Scotties are reported to have the highest rate of bladder cancer of any AKC breed, and the rate for our bitches is twice that for our dogs. Owners should know of a bladder-cancer drug therapy that’s still new to many veterinarians.
My Scottie Lucky started having accidents in late 1991 at age 9. By September ’92, she had chronically bloody urine, X-ray dye studies showed an obstructive growth that was diagnosed as transitional cell carcinoma of the bladder. The options were surgery, radiation, chemotherapy or nothing. We chose the latter because the closest veterinary specialist was 300 miles away and we feared Lucky would return incontinent and crippled. Thinking she had just a few weeks left, we took last photos and investigated cremation.
But our vet Dr. Scott Burt found a fifth option. TexasA & MUniversity veterinary oncologists were having success with the piroxicam (Feldene) cancer therapy pioneered at PurdueUniversity, and he suggested it for Lucky. This nonsteroidal anti-inflammatory drug is used to treat arthritis in humans. Clinical trials have shown it especially effective against transitional cell carcinoma of the bladder, but it was very new in the arsenal of veterinary oncology at the time.
Results of later research were even more definitive. In a 1994 Purdue report published in the Journal of Veterinary Internal Medicine (volume 3, number 4, pages 273-278), 34 dogs (including eight Scotties) with inoperable transitional cell carcinoma of the bladder were treated with a daily oral dose of 0.3 mg piroxicam/kg of body weight. At 56 days, in two dogs the tumors were in complete remission and in four they were in partial remission. The disease was stable in 18 dogs and had progressed in 10. One of the two dogs that was in full remission lived for 20 months; the other lived for two years. The median survival of all dogs was 181 days. (It should be noted that piroxicam can cause serious gastrointestinal problems and should be used only under a vet’s direction.)
Lucky lived 10 months after beginning piroxicam treatment. Five months into the therapy, I wrote, “Our dog acts like a 10-year-old puppy.” She delighted I life, including her favorite sport, solo soccer, until she stretched out in the sun in the yard at 11 years, 7 months and slept forever. Bladder cancer did kill her, but her 10 months of life after diagnosis were of high quality.
My article, “Promising New Treatment for Malignancies” (“The Bagpiper”, 1993:3, pages 50-52), has prompted other Scottie owners to try this treatment. I can’t run all their testimonials, but when Margaret E. Plumb’s champion, Heather, was diagnosed with transition cell carcinoma of the bladder in March 1994, the prognosis was two months. Heather responded miraculously to the Feldene treatment and lived to-and-a-half years longer. (For other Scottie cancer information, see the 1986 Scottish Terrier Club of America Handbook articles “Diagnosis and Treatment of Some Common Malignancies in the Scottish Terrier” and “Hospital Prevalence of Cancer in the Scottish Terrier.”)
On another health front, Dr. Patrick Venta of the Michigan State University School of Veterinary Medicine (517-432-2515), one of researchers who identified the von Willebrand’s disease gene in Scotties and developed the DNA test for it, is collecting DNA samples for a possible study to identify carrier, clear or affected status for craniomandibular osteopathy in Cairn, Scottish and West Highland White Terriers. He needs DNA samples from affected dogs pus both (or at least one) of their parents, and will provide owners with a free, easy-to-use sample collection kit. For more information, call him or me. Let’s make the search for the CMO gene a reality
Original Doc: Promising Cancer Treatment.doc
Veterinary Oncology: Treatment of Nasal Tumors
Authors: Clinical Oncology Service
Affiliations: Veterinary Hospital of the University of Pennsylvania (VHUP)
Posting Date: May 10, 1998
Last Revision Date: Thursday, 26-Aug-1999 22:27:31 EDT
Tumors of the nasal passages and sinuses account for 1-2% of all cancers in dogs. These tumors tend to grow into surrounding tissues, but have a low chance of spreading (metastasis) to other parts of the body. When they do spread, the most likely sites are the regional lymph nodes and the lungs. If no treatment is done, dogs live an average of 3-5 months after being diagnosed.
Chemotherapy alone can offer improvement in a dog's clinical signs, but it does not prolong survival. Similarly, surgery alone does not generally result in prolonged survival. Radiation therapy with or without surgery (depending on the type of radiation used) provides the longest survival attained so far in dogs with nasal tumors. Dogs live an average of 1 to 1 1/2 years with this treatment.
However, most dogs eventually die as a result of their tumor. It is important to realize that any individual dog might do much better or much worse than this "average". At VHUP, treatment for nasal tumors consists of a combination of surgery and low energy radiation. Other facilities on the East Coast offer high-energy radiation, which eliminates the need for surgical removal of the tumor. In selected cases, chemotherapy may be recommended as well.
