It was clear that you not only felt for us-but with us.
Pamela and David
Upper Chichester, PA
WHAT IS LYMPHOMA?
Lymphoma (LSA) is one of the most common cancers in dogs. It is a cancer of lymphocytes which are cells of the immune system. LSA comes in several forms, including: gastrointestinal, mediastinal (chest), multicentric (involving many lymph nodes) and extranodal (involving organs such as the eyes, brain, kidney, skin, etc). Most dogs are diagnosed with the multicentric form (80-85%). The “typical” canine lymphoma patient is a middle-aged dog presented to the veterinarian because one or more lumps have been found. Usually the dog has not been showing any signs of illness and the lymph nodes are not painful to the dog.
Diagnosis is based upon either cytology or biopsy of a lymph node or affected organ. A workup for LSA involves the following: CBC and serum chemistry to evaluate all body systems; Chest radiograph (x-ray) to look for evidence of spread to the chest cavity or lungs; Aspirates of the lymph nodes to determine the phenotype (T cell or B cell), and in some cases an abdominal ultrasound to evaluate the spleen, liver and abdominal lymph nodes for evidence of the cancer.
We generally break LSA in three groups, B cell (~2/3 of the dogs), T cell (~1/3) and null cell (<2%). This information may be obtained through either biopsy or more novel techniques that are less invasive such as immunocytochemistry (ICC), flow cytometry, or PCR for antigen receptor gene rearrangement (PARR). Phenotyping of LSA is important as the result plays a role in prognosis (as B cells carry a better prognosis) and in therapy (as we treat B and T cell LSA with different protocols).
For many years, the “standard of care” treatment for most canine lymphomas has been doxorubicin-based combination chemotherapy, often referred to as CHOP chemotherapy. The acronym “CHOP” denotes the four drugs thought to have the greatest activity against lymphomas: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Vincristine, Cyclophosphamide. Oncologists are now modifying protocols depending upon whether the patient has a B cell or T cell lymphoma, thus each are treated at Hope VS differently.
WHAT ARE MONOCLONAL ANTIBODIES?
In human oncology, lymphoma is treated with a combination of chemotherapy, such as CHOP, and monoclonal antibodies. A monoclonal antibody (mAb) can be used to specifically bind to target cells or proteins. This may then stimulate the patient’s immune system to attack those targeted cells and remove them from the body. Normal lymphocytes can be replenished, as stem cells within the bone marrow are not targeted and as such normal cells are replenished but the cancer lymphocytes are not. These have now become standard of care therapy in human oncology.
In veterinary medicine, we now have a B cell and T cell monoclonal antibodies for use in our patients. The monoclonal antibodies are produced by Aratana Therapeutics. The B cell monoclonal antibody has gained full approval by the USDA and the T cell monoclonal conditional approval.
HOW CAN MY DOG RECEIVE THE MONOCLONAL?
- We are currently enrolling patients in a clinical trial for dogs with T cell lymphoma. Patients deemed eligible will be enrolled to receive chemotherapy +/- a T cell monoclonal antibody. This study is fully funded.
- We are partnering with Aratana therapeutics on a T cell experience program in which patients with T cell lymphoma can receive the monoclonal antibody. This is not a trail and patients with T cell lymphoma can be receive any chemotherapy protocol with the monoclonal (no restrictions). The owner is responsible for costs associated with the monoclonal and its administration.
WHAT ABOUT B CELL LYMPHOMA?
Hope VS has received a B cell specific monoclonal antibody through Aratana and can treat patients that meet very specific criteria.
- Patients need to have been screened for T-Lab and deemed a “screen failure” due to the diagnosis of B cell lymphoma
Patients that fit this criteria can then go on to receive B cell monoclonal along as part of the B cell experience program along with any chemotherapy protocol (no restrictions on protocol). The monoclonal antibody itself is provided AT NO COST with owners covering only cost of its administration. Any costs associated with bloodwork, visits or concurrent chemotherapy are owner responsibility.
This is a very exciting time in veterinary oncology and HopeVS is excited to be on the forefront and provide the B and T cell monoclonal antibodies to patients in our region.
WHO DO I CONTACT FOR ELGIBILITY?
