In veterinary oncology there are really few clearly identified primary protocols for many of the diseases that we deal with on a regular basis other than for lymphoma. When first-line treatment fails, there is usually not a recognised rescue protocol of first choice. I will outline my approach to these cases and provide some options that might help. Care is required as not all options are suitable for all patients and careful selection is required.
Treatment failures are seen in two situations: the first is where there has been an initial response and then failure, the second when the initial treatment fails to lead to a response. There will be some differences in the approach to these two situations.
Many types of treatment failure are seen and they will vary depending on the type or combination of treatment being used. In patients being treated for systemic disease such as lymphoma, then a failure would be a relapse. If the primary treatment is surgery, then we can see local recurrence as the failure or metastatic disease. Radiation failures are similar to surgery.
When we have a patient that has been successfully undergoing treatment for a cancer who becomes unwell or displays signs that could be associated with a recurrence or relapse, it is important to confirm this. Most of the time we will be dealing with the same disease, but there are some times when there is another disease present. Studies have shown that about 5% of canine cancer patients will have a second malignancy, and a higher proportion will have other systemic illnesses. Even if there is a regrowth of a mass at a prior surgery or radiation site, taking an aspirate to confirm that it is the same tissue type is advisable. Lymphoma patients can have a much wider range of problems. These are immune-compromised patients and can develop both infectious and immune-mediated diseases. These latter diseases can cause a generalised lymphadenopathy, though usually not the extent of lymphoma, and so can be mistaken.
The first step, therefore, is to ensure that the patient has the same disease for which they were being treated the first time and with no other confounding problems. Obtaining a thorough history from the client and performing a good physical examination are the starting point. The key is to identify any changes that might suggest a more complex situation. In a lymphoma patient we know that the disease will alter the immune function of the patient and they are often treated with glucocorticoids that will further alter the function and so infections are possible. A full blood profile and urinalysis would be the minimum evaluation with further testing dependent on the signs the patient is displaying. If there is dyspnoea, then thoracic radiographs are indicated. If there is abdominal signs, such as pain or gastroenteritis, then abdominal imaging, usually ultrasonography, is important. But some patients with systemic disease will relapse in very different locations. A patient with generalised lymphoma can relapse with central nervous system disease only. In some patients, full restaging is not necessary.
We now need to consider why the patient failed. Was this the expected course of the disease, such as being 18 months from diagnosis in a dog with generalised lymphoma? If this is the case, then I would not consider this case a failure and most, about 80%, will respond to a repeat of the previous protocol. Was there something that was missed in the initial investigations? If a patient with lymphoma has relapsed earlier than anticipated, was immunophenotyping performed during the initial evaluation? There is beginning to be some evidence that modifications of the CHOP protocols work better in the management of T cell lymphoma than the standard protocol. If there was an unexpected regrowth of a tumour removed surgically, was the original diagnosis confirmed and were margins evaluated on the submitted samples. Tumours are heterogenous and it is possible that the original pathological evaluation did not include a more aggressive area of the tumour. Identifying the cause of treatment failure is important when trying to regain control and also to help reduce the risk in future cases.
Patients that do not respond to treatment at all or who have very early relapses often have a much worse prognosis. There are exceptions, such as the use of inappropriate level or type of treatment at the outset. A reasonably common cause that I see is when the initial surgery was attempted without first obtaining a diagnosis. Without a diagnosis we cannot undertake proper planning and evaluations for the patient. The most frequent occurrence is with soft-tissue sarcomas and mast cell tumours.1
There are some diseases that are innately resistant to treatment. There are some newly diagnosed lymphoma patients whose disease has high levels of ABCB1 gene expression leading to increased levels of the drug efflux pump, p-glycoprotein.2 This will lead to reduced intracellular levels of chemotherapy drugs such as vincristine and doxorubicin. If in addition, they have abnormal apoptotic pathways, the major pathway of cell death after the use of chemotherapy, then this will increase the resistance of the cancer cells to treatment. These are not tests that are routinely evaluated in canine or feline lymphoma but are not common.
A careful discussion with the owners of the pet is required in any patient where there has been treatment failure. If we know why the treatment failed, we can more readily address the questions about how the patient will do if we continue to treat them. Rescue treatments can be more involved, which equates to being more expensive usually, and they can have a higher rate of morbidity and complication than the primary treatment. It is our responsibility as veterinarians to be advocates for the patient as some owners do not appreciate the impact treatments can have on the quality of life of their pet.
In a patient with a regrowth of a low-grade soft-tissue sarcoma on the limb that had a previous marginal excision, repeat surgery with more aggressive surgery might be possible. This is not always possible as all of the tissue disturbed in the original surgery ideally is removed with margins along with the regrowth. There is the option of doing something different. If surgery alone was used the first time, a marginal excision could be repeated and then followed with curative intent radiation therapy where this is available. The use of chemotherapy impregnated polymers in the surgical bed have been described and shown benefit. A more radical surgery, including amputation, can be considered. The use of standard chemotherapy has not shown a lot of benefit, if any, in this situation, but the use of low-dose continuous (metronomic) chemotherapy will reduce the risk of or delay the occurrence of regrowth.3 A second marginal excision with no further treatment is not advised.
