stage III lymphoma.



Canine Osteosarcoma

Author(s): Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine, Oncology)
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15722&O=Generic

Amputation

Surgical treatment of osteosarcoma by amputation is palliative and increases survival by pain relief, thereby delaying euthanasia. Amputation usually eliminates the primary tumor and causes little to no reduction in mobility and quality of life for the dog. Although most clients do not initially embrace the concept that their dog will have three legs, the procedure is very acceptable to caregivers after amputation. In two studies in the United States and Europe, dogs learned to walk well on three legs within a month, which exceeded most clients' expectations. It is also our experience, after sending many hundreds of dogs to amputation, that clients are very happy with their decision; the veterinarian should be confident in offering amputation to these clients. For lesions in the forelimbs, complete forequarter amputation, including the scapula, provides cosmetically and functionally good results. For distal hindlimb tumors, amputation at the proximal third of the femur is performed. For distal femoral tumors, a hip disarticulation is performed; proximal femoral lesions are treated by hemipelvectomy.

In one study, the median survival of 65 dogs treated with amputation was 126 days; only 10.7% of dogs were alive 1 year after surgery.3 A larger study of 162 dogs treated with amputation corroborated these data.6 Surgery of any type is only palliative, and dogs with appendicular osteosarcoma should be given chemotherapy.

Limb-sparing Surgery

Limb-sparing surgery is important in human patients, for whom cosmetic appearance and function are impaired by amputation. This procedure may be appropriate for dogs that are poor candidates for amputation (e.g., very large dogs, dogs with other orthopedic or neurologic problems) or for dogs whose owners refuse amputation.4,5 Caution is advised because dogs that are not good candidates for amputation may not be good candidates for limb-sparing surgery due to the prolonged period of postoperative recovery. During limb-sparing surgery, a cortical bone graft is used to replace the widely excised tumor, and arthrodesis of the nearby joint is usually performed. The best results are obtained with distal radial lesions or lesions of the ulna. It is possible to perform limb salvage for proximal humeral or scapular lesions, but function is poor, and the rate of postoperative complications is high, including a high rate of incomplete resection.6 Good functional results have been reported for partial or complete scapulectomy in dogs with osteosarcoma.7

Limb salvage is not an option for large lesions that involve more than 50% of the bone, tumors that invade adjacent soft tissue, and tumors of the hindlimb. Complications of limb salvage include allograft rejection and implant failure. Complications occurred in 86 (55%) of 145 dogs treated with limb salvage in one study.43 Implant failure was seen in 12 dogs (8%) and infection in 71 (49%). Infection required allograft removal or limb amputation in 16 dogs (11%).5 Local recurrence of osteosarcoma is a frequent problem with limb salvage procedures and affects up to 40% of dogs. Even at institutions that perform limb salvage frequently and use adjunctive chemotherapy, recurrence rates of 17% to 27% are seen.7,8 Local recurrence is not a significant problem when amputation is performed.

Another disadvantage of limb-sparing procedures is the need for allografts from normal donors (usually dogs euthanized for another disease). These grafts must be stored, and fitting to the patient is always approximate. Pasteurized excised tumor has been used as an autograft for dogs with distal radial osteosarcoma. Local recurrence and infection rates were similar to those from the use of an allograft.

Some surgeons use surgical metallic 'spacers' attached to the surgical plate. These devices fill the space where the tumor is excised. Benefits include the lack of need for a bone bank and, potentially, a lower complication rate. Another technique adapted by surgeons at Colorado State University has been used on a small number of dogs with osteosarcoma that does not involve the bone or cartilage at or near a joint. In this procedure, the involved bone is stripped of attachments to soft tissues. A cut is made distal to the tumor, and the bone containing the tumor is exteriorized surgically. The tumor in the bone is given very high dosages of external beam radiation therapy and then replaced in its normal position and fixed in place with a surgical plate.

Before limb salvage is performed, intra-arterial cisplatin, with or without radiation therapy, often increases tumor necrosis and reduces the risk of local recurrence.10 In addition, a locally implanted polymer impregnated with cisplatin (open polylactic acid-cisplatin or OPLA-Pt) can be used. OPLA-Pt releases cisplatin slowly into the tumor bed, and its use reduces local recurrence rates from 27% to 17%. The survival time and disease-free interval for dogs treated with OPLA-Pt are similar to those of dogs receiving systemic cisplatin, presumably because locally implanted cisplatin is dispersed systemically. Because cisplatin release is slow, systemic toxicity is reduced.

Chemotherapy

Cisplatin markedly improves survival rates to a median survival of between 6 and 13 months and 1-year survival rates to between 30% and 62%; 2-year survival rates are between 7% and 21%.11-16 Whether the drug is administered intravenously or intra-arterially does not appear to affect efficacy.

Other methods of administration have been investigated. OPLA-Pt appears to release a controlled amount of cisplatin over a prolonged period as well as provide high local concentrations in the site of limb-sparing surgery. OPLA-Pt was implanted in the surgical wound of 39 dogs that had an amputation. Median survival was 8 months, and 1-year survival rate was 41%, which was similar to that achieved with systemic chemotherapy.16 In another study, OPLA-Pt was related to nonunion of limb salvage grafts.17 OPLA-Pt is not readily obtainable, so another study evaluated the utility of subcutaneously administered cisplatin and saline for slow-release chemotherapy; renal, gastrointestinal, and bone marrow toxicities and local tissue reaction were seen in five of six dogs, and this treatment is not recommended.18 Intramedullary cisplatin administration led to resolution of osteosarcoma in one dog with apparent survival benefit but was not so successful in three other dogs. Cisplatin is best given intravenously with saline diuresis.

Early reports of doxorubicin failed to show efficacy. Larger studies have shown benefit for the use of doxorubicin given as five biweekly doses at a dosage of 30 mg/m2. In one study, two or three doses were given before surgery; subsequent doses were given the day after surgery and 2 weeks later. Median survival was 12 months, and the efficacy approached that of cisplatin; 50% of the dogs were alive at 1 year, and 10% were alive at 2 years. Another group of more than 300 dogs received five doses of doxorubicin every 2 weeks, starting 2 weeks after amputation. Median survival was 8 months, and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively, which is very similar to results from cisplatin chemotherapy. Survival times were greater in younger dogs, lighter-weight dogs, and dogs with normal T-ALP and B-ALP.

Carboplatin (300 mg/m2 IV) was given adjunctively after surgery to 48 dogs. Median survival was 10.5 months; 35% of the dogs were alive 1 year after surgery. In this study, smaller dogs had longer survival times. Slightly lower survival rates were seen in a smaller group of dogs, but overall results are similar to that achieved with other drugs.

Single-agent treatment with carboplatin or doxorubicin seems to be as effective as cisplatin in treating canine appendicular osteosarcoma, and the choice of which drug to offer may depend on other factors. For example, doxorubicin may be less expensive than either of the platinum drugs; however, doxorubicin causes a cumulative cardiotoxicity, the risk of which is higher in breeds predisposed to cardiomyopathy. Many dogs with osteosarcoma are also breeds that are at risk for cardiomyopathy (e.g., Dobermans, great Danes), so doxorubicin may not be a good choice for these dogs. Even with prescreening of prospective patients and elimination of those with early cardiac changes or significant breed risk, more than 7% of patients developed cardiomyopathy in one study of more than 300 dogs treated with five doses of doxorubicin. Similarly, the fluid diuresis required to prevent renal toxicity of cisplatin may make it unsuitable for a dog with clinical or subclinical heart disease. Dogs that cannot be admitted as day patients for fluid diuresis and cisplatin may be better treated with carboplatin or doxorubicin because these drugs can be given on an outpatient basis.

