Principles of cancer chemotherapy

3 Principles of cancer chemotherapy


A basic understanding of the mechanisms of action and particular uses of chemotherapy is vital if we are to give the best-quality, compassionate and safe care to our cancer patients. It is important to remember that people can suffer markedly during chemotherapy, so from the outset we have to explain that in veterinary medicine it is generally considered ethically unjustifiable to allow our patients to experience such side effects, so we will attempt to make our chemotherapy side-effect-free where possible (which should be the majority of cases). However, in order to achieve this aim we have to use lower dosages than those used in human medicine with the inevitable consequence that veterinary chemotherapy usually has a lower success rate in terms of remission rates and durations when compared to such treatment in humans.


Although cancer development is an extremely complex series of events at a genomic level, cancer cells only vary from normal cells in six main ways. They:


• Have self-sufficient growth ability

• Are insensitive to natural antigrowth signals

• Are able to evade preprogrammed cell death (apoptosis)

• Have limitless replicative potential

• Are able to promote sustained angiogenesis

• Are able to invade tissue and develop metastasis.

Tumours develop, therefore, because of an imbalance between normal cell growth/division and natural cell death. As a result, understanding the cell cycle is fundamental to understanding cancer biology. The cell cycle has four phases, as shown in Figure 3.1.


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Figure 3.1 The four phases of the cell cycle S = period of DNA synthesis; G1 = RNA and protein synthesis; G2 = second period of RNA and protein synthesis and G0 = resting cells


Most normal cells are in the G0 stage, obviously depending upon their location and function, but it is important to remember that cells in G0 may still act as a reservoir from which further tumour cells may develop. In addition, the cell cycle is important clinically because many therapeutic modalities used in oncology only affect dividing cells, so the cell cycle specificity of various treatments may affect the choice and efficacy of treatment used. As a general rule, chemotherapeutics are either cell cycle specific or cell cycle nonspecific.


Chemotherapy drugs can act by damaging DNA and thus preventing cellular replication, inducing apoptosis, or they may interfere with a specific phase of the cell cycle. Actively dividing cells are obviously more sensitive to DNA damage.



BASIC CONCEPTS OF TUMOUR GROWTH


Most tumours are detected late in the course of the disease, at which stage there are many millions of cells making up the tumour (e.g. a mass of approximately 1-cm diameter contains 109 cells whilst an average 20-cm mass contains 1012 cells). Tumour cell growth pattern generally follows ‘Gompertzian’ growth kinetics; that is, initially exponential cell division resulting in a rapid growth phase but as cell numbers increase the rate of cell division starts to tail off. This means that because large tumours contain a very high number of cells, only a small proportion of them will be dividing when compared to when the tumour was very small, and therefore there will be fewer cells that are susceptible to chemotherapy. Conversely, smaller tumours with a higher growth fraction theoretically have a greater potential response to chemotherapy because they contain a greater number of proliferating cells. This principle is illustrated graphically in Figure 3.2.


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Figure 3.2 Rate of tumour cell growth relating to clinical detection and response to medical management


This graph also illustrates why surgical debaulking and follow-up chemotherapy or radiotherapy can theoretically be useful in tumours which display sensitivity to the follow-up treatment. By reducing the number of cancer cells in the mass, the growth curve can be shifted to the left, thereby generating a possible window of opportunity for the adjunctive treatments to be more effective than they would otherwise be without the surgery. Obviously, inherent tumour resistance, vascular supply and the type and grade of the tumour all impact on this principle so it is not possible to apply it to all conditions. However, the basic theory that chemotherapy and radiotherapy work most effectively on microscopic disease does generally apply, hence multimodal treatment should always be undertaken if possible.



INDICATIONS FOR CHEMOTHERAPY


Chemotherapy is rarely effective in veterinary medicine if used as the sole treatment modality, except in lymphoproliferative diseases such as lymphoma. There are therefore four main indications to use chemotherapy:


1. In patients with a tumour with known (or strongly presumed) sensitivity to chemotherapy, e.g. lymphoma, multiple myeloma, transmissible venereal tumour

2. As an adjunctive treatment to surgery aiming to eradicate or reduce occult micrometastases (e.g. in canine osteosarcoma and haemangiosarcoma)

3. In patients for whom palliative treatment for systemic or metastatic cancer is required and for whom surgical management is not considered viable

4. To sensitize tissues to the effects of radiation therapy.

OUR GOALS: to control the cancer and prolong survival while still maintaining a good, acceptable quality of life.



DRUG DOSAGE AND TIMING


The aim of chemotherapy is to administer the maximum possible doses at the shortest possible dosing interval (dose intensity). Any decrease in the administered dose can result in a significant reduction in drug efficacy, so giving optimal doses is vital. The efficacy of chemotherapy can be further enhanced in many situations by administering chemotherapy using several different drugs that have different mechanisms of action, known as ‘combination chemotherapy’. To make this as effective as possible without causing toxicity, several rules need to be followed:


• Administer therapies as close together as the maximal tolerable dose allows (therefore the most effective dose in most cases is very near to the toxic dose)

• Do not use drugs with overlapping drug toxicities simultaneously

• Use drugs with known activity against the tumour of interest.

