Primary cancer chemotherapy

Before you give any cytotoxic agent, you must decide if the misery its side-effects will certainly cause, will outweigh the benefit you expect it to have. Chemotherapy is one of the treatment methods for which compliance is particularly necessary. If patients will not complete their courses of tuberculosis treatment satisfactorily, how likely are they to persist with a regime with much more unpleasant side-effects? The indications for chemotherapy under the conditions for which we write are limited.

To those who say that there is no place whatever for ''primary cancer chemotherapy', we reply that: (1) If you don't treat patients, it is probable that nobody else will either. (2) Some drugs are comparatively cheap, and some regimes are practical and highly effective, even under your circumstances, particularly those for Burkitt's lymphoma. (3) Treatment may be urgent. (4) Some district hospital doctors have been doing chemotherapy successfully for many years. (5) Patients and their families much prefer to be treated near their own homes. (6) Some patients, particularly health workers and teachers, are sufficiently compliant to complete even unpleasant courses of treatment.

If you doubt that there is a case for ''primary cancer chemotherapy', read this story:

NARUNDRNATHAN (2[1/2] years) complained of a loose tooth and swelling of his upper jaw, which had started 2 weeks previously. He was taken to a dentist, who noticed proptosis in his left eye, and referred him to the children's ward. Here he was found to have several abdominal masses, was diagnosed as having Burkitt's lymphoma, and was referred to the teaching hospital. There was no money left in the transport vote to buy petrol for the hospital ambulance, so his parents took him there by bus. The consultant oncologist was away at a conference in Oxford, so he was sent back again, and asked to reattend a week later. While he was waiting to be sent to the oncologist again, he died, after a total history of less than a month. LESSONS (1)The diagnosis of Burkitt's lymphoma is usually sufficiently distinctive for treatment to be started without waiting for a biopsy report. (2) Burkitt's lymphoma needs urgent treatment, which should begin within 48 hours, is not expensive, and is highly effective. (3) Treatment is easily possible in a district hospital. Unfortunately, there are no other tumours which are quite so readily treated by chemotherapy as Burkitt's lymphoma. Here is a modification of WHO's tumour categories, which describe what cytotoxic drugs, and hormones can do, sometimes assisted by surgery. Tumours which are treated by surgery alone, squamous cell carcinoma 32.19, for example, are not included in this list. This is a surgical manual, so we are only concerned with ''surgical' oncology, and not with the chemotherapy of leukaemia.

Category 1 Chemotherapy will cure or significantly prolong the life of some patients: Acute lymphoblastic leukaemia, acute non-lymphoblastic or myelogenous leukaemia, Hodgkin's disease, non-Hodgkin's disease, Burkitt's lymphoma, gestational/trophoblastic cancers, germ cell tumours of the testis, nephroblastoma (Wilm's tumour), Ewing's sarcoma, paediatric soft tissue sarcomas, lung cancer (small cell type), classical Kaposi's sarcoma (not the AIDS-related variety).

Category 1[nd]2 There is controversial evidence that chemotherapy as an adjuvant to surgery may prolong survival: premenopausal breast cancer (in the early stages), postmenopausal breast cancer (responding to tamoxifen), osteosarcoma.

Category 2 Chemotherapy makes tumours shrink, almost certainly improves the quality of life and may prolong life marginally: chronic lymphocytic leukaemia, chronic myelogenous leukaemia, multiple myeloma, ovarian carcinoma, endometrial carcinoma, prostatic carcinoma (oestrogen therapy puts it in this category, otherwise it would be in Category 3), neuroblastoma.

Category 2[nd]3 The tumour may shrink but it is not clear that clinical benefit outweighs toxicity. Any improvement in survival is marginal and controversial: gastric cancer, head and neck cancers, primary cancers of the central nervous system, bladder cancer (intravesical), adrenal cancer, hepatoma.

Category 3 There are no effective drugs. Although the tumour may shrink, the effect is so marginal that it is unlikely that the quality of life will be improved. Chemotherapy will compromise it in most patients, and shorten their lives: lung cancer (epidermoid, adenocarcinoma, and large cell type), oesophageal carcinoma, large gut carcinoma, pancreatic carcinoma (non-endocrine), carcinoma of the cervix, carcinoma of the penis, renal carcinoma, melanoma.