Combination Chemotherapy

A protocol alternating cisplatin (60 mg/m2) with doxorubicin (30 mg/m2) every 21 days for two cycles was delivered after amputation to 19 dogs with appendicular osteosarcoma. The median survival was 10 months, with 37% of dogs alive at 1 year and 26% alive at 2 years. Despite the lower dose intensity (0.76) of the two drugs compared with single-agent protocols, survival rates were comparable to those for cisplatin chemotherapy alone.

Another study delivered doxorubicin (15-25 mg/m2) and cisplatin (60 mg/m2) on the same day (doxorubicin in postdiuresis fluids) to 102 dogs with osteosarcoma. Median survival was 11.5 months, and 1-year, 2-year, and 3-year survival rates were 47%, 28%, and 17%, respectively. The dose intensity of this protocol was greater than that of either single agent. A later evaluation of toxicity showed that a 20-mg/m2 dose of doxorubicin was well tolerated in these dogs.25 A small pilot study of 19 dogs that used lower doses of doxorubicin and cisplatin (15 mg/m2 and 50 mg/m2, respectively; dose intensity: 1.04) showed a greater median survival, but as more dogs were added to the study, the median survival decreased, illustrating the need for larger numbers to adequately assess efficacy.

Carboplatin (300 mg/m2) and doxorubicin (30 mg/m2) were given in an alternating protocol every 3 weeks for three cycles for a dose intensity of 1.0. Median survival was 10.5 months, and 1-year and 2-year survival rates were 48% and 18%, respectively. The dogs that finished the protocol had a median survival of 18 months. Clients often want to know how their pet is likely to do after completing a course of chemotherapy; this finding serves as encouraging news for dogs that have not developed metastatic disease during chemotherapy.

Palliative Radiation Therapy

If caregivers refuse definitive treatment for a pet with osteosarcoma, or if an animal is not considered eligible for amputation or limb-sparing surgery, consideration may be given to palliation of tumor pain with radiation therapy.

Radiation delivered in two to four weekly fractions of 8 to 10 Gy has been reported as a palliative treatment for 125 dogs with pain or other symptoms related to osteosarcoma. Improved limb function was seen in approximately 75% of dogs treated with either 8 Gy on days 0, 7, 14, and 21; 10 Gy on days 0, 7, and 21; or 8 Gy on days 0 and 7. Improvement lasted for a median of 2 to 3 months regardless of the protocol, and toxicities were rare and acute. Chemotherapy appeared to improve response rate and duration. Dogs with large lesions extending to involve a greater length of limb were less likely to respond for long. Many radiation therapists agree that a reasonable clinical approach may be to deliver a single large dose to the affected site and then to repeat a single dose as necessary to maintain pain control.

Targeted stereotactic "radiosurgery" may offer some advantages in delivering a single high dose of 30 Gy to the tumor alone. Preliminary results are encouraging.

Other Palliative Therapy

Bisphosphonates are inhibitors of osteoclast activity that have been used in human patients with osteolytic disease, including metastatic neoplasia. Pamidronate is an intravenously administered drug that has anecdotally been associated with decreased pain from osteosarcoma.

Pamidronate has also been used in combination with radiation therapy; it is difficult to decide whether the subjective improvement is due to the combination or the individual components.



Key Surgical, Medical Advances for Treating Osteosarcoma

Author(s): Jolle Kirpensteijn , DECVS, DACVS; Antony Moore , BVSc, MVSc, DACVIM (Oncology); Gregory K. Ogilvie , DVM, DACVIM (Internal Medicine, Oncology)
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15872&O=Generic

Introduction

Osteosarcoma (OSA) is the most common bone tumor in dogs and is characterized by a highly invasive and metastatic behavior. The tumor is less common in cats. This tumor frequently affects middle-aged, large breed dogs (less than 5% occur in breeds smaller than 12 kg) and arises in 75% of cases in the metaphyseal area of bones of the appendicular skeleton. The median age of dogs with OSA is 6-7 years. Males are more commonly affected than females. A cause for OSA is unknown although many etiologies have been stipulated (radiation, microtrauma, genetics, implants, nutrition). Most cats are older and a higher number of OS arose from extraskeletal sites (38%).

Pathology

OSA is a malignant spindle-cell tumor characterized by direct formation of bone or osteoid tissue by tumor cells. OSA is an aggressive tumor with a locally invasive behavior and a high rate of metastasis and can be subdivided in chondroblastic, osteoblastic, fibroblastic, telangiectatic, and mixed type tumors. Common locations for OSA include the distal radius, proximal humerus, distal femur, proximal tibia, distal tibia, proximal femur, ulna and scapula. The remainder of OSA (25%) occurs in the axial skeleton (mandible, maxilla, vertebrae and ribs). Multicentric OSA is rare (< 10% of cases). Fifty-five percent of feline OS occur in the appendicular skeleton. OS Pulmonary metastases are present in more than 90% of the patients at time of initial diagnosis. The prognosis for dogs with OSA without therapy is poor, less than 5% will survive longer than one year after diagnosis. The prognosis for cats seems to be better, but small numbers have not allowed a good scientific comparison between groups.

History, Clinical Signs, and Differential Diagnosis

Dogs and cats with OS are often presented with an acute or chronic lameness and a visible swelling at the affected site. The owner often backdates the lameness to a minor traumatic incident and pain can be elicited upon palpation. Muscle atrophy, a history of progressively decreased weight bearing, and pathologic fractures may be present. Differential diagnoses include other primary bone tumors (fibrosarcoma, chondrosarcoma, etc.), metastatic tumors (especially in cats), bone cysts and bacterial or fungal osteomyelitis.

Diagnosis

The presumptive diagnosis of a bone tumor is easily obtained by regional radiography. Radiographic changes include a mixed pattern of osteolysis and bony proliferation and either change can predominate. Macroscopic pulmonary metastases (> 5 mm) are evident in 10% of cases at initial radiographic examination. Metastatic nodules have the 'canon-ball' appearance and are often located in the periphery. Feline pulmonary metastases can have a miliary pattern. The definite diagnosis is obtained by bone biopsy and histologic examination. The biopsy can be performed using a Jamshidi biopsy needle or Michele bone trephine. Two biopsy specimens, one obtained from the centre and one from the tumor-normal tissue transition zone, will allow proper diagnosis in 92% of cases. Additionally, scintigraphy may be used to diagnose multicentric or metastatic OS. However, scintigraphy will not differentiate benign (non-tumorous) from malignant lesions, and should be followed by radiography of regions with increased uptake. CT- and MRI-scans can be used to estimate the extent of bony and surrounding soft tissue involvement.

Histology

Evaluation of the histologic characteristics of OS substantiated the importance of tumor grading. Dogs with more aggressive tumors (grade III) had a worse prognosis after multivariate analysis compared to dogs with lower grade tumors. Also, preoperative, non-steroid-induced plasma alkaline phosphatase elevation was associated with a poor prognosis. Comparisons for cats are researched at this moment.

