Small Animal Clinical Services College of Veterinary Medicine, University of Florida
Gainesville, FL, USA
By definition a relapse is the recrudescence of clinical signs such as enlarging lymph nodes after the animal has undergone remission or partial remission. Relapse would in clinical terms be staged as progressive disease. Relapse is caused by the manifestation and proliferation of chemo-resistant cell clones in the cancer. This is considered acquired resistance. In same cases resistance to chemotherapy can occur even before the use of chemotherapy and is considered intrinsic resistance. Acquired resistance is thought to occur for the following two reasons. First, spontaneous mutation occurs irrespective of the presence of drug or not. The rate of spontaneous mutation can be predicted based on the rate of mitosis. Clones of cells that undergo mutations that are resistant to the drug will have a growth advantage, in other words a selection process will occur favoring resistant cells. In addition the more cells there are the greater the mutation rate, thus larger tumors are likely to have more mutations.
The second source of acquired resistance is by gene amplification e.g., multiple drug resistance gene-1 (MDR-1). Drugs that stop the cell cycle in the M-phase are most responsible for this phenomenon.
To understand the concept of cancer cell resistance we need to consider some general principles of how chemotherapy works. The biological basis for chemotherapy rest on knowledge of the three aspects of cell kinetics, the cell cycle, growth classes of tissue and Gompertzian growth of tumors. Drugs are classified either as cell-cycle specific or non-specific. A drug like vincristine is cell-cycle specific and therefore requires cell to be dividing to be effective. In general chemotherapeutic drugs can exert their affect by damaging DNA directly such as alkylating agents or indirectly by free oxygen radical e.g., doxorubicin or by other means. In broad terms in order for the effect (cell death) to be realized the cell must divide. During this process the cell has mechanisms in place which survey the damage and either repair it or induce the cell to under go programmed cell death (apoptosis). This implies that chemotherapeutic drugs are more effective against rapidly dividing cells than non-dividing. In addition cell types differ in their sensitivity to chemotherapy e.g., hemopoietic cells or more sensitive than muscle cells to affects of chemotherapy. Gompertzian growth kinetics indicate that the growth portion (proliferating cells) is not constant, generally small tumors have more cells dividing than larger tumors. This means that chemotherapy is less effective on larger tumors that have less dividing cells. Another principle that applies is that chemotherapeutic drugs kill a constant fraction of tumor cells independently of the total number of cells, and that fraction of cells killed is independent of that killed by another drug. This in essence says two things; repeated doses are required to reduce the number cells, and that combination of drugs which individually show efficacy will in all probability have a synergistic effect on cancer cells.
Unfortunately drug resistance is a common sequel to the use of chemotherapy. In light of what was discussed previously, resistance can occur and cancer cells posses the biological mechanisms that result in resistance. Generally the some of the mechanisms that have been identified are:
Increased drug inactivation by enzymes e.g., glutathione.
Increased concentrations of targeted enzyme e.g., high levels of asparagine in the case of l-asparaginase treatment.
Altered affinity of the target for the drug e.g., altered tubulin results in resistance to vincristine.
Increased DNA repair, especially important with alkylating drugs.
Increase in alternate metabolic pathways that bypass drug inhibition.
Altered drug binding to topoisomerase II,
Importantly, increased efflux of the drug from the cell. This is due to the upregulation of the MDR-1 gene (multiple drug resistance gene) whose product is p-glycoprotein. P-glycoprotein functions as the cells efflux pump and pumps out of the cell any potentially harmful xenobiotics e.g., drugs.
Both altered drug binding and MDR-1 upregulation contribute to the phenomenon of multi drug resistance (MDR).It is worth noting that normal cells do not develop resistance to antitumor drugs. This means that signs of drug toxicity will continue to occur even though the tumour is resistant to treatment. The above causes of resistance are areas of intense research of ways to prevent or reduce the impact of drug resistance. However, some certain general principles can be applied to reduce or slow down resistance, and these are:
Don't use drugs at sub-therapeutic dosages
Combine drugs that have known efficacy as single agents
Don't combine drugs that are closely related, as toxicity increases and efficacy diminishes
Combine drugs that target different metabolic pathways
Schedule drugs administration at the correct intervals and at the correct rate. Doxorubicin should be administered over a 20 min period to improve kinetics.
Having discussed the theory the practical decision of what to do next when relapses occur, depends on a number factors. At the University of Florida we use the following questions in our decision making process on what treatment to use next, these are:
Is the dog on any chemotherapy at the moment? The importance of this question lies in the reported observations that dogs that are on chemotherapy at the time of relapse tend to do more poorly than dogs not on chemotherapy. The decision stop therapy at a certain time prior to a relapse is important and relevant to the above question. It was generally accepted that protocols like the Wisconsin protocol should be continued in its maintenance phase long-term. A recent report however, indicates that the shortened 25 week protocol gives similar results when compared to historical controls (1).
What protocol is currently being used? The answer is variable depending on the protocol. Some oncologists prefer to use single agent drugs e.g., doxorubicin to initiate therapy so as reserve other drugs for future relapses. In the case of the Wisconsin protocol which we use at UF, multiple drugs are utilized, six to be precise. This in effect reduces drug options that can be used for relapses. Our typical approach depending on answers from the questions below would be to re-induce with the Wisconsin protocol. We have founds this to be a good approach as we have a number dogs responding favorably with durable second remissions.
Where in the protocol has the relapse occurred? Has the relapse occurred in the induction or maintenance phase of the protocol? It has generally been our experience at UF that cases that relapse during the early induction phase (first 5 weeks) are more difficult to re-induce and seem to have reduced survival times. These cases are often reinduced with drugs such as lomustine (CCNU) which been reported to show promise as a rescue therapy agent (2). In the case of dogs that relapse later in the maintenance portion of the protocol, we will re-induce the dog with the induction-phase of the Wisconsin protocol e.g., vincristine and l-asparaginase.
Has the maximum dose of doxorubicin been reach 180 mg/m2? If the maximum dose of doxorubicin has been achieved our approach is to substitute doxorubicin with actinomycin-D (3). Actinomycin-D is not cardiotoxic but may not be as effective as doxorubicin. Mitoxantrone may also be used in place of doxorubicin (4).
What was the drug that as last used? Generally our experience has been that when dogs relapse, they do so rapidly between treatments. Our approach is then to look at what was the last drug used and to substitute drug in the protocol with a similar mechanism action and hopefully no cross resistance into the protocol, but start at the induction phase. For example we would use dactinomycin-D in place of doxorubicin. In place of cyclophosphamide we would substitute chlorambucil (5). Even though chlorambucil is similar to cyclophosphamide cross resistance does not always occur.
Is the relapse different to the original staging? A small number of cases will relapse with manifestation different from the original appearance. We have had dogs relapsing with skin lesions and ocular signs. CNS signs are also possible. This may make it necessary to change to drugs that cross the blood brain barrier e.g., cytosine arabinoside or lomustine.
Is this the first relapse? More than one relapse is certainly possible, and logically becomes more difficult to re-induce with each relapse. In most cases owners elect euthanasia after the second relapse.
Is there evidence of toxicity e.g., hematological, hepatic is concurrent with the relapse? The presence of cytopenias may impact the choice of drug substitution. As mentioned earlier toxicity occurs even though progressive disease is present. Dog with significant thrombocytopenias would not be re-induced using myelosuppressive drug e.g., lomustine, rather a drug such as l-asparaginase would be used. Evidence of hepatotoxicity (increased level of bilirubin) would also be a reason to reduce dosages or eliminated drugs such as doxorubicin.
A number of protocols exist which can be used as rescue therapy and are listed with references. As previously mentioned we utilize lomustine when re-induction with the Wisconsin protocol is not possible (6). Other protocols specifically designed as rescue protocols include MOPP (7), D-MAC (8), ADIC (9). This is not a complete list and it is strongly recommended that the reader consults current veterinary oncology texts. Since many of these drugs used require special handling, readers as strongly urged to consult the relevant literature on safe handling and administration. It is also worth noting that no chemotherapy drugs are FDA approved for use in animals, and owners should be made aware of this. Consideration has been given to the use of multimodality therapy such as hemibody radiation (10). Currently it employed palliatively.
1. Garrett LD, Thamm DH, Chun R, Dudley R, Vail DM. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2002; 16(6):704-9.
2. Moore AS, London CA, Wood CA, Williams LE, Cotter SM, L'Heureux DA et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J Vet Intern Med 1999; 13(5):395-8.
3. Khanna C, Lund EM, Redic KA, Hayden DW, Bell FW, Goulland EL et al. Randomized controlled trial of doxorubicin versus dactinomycin in a multiagent protocol for treatment of dogs with malignant lymphoma. J Am Vet Med Assoc 1998; 213(7):985-990.
4. Moore AS, Ogilvie GK, Ruslander D, Rand WS, Cotter SM, Getzy DM et al. Evaluation of mitoxantrone for the treatment of lymphoma in dogs. J Am Vet Med Assoc 1994 Jun 15 1995; 204:1903-1905.
5. Keller ET, MacEwen EG, Rosenthal RC, Helfand SC, Fox LE. Evaluation of prognostic factors and sequential combination chemotherapy with doxorubicin for canine lymphoma. J Vet Intern Med 1993; 7(5):289-95.
6. Moore AS, London CA, Wood CA, Williams LE, Cotter SM, L'Heureux DA et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs [see comments]. J Vet Intern Med 1999; 13(5):395-398.
7. Rassnick KM, Mauldin GE, al-Sarraf R, Mauldin GN, Moore AS, Mooney SC. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000). J Vet Intern Med 2002; 16(5):576-80.
8. Ward H, Hammer AS, Peterson JL, Harris C, Couto CG. Treatment of relapsing canine lymphoma with D-MAC chemotherapy. 1994. Ref Type: Personal Communication
9. VanVechten M, Helfand S, Jeglum KA. Treatment of relapsing lymphoma with doxorubicin and dacarbazine. J Vet Intern Med 1990; 4:187-191.
10. Meleo KA. The role of radiotherapy in the treatment of lymphoma and thymoma. Vet Clin North Am Small Anim Pract 1997; 27(1):115-29.