Updated: Feb 4, 2021
IN THIS ARTICLE
Western Biomedicine Perspective on Lymphoma
Standard of Care Conventional Medicine Treatment and General Prognosis
The importance of LSA subtypes in evaluating response to novel treatments
An Integrative Approach to Lymphoma Management
Being aware of quality and potential herb-drug interactions
WESTERN BIOMEDICINE PERSPECTIVE
Lymphoma is the most common hematologic malignancy in dogs. Chemotherapy is the standard of care at this time and survivals are highly variable due to the differences between the sub-types within the disease "lymphoma". In particular, T cell lymphoma can have a wide variation in response to treatment and survival depending on the sub-type, making "phenotyping" of this disease beyond B cell and T cell beneficial to determining a more accurate estimation of outcome with therapy. Multi-drug chemotherapy protocols, in general, result in survival times of about 12 months. However, for certain low grade lymphomas survival times may approach 2 years with less aggressive oral chemotherapy protocols and certain variants of B cell lymphoma are associated with a prognosis of only 7 months with a multi-drug chemotherapy protocol.
The past 20 years has shown little progress in extending survival for lymphoma in veterinary patients. Ultimately, most cases of lymphoma relapse and eventually develop resistance to chemotherapy. While chemotherapy is currently the most effective treatment to significantly prolong survival in patients with most types of lymphoma, use of high dose chemotherapy regimens does this by killing chemotherapy sensitive cells. This ultimately means the cancer cells that survive are chemotherapy resistant clones. This is a recognized phenomenon called “competitive release”. Thus cancer cell populations are generally more and more resistant to therapy with each relapse. Treatment interventions which circumvent or suppress the mechanisms involved in drug resistance, or which limit the growth of these remaining cells after completing chemotherapy, are therefore vital to our advancement in treatment of this disease.
Many drugs that address the processes involved in chemotherapy resistance are currently under investigation. Interestingly, many compounds isolated from herbal therapies show potential to act at these targets as well. This has motivated an enthusiastic race to mine traditional herbal therapies for compounds which can be made into drugs. From this perspective, herbal therapies become interesting, affordable and readily available adjunctive treatment considerations for improving disease control and patient outcomes.
A diagnosis of lymphoma can usually be made through a procedure called a "fine needle aspirate and cytology" where cells are collected using a small needle, gently put on a slide and sent to a pathologist to be evaluated under the microscope. While many cases can be diagnosed as lymphoma via cytological evaluation of affected lymph nodes, cytology cannot provide information on prognosis or subtype of lymphoma. More advanced techniques like immunocytochemistry are now available at many laboratories, allowing differentiation into B-cell or T-cell lineage. However, the subtype of B- and T-cell lymphoma cannot be determined by this type of test on a slide sample.
An additional limitation of cytology includes inability to distinguish reactive lymph node processes (like inflammation) from early lymphoma. Tests called "PARR" or "PCR" and "flow cytometry" can be helpful in obtaining a diagnosis in these cases. For this reason, I recommend performing both PCR and flow cytometry in cases where cytological diagnosis of lymphoma is in question and prognostic information is desired.
Histologic classification of lymphoma requires a surgical biopsy of the lymph node. Surgical biopsy is most often performed when other less invasive tests are unable to provide a diagnosis or when rapid diagnosis and evaluation of the whole lymph node architecture are desired. Histological characteristics along with special stains on the tissue (Immunohistochemistry) allow classification of canine lymphoma into a number of different recognized types based on the classification schemes utilized in human medicine. Data regarding association of histopathological subtype and prognosis, however, is limited compared to that available with flow cytometry results.
Advanced Molecular Diagnostics
Flow cytometry can be run on blood, fluid samples or on aspirate samples from solid tissue suspended in a serum solution. Colorado State University’s Pathology lab has an extensive database of flow cytometry results and related survival time, making this test useful in providing prognostic information for most types of lymphoma without the necessity of surgical biopsy.
The most common T-cell immunophenotype diagnosed via flow cytometry from lymph node aspirates in dogs is CD4+ T-cell Lymphoma. Boxers are over-represented, with this subtype of lymphoma comprising over 80% of the cases in the breed. Median survival with prednisone therapy alone is 2.6 months, versus 8 months with CHOP chemotherapy. When further subclassified, those tumors classified as CD4+/CD45+ (histologically classified as lymphoblastic T cell lymphoma) were associated with a median survival time of 5.3 months, while those classified as CD4+/CD45- (histologically classified as indolent T-zone lymphoma or small clear-cell T-cell LSA) were associated with a prolonged clinical course in some patients of over 7.6 months to 2.8 years. Golden Retrievers, comprising over 50% of the cases, and Shih Tzu dogs were the most common breeds diagnosed with CD4+/CD45- T-zone lymphoma. Peripheral lymphocytosis was documented in 50% of CD4+/CD45-cases and the disease followed an indolent clinical course.
