I CANNOT thank you all sufficiently for your professional and kind approach.
Lymphoma is one of the most common cancers in both dogs and cats and one of the most commonly treated cancers in veterinary medicine. As a veterinary oncologist, I cannot remember a more exciting time in this field, as there are now some wonderful new therapeutic options available, including monoclonal antibody therapy for both T and B cell lymphoma in dogs.
Antibodies are proteins produced by plasma cells (mature B cells) used by the immune system to identify and neutralize foreign antigens like bacteria, viruses, parasites, and cancer cells. Each antibody recognizes a specific antigen and monoclonal antibodies are identical antibodies that each recognize a single, specific antigen. The scientist who discovered monoclonal antibodies shared the Nobel Prize in Medicine in 1984, signifying how important this discovery was to the world.
The immune system attacks foreign proteins (parasites, viruses, bacteria) in your body, but it doesn’t always recognize cancer cells as foreign. Therapeutic monoclonal antibodies can be directed to attach to certain parts of a cancer cell, and therefore allow the immune system to more easily detect and eliminate the cell. Monoclonal antibodies do this through a variety of mechanisms: activating Antibody Dependent Cellular Cytotoxicity (ADCC); blocking growth factor signaling; stopping new blood vessels from forming; delivering radiation to cancer cells; and delivering chemotherapy to cancer cells
As canine lymphoma is incredibly similar to non-Hodgkin’s lymphoma (NHL) in people, it is helpful to look at the “human” experience with monoclonal antibodies. In the late 1990’s a large group of oncologists tested the various chemotherapy regimens for NHL and found that the standard CHOP regimen was just as good as the other more intense chemotherapy regimens. (see chart #1)
Chart 1. Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for Advanced Non-Hodgkin’s Lymphoma:
Fisher RI et al. N Engl J Med 1993;328:1002-1006.
It wasn’t until the development of Rituximab that there was any significant advancement in the treatment of NHL in people (see chart #2). The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.
“The most substantial advancement in the treatment of B-cell malignancies, since the advent of combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab (Rituxan).” -Pharmacy and Therapeutics 2010 Mar; 35(3): 148–157.
Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin’s Lymphoma
Chart 2. JCO, Feugier, et al, 2005
The veterinary oncology community has also been testing an anti-CD20 monoclonal antibody, also from Aratana. In the first trial, dogs were treated with either 1 cycle of CHOP along with the anti-CD20 MAb or 1 cycle of CHOP alone. The results are quite impressive (see chart #3) in that the median progression free survival times and the median overall survival times of the dogs treated with MAbs were 167 and 325 days, respectively, compared to 93.5 and 177 days for the placebo arm. In the second trial dogs were treated with either single agent doxorubicin and the anti-CD20 MAb or single agent doxorubicin alone. The number of dogs achieving a complete remission was greater in the group receiving the MAb than in the group receiving doxorubicin alone.
Monoclonal antibody therapy for T cell lymphomas in dogs is also available. T cell lymphomas are typically more aggressive than the B cell lymphomas in both dogs and people. There are however, indolent forms of T cell lymphoma that dogs can survive with for years. Not all T cell lymphoma are “terrible”. For those T cell lymphomas that are not indolent, the response to chemotherapy alone is not robust. In people, the addition of monoclonal antibodies to chemotherapy for T cell lymphomas has increased survival times and response rates. Clinical responses to the anti-CD52 antibody, alemtuzamab, were observed in over 33% of people with chemotherapy-refractory or relapsed peripheral T cell lymphoma. The canine (“caninized”) monoclonal anti-CD52 antibody developed by Aratana was granted a conditional license in Jan 2014. Since that time there have been 3 clinical programs involving the antibody—T-CHOMP, T-LAB and T-CEP.
T-CHOMP was a clinical study evaluating the anti-CD52 antibody in conjunction with a multi-agent chemotherapy protocol. T-LAB is the clinical trial in which the monoclonal therapy is used in addition to a short protocol involving single agent CCNU. Final results regarding the efficacy of the drug has not been published, but in our experience, the drug was well tolerated and safe. The T-CEP or Clinical Experience Program is the third piece in this program. This program is designed to determine in what scenario or scenarios this therapy is most effective—at the start of chemotherapy, after chemotherapy, when the pet has achieved minimal residual disease status, as maintenance therapy or as induction therapy.
