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Lecture 2: Treating lymphoma in the dog and cat What are the prognostic factors for lymphoma in the dog and cat? The importance of thorough evaluation of the lymphoma patient and comprehensive clinical staging is borne out when considering the prognostic factors for this group of diseases. Clinical stage In the dog, there is a moderate association between clinical stage and disease outcome. In some studies there has been no correlation demonstrated between clinical stage and likelihood of achieving a complete remission on treatment; in other studies, patients of stage I-III responded more favourably to treatment than those of stage IV or V. Duration of remission and survival time has been shown to be longer in patients of stage I-III disease versus higher stages; other studies suggest that stage IV patients did best. Dogs with stage I or II disease are rarely encountered but may perform best in terms of duration of disease remission compared to other stages. As previously described however, the aggressiveness of clinical staging (e.g. whether a blood smear or bone marrow cytology is performed) has been shown to result in stage migration in the dog. Only small studies are available in cats regarding prognostic value of clinical stage. However one study showed a significant survival advantage in cats with stage I or II disease compared to those with more advanced disease. However the heterogeneity of anatomic forms of lymphoma in cats makes specific prognostication more problematic. Clinical substage There is a strong association between clinical substage of disease and outcome in the dog. Dogs with substage b disease (clinical signs present) have a shorter remission duration and survival time compared to those in substage a. In cats, one study showed that patients with substage a disease had a median survival time of 9.5 months versus 3.5 months for patients with substage b disease. Histological type Several histological grading systems have been developed in an attempt to sub-classify lymphoma in the dog, similar to methods used for human patients (Rappaport System, NCI-Working Formulation, and Kiel Classification). Canine lymphoma is morphologically heterogeneous, diffuse and usually intermediate to high grade (diffuse large cell, centroblastic, immunoblastic) and the subclassification of the disease has unfortunately failed to have significant impact on clinical decision making regarding treatment or prognosis. Overall however, high grade disease is associated with a high proportion of ‘cycling’ cells in the tumour, enhancing chemotherapy sensitivity and response rates to treatment. Low grade lymphomas are rare in the dog, accounting for 5-10% of cases. Response rates to high dose treatments tend to be lower than for their higher grade counterparts however survival times in patients responding to treatment may be long due to the associated indolent clinical course. Very little information is available for cats however patients with a high proliferative fraction of their tumour cells had longer survival times than those with low proliferative fraction. T cell immunophenotype Only 20-25% of lymphomas in the dog are T-cell type. Dogs with T-cell lymphoma appear to have reduced response rates, remission durations and survival times versus their B-cell counterparts. Hypercalcaemia Dogs with hypercalcaemia are by convention considered to be in clinical substage b. 43% of dogs with hypercalcaemia will have a cranial mediastinal mass and the presence of a cranial mediastinal mass is prognostic for survival (mass present = 3 months vs. no mass = 9.5 months). Dogs with hypercalcaemia are much more likely to be affected by lymphoma of T-cell origin and it may be this that is the most important prognostic factor rather than hypercalcaemia per se. Gender Small studies suggest that female dogs have a more favourable prognosis than male dogs. Body size Small dogs may have a more favourable prognosis than large dogs due to increased dose intensity. Pre-treatment with corticosteroids Glucocorticoids should not be given to dogs with lymphoma if future combination chemotherapy is planned. In two studies, prior treatment with prednisolone resulted in reduced remission duration and survival times however the critical length of exposure time is unknown. There is little information about the effects of previous steroid exposure in cats on response to chemotherapy. Steroids have been shown to be potent inducers of P-gp expression and activity. P-glycoprotein expression P-glycoprotein expression and drug resistance: P-glycoprotein (gp170) is transmembrane pump that removes xenobiotics from the cell cytoplasm. This effectively extrudes drugs from cancer cells thereby limiting the cytotoxicity of the drug at its cellular site of action. The protein is expressed on various normal tissues that include the kidney, liver, selected bone marrow cells and the blood brain barrier. Ivermectin sensitivity and neurotoxicity in Collie dogs can be accounted for by their expression of mutant P-gp. Expression of P-gp gives