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The Treatment of Multicentric Canine Lymphoma
Clinical Management of the Cancer Patient
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The Treatment of Multicentric Canine Lymphoma Robert C. Rosenthal, DVM, MS, PhD*
Canine lymphoma (LSA, malignant lymphoma, lymphosarcoma) is a commonly diagnosed disease. Incidence rates from 6 to 24 cases per 100,000 dogs per year have been reported. 62 Within the past decade, general reviews of canine LSA have been published frequently. 5 • 21 • 24 • 38• 43 • 51 · 73 Most discuss primarily the most common presentation of the disease, the multicentric form, but cutaneous LSA is a problematic presentation in terms of both diagnosis and therapy. 1• 12• 22 There is little doubt that those in companion animal practice will encounter LSA and be asked to treat it in its various forms. The World Health Organization (WHO) has developed a clinical staging system for canine lymphoma. 55 The WHO system describes the disease in terms of its anatomic type and includes a stage grouping based on the distribution of involvement oflymph nodes (stages 1-111), 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 canine LSA is usually fatal in a short period from the time of diagnosis if untreated, most dogs will respond well to therapy. 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 one early study, an admittedly inexact estimate of 2 to 6 months' survival was made. 6 ·3 Other authors reported a median survival time of only 2 1/2 weeks with a range of 1 to 4 weeks. 10 Others have reported survival times in untreated canine LSA to have mean values of from less than 10 days to about 1 month. 44 · 53 Most *Diplomate, American College of Veterinary Internal Medicine (Medicine and Oncology); Assistant Professor of Medicine/Oncology, Department of Medical Sciences, School of Veterinary Medicine, and Associate Member, Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin Veterinary Clinics of North America: Small Animal Practice-Vol. 20, No. 4, July 1990
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veterinary oncologists consider the median survival time in untreated canine LSA patients to be between 30 and 60 days. Canine LSA, however, is responsive to various types of chemotherapeutic and immunotherapeutic intervention. Dogs usually respond well and achieve complete remission (CR), that is, the complete disappearance of clinical signs of disease. It should be remembered that CR does not mean cure, the elimination of the last cancer cell with the patient having a normal life span without further therapy. DIAGNOSIS The diagnosis of multicentric canine LSA is usually straightforward and is based on history, physical examination, and other supportive studies including a complete blood count, a platelet count, a biochemical panel, a urinalysis, abdominal and thoracic radiographs, and an evaluation of the cells and tissues involved. 5 • 21 • 24 • 38• 43 • 51 · 73 Fine-needle aspiration of affected nodes is very helpful in making a diagnosis, but the definitive diagnosis should rest on biopsy samples. Excisional biopsy provides the pathologist with the best opportunity to assess nodal architecture. Most dogs are diagnosed when they are in clinical stage III or higher. More than 80% of these patients are presented with painless lymphadenopathy. When present, clinical signs of LSA are not pathognomonic and will vary with the distribution of the disease and the presence of paraneoplastic syndromes, primarily hypercalcemia. Dogs with the multicentric form may be presented with such nonspecific signs as pallor, lethargy, anorexia, and weight loss in addition to generalized peripheral lymphadenopathy. Gastrointestinal disturbances and polyuria/polydipsia may be present if the dog is hypercalcemic. In dogs with other presentations (mediastinal, alimentary, extranodal), signs may be equally vague. In some, clinical signs may be suggestive of certain patterns of involvement. For example, the patient with mediastinal LSA may be dyspneic and exercise intolerant; with alimentary involvement, melena, hematemesis, and protein-losing enteropathy may be evident. 21 • 38 The differential diagnosis of multicentric LSA should include systemic mycoses, Ehrlichiosis, reactive hyperplasia of lymph nodes, leukemia, and salmon poisoning. The mediastinal form should be differentiated from thymoma, ectopic thyroid carcinoma, pleural carcinomatosis, pulmonary metastases from other neoplasms, congestive heart failure, pyothorax, chylothorax, and hemothorax. The alimentary form may be similar in presentation to foreign bodies, gastrointestinal ulceration, systemic mycoses, lymphocytic-plasmacytic enteritis, lymphangectasia, or other gastrointestinal tumors. 21 This data base may need to be expanded if necessary to secure a certain diagnosis. THERAPY Many approaches have been considered in the therapy of canine LSA. This discussion will center on the therapy of multicentric canine LSA. The
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reader is referred to other sources for comments on the management of cutaneous LSA1 · 7· 12• 22 • 29· 52 and on some unique problems associated with and potential approaches to extranodal LSA. 20 Chemotherapy Chemotherapy is the mainstay of the management of canine LSA. A wide variety of protocols employing either single agents or combinations of drugs have been effective in inducing remission. There is, however, no consensus regarding the optimal treatment in terms of efficacy (remission induction, survival), toxicity, and overall cost. In general, combination chemotherapy is the most widely used approach and is considered the most efficacious. Doxorubicin (ADR; Adriamycin, Adria Laboratories, Dublin, OH), cyclophosphamide (CYC; Cytoxan, Mead-Johnson, Evansville, IN), and corticosteriods have all been used as single agents. Corticosteroids as single agents may be offered as a low-cost, relatively nontoxic, relatively efficacious therapy to owners seeking palliative therapy. Squire and coworkers63 reported a mean survival of 53 days in responding dogs with various stages of LSA treated with prednisone only (range: 14 to 210 days); 84% of the dogs treated went into remission. More recently, Bell and others6 reported a lower rate of complete remission (17%) and a mean remission time of 1 to 2 months in animals with various forms of lymphoblastic lymphoma treated with prednisone alone. It is widely believed that those animals treated with corticosteroids only for prolonged periods (more than 2 weeks?) first are less likely to respond to combination chemotherapy. 5 · 18 The use of CYC alone in 32 dogs resulted in only 13 remissions, with a mean remission time among responders of only 62 days (range: 17 to 130). 63 ADR also has been evaluated as single agent therapy for canine LSA and appears to be more effective than either prednisone or CYC used alone. 14• 58 A retrospective study of 41 cases indicated that ADR was as effective as a combination of CYC, vincristine (VCR; Oncovin, Eli Lilly, Indianapolis, IN), and prednisone (COP) in inducing remission. Dogs that received ADR as induction therapy had longer survival times, but the difference was not statistically significant (mean: 265.4 vs 207.5 days); this difference appeared to be due not to the time of first remission, but rather to the better response to subsequent therapy. In this report, WHO stage III dogs survived longer than those with other presentations; dogs with high-grade tumors (histopathologically aggressive) were more likely than others to respond, but there was no statistical difference in remission duration or survival time. 14 Among 37 dogs treated with ADR alone, the overall response (partial plus CR) 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. 58 ADR has also been evaluated as a single agent rescue drug for dogs that had become resistant to combination therapy with VCR, CYC, L-asparaginase (ASP; Elspar, Merck Sharp & Dohme, West Point, PA), methotrexate (MTX; Methotrexate, Lederle Laboratories, Wayne, NJ), and prednisone. Four of 12 treated dogs attained a second CR following the administration of ADR.
