What's next? Rescue protocols for canine lymphoma

Lymphoma is the third most-common cancer in dogs and is considered to be very responsive to chemotherapy. With standard CHOP-L protocols (those that include L'asparaginase, vincristine, cyclosphosphamide, doxorubicin and prednisone), reported first-remission rates are 80 percent to 90 percent, with the average first remission between eight and 12 months.

There are several CHOP-L protocols published for use, including the Wisconsin-Madison protocol, AMC protocol and VELCAP (Moore 2001). Although there are some differences among them in terms of scheduling, dosages and addition of other chemotherapeutics, the differences are minor and the protocols are considered to be equally effective.

There is some debate as to whether treatment should include a maintenance phase, lasting one to three years, or whether treatment should be discontinued sooner. The trend has been to use shorter-term protocols (12 to 24 weeks), with the theory that the development of drug resistance may be delayed as lymphoma cells are not continuously being exposed to chemotherapy.

Short-term protocols have the advantages of being less expensive, requiring fewer visits and potentially having fewer side effects.

When deciding on what protocol to use for initial treatment, it is important to take into account prognostic factors, including anatomic location, stage, grade, substage, immunophenotype and presence of hypercalcemia or a mediastinal mass.

Most "average" dogs (Stage II-IVa B-cell intermediate to high-grade lymphoma) will benefit from a CHOP-L type of protocol.

It has not been documented whether dogs with negative prognostic factors (i.e., substage b) will have the same remission duration with a short-term protocol compared to "average" dogs with lymphoma. These dogs may be more effectively treated with protocols that include a maintenance phase.

Those with T-cell lymphoma or certain anatomic locations (cutaneous or gastrointestinal) may benefit from the use of protocols such as MOPP as a first-line treatment.

First remissions tend to be easier to achieve and treatment protocols are more standardized. Subsequent remissions can be more difficult to achieve as well as being shorter in duration. Most rescue protocols will have response rates of around 30 percent to 50 percent, with a duration of 60 to100 days. There are fewer "rules" that influence the selection of rescue protocols compared to the initial protocol.

When selecting a rescue protocol, factors that need to be taken into account include what drugs were used initially, how long the first remission was, what toxicity was seen during the first remission, owner expectations and the overall clinical status of the patient.

In general, the risk of side effects is similar although chronic myelosuppression, particularly thrombocytopenia, can be seen with dogs that are heavily pre-treated. This may necessitate dose reductions, treatment delays or cessation of treatment.

The length of treatment with a rescue protocol is not standard. In our clinic, most rescue protocols are administered for no less than six months but no more than a year, providing that the patient continues to respond.

Drug resistance

It is important to understand some principles of drug resistance in order to rationally select a rescue protocol (Ogilvie, 1995). Drug resistance is responsible for the failure of chemotherapy in those cancers that initially are considered to be "chemoresponsive." Resistance can either be de novo (present prior to any treatment) or acquired.

There are multiple mechanisms that can convey drug resistance and, for many drugs, there is more than one mechanism that can induce resistance (Table 1).

Table 1. Mechanisms of drug resistance

One of the most common mechanisms for drug resistance in lymphoma is the up-regulation of P-glycoprotein.This up-regulation confers multi-drug resistance on the cell. P-glycoprotein is a membrane pump that can transport multiple substrates out of the cell where they have no effect. Substates for this pump often are structurally unrelated but include many of the natural products or their derivatives (Table 2).

Table 2. Drugs affected by MDR

P-glycoprotein normally is expressed in tissues such as the kidney, adrenal gland, lung, liver and colon, which most likely accounts for the de novo resistance of cancers arising from these organs. Drugs that are affected by this mechanism include steroids, vinca alkaloids, anthracyclines and the taxanes. Resistance to one drug may convey resistance to several others. It has been shown that lymphoma cells have lower levels of p-glycoprotein prior to treatment and that these levels increase at relapse. In addition, dogs that have high levels pre-treatment have been found to have lower response rates.

Prednisone is capable of upregulating p-glycoprotein, which may explain the decreased response rates in those patients pre-treated with steroids.