The surgery (rhinotomy) involves removing all the tissues within the nasal passages through an incision over the bridge of the nose. The procedure takes about two hours, and a blood transfusion is sometimes administered during or after the surgery. Your dog will be hospitalized for 2 to 3 days to monitor for excessive bleeding, swelling, or air accumulation around the incision site. After the surgery, there will be a drain placed in the nasal passages for several days.
During this time, an "Elizabethan" collar (a large plastic cone) must be worn to prevent your dog from dislodging the drain. There will be nasal discharge, at times bloody, for 1-2 weeks after the surgery. There may also be swelling and puffiness around the face and head during this time. Radiation therapy is started as soon as the surgical site has healed, which typically takes about 2-3 weeks. Treatment is given in twelve sessions on a Monday-Wednesday-Friday schedule for 4 weeks. Each session requires a brief anesthetic period to insure that your dog does not move during the treatment, which takes about 10 minutes. The entire treatment period (from when you arrive at VHUP to when you leave) takes about 1-2 hours. Your dog should have no food after 8 PM the nights before a radiation treatment, but water should be available throughout the night. No topical medications should be placed on the radiated area the mornings of treatment.
Your dog will develop radiation dermatitis and mucositis, also known as radiation "burns", starting during the third to fourth week of radiation therapy, and lasting for a total of 2-4 weeks. The side effects are limited to the treatment field, and will include the oral cavity and one eye. There will be loss of hair, redness, and oozing. During this time, your dog will again need an Elizabethan collar to prevent scratching or rubbing of the area, and topical medications for the skin and eyes may also be used. Additional medications may include antibiotics and pain medications. Your dog should be encouraged to eat soft, moist foods during the recovery period. When the burns heal, the skin will initially be pink and hairless. The area will become freckled, and after several months hair may start to regrow, which is usually sparse and of a different color. Over months, tear production will slowly decrease, and your dog will need artificial tears. The eye within the treatment field may gradually lose vision over months to years. As a result of changes to the nasal passages caused by both the surgery and radiation, your dog will probably have a mild, persistent mucus nasal discharge. There is a very small risk (less than 5% of cases) of serious complications that could require additional treatment, such as a non-healing skin wound.
Treatment of nasal tumors requires a large commitment of time, energy, and supportive care, as well as finances. This treatment option may not be the most appropriate choice for every dog or every owner. There are many factors besides medical ones that must be taken into consideration, and there is no "right" or "wrong" treatment decision, only what is best for your pet and your family.
OncoLink is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through OncoLink should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your health care provider.
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Original Doc: nasaltumors.doc
Caring for Pets with Cancer - Y2K Edition: Tumors of the Skin & Soft Tissues
By Robert C. Rosenthal, DVM, PhD, and E. Gregory MacEwen, VMD
From the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Dr West, Madison, WI 53706
Lymphoma (also known as malignant lymphoma and lymphosarcoma [LSA]) is connnonly diagnosed in dogs. Incidence rates from 6 to 24 cases/100,000 dogs/yr have been reported.(1) Within the past decade, general reviews of lymphoma in dogs have been published frequently.(2-8) Most discuss the usual form of the disease, the multicentric form, but cutaneous lymphoma is problematic in terms of diagnosis and treatment.(9-11) There is little doubt that those in companion animal practice will encounter lymphoma in dogs and be asked to treat it in its various forms.
The World Health Organization (WHO) has developed a clinical staging system for lymphoma in dogs.(12) The WHO system describes the disease in terms of its anatomic type and includes a stage grouping based on the distribution of involvement of lymph nodes (stages I to III), liver and/or spleen (stage IV), and blood, bone marrow, or other organs (stage V), in addition, each stage is subclassified as (a) without systemic signs or (b) with systemic signs. Some investigators have used other, usually similar, staging systems, retaining the convention that higher stages indicate more widespread involvement.
It is important to remember that, although multicentric lymphoma in dogs is fatal if untreaeted, most dogs will respond well to treatment. Median survival times in untreated dogs are difficult to determine with great precision because of the variability in the time from the onset of disease to the time of diagnosis and the impact of owners' decisions about euthanasia. In a 1973 study,(13) an addmittedly inexact estimate of 2 to 6 months' survival was made. Other authors reported a median survival time of only 2.5 weeks, with a range of 1 to 4 weeks.14 Others have reported mean survival times in untreated dogs to range from <10 days to about 1 month.(15,16) Most veterinary oncologists consider the median survival time in untreated dogs to be between 30 and 60 days. Lymphoma, however, is responsive to various types of chemotherapeutic and immunotherapeutic intervention. Dogs usually respond well and achieve complete remission, ie, the complete disappearance of clinical signs of disease. It should be remembered that complete remission does not mean cure, ie, the elimination of the last cancer cell with the dog having a normal life-span without further therapy.