The fact that monoclonal antibody therapy for canine lymphoma is now available is hugely important to veterinarians and pet owners alike.
Gerald Post, DVM, MEM, DACVIM (Oncology)
For more information about monoclonal antibody clinical trials and treatment options at Hope VS, please visit HERE
Hemangiosarcoma (HSA) is a highly malignant tumor of endothelial cells and is diagnosed more frequently in dogs than in any other domestic species. Accounting for approximately 2 % of all canine tumors, HSA tends to affect older dogs of either gender, with a median age of 10 years at diagnosis. While dogs of any breed can develop HSA, German shepherds, Golden retrievers appear predisposed. HSA can develop anywhere in the body. The four most common primary sites are the spleen, heart (right atrium or auricle), skin or subcutaneous tissues, and liver. (Figure 1)
The definitive cause of canine HSA remains uncertain, though the strong breed association suggests heritable factors are present to explain this genetic predisposition and, in fact, gene expression phenotypes were shown to vary between HSA cells from different breeds in a recent study. It has been identified that HSA originates for circulating endothelial precursors and not from mature endothelial cells within an organ.
With the advent of platforms enabling evaluation of genome wide gene expression, we are beginning to identify genes associated with HSA. Differences between HSA cells and non-malignant endothelial cells in regards to increased expression of genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning have been documented. Importantly, this “signature” reflected not only a cancer-associated angiogenic phenotype, but could distinguish HSA from other non-endothelial, angiogenic bone marrow-derived tumors such as lymphoma, leukemia, and osteosarcoma. Specific abnormalities in oncogenes (genes that promote growth), and tumor suppressor genes (genes that retard growth) have been identified, all of which play a role in tumor formation. More specifically may cancer“driver” genes and their associated signal pathways have been identified with HSA.
Since clinical stage affects prognosis and HSA is a highly metastatic cancer, complete clinical staging is highly recommended at diagnosis when the patient is sufficiently stable. Complete clinical staging should ideally include three-view high-detail thoracic radiographs (Figure 2), abdominal ultrasonographic study, and echocardiography, in addition to standard bloodwork. In select cases, additional imaging techniques (computed tomography or magnetic resonance imaging). Studies of splenic and hepatic lesions have shown that MRI and CT carry a high sensitivity and specificity in determining benign from malignant processes. Furthermore, the increased sensitivity of thoracic CT for early pulmonary metastasis detection has been reported. With the increasing use of such diagnostic techniques in veterinary medicine, they are gradually incorporated in the thorough staging of dogs with HSA.
The definitive diagnosis of HSA is obtained with histopathology and this generally obtain via surgery. A few studies evaluating dogs with nontraumatic hemoabdomens noted that 65-70% were diagnosed with HSA. Interestingly, a recent study evaluating 65 dogs that underwent splenectomy, including 30 dogs (46%) with HSA, documented larger splenic masses, or higher mass-to-splenic volume ratio, and heavier spleens (as a % of body weight) were more likely to be benign. The development of noninvasive biomarkers with specificity to HSA would be clinically useful for not only early detection and treatment but also to monitor for progression of disease. Several recent studies have evaluated such markers in both the blood and effusion of dogs with HSA. For cardiac HSA, cardiac troponin I (cTnI) has proven to be a highly specific and sensitive marker for myocardial cellular damage in many mammalian species. A recent study noted a specific plasma cTnI concentration (> 0.25 ng/mL) could identify cardiac involvement in dogs with HSA at any site (sensitivity, 78%; specificity, 71 %), and could identify HSA in dogs with pericardial effusion (sensitivity, 81%; specificity, 100%). Evaluation of a fragment of collagen XXVII noted high concentrations in serum of dogs diagnosed with advanced stage HSA. Thymidine kinase (TK) is a cytosolic enzyme whose activity is closely correlated with the DNA synthesis and its expression is generally restricted to proliferating cells. Serum TK1 activity was significantly higher in dogs with HSA than in normal dogs. Even though a prospective evaluation of TK1 in 62 dogs with hemoabdomen due to benign splenic masses or HSA was unable to distinguish between the two, the ability to discriminate between the two became significant when a specific two tiered cut off system was implemented, making TK1 an attractive biomarker.
