All of the staff, from the front desk to the nurses to the doctors, not only took care of my Lex, but they also took care of me - and for that I am grateful!
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.
Conventional cancer treatment utilizes chemotherapy at the maximally tolerated dose (MTD), or the highest dose shown to be both cytotoxic and tolerable for the patient. MTD chemotherapy targets rapidly dividing cells including: tumor cells and normal cells of the gastrointestinal tract and bone marrow1. Since MTD chemotherapy targets normal cells, a mandatory hiatus between treatments is required to allow these cells to recover and repopulate. During this recovery time, the tumor cells also have the opportunity to repopulate and acquire genetic changes which lead to drug resistance1.
In an attempt to avoid these pitfalls of conventional chemotherapy treatment, metronomic chemotherapy was developed. Much like a metronome keeps continuous rhythm; metronomic chemotherapy is the administration of low doses of chemotherapy at continuous, regular intervals2. Due to higher dosing frequency, the cytotoxic agent must be administered at dosages lower than MTD to ensure tolerability, and administered in a form that enables ease of use. The majority of metronomic chemotherapy protocols that have been studied in veterinary medicine use oral anti-neoplastic agents, such as cyclophosphamide, lomustine, or chlorambucil3-6. This relatively new method of chemotherapy administration is still under investigation, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. However, the low cost, ease of administration, and acceptable toxicity profiles potentially associated with this therapeutic strategy make metronomic chemotherapy protocols attractive and suitable to veterinary patients.
How Does it Work?
The main mechanism of action of metronomic drug delivery is the inhibition of tumor angiogenesis2-7. The process of angiogenesis, or new blood vessel formation, is imperative for the tumor cells to grow and metastasize7. The metronomic strategy is based on the fact that blood vessel endothelial cells are highly sensitive to continuous exposure to low doses of chemotherapeutic drugs2-7. There are several proposed mechanisms for the anti-angiogenic effects of metronomic chemotherapy including5-7:
1. Targeting the drug-sensitive endothelial cells of tumors
2. 2. Inhibiting the mobilization of endothelial precursors from the bone marrow
3. Stimulating the production of thrombospondin-1, an endogenous anti-angiogenic protein
Metronomic chemotherapy has also been shown to alert the immune system of the tumor and exert anti-tumor immunity through inhibition of regulatory T cells (Tregs)8. Tregs are a subset of CD4+ lymphocytes that normally function to keep the immune system in check and prevent autoimmunity. Several studies have documented a high level of circulating Tregs in both human and canine cancer patients9-10. In these cases, Tregs prevent the patient’s endogenous immune system from attacking and destroying the cancer cells. Studies have shown that the administration of metronomic cyclophosphamide in both human and canine cancer patients selectively decreases circulating Treg numbers, thereby promoting the host immune response to destroy tumor cells8-10. A recent study demonstrated that toceranib (Palladia), a small molecule inhibitor which targets genetic mutations within the tumor cell, decreased the number of circulating Tregs in dogs with cancer after 2 weeks of therapy, and when combined with metronomic cyclophosphamide, the effect on Tregs was even more profound18.
The majority of metronomic chemotherapy protocols incorporate anti-inflammatory drugs, specifically cyclooxygenase (COX) inhibitors. COX is a prostaglandin synthase enzyme which has been implemented in tumor cell promotion and progression11. One of the proposed mechanisms by which this occurs is through upregulation of angiogenesis through the production of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF), transforming growth factor beta, and endothelin – 111. More recent research suggests cyclooxygenase may stimulate tumor cell production of Tregs, thereby downregulating anti-tumor immunity12. In veterinary patients, COX inhibitors, such as piroxicam or deracoxib, have been shown to elicit antitumor activity in patients with transitional cell carcinoma13-14, prostatic carcinoma15, oral squamous cell carcinoma16, oral malignant melanoma16, and inflammatory mammary carcinoma17. The potential anti-angiogenic effects of these drugs support their inclusion in metronomic protocols.
What Do the Experts Say?
There have been several published reports evaluating metronomic protocols for spontaneously developing tumors in dogs3-6, 18-20 and only one in cats21. When evaluating these studies, it is important to keep in mind that the majority are retrospective in nature, an appropriate control group may be lacking (using historical controls or no control group at all), and in many, the sample size is low. These factors make it difficult for most veterinary oncologists to offer metronomic therapy as a ‘first-line’ treatment option for our patients. In most cases, surgery, radiation and/or MTD chemotherapy is offered as ‘standard of care’ for the majority of tumor types; while metronomic chemotherapy may be offered as a ‘maintenance’ therapy after standard of care treatment is complete, or offered as a more conservative treatment option, in cases where a client declines standard of care.