Chemotherapy is the mainstay of the management of lymphoma. A wide variety of protocols, using single agents or combinations of drugs, have been effective in inducing remission. here is, however, no consensus regarding the optimal treatment in terms of efficacy (remission induction and survival), toxicity, and overall cost.
In general, combination chemotherapy is the most widely used approach and is considered the most efficacious. Doxorubicin,a cyclophosphaniide,b and cor- ticosteroids have all been used as single agents.
Compared with other cytotoxic drugs alone or in combination, corticosteroids as single agents are low in cost, relatively nontoxic, relatively efficacious drugs that provide palliative treatment. Squire et al(13) reported a mean survival of 53 days in responding dogs with various stages of lymphoma treated with prednisone only (range, 14 to 210 days); 84% of the dogs treated went into remission. More recently, Bell et al(I7) reported a lower rate of complete remission (17%) and a mean remission time of 1 to 2 months in dogs with various forms of lymphoblastic lymphoma treated with prednisone alone. It is widely believed that dogs treated initially with only corticosteroids for prolonged periods (perhaps 2 weeks or more) are less likely to respond to combination chemotherapy.(4,18) The use of cyclophosphamide alone in 32 dogs resulted in remissions in only 13 dogs, with a mean remission time among responders of only 62 days (range, 17 to 130 days).(13)
Doxorubicin also has been evaluated as a single agent for treatment of lymphoma in dogs and appears to be more effective than either prednisone or cyclophosphamide used alone.(19,20) A retrospective study of 41 cases indicated that doxorubicin was as effective as a combination of cyclophosphamide, vincristine,c and prednisone (CVP) in inducing remission. Dogs that received doxorubicin as induction treatment had longer survival times, but the difference was not significant (mean, 265.4 vs 207.5 days); this difference appeared to be related not to the time of first remission, but rather to the better response to subsequent treatment.(19) In this report, dogs with WHO stage-III lymphoma survived longer than those in other stages; dogs with high-grade tumors (histopathologically aggressive) were more likely than others to respond, but there was no significant difference in remission duration or survival times.19 Among 37 dogs treated with doxorubicin alone, the overall response (partial plus complete remission) rate was 81% with median remission and survival times of 131 and 230 days, respectively; the WHO stage of the disease was not important in determining the outcome.(20) Doxorubicin also has been evaluated as a single-agent rescue drug for dogs that had become resistant to combination treatment with vincristine, cyclophosphamide, L-asparaginase,d methotrex- ate,e and prednisone. Four of 12 treated dogs attained a second complete remission following the administration of doxorubicin. Those that did respond did so quickly; remission was complete within 48 hours. If there was no response to the first dose of doxorubicin, later treatments were not helpful. Second remissions were from 35 to 219 days in duration.(21)
Most dogs given a combination of chemotherapeuuc agents are treated with 1 of 2 CVP-based protocols.16,22 The combination of sequential vincristine, L-asparaginase, cyclophosphamide, and methotrexate in conjunction with decreasing doses of prednisone was found to be safe and efficacious. Fifty-three of 59 dogs (89.8%) in all non-WHO stages attained complete remission, with a median remission duration of 132 days and median survival time of 219 days.(16) Important prognostic factors were body weight and stage. Smaller dogs had longer survival times, and dogs with stage-I lymphoma (comparable to WHO stage IIIa) lived longer (median, 453 days) than those in other stages (median survival times for stages II, III and IV [comparable to WHO stages IVa, IVb, and Vb, respectively] were between 210 219 days). None of the dogs died from toxic side effects, although anemia, leukopenia, sterile hemorrhagic cystitis, and anaphylactic reactions were noticed.(16) A protocol of intermittent high-dose cyclophos- phamide combined with vincristine and prednisone resulted in an overall complete remission rate of 75% and an overall median survival of 6 months. Ninety percent of dogs with non-WHO stage-I lymphoma (comparable to WHO stage I, including substages a and b) attained complete remission and had a median remission duration of 15 months. Less than half of the dogs with non-WHO stage-IV lymphoma (comparable to WHO stage Va and Vb) attained complete remission, and remission did not last longer than 8 months (median, 5 months).(22) The addition of doxorubicin to CVP as a maintenance protocol benefited only dogs with non-WHO stage-III lymphoma (comparable to WHO stage III and IV); overall median remission times for CVPand CVP plus doxorubicin were 6 and 7 months, respectively.(23)
A recent review focused on the use of asparaginase in the treatment of lymphoma in dogs.24 Several preliminary reports suggest that a polyethylene glycol conjugate of asparaginase may have an important role in the treatment of lymphoma in dogs.25,f,g Early studies indicated that the polyethylene glycol conjugate of asparaginase was not toxic for clinically normal dogs and that it appeared to have a place in both the induction and maintenance of lymphoma remissions.25 Two preliminary reports indicated that dogs treated with the polyethylene glycol conjugate of asparaginase had longer remission times than those treated with native asparaginase and that there was less evidence of toxicosis (eg, anaphylaxis, urticaria, anorexia, vomiting, pancreatitis) in the group treated with the conjugated preparation.f,g The results of subsequent clinical evaluation did not support the preliminary work in all respects, however. The overall results for remission and survival times were the longest reported to date with combination chemotherapy (median, 214 and 351 days, respectively), but there was no difference in either remission or survival times between the group treated with the polyethylene glycol conjugate of asparaginase and the group treated with native asparaginase. There was, however, less toxicosis noticed in the group treated with the conjugated asparaginase.h
Chemotherapy has been a useful treatment modality for lymphoma in dogs, but the optimal protocol for all dogs is not known. The chemotherapeutic management of canine lymphoma remains an area of active investigation. New drugs and new drug combinations and schedules will continue to be investigated. Presently, studies of dacarbazine, cytosine arabinoside, VP-16, actinomycin-D, and other drugs are underway.