There are other mechanisms of resistance important to lymphoma patients. These would include increased DNA repair, inactivation of drugs, increase in drug catabolism or altered drug targets. Resistance to alkylating agents often is acquired by increased DNA repair or drug inactivation. However, resistance to one alkylating agent does not confer resistance to others.

Employing different alkylating agents is a strategy often seen in the design of rescue protocols for lymphoma dogs. Resistance to anti-metabolites can be conferred by alteration of target enzymes, increased drug catabolism and decreased drug activation.

Commonly used rescue protocols

CHOP-L

For dogs t treated with a CHOP-L type of protocol and then taken off treatment for a while, an effective strategy may be re-induction with a similar CHOP-L protocol. In dogs that were treated with VELCAP-S, it was reported that 87 percent achieved a second remission when re-induced with a similar protocol. (Moore 2001).

For dogs achieving a second remission, the decision that must be made is whether to treat them with a short-term protocol again or continue them on one that includes a maintenance phase. In our clinic, dogs that relapse prior to one year receive maintenance chemotherapy while those that relapse after one year repeat a short-term protocol.

For those dogs that finish a second protocol and subsequently relapse, it is possible to consider using a CHOP-L protocol a third time. It should be kept in mind that the cumulative dose of doxorubicin is 180 mg/m2, so that an alternative drug such as mitoxantrone or actinomycin-D should be used instead, once the cumulative dose is reached.

Doxorubicin

For dogs that have failed a COP protocol, single-agent doxorubicin or actinomycin-D may be an effective alternative. In one study, 25 percent of dogs had either a complete or partial response to doxorubicin with a mean remission time of 134 days (Leifer 1981). However, resistance to vincristine or prednisone also may confer resistance to doxorubicin or actinomycin-D, due to up-regulation of P-glycoprotein. \When used s a single agent, doxorubicin is given once every 21 days, up to a cumulative dose of 180 mg/m2.

Mitoxantrone

Mitoxantrone is considered inferior to doxorubicin for the treatment of canine lymphoma, so its use has been limited to a substitute for doxorubicin for those dogs that have pre-existing cardiac disease or once the cumulative limit is reached.

Despite the similarities of these drugs, it has been shown that these two drugs can have different mechanisms of action and resistance, so that mitoxantrone may be effective when doxorubicin is not.

Seven out of 15 dogs that had previously received doxorubicin achieved a complete response with mitoxantrone for a median of 84 days (Madewell, 1998). Mitoxantrone has the advantage of not having a cumulative limit, so that longer-term treatment is possible. Mitoxantrone also given intravenously once every 21 days.

CCNU +/- L'asparaginase

CCNU is an alkylating agent and a good choice for dogs that have failed CHOP-L protocols. In those treated with CCNU alone as a rescue, the reported complete and partial response rate was 25 percent for a duration of 86 days (Frimberger 1999). This response is typical for most rescue protocols.

L'asparaginase usually is not used as a maintenance agent in most CHOP-L protocols and is not subject to multi-drug resistance. The use of L'asparaginase and CCNU combined may be more effective, given the different mechanisms. The toxicities are non-overlapping, making this a well-tolerated protocol. Both drugs are given once every three weeks.

L'asparaginase can cause allergic reactions when used multiple times, so pre-medication with Benadryl +/- steroids can be considered. CCNU can cause hepatoxicity, so periodic evaluation of liver enzymes is advised.

MOPP

MOPP (Mustargen, vincristine, prednisone and procarbazine) is one of the first protocols developed to treat lymphoma in humans. It no longer is used as a standard treatment option in humans but is used either as a first-line protocol for T-cell lymphoma or as a first-line rescue protocol in canine patients.

Both Mustargen and procarbazine are alkylating agents, so may be effective in dogs that have failed CHOP-L protocols. In one study, 31 percent of dogs achieved a complete remission for a median duration of 63 days (Mooney 2002).

D-MAC

D-MAC (dexamethasone, actinomycin-D, cytosine arabinoside and melphalan) is a multi-drug rescue protocol reported to have a combined response rate (PR +CR) of 72 percent (Cuoto 2006).