rise to the MDR or multidrug resistance phenotype. As the name suggests, the MDR state confers simultaneous resistance to many different structurally unrelated drugs, including vinca alkaloids, epipodophyllotoxins, anthracyclines, dactinomyicn and taxanes. Such drugs are typically derived from natural sources and are hydrophobic but otherwise have few similarities in their mechanisms of action or chemical structures. Resistance to chemotherapeutic agents is therefore potentially associated with drug induced over-expression of P-gp. Other proteins that are expressed and may confer drug resistance in the absence of P-gp over expression include the multi-drug resistance related protein (MRP), the lung resistance related protein (LRP), DNA topoisomerase mutations, dihydrofolate reductase, O 6- alkylguanine DNA alkyltransferase and apoptosis resistance-related multidrug resistance. The basic structure of the feline MDR1 gene has been sequenced and is essentially the same as that of multidrug- resistance genes of other species. In vitro research has shown that expression of P-gp appeared to be one of the mechanisms responsible for the development of multidrug resistance in feline lymphoma cell lines and therefore it is likely that this is a mechanism of drug resistance in vivo. PDF (259.691 KB) PDF Plus (281.542 KB) Cat? Anatomic location Leukaemia, diffuse cutaneous and alimentary and hepato-splenic forms of lymphoma are associated with reduced response rates, disease free remissions and median survival times. In addition, a number of case reports have demonstrated that dogs with cranial mediastinal lymphadenopathy have shorter remission durations and median survival times. Involvement of the CNS usually carries a poor prognosis due to difficulty in achieving drug penetration to ‘privileged’ anatomical sites. Cats with nasal lymphoma appear to have longer remission durations and survival times compared to cats with other anatomical forms of the disease. In a paper in 2009, the median survival time was 536 days. Anaemia The presence of anaemia has been linked to shorter remission durations. Hypoalbuminaemia In one study the presence of hypoalbuminaemia prior to treatment was a poor prognostic indicator. Tumour proliferation markers Monoclonal antibodies have been raised against several cell surface proteins associated with markers of cell proliferation. Proliferating cell nuclear antigen (PCNA) is a non-histone protein detected 1st in the mid-G1 phase of the cellcycle, reaching a maximum in S and declining in G2. It is not expressed in mitosis. Ki-67 is a nonhistone nuclear protein that is expressed in early G1,S, G2, and M phases of the cell cycle.Silver staining of proteins associated with AgNORs of interphase chromosomes may be used on cytologic or histologic preparations for assessment of proliferation rates. In canine lymphoma, a high Ki-67 index was associated with a prolonged first remission duration. In normal cells, silver staining nucleolar orginising regions (AgNORs) are usually tightly organized in nucleoli, whereas in malignant cells, they desegregate from the nucleoli and tend to disperse throughout the nucleus. Because AgNORs are related to DNA synthesis and metabolic activities, their size and number are used to reflect nuclear activity. The amount of AgNOR increases progressively in cells from G0 to S phase. AgNOR numbers have been correlated with response to chemotherapy in canine lymphoma. Unfortunately in feline lymphoma there has been no correlation between proliferation indices and response to chemotherapy. Response to therapy Intuitively, response to therapy may influence survival times in canine lymphoma patients due to the direct impact on the owner’s willingness to persevere with treatment for the disease. In cats, response to treatment has been found to be one of the few reliable prognostic indicators. In a large study (n=145 cats) those achieving a complete remission had a disease free interval of 7.5 months and survival time of 8.5 months compared to 3 weeks and 7 weeks respectively for cats achieving a partial remission. In some studies, cats that received doxorubicin as part of their treatment protocol had longer disease remissions than those that did not. FeLV status (cats) In cats that tested positive for FeLV, the remission duration and survival time were 4 weeks and 5 weeks respectively versus 5 months and 6 months for those that tested FeLV negative. Prognostic Factor Clinical Stage Clinical substage (a) or (b) Histological Type T-cell immunophenotype Hypercalcaemia Prior steroid treatment p-glycoprotein expression Anatomic location Anaemia Hypoalbuminaemia Prognostic Factors in Canine Lymphoma Remission Duration Survival Time I-II (best); I-III > IV or V I-III > IV or V 7-12 m (a) 3-5 months (b) 8-18 months (a) 4-6 months (b) Immunoblastic > other high Immunoblastic > other high grade types grade types Low grade lymphomas Low grade lymphomas responding to treatment have a responding to treatment have a long clinical course long clinical course 50-67% achieve remission vs. 50d (T-cell type) vs. 200d (B-cell 81-84% for B-cell type type); only long term survivals associated with B-cell type Neg prognostic factor due to Neg prognostic factor due to association with clinical association with clinical substage b, T-cell substage b, T-cell immunophenotype, presence immunophenotype, presence of a cranial mediastinal mass of a cranial meditational mass and altered organ function and altered organ function (renal effects) (renal effects) 110d (prior treatment) vs. 180d (no prior treatment) 7.4m (p-gp expressed) vs. 12m (p-gp not expressed) Gastrointestinal tract: 26d Gastrointestinal tract: 77d (partial response to treatment) Hepato-splenic: 7d vs. 86 days (complete response) Diffuse splenic: 1m Cutaneous/epitheliotrophic: Cranial mediastinal lymph node 96d, 106d involvement: 6.4m (cranial mediastinal LN enlargement, Bcell type) vs. 10.8m (no cranial mediastinal LN enlargement, Bcell type) 3.4m (cranial mediastinal LN enlargement, T-cell type) vs. 6.4m (no cranial mediastinal LN enlargement, T-cell type) 6.2m (anaemic) vs. 11.4m (normal haematocrit) 3.5m (low serum albumin) vs. 7m (normal albumin) How is lymphoma treated? Chemotherapy is the cornerstone for the treatment of lymphoma in dogs and cats. Untreated, dogs affected with malignant lymphoma live an average of only 6 weeks once a diagnosis has been made. In the UK, a survey indicated that 87% of small animal practitioners treated more than half of the cases of lymphoma that they diagnosed. Most used a protocol based on 3 drugs – vincristine, cyclophosphamide and prednisolone (COP protocol) and the remainder used prednisolone alone with the exception of 2% who used doxorubicin as a first line therapy. What are the principles of chemotherapy? Goals The goal of chemotherapy is to control cancer and prolong survival while maintaining a good quality of life for the patient. Combination chemotherapy has three additional aims: To maximise tumour cell kill with minimal associated toxicity by using a combination of drugs with different mechanisms of action used at dosages as close to the maximum tolerated dose as possible To target a heterogeneous population of tumour cells To slow the onset of drug resistance in tumour cells Chemotherapy combinations use drugs that have demonstrated activity as single agents and are used on a schedule that minimises the risk of overlapping toxicities. Factors that affect the efficacy of chemotherapy The duration of tumour exposure to an effective concentration of drug (equivalent to [concentration]drug x exposure time to drug) Intrinsic or acquired drug resistance Up-regulation of drug inactivating enzymes Impaired transport of drug into the cells Upregulation of drug detoxification pathways Dysregulation of apoptotic or cell proliferation pathways Phases of a multidrug protocol Treatment Induction Description Intense initial anti-neoplastic treatment Toxicity High risk Response Greatest chance of response Consolidation Unrelated drugs effective after induction Less intense course, using induction drugs Moderate risk Further reduces surviving cancer cells Slows time to relapse Unrelated drugs used upon Moderate to high risk Maintenance Rescue Lower risk Lower chance of response Example First 9 weeks of Madison Wisconsin Protocol; first 4 weeks of high dose COP protocol Decreased administration frequency vs. induction phase Alkylating agents often used or relapse other combination protocols Commonly used terms in chemotherapy Therapeutic Index: The dose of a drug required to produce a given level of damage to normal tissues divided by the dose of the drug required to produce anticancer effects. Optimizing the therapeutic index is the goal of modern clinical chemotherapy. Therapeutic Index = Dose of drug required to produce a given level of damage to normal tissues Dose of drug required to produce anti-cancer effects Induction therapy: The goal of induction therapy is to dramatically reduce cancer cell numbers and ideally induce a complete remission. Consolidation therapy: The goal is to continue to reduce tumour cell numbers and hopefully to achieve a complete remission in patients that did not achieve complete remission on induction therapy. Maintenance chemotherapy: The goal is to maintain remission and prevent disease relapse. Rescue therapy: The goal is to achieve reinduction of remission after disease relapse Complete remission (CR): complete resolution of measureable tumour burden based on physical examination, haematological and biochemical monitoring or diagnostic imaging. Partial remission (PR): >50% but <100% resolution of measureable tumour burden based on physical examination, haematological and biochemical monitoring or diagnostic imaging. Stable Disease (SD): <50% resolution of measureable tumour burden based on physical examination, haematological and biochemical monitoring or diagnostic imaging and <25% increase of measureable tumour burden based on physical examination, haematological and biochemical monitoring or diagnostic imaging and no new lesions. Progressive Disease (PD) : >25% increase of measureable tumour burden based on physical