Primary Contacts at HopeVS: Dr. Craig Clifford and Dr. Kate Vickery
Phone: (610) 296-2099
Dr. Dennis Burkett will be at the WPVMA meeting this Sunday, April 12, 2015
9:00 – 11:30 AM – The ECG: Origin, Overview, Clinical Relevance and Practical Applications in the Emergency Setting
1:00 – 2:00 PM – Do You Hear What I Hear? Heart and Lung Sounds in Dogs and Cats
2:00 – 3:00 PM – Bureaulogical Disorders: What Else Besides the Medicine Do You Need to Know to Be Successful?
3:00 – 4:00 PM – Open Forum, Questions and Answers for the Cardiologist. Heartworm Treatment Guidelines for Dogs
Penny, a 5.5 year old female spayed Boxer, initially presented to her primary care veterinarian for rapidly progressive circling, ataxia, behavior changes and mental dullness. Due to the severity of neurologic signs, advanced imaging (MRI) was recommended. An MRI revealed an intra-axial mass in the right prosencephalon that was heterogeneous, hyperintense on T2 weighted images, hypointense on T1 weighted mages and peripherally contrast enhancing. This mass was in the area of the rostral internal capsule and right caudate nucleus. The mass measured 1.5 x 2.4 x 3.2 cm. There was a second 2 cm mass present in the white matter of the rostral left pyriform lobe with similar imaging characteristics. The 2 masses were equivocally connected by a thin bridge of tissue. Focal susceptibility artifacts in the center of the masses were noted, consistent with hemorrhage and a significant amount of perilesional edema was associated with both lesions. The top differential in this case was a malignant glioma. Other differentials include other types of neoplasia and granulomatous inflammation of the brain. (Figure 1.)
Penny was started on prednisone 0.5 mg/kg and mannitol 0.5 g/kg IV as needed. During hospitalization, mild focal seizures developed and treated with Levetiracetam 20 mg/kg and Phenobarbital 2 mg/kg as well as a valium CRI. A radiation oncology consult was performed to discuss the biologic behavior of this tumor and treatment options. The concept of stereotactic radiation therapy in the form of Cyberknife was discussed with the owners. CyberKnife is a linear accelerator that is mounted on a robotic arm which has multiple degrees of freedom. This allows radiation to be delivered from up to 1200 different angles around a patient. Hundreds of small beams of radiation are targeted to the tumor using constant image guidance which relies on bony anatomy or the placement of fiducual markers, which are small radiopaque seeds. A large dose of radiation is delivered to the target, while a very low and clinically insignificant dose is delivered to surrounding, healthy tissue. CyberKnife relies on steep dose gradients between neoplastic and healthy tissue, which is why it is best utilized for cancers that are well-defined, macroscopic targets.
Specifically for Penny, CyberKnife radiotherapy was chosen in order to deliver a larger dose of radiation in a much more rapid time frame. In addition, the precision with which the radiation is delivered eliminates much of the normal brain tissue that would be included in a field using conventional radiation therapy. Lastly, since CyberKnife radiotherapy also requires far fewer anesthetic episodes and given her altered neurologic state, fewer times under anesthesia was considered favorable (Figure 2).
Figure 2. CyberKnife treatment planning images. The top image is an axial orientation showing an MRI image of the brain tumor. The colored lines represent isodose lines, which show the various levels of radiation being received by the tumor and surrounding tissue. The thick yellow line is the prescription isodose line, which means that any tissue contained within this area is receiving the prescribed dose of radiation. The bottom image is a sagittal CT image showing a different orientation the treatment area. These treatment planning images show the concentrated dose of radiation within the tumor and the relatively small amount of radiation being received by surrounding brain tissue.
Three treatments of CyberKnife were administered over a one-week period. Initially, her neurologic state deteriorated to the point that she was obtunded and not able to stand on her own. Over a 2-3 day period, in between her second and third treatments with radiation, Penny’s abnormal neurologic signs improved drastically so that she was able to ambulate on her own and could interact with her owners. She was discharged from the hospital 1 day after her third treatment with radiation. Her neurologic state continued to improve and she was able to run, play/ catch balls and have a normal quality of life.