One of the first reports evaluated the safety and efficacy of metronomic cyclophosphamide, etoposide, and piroxicam as adjuvant therapy for dogs with stage II splenic hemangiosarcoma6. A total of nine dogs were enrolled in the study. Their treatment outcomes were compared to historical controls consisting of 24 dogs with stage II splenic hemangiosarcoma treated with the standard of care chemotherapy, adjuvant doxorubicin. The study found that the treatment protocol was well tolerated by the majority of dogs and that the disease-free interval was improved in dogs receiving the metronomic protocol over the dogs receiving doxorubicin. The authors concluded that the results showed promising preliminary evidence that metronomic protocols are safe and may be effective, however the results should be interpreted with caution due to the small number of dogs included as well as the use of historical controls.
Metronomic cyclophosphamide and piroxicam in dogs with incompletely excised soft tissue sarcomas has been evaluated5. Eighty-five dogs were included in the study, 55 dogs were used as contemporary controls while 30 dogs were given treatment. The majority of the patients in both arms of the study had grade 2 tumors. 40% of the treated dogs developed mild side effects including: anorexia, vomiting, increase serum creatinine concentration, and sterile hemorrhagic cystitis. The study revealed that dogs receiving treatment had a longer disease-free interval of approximately 400 days compared to dogs that received surgery alone (disease-free interval of 211 days). The authors of this study concluded that this treatment protocol was fairly well tolerated and it was effective in delaying tumor recurrence in dogs with incompletely resected soft tissue sarcomas. These results should be interpreted with caution due to the retrospective nature of the study.
The tolerability of metronomic lomustine has been evaluated in eighty-one dogs with a variety of naturally occurring primary or metastatic tumors.4 Treatment was discontinued in nearly 30% of dogs due to severe toxicosis. Side-effects described include: gastrointestinal, thrombocytopenia, increased alanine transferase, neutropenia, and progressive azotemia. Nearly 10% of dogs developed some degree of azotemia during the treatment protocol. The authors concluded that metronomic lomustine was tolerated in dogs without pre-existing renal compromise but that caution should be used when administering this agent as the risk for side effects was fairly high in this study.
Another recent study evaluated the safety and efficacy of metronomic chlorambucil in dogs with cancer3. Thirty-six dogs with a variety of tumors were included in the study. The majority of patients tolerated the treatment well with only 11% of dogs reporting low grade gastrointestinal side effects. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumor, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration). The overall remission rate for the study was 11% (4 of 36 dogs). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. The authors concluded that chlorambucil given in a metronomic protocol showed low toxicity profile and antitumor activity in dogs with a variety of naturally occurring cancers. The results of the study should be interpreted with caution due to variety of tumor types included and the small sample size in each tumor population.
The same group looked prospectively at a population of 31 dogs with bladder transitional cell carcinoma (TCC), 29 dogs were not previously treated (naïve) and 2 dogs had tumors that progressed in the face of prior treatments19. This group of dogs received metronomic chlorambucil, toxicity and tumor responses were evaluated. 70% of the dogs had partial remission (3%) or stable disease (67%) for a median progression free interval of 119 days (range, 4-728 days) and median survival time (from time of chlorambucil treatment to death) of 221 days (range, 7-747 days). One only dog discontinued the study because of toxicosis. This group concluded that metronomic chlorambucil is a viable option for dogs with TCC; however the majority of the dogs on study had stable disease only, treatment with this protocol did not provide remission for the majority of cases.
One group evaluated metronomic cyclophosphamide and piroxicam in conjunction with MTD chemotherapy for dogs with osteosarcoma who had received amputation20. A total of 30 dogs were evaluated retrospectively. Nearly half received MTD carboplatin and the other half received combination of MTD doxorubicin and carboplatin. Both groups received the metronomic protocol at the start of MTD chemotherapy. Results indicated that more dogs in the carboplatin alone group had side effects with the protocol compared to the other group. The survival times for both groups were similar to historical controls for dogs with osteosarcoma, receiving amputation and MTD chemotherapy. In other words, it did not appear that the metronomic protocol provided benefit to this group; however the results must be interpreted with caution due to retrospective nature and small sample size.
To the author’s knowledge there is only one published study evaluating metronomic chemotherapy in pet cats with cancer21. This study evaluated 24 cats receiving metronomic cyclophosphamide for a variety of tumor types. The majority of cases were advanced stage disease, with nearly 30% with metastasis and 70% with bulky disease (non-resectable tumors). The study found that metronomic cyclophosphamide was well tolerated for the majority of cats; however follow-up longer than 1-month occurred in only 15 cases, due to the advanced stage of most cases (cases not available for study due to tumor progression, death, etc). The results of this study must be interpreted with caution due to retrospective nature, small sample size, and limited follow-up period.