examination, haematological and biochemical monitoring or diagnostic imaging or the appearance of new lesions. Disease free interval: describes the time to progression of local or systemic disease after induction of a CR with treatment. Median survival time: describes the point at which half the patients have relapsed or died and half are still in remission or are alive Which treatment protocols should you choose for managing lymphoma in the dog and cat? Lymphoma is one of the most responsive forms of cancer presented to the practitioner and is therefore very rewarding to treat. It is extremely important however to counsel the client in detail about the range of treatment options that are available and their associated prognoses. In general, clients want to know the likely chances of achieving a remission of disease in their pet, how long the remission will last, what cost, time commitment and side effects are associated with treatment and what options there are for follow up treatment when first line therapy fails. It is extremely important to emphasise that the patient’s quality of life is central to all treatment considerations. If chemotherapy is negatively impacting the quality of life of a pet then either a dose reduction, treatment change or treatment cessation will be required. The clients should be aware of the supportive care options that are available to minimise chemotherapy side effects (e.g. anti-nausea medications, gut protectants) and how to distinguish mild side effects from those that are more serious, so that medical attention can be sought promptly as required. Once the client has been given all the options, the best option should be used first. As a general rule, combination chemotherapy is superior to single-agent therapy. Each time an effective drug is added to the protocol, the remission duration increases; however, so do the cost and the potential for toxicity. It is also important that clients realize that a second or third remission is possible with appropriate therapy but that these subsequent remissions are more difficult to attain and that their duration is generally half the duration of the previous remission. It is imperative that as a practitioner giving chemotherapy, you familiarise yourself with the procedures for safe handling of chemotherapy agents and understand the drug specific dosing schedules, considerations for safe administration of each agent and drug specific toxicities. The treatment options below are tiered according to risk of toxicity, cost, and effi cacy. First-level protocols provide a low risk of toxicity at low cost but have low effi cacy. Prednisolone: For clients who cannot afford or for whatever reason will not accept a combination chemotherapy protocol due to the risks of toxicity, a protocol using prednisolone alone (2mg/kg PO daily for 7 days then every other day) or in combination with chlorambucil (6 to 8 mg/m2 PO every other day) may provide palliation with few risks of side effects. Approximately 50% of dogs will achieve a CR or PR with average remission duration of 1-2 months. In cats, single agent prednisolone is not considered to be an effective therapy for lymphoma. Doxorubicin/Epirubicin Doxorubicin is considered to be the most active single agent in the treatment of canine lymphoma and therefore protocols that include doxorubicin appear to have superior efficacy to those that do not. There are specific toxicities associated with the use and administration of doxorubicin and epirubicin (see later). Cumulative cardiotoxicity (a primary dose limiting toxicity for the use of these agents, may be less severe with epirubicin compared to doxorubicin.) In cats, the use of doxorubicin as an induction agent found that fewer than 30% of patients achieved a CR. However the inclusion of doxorubicin in multidrug protocols improved remission duration significantly. Second- level protocols COP protocol: This is the most widely used chemotherapy protocol in practice and was the foundation for the most currently advanced chemotherapy protocols. It is a relatively inexpensive chemotherapy protocol with a low risk of toxicity Overall, COP chemotherapy causes CR in 70% of dogs with lymphoma for a median of 4.3 months. In cats, COP protocol has been found to be highly effective in treating lymphoma although the results are quite variable most likely due to the heterogeneity of clinical presentation of the disease in this species. In one study, 74% of cats had a CR lasting 2-42 months. There was 100% response rate for multicentric lymphoma and 50% response rate for extranodal lymphoma. The median duration of remission ranged from 4.5 months for alimentary lymphoma to 28 months for multicentric disease however all anatomical groups had patients that lived longer than 1 year. A more recent study from Europe described the results for 61 cats with malignant lymphomas in various anatomical locations. 