Expression of class II Major Histocompatibility Complex (MHC) and cell size have been correlated with prognosis for B-cell LSA. High class II MHC expression was associated with a MST of 11 months, versus MST of 4 months for low class II MHC expression. Large cell size was associated with a 4.6 month MST versus 9 months for smaller cell size. These results support other studies showing poor MST for certain subtypes of B-cell lymphoma.
PCR for antigen receptor gene rearrangement (PARR) can be used to identify malignant lymphoid cells and distinguish between T-cell and B-cell lymphoma through evaluation of the cancer cell DNA. This test can be run on lymph node or tissue aspirates (stained or unstained slides) tissue biopsy, fluid samples, peripheral blood, or bone marrow. The test works by evaluating areas on the cancer cell that undergo mutation during cell maturation. In the case of a cancerous condition, a clonal population occurs, in which the daughter cells all carry the identical gene makers. PARR detects these clonal expansions. In approximately 20% of lymphoma patients, the cancerous cells may not carry the markers for this test, causing a negative result respite the presence of lymphoma. Amplification techniques available for PARR, however, allow detection of lymphoma in smaller sample sizes than flow cytometry. One of the strengths of this test, then, is the ability to detect a cancerous cell population with a reactive lymphoid process, making it useful in differentiating a reactive lymph node from one with early lymphoma.
CONVENTIONAL MEDICINE TREATMENT AND GENERAL PROGNOSIS
Individual responses to chemotherapy vary and overall prognosis is most dependent on ability to obtain a complete remission with chemotherapy. Patients that are feeling well at the time of diagnosis are considered a substage “a”, which generally carries a better prognosis than patients who are sick from their disease (substage “b”).
Most lymphomas diagnosed in dogs are intermediate/high grade (over 75%). This type of lymphoma is biologically more aggressive and, without treatment, is fatal in most dogs within 4-6 weeks. Intermediate/high grade lymphoma is highly responsive to chemotherapy and many different chemotherapy protocols have been described for treatment. The CHOP multi-drug chemotherapy protocol (also called the University of Wisconsin-Madison protocol) statistically offers the best remission rates (85-90%) and survival times (approximately one year survival time, 10% two year survival time, 4% three year survival time). One study of 127 dogs diagnosed with high-grade lymphoma and treated with the CHOP chemotherapy protocol evaluated predictors of long-term prognosis (over 2 years). Predictors of a favorable prognosis were the following: larger dogs over 10 kg, dogs that were not anemic and who were normocalcemic at diagnosis, dogs with B cell lymphoma that had not previously been treated with steroids, and dogs with stage I through IV disease (not stage V).
Using the flow cytometry test described above, we are now able to provide more accurate patient-specific prognosis for our canine lymphoma patients by identifying the subtype of lymphoma. Although B cell lymphoma is commonly thought of as having a better prognosis, we have been seeing a rising incidence of a more aggressive variant of B cell lymphoma that has a prognosis of about 7 months with CHOP chemotherapy. Additionally, we have also identified a less aggressive form of T cell lymphoma that can have a prolonged clinical course with less aggressive chemotherapy protocols.
Other chemotherapy options for high-grade lymphoma are single agent protocols using either Adriamycin or CCNU. Single agent Adriamycin provides an approximately 75% response rate with MST of approximately 6-10 months. Single agent CCNU provides a 50% response rate for MST of 4 months. Prednisone therapy alone can provide an average survival time of 2-3 months.
AN INTEGRATIVE APPROACH TO DISEASE CONTROL
I often use, with informed consent from clients, traditional Chinese Medicine (TCM) herbal formulas in conjunction with chemotherapy to manage patients with lymphoma. Herbal therapies can be useful to mitigate side effects of chemotherapy or the cancer itself, such as poor appetite, low energy, and low blood cell counts. There are numerous reports in the human literature evaluating use of TCM herbal therapies for supportive care. There have also been studies recently published on the use of specific Chinese Herbal formulas in dogs which show how these treatments work to improve appetite and energy level.
There have been many studies recently published in human medicine suggesting that certain herbs or herbal formulas may increase sensitivity of cancer cells to chemotherapy. In addition, many herbal medicines have antitumor properties (antiangeogenic, antimetastatic), often with numerous anti-tumor pathways targeted in a single formula. In my practice these treatments are generally started after the first cycle of chemotherapy.