The duration of remission was 112 weeks for complete responders and 44 days for partial responders. Actinomycin-D is an anthracycline similar to doxorubicin but does not carry the risk of cardiomyopathy.

Cross-resistance between actinomycin-D and doxorubicin can be an issue. Cytosine is an anti-metabolite while melphalan is an alkylating agent so cross-resistance is not an issue with these two drugs.

Doxorubicin/dacarbazine

Doxorubicin remains one of the most effective chemotherapeutics for the treatment of canine lymphoma. However, the development of resistance ultimately limits its use as a rescue agent.

Dacarbazine is a non-traditional alkylating agent that is not part of first line agents for lymphoma due to limited efficacy as a single agent.

When these two drugs are given in combination, there appears to be a synergy that can reverse drug resistance to doxorubicin.

In one study, five of 15 dogs who were resistant to doxorubicin were found to achieve a response with a median survival time of 105 days (Van Vechten 1990). The cumulative dose of doxorubicin should not exceed 180 mg/m2.

Radiation therapy

Radiation therapy has been an effective modality in the treatment of lymphoma in humans.

Different applications would include localized or regional radiation therapy, half-body radiation therapy or total-body irradiation (TBI).

If there is only a single node or set of lymph nodes that are resistant, radiation therapy protocols that involve multiple daily fractions of radiation therapy can be considered.

Half-body radiation therapy has been used for dogs that have failed systemically.

Half-body radiation resulted in complete or partial response in five of 14 dogs with a mean duration of 102 and 54 days, respectively (Laing et al., 1989).

The cranial and caudal halves of the body are treated separately and need to be separated by three to four weeks to allow for bone-marrow recovery in the treated half.

Potential toxicities include alopecia, bone-marrow suppression and gastrointestinal toxicity.

Effective protocols for the use TBI as a rescue therapy have not been published because one limiting factor is severe myelosuppression.

Dr. Cronin earned her DVM degree from Cornell University in 1990. She completed an internship at the Animal Medical Center in New York and a medical oncology residency at North Carolina State University. She is a diplomate of the American College of Veterinary Internal Medicine in the specialty of oncology. After completing her residency, she was lecturer at the University of Pennsylvania Veterinary Teaching Hospital and a medical oncologist at Angell Memorial Animal Hospital in Boston. In 2001, she co-founded the New England Veterinary Oncology Group in Waltham, Mass.

SUGGESTED READING

• L'Heureux DA, Moore AS et al. Evaluation of a Discontinuous Protocol (VELCAP-S) for Canine Lymphoma. J Vet Intern Med 2001; 15:348-354.

• Ogilvie GK, Berman PJ. Drug Resistance and Cancer Therapy. Compendium 1995; 17:549-556.

• Page RL, Lee JJ et al. P-Glycoprotein Expression in Canine Lymphoma. Cancer 1996;77:1892-1898.

• Leifer CE, Calvert CA. Doxorubicin for Treatment of Canine Lymphosarcoma After Development of Resistance to Combination Chemotherapy. JAVMA 1981;179:1011-1012.

• Madewell BR, Lucroy MD et al. Evaluation of Single-Agent Mitoxantrone as Chemotherapy for Relapsing Canine Lymphoma. J Vet Inter Med 1998;12:325-329.

• Mooney SC, Rassnick KM. MOPP chemotherapy for the treatment of resistant lymphoma in dogs: a retrospective study of 177 cases (1989-2000). J Vet Intern Med 2002;16:576-580.

• Cuoto GC, Alvarez FJ et al. Dexamethasone, Melphalan, Actinomycin D, Cytosine Arabinoside (DMAC) Protocol for Dogs with Relapsed Lymphoma. J Vet Intern Med 2006;20:1178-1183.

• Van Vechten M, Hefland SC. Treatment of Relapsed Canine Lymphoma with Doxorubicin and Dacarbazine. JVIM 1990; 4:187-191.

• Laing EJ, Fitzpatrick PJ. Half-Body Radiation Therapy in the Treatment of Canine Lymphoma. J Vet Intern Med 1889: 3:102-108.