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Those that did respond did so quickly, and remission was complete within 48 hours. If there was no response to the first ADR injection, later treatments were not helpful. Second remissions were from 35 to 210 days. 13 Most canine LSA patients receiving combination chemotherapy are treated with COP-based protocols; ASP, ADR, and MTX are also often part of these protocols. Two protocols in wide use are those published by MacEwen et al and Cotter. 19· 44 The combination of sequential VCR, ASP, CYC, and MTX, in conjunction with decreasing doses of prednisone, was found to be safe and efficacious. Fifty-three of 59 dogs (89.8%) in all (nonWHO) stages attained CR, with a median remission duration of 132 days and a median survival time of 219 days. 44 Important prognostic factors were body weight and stage. Smaller dogs had longer survival times, and dogs with stage I LSA (comparable to WHO stage lila) 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, respecitvely-were between 210 and 219 days). No dog died from toxic side effects, although anemia, leukopenia, sterile hemorrhagic cystitis, and anaphylactic reactions (to ASP) were all noted. 44 A protocol of intermittent high-dose CYC combined with VCR and prednisone resulted in an overall CR rate of 75% and an overall median survival of 6 months. (Non-WHO) stage I dogs (comparable to WHO stage I, including substages "a" and "b") attained CR in 90% of the cases and had a median remission duration of 15 months. (Non-WHO) stage IV dogs (comparable to WHO stage Va and Vb) fared less well; fewer than half attained CR, and no remission lasted longer than 8 months (median: 5 months). 19 The addition of ADR to COP as a maintenance protocol benefited (non-WHO) stage III dogs (comparable to WHO stage III and IV) only; overall median remission times for COP and COP plus ADR were 6 and 7 months, respectively. 17 A recent review focused on the use of ASP in the therapy of canine LSA. 59 Several preliminary reports suggest that a polyethylene glycol conjugate of ASP (PEG) may have an important role in the therapy of canine LSA. 48 • 49 • 64 Early studies indicated that PEG was not toxic for normal dogs and that PEG appeared to have a place in both the induction and maintenance of LSA remissions. 48 Two subsequent preliminary reports indicated that PEG-treated canine LSA patients had longer remission times than those treated with ASP, and that there was less toxicity (anaphylaxis, urticaria, anorexia, vomiting, pancreatitis) in the PEG group. 49 • 64 More recent, as yet unpublished, follow-up in these patients indicates that there is little difference between ASP and PEG in terms of overall remission or survival, although PEG-treated dogs have less toxicity (EG MacEwen, RC Rosenthal, unpublished data, 1989). Chemotherapy has been a useful treatment modality for canine LSA, but the optimal protocol for all patients is not known. The chemotherapeutic management of canine LSA remains an area of active investigation. New drugs and new drug combinations and schedules will continue to be investigated as will potential problems in the management of adverse reactions to therapy, such as the tumor lysis syndrome. 40 • 56 Studies of dacarbazine, cytosine arabinoside, VP-16, actinomycin, and other drugs are now underway.
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Immunotherapy Immunotherapy (biologic response modification) has been used as a means of treating canine LSA. Although not all immunotherapeutic approaches have met with great success, 46 · 47 there is interesting evidence that such therapy holds great promise if it can be made more widely available to the practitioner. 23 · 35• 36• 65 • 71 In a study evaluating the use of autologous tumor cell vaccine following induction with combination chemotherapy, overall, dogs treated with drug therapy .alone had a mean survival of 138 days compared to 341 days in dogs that also received tumor vaccine. More specifically, WHO stage Ilia dogs with chemotherapy alone had a median survival of 150 days compared to 274 days in 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 no WHO stage Illb or IVb dogs received chemoimmunotherapy, no further comparisons were possible. Dogs responded best when they were vaccinated while in CR. 65 Other reports corroborate the advantages of chemoimmunotherapy using autologous tumor vaccines. Median remission durations and survival times were significantly longer in dogs treated with chemoimmunotherapy than with chemotherapy alone in a study of 32 dogs with LSA, For dogs treated with chemotherapy alone, median remission duration and survival time were 28 and 196 days, respectively; for dogs treated with chemoimmunotherapy, the spans were 69 and 336 days. 23 A subsequent report indicated prolonged remission and survival times, compared to a historical control, for unmodified tumor extracts plus Freund's complete adjuvant (FCA), for chemically modified tumor extracts plus FCA, and for FCA alone, but there was no difference in remission duration or survival among the three chemoimmunotherapy groups. 71 More recent work is somewhat less clearly supportive of the advantages of chemoimmunotherapy. In a study of 30 dogs treated with chemotherapy followed by intralymphatic autochthonous tumor cell vaccine, the median survival was 13 months; however, the dogs received additional 4-week cycles of chemotherapy as needed to maintain remission along with additional immunotherapy following the initial irpmunotherapy. The firstremission duration after chemotherapy and immunotherapy was 16 weeks. 35 When 28 dogs that received intralymphatic autochthonous tumor vaccine following chemotherapy were compared to 30 dogs that received chemotherapy only, there was no significant difference in survival times. 36 Dogs that responded had significant increases in the amount ofhumoral antibody against anti-lymphoma cell associated antigen compared to those that did not respond. 34 Other immunotherapeutic approaches may be fruitful. 37· 50 A phase I clinical trial with a murine-derived anti-canine lymphoma monoclonal antibody has not revealed any significant toxicity. Further phase II studies indicated that monoclonal antibody therapy as an adjunct to chemotherapy resulted in statistically significantly longer remission duration (median: 142 days) and survival time (median: 491 days) than did a historical chemotherapy control group. 37
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Surgery Because can1ne LSA is usually a multicentric disease, it is best treated with a systemic rather than a local therapy. Certainly, surgery has a useful place in the diagnosis of LSA as accurate histopathologic diagnosis based on appropriate biopsy specimens continues to grow in importance. Therapeutic surgery seems less reasonable, except perhaps in early stage I or II disease with a limited extent of involvement or in some cases of localized cutaneous LSA. Some authors have considered the role of surgery, specifically splenectomy, in the management of LSA. 11 • 53 An early report on the treatment of canine LSA with splenectomy followed by the use of CYC as a single agent is complicated by the apparent late presentation of the dogs, the frequent overdosing of CYC, and a concurrent epizootic of nonspecific viral pneumonia. Untreated dogs in this report lived a mean of only 9.8 days after diagnosis. The median survival time for treated dogs was 40 days. 53 A more recent report considered the role of splenectomy in 16 dogs with LSA that had surgery to relieve signs associated with massive splenomegaly and splenic rupture. Five dogs died within 6 weeks 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 CR rate of 66%. Seven dogs followed until death had a median survival time of 14 months. 11 These results are comparable to other reports of chemotherapeutic response, and splenectomy to relieve signs associated with massive splenomegaly seems indicated and not necessarily an indicator of a poor prognosis. Radiation Therapy The systemic nature of canine LSA in most presentations has limited the usefulness of radiation therapy for this disease. Lymphocytes are very radiosensitive, however, and the concept of treating canine LSA with radiation therapy is . appealing. It has been shown that normal dogs can tolerate two half-body 7 or 8 Gy doses of 60 Co radiation delivered at 1 Gy per minute when the doses are delivered 1 month apart. The dogs had transient bone marrow suppression and radiation sickness, but no lifethreatening problems were encountered. 41 Half-body radiation therapy has been used as the sole therapy for canine LSA in a limited number of cases. bogs with LSA had more severe problems with the radiation than did normal dogs. Of 14 dogs treated with two 7-Gy half-body doses of 6°Co radiation delivered at 1 Gy per minute, only 2 were in CR 1 week after the second treatment. Three other dogs were in partial remission 1 week after the second treatment. For these five dogs, the median response and survival times were 60 and 84 days, respectively; the two dogs that attained CR survived 84 and 155 days. 42 Autologous Bone Marrow Transplantation Although chemotherapy is widely practiced for canine LSA with good results and immunotherapy holds great promise for the future, most dogs