7.4% of cats were FeLV positive. CR was achieved in 75.4% of cats. The estimated 1- and 2-year disease-free intervals in the cats with CR were 51.4 and 37.8%, respectively, whereas the median duration of remission was 251 days. Response to treatment was predictive of outcome; only long term survival was possible in cats that had a CR. Third-level protocols CHOP protocol: The addition of doxorubicin (or epirubicin) to a COP protocol, defines the acronym CHOP. The best known CHOP based protocol was developed by the University of Wisconsin-Madison and as a result is named after this institution. CR rates for dogs are greater than 90% with a median survival time of 12 months. About 25% of dogs are long term survivors (longer than 2 years) and some (perhaps 5%) are cured. Typically, L-asparaginase is incorporated into the CHOP protocol during the induction phase however studies have failed to show that this increases the percentage of dogs achieving a CR, the time to achieve a CR or the first remission duration. As a result, I frequently elect to use L-asparaginase in the setting of rescue therapy. A number of different prognostic factors have been discussed previously. In a study of 55 dogs treated with MadisonWisconsin protocol, CD3 +ve (T-cell immunophenotype) patients had a median survival time of 159 days vs. CD3 –ve patients with a median survival time of 389 days. Substage b animals had a median survival time of 44 days versus substage a with a median survival time of 345 days. When evaluating treatment outcomes for the Madison-Wisconsin protocol, researchers either included a maintenance phase of treatment or discontinued the treatment after 6 months. Fiftythree dogs with multicentric lymphoma were treated with a 6-month modified version of the University of Wisconsin (UW)-Madison chemotherapy protocol. Remission duration and survival were compared to a historical control group of 55 dogs treated with a similar protocol with a prolonged maintenance phase. Remission rate for the study dogs was 94.2%. The remission and survival between the 2 groups did not differ significantly. Thus, we and others believe the 6-month chemotherapy protocol based on CHOP with no maintenance phase provides is equal to a similar protocol with a prolonged maintenance phase. It is now customary to use discontinuous protocols in the referral setting. The chemotherapy break allows a period of time to identify dogs that may have been cured of the disease, provides a time commitment and financial break for the owner and a chemotherapy break for the patient. Relapse typically occurs between 3-4 months after cessation of chemotherapy. Reinduction with the same protocol has an approximately 80% success rate at achieving remission a second time. In cats, the addition of doxorubicin to a COP protocol historically resulted in improved response rates and remission durations however recent publications (see above) have shown impressive results using COP protocol alone. A recent study evaluating the response to Madison-Wisconsin protocol in cats showed a 47% CR rate and a 37% PR rate. For cats with a CR, the remission duration was 654 days versus 114 days for cats with a PR. The overall duration of first remission was 156 days and median survival time was 210 days. Initial response to treatment was the only significant predictor of outcome again, age, stage and anatomical form of disease did not influence outcome. Treatment outcomes for chemotherapy protocols in dogs Drug/Protocol #Dogs in CR #dogs treated % CR Remission Duration Prednisolone 26 57 46 Median 53 days (range 0.5 -7 months) Doxorubicin Various Various Approx 70% 4-7 months studies studies Epirubicin 26 37 70% 143 days COP protocol Various Various Various Various studies studies studies studies 4.3 months 70% CHOP protocol 47 51 94% 9.1 months, survival 13.2 months 2006 World Congress WSAVA/FECAVA/CSAVA What is the quality of life for patients receiving chemotherapy? The owners of 25 dogs with multicentric lymphoma which were treated by multidrug chemotherapy were interviewed to assess the quality of their pet's life during treatment. Sixty-eight per cent of the owners considered their dog's quality of life to be the same as before the lymphoma occurred, and the remaining 32 % felt that their pet's quality of life on chemotherapy treatment was acceptable but poorer than before the lymphoma occurred. Treatment complications were reported by 52 % of owners. Ninety-two per cent of owners had no regrets about treating their dog with multidrug chemotherapy. Questionnaires regarding the perceptions of chemotherapy and its impact on the quality of life (QoL) of their cat were received from owners of 31 cats treated for lymphoma between 2002 and 2006 with COP (cyclophosphamide, vincristine, prednisolone) chemotherapy. The QoL scores prior to the onset of cancer were significantly higher than the ratings given after the onset of cancer but before commencement of chemotherapy. The QoL scores during were also significantly lower than prior to the onset of cancer, but significantly higher during treatment than prior to starting treatment. Adverse effects were experienced by 87% cats during the course of chemotherapy. Eighty three percent of clients were happy they treated their cat and 87% would treat another cat.