Traditional therapy for HSA, as for other cancers, involves surgery, radiation therapy, and systemic cytotoxic chemotherapy, alone or in a multimodality setting.
Surgery – Splenectomy, liver lobectomy, excision of a dermal or resectable subcutaneous nodule, and right auriculectomy have all been reported. Such surgeries are performed to remove all macroscopic tumor tissue, and prevent further risk of acute hemorrhage, development of disseminated intravascular coagulation, or death. Surgery alone for splenic, cardiac, subcutaneous/intramuscular, or hepatic HSA is generally considered purely palliative, with median survival times (MST) typically averaging 1-3 months with splenectomy alone.
Conventional chemotherapy – Doxorubicin (DOX)-based adjuvant chemotherapy, with or without the addition of cyclophosphamide or vincristine is considered “standard of care”. Common protocols include single agent DOX, DOX and cyclophosphamide (AC protocol), and vincristine, DOX and cyclophosphamide (VAC protocol). Survival times ranging from 140 to 202 days have been reported for the various doxorubicin-based protocols, however, no protocol is regarded as clearly superior. Although, small numbers (n=9 and HSA of several locations), a recent study evaluating Adriamycin and Dacarbazine (DTIC) noted a median survival >550 days for dogs post surgical resection.
Conventional chemotherapy also has been evaluated with macroscopic HSA. In 18 dogs with inoperable subcutaneous HSA treated with DOX monotherapy, the overall response rate was 38.8% using World Health Organization (WHO) criteria, 38.8% using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 44% using tumor volume criteria, for an overall median response duration of 53 days (range 13-190 days). An aggressive protocol combining dacarbazine, DOX and vincristine (DAV protocol) was evaluated in 24 dogs with advanced-stage inoperable HSA and showed a response rate approaching 50%, including five complete and four partial responses, for a median time to tumor progression or 101 days and a reported MST of 125 days.
Radiation therapy – A study of 20 dogs with measurable, histologically-confirmed nonsplenic HSA treated with palliative radiation therapy showed subjective reduction in tumor size in 14 dogs (70%), with 4 complete responses and a MST of 95 days. In such cases, palliation is obtained by decreasing pain and bruising, in addition to tumor shrinkage, and will generally be combined with systemic doxorubicin-based chemotherapy.
Since the combination of traditional therapeutic modalities has reached a plateau unlikely to be surpassed, with median survival times averaging 6-7 months, new therapies are impatiently awaited. The growing body of knowledge on the molecular alterations observed in canine HSA cells may hopefully unveil numerous novel targets. Antiangiogenic therapy in the form of tyrosine kinase inhibitors designed to block aberrant signal pathways in HSA have shown promise in vitro. A recent study evaluating Toceranib (Palladia; Zoetis) in dogs with splenic HSA following surgery and standard doxorubicin therapy noted no significant improvement in overall survival. The use of traditional chemotherapy agents is being revisited through novel methods or schedules of administration. A pilot study evaluating inhalational therapy with DOX and paclitaxel demonstrated encouraging results on canine patients with pulmonary metastasis from HSA. The daily administration of low doses (metronomic dosing) of traditional cytotoxic chemotherapy agents is another new approach. The therapeutic target is then shifted from the cancer cells to the endothelial cells by administering frequent low doses of chemotherapy. By so doing, the common problems of toxicities and drug resistance can be largely avoided. A small pilot study evaluated a continuous low-dose protocol of cyclophosphamide, piroxicam and etoposide in 9 dogs with stage II splenic HSA in the adjuvant setting. When comparing their median survival time to that of historical controls treated with DOX, no difference was observed. Two recent studies have documented responses of HSA in the macroscopic disease setting to continuous low-dose administration of CCNU (lomustine) and chlorambucil. The authors have recently completed a large study evaluating the addition of a metronomic protocol to standard doxorubicin.
