Treatment
To treat or not to treat? THE decision whether to treat a lymphoma patient should not be taken lightly.
Chemotherapy of lymphoma can be extremely rewarding, but requires significant investment on the part of the client both of money and time, and the likelihood of cure is low; it must be remembered that the aim of veterinary chemotherapy is a quality of life rather than quantity.
Patient selection is important: some dogs find injections or regular visits to the vet extremely stressful (or are aggressive) and for these patients a long course of treatment may not result in a good quality of life.
It must also be kept in mind that the drugs involved are potentially hazardous to handle. Owners must also be made aware of the potential hazards of exposure to drug residues, and special attention drawn to the potential dangers to pregnant women, who should NEVER be placed at risk of exposure to the drugs or residues.
A clinician must have a candid discussion with the owners so that they can make an informed decision based upon as much information as possible before proceeding.
First-line chemotherapy
Multiple drug cytotoxic chemotherapy currently represents the treatment of choice for most forms of lymphoma. It is generally accepted that the best response is gained by using a combination of
drugs that target different stages in the cell’s reproductive cycle.
Most standard protocols contain vincristine, cyclophosphamide doxorubicin and prednisolone and are referred to as “CHOP” protocols.
They are based upon a protocol developed at the University of Wisconsin-Madison in the 1990s and there are many published variations on the original; whist in general they are all associated with similar response rate and overall survival times (median survival is generally accepted to be in the region of 10-12 months), none has demonstrated significant superiority over the others.
Therapy is typically discontinued after six months if the patient is in complete remission at that stage.
“COP” protocols, excluding an anthracycline, remain popular and are fairly effective and well tolerated, though they are generally associated with shorter remission times with a median of 6-9 months. Single agent protocols have the advantage of requiring fewer visits to the surgery but are generally less effective than multi-drug approaches; the most effective single drug is doxorubicin. The author currently uses a 25week CHOP-type protocol without L-Asparaginase (Figure 1) for clinically well patients, reserving LAsparaginase either for patients who are clinically unwell at the time of diagnosis or for rescue protocols. It is frequently necessary to tailor a protocol to the individual patient; for instance, patients developing cystitis have chlorambucil substituted in place of cyclophosphamide, and those with evidence of cardiac disease will have actinomycin-D instead of epirubicin.
Treatment may be tailored for certain forms of lymphoma: for example, the author currently uses lomustine and prednisolone as first line for epitheliotrophic lymphoma. Some oncologists incorporate lomustine when treating T-cell lymphoma, though conclusive evidence supporting this is lacking. For those clients who decline cytotoxic chemotherapy, prednisolone can be used as a single agent with a degree of success. However, remission due to prednisolone alone is usually very short (typically little more than a month) and, should a client change his or her mind, treatment with prednisolone will render subsequent attempts at cytotoxic chemotherapy less effective.
Monitoring of progress
Whilst treatment monitoring can be fairly straightforward for multicentric forms (e.g. measuring lymph nodes), it is particularly important to schedule re-staging for patients with occult disease to determine if therapy is successful.
As discussed in the previous part of this article, initial staging provides a useful benchmark against which to measure progress. A patient should ideally be in complete remission by the end of the most intensive induction phase of treatment protocol and the protocol reviewed if this is not the case.
If a patient is in complete remission at the end of a discontinuous protocol (typically 25 weeks with a CHOP-type protocol, or 52 weeks with a COP), then it is usual to discontinue treatment at that stage.
Following discontinuation of a protocol, it is extremely important to reassess the patient regularly so that re-induction therapy can be started promptly if required.
Prognosis
Lymphoma is potentially very rewarding to treat (Figure 2) with around 90% of multi-centric lymphoma patients going into remission. It is difficult accurately to compare previous data, as various authors have reported different outcome measures; however, median survival times are generally accepted to be in the range of 10-12 months for CHOP-type protocols.
There seems to be a “brick wall” effect with no studies reporting median survival times much longer than this, though there is massive individual patient variation in survival times.
Distinct subpopulations of dogs seemingly survive for significantly shorter – or longer – periods than the average; up to 25% of patients will still be in complete remission at two years after diagnosis and a very small proportion (maybe 510%) will be cured. This difference in survival is likely to reflect distinct phenotypes of the disease, as discssed in the first part of this article.