In a clinically detectable tumour (i.e. approx 109 cells or more) the tumour will not contain a homogeneous population of cells. It has been hypothesized that tumours develop intrinsically resistant cell lines because of their inherent genetic instability, leading to the observation that in any tumour containing > 106 cells, drug resistance will often already have developed. This led to the development of multidrug protocols based on the activity of individual drugs against a specific tumour type, drug toxicity and mechanism of actions. The aims of combination chemotherapy therefore are to:


• Maximize cell kill but maintain an acceptable toxicity range

• Broaden the range of therapy against a heterogeneous tumour population

• Prevent/slow the development of new resistant lines.


TOXICITY


The most clinically important toxicoses include bone marrow suppression, alopecia and gastrointestinal toxicity (i.e. a ‘BAG’ of adverse effects).



Bone marrow toxicity


This is caused by damage to the rapidly dividing bone marrow stem cells and it occurs because chemotherapeutics are nonselective; they have the potential to kill any rapidly dividing cells and this includes normal bone marrow cells. Bone marrow toxicity can be assessed by taking blood for a complete blood count (CBC) and blood smear examination. Chemotherapy should be delayed in any patient with a neutrophil count of < 2.5 × 109/L or a platelet count < 50.0 × 109/L. Possible clinical signs associated with myelotoxicity include those related to sepsis, petechial or eccymotic haemorrhage and pallor and weakness. However, anecdotally in the authors’ experience, inappetance and marked lethargy are the complaints most commonly cited by the owners of animals with leucopaenia, whilst pyrexia is the most common clinical finding. Usually only patients with clinical signs should be treated, with treatments including:


• Following careful aseptic techniques

• Minimizing trauma and controlling any bleeding if thrombocytopaenic

• Culture of urine, blood and any other exudates which may be significant

• The administration of broad-spectrum antimicrobials, intravenous fluids and/or blood-product transfusions etc., as required.

Recombinant human granulocyte–monocyte colony-stimulating factor (GM-CSF) boosts endogenous production of neutrophils but its use is not routine in veterinary medicine, firstly because the bone marrow usually recovers naturally within approximately 5 days following administration of a chemotherapeutic, and secondly because antibodies can develop to GM-CSF within a few weeks of administration.


It is obviously important to discontinue the drugs that induce bone marrow suppression until blood counts have recovered, but then it would be usual to re-institute the therapy, albeit at a reduced dose. Most animals with chemotherapy-induced leucopaenia respond well to treatment as long as the problem is identified and treated rapidly, and will often only have a hospitalization period of approximately 3–5 days.



Alopecia


This is an uncommon complication but can be seen in dogs with constantly growing hair coats, such as Afghan hounds and old English sheepdogs. The author has also seen periorbital and facial alopecia in West Highland white terriers and Scottish terriers given doxorubicin (Figs 3.3, 3.4). Cats can lose their whiskers, especially with long-term vincristine therapy but more generalized alopecia is less common in cats than in dogs. If affected, the hair coat normally regrows on completion of the chemotherapy.


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Figure 3.3 A Bedlington terrier which developed generalized alopecia following doxorubicin therapy as part of a modified Madison-Wisconsin protocol to treat mesenteric lymphoma. He went into permanent complete remission and his hair regrew on cessation of his treatment


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Figure 3.4 A West Highland white terrier which developed periorbital alopecia after receiving doxorubicin, also as part of a Madison-Wisconsin protocol, used to treat his multicentric lymphoma



Gastrointestinal toxicity


The obvious clinical signs of gastrointestinal (GIT) toxicity are vomiting, anorexia and diarrhoea. The development of such signs is either secondary to direct damage to GIT epithelial cells or via efferent nervous stimulation of the chemoreceptor trigger zone or the higher vomiting centres. Anorexia is certainly a relatively common side effect after the administration of many chemotherapeutics, but this usually only lasts 24–36 hours. If there is a major concern regarding GIT toxicity then post-chemotherapy administration of antiemetics may be justified, and certainly, the author frequently recommends 5-day courses of an antiemetic (maropitant or metoclopramide) after a patient has received doxorubicin or carboplatin.


Chemotherapy-induced diarrhoea usually responds to conservative treatment (no food for 12–24 hours, oral rehydration fluids and a bland, easily digested diet for the following 3–5 days). Some cases may require the use of treatments such as metronidazole for 5–7 days. If the diarrhoea is accompanied by significant signs of systemic illness then a blood sample for CBC analysis should be obtained to ensure that the animal has not become neutropaenic. The faeces should also be cultured for pathogenic bacteria with follow-up antibiosis based on the bacteriology results where appropriate. However, in general, as with bone marrow toxicity, GIT toxicity is rarely a major problem if the chemotherapy has been administered at the correct dose and frequency and if owners have been correctly counselled and supported by the clinical team.