Genetic Alterations

Canine OS contain genetic alterations comparable to human OS. P53 mutations were common (42%) and were associated with poor outcome using multivariate analysis. Most alterations consisted of point mutations.

The role of growth hormone (GH) expression within the tumor is unclear. After we determined that local GH expression is present in 25% of the dogs, a large number of dogs were evaluated for the clinical importance of this finding. Local GH expression was associated with a poor prognosis. Local GH production may indicate the presence of an autocrine phenomenon, in which the tumor stimulates itself.

Therapy

Successful treatment of OS includes local tumor control as well as the treatment of systemic tumor spread. Local marginal resection as sole treatment will result in high recurrence rates, dysfunction of the leg and undiminished metastatic spread of tumor and should be avoided if adjunctive therapy is not available. In dogs, amputation alone provides good primary local tumor control, but otherwise does not prolong survival time. A median survival time of 19 weeks is observed after amputation. More than 90% of these dogs will die within a year because of the development of distant metastases. After amputation, recovery from surgery and adaptation to three legs is fast. Most dogs, even the larger breeds, function extremely well three-legged and most owners are satisfied with the animal's quality of life. Recovery after amputation is faster than many owners expect. Most dogs are at ease with walking on three legs within a month and dogs with bone tumors are able to ambulate well within 7 days. The owner's satisfaction with the procedure is very high and complications are rare. Force plate analysis of amputees showed significant changes in ground reaction forces. Dogs with front leg amputations may have more problems recovering after the surgery in the beginning because of these GRF changes. Cats seem to have not problem with walking on three legs and thus amputation is the therapy of choice in appendicular OS.

Amputation in combination with chemotherapy enhances survival in canine OS because it decreases the occurrence of metastases. The best-known chemotherapeutic agent, cisplatin, has been shown to significantly prolong the disease-free intervals and survival times in dogs, and remains the drug of choice. Cisplatin is administered intravenously at 60-70 mg/m2 for 4-6 doses, at three-week intervals. Cisplatin is associated with the risk of severe side effects (nephrotoxicity, gastrointestinal toxicity, myelosuppression, and ototoxicity) if given as a sole agent. Most side effects can be prevented by a concurrent 4-hour saline diuresis protocol; however, mild vomiting and bone marrow suppression often will occur. Median survival intervals of dogs treated with cisplatin chemotherapy and resection of the primary tumor is significantly higher than dogs without chemotherapy. A one-year survival percentage of 45-55% has been reported. The median survival interval of dogs treated with chemotherapy before resection of the primary tumor compared to postoperative chemotherapy was not significantly different. Also, the route of administration (IV versus IA) did not influence survival. Dogs that receive more than three doses of cisplatin will survive longer than dogs that receive two or less. Currently, it is recommended to give at least four doses of cisplatin.

Other agents, used for canine OS, that have shown a beneficial effect include doxorubicin, liposome encapsulated muramyl tripeptides (liposome/MTP) and carboplatin. Doxorubicin has been shown to prolong survival in combination with cisplatin and as single agent. Dogs treated for OS with liposome/MTP survived significantly longer than those treated with placebos. Carboplatin, a second-generation platinum compound, does not induce nephrotoxicity and can be given as a 15-minute bolus injection without saline diuresis. Carboplatin significantly increased survival times compared to dogs with amputation alone and was comparable to cisplatin chemotherapy. Carboplatin is given intravenously on an every 21-day schedule at 300 mg/m2.

Instead of amputation, local control may also be obtained by limb-sparing procedures. The goal of limb sparing is to obtain local tumor control, while providing a pain-free and functional leg. The procedure usually involves (marginal) local surgical excision of the tumor in combination with chemotherapy or radiation therapy. Common locations amenable for performing limb sparing are the distal radius, proximal humerus, scapula and ulna. OS of the distal radius and proximal humerus are removed by marginal resection, replaced by an allograft and affixed to the host bone using a bone plate. Arthrodesis of the adjacent joint is often necessary. Recovery after surgery is often fast with dogs bearing weight within a week. Eighty percent of dogs return to normal function after limb-sparing procedures in 6-8 weeks. OS of the ulna and scapula may be resected without the use of an allograft. Ulnectomies distal to the elbow joint and partial scapulectomies are extremely well tolerated. Complications associated with limb-sparing procedures include infection, recurrence and implant failure. The use of cemented allografts has decreased the number of complications associated with allograft failure significantly.

The incidence of local tumor recurrence after limb sparing varies between 25-50%. Methods to prevent local recurrence include preoperative radiation and preoperative administration of chemotherapy by intra-arterial route, local intravenous perfusion, or slow release polymers. Any of these therapies should be considered in tumors that have extended through the bony cortex and have invaded in the surrounding soft tissues. The use of intravenous, systemic chemotherapy has been unrewarding in preventing recurrence after incomplete resection.

In cats, the advantage of adjunctive therapy after surgical excision is unclear. Some authors clearly state that feline OS behave comparable to canine while others debate the effectiveness of chemotherapy in the cat. One thing is for sure, however, cats are extremely sensitive for cisplatin and life-threatening pulmonary edema occurs after administration of this drug.

Metastatic Osteosarcoma

OS is a highly metastatic tumor and most metastases are observed in the lungs. Macroscopic metastatic disease in canine OS is not responsive to chemotherapy and the prognosis is often poor. Surgical resection of pulmonary metastasis is useful in limited numbers of patients if less than three nodules are present, if the tumor size has not doubled in a month, and if the disease-free interval is longer than 300 days from the initial date of diagnosis. No data are available for cats concerning metastasectomy in cats.

References

  1. Brodey RS, Abt DA. Results if surgical treatment in 65 dogs with osteosarcoma. J Am Vet Med Assoc 1976; 168: 1032.
  2. Kirpensteijn J, Straw RC, Withrow SJ, et al. Partial and total scapulectomy in the dog. J Am Anim Hosp Assoc 1994; 30: 313.
  3. Kirpensteijn J. Current developments in canine osteosarcoma. Vet Quart 1994; 16s: 31.
  4. Kirpensteijn J, van den Bos R, van den Brom, W, Hazewinkel HAW. Ground reaction force analysis of large breed dogs when walking after amputation of a limb. Vet Rec 2000; 146: 155-159.
  5. Kirpensteijn J, van den Bos R, Endenburg N. Adaptation of dogs to the amputation of a limb and their owner's satisfaction with the procedure. Vet Rec 1999; 144: 115-118.
  6. Kirpensteijn J, Steinheimer DN, Park RD, Withrow SJ, Straw RC, Comparison of cemented and noncemented cortical allografts for limb sparing procedures in dogs, Vet Comp Orthop Traumatol 1998; 11: 178-184.
  7. Kirpensteijn J. Clinical and pathogenetic studies in canine osteosarcoma. Thesis Utrecht University, The Netherlands 1999; 1-174.
  8. O'Brien MG, Straw RC, Withrow SJ, et al. Resection of pulmonary metastases in canine osteosarcoma: Thirty-one cases. Vet Surg 1993; 22:105.
  9. Straw RC, Withrow SJ, Richter SL, et al. Amputation and cisplatin for treatment of canine osteosarcoma.J Vet Intern Med 1991; 5: 205.
  10. Heldmann E, Anderson MA, Wagner-Mann C. Feline osteosarcoma: 145 cases (1990-1995).J Am Anim Hosp Assoc 2000; 36: 518-21.
  11. Chun R, Garrett LD, Henry C, Wall M, Smith A, Azene NM. Toxicity and Efficacy of Cisplatin and Doxorubicin Combination Chemotherapy for the Treatment of Canine OsteosarcomaJ Am Anim Hosp Assoc. 2005; 41(6): 382-38


Nutrition and Cancer: Frontiers for Cure!