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with LSA are not cured. Many therapies for dogs are not aggressive enough to rid the body of the last cancer cell because of the limitations of systemic toxicity, bone marrow suppression in most cases. Bone marrow transplantation (BMT) offers a means of rescuing dogs from fatal myelotoxicity and therefore allows more aggressive chemotherapy and radiation therapy. Some aspects of BMT in dogs have recently been reviewed. 32 For at least 20 years, canine LSA has served as a useful model for the .study of aspects of BMT applicable to human patients, 28 • 30 and autologous BMT (ABMT) is recognized as a potential therapy in dogs as well. 2 • 8 • 25 • 60 • 61 • 68 • 69 Various aspects of the PI:Ocess including the role of total-body irradiation regimen, 25 • 27 the effects of various antibiotic regimens, 26 • 67 and post-therapy immunosuppression66 have been investigated in dogs. Over the span of years, the complications associated with ABMT have been better controlled, and response and long-term survival rates have increased. 2• 8 • 68 · 69 It is now possible to expect that as many as 25% of canine LSA patients treated with ABMT may become long-term survivors 2 (also indicated by the author's recent unpublished data). In one study, the median survival of 9 long-term survivors (among 38 treated dogs) was over 31 months, with a range of 18 to 82 months. Two dogs in this group had died, 1 at 31 months from parvovirus and 1 at 52 months who was euthanized for "old age and infirmity"; neither of the dead dogs had any signs of LSA at the time of death. 2 ABMT is still an investigational therapy, but selected cases may be treated successfully. Some dogs have limited survival times owing to complications of radiation therapy, sepsis, hemorrhage, or failure to engraft, but most will at least demonstrate a positive response and some seem to be, indeed, cured 2 (also indicated by the author's recent, unpublished data). It has been possible to attain similar results with the use of peripheral blood mononuclear cells following chemotherapy-induced expansion of the stem cell pool, 3 which SJ.lggests a possible role for the use of hemopoietic factors such as granulocyte or granulocyte-macrophage colonystimulating factors 9 • 54 as appropriate products for dogs are developed. 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 World Health Organization has prognosis as one major aim, 55 but to date there has not been agreement about the true impact of staging on prognosis for canine LSA. In fact, both MacEwen and Cotter have used modified protocols in an attempt to find meaning in clinical staging. Various studies disagree on the importance of clinical staging as a prognostic indicator. MacEwen et al44 reported that stage I dogs (comparable to WHO stage Ilia) had significantly longer survival than those with stage II, III, or IV disease (comparable to WHO stage IVa, IVb, and Vb, respectively), although the stage of disease was not significantly related to the duration of remission. In a later publication, MacEwen and coworkers 45 reported that clinical stage was not significantly related to survival when WHO stage III, IV, and V disease was considered. Cotter, 19 on the other hand, reported
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that stage I dogs (comparable to WHO stage I) maintained longer remissions than those with higher stages. Cotter and Goldstein 17 further reported that when dogs maintained on COP were compared with those maintained on COP plus ADR, only stage III dogs (comparable to WHO stage III and IV) had longer remission times. Pastorino and coworkers, 58 however, reported no significance to WHO clinical staging. Perhaps it is not the distribution of involvement that has prognostic significance, but rather the subclassification ("a" or "b") which describes whether the animal is clinically normal ("a") or affected ("b"). ~5 Here again, there is a lack of consensus. The most detailed report on this matter concerns specifically the presence of hypercalcemia, a "b" finding. A comparison of the response and survival of hypercalcemic canine LSA patients with historical controls revealed 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. 72 Some investigators have noted no difference in the responses and survivals of "a" and "b" dogs (although only one of these reports 58 specifies hypercalcemia as the sole determining factor). 17• 19 The animal's age, weight, and sex have been considered as possible prognostic factors. Age has not been found to be a significant prognosticator for either response or survival duration. 44 • 45 • 58 The weight of the patient as a prognostic indicator has not been consistently shown. In one study, dogs less than 15 kg had longer survival times than those over 15 kg (median survival: approximately 200 versus 300 days). 44 Later work failed to corroborate this finding, with no significant differences among median survival times of 290 days for dogs less than 15 kg, 268 days for dogs between 16 and 29 kg, and 212 days for those over 30 kg. 45 There is disagreement regarding the influence of sex on prognosis. One study found no difference in response or survival related to sex, 45 but another found a significant prolongation of survival among females. 58 Beyond the easily determined clinical features of stage, age, weight, and sex, there looms the possibility of prognostic information being found in the histopathologic and cytologic evaluation of canine LSA. 15• 16• 31 · 57• 70 The World Health Organization has defined the histologic subtypes of LSA as (1) poorly differentiated, (2) lymphoblastic, (3) lymphocytic and prolymphocytic, and (4) histiocytic, histioblastic, and histiolymphocytic, 33 but few investigators seem to find this a useful description. Alternative classification schemes adopted from those used by human pathologists have been used to describe the cytologic and histopathologic features of canine LSA in several reports. 15• 16• 31 · 57• 70 There is great potential for confusion, and the need for consensus is obvious. Another untapped source of potentially useful prognostic information related to treatment is phenotyping. Although there was no notable relationship between histopathology and response to therapy in one study, 4 investigation of the cell surface antigens by the use of monoclonal antibodies revealed that within histologic subgroups there was variation of cell surface marker expression. However, among 24 available for therapy, those that had markers for both B and T cells responded more frequently than did
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those that had B or T cell markers only or that lacked any markers. Furthe.rmore, 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 therapy. 4 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. 39 More work will surely be done in this area as part of the continuing effort to relate various prognostic factors to therapy.