Routine performance of flow cytometry to determine the sub-type of lymphoma at the time of diagnosis is important in gaining an accurate clinical picture of the impact herbal interventions may be having on survival time in patients receiving an integrative treatment approach. This phenotyping is accomplished easily by having your oncologist perform a flow cytometry on a lymph node aspirate before treatment is started.
Potential Increased Survival for Aggressive Subset of B-Cell Lymphoma with Chinese Herbal Formulas and CHOP chemotherapy: a report of my clinical experience
I have treated a number of sequential patients with CHOP chemotherapy and herbs who seem to be showing improved survivals over published statistics for their Lymphoma sub-type. Others I have treated with herbs with or without non-CHOP chemotherapy protocols. I am currently in the process of accruing this patient data for publication and all of my integrative oncology patients and their people are helping to get this information out into the world. For that, I thank and honor all my amazing clients and patients.
In my practice, herbs are generally started after the first round of chemotherapy, when patients are in clinical remission and their response to the drugs without herbs has been clinically assessed.
Many of my lymphoma patients receiving integrative therapy with herbs are experiencing survivals longer than predicted by their flow cytometry test results, which reports prognosis with CHOP chemotherapy alone.
As an example, there is a subtype of B cell lymphoma which is more aggressive with reported median survival of 7 months (200 days) with the CHOP protocol. Of the last 5 sequential patients treated with CHOP chemotherapy and herbal therapies in my practice, survivals were 8.3 months, 13.9 months, 14.1 months, 18.4 months, and one currently alive and in remission over 10 months after diagnosis. You can see that without knowing the subtype of lymphoma, these survival times would not be as interesting because we generally say "there is a 12 month average survival time for canine lymphoma treated with chemotherapy".
These cases serve to illustrate examples of integrative management survival outcomes in my practice. A larger number of cases, and ideally randomized, double-blinded placebo-controlled prospective clinical trials, would be needed to determine the repeatability of these responses and the true prognostic significance of an integrative protocol versus standard chemotherapy. These cases, at very least, demonstrate the feasibility and low toxicity associated with select herbal formulas in conjunction with chemotherapy and other pharmaceutical management approaches to this common canine cancer. And the survivals suggest lack of clinically relevant interference with chemotherapy efficacy, as survivals are not worse than historical published statistics.
One randomized prospective clinical trial in performed in 1997 in China on human patients with non-hodgkins LSA treated with chemotherapy versus chemotherapy with Chinese herbs showed decreased side effects and improved immune function in the herb-receiving group. In the chemotherapy only group (n=55), effective rate (CR+PR) was 72.73% and 1-, 3- and 5-year survival rates were 76.4%, 38.2% and 18.2% respectively, and the median survival time was 465 days. In the chemotherapy plus herbs group (n=112), effective rate (CR+PR) was 91.96% and survival rates of 1-, 3- and 5-year were 85.7%, 54.5% and 29.5% respectively, and median survival time was 554 days. The difference of effective rates or 3-year survival rates between two groups was significant (P < 0.05).
BE AWARE OF POTENTIAL HERB-DRUG INTERACTIONS
Within the last 10 years, and more so within the last 5 years, the research on herbal therapies in management of cancer patients is progressing at a rapid pace. There are now many in vivo (bench-top or "petri dish") studies in laboratory animals evaluating pharmacokinetics, pharmacodynamics and metabolomics. The number of companion animal studies, however, is still sparse. While herbal therapies have a long history of use and are generally considered safe when prescribed as intended within their respective traditions, caution and careful monitoring is advised when prescribing herbal formulas, especially concurrent with pharmaceutical drugs as drug-herb interactions are definitely possible and some have been reported. In my clinical experience with Chinese herbs over the past decade, however, adverse interactions are rare when prescribed on a patients specific basis using reputable products and monitored appropriately. Additionally, remember, not all herb-drug interactions are "bad". Some help each treatment work better. This is called a "synergistic" herb-drug interaction.
For this reason, it is always recommended to work with a veterinarian trained in herbal medicine if you are interested in using these treatments in your pet, especially if they are receiving other medications like chemotherapy. Just like in human medical universities, veterinarians do not receive training in herbal medicine in veterinary school. This requires extensive, expensive and time-consuming additional post-graduate training.
Herbal treatments, like any other prescribed treatment, should always be used with your informed consent regarding what is and is not known about efficacy, toxicity and combination therapies. Use discretion and enlightened caution when reading company claims of product efficacy on the internet. Not everyone, I'm sad to say, has your pet's best interest at heart. Cancer is a highly emotionally charged diagnosis and a very attractive marketing niche. There are, conversely, many ethical companies who are putting in the financial resources, time and effort to perform research on their products and independently ensure good product quality control. This is an exciting time for evidence-informed healing which brings us back around to the importance and power of nutrients and supporting the body's innate healing processes.