Author(s): Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine, Oncology)
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15873&O=Generic

Using specifically formulated diets or dietary supplements to prevent and to treat cancer is in its infancy; however, enough information exists to begin making some recommendations to prevent and treat cancer in people and dogs. In human medicine, several nutritional factors have been found to increase the risk and rate of developing cancer, including :

  • Obesity
  • Consumption of nutrient-sparse foods, such as concentrated sugars and refined flour products
  • Low fiber intake
  • Inadequate consumption of polyunsaturated fatty acids of the n-3 series (n-3 PUFAs) and an increase consumption of PUFAs of the n-6 series (n-6 PUFAs)

Carbohydrates and Cancer

Evidence is mounting that simple carbohydrates may be contraindicated for the nutritional management of cancer in dogs:

  • Dogs with a wide variety of malignant conditions have elevated resting insulin and lactate levels compared to control animals. It is unknown if the elevated insulin levels are a response to cancer or if they precede and possibly contribute to the development of cancer via stimulation of insulin-like growth-factor (IGF) pathways.
  • Elevated lactate and glucose levels do not improve after dogs with cancer are rendered free of disease with chemotherapy and surgery.8 This suggests that the malignancy causes a fundamental change in metabolism that persists after all clinical evidence of cancer is eliminated.
  • Elevated lactate levels can result in inefficient Cori cycle activity to convert lactate back to glucose; this results in a net energy loss by the patient.
  • The administration of lactate-containing parenteral fluids such as lactated Ringer's solution has been shown to increase lactate levels in dogs with lymphoma, suggesting that these types of fluids may place an additional energy burden on the host.
  • Before the development of severe malnutrition, human patients with colon, gastric, sarcoma, endometrial, prostate, localized head, neck, or lung cancer have many of the metabolic abnormalities of type II (non-insulin-dependent) diabetes mellitus. These metabolic abnormalities include glucose intolerance; an increase in hepatic glucose production, glucose recycling, and insulin resistance; and an increase in anaerobic glycolysis causing increased lactate production. These are essentially the same findings as in dogs with cancer.

The metabolic abnormalities noted above are only important if they affect the patient clinically. Studies done in human patients suggest that alterations in carbohydrate metabolism influence cancer prevention and outcome once cancer is diagnosed. For example, one study evaluated the hypothesis that glucose, insulin, and IGFs contribute to breast cancer development in 10,786 women. It was concluded in this research that higher levels of glucose, insulin, and IGF-1 were associated with a higher risk of developing breast cancer and a poorer survival after diagnosis. A second study involving 603 breast cancer patients was performed to test the hypothesis that excess insulin and related factors are directly related to mortality after a diagnosis of breast cancer. It was concluded in that study that high levels of insulin were associated with poorer survival for postmenopausal women.

Proteins and Cancer

Dogs with cancer have alterations in protein metabolism that are very similar to those observed in humans and laboratory animals with cancer. For example, there is a significant decrease in a wide variety of amino acids, suggesting that a high-quality, highly bioavailable protein source would be beneficial to the animal and to the tumor. Amino acids of particular importance to patients with cancer are glutamine, cysteine, and arginine.

Glutamine supplementation may enhance the therapeutic index of chemotherapy and radiation by enhancing the efficacy of these treatments while reducing adverse effects such as mucositis, diarrhea, neuropathy, and cardiotoxicity. Glutamine is conditionally essential for the health and function of the bowel. At least some of this amino acid is destroyed in the process of making many types of dried and canned pet food.

Cysteine is critically important to replenish the glutathione antioxidant system. This system is the principal protective mechanism of the cell and is a crucial factor in the development of the immune response. Cysteine supplementation has been shown to have anticancer activity via the glutathione pathway, the induction of p53 protein in cancer cells, and inhibition of neoangiogenesis.

Arginine is a conditionally essential amino acid that is necessary during periods of growth and recovery after injury. Arginine promotes wound healing, has several immunomodulatory effects such as stimulating T- and natural-killer cell activity, and influences proinflammatory cytokine levels. L-Arginine is the sole precursor for the multifunctional messenger molecule nitric oxide, which appears to influence tumor initiation, promotion, and progression; tumor-cell adhesion; apoptosis angiogenesis; differentiation; chemosensitivity; radiosensitivity; and tumor-induced immunosuppression. The administration of arginine to human and veterinary cancer patients has resulted in positive outcomes.

Lipids and Cancer

Serum lipid profiles were performed in dogs with lymphoma before and after they were put into remission with chemotherapy. These profiles were compared to those of normal dogs before and after they were given the same anticancer drug.

  • The dogs with cancer had significantly lower levels of high-density lipoproteins. The total triglyceride levels and very low-density triglycerides of untreated dogs with lymphoma were significantly higher than those of untreated control dogs.
  • After a total of five doses of doxorubicin chemotherapy, the total cholesterol level increased in dogs with lymphoma but decreased in treated control dogs.
  • All other parameters remained unchanged after doxorubicin therapy, suggesting that lipid abnormalities do not improve significantly, even after a clinical remission is obtained.

We tested the hypothesis that diets relatively high in fat may be beneficial for animals with cancer compared to diets that are high in simple carbohydrates, assuming that the protein content, caloric density, and palatability remain constant. One study suggested that a high-carbohydrate, low-fat diet induced elevated lactate and insulin levels compared to a diet relatively high in fat and low in carbohydrates. It also suggested that a high-fat diet may result in a higher probability of going into remission with chemotherapy as well as a longer survival time. The kind of fat in the diet, rather than the amount, may be the important factor. For example, n-3 PUFAs have been shown experimentally to have many beneficial properties.

Emerging Role of PUFAs

For the last decade, investigators have searched for dietary lipids associated with a delay in cancer relapse. The use of long-chain polyunsaturated fatty acids (LC-PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as adjuvant therapies to enhance the effect of chemotherapy and radiation therapy shows promise. LC-PUFAs have been shown to enhance disease-free interval, survival, and quality of life after surgery by reducing the rate of cancer development or incidence. This concept, known as 'cancer prevention by delay' or clinical cancer chemoprevention, is an important mechanism behind the successes of several therapeutic agents, including tamoxifen, retinoids and interferon-alfa, and nonsteroidal anti-inflammatory drugs.