Chemotherapy in a district hospital is never easy. Your laboratory facilities will be minimal, your drugs limited, your nurses may be inexperienced with chronic cancer patients, and your rehabilitation facilities rudimentary. You do however have two advantages; you can follow up a patient more easily than a referral centre, and his relatives are likely to live much nearer.

Before you start treatment, decide on your goal. Although a particular tumour may be curable, not all patients with it may be cured. Base your decision to treat a patient on: the stage of his tumour, the sites of its metastases, its particular histology, the state of his vital organs, his nutrition, his willingness to accept toxic symptoms, and the staff and facilities you have to treat any complications he might get.

The drugs we describe have mostly been selected from WHO's list. Use these drugs only, and gain experience in their use. Don't use them unless: (1) You know or are prepared to look up their general mode of action. (2) You know their toxic effects and dangers, and have the minimal facilities to monitor these. (3) You have decided what you are aiming for[md]cure or palliation? (4) You remember that an overdose can be fatal. Even a normal dose can sometimes be fatal. So carefully follow the rules about reducing the dose and stopping treatment when necessary. Remember that experienced doctors with compliant patients sometimes have disasters[md]a patient can die from septicaemia in 48 hours.

If you do attempt cancer chemotherapy, you will have to know your limitations, and care for patients meticulously. You will also have to do regular ward rounds[md]a complication can appear in 24 hours. Finally, do your utmost to see that a patient completes his course and is not abandoned. Either strive to give him a full course, or don't attempt chemotherapy. There is no justification for the the attitude ''He's hopeless, let's try a little cyclophosphamide[...]''

Most cytotoxic drugs have their main action on rapidly dividing cells, which unfortunately include the cells of the bone marrow and the mucosa. Malignant cells divide continuously, whereas marrow cells are quiescent for part of the time. Intermittent doses ]]allow the marrow to recover, whilst maintaining an antitumour effect; but don't wait so long that the tumour regrows between courses. A common regime is to give high intermittent doses during less than 24 hours, and to repeat them every 2, 3, or 4 weeks, to allow the marrow to recover, without waiting so long that the tumour regrows between courses.

Cytotoxic drugs are commonly used in combination because: (1) They often act synergistically at different stages in cell division, or in different ways. (2) Smaller doses can be used. (3) If they have different toxic effects, their combined toxicity is minimized, because doses can be smaller. (4) The tumour is less likely to become resistant. But: (1) combined therapy is more expensive, and (2) there may be more toxic effects, although each is less severe.

Tumour cells tend to multiply at a constant rate, depending on the proportion of cells dividing. Some grow very fast[md]Burkitt's lymphoma may double in size in 24 hours. Because of the constant rate of cell multiplication, a tumour grows exponentially, and its bulk increases more rapidly as it grows. Similarly, chemotherapy kills a constant proportion of dividing cells, so that if it is sensitive, its size is also reduced exponentially. A large tumour may thus shrink rapidly to begin with, and then more slowly as it gets smaller.

Many cytotoxic drugs are very irritant indeed. If they extravasate into the tissues, they cause large necrotic ulcers. Some, such as vincristine, actinomycin D, and nitrogen mustard, are best given into a freely running drip. Others can be given by bolus intravenous injection[md]with care! Although some can be given by mouth, most are better given into a vein, because this ensures high intermittent levels of the drug in the tissues. Injecting irritant drugs into veins can cause thrombophlebitis. Over a long period, this can easily make all his accessible veins useless for chemotherapy. Careful venipuncture is the ony way to reduce this difficulty. Few cytotoxic drugs can be given intramuscularly.

When your patients die from the complications of cytotoxic drugs, there is an 80% chance that they will die from infection, usually septicaemia, and a 20% chance that they will die from intracranial haemorrhage, as the result of an abnormal tendency to bleed. Careful monitoring will minimize these dangers. If he has a total white count of 2000 [gm]l, or more, or a platelet count of 100 000 [gm]l, or more, he should have his chemotherapy, but you will have to have resources available to treat any infection or bleeding that may then arise. These include powerful antibiotics, and platelet transfusions or fresh blood. If you don't have them, and especially if he has a disease with a small or no chance of cure, you may do him more good by withholding chemotherapy completely, until his white count rises above 3000.