Polysaccharopeptide (PSP), the bioactive agent of the mushroom Coriolus versicolor
(aka Cloud mushroom, turkey tail, or Yunzhi mushroom) was evaluated in a small study of 15 dogs receiving three dosings. In the patients receiving the high dose (n=5), a median survival of 112 days was noted. A current three arm study evaluating doxorubicin alone, doxorubicin + PSP (I’m Yunity) or PSP alone is ongoing. Yunnan Baiyao is a hemostatic powdered alternative medicine used anecdotally to decrease hemorrhage. The company website mentions that the steroid progesterone is in the formula, in addition to several saponins, alkaloids and calcium phosphate. In vitro data exists with canine HAS cell lines, however, no in vivo studies exist.
Canine HSA remains an aggressive, highly metastatic cancer, and the survival times obtained with traditional therapy have not been surpassed in recent years. Hope for improved prognosis in the near future remains, and is based on ongoing research promising mainly earlier diagnosis and successful novel targeted therapies.
Submitted by Craig A Clifford DVM, MS, DACVIM (Oncology)
Gorden BH, Kim JH, Sarver AL, et al. Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization The American Journal of Pathology 2014;184:985–995.
Finotello R, Stefanello D, Zini E, et al. Comparison of doxorubicin–cyclophosphamide with doxorubicin–dacarbazine for the adjuvant treatment of canine hemangiosarcoma. Veterinary and Comparative Oncology
Clendaniel DC, Sivacolundhu RK, Sorenmo KU, et al. Association Between Macroscopic Appearance of Liver Lesions and Liver Histology in Dogs With Splenic Hemangiosarcoma: 79 Cases (2004–2009). Journal of the American Animal Hospital Association 50.4 2014: e6-e10.
Figure 1. Splenic hemangiosarcoma. Note the multilobulated nature of the tumor. Photo courtesy of JuliusLiptak, BVSc, MVetLinStud, FACVSc, DACVS, DECVS.
Figure 2. Three-view thoracic radiographs from a 12 year old spayed female Labrador retriever. Numerous poorly to well defined small soft tissue nodules are present throughout the lungs consistent with metastatic hemangiosarcoma. Images and description courtesy of Chris Ryan, VMD, DABVP, DACVR.
Drs. Craig Clifford and Christine Mullen of Hope VS contributed to the July 2015 edition of Clinician’s Brief.
Dr. Tom Garg, PVMA District 7 Trustee and Chair, Legislative & Regulatory Affairs Committee as well as an Emergency Veterinarian at Hope Veterinary Specialists weighs in on the Fairness to Pet Owners Act legislation. Click on the link below to read the full article from PVMA.
The Fairness to Pet Owners Act is a piece of legislation that has been introduced on the federal level for the last few sessions. It is championed by large pharmacies such as Walgreens and Walmart. The act would require veterinarians to provide a written prescription for any medication that is prescribed regardless of whether the client has requested a prescription. Only after writing a prescription and physically handing it to the client could a veterinarian offer to fill that prescription. If the client elected to have the prescription filled by the veterinarian, the veterinarian would then be required to take back the written prescription that he or she had just handed to the client. The large pharmacies promote the act by stating that it would increase competition and therefore control cost for the end consumer.
A 10 year 6 month old, FS, German shepherd, initially presented to her primary veterinarian for vomiting yellow liquid 2-3 times per week for the past 1-2 months. Also, she was straining to defecate with no production when going on walks but was having normal bowel movements in the yard prior to going on walks. On physical examination she was noted to have a 1-2 cm mass in the left anal sac. Abdominal radiographs (not available for review) and a FNA of the anal sac mass were performed. Cytology results revealed an anal sac adenocarcinoma and referral to an oncologist was recommended.
She was evaluated by the oncology service at Hope Veterinary specialists 10 days later. Complete blood work was performed which was unremarkable. Three view thoracic radiographs revealed no evidence of metastasis and abdominal ultrasound showed an enlarged left sublumbar lymph node that measured 1.75 x 4.19 cms (Figure 1) and was normoechoic with diffusely heterogenous parenchyma.