Cancer prevention by delay is a valuable clinical tool until more effective cancer therapeutics can be developed. Unfortunately, while use of the most effective cancer therapies (i.e., surgery, radiation, and chemotherapy) is effective for improving the disease-free interval of many patients up to a point, it has not increased the cancer cure rate or survival time dramatically in the last 10 years. Therefore, it seems logical to add on relatively nontoxic therapies that can extend the disease-free interval, even if the absolute cure rate is not increased. Tamoxifen, retinoids, and nonsteroidal anti-inflammatory agents are all recognized to improve disease-free interval without necessarily improving the absolute cure rate. Tamoxifen has been shown to significantly diminish the risk of human breast cancer; retinoids and interferon-alfa to reduce the risk of head and neck cancer in dogs, cats, and humans; and nonsteroidal anti-inflammatory drugs to delay or reduce the development of colorectal cancer in humans and transitional cell and squamous cell carcinomas in dogs.

Dietary lipids such as DHA and EPA appear to influence the growth of many types of cancer, including breast and prostate cancer. A group of investigators in France used adipose tissue sampled during surgery as a biomarker of past dietary intake of PUFAs in a cohort of women treated for localized presentations of breast cancer. They found elevated n-3 PUFAs, especially DHA, to be associated with a higher metastasis-free survival, suggesting that these PUFAs could potentially delay metastasis by decreasing tumor growth or development. Using a case-control approach comparing the fatty acid composition of adipose breast tissue obtained at the time of surgical removal of either malignant or benign breast tumors, they also found α-linoleic acid and docosahexaenoic acid to be positively associated with a decreased risk of having breast cancer.

The French group also explored the role of n-3 PUFAs in mammary tumor growth using the experimental system of N-methylnitrosourea (NMU)-induced mammary tumors in rats. Because PUFAs are substrates for lipid peroxidation processes, the investigators studied the effects of n-3 PUFAs on tumor growth in interaction with anti- or pro-oxidant compounds. They found that dietary n-3 PUFAs, in the form of DHA-containing fish oil, inhibited tumor development. This inhibition was most evident in the absence of the antioxidant vitamin E. Inhibition of tumor growth was even greater when n-3 PUFAs were given in the presence of pro-oxidants. Such effects were not found when the lipid diet was low in PUFAs. These data suggest that oxidized n-3 PUFAs have an inhibiting effect on tumor growth and emphasize the importance of the interaction of anti- and pro-oxidant compounds with n-3 PUFAs.

There is a growing body of data that suggests that the presence of n-3 PUFAs such as DHA and EPA affects several steps of tumor formation. N-3 PUFAs:

  • Inhibit tumor vessel formation (angiogenesis).
  • Inhibit cell proliferation in several epithelial cell lines.
  • Enhance the rate of tumor cell death.
  • Induce lipid peroxidation, which enhances the efficacy of radiation- and chemotherapy-induced cancer cell death; this effect is diminished or reduced dramatically with vitamin E.
  • Suppress the expression of cyclooxygenase-2 in tumors, thereby decreasing cancer cell proliferation.
  • Suppress nuclear factor κB activation and BCL-2 expression, thus allowing apoptosis of cancer cells.

Dietary lipids have been shown to modify the sensitivity of tumors to reactive oxygen species-generating anticancer drugs. For example, when dogs with lymphoma were treated with doxorubicin chemotherapy and a diet supplemented with n-3 PUFAs in the form of fish oils, there was a direct correlation between the level of DHA in the blood and improved disease-free interval.18 Another study, using the same randomized study design, was used to assess the efficacy of n-3 PUFAs in combination with doxorubicin chemotherapy to improve the disease-free interval in dogs with hemangiosarcoma, a highly metastatic, rapidly fatal malignancy. There was a statistically significant positive correlation between the n-3 PUFAs levels in the serum and disease-free interval. A similar approach was used in rats bearing autochthonous, NMU-induced mammary tumors. It was found that dietary supplementation with fish oil or DHA increased the sensitivity of mammary tumors to anthracyclines, compared with dietary supplementation with saturated fatty acids.

Because DHA is the most polyunsaturated of the PUFAs, lipoperoxidation is a likely molecular mechanism implicated in the enhancement of the response of cancer cells to cytotoxic drugs. Addition of vitamin E to the diet provided to rats with mammary tumors abolished the enhancing effect of DHA on tumor sensitivity to anthracyclines. In all studies done to date, there has been no clinically significant toxicity other than transient gastrointestinal (GI) distress linked to the dietary change. Therefore, based on the safety and efficacy profile of n-3 PUFAs, it seems reasonable to further define the efficacy of n-3 PUFAs, especially DHA, for the treatment of spontaneously occurring cancer in dogs, with the intent to provide evidence for their use in randomized human clinical trials.

DHA and EPA also augment the efficacy of chemotherapy and radiation therapy, potentially enhancing the efficacy of traditional cancer therapies. Radiation therapy is currently the most effective treatment for many localized malignancies. Research is under way to identify methods to maximize its efficacy while minimizing the adverse effects associated with it. Among the agents being evaluated to minimize the damage to normal tissue are n-3 LC-PUFAs, which are readily incorporated into cell membranes and ameliorate inflammation and carbohydrate dyshomeostasis. In one study, 12 dogs with histologically confirmed malignant carcinomas of the nasal cavity were randomized to receive isocaloric amounts of a diet supplemented with menhaden fish oil, including DHA (experimental diet), or an otherwise identical diet supplemented with corn oil (control diet). Megavoltage radiation was delivered to all dogs. The data in this study suggest that feeding a diet supplemented with fish oil and arginine is associated with decreased concentrations of inflammatory mediators involved with radiation damage in skin and mucosa and with improved performance scores in dogs with malignant nasal tumors.

The ability of PUFAs to sensitize tumors to radiation has been investigated. Vartak et al studied the in vitro response of a chemically induced rat malignant astrocytoma cell line to radiation after the cell culture medium was supplemented with g-linoleic acid (GLA) or n-3 LC-PUFAs. They found that n-3 PUFAs enhanced radiation-induced cell cytotoxicity. In a separate study, Colas et al44 documented enhanced radiosensitivity of rat autochthonous mammary tumors after administration of dietary DHA.

Whether use of dietary n-3 PUFAs can enhance sensitivity of tumor tissue in the absence of a similar increase in the radiosensitivity of nontumor tissue remains a critical issue. Several studies have suggested that PUFAs do not sensitize normal tissue to radiation. For example, because ionizing radiation generates reactive oxygen species, we initiated a study to determine whether dietary DHA might sensitize mammary tumors to irradiation using a model in which mammary tumors were induced by NMU in Sprague-Dawley rats. In the study, we showed that dietary DHA sensitized mammary tumors to radiation. The addition of vitamin E inhibited the beneficial effect of DHA, suggesting that this effect might be mediated by oxidative damage to the peroxidizable lipids.



Recent Advances in Mast Cell Tumors

Author(s): Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine, Oncology)
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15867&O=Generic

Very few tumors present in such a wide variety of clinical signs: they are indeed the great impostors! They can look like anything and behave differently depending on the histologic type, location and the extent of the disease. The following is a brief discussion about these tumors. Some highlights are as follows:

  • Mast cell tumor granules do not stain well with Diff Quick type stains unless they are "soaked" in the alcohol for several minutes prior to staining.
  • Some important prognostic indicators include duration of presence, location and histologic type in the dog.
  • Mast cell tumors tend to metastasize to nodes, liver spleen and bone marrow ... rarely to lungs.
  • Radiation therapy is extremely effective for controlling local disease.
  • Prednisone and vincristine when used as single agents induce a remission (partial or complete) in about 23% of the tumors.