WHO. ''Essential drugs for cancer chemotherapy: Memorandum from a WHO Meeting'. WHO Bulletin. 1985:63 (6);999[nd]1002 DON'T COMPROMISE A PATIENT'S QUALITY OF LIFE FOR THE SAKE OF A SHORT REMISSION Fig. 32-1b THE EFFECT OF CHEMOTHERAPY on the size of a tumour cell population. A, B, C, and D, represent differences in a patient's clinical condition. In A, he has no evidence of a tumour. In B, it can only be shown by special laboratory tests. In C, he has radiological or clinical evidence of disease. In D, he has symptoms. The growth of his tumour untreated is assumed to be exponential (U). Three courses of chemotherapy (shown by arrows), at the same dose destroy the same proportion of his tumour cells, whatever the total number of cells he has when treatment begins. In 2, his symptoms are relieved, but he still has clinical and radiological signs of the disease. In 4, his symptoms are relieved, and all clinical and laboratory evidence of his tumour disappears. In 4a, he is treated when he is apparently healthy.

After the effect of treatment has worn off, his tumour grows at the same rate as it did before. In 3, his symptoms return rapidly. After 4, further growth is arrested by course 4a, which delays the return of symptoms (5). Maintenance therapy, at a low dosage that sustains a steady state, does not relieve symptoms in 1 and does not cause any regression in 1a. Maintenance treatment is continued in 1b, but the tumour has become resistant to treatment. From the Oxford Textbook of Medicine.

CYTOTOXIC DRUGS WHICH DRUGS? The regimes described here treat 18 tumours with 10 drugs. Most regimes use either vincristine (expensive) or cyclophosphamide (fairly cheap), and usually both. The next most useful drug is methotrexate, which is fairly cheap in the low dose range used for most methods, and which does not require folinic acid rescue. So try to stock these three drugs, with some actinomycin D, if possible.

If you are in the Burkitt zone, you must be able to treat Burkitt's lymphoma (common) for which you will need the first three, but you can use cyclophosphamide alone. Next in order of benefit comes Hodgkin's (nitrogen mustard, vincristine, procarbazine) and non-Hodgkin's lymphoma (cyclophosphamide, vincristine).

The remaining drugs listed are much less important: melphalan, 5 fluoruracil, doxorubicin (''Adriamycin'), etoposide.

ADMISSION. You will probably find it convenient to admit a patient for about 5 days for the initial assessment and investigation, and for the first course; then to discharge him, and readmit him for about 5 days for each course.

PRIOR INFECTION. Be sure to deal with all treatable infections before starting chemotherapy. An infection which cannot be controlled is a contraindication to the use of cytotoxic drugs.

PREPARATION AND MONITORING FOR CHEMOTHERAPY. You will need to prepare him before you start chemotherapy. One purpose of this is to establish a baseline, from which you can monitor his response to treatment. Monitor him weekly, and before each course of treatment. Monitor: (1) His clinical condition on the Karnofsky performance scale. (2) The size of his tumour, measured with a tape measure in two planes at 90[de]. If he has a lymphoma, or metastatic glandular deposits, count all his nodes and measure them with a tape. Assess the degree of involvement of any organs that are infiltrated. (3) Watch for toxic effects, and infection, clinically at least 3 times a week. (4) Measure his haemoglobin, do a total and differential white count, and if possible count his platelets. Culture his urine. (5) Do other tests as necessary, for example his blood urea.

If he has a haemoglobin of [lt]90 g/l before you start, transfuse him, if necessary, repeatedly.

INTRAVENOUS INJECTION Oral chlorpromazine 1 to 2 hours before the injection will help him considerably, by reducing nausea and vomiting (50 mg for an average adult, 25 mg if he is an outpatient). He may need further doses of this or other drugs, such as metaclopromide or cyclizine, if he continues to be sick. Haloperidol, droperidol, and possibly domperidone can also be used.

If you are giving the drug by bolus intravenous injection, have all your material ready[md]adhesive tape in the proper lengths, an infusion set or syringe ready for use, and the drug already drawn up in a syringe and well diluted! Use his arm and hand veins if you can. Start with his distal veins and use them in rotation. Use a 0.8 mm needle, and if necessary, a scalp-vein needle in children.