Treatment options were discussed including the most aggressive option of surgery followed by adjuvant treatment such as radiation +/- chemotherapy vs. a palliative approach including radiation to the mass and lymph nodes with systemic therapy; either Palladia or chemotherapy.
The owners opted to pursue surgery and a left anal sacculectomy/mass resection and left sublumbar lymph node excision were performed without complications. Histopathology results revealed an anal sac adenocarcinoma with lymphatic invasion and narrow excision. The left medial iliac lymph node showed metastatic anal sac adenocarcinoma.
A follow-up appointment with the surgery service for suture removal and with the oncology service was performed at 16 days postop. The sutures were removed and chemotherapy (carboplatin IV q 3 weeks x 4-6 cycles) +/- radiation to the draining lymph nodes was discussed. The owner opted for chemotherapy alone and carboplatin was started that day. A recheck CBC in one week had no concerning findings. A recheck examination was performed by the oncology service 3 weeks after receiving her first dose of carboplatin and the owner reported that the first dose had affected her appetite slightly for a few days but had since resolved. A CBC had no concerning findings and the second dose of carboplatin was administered and maropitant citrate was prescribed. A recheck ultrasound to evaluate her lymph nodes is to be performed after two cycles of Carboplatin.
Tumors of the anal sac are uncommon and represent a small percentage of all tumors in dogs (<1%). The most common malignant tumor of the perianal region is the anal sac (gland) carcinoma accounting for 16.5% of all perianal tumors. These tumors are locally invasive and metastasize early in the course of disease. There does not appear to be a breed or sex predilection for this tumor and no consistent etiology has been noted.
In many cases these tumors are noted as an incidental finding on a routine rectal examination and can range in size from very small to very large before clinical signs occur. In dogs with clinical signs, perianal swelling, straining to defecate, licking at the perianal region, and bleeding were most commonly seen and are a result of a large anal sac tumor or severely enlarged regional lymph nodes. In other cases the increased drinking and urination was noted as a result of high calcium in the blood. This paraneoplastic syndrome is associated with release of the parathyroid related protein (PTHrp) which elevates the blood calcium, in some cases leading to significant kidney damage. It has been shown that up to 25% of dogs with anal sac tumors will have elevated calcium levels in the blood.
A diagnostic workup for anal sac adenocarcinoma includes; bloodwork (CBC, serum chemistry), urinalysis, chest radiographs, abdominal ultrasound and aspirates of the tumor or regional lymph nodes (if enlarged). A definitive diagnosis is obtained either by aspirates of the tumor or lymph node or biopsy of the tumor. Metastasis is relatively common with this tumor and may be present in 36-96% of the dogs.
Once a diagnosis has been obtained therapy will be determined based upon the size of the tumor and ability of the surgeon to remove the tumor without complications. Surgery offers the only chance for a cure and involves removing the anal sac and regional lymph nodes if affected. In cases where surgery is not complete, then radiation therapy offers good local control. At the same time radiation therapy is also directed at the regional lymph nodes (sublumbar) prophylactically.
The benefits of chemotherapy for this cancer are unknown, however, chemotherapy is added to most protocols due to the high chance of metastasis by the time therapy is instituted. Commonly used chemotherapy agents include Carboplatin
In some cases multimodality therapy are used (surgery, chemotherapy, radiation therapy) in the treatment of dogs with anal sac carcinoma and in one study of dogs treated with surgery, radiation therapy (15 treatments) and chemotherapy (mitoxantrone) a median survival of > 900 days was noted. Although the survival was quite favorable, significant radiation therapy induced side effects were noted in majority of dogs.
Lastly, a novel class of drugs exist called “signal blockers ” which have been shown to have efficacy against this cancer (Palladia). It inhibits signals used by the tumor to create new blood vessels and thus can be used against a variety of tumors, including anal sac adenocarcinomas. In a study of dogs receiving Palladia nearly a 70% response rate was noted and the response duration was ~23 weeks.
Submitted by Dr Lauren May VMD, DACVS
Ultrasound image showing an enlarged left medial iliac lymph node (1.75 x 4.2 cms).