In summary, preliminary veterinary studies3-6, 18-21 have shown promise for metronomic chemotherapy although both the human and veterinary medical community has a great deal to learn, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. The low cost, ease of administration, and acceptable toxicity profiles make these protocols attractive and suitable to veterinary patients. These protocols, however, should be used with caution as they are still considered investigational and the studies noted above3-6, 18-21 just skim the surface on safety and efficacy. Larger, case-controlled, prospective trials are needed before these protocols become widely accepted or considered ‘first-line’ therapies. These protocols should not be used in place of the standard of care treatment and clients should understand the investigational nature of these protocols before initiating treatment on their pet.
Submitted by: Dr Kate Vickery, VMD, MS, DACVIM (Oncology), CVA
Hope Veterinary Specialists
- Cancer Chemotherapy and Biotherapy. 3rd ed. 2001.
- Buckstein, R, et al. High-dose celecoxib and metronomic ‘low-dose’ cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology
Non-Hodgkin’s Lymphoma. Clin Cancer Res 2006; 12(17): 5190-5198. http://www.ncbi.nlm.nih.gov/pubmed/term=Highdose+celecoxib+and+metronomic+%E2%80%98lowdose%E2%80%99+cyclophosphamide+is+an+effective+
- Leach TN, et al. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol. 2012 Jun;10(2):102-12.
- Tripp CD, et al. Tolerability of metronomic administration of lomustine in dogs with cancer. J Vet Intern Med. 2011 Mar-Apr;25(2):278-84.
- Elmslie RE, et al. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas.
J Vet Intern Med. 2008 Nov-Dec;22(6):1373-9.
- Lana S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma dogs. J Vet Intern Med. 2007 Jul-Aug;21(4):764-9.
- Kerbel RS. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews. Cancer 2004; 4: 423-436. http://www.nature.com/nrc/journal/v4/n6/full/nrc1369.html
- Burton JH, et al. Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. J Vet Intern Med. 2011 Jul-Aug;25(4):920-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=Low-dose+cyclophosphamide+selectively+decreases+regulatory+T+cells+and+inhibits+angiogenesis+in+dogs+with+soft+tissue+sarcoma.+J+Vet+Intern+Med.+2011
- Wilke CM, et al. Prognostic significance of regulatory T cells in tumors. Int J Cancer 2010; 127: 748-758.
- Biller, BJ. Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet Immunol Immunopathol 2007; 116: 69-78.
- Flory, AB, et al. The role of cyclooxygenase in carcinogenesis and anticancer therapy. Compendium for Continuing Education Aug 2005; 616-627.
- Baratelli, F, et al. Prostaglandin E2 induces FoxP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 2005; 175: 1483-1490.
- Henry CJ, et al. Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma. Clin Cancer Res. 2003 Feb;9(2):906-11.
- McMillan SK, et al. Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. J Am Vet Med Assoc. 2011 Oct 15;239(8):1084-9.
- Sorenmo KU, et al. Evaluation of cyclooxygenase-1 and cyclooxygenase-2 expression and the effect of cyclooxygenase inhibitors in canine prostatic carcinoma. Vet Comp Oncol. 2004 Mar;2(1):13-23. http://www.ncbi.nlm.nih.gov/pubmed/?term=Evaluation+of+cyclooxygenase-1+and+cyclooxygenase2+expression+and+the+effect+of+cyclooxygenase+inhibitors+in+canine+prostatic+carcinoma.+Vet+Comp+Oncol.+2004
- Boria PA, et al. Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs. J Am Vet Med Assoc. 2004 Feb 1;224(3):388-94.
- de M Souza, et al. Inflammatory mammary carcinoma in 12 dogs: clinical features, cyclooxygenase-2 expression, and response to piroxicam Can Vet J. 2009 May;50(5):506-10.
- Mitchell L, et al. Clinical and immunomodulatory effects of toceranib combined with low-dose cyclophosphamide indogs with cancer. J Vet Intern Med. Mar-Apr;26(2):355-62.
- Schrempp DR, et al. Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma. J Am Vet Med Assoc. Vol. 242, No. 11, Pages 1534-1538.http://www.ncbi.nlm.nih.gov/pubmed/?term=Metronomic+administration+of+chlorambucil+for+treatment+of+dogs+with+urinary+bladder+transitional+cell+carcinoma.+J+Am+Vet+Med+Assoc.+2013
- Bracha S, et al. Evaluation of toxicities from combined metronomic and maximal-tolerated dose chemotherapy in dogs with osteosarcoma. J Sm Anim Pract. 2014. Vol 55,Issue 7, pages 369–374.
- Chiara L. Evaluation of low-dose metronomic (LDM) cyclophosphamide toxicity in cats with malignant neoplasia. J Fel Med Surg. 2014. V 16no. 8, pages 671-678.
Hope will be at the Penn Conference on March 11th and 12th. Stop by booth 202 in the exhibit hall to say hello!
Penn Annual Conference 2015 (CE)
Mar. 11&12, 2015 8:00am – 6:00pm
Sheraton Philadelphia Downtown Hotel
201 North 17th Street
Philadelphia, PA 19103