Because lymphoma in dogs is so responsive to chemotherapy, there has been some concern about the possible deleterious effects of the sudden release of tumor breakdown products following effective therapy. A study of serum uric acid and phosphorus concentrations in dogs with uncomplicated lymphoma was conducted to evaluate these factors before and after treatment. Serum uric acid concentrations were higher in dogs with lym- phoma but did not change after treatment. Phosphorus excretion increased after treatment, possi bly because of the effect of chemotherapeutic agents on the volume of urine excreted.(26) Untoward responses related to rapid tumor destruction and the release of cell breakdown products following chemotherapy (tumor lysis syndrome) have been documented.(16,27) It has been suggested that dogs at risk are those with heavy tumor burdens, high alkaline phosphatase values (indicating hepatic involvement), and rapid response to treatment. Hyperuricemia, hyperphosphatemiia, and lactic acidosis lead to cardiac decompensation associated with acid-base and electrolyte disturbances. Because treatment for the tumor lysis syndrome is seldom effective once signs are apparent, awareness of the possibility of problems and early administration of fluids are keys for avoiding problems.(27)
Immunotherapy (biological response modification) has been used as a means of treating lymphoma in dogs. Although not all immunotherapeutic approaches have met with great success,28,29 there is interesting evidence that such treatment holds great promise if it can be made more widely available to the practitioner.30-34 In a study evaluating the use of autologous tumor cell vaccine following induction with combination chemotherapy, dogs treated with drugs alone had a mean survival of 138 days, compared with 341 days in dogs that also received tumor vaccine. More specifically, dogs with WHO stage-IIIa lymphoma given standard chemotherapeutic agents alone had a median survival of 150 days, compared with 274 days for those that received tumor vaccine; for WHO stage-IVa dogs, the figures were 123 days and 213 days for the chemotherapy and chemoimmunotherapy groups, respectively. Because none of the dogs with WHO stage-IIIb or -IVb lymphoma received chemo- immunotherapy, further comparisons were not possible. Dogs responded best when they were vaccinated while in complete rernission.30 Other reports corroborate the advan- tages of administering autologous tumor vaccines. In a study of 32 dogs with lymphoma, median remission durations and survival times were significanty longer in dogs treated with chemoimmunotherapuetic agents than with chemotherapeutic agents alone. For dogs treated with chemotherapeutic agents alone, median remission duration and survival time were 28 and 196 days, respectively; for dogs treated with chemoimmunotherapeutic agents, the spans were 69 and 336 days, respectively.(31) A subsequent report indicated prolonged remission and survival times compared with a historical control for unmodified tumor extracts plus Freund complete adjuvant, for chemi- cally modified tumor extracts plus Freund com- plete adjuvant, and for Freund complete adjuvant alone, but there was no difference in remission duration or survival among the 3 chemo-immunotherapy groups.(32)
More recent work is somewhat less supportive of advantages for chemo-immunotherapy. In a study of 30 dogs treated with chemotherapeutic agents followed by intralymphatic administration of autochthonous tumor cell vaccine, the median survival was 13 months; however,the dogs underwent additional 4-week cycles of chemotherapy as needed to maintain remission, along with additional immunotherapy following the initial treatments. The first remission duration after chemotherapy and immunotherapy was 16 weeks.33 When 28 dogs that received intralymphaticly ad- ministered autochthonous tumor vaccine following chemotherapy were compared with 30 dogs that received chemotherapeutic agents only, there was no significant difference in survival times.34 Dogs that responded had significant increases in humoral antibody compared with those that did not respond.31
Other immunotherapeutic approaches may be fruitful.36,37 A phase-I clinical trial with a murinederived anti-canine lymphoma monoclonal antibody has not revealed any significant toxicity.36 Further phase-II studies indicated that administration of monoclonal antibody as an adjunct to chemotherapy resulted in significantly longer remission duration (median, 142 days) and survival time (median, 491 days) than did an administration of chemotherapeutic agents alone in a historical control group (remission and survival times not specified).36