Diagnostics

Diagnosis of mast cell tumors often can be made by a fine needle aspiration cytology but excisional biopsy is required if accurate histologic grading of the tumor is desired. Mast cell tumors are classified as round cell tumors along with lymphosarcoma, histiocytomas and transmissible venereal tumors.

Diagnostic workup of mast cells usually includes a number of procedures. These include a complete blood cell count (CBC), serum chemistry profile, and urinalysis. In addition, fine needle aspiration of the lesion, regional lymph nodes and examination of buffy coats or bone marrow helps to determine the extent of tumor involvement. A CBC is valuable in assessing animals with mast cell tumors because those animal patients with systemic mastocytosis occasionally have peripheral eosinophilia and basophilia in addition to circulating mast cells. Mastocytemia is a more common clinical phenomenon in the cat than in the dog. The CBC may also give evidence of gastrointestinal bleeding or gastrointestinal perforation. In general, mastocytosis associated with primary cutaneous tumors is more easily detected by examination of the buffy coat or bone marrow than by examination of peripheral blood. Care must be exercised in interpreting buffy coats since mastocytemia has been reported in a variety of acute inflammatory diseases of the dog including parvovirus infections. Peripheral mast cell counts may be high in cats with mastocytosis and have accounted for up to 25% of the total white cell count.

Therapy

Surgical considerations include wide surgical margins with at least 3 cm of normal looking skin around the tumor should be removed when possible. The 3 cm recommendation is a guideline and might not be feasible when the tumor is located on the face, lower limbs or in the inguinal region. It should be remembered that most mast cells extend laterally to adjacent tissue rather than deep into underlying muscles. All excised tumor should be examined histologically for the completeness of excision. Extension of the tumor beyond the surgical borders should prompt either wider excision or radiation therapy of the tumor bed. Approximately 50% of the mast cell tumors recur at the surgical site traditionally. Histologic grade is an important factor in predicting recurrence at the surgical site. Those that are undifferentiated tend to have a higher recurrence rate. Cats with mast cell tumors with splenic involvement often will benefit from splenectomy. Survival times of 10 weeks to 30 months have been reported following splenectomy, even in patients with evidence of systemic mastocytosis.

Seguin et al (J Am Vet Med Assoc 218[7]:1120-1123 2001) evaluated 60 mast cell tumors that were surgically excised with clean margins in 55 dogs were included. Median follow-up time was 540 days. Three mast cell tumors recurred locally; median time to local recurrence was 62 days. Six dogs developed another mast cell tumor at a different cutaneous location; median time to a different location was 240 days. Three dogs developed metastases; median time to metastasis was 158 days. The authors concluded that additional local treatment may not be required after complete excision of grade-II mast cell tumors and that most dogs do not require systemic treatment.

Glucocorticoid therapy frequently results in partial or occasionally complete remissions in canine mast cell tumors. However, cats appear to be less responsive to glucocorticoid treatment. The effect of glucocorticoids is to reduce markedly the number of mast cells in the mast cell tumor. The exact mechanism by which glucocorticoids exert their cytotoxic effects on mast cell tumors is unknown although it may be similar to the effects of glucocorticoids on lymphocytes. The susceptibility of mast cell tumors might depend on the presence of intracytoplasmic glucocorticoid receptor sites. Glucocorticoid receptor sites have recently been found in the cytoplasm of canine mast cell tumors. Although sex steroid receptors for progesterone and estrogen have been recently described in dogs with canine mast cell tumors, the role of sex steroids in the treatment of canine mast cell tumors has yet to be investigated. The type of glucocorticoids administered appears to be unimportant but it has been suggested that intralesional corticosteroid may be more effective than systemic therapy for local disease. Fewer Cushingoid side effects have been seen with short-acting glucocorticoids such as prednisone or prednisolone when used in the dog. The usual dose of prednisone is .5 mg/kg orally administered once daily and that of triamcinolone is 1 mg for every cm diameter of tumor intralesionally, administered every two weeks. Remission times are usually 10 to 20 weeks. Dogs that are tumor free after six months however have a low incidence of recurrence and therefore therapy is usually discontinued at this time. Tumor resistance may be caused by the emergence of mast cells with fewer or ineffective glucocorticoid receptors. Survival data based on histologic grade correlates with various chemotherapeutic regimens has not been reported.

Vinblastine and prednisone or CCNU appear to be the most favored drug protocols for the treatment of mast cell tumors. The use of these drugs is always with surgery.

Rassnick and colleagues (J Vet Intern Med 13[6]:601-605, 1999) evaluated the efficacy and toxicity of CCNU in 23 dogs with measurable mast cell tumors (MCT). Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, 21-254 days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU.

Thamm et al (J Vet Intern Med 13[5]:491-497, 1999) evaluated 41 dogs with mast cell tumors treated with oral prednisone and vinblastine both in the adjuvant setting and in dogs with gross disease. Adverse effects were noted in 20% of the patients, usually after the 1st dosage. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade 111 MCT was 331 days, with 45% of dogs alive at 1 and 2 years.

Ancillary drug therapy is important with canine mast cells. Animals with mastocytosis or palpable mast cell disease should receive H2 antagonists. Cimetidine (Tagamet) reduced gastric acid reduction by competitive inhibition of the action of histamine on H2 receptors of the gastric parietal cells. Ranitidine (Zantac, Glaxo Inc, Fort Lauderdale, FL), a newer H2 antagonist that requires less frequent administration, is in some clinics. The objective of the therapy is to prevent gastrointestinal ulceration associated with elevated levels of histamine and to treat ulcers already present. Some new evidence indicates that cimetidine may also alter the immune response to this tumor as well as activation of certain alkylating agents. Dogs and cats with evidence of gastrointestinal ulceration and bleeding might also benefit from sucralfate (Karafate, Marion Labs Inc, Kansas City, MO) therapy. Sucralfate reacts with stomach acid to form a highly condensed viscous adherent paste-like substance that binds to the surface of both gastric and duodenal ulcer sites. The barrier formed at the ulcer site protects the ulcer from potential ulcerogenic properties of pepsin, acid and ile allowing the ulcer to heal.

Radiotherapy has been used alone or in combination with other treatment modalities. Most reports indicate remission rates of 48 to 77%. Doses of 3,000 to 4,000 rads were used in these studies. Total radiation therapy is usually fractionated and delivered over a period of three to four weeks. The use of radiotherapy is somewhat expensive and is confined to referral centers. Mast cell tumors in regional lymph nodes and bone marrow appear to be more resistant to the effects of radiotherapy than those confined to the skin. Response of mast cell tumors to radiation therapy may correlate to histologic grade but has not been studied.

Summary

Grade 1 Mast Cell Tumors

Dogs with grade 1 MCTs have a high likelihood of complete tumor control after complete surgical excision. A recent study showed that all grade 1 MCTs were completely excised with a 1-cm clinical margin. However, because tumor grading is performed histologically, not on cytology, all MCTs for which a grade is as yet uncertain should be excised for biopsy with wide (2 to 3 cm) margins.