A repeat MRI was performed 2 weeks after the completion of Penny’s CyberKnife radiation therapy protocol. This time frame was chosen due to her rapid improvement in clinical signs and due to our interest in the changes radiation therapy may have induced in the tumor to bring about such drastic positive changes. The repeat MRI showed a slightly smaller tumor with evidence of decreased swelling of the surrounding brain, evidenced by improved visualization of the subarachnoid space. The mass showed an altered contrast enhancing pattern. There was also a visible improvement in the degree of mass effect within the brain as evidenced by a decreased midline shift (Figure 3).
Two months after the completion of Cyberknife, her owners noted a clinical decline in her neurologic status and alterative options were discussed. Differentials for this change are transient demyelination, tumor necrosis, or tumor progression. Transient demyelination is a temporary and reversible side effect that is typically managed with increased doses of steroids. Her owners elected against repeat advanced imaging and decided to pursue adjuvant chemotherapy with oral Lomustine.
Historically, gliomas and other intra-axial neoplasia are rapidly progressive and may be associated with a worse prognosis than extra-axial neoplasia. Many veterinarians may not recommend treatment with radiation due to the assumed poor prognosis. Gliomas are invasive into the surrounding brain parenchyma and difficult to remove surgically. A paucity of information exists in the veterinary literature regarding treatment with conventional radiation therapy or stereotactic radiosurgery, and, to the author’s knowledge, there are no reports of the utilization of CyberKnife radiotherapy.1-4 This case report describes the use of CyberKnife to treat a malignant glioma in a dog after which a rapid improvement in neurologic status was noted. It is unknown whether the recent change in clinical status is truly disease related, however, further imaging was not performed. Further prospective studies are needed to establish the long-term benefit of this type of therapy.
CyberKnife radiotherapy is offered locally in Malvern, PA at the Veterinary CyberKnife Cancer Center (VC3), which is directly adjacent to Hope Veterinary Specialists. VC3 is staffed by an on-site radiation oncologist, anesthesiologist, medical physicists and radiation therapist to ensure total care of referral patients. If you have a case that you think may be a candidate for CyberKnife therapy, please call VC3 at (844) 738-2927.
Submitted by Dr Siobhan Haney
- Frameless stereotactic radiosurgery for the treatment of primary intracranial tumours in dogs.Journals: Vet Comp Oncol 0 2014, C L Mariani; T A Schubert; R A House et al
- Radiosurgery using a stereotactic headframe system for irradiation of brain tumorsin dogs Journals: J Am Vet Med Assoc 219 December 2001: 1562-7, 1550, N V Lester; A L Hopkins; F J Bova et al
- Primary irradiation of canine intracranial masses. Journals: Vet Radiol Ultrasound 41 2000 Jul-Aug: 377-80, E P Spugnini; D E Thrall; G S Price et al
- Hypofractionated radiationtherapy of brainmasses in dogs: a retrospective analysis of survival of 83 cases (1991-1996) Journals: J Vet Intern Med 13 1999 Sep-Oct: 408-12, M J Brearley; N D Jeffery; S M Phillips; R Dennis
**Funding for the second MRI scan was provided by Veterinary Imaging Partners, Van Buren Ave, Norristown, PA
The past few years have seen tremendous progress in the treatment of this disease and based upon some very interesting early research, the next few years look bright as well.
Transitional cell carcinomas (TCC) are the most common tumor of the urinary system in dogs. The triad of hematuria, stranguria and pollakiuria are the cardinal clinical signs associated with this tumor. It is the progression of these signs by the local tumor that causes most of the morbidity and ultimate mortality from TCCs. Metastatic disease is uncommon at presentation but becomes increasingly common as the pet lives longer. The most common metastatic sites are the iliac / sublumbar nodes, liver, lungs and vertebrae.
The advances for the treatment of TCC have been in two major areas, chemotherapy and interventional surgery.