Because lymphoma in dogs usually is a multicentric disease, it is best treated with medications that act systemically rather than locally. Certainly, surgery has a useful place in the diagnosis of lymphoma, because accurate histopathologic diagnosis based on microscopic examination of appropriate biopsy specimens continues to grow in impor-tance. Therapeutic surgery seems less reasonable, except, perhaps, in early stage-I or -II disease or in some cases of localized cutaneous lymphoma. Some investigators have considered the role of surgery, specifically splenectomy, in the management of lymphoma in dogs.15,38 The results of an early study on the treatment of lymphoma in dogs by splenectomy followed by the administration of cyclophosphamide as a single agent are difficult to interpret because of the advanced stage of the disease, the frequent overdosing of cyclophosphamide, and a concurrent epizootic of nonspecific viral pneumonia. Untreated dogs in that report lived a mean of only 9.8 days after diagnosis. The median survival time for treated dogs was 40 days.15 A more recent study considered the role of spienectomy in 16 dogs with lymphoma that had surgery to relieve signs associated with massive spienomegaly and splenic rupture. Within 6 weeks of splenectomy, 5 of those dogs died of disseminated intravascular coagulation and/or sepsis, but the precise relationship of the surgery and those complications could not be determined. Any dog with neoplastic disease may develop these complications. Subsequent chemotherapy in the remaining 11 dogs was beneficial, with a complete remission rate of 66%. Seven dogs evaluated until their death had a median survival time of 14 months.38 These results are comparable to other reports of chemotherapeutic response, and splenectorny to relieve signs associated with massive splenomegaly seems indicated and is not necessarily an indicator of a poor prognosis.
The systemic nature of lymphoma in most dogs has limited the usefulness of radiotherapy for this disease. Lymphocytes are radiosensitive, however, and the cocept of treating lymphoma in dogs with radiotherapy is appealing. Laing et al39 determined that clinically normal dogs can tolerate 2 half-body 7- or 8-GY doses of 60Co radiation delivered at 1 Gy/min when the doses are delivered a month apart. The dogs treated had transient bone marrow suppression and radiation sickness, but life-threatening problems were not encountered. Half-body radiotherapy has been used as the sole treatment for lymphoma in a limited number of dogs. Dogs with lymphoma had more severe problems following radiotherapy than did clinically normal dogs. Of 14 dogs treated with two 7-Gy half-body doses of 60Co radiation delivered at 1/Gy/min,40 only 2 were in complete remission 1 week after the second treatment. Three other dogs were in partial remission one week after the second treatment. For these 5 dogs, the median response and survival times were 60 and 84 days, respectively; the 2 dogs that attained complete remission survived 84 and 155 days.40
Autologous bone marrow transplantation
Although chemotherapy is widely practiced for lymphoma in dogs with good results and immunotherapy holds great promise for the future, most dogs are not cured. Many treatments for dogs are not aggressive enough to rid the body of the last cancer cell, because of the limitations of toxicoses such as bone marrow suppression. Bone marrow transplantation offers a means of rescuing dogs from fatal myelotoxicosis and therefore allows more aggressive use of chemotherapy and radiotherapy. For at least 20 years, dogs with lymphoma have served as useful models for the study of aspects of bone marrow transplantation applicable to human patients,41-43 and autologous bone mar- row transplantation is recognized as a potential treatment in dogs as well.44-49,i Various aspects of the process, including the role of total body irradiation, 48,50 the effects of vrious antibiotic regimens,51,52 and posttherapy immunosuppression,53 have been investigated in dogs. Over the span of years, complications including sepsis and thrombocytopenia have been better controlled, and response and long-term survival rates have increased.44-47
It is now possible to expect that as many as 25% of appropriately selected dogs with lymphoma treated with autologous bone marrow transplantation may become long-term survivors.47 In one study, the median survival of 9 long-term survivors (among 38 treated dogs) was > 31 months, with a range of 18 to 82 months. Two of the 9 died: one of parvovirus infection at 31 months, and the other was euthanatized at 52 months for "old age and infirmity." Neither of the dead dogs had any signs of lymphoma at the time of death.17 Use of autologous bone marrow transplantation is still investigational, but selected dogs may be treated successfully. Some dogs have limited survival times because of complications related to radiotherapy, sepsis, hemorrhage, or failure to engraft, but most responded and some seem to be, indeed, cured.47 It has been possible to attain similar results with the administration of blood mononuclear cells following chemotherapy-induced expansion of the stem cell pool,54 which suggests a possible role for the use of hemopoietic factors such as granulocyte or granulocyte-macrophage colony-stimulateing factors55,56 when appropriate products for dogs are developed and become available.