Other than the ‘BAG’ of side effects, there are several other major possible problems associated with chemotherapy treatment:


1. Cardiac toxicity. This is a well-recognized possible complication of doxorubicin therapy. Doxorubicin is known to induce dilated cardiomyopathy (DCM) with high cumulative doses and is also associated with transient arrhythmias during administration. In human medicine the incidence of doxorubicin-associated cardiomyopathy is quoted as being up to 1% with a total dose of 500 mg/m2, rising to over 10% with total doses of 600 mg/m2. However, in veterinary medicine, dogs appear to be more sensitive to the cardiac toxicity of doxorubicin compared to people and this effect is possibly exacerbated by the fact that doxorubicin is most commonly used in cases of canine lymphoma and there is a predilection for this condition in some breeds of dog that are also more prone to developing DCM. The current recommendation therefore is to not exceed a total dose of 180 mg/m2. Some authors have recommended using total doses of up to 240 mg/m2 in small-breed dogs in whom concurrent cardiac monitoring is performed but the safety of this has not been clearly proven. It is therefore advisable to use doxorubicin with caution in breeds of dog predisposed to DCM, and routine ECG and echocardiographic assessment are also recommended in appropriate cases. It may also be advisable to auscultate or perform continuous ECG monitoring whilst administering doxorubicin in patients for whom there is any concern regarding cardiac function and the administration should not be over a period of less than 20 minutes.

2. Haemorrhagic cystitis. This can develop following cyclophosphamide administration, due to the production of a metabolite of cyclophosphamide called acrolein that is directly toxic to the bladder epithelium. Cyclophosphamide-induced haemorrhagic cystitis can be difficult to treat when it develops so it is worth asking owners to undertake regular dipstick assessment of the animal’s urine whilst it is receiving cyclophosphamide and if there is any indication of the presence of blood in the urine, cyclophosphamide therapy should be stopped immediately and substituted with an alternative alkylating agent (e.g. chlorambucil or melphalan). Treatment of the cystitis is usually symptomatic, with antibiotics, anti-inflammatory analgesics and urinary glycosoaminoglycan supplements having all anecdotally been reported to be beneficial. Intravesicular administration of dimethyl sulphoxide (DMSO) has been reported to be successful in some cases and this has been used successfully in the authors’ hospital. The concurrent administration of frusemide at the same time as cyclophosphamide also appears to reduce the incidence of this problem.

3. Neurotoxicity. This has been reported following administration of vincristine (peripheral neuropathy), 5-fluorouracil (seizures and disorientation) and cisplatin (deafness). The neurological signs following the administration of 5-fluorouracil are significant in cats so the use of this drug is contraindicated in this species.

4. Severe cellulitis. Doxorubicin, actinomycin D, vincristine, vinblastine and mechlorethamine are known to cause a severe localised cellulitis if extravasated during administration. Briefly the treatment for this is:
• Stop injection if there is any suspicion at all that there has been, or may have been extravasation

• Carefully examine the catheter and surrounding tissue, looking for perivascular swelling/’blown vein’ appearance

• If extravasation is confirmed, attempt to aspirate drug and 5 ml of blood if possible back into the administration syringe

• Apply an ice pack and topical steroid cream to the affected area. The intravenous administration of Dexrazoxane has also been recommended if doxorubicin extravasation occurs

• Refer to a surgical specialist for possible surgical lavage and wound management. The level of treatment required will depend on the amount of soft-tissue damage that develops but may include the use of wet-to-dry dressings to remove necrotic tissue, careful daily bandage changes, reconstructive surgery and in a worst-case scenario, possibly even amputation of the limb.

For this reason it is mandatory that all intravenous chemotherapeutic agents are administered through a well-placed intravenous catheter and never directly via a needle or butterfly catheter. Placement of the catheter must follow standard aseptic techniques and ensure that the catheter is securely fixed in place (Figs 3.5–3.12).


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Figure 3.5 Preparation of the equipment required to place an intravenous chemotherapy catheter


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Figure 3.6 After clipping the hair from over the vein to be used, the skin should be cleaned with an antibacterial solution such as Hibiscrub and then surgical spirit which is allowed to dry


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Figure 3.7 With the animal appropriately restrained, the catheter is placed into the vein. If the catheter appears to pass through the vein and not stay within the lumen, use of this vein should be abandoned and an alternative vein used


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Figure 3.8 Once blood has been seen in the hub of the stylette, the catheter is then carefully advanced off the stylette


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Figure 3.9 With the catheter fully advanced, the stylette is removed and the catheter taped in place. Fixing the catheter in place by firstly ensuring that the tape used is adhered to the catheter as shown above is recommended


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Figures 3.10 and 3.11 Once the catheter has been secured with one or two further pieces of tape, a T-port is attached and the catheter patency assessed by withdrawing blood. Once satisfied that the catheter is well placed and patent, it is then thoroughly flushed using 10-ml sterile saline


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Figure 3.12 The T-port itself is then taped in place in the same manner as the catheter before a bandage is placed over the whole catheter to keep it clean and prevent the patient from trying to remove it!

Related posts:

  1. Principles of cancer surgery
  2. The dysphagic/gagging/regurgitating cancer patient
  3. The cancer patient with halitosis and/or hypersalivation
  4. The cancer patient with general lumps and bumps

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Principles of cancer chemotherapy

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