SUMMARY Canine LSA is a fatal disease if untreated, but fortunately it is also a disease that is very responsive to therapeutic intervention. It is likely that most cases seen and treated by practitioners will be managed with the currently effective drugs and with new protocols as they are developed. Other approaches, including immunotherapy and BMT, 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 canine LSA has been widely treated; it is reasonable that similar progress is to be expected in the years to come.
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37. Jeglum KA: Chemoimmunotherapy of canine lymphoma. Proc Am Coli Vet Intern Med 7:922-925, 1989 38. Jeglum KA: Malignant lymphoma in the dog. Comp Cont Ed Pract Vet 1:503-509, 1979 39. Ladiges. WC, Keast M, Appelbaum FR, et al: Phenotypic characterization of canine lymphoma, using monoclonal antibodies and a microlymphocytoxicity assay. Am J Vet Res 49:870-872, 1988 40. Laing EJ, Carter RF: Acute tumor lysis syndrome following treatment of canine lymphosarcoma. JAm Anim Hosp Assoc 24:691-696, 1988 41. Laing EJ, Fitzpatrick PJ, Norris AM, et al: Half-body radiotherapy: Evaluation of the technique in normal dogs. J Vet Intern Med 3:96-101, 1989 42. Laing EJ, Fitzpatrick PJ, Binnington AG, et al: Half-body radiotherapy in the treatment of canine lymphoma. J Vet Intern Med 3:102-108, 1989 43. Leifer CE, Matus RE: Canine lymphoma: Clinical considerations. Semin Vet Med Surg (Small Anim) 1:43-50, 1986 44. MacEwen EG, Brown NO, Patnaik AK, et al: Cyclic combination chemotherapy of canine lymphosarcoma. JAm Vet Med Assoc 178:1178-1181, 1981 45. MacEwen EG, Hayes AA, Matus RE: Some prognostic factors for advanced multicentric canine lymphosarcoma. JAm Vet Med Assoc 190:564-568, 1987 46. MacEwen EG, Hayes AA, Mooney SA, et al: Levamisole as adjuvant to chemotherapy for canine lymphosarcoma. J Bioi Resp Mod 4:427-433, 1985 47. MacEwen EG, Hess PW, Hayes AA, et al: A clinical evaluation of the effectiveness of immunotherapy combined with chemotherapy for canine lymphosarcoma. Proc Symp Comp Res Leuk Rei Dis 8:162, 1977 48. MacEwen EG, Rosenthal RC, Matus RE, et al: A preliminary study on the evaluation of asparaginase polyethylene glycol conjugate against canine malignant lymphoma. Cancer 59:2011-2015, 1987 49. MacEwen EG, Rosenthal RC, Loar AS, et al: PEG-asparaginase therapy for canine lymphoma. Proc Am Coli Vet Intern Med 6:755, 1988 50. MacEwen EG: Current concepts in cancer therapy: Biologic therapy and chemotherapy. Semin Vet Med Surg (Small Anim) 1:5-16, 1986 51. Madewell BR: Canine lymphoma. Vet Clin North Am [Small Anim Pract] 15:709-722, 1985 52. McKeever PJ, Grindem CB, Stevens JB, et al: Canine cutaneous lymphoma. J Am Vet Med Assoc 180:531-536, 1982 53. Moldovanu G, Friedman M, Miller DG: Treatment of canine malignant lymphoma with surgery and chemotherapy. JAm Vet Med Assoc 148:153-156, 1966 54. Neinhuis AW, Donahue RE, Karlsson S, et al: Recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model. J Clin Invest 80:573-577, 1987 55. Owen LN (ed): TNM Classification of Tumors in Domestic Animals. Geneva, World Health Organization, 1980 56. Page RL, Leifer CE, Matus RE: Uric acid and phosphorus excretion in dogs with lymphosarcoma. Am J Vet Res 47:910-912, 1986 57. Parodi AL, Dargent F, Crespeau F: Histological classification of canine malignant lymphomas. J Am Vet Med Assoc 35:172-198, 1988 58. Pastorino NC, Susaneck SJ, Withrow SJ, et al: Single agent therapy with Adriamycin for canine lymphosarcoma. JAm Anim Hosp Assoc 25:221-225, 1989 59. Rogers KS: L-asparaginase for treatment of lymphoid neoplasia in dogs. J Am Vet Med Assoc 194:1626-1630, 1989 60. Rosenthal RC, Kurzman I, Smith B, et a!: Whole body irradiation and autologous bone marrow transplantation in dogs. Proc Am Coli Vet Intern Med 5:908, 1987 61. Rosenthal RC: Autologous bone marrow transplanation for lymphoma. Proc Am Coli Vet Intern Med 6:397-399, 1988 62. Rosenthal RC: Epidemiology of canine lymphosarcoma. Comp Cont Ed Pract Vet 10:855860, 1982 63. Squire RA, Bush M, Melby EC, et a!: Clinical and pathologic study of canine lymphoma: Clinical staging, cell classification, and therapy. J Nat! Cancer Inst 51:565-574, 1973 64. Teske E, Rutteman GR, van Heerde P, et al: L-asparaginase vs PEG-L-asparaginase in
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non-Hodgkins's lymphoma: A phase III clinical trial in a canine model. Anticancer Res 8:1117, 1988· Theilen GH, Worley M, Benjamini E: Chemoimmunotherapy for canine lymphosarcoma. JAm Vet Med Assoc 170:607-610, 1977 Vriesendorp HM, Halliwell RE, Johnson PM, eta!: Immunoglobulin levels in dogs after total-body irradiation and bone marrow transplantation. Transplantation 39:583-588, 1985 Vriesendorp HM, Heidt PJ, Zurcher C: Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation. Exp Hematol 9:904-916, 1981 Weiden PL, Storb R, Deeg HJ, et a!: Prolonged disease-free survival in dogs with lymphoma after total-body irradiation and autologous marrow transplantation consolidation of combination-chemotherapy-induced remissions. Blood 5:1039-1049, 1979 Weiden PL, Storb R, Lerner KG, eta!: Treatment of canine malignancies by 1200 R total body irradiation and autologous marrow grafts. Exp Hematol 3:124-134, 1975 Weller RE, Holmberg CA, Theilen GH, et a!: Histologic classification as a prognostic criterion for canine lymphosarcoma. Am J Vet Res 41:1310-1314, 1980 Weller RE, Theilen GH, Madewell BR, eta!: Chemoimmunotherapy for canine lymphosarcoma: A prospective evaluation of specific and nonspecific immunomodulation. Am J Vet Res 4:516-521, 1980 Weller RE, Theilen GH, Madewell BR: Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia. JAm Vet Med Assoc 181:891-893, 1982 Weller RE: Canine lymphoma: Current and future considerations. Proc Kal Kan Symp 10:75-78, 1987