Grade 2 Mast Cell Tumors

Three recent studies have challenged early assumptions that dogs with grade 2 MCTs have a high likelihood of local recurrence even after apparently complete excision. These studies showed that with a more aggressive surgical technique and histology to examine margins (rather than the surgeon's clinical impression), dogs with grade 2 MCTs have a much lower rate of local recurrence and longer survival rates than previously reported. Specifically, between 5% and 10% of dogs had a local recurrence of MCT a median of 7 months after surgery (range: 2 to 24 months). More than 30% of these dogs had an MCT on the limb, for which some limbs were amputated. On the other hand, many of these dogs developed another MCT at a distant cutaneous site. These were considered to be de novo tumors (rather than cutaneous metastases, which have not been reported) and were diagnosed from 2 months to 4 years later, with a median time to diagnosis of about 1 year. Metastasis was rare, occurring in fewer than 3% of dogs.

Grade 3 Mast Cell Tumors

One study found that grade 3 tumors were more likely to be incompletely excised and more likely to metastasize than grade 1 or 2 MCTs. Radiation therapy is probably warranted (see below), and chemotherapy should be considered for grade 3 MCTs.

Prognosis

The natural behavior of mast cells suggests prognosis of this tumor depends on the species, breed, histologic grade, tumor location, clinical stage and growth rate. In general, cutaneous mast cell tumors carry a more guarded prognosis in the dog than in cat. Mast cell tumors in the boxer are usually of a lower histologic grade than when found in other breeds. Mast cell tumors in Siamese are of the less malignant histiocytic type. Histologic grade has been shown to correlate with survival following surgical excision by at least two investigators. The higher the histologic grade (more undifferentiated tumor), the poorer the prognosis. This criteria has not had universal acceptance however, probably due to the precise nature of histologic grading as well as tumor heterogeneity. Clinical staging and the extensiveness of microscopic tumor masses beyond what might be detected clinically also plays an important role in the failure of universal acceptance of the histologic grading system. In the cat, in addition to the histologic grading system described for the dog, the histiocytic mast cell variant tends to carry a better prognosis than the traditional mast cell. Tumor location is considered by many investigators to be an important prognostic feature. Tumors located in the perineal or preputial area are likely to metastasize both locally and to deep lymph nodes. Clinical stage is a clinical means of assessing tumor spread of the disease process. The higher the clinical stage, the more guarded the prognosis. A high histologic grade, however, should increase the clinical stage at least one level. Growth rate but not tumor size is determined also to be an important prognostic indicator. Growth rate reported by Bostock indicates that dogs that have tumors that grow greater than 1 cm per week have only a 25% chance of living an additional 30 weeks.

References

  1. Ogilvie GK, Moore AS. Mast Cell Tumors. In: Managing the Veterinary Cancer Patient: A Practice Manual. Trenton: Veterinary Learning Systems. 1995: 503-514.
  2. Rassnick KM, Moore AS, Williams LE, London CA, et al. Treatment of Canine Mast Cell Tumors with CCNU (Lomustine) J Vet Intern Med 13[6]: 601-605 1999.
  3. Thamm DH, Mauldin EA, Vail DM. Prednisone and Vinblastine Chemotherapy for Canine Mast Cell Tumor -- 41 Cases (1992-1997) J Vet Intern Med 13[5]: 491-497 1999
  4. Seguin B, Leibman NF, Bregazzi VS, et al. Clinical Outcome of Dogs with Grade-II Mast Cell Tumors Treated with Surgery Alone: 55 Cases (1996-1999). J Am Vet Med Assoc 218[7]: 1120-1123, 2001.


Top Ten Advances in Veterinary Oncology 2005/2006

Author(s): Gregory K. Ogilvie , DVM, DACVIM (Internal Medicine, Oncology); Antony Moore , BVSc, MVSc, DACVIM (Oncology); Jolle Kirpensteijn , DECVS, DACVS
Address (URL): http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=WSAVA2006&PID=15870&O=Generic

The popularity of oncology is increasing dramatically in veterinary medicine in part because of the many advances in veterinary cancer diagnostics and therapeutics. The objectives of the following document are to recognize ten of the most amazing advances in veterinary oncology and to:

  • Discuss the integration of cancer prevention into health and wellness programs to increase cancer cure rates.
  • Examine how clients and the veterinary health care team perceive cancer, dispel the myths associated with cancer treatment and replace these myths with accurate concepts about how dogs and cats with cancer and their caregivers should be approached, supported and treated.
  • Discuss key advances in cancer care including the management of transitional cell carcinomas, hemangiosarcoma, transitional cell carcinoma, and primary lung tumors.
  • Briefly review a condition that may be a debilitating consequence of caring called 'compassionate fatigue'.

Cancer Prevention

Cancer care will succeed if the profession is active at developing health and wellness programs that incorporates cancer prevention and screening. Cancer prevention and early detection and diagnosis are the key to reducing cancer related deaths in veterinary medicine. The initiation of these prevention and screening programs for all stages of life is not only the right thing to do for the patient, but it is the correct thing to do for the concerned client.

Cancer can be prevented if the known risk factors are identified. Lifetime obesity is one risk factor. Eicosapentaenoic and docosahexaenoic acids have been shown consistently to inhibit the proliferation of breast and prostate cancer cell lines in vitro and to reduce the risk and progression of these tumors in many species (Am J Epidemiol 141(4): 352-359, 1995).

A lifetime study of restricted daily intake of the same food was done with Labrador retrievers that came from seven litters (J Am Vet Med Assoc 220; 1315-1320, 2002). The median life span of the restricted-fed group was significantly longer. While the prevalence of cancer between groups was similar, the mean age due to cancer-related deaths was 2 years later in the dogs that received the restricted diet.

Secret #1. Lifetime weight management is associated with decreased risk of developing cancer and other diseases such as diabetes mellitus. DHA and EPA may reduce the risk of cancer.

Dogs have been shown to have an increased risk of developing cancer of the respiratory tract, especially of the lung and nasal cavity, when exposed to coal and kerosene heaters and passive tobacco smoke. Mesothelioma is more common in dogs owned by people who worked in the asbestos industry. The use of chemicals by owners, specifically 2,4-dichlorophenoxyacetic acid, paints, asbestos or solvents, as well as radiation and electromagnetic field exposure were associated with increased risk for several types of cancer in pet dogs. Application of insecticides (but not in a spot-on formulation) increased the risk of bladder cancer in Scottish terriers in another study (Environ Res 32(2): 305-313, 1983).

Secret #2. It is important to eliminate exposure to environmental carcinogens such as pesticides, coal or kerosene heaters, herbicides such as 2,4-dichlorophenoxyacetic acid, passive tobacco smoke, asbestos, radiation, and strong electromagnetic field exposure.

These steps may be particularly important for clients of susceptible breeds (e.g., a Scottish terrier) and herbicide exposure.

Commandments

Perhaps the greatest barrier to enhanced cure and control of cancer is that the caregiver, and the veterinary health care team often have preconceived notions about cancer and its treatment. This is true regardless if you are talking about cancer prevention or treatment. The first and possibly the most difficult task facing the veterinary health care team is the dissolution of the negative myths and misperceptions regarding cancer and the efficacy and toxicity of cancer therapy. The first step is to recognize the fears associated with cancer and to address those head on. The approaches to the biggest fear about cancer are called the commandments of cancer care.