Lymphoma involving the skin of dogs may be one manifestation of systemic disease or may be a primary entity. The nomenclature of primary cutaneous lymphoma in dogs is confusing.10,17 Some authors suggest the epidermotropic form should be called mycosis fungoides,57,58 but others prefer either cutaneous T cell-like lymphoma or other pathologic descriptors.11
When cutaneous lesions are seen in conjunction with multicentric disease, the treatment need not be changed from the usual chemotherapeutic protocols. In primary form, cutaneous lymphomas in dogs are difficult to treat successfully.9-11,59 In cases of solitary lesions, surgical excision appears to be the treatment of choice and may result in prolonged remissions.11,59
Some dogs will respond to prednisone for limited periods, although response is less likely in the advanced stage of the disease (tumor stage). Primary cutaneous lymphomas may respond to chemotherapy with CVP plus cytosine arabinosidej or CVP plus doxorubicin. Five of 6 dogs with generalized cutaneous lymphoma treated with CVP plus cytosine arabinoside attained partial or complete remission, with a median remission of > 250 days and a median survival time of > 399 days.11 Some dogs have been treated topically with mechlorethamine,k but the advisability of this approach is limited by the demanding schedule and the dangers inherent in handling the aqueous preparation of this agent, which is likely to cause contact dermatitis in human beings.9,10.59
Other approaches, including immunotherapy, electron beam therapy, and photochemotherapy, have been mentioned but not fully evaluated.10,11,60
Factors affecting prognosis with therapy
It would be helpful to the clinician to have a clear set of prognostic variables as a guide to advise owners. The staging system established by the WHO has prognosis as one major aim,61 but, to date, there is not agreement about the true impact of staging on prognosis for lymphoma in dogs. In fact, modified protocols16,22 have been used in an attempt to find meaning in clinical staging. Various investigators disagree on the importance of clinical staging as a prognostic indicator. In one report,16 it was indicated that dogs with stage-I lymphoma (comparable to WHO stage IIIa) had significantly longer survival than those with stage-II, -III, or -IV disease (comparable to WHO stage IVa, lVb, and Vb, respectively), although the stage of disease was not significantly related to the duration of remission. In a later publication, it was reported that clinical stage was not significantly related to survival when WHO stage-III, -IV, and -V disease was considered.61 Cotter,22 on the other hand, reported that dogs with
stage-I lymphorna (comparable to WHO stage I) maintained longer remissions than those with higher stages. Cotter and Goldstein23 further reported that when dogs main- tained on CVP were compared with those maintained on CVP plus doxorubicin, only dogs with stage-III lymphoma (comparable to WHO stage III and IV) had longer remission times. Postorino et al,20 however, reported no significance to WHO clinical staging.
It has been considered that perhaps it is not the distribution of involvement that has prognostic significance but rather the subclassification (clinically normal [a] or affected [b]).12 Here again there is a lack of consensus. The most detailed report on this matter concerns specifically the presence of hypercalcemia, which would put a dog in subclass b. A comparison of the response and survival of hypercalcemic dogs with lymphoma with historical controls indicated that, although hypercalcemic dogs were as likely to enter and maintain remission, their survival was significantly shorter. Hypercalcemic dogs had a median survival time of 112 days; in the historical control group, median survival was 196 days.62 Some investigators have noticed no difference in the response and survival of dogs in either subclass (although only one of these reports20 specifies hypercalcemia as the sole determining factor).22,23 Hypercalcemic dogs may have prolonged survival; 25% of hypercalcemic dogs with lymphoma treated with chemotherapeu tic agents survived > 14 months.1
The dogs' age, weight, and gender have been considered as possible prognostic factors. Age has not been found to be a significant prognostic indicator for either response or survival duration.16,20.61 Findings differ on whether the weight of the dog is a reliable prognostic indicator. In one study, dogs <15 kg had longer survival times than those >15 kg (median survival, approximately 200 vs 300 days).16 Later work failed to corroborate this finding, with no significant differences among median survival times of 290 days for dogs <15 kg, 268 days for dogs between 16 and 29 kg, and 212 days for those >30 kg.61 There is disagreement regarding the influence of gender on prognosis. One study failed to find differences in response or survival related to gender,16 but an-other found a significant prolongation of survival among females.61
Beyond the easily determined clinical features of stage, age, weight, and gender, prognostic infor mation may be found in the histopathologic and cytologic evaluation of lymphoma.61-65 The WHO has defined the histologic subtypes of lymphoma in dogs as (1) poorly differentiated, (2) lymphoblastic, (3) lymphocytic and prolymphocytic, and (4) histiocytic, histioblastic, and histiolymphocytic,66 but few investigators seem to find this a useful description. Alternate classification schemes adopted from those used for human beings have been used to describe the cytologic and histopathologic fea tures of lymphoma in dogs in several reports. The following summaries indicate the potential for confusion and the need for consensus.