Address reprint requests to Robert C. Rosenthal, DVM, MS, PhD Department of Medical Sciences School of Veterinary Medicine University of Wisconsin 2015 Linden Drive West Madison, WI 53706
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The Treatment of Multicentric Canine Lymphoma Robert C. Rosenthal, DVM, MS, PhD*
Canine lymphoma (LSA, malignant lymphoma, lymphosarcoma) is a commonly diagnosed disease. Incidence rates from 6 to 24 cases per 100,000 dogs per year have been reported. 62 Within the past decade, general reviews of canine LSA have been published frequently. 5 • 21 • 24 • 38• 43 • 51 · 73 Most discuss primarily the most common presentation of the disease, the multicentric form, but cutaneous LSA is a problematic presentation in terms of both diagnosis and therapy. 1• 12• 22 There is little doubt that those in companion animal practice will encounter LSA and be asked to treat it in its various forms. The World Health Organization (WHO) has developed a clinical staging system for canine lymphoma. 55 The WHO system describes the disease in terms of its anatomic type and includes a stage grouping based on the distribution of involvement oflymph nodes (stages 1-111), 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 canine LSA is usually fatal in a short period from the time of diagnosis if untreated, most dogs will respond well to therapy. 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 one early study, an admittedly inexact estimate of 2 to 6 months' survival was made. 6 ·3 Other authors reported a median survival time of only 2 1/2 weeks with a range of 1 to 4 weeks. 10 Others have reported survival times in untreated canine LSA to have mean values of from less than 10 days to about 1 month. 44 · 53 Most *Diplomate, American College of Veterinary Internal Medicine (Medicine and Oncology); Assistant Professor of Medicine/Oncology, Department of Medical Sciences, School of Veterinary Medicine, and Associate Member, Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin Veterinary Clinics of North America: Small Animal Practice-Vol. 20, No. 4, July 1990
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veterinary oncologists consider the median survival time in untreated canine LSA patients to be between 30 and 60 days. Canine LSA, however, is responsive to various types of chemotherapeutic and immunotherapeutic intervention. Dogs usually respond well and achieve complete remission (CR), that is, the complete disappearance of clinical signs of disease. It should be remembered that CR does not mean cure, the elimination of the last cancer cell with the patient having a normal life span without further therapy. DIAGNOSIS The diagnosis of multicentric canine LSA is usually straightforward and is based on history, physical examination, and other supportive studies including a complete blood count, a platelet count, a biochemical panel, a urinalysis, abdominal and thoracic radiographs, and an evaluation of the cells and tissues involved. 5 • 21 • 24 • 38• 43 • 51 · 73 Fine-needle aspiration of affected nodes is very helpful in making a diagnosis, but the definitive diagnosis should rest on biopsy samples. Excisional biopsy provides the pathologist with the best opportunity to assess nodal architecture. Most dogs are diagnosed when they are in clinical stage III or higher. More than 80% of these patients are presented with painless lymphadenopathy. When present, clinical signs of LSA are not pathognomonic and will vary with the distribution of the disease and the presence of paraneoplastic syndromes, primarily hypercalcemia. Dogs with the multicentric form may be presented with such nonspecific signs as pallor, lethargy, anorexia, and weight loss in addition to generalized peripheral lymphadenopathy. Gastrointestinal disturbances and polyuria/polydipsia may be present if the dog is hypercalcemic. In dogs with other presentations (mediastinal, alimentary, extranodal), signs may be equally vague. In some, clinical signs may be suggestive of certain patterns of involvement. For example, the patient with mediastinal LSA may be dyspneic and exercise intolerant; with alimentary involvement, melena, hematemesis, and protein-losing enteropathy may be evident. 21 • 38 The differential diagnosis of multicentric LSA should include systemic mycoses, Ehrlichiosis, reactive hyperplasia of lymph nodes, leukemia, and salmon poisoning. The mediastinal form should be differentiated from thymoma, ectopic thyroid carcinoma, pleural carcinomatosis, pulmonary metastases from other neoplasms, congestive heart failure, pyothorax, chylothorax, and hemothorax. The alimentary form may be similar in presentation to foreign bodies, gastrointestinal ulceration, systemic mycoses, lymphocytic-plasmacytic enteritis, lymphangectasia, or other gastrointestinal tumors. 21 This data base may need to be expanded if necessary to secure a certain diagnosis. THERAPY Many approaches have been considered in the therapy of canine LSA. This discussion will center on the therapy of multicentric canine LSA. The