Place a tourniquet above the site of venipuncture, and rub his skin hard with spirit. Insert the needle bevel upwards. When you are under the skin, enter the vein, then secure the needle with a piece of tape.

Connect the syringe to the needle, and inject some saline, to be sure that it is properly in a vein. When you are sure it is in the vein, start the injection, beginning with the most irritant drug. Inject slowly over 10 minutes

If the needle becomes dislodged, start again with a fresh one. At the end of the injection, flush the vein with 10 ml of saline. Pull out the needle, and apply gentle pressure to the puncture site with a piece of dry cotton wool. If bleeding has stopped, there is no need to apply a dressing.

CAUTION ! (1) Use an absolutely clean technique[md]don't touch the tip of the needle or the infusion set. If you happen to contaminate them, discard them and use fresh ones. (2) Preferably, give nitrogen mustard, vincristine, and actinomycin D into a free-flowing drip.

If you are giving the drug into a running drip, inject the drug into the tubing of the drip. A drip adds considerably to the expense of treatment.

ALKYLATING AGENTS These combine with DNA, prevent mitosis, and cause chromosome fragmentation, so that cells die.

NITROGEN MUSTARD [s7](''Mustine') INDICATIONS. Hodgkin's disease. Nitrogen mustard is cheap, but its indications are limited.

ADMINISTRATION. Intravenously, 10 mg vials. Reconstitute these with 10 to 20 ml of water or saline, and use the solution immediately. Give it through a running intravenous drip, or well diluted as a bolus intravenous injection. It is very irritant[md]protect the patient's eyes and skin (and yours!), and don't let it leak into his subcutaneous tissues.

DOSE. 5 to 10 mg/m['2].

ACTION. Rapidly hydrolysed. 90% is cleared from the blood in a minute. Short plasma half life. 50% appears in the urine as a metabolite in 24 hours.

TOXICITY. Considerable. (1) Gastrointestinal tract: nausea and vomiting for 8 hours, anorexia for 24 hours. (2) Marrow: dose-related leucopenia, and thrombocytopenia (uncommon). (3) Local irritation can be severe, venous thrombosis.

CYCLOPHOSPHAMIDE INDICATIONS. A basic drug, 13 regimes require it.

ADMINISTRATION. Intravenously, vials of 100 mg, 200 mg, 500 mg and 1 g. Reconstitute with sterile water, and use within 2 hours. Orally, tablets of 10 mg and 50 mg.

DOSE. As a single agent give 1 g to 1.5 g/m['2] intravenously. Reduce this dose with combined therapy. Orally, see under the various tumours.

ACTION. The active agent is a hepatic metabolite. Plasma half-life 4 to 6 hours. 50% to 70% is excreted in the urine in 48 hours, and some in the bile. Two-thirds is excreted as an inactive metabolite, and one-third as an active metabolite.

TOXICITY. Less than nitrogen mustard, to which it is related chemically. (1) Anorexia, nausea, and vomiting for 6 to 12 hours. (2) Stomatitis. (3) Dose-linked depression of the marrow, especially 10 to 14 days after administration. Anaemia, thrombocytopenia (uncommon). (3) Haemorrhagic cystitis is quite common, and may be dose-limiting. A high fluid intake is mandatory in preventing this. The simple chemical, mesna, reacts specifically with the metabolite that causes the cystitis, and reduces its severity, without interacting with the parent drug. Give 200 mg of mesna intravenously per gram of intravenous cyclophosphamide, and repeat it after 4 or 8 hours. (4) Alopecia (common), skin hyperpigmentation.

MELPHALAN INDICATIONS. Myelomatosis only.

ADMINISTRATION AND DOSE. Orally, 10 mg/m['2], see myelomatosis (32.17).

ACTION. Well absorbed orally. Plasma half-life 4 hours. Slowly excreted in the urine.

TOXICITY. (1) Anorexia, nausea, and vomiting. (2) Dose- related leucopenia, thrombocytopenia, and anaemia.

ANTIMETABOLITES

These resemble the natural compounds that are essential for the synthesis of DNA and RNA, and inhibit the enzymes that are responsible for synthesis.