Historically, the three most common chemotherapeutic agents used for TCCs are mitoxantrone, doxorubicin, and carboplatin. Within the past few years two others have been added to this armamentarium, vinblastine and chlorambucil. In, 2011, Arnold et al published a paper showing that vinblastine was an effective agent in the treatment of TCCs in dogs. The median survival time reported was approximately 150 days with some of the dogs surviving for over 900 hundred days after diagnosis. This research and our own experience with this protocol caused some of our oncologists to switch from mitoxantrone to vinblastine as their first-line treatment for TCCs. The other major advance in medical oncology is the use of chlorambucil in the management of this disease. Unlike the prior injectable chemotherapeutics, Schrempp et al used chlorambucil in a metronomic setting-daily low dose of a chemotherapeutic agent. The median survival time of dogs from the beginning of treatment was over 200 days with some dogs surviving over 700 days. As you can see, these survival times can be considerable and the addition of two new chemotherapy options is significant.
Interventional surgery, in the form of both stenting and laser ablation has given veterinarians two additional options to discuss with their clients. Stenting is a palliative procedure designed to address the local complications of TCC either in the trigone/urethra or ureters. The placement of these stents is usually a rapid and safe procedure and is typically effective at restoring luminal patency. In addition, there were no major complications reported. Quality of life is restored and pets can survive for a significant amount of time after stent placement. Laser ablation therapy has already been reported both as a palliative single therapy as well as in conjunction with chemotherapy. Here too, survival times and quality of life can be significantly improved, with some pets living for over 1500 days.
More options are not always better options. However, for TCCs, the four developments of vinblastine, chlorambucil, stenting and laser ablation have indeed given veterinarians both more and effective alternatives to traditional therapies.
Ultrasound image of Transitional Cell Carcinoma
Ultrasound Image of Transitional Cell Carcinoma
(Fluoroscopic image after urethral stent placement from http://www.viries.org/portfolio-item/urethral-stenting-for-malignant-obstruction/)
Submitted by Gerald Post, DVM, MEM, DACVIM (Oncology)
- Arnold, E.J., M.O. Childress, L.M. Fourez, K.M. Tan, J.C. Stewart, P.L. Bonney, and D.W. Knapp. “Clinical Trial of Vinblastine in Dogs with Transitional Cell Carcinoma of the Urinary Bladder.” Journal of Veterinary Internal Medicine 25, no. 6 (November 2011): 1385–90. doi:10.1111/j.1939-1676.2011.00796.x.(http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2011.00796.x/epdf)
- Schrempp, Diane R., Michael O. Childress, Jane C. Stewart, Tiffany N. Leach, Kean Ming Tan, Andrew H. Abbo, Amalia E. de Gortari, Patty L. Bonney, and Deborah W. Knapp. “Metronomic Administration of Chlorambucil for Treatment of Dogs with Urinary Bladder Transitional Cell Carcinoma.” Journal of the American Veterinary Medical Association 242, no. 11 (2013): 1534–38. (http://www.ncbi.nlm.nih.gov/pubmed/23683018)
- Weisse, Chick, Allyson Berent, Kim Todd, Craig Clifford, and Jeffrey Solomon. “Evaluation of Palliative Stenting for Management of Malignant Urethral Obstructions in Dogs.” Journal of the American Veterinary Medical Association 229, no. 2 (2006): 226–34. (http://avmajournals.avma.org/doi/abs/10.2460/javma.229.2.226).
- McMillan, Sarah K., Deborah W. Knapp, José A. Ramos-Vara, Patty L. Bonney, and Larry G. Adams. “Outcome of Urethral Stent Placement for Management of Urethral Obstruction Secondary to Transitional Cell Carcinoma in Dogs: 19 Cases (2007–2010).” Journal of the American Veterinary Medical Association 241, no. 12 (2012): 1627–32. (http://avmajournals.avma.org/doi/abs/10.2460/javma.241.12.1627)
- Cerf, Dean J., and Eric C. Lindquist. “Palliative Ultrasound-guided Endoscopic Diode Laser Ablation of Transitional Cell Carcinomas of the Lower Urinary Tract in Dogs.” Journal of the American Veterinary Medical Association 240, no. 1 (2012): 51–60. (http://avmajournals.avma.org/doi/abs/10.2460/javma.240.1.51)
- Upton, Melinda L., C. H. Tangner, and Mark E. Payton. “Evaluation of Carbon Dioxide Laser Ablation Combined with Mitoxantrone and Piroxicam Treatment in Dogs with Transitional Cell Carcinoma.” Journal of the American Veterinary Medical Association 228, no. 4 (2006): 549–52. (http://avmajournals.avma.org/doi/abs/10.2460/javma.228.4.549)
Bladder, urethral and prostatic tumors are primarily a local problem in dogs and cats. These tumors can spread to the regional lymph nodes and eventually to other organs. However, the majority of patients die or are euthanized because of progression of their local tumor, causing progression of clinical signs and eventual obstruction of either the urethra or ureters. Chemotherapy and non-steroidal anti-inflammatory drugs, (NSAIDS) have all been shown to result in tumor responses and may help control the disease for a period of time. However, long term control of bladder tumors is rare. (Henry, 2003)
Given the local or loco-regional nature of these cancers, it would make sense to consider radiation therapy as an additional treatment option, since it can allow for the treatment to be directed to where the problem is.