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reader is referred to other sources for comments on the management of cutaneous LSA1 · 7· 12• 22 • 29· 52 and on some unique problems associated with and potential approaches to extranodal LSA. 20 Chemotherapy Chemotherapy is the mainstay of the management of canine LSA. A wide variety of protocols employing either single agents or combinations of drugs have been effective in inducing remission. There is, however, no consensus regarding the optimal treatment in terms of efficacy (remission induction, survival), toxicity, and overall cost. In general, combination chemotherapy is the most widely used approach and is considered the most efficacious. Doxorubicin (ADR; Adriamycin, Adria Laboratories, Dublin, OH), cyclophosphamide (CYC; Cytoxan, Mead-Johnson, Evansville, IN), and corticosteriods have all been used as single agents. Corticosteroids as single agents may be offered as a low-cost, relatively nontoxic, relatively efficacious therapy to owners seeking palliative therapy. Squire and coworkers63 reported a mean survival of 53 days in responding dogs with various stages of LSA treated with prednisone only (range: 14 to 210 days); 84% of the dogs treated went into remission. More recently, Bell and others6 reported a lower rate of complete remission (17%) and a mean remission time of 1 to 2 months in animals with various forms of lymphoblastic lymphoma treated with prednisone alone. It is widely believed that those animals treated with corticosteroids only for prolonged periods (more than 2 weeks?) first are less likely to respond to combination chemotherapy. 5 · 18 The use of CYC alone in 32 dogs resulted in only 13 remissions, with a mean remission time among responders of only 62 days (range: 17 to 130). 63 ADR also has been evaluated as single agent therapy for canine LSA and appears to be more effective than either prednisone or CYC used alone. 14• 58 A retrospective study of 41 cases indicated that ADR was as effective as a combination of CYC, vincristine (VCR; Oncovin, Eli Lilly, Indianapolis, IN), and prednisone (COP) in inducing remission. Dogs that received ADR as induction therapy had longer survival times, but the difference was not statistically significant (mean: 265.4 vs 207.5 days); this difference appeared to be due not to the time of first remission, but rather to the better response to subsequent therapy. In this report, WHO stage III dogs survived longer than those with other presentations; dogs with high-grade tumors (histopathologically aggressive) were more likely than others to respond, but there was no statistical difference in remission duration or survival time. 14 Among 37 dogs treated with ADR alone, the overall response (partial plus CR) 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. 58 ADR has also been evaluated as a single agent rescue drug for dogs that had become resistant to combination therapy with VCR, CYC, L-asparaginase (ASP; Elspar, Merck Sharp & Dohme, West Point, PA), methotrexate (MTX; Methotrexate, Lederle Laboratories, Wayne, NJ), and prednisone. Four of 12 treated dogs attained a second CR following the administration of ADR.
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Those that did respond did so quickly, and remission was complete within 48 hours. If there was no response to the first ADR injection, later treatments were not helpful. Second remissions were from 35 to 210 days. 13 Most canine LSA patients receiving combination chemotherapy are treated with COP-based protocols; ASP, ADR, and MTX are also often part of these protocols. Two protocols in wide use are those published by MacEwen et al and Cotter. 19· 44 The combination of sequential VCR, ASP, CYC, and MTX, in conjunction with decreasing doses of prednisone, was found to be safe and efficacious. Fifty-three of 59 dogs (89.8%) in all (nonWHO) stages attained CR, with a median remission duration of 132 days and a median survival time of 219 days. 44 Important prognostic factors were body weight and stage. Smaller dogs had longer survival times, and dogs with stage I LSA (comparable to WHO stage lila) 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, respecitvely-were between 210 and 219 days). No dog died from toxic side effects, although anemia, leukopenia, sterile hemorrhagic cystitis, and anaphylactic reactions (to ASP) were all noted. 44 A protocol of intermittent high-dose CYC combined with VCR and prednisone resulted in an overall CR rate of 75% and an overall median survival of 6 months. (Non-WHO) stage I dogs (comparable to WHO stage I, including substages "a" and "b") attained CR in 90% of the cases and had a median remission duration of 15 months. (Non-WHO) stage IV dogs (comparable to WHO stage Va and Vb) fared less well; fewer than half attained CR, and no remission lasted longer than 8 months (median: 5 months). 19 The addition of ADR to COP as a maintenance protocol benefited (non-WHO) stage III dogs (comparable to WHO stage III and IV) only; overall median remission times for COP and COP plus ADR were 6 and 7 months, respectively. 17 A recent review focused on the use of ASP in the therapy of canine LSA. 59 Several preliminary reports suggest that a polyethylene glycol conjugate of ASP (PEG) may have an important role in the therapy of canine LSA. 48 • 49 • 64 Early studies indicated that PEG was not toxic for normal dogs and that PEG appeared to have a place in both the induction and maintenance of LSA remissions. 48 Two subsequent preliminary reports indicated that PEG-treated canine LSA patients had longer remission times than those treated with ASP, and that there was less toxicity (anaphylaxis, urticaria, anorexia, vomiting, pancreatitis) in the PEG group. 49 • 64 More recent, as yet unpublished, follow-up in these patients indicates that there is little difference between ASP and PEG in terms of overall remission or survival, although PEG-treated dogs have less toxicity (EG MacEwen, RC Rosenthal, unpublished data, 1989). Chemotherapy has been a useful treatment modality for canine LSA, but the optimal protocol for all patients is not known. The chemotherapeutic management of canine LSA remains an area of active investigation. New drugs and new drug combinations and schedules will continue to be investigated as will potential problems in the management of adverse reactions to therapy, such as the tumor lysis syndrome. 40 • 56 Studies of dacarbazine, cytosine arabinoside, VP-16, actinomycin, and other drugs are now underway.