In a patient being treated with chemotherapy for systemic disease, a change in protocol is indicated. It would be ideal to know the mechanism of the drug resistance that has occurred, but this is usually not possible. In lymphoma patients that have failed a CHOP protocol, an alkylating drug combination is the most common first choice. The most common is MOPP (Mustargen, Vincristine, Procarbazine and Prednisolone) or variations of this with drugs such as lomustine or busulfan.4,5 In some patients the owners cannot afford repeated combination protocols and single agent options are used such as lomustine or mitoxantrone. In general, the chance of response to a rescue protocol in a lymphoma patient is about half the chance in a naïve case, usually around 40%. There are some patients that will have multiple responses to a combination of repeated and rescue protocols. There has been documented use of half-body or whole-body radiation in these cases. This is probably best used to consolidate remission induced with chemotherapy, but it can be used as a rescue.6
For diseases other than lymphoma, we have less documented evidence of best options. Changing the protocol to something novel is used, but there is no consensus in many cases as to the best option. Mast cell tumours being treated with the tyrosine kinase inhibitor toceranib and be changed to masitinib or in some cases imatinib, the human product. If there was minimal response to the tyrosine kinase inhibitor, the use of cytotoxic chemotherapy using vinblastine and/or lomustine can be tried. Combination treatments including surgery and radiation are also used.
Metronomic chemotherapy is being used more widely in situations where we do not have good standard treatment options. Cyclophosphamide, usually combined with a nonsteroidal anti-inflammatory drug, is the most often used. As there are some cytotoxic effects, but also effects on angiogenesis and immune modulation, the effects are not tumour-type specific. For most tumours there is no specific information on response rates or duration. Tyrosine kinase inhibitors have also been used in similar circumstances with anecdotal reports of success. For both of these options, in some patients prolonged stable disease is achieved rather than remission. This might not be sufficient for some patients.
No matter what options are used, it is important that we palliate the patient. If we cannot get the patient to achieve a good quality of life within a reasonable time period, euthanasia is an option, sometimes the best one. The mainstay of palliation is relief of signs. For a lymphoma patient, this can often be achieved with the use of glucocorticoids. For patients with mast cell tumours, the use of new-generation antihistamine, H2-blockers, and glucocorticoids can be very efficient. For patients with nausea or vomiting, antiemetics such as maropitant, metoclopramide or a 5-HT3 receptor antagonist should be used. Severe diarrhoea is much more difficult to reduce if the primary cause cannot be eliminated.
Pain relief has to be considered.7 This is not present in many diseases, but it is something that many clients will be concerned about. But the signs, particularly of chronic pain, can be subtle and missed and only recognised when pain relief is used. There are many options for pain relief including narcotic-like drug tramadol or narcotics (codeine, buprenorphine) for moderate to severe pain; nonsteroidal anti-inflammatory drugs or glucocorticoids where inflammation is the cause of pain. Paracetamol (acetaminophen) can be used judiciously in dogs. If there is neuropathic pain, we can use drugs such as gabapentin.
For bone pain we can use palliative radiation, bone-seeking radionucleotides such as samarium and bisphosphonates such as pamidronate or zoledronate.
If the patient is not eating or is struggling to eat, we can consider the use of feeding tubes. If the reason for not eating is that the patient is feeling unwell, then we need to know that we have a reasonable chance of reversing this prior to placing a tube. If there are mechanical reasons for the anorexia, then feeding tubes can be medium- to long-term options.
There is a wide range of other palliative options that can be used. The use of expandable stents for urinary tract obstruction can be beneficial. Palliative radiation to reduce the size of sublumbar lymph nodes causing pelvic canal obstruction and constipation is another example. There is a very extensive list now of options, but cost and overall efficacy can be limiting.
When I am treating a patient with palliative intent, it can be hard to decide on when enough is enough. I have found that we need to consider the patient's quality of life. It does not have to be normal, but it has to be reasonable. One way of helping to make these end-of-life decisions is to try and decide if we are prolonging the patient's life, or are we prolonging the process of dying?
References
1. Ettinger SM. Principles of treatment for soft-tissue sarcomas in the dog. Clinical Techniques in Small Animal Practice. 2003;18:118–122.
2. Bergman PJ, Ogilvie GK, Powers BE. Monoclonal antibody C219 immunohistochemistry against P-glycoprotein: sequential analysis and predictive ability in dogs with lymphoma. Journal of Veterinary Internal Medicine. 1996;10:354–359.
3. Elmslie RE, Glawe P, Dow SW. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. Journal of Veterinary Internal Medicine. 2008;22:1373–1379.
4. Rassnick KM, Mauldin GE, Al-Sarraf R, et al. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989–2000). Journal of Veterinary Internal Medicine. 2002;16:576–580.
5. LeBlanc AK, Mauldin GE, Milner RJ, LaDue TA, Mauldin GN, Bartges JW. Veterinary and Comparative Oncology. 2006;4:21–32.
6. Parshley DL, LaRue SM, Kitchell B, Heller D, Dhaliwal RS. Abdominal irradiation as a rescue therapy for feline gastrointestinal lymphoma: a retrospective study of 11 cats (2001–2008). Journal of Feline Medicine and Surgery. 2011;13:63–68.
7. Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Veterinary Clinics of North America: Small Animal Practice. 2008;38:1173–1186.