The Kiel classification was used to evaluate 37 cases of lymphoma in dogs to determine whether histopathologic findings might serve as a possible indicator of prognosis. This system categorizes lymphomas as mycosis fungoides, lympho-plasmacytoid (immunocytoma), centroblastic-centrocytic, immunoblastic, or lymphoblastic. The investigators did not establish any association between cytologic type and prognosis.64
The Rappaport scheme for classification has been used in 5 studies to try to differentiate response to treatment on a histopathologic basis. Simply stated, the Rappaport scheme as used described the lymphomas in terms of diffuse or nodular distribution and histiocytic or lymphoblastic cells. In none of the studies was a differential response to treatment based on histopathologic differences noted.13,33.34,63,67
Another study used the Anderson Hospital Nomenclature of Neoplastic Disease which described the tumors as lymphoblastic (lymphocytic poorly differentiated), histiocytic, and mixed.68 The authors noted that lymphoblastic tumors re sponded to doxorubicin as a single agent, but that histiocytic types required the addition of dacarbazinem for any response to be noticed. Median survival of 4 dogs with lymphoblastic lymphoma that lived past the initial cycle of doxorubicin was 195 days (range, 159 to 421 days), and the median survival time for 7 dogs with histiocytic lymphoma was 108 days (range, 77 to 352 days).68 It appears that there was a difference in response based on cell type, although this is difficult to ascertain because different treatments were used and statistical comparison was not made.
A study in which the National Cancer Institute Working Formulation to classify lymphomas in dogs was used evaluated response to doxorubicin or CVP based on histopathologic type. The Working Formulation recognizes 10 basic cell types which are then associated with low-, intermediate-, or high-grade tumors on the basis of clinical behavior and 5-year survival rates in human beings.63 Most of the dogs with lymphoma had high-grade tumors, which were the type most likely to respond to chemotherapy. A difference in survival time associated with grade was not noticed.19
A study of 40 dogs with lymphoma, including histologic classification of the tumors by the Rappaport, Keil, and Lukes schema, and by the Working Formulation, attempted to correlate histologic type of response to treatment. A relationship between histologic classification and response to treatment was not noticed.68 It seems that veterinary oncology has yet to take full advantage of histopathologic grading for prognosis.
Another untapped source of potentially useful prognostic information related to treatment is phenotyping. Although there was not a notable relationship between histopathologic findings and response to treatment in one study,69 investigation of the cell surface antigens by use of monoclonal antibodies revealed some interesting information. Within histologic subgroups, there was variation of cell surface marker expression, but as noted, histologic classification did not predict response to treatment. However, among 24 dogs evaluable for response to treatment, those that had markers for both B and T cells were more likely to respond than were those that had B or T cell markers only or that lacked any markers. Furthermore, reactivity with the murine monoclonal antibody DLy-6 (which appears to react with a differentiation antigen on canine B and T cells) strongly predicted a poor initial response to treatment.69 A later study, however, failed to confirm the utility of the DLy-6 antigen to predict response and further indicated that none of the specific phenotypes investigated appeared to correlate with complete response to chemotherapy.70 More work will surely be done in this area as part of the continuing effort to relate various prognostic factors to treatment.
Lyrnphoma is a fatal disease in dogs if unereated, but fortunately, is also a disease that is responsive to therapeutic intervention. It is likely that most cases seen and treated by practitioners will be managed with the drugs currently known to be effective and with new protocols as they are developed. Although such treatments are rewarding, they should not be undertaken without a clear understanding of 2 important factors- (1) the toxicity of the chemotherapeutic agents,71 which limits amount of chemotherapy ultimately delivered and (2) the potential risks of exposure to anticancer drugs by those handling them.72,73 Other approaches including immunotherapy and bone marrow transplantation are likely to remain more in the arena of the academic institution, but should be available in the referral setting for appropriate cases. Great strides have been made in the less than 30 years that lymphoma in dogs has been widely treated; it is reasonable to expect similar progress in the years to come.
