By definition a relapse is the recrudescence of clinical signs such as enlarging lymph nodes after the animal has undergone remission or partial remission. Please see the definitions of remission status duration response definitions by Vail et al.¹ Relapse is caused by the manifestation and proliferation of chemo-resistant cell clones in the cancer. This is considered acquired resistance. In some 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. 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. 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.

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.

General principles

 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 (e.g., 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, 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. It was generally accepted that protocols like the Wisconsin protocol should be continued in its maintenance phase long-term. However, reports indicates that the shortened 25-week protocol gives similar results when compared to historical controls.²

 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 and in some cases third 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 can be re-induced with a protocol containing drugs such as lomustine (CCNU) which has been reported to show promise as a rescue therapy agent.^3-5 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 MW-protocol.

 Has the maximum dose of doxorubicin been reached 180 mg/m²? If the maximum dose of doxorubicin has been achieved our approach is to substitute doxorubicin with actinomycin-D.^6,7 Actinomycin–D is not cardiotoxic but may not be as effective as doxorubicin. Mitoxantrone may also be used in place of doxorubicin.⁸ However our experience has been that mitoxantrone as a single agent is of limited value, but can be a substitute for doxorubicin in the MW-protocol.^9,10

 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.

 Is the relapse different to the original staging? A small number of cases will relapse with manifestation different from the original appearance (e.g., CNS). This may make it necessary to change to drugs that cross the blood brain barrier.

 Is this the first relapse? More than one relapse is certainly possible, and logically becomes more difficult to re-induce with each relapse.

 Is there evidence of toxicity (e.g., hematological, hepatic) 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.

As previously mentioned we utilize lomustine based protocol when re-induction with the Wisconsin protocol is not possible.⁵ Other protocols specifically designed as rescue protocols include MOPP,¹² UF-LOPP,^3,5 and ADIC¹³. 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 are strongly urged to consult the relevant literature on safe handling and administration.

It is also worth noting that the majority chemotherapy drugs are not FDA approved for use in animals, and owner signed consent should be sought.

References

1.  Vail DM, Michels GM, Khanna C, Selting KA, London CA, Veterinary Cooperative Oncology Group. Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0) - a veterinary cooperative oncology group (VCOG) consensus document. Vet Comp Oncol. 2010;8(1):28–37.

2.  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):704–709.

3.  LeBlanc AK, Mauldin GE, Milner RJ, LaDue TA, Mauldin GN, Bartges JW. Efficacy and toxicity of BOPP and LOPP chemotherapy for the treatment of relapsed canine lymphoma. Vet Comp Oncol. 2006;4(1):21–32.

4.  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):395–398.

5.  Fahey CE, Milner RJ, Barabas K, Lurie D, Kow K, Parfitt S, et al. Evaluation of the University of Florida lomustine, vincristine, procarbazine, and prednisone chemotherapy protocol for the treatment of relapsed lymphoma in dogs: 33 cases (2003–2009). J Am Vet Med Assoc. 2011;239(2):209–215.

6.  Khanna C, Lund EM, Redic KA, 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.

7.  Moore AS, Ogilvie GK, Vail DM. Actinomycin D for reinduction of remission in dogs with resistant lymphoma. J Vet Intern Med. 1994;8(5):343–344.

8.  Lucroy MD, Phillips BS, Kraegel SA, Simonson ER, Madewell BR. Evaluation of single-agent mitoxantrone as chemotherapy for relapsing canine lymphoma. J Vet Intern Med. 1998;12(5):325–329.

9.  Daters AT, Mauldin GE, Mauldin GN, Brodsky EM, Post GS. Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma. Vet Comp Oncol. 2010;8(1):11–22.

10. Wang S-L, Lee J-J, Liao AT. Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma. Can Vet J. 2016;57(3):271–276.

11. 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):289–295.

12. 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):576–580.

13. Van Vechten M, Helfand SC, Jeglum KA. Treatment of relapsed canine lymphoma with doxorubicin and dacarbazine. J Vet Intern Med. 1990;4(4):187–191.