Based on the published research of human cases and personal clinical experience, integration of properly prescribed Chinese Herbal Formulas as part of an integrative cancer treatment regimen seems to be well-tolerated with no overt evidence that TCM physician-prescribed Chinese herbal formulas decrease survival or increase toxicity when administered with chemotherapy in most of these populations. A number of recent studies suggest Chinese herbal formulas have the potential to decrease side effects often experienced by humans receiving chemotherapy. This also fits with my clinical experience in veterinary medicine. In fact, many studies suggest the potential for improving disease control and/or decreasing toxicities, motivating development of prospective clinical trials. It is important to be aware that while there are hundreds of bench-top research studies and laboratory animal studies and more and more human clinical trials being published every month, there are still very few clinical trials evaluating these interventions in veterinary cancer patients. This makes working with an experienced veterinary herbalist important.
Argyle DJ, Pecceu E. Canine and feline lymphoma: challenges and opportunities for creating a paradigm shift. Vet Comp Oncol. 2016;14(1):1-7.
Ponce F, Magnol JP, Ledieu D, et al. Prognostic significance of morphological subtypes in canine malignant lymphomas during chemotherapy. Vet J. 2004;167(2):158-66.
Aresu L, Martini V, Rossi F, et al. Canine indolent and aggressive lymphoma: clinical spectrum with histologic correlation. Vet Comp Oncol. 2015;13(4):348-62.
Valli VE, Vernau W, de Lorimier LP, et al. Canine indolent nodular lymphoma. Vet Pathol. 2006;43(3):241-56.
Flood-Knapik KE, Durham AC, Gregor TP, et al. Clinical, histopathological and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol. 2013;11(4):272-86.
Mizutani N, Goto-Koshino Y, Takahashi M, et al. Clinical and histopathological evaluation of 16 dogs with T-zone lymphoma. J Vet Med Sci. 2016;78(8):1237-44.
Lurie DM, Milner RJ, Suter SE, et al. Immunophenotypic and cytomorphologic subclassification of T-cell lymphoma in the boxer breed. Vet Immunol Immunopathol. 2008;125(1-2):102-10.
Avery PR1, Burton J, Bromberek JL, et al. Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases. J Vet Intern Med. 2014;28(2):538-46.
Seelig DM1, Avery P, Webb T, et al. Canine T-zone lymphoma: unique immunophenotypic features, outcome, and population characteristics. J Vet Intern Med. 2014;28(3):878-86.
Rao S1, Lana S, Eickhoff J, et al. Class II major histocompatibility complex expressionand cell size independently predict survival in canine B-cell lymphoma. J Vet Intern Med. 2011;25(5):1097-105.
Marconato L, Stefanello D, Valenti P, et al. Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc. 2011;238(4):480-5.
Guo XM, Li JX, Yang XF. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997;17(6):325–327.
HERB PK AND CONSIDERATIONS FOR POTENTIAL HERB-DRUG INTERACTIONS
Saruwatari J, Nakagawa K, Shindo J, Nachi S, Echizen H, Ishizaki T. The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man. J Pharm Pharmacol. 2003;55(11):1553–1559.
Fan XH, Shi WZ, Cheng YX, Zou KJ, Yang XF. Zhongguo Zhong Yao Za Zhi. 2014;39(22):4453–4458.
Fan XH, Shi WZ, Cheng YX, Yang XF. Effects of Buyang Huanwu Decoction on antioxidant and drug-metabolizing enzymes in rat liver. Chin J Nat Med. 2014;12(6):449–454.
Ito K, Satoh T, Watanabe Y, et al. Effects of Kampo medicines on CYP and P-gp activity in vitro. Biol Pharm Bull. 2008;31(5):893–896.
Satoh T, Watanabe Y, Ikarashi N, Ito K, Sugiyama K. Effects of Kampo medicines on P-glycoprotein. Biol Pharm Bull. 2009;32(12):2018–2021. doi:10.1248/bpb.32.2018
Watanabe Y, Ikarashi N, Satoh T, Ito K, Ochiai W, Sugiyama K. Inhibitory effects of daiokanzoto (da-huang-gan-cao-tang) on p-glycoprotein. Evid Based Complement Alternat Med. 2012;2012:361516.
Shinohara Y, Nishino Y, Yamanaka M, et al. Efficacy of Juzen-taiho-to against vincristine-induced toxicity in dogs. J Vet Med Sci. 2019;81(12):1810–1816.