5 FLUOROURACIL [s7](''5FU') INDICATIONS. Carcinoma of the breast (21.5).

ADMINISTRATION. Intravenously, in ampoules of 250 mg in 5 ml of sterile water. The solution is stable. Topically, in a 5% cream.

DOSE. Intravenously, 12 mg/kg daily for 3 to 5 days, repeated every 4 weeks. Or, 15 mg/kg intravenously weekly for 6 weeks (maximum dose 1 g). Decrease the dose in patients with impaired liver, kidney, or bone marrow function.

ACTION. Erratically absorbed by mouth. After intravenous injection the plasma half-life is 10 to 30 minutes. There is no intact drug after 3 hours, but intracellular drug is present much longer. 60% to 90% is excreted as respiratory CO[,2], and 10 to 15% in the urine. It enters the CSF and effusions, but not in therapeutic doses.

TOXICITY. (1) Anorexia, nausea, and vomiting are common. (2) Stomatitis and diarrhoea are an indication to stop treatment. (2) Dose-limiting leucopenia is maximal at 7 to 14 days. Thrombocytopenia and anaemia (uncommon). (3) Alopecia, dermatitis, and skin hyperpigmentation. (4) Cerebellar ataxia (uncommon).

METHOTREXATE [s7](''Amethopterin') INDICATIONS. A basic drug, 9 regimes require it.

ADMINISTRATION. (1) Orally, tablets of 2.5 mg. (2) Intravenously as: (a) solutions of 2.5 mg, 5 mg, 50 mg, and 250 mg in vials, or (b) a powder of 50 mg or 500 mg for reconstitution with 2 ml or 10 ml of sterile water.

DOSE. There are two dose ranges:

The low dose range for most regimes: Orally, 15 mg/m['2] daily for 4 days, repeated every 14th day. Or, intravenously or intramuscularly 30 mg/m['2] weekly, if the blood urea is less than 7 mmol/l (40 mg/dl). The intramuscular use of methotrexate is one of the exceptions to the rule that cytotoxic drugs should be given intravenously.

The high dose range for carcinoma of the nasopharynx (150 mg/m['2], 32.28), and choriocarcinoma (100 mg/m['2], 32.37) is described under these tumours, and requires folinic acid ''rescue' to counter the side-effects of methotrexate. An intermediate dose can be given for carcinoma of the mouth (40 mg/m['2], 32.22).

ACTION. An antimetabolite active orally and absorbed readily. Orally, the plasma half-life is 8 to 10 hours. Intravenously, it is 4 to 6 hours. 50% of the drug is bound to plasma proteins. The CSF concentration is 10% that of blood. 50% to 90% is excreted unchanged in the urine within 24 hours.

TOXICITY. (1) Stomatitis (common) and diarrhoea (not uncommon) are indications to delay a dose or stop treatment. Bleeding and perforation are rare. (2) Hepatic toxicity is usually subclinical. (3) Leucopenia, anaemia and thrombocytopenia are uncomon with standard doses. (5) Alopecia and dermatitis (uncommon). (4) Osteoporosis occurs in children on long-term treatment. (5) Pneumonitis (uncommon). (6) Renal tubular necrosis is rare except with high doses, or if the patient is dehydrated. If signs of toxicity occur, it is too late to counter it with folinic acid, and it is safer to give no more methotrexate.

CAUTION ! (1) Don't give methotrexate, if the blood urea is over 17 mmol/l (100 mg/dl), because it accumulates when renal function is impaired. (2) Don't give it in the presence of an effusion (pleural or ascitic), because it acculumates in the fluid, and so stays in the body long enough to give an overdose. (3) Don't give aspirin with methotrexate.

VINCA ALKALOIDS These act at the metaphase of mitosis and inhibit RNA synthesis.

VINCRISTINE [s7](''Oncovin') INDICATIONS. A basic drug, 14 regimes require it.

ADMINISTRATION. Intravenously as 1 mg and 2 mg vials. Reconstitute with the diluent supplied. The reconstituted solution can be stored for 14 days in a refrigerator. Give into a running drip, or well diluted by slow intravenous injection. Extravasated solution is very irritant, and causes ulcers. Never give it intramuscularly.