Cranial mediastinal lymphoma generally carries a poorer prognosis than multicentric, though this may be because they are usually T-cell. Alimentary lymphoma also tends to respond less favourably to therapy – though good responses do sometimes occur – and epitheliotrophic lymphoma carries a poor prognosis with median survival times of around four months even with aggressive treatment.
Known negative prognostic indicators include a patient being clinically ill at the time of diagnosis, advanced stage, T-cell phenotype and hypercalcaemia, though it is likely
that further prognostic factors will be discovered in the future.
Re-induction and rescue protocols
If a patient relapses after having successfully completed a primary course of CHOP-based chemotherapy, there is a good chance that reinduction with the same protocol will be effective.
However, if a lymphoma becomes resistant to first-line chemotherapy (as the majority of lymphomas eventually do) then rescue therapy can be attempted with novel agents, and various different protocols have been described for this purpose.
Unfortunately however, response to rescue protocols is generally poor (typically only around 30% achieve complete remission) and response is often less durable than initial remission as many lymphomas ultimately develop multiple drug resistance.
Practical Aspects
Handling and administration
Cytotoxic drugs are potentially hazardous to handle, and great care must be taken to ensure the safety of all involved. Clinicians should not feel under pressure to use any drug that he or she is not confident in handling; advice from an oncologist should be sought if unsure and pregnant women must NEVER handle these drugs.
Personal protective equipment (Figure 3) must always be worn. Drugs should be drawn up within a laminar flow cabinet (Figure 4) and administered by a closed, needle-free delivery system (such as Phaseal or Clave, Figure 5) to eliminate aerosols and minimise the risk of exposure for the handler.
It is extremely important that IV drugs be given via a well-secured catheter placed first stick as many cytotoxics are vesicants and can produce marked blistering if given perivascularly; if there is any question over the placement and patency of a catheter then another vein should be used.
There are various protocols to be followed to minimise damage if extravasation occurs (for example, subcutaneous hyaluronidase in the case of the vinca alkaloids) but in the case of doxorubicin or epirubicin it can result in very severe blistering and even loss of a limb whatever measures are taken.
Monitoring for side-effects
Cytotoxics essentially target fastdividing cells so have a very crude selectivity for cancer cells, but other rapidly dividing cells such as bone marrow and GI mucosal cells will also be targeted. Owners should be asked to look out for signs of fever, which may indicate myelosupression.
Haematology should be monitored prior to each cytotoxic dose and treatment postponed if there is evidence of myelosupression. Side-effects are frequently selflimiting though may necessitate antiemetics, antibiotics or IV fluid therapy.
In the case of severe myelosupression or GI signs, a dose reduction may be necessary, though this decision should not be taken lightly as a reduction in dose intensification can significantly reduce efficacy.
Those breeds susceptible to ivermectin toxicosis (e.g. rough collies, Australian shepherds) should be genetically tested for MDR 1 mutation before commencing vincristine or doxorubicin as these drugs are both MDR1 substrates and patients with this mutation are sensitive to these drugs.
Doxorubicin and to a lesser extent epirubicin treatment can result in cardiotoxicity; chlorphenamine premedciation should be given and these drugs should be administered slowly over around half an hour via a free-flowing saline drip and heart rate and rhythm monitored, though toxicity is more commonly chronic and cumulative. Ideally, dogs considered at risk from DCM should have an echocardiogram before receiving these drugs.
Cyclophosphamide can result in sterile haemorrhagic cystitis and owners should be asked to be vigilant for clinical signs of this. If it occurs then chlorambucil should be substituted in place of cyclophosphamid
The Future
The tailoring of protocols to various phenotypes is the subject of ongoing research and as more different lymphomas are discovered different therapeutic strategies may be developed in the future, and are likely to lead to modest improvements in survival.
There is interest in strategies to inhibit multidrug efflux proteins (in no small part responsible for resistance) though this route of investigation has yet to translate into improvements in survival.
The development of monoclonal antibodies directed against cell surface proteins (for example, rituximab, directed against the CD20 protein on the surface of human B-lymphocytes) have led to very significant progress in human oncology.
Work is under way to develop similar monoclonal antibodies against canine cell surface proteins – including a molecule targeting canine CD20 – so it is exciting to think that such treatments could well be available to veterinary oncologists in the future; however, it is likely to be some time before they are readily available and financially viable treatment options.