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Immunotherapy Immunotherapy (biologic response modification) has been used as a means of treating canine LSA. Although not all immunotherapeutic approaches have met with great success, 46 · 47 there is interesting evidence that such therapy holds great promise if it can be made more widely available to the practitioner. 23 · 35• 36• 65 • 71 In a study evaluating the use of autologous tumor cell vaccine following induction with combination chemotherapy, overall, dogs treated with drug therapy .alone had a mean survival of 138 days compared to 341 days in dogs that also received tumor vaccine. More specifically, WHO stage Ilia dogs with chemotherapy alone had a median survival of 150 days compared to 274 days in 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 no WHO stage Illb or IVb dogs received chemoimmunotherapy, no further comparisons were possible. Dogs responded best when they were vaccinated while in CR. 65 Other reports corroborate the advantages of chemoimmunotherapy using autologous tumor vaccines. Median remission durations and survival times were significantly longer in dogs treated with chemoimmunotherapy than with chemotherapy alone in a study of 32 dogs with LSA, For dogs treated with chemotherapy alone, median remission duration and survival time were 28 and 196 days, respectively; for dogs treated with chemoimmunotherapy, the spans were 69 and 336 days. 23 A subsequent report indicated prolonged remission and survival times, compared to a historical control, for unmodified tumor extracts plus Freund's complete adjuvant (FCA), for chemically modified tumor extracts plus FCA, and for FCA alone, but there was no difference in remission duration or survival among the three chemoimmunotherapy groups. 71 More recent work is somewhat less clearly supportive of the advantages of chemoimmunotherapy. In a study of 30 dogs treated with chemotherapy followed by intralymphatic autochthonous tumor cell vaccine, the median survival was 13 months; however, the dogs received additional 4-week cycles of chemotherapy as needed to maintain remission along with additional immunotherapy following the initial irpmunotherapy. The firstremission duration after chemotherapy and immunotherapy was 16 weeks. 35 When 28 dogs that received intralymphatic autochthonous tumor vaccine following chemotherapy were compared to 30 dogs that received chemotherapy only, there was no significant difference in survival times. 36 Dogs that responded had significant increases in the amount ofhumoral antibody against anti-lymphoma cell associated antigen compared to those that did not respond. 34 Other immunotherapeutic approaches may be fruitful. 37· 50 A phase I clinical trial with a murine-derived anti-canine lymphoma monoclonal antibody has not revealed any significant toxicity. Further phase II studies indicated that monoclonal antibody therapy as an adjunct to chemotherapy resulted in statistically significantly longer remission duration (median: 142 days) and survival time (median: 491 days) than did a historical chemotherapy control group. 37
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Surgery Because can1ne LSA is usually a multicentric disease, it is best treated with a systemic rather than a local therapy. Certainly, surgery has a useful place in the diagnosis of LSA as accurate histopathologic diagnosis based on appropriate biopsy specimens continues to grow in importance. Therapeutic surgery seems less reasonable, except perhaps in early stage I or II disease with a limited extent of involvement or in some cases of localized cutaneous LSA. Some authors have considered the role of surgery, specifically splenectomy, in the management of LSA. 11 • 53 An early report on the treatment of canine LSA with splenectomy followed by the use of CYC as a single agent is complicated by the apparent late presentation of the dogs, the frequent overdosing of CYC, and a concurrent epizootic of nonspecific viral pneumonia. Untreated dogs in this report lived a mean of only 9.8 days after diagnosis. The median survival time for treated dogs was 40 days. 53 A more recent report considered the role of splenectomy in 16 dogs with LSA that had surgery to relieve signs associated with massive splenomegaly and splenic rupture. Five dogs died within 6 weeks 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 CR rate of 66%. Seven dogs followed until death had a median survival time of 14 months. 11 These results are comparable to other reports of chemotherapeutic response, and splenectomy to relieve signs associated with massive splenomegaly seems indicated and not necessarily an indicator of a poor prognosis. Radiation Therapy The systemic nature of canine LSA in most presentations has limited the usefulness of radiation therapy for this disease. Lymphocytes are very radiosensitive, however, and the concept of treating canine LSA with radiation therapy is . appealing. It has been shown that normal dogs can tolerate two half-body 7 or 8 Gy doses of 60 Co radiation delivered at 1 Gy per minute when the doses are delivered 1 month apart. The dogs had transient bone marrow suppression and radiation sickness, but no lifethreatening problems were encountered. 41 Half-body radiation therapy has been used as the sole therapy for canine LSA in a limited number of cases. bogs with LSA had more severe problems with the radiation than did normal dogs. Of 14 dogs treated with two 7-Gy half-body doses of 6°Co radiation delivered at 1 Gy per minute, only 2 were in CR 1 week after the second treatment. Three other dogs were in partial remission 1 week after the second treatment. For these five dogs, the median response and survival times were 60 and 84 days, respectively; the two dogs that attained CR survived 84 and 155 days. 42 Autologous Bone Marrow Transplantation Although chemotherapy is widely practiced for canine LSA with good results and immunotherapy holds great promise for the future, most dogs
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with LSA are not cured. Many therapies for dogs are not aggressive enough to rid the body of the last cancer cell because of the limitations of systemic toxicity, bone marrow suppression in most cases. Bone marrow transplantation (BMT) offers a means of rescuing dogs from fatal myelotoxicity and therefore allows more aggressive chemotherapy and radiation therapy. Some aspects of BMT in dogs have recently been reviewed. 32 For at least 20 years, canine LSA has served as a useful model for the .study of aspects of BMT applicable to human patients, 28 • 30 and autologous BMT (ABMT) is recognized as a potential therapy in dogs as well. 2 • 8 • 25 • 60 • 61 • 68 • 69 Various aspects of the PI:Ocess including the role of total-body irradiation regimen, 25 • 27 the effects of various antibiotic regimens, 26 • 67 and post-therapy immunosuppression66 have been investigated in dogs. Over the span of years, the complications associated with ABMT have been better controlled, and response and long-term survival rates have increased. 2• 8 • 68 · 69 It is now possible to expect that as many as 25% of canine LSA patients treated with ABMT may become long-term survivors 2 (also indicated by the author's recent unpublished data). In one study, the median survival of 9 long-term survivors (among 38 treated dogs) was over 31 months, with a range of 18 to 82 months. Two dogs in this group had died, 1 at 31 months from parvovirus and 1 at 52 months who was euthanized for "old age and infirmity"; neither of the dead dogs had any signs of LSA at the time of death. 