40% have weight loss, lethargy, anorexia, febrile episodes
splenomegaly usu in advanced stage
Other syndromes in lymphoma
spinal cord compression
any body location possible
ALL - Pathology and Natural Behavior
lasts always infiltrate marrow
variable degrees of anemia, thrombocytopenia, neutropenia
splenic and hepatic involvement common
extramedullary sites common
may develop lymphadenopathy
CLL - Pathology and Natural Behavior
marrow infiltration of small, well differentiated lymphs, amount less than ALL or MPD
mild anemia, other stem lines mildly affected
nodes minimally enlarged
cells appear normal, function abnormally
some accompanying gammopathy
immunoglobulin spike assoc with leukemic B cells
usu IgM (macrogammaglobulinemia)
Lymphoma - Histologic Classifications
most lymphomas are diffuse and intermediate/high grade
o reflects either aggressive behavior or late presentation
o does not take into account immunology
o majority of tumors are B cell but tumors are heterogeneous
History and Signs
multicentric form, with or without hepatosplenomegaly most common
assoc with weight loss, anorexia, lethargy
differentials of lymphadenopathy include bacterial or viral infection, parasites, neorickettsia,
fungal, metastatic tumor, immune-mediated disease
respiratory compromise by space occupying mass
thoracic mass differentials include mediastinal lymphoma, thymoma, metastatic thyroid
pulmonary infiltrate differentials include fungal infection, primary or metastatic tumor
weight loss, cachexia, malabsorption, vomiting and diarrhea
straining to defecate or hematochezia
Nonregenerative anemia of chronic disease
o indirect tumor osteolysis
o osteolysis by prostaglandins of the E series
o ectopic production of parathyroid-like hormone
o ectopic production of osteoclast-like activating factor (OAF)
o usu OAF-like in canine lymphoma
Resulting in hypercalemic nephropathy, anorexia, weight loss, PUPD, lethargy, muscular
weakness, lethargy, rare CNS
Diagnostics and Workup
CBC with differential
bone marrow aspiration cytology
serum electrophoresis if total protein elevated
monoclonal gammopathies in 6%
infiltration of marrow hallmark of ALL and CLL
Lymphoma - Fundamentals of Therapy
lymphoma is a whole body disease
o cures are rare, if not impossible
o single, extranodal sites (skin, oral cavity) may be treated with surgery or irradiation
the true goal of lymphoma therapy is provide the pet with a good quality of life
this is accomplished by inducing, maintaining, and reinducing remission
Key points about lymphoma therapy
combination therapy results in the longest responses
maintaining first remission easier than second remission
most protocols report a 75-80% CR rate
most protocols report a median survival of 8-14 mos
Response varies with
extent of disease
presence of concurrent medical problems
Relapse can occur if
dose or freq of drugs given is reduced too early
tumor cells resistant to the drug schedule or drugs used
Chemotherapy Protocols and Results
There are numerous protocols with variable results. Please consult with an Oncologist! In general, combination protocols work best (the more drugs that are used and the more often they are used, the better the prognosis).
Single Drug Therapy
Prednisone: 84% CR, med rem 53 days
Cytoxan: 44% CR, med rem 62 days
Vincristine: 67% CR, med rem 77 days
L-asparaginase: 90% CR, med rem 143 days
81% CR and PR
med rem 131 days
longer for Stage III
Adriamycin after Combination Therapy
4/12 second CR, range 35-210 days
45% CR and PR
CR = 93-127 days
PR = 40-42 days
76% CR and PR
CR = 143 days
66% CR and PR
CR = 123 days in cats
23% CR and PR
CR = 63 days
PR = 28 days
MAb 231 after c/t induction
med rem 142 days
med surv 491 days
longer than historical controls
40% response, 20% CR and 20% PR using vincristine and pred
8-241 day survival
doxorubicin and elspar may incr response
100% CR on bone marrow and peripheral blood exam
weekly chemo, with 2 week rest after doxorubicin
few dogs evaluated, should be better than vinc/pred
indolent disease, whether to treat controversial
observe and treat only during blast crisis
chlorambucil and pred, or use a platelet sparing drug, cytoxan
therapy usu considered palliative, CR rare
survival 2-3 yrs
may discontinue therapy if counts are stable
Tumor lysis syndrome
massive tumor destruction resulting in hyperuricemia, hyperkalemia, hyperphosphatemia,
renal failure and sudden death due to calcium and electrolyte imbalances