Background/The Clinical Problem
The main issue with radiation for bladder tumors is that treating this area usually requires giving high doses of radiation to the colon and normal bladder tissue. More recent studies have demonstrated that by using a low dose per fraction (less than 3 Gy) relatively high doses of radiation (around 54 Gy) can be given safely to the pelvic area. (Arthur, 2008; Anderson, 2002) However, it is not clear whether this is enough radiation to result in a significant effect on tumor control.
In early studies one method attempted to try to get around this issue was to perform intraoperative RT. This allowed large single doses of radiation to be given directly to the tumor, with most of the critical normal structures pushed out of the way. This was very effective in controlling the bladder tumors. However, almost half of the dogs treated this way developed significant problems caused by the radiation, including incontinence, stranguria, pollakiuria and cystitis. (Walker 1987) Another concern is that giving a single high dose to the urinary tract can significantly increase the risk of radiation induced tumors. (Johnstone, 1996)
One way that radiation has been used in an effective manner recently for bladder tumors has been palliative radiation, in combination with chemotherapy and NSAIDS. In the only study published to date evaluating this combination, 9 out of 10 dogs had amelioration of their clinical signs and average survival was approximately 11 months. (Poirier, 2004)
Probably the most exciting radiation option for urogenital tumors is intensity modulated radiation (IMRT). This technique allows the dose of radiation to be targeted more accurately to the tumor, while avoiding the critical normal structures such as the colon. With this technique it is possible to give 54 to 58 Gy to the tumor over 20 treatments. Survival time in these dogs was almost 22 months with minimal significant side effects. (Nolan, 2012). This new and exciting treatment modality may help us to prolong survival and quality of life for dogs with these tumors.
Submittted by Dr. John Farrelly DVM, MS,
ACVIM (Oncology), ACVR (Radiation Oncology)
Radiation Oncologist/Medical Oncologist at The Veterinary Cancer Center
Henry CJ. Management of transitional cell carcinoma. Vet Clin North Am Small Anim Pract. 2003 May;33(3):597-613. Review.
Arthur JJ, Kleiter MM, Thrall DE, Pruitt AF. Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation. Vet Radiol Ultrasound. 2008 Jan-Feb;49(1):85-9.
Anderson CR, McNiel EA, Gillette EL, Powers BE, LaRue SM. Late complications of pelvic irradiation in 16 dogs. Vet Radiol Ultrasound. 2002 Mar-Apr;43(2):187-92.
Walker M, Breider M. Intraoperative radiotherapy of canine bladder cancer Vet Radiol. 1987 Nov; 28 (6):200–204, November 1987
Johnstone PA, Laskin WB, DeLuca AM, Barnes M, Kinsella TJ, Sindelar WF. Tumors in dogs exposed to experimental intraoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):853-7.
Poirier VJ, Forrest LJ, Adams WM, Vail DM. Piroxicam, mitoxantrone, and coarse fraction radiotherapy for the treatment of transitional cell carcinoma of the bladder in 10 dogs: a pilot study. J Am Anim Hosp Assoc. 2004 Mar-Apr;40(2):131-6.
Nolan MW, Kogan L, Griffin LR, Custis JT, Harmon JF, Biller BJ, Larue SM. Intensity-modulated and image-guided radiation therapy for treatment of genitourinary carcinomas in dogs. J Vet Intern Med. 2012 Jul-Aug;26(4):987-95.