2 ABMT is still an investigational therapy, but selected cases may be treated successfully. Some dogs have limited survival times owing to complications of radiation therapy, sepsis, hemorrhage, or failure to engraft, but most will at least demonstrate a positive response and some seem to be, indeed, cured 2 (also indicated by the author's recent, unpublished data). It has been possible to attain similar results with the use of peripheral blood mononuclear cells following chemotherapy-induced expansion of the stem cell pool, 3 which SJ.lggests a possible role for the use of hemopoietic factors such as granulocyte or granulocyte-macrophage colonystimulating factors 9 • 54 as appropriate products for dogs are developed. 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 World Health Organization has prognosis as one major aim, 55 but to date there has not been agreement about the true impact of staging on prognosis for canine LSA. In fact, both MacEwen and Cotter have used modified protocols in an attempt to find meaning in clinical staging. Various studies disagree on the importance of clinical staging as a prognostic indicator. MacEwen et al44 reported that stage I dogs (comparable to WHO stage Ilia) had significantly longer survival than those with stage II, III, or IV disease (comparable to WHO stage IVa, IVb, and Vb, respectively), although the stage of disease was not significantly related to the duration of remission. In a later publication, MacEwen and coworkers 45 reported that clinical stage was not significantly related to survival when WHO stage III, IV, and V disease was considered. Cotter, 19 on the other hand, reported
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that stage I dogs (comparable to WHO stage I) maintained longer remissions than those with higher stages. Cotter and Goldstein 17 further reported that when dogs maintained on COP were compared with those maintained on COP plus ADR, only stage III dogs (comparable to WHO stage III and IV) had longer remission times. Pastorino and coworkers, 58 however, reported no significance to WHO clinical staging. Perhaps it is not the distribution of involvement that has prognostic significance, but rather the subclassification ("a" or "b") which describes whether the animal is clinically normal ("a") or affected ("b"). ~5 Here again, there is a lack of consensus. The most detailed report on this matter concerns specifically the presence of hypercalcemia, a "b" finding. A comparison of the response and survival of hypercalcemic canine LSA patients with historical controls revealed 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. 72 Some investigators have noted no difference in the responses and survivals of "a" and "b" dogs (although only one of these reports 58 specifies hypercalcemia as the sole determining factor). 17• 19 The animal's age, weight, and sex have been considered as possible prognostic factors. Age has not been found to be a significant prognosticator for either response or survival duration. 44 • 45 • 58 The weight of the patient as a prognostic indicator has not been consistently shown. In one study, dogs less than 15 kg had longer survival times than those over 15 kg (median survival: approximately 200 versus 300 days). 44 Later work failed to corroborate this finding, with no significant differences among median survival times of 290 days for dogs less than 15 kg, 268 days for dogs between 16 and 29 kg, and 212 days for those over 30 kg. 45 There is disagreement regarding the influence of sex on prognosis. One study found no difference in response or survival related to sex, 45 but another found a significant prolongation of survival among females. 58 Beyond the easily determined clinical features of stage, age, weight, and sex, there looms the possibility of prognostic information being found in the histopathologic and cytologic evaluation of canine LSA. 15• 16• 31 · 57• 70 The World Health Organization has defined the histologic subtypes of LSA as (1) poorly differentiated, (2) lymphoblastic, (3) lymphocytic and prolymphocytic, and (4) histiocytic, histioblastic, and histiolymphocytic, 33 but few investigators seem to find this a useful description. Alternative classification schemes adopted from those used by human pathologists have been used to describe the cytologic and histopathologic features of canine LSA in several reports. 15• 16• 31 · 57• 70 There is great potential for confusion, and the need for consensus is obvious. Another untapped source of potentially useful prognostic information related to treatment is phenotyping. Although there was no notable relationship between histopathology and response to therapy in one study, 4 investigation of the cell surface antigens by the use of monoclonal antibodies revealed that within histologic subgroups there was variation of cell surface marker expression. However, among 24 available for therapy, those that had markers for both B and T cells responded more frequently than did
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those that had B or T cell markers only or that lacked any markers. Furthe.rmore, 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 therapy. 4 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. 39 More work will surely be done in this area as part of the continuing effort to relate various prognostic factors to therapy.
SUMMARY Canine LSA is a fatal disease if untreated, but fortunately it is also a disease that is very responsive to therapeutic intervention. It is likely that most cases seen and treated by practitioners will be managed with the currently effective drugs and with new protocols as they are developed. Other approaches, including immunotherapy and BMT, 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 canine LSA has been widely treated; it is reasonable that similar progress is to be expected in the years to come.
REFERENCES 1. Ackerman L; Cutaneous T cell-like lymphoma in the dog. Comp Cont Ed Pract Vet 6:37-42, 1984 2. Appelbaum FR, Deeg HJ, Storb R, eta!: Marrow transplant studies in dogs with malignant lymphoma. Transplantation 39:499-505, 1985 3. Appelbaum FR, Deeg HJ, Storb R, et a!: Cure of malignant lymphoma in dogs with peripheral blood stem cell transplantation. Transplantation 42:19-22, 1986 4. Appelbaum FR, Sale GE, Storb R, eta!: Phenotyping of canine lymphoma with monoclonal antibodies directed at cell surface antigens: Classification, morphology, clinical presentation and response to chemotherapy. Hematol Oncol 2:151-168, 1984 5. Barton CL: The diagnosis and management of canine lymphosarcoma. Proc Am Anim Hosp Assoc 50:345-349, 1983 6. Bell R, Cotter SM, Lillquist A, et a!: Characterization of glucocorticoid receptors in animal lymphoblastic disease: Correlation with response to single agent glucocorticoid treatment. Blood 63:380-383, 1984 7. Bender WM: Nontraditional treatment of mycosis fungoides in a dog. J Am Vet Med Assoc 185:900-901, 1984 8. Bowles CA, Bull M, McCormick K, et a!: Autologous bone marrow transplantation following chemotherapy and irradiation in dogs with spontaneous lymphomas. J Nat! Cancer Inst 65:615-620, 1980 9. Brandt SJ, Peters WP, Atwater SK, eta!: Effect of recombinant granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Eng! J Med 318:869-876, 1988 10. Brick JO, Roenigk WJ, Wilson GP: Chemotherapy of malignant lymphoma in dogs and cats. JAm Vet Med Assoc 153:47-52, 1968 11. Brooks MB, Matus RE, Leifer CE, et a!: Use of splenectomy in the management of lymphoma in dogs: 16 cases (1976-1985). JAm Vet Med Assoc 191:1008-1010, 1987 12. Brown NO, Nesbitt GH, Patnaik AK, et a!: Cutaneous lymphosarcoma in the dog: A
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