  • Do not let them hurt: Providing an active, preemptive, and ongoing pain management/prevention program for the dog with cancer is absolutely imperative. This reassures the caregiver that quality of life is optimal. Management should begin with comfort care and then, when needed, include oral medications (morphine, codeine, piroxicam (Feldene), carprofen, or others), transdermal delivery systems (fentanyl patches), acupuncture or more advanced analgesic delivery systems (e.g., constant rate intravenous infusion, epidural catheters, intrathoracic pleural analgesia).
  • ;Do not let them vomit or have diarrhea. Dispensing oral medication such as metoclopramide to the caregiver each and every time a potentially nauseating drug is administered, empowers the caregiver to prevent this symptom at home. In addition, we must be prepared to stop nausea and vomiting should it occur, ensuring that medications and supportive care are immediately available. Having access to drugs such as ondansetron hydrochloride and dolasetron mesylate, although costly, will provide this level of assurance for all members of the team. Some believe that tylosin, metronidazole and imodium can reduce the risk of small and large bowel diarrhea and often dispense these drugs to their cancer patients to prevent problems. Enhancing fiber content can be of great value at enhancing bowel health.
  • Do not let them starve: Nursing care (e.g., warming food, providing aromatic foods and comfortable environments), medicinal appetite stimulants, and, when needed, assisted feeding techniques such as esophagostomy, gastrostomy, or jejunostomy tube placement should be employed. All of these components of nutritional care must be available early in the course of disease, and weight loss must not be tolerated, particularly in dogs that have fewer reserves due to their small size. To our caregivers, appetite is a vital, objective assessment of quality of life that must not be overlooked or left to chance.

Secret #3. Meeting the medical needs of the patient and the non-medical needs of the client can be done by preventing and treating pain, nausea, vomiting and anorexia early and often.

Recent Advances in Cancer Care

Gene therapy has been around, at least conceptually for forty years, however the technology to manipulate genes and to deliver them safely has only recently been realized. In its simplest definition, gene therapy is the introduction of a gene or genes into a cell to treat or prevent cancer. One recently completed trial of xenogeneic DNA vaccination in canine advanced oral malignant melanoma using the human tyrosinase gene was performed (Clin Cancer Res 9(4): 1284-1290, 2003). This novel approach using a gene from another species elegantly and simply induced a good immune response against the malignant melanoma, but not the patient's own tissue. The Kaplan-Meier median survival time for all nine dogs in this study was 389 days with some of the dogs having stabilization of disease or reduction in the size of the cancer. The investigators concluded that xenogeneic DNA vaccination of dogs with advanced malignant melanoma is a safe and potentially therapeutic modality.

Secret #4. Gene therapy provides and exiting option for cancer control and cure.

Doxorubicin has been shown to improve the disease free interval in dogs that have had incompletely excised soft tissue sarcomas (Selting, Proceedings Vet Cancer Society 2004). Local lymph node involvement was a significant negative prognostic factor. Similarly, doxorubicin has been shown to be of value for the treatment of surgically resected hemangiosarcoma (J Vet Intern Med 10(6): 379-84, 1996). A pilot study by an Australian group (Langova et al) presented at the Veterinary Cancer Society in 2004 utilizing alternating carboplatin and doxorubicin with piroxicam for the treatment of nasal tumors resulted in a median survival time of 550 days with 4/8 CR and 2/8 PR.

Secret #5. Doxorubicin is the most effective agent for the treatment of lymphoma and it has efficacy for the treatment of hemangiosarcoma, soft tissue sarcomas and osteosarcoma.

CCNU is an oral alkylating agent that has been shown to result in a 50% response rate (8.3% CR) and median survival time of 128 days by Skorupski et al against histiocytic sarcoma (Proceedings, Veterinary Cancer Society 2004). Similarly, this drug has recently been shown to be helpful for treating mycosis fungoides. Thrombocytopenia and hypoalbuminemia at the time of diagnosis were significant negative prognostic factors. Fifty-seven dogs with MCT were treated with prednisone and alternating vinblastine/Lomustine (Hershey); almost all as an adjuvant to surgery, and about twenty percent for non-resectable disease. The median DFI is > 375 days and most dogs had a measurable response.

Secret #6. CCNU is effective for the treatment of lymphoma, histiocytic sarcoma, mycosis fungoides, and mast cell tumors.

Piroxicam and possibly other NSAIDs have been shown to have anticancer effects. Several studies have been performed confirming that piroxicam is effective for the treatment of transitional cell carcinoma and oral squamous cell carcinoma. Some oncologists favor the combination of mitoxantrone and piroxicam. In one study, Forty-eight dogs with histologically confirmed transitional cell carcinoma were treated with mitoxantrone and piroxicam (Clin Cancer Res. 2003 Feb; 9(2): 906-11). Forty-eight dogs were treated with the following responses: one complete response, 16 partial responses, 22 with disease stabilization, and 9 with progressive disease for an overall 35.4% measurable response rate. Subjective improvement occurred in 75% of treated dogs. Median time-to-treatment failure and ST were 194 and 350 days, respectively.

Secret #7. Piroxicam has been shown to be very effective for the treatment of transitional cell carcinoma and squamous cell carcinoma in the dog.

Primary lung tumors have been ineffectively treated until vinorelbine was shown to be effective (J Vet Intern Med 18(4):536-9, 2004). The investigators concluded that the well-tolerated toxicity profile and clinical activity observed in dogs with bronchoalveolar carcinoma treated with vinorelbine warrants further investigation.

Secret #8. Vinorelbine is a promising new agent for the treatment of pulmonary tumors in dog and cats.

Inadequately excited mast cell tumors have been shown to be effectively treated with vinblastine and prednisone. In one study, 27 dogs with inadequately excised, cutaneous mast cell tumors were treated with a vinblastine and prednisolone chemotherapeutic protocol. Twenty dogs were available for follow-up examination after 12 months. Over half were disease free after one year.

Secret #9. Vinblastine is a relatively safe and effective therapy for mast cell tumors in the dog.

Compassion Fatigue

When we care for our patients with compassionate care, we must do so by expressing empathy. The act of extending empathy as we care for our patients and their clients can lead to compassion fatigue. When any member of the veterinary health care team finds themselves giving more without allowing themselves to be replenished emotionally, it is only a matter of time before there will be a shortage of compassion. Simply put, compassionate fatigue results when there is a depletion of emotional resources from within as we care and provide compassion for others. This depletion is not a reflection of the character, professionalism, or even the professional skill level of the veterinary health care team member. Rather, the strength and willingness to be emotionally engaged with another being is affected. All members of the veterinary health care team joined the profession to care, from their minds through medical/surgical/preventative skills and through their hearts by supporting and providing for the emotional needs of caregivers. It is vital to the success of veterinary care to allow for this level of compassionate care and to support those individuals who provide it. By appreciating the issue of Compassion Fatigue and providing mechanisms within a practice to mitigate its effects, a practice can thrive by providing the finest in compassionate care.

Key Points for Prevention

  • Educate the entire veterinary health care team
  • Establish weekly debriefing sessions for entire staff
  • Identify and work with professionals within the community who clearly understand the condition
  • Define and preserve a 'comfort room'
  • Allow team to have adequate closure at the end of any patient's life
  • Define and teach team member limits and boundaries
  • Employ humor whenever appropriate
  • Find a colleague who understands and share

Secret #10. Recognizing and treating compassion fatigue is essential to enhance professional, personal and financial success.