DOSE. Intravenously 1.4 mg/m['2]. Maximum dose 2 mg. For example, a 2 m['2] patient gets 2 mg not 2.8 mg. Every 2 to 4 weeks. Decrease the dose in liver disease.

ACTION. Poorly absorbed orally. Plasma half-life 3 hours. Incompletely metabolized by the liver and excreted in the bile. 70% excreted in the faeces, 5 to 15% in the urine.

TOXICITY. No gastrointestinal symptoms, and little effect on the marrow. (2) A mild sensory neuropathy, presenting as impaired sensation and paraesthesiae, is common and is not dose- limiting. If there are severe paraesthesiae, with loss of reflexes and foot drop (even muscle power Grade 4, see Section 27.2), stop the drug. (3) Constipation and abdominal pain usually respond to enemas and laxatives; limit the dose if these are severe. (4) Cranial nerve palsies (uncommon). (5) Alopecia in 20% of patients.

ANTITUMOUR ANTIBIOTICS etc These inhibit cell division, and form irreversible complexes with DNA. They also block DNA-dependent RNA synthesis. Etoposide inhibits DNA repair enzymes.

ACTINOMYCIN D [s7](''Dactinomycin', ''Cosmegan') INDICATIONS. Needed by 7 regimes, notably choriocarcinoma.

ADMINISTRATION. Intravenously, 0.5 mg vials. Reconstitute with 2.2 ml of sterile water. Can be refrigerated for 24 hours. Give into a running drip. Intensely irritant subcutaneously.

DOSE. 2 mg/m['2] every 3 weeks. Or, 1 mg/m['2] on days 1 and 3. Use with care in liver disease.

ACTION. Poorly absorbed orally. Long plasma and tissue half-life. Not metabolized. 50% excreted in the bile and 10% in the urine during the first 24 hours.

TOXICITY. (1) Anorexia, nausea, and vomiting, usually within the first few hours of administration. (2) Diarrhoea. (3) Stomatitis, glossitis, and proctitis are usually dose-limiting. (4) Bone marrow depression starts 1 to 7 days after the dose. Thrombocytopenia is often seen first. Leucopenia may be dose- limiting. Anaemia (uncommon). (5) Alopecia, erythema, desquamation, hyperpigmentation, especially in areas subject to irradiation. Reversible acne.

DOXORUBICIN (''Adriamycin') INDICATIONS. This is very expensive, so it one of the less valuable drugs in the developing world; 7 mostly alternative regimes, retinoblastoma.

ADMINISTRATION. A red powder in 10 mg and 50 mg vials; reconstitute with saline or sterile water without preservative. It is stable for 48 hours in a refrigerator.

DOSE. Intravenously 60 to 75 mg/m['2] up to a maximum of 100 mg as a single dose every 3 weeks. Avoid if the patient has heart disease, and reduce with hepatic dysfunction. Don't exceed a cumulative dose of 600 mg/m['2], because the risk of heart failure becomes serious with higher doses.

ACTION. Poorly absorbed orally. Biphasic plasma clearance with half lives of 1 hour and 16 hours. Slow release from tissue binding. Rapidly metabolized by the liver. 50% excreted in the bile unchanged, 25% as the active metabolite. 10% in the urine.

TOXICITY. (1) Anorexia, nausea, and vomiting, usually mild but occasionally severe. Stomatitis. Diarrhoea (uncommon). (2) Bone marrow depression is dose-limiting. Leucopenia is maximal at 10 to 15 days, and usually returns to normal at 21 days. Thrombocytopenia and anaemia are less common. (3) Sinus tachycardia, T wave flattening ST depression, voltage reduction, and arrhythmia[md]stop or defer treatment. Congestive cardiac failure due to cardiomyopathy[md]stop treatment. (4) Alopecia (common) usually starts at the 3rd or 4th week. Hair usually regrows after treatment is stopped. (5) The drug colours the urine red.

ETOPOSIDE [s7](VP16[nd]213, ''Vepesid') INDICATION. Choriocarcinoma.

DOSE. 100 mg/m['2] on 2 consecutive days as part of the EMA regime (32.38). Infuse the dose in 250 ml of 0.9% saline over 30 minutes. Use the solution within 6 hours of preparation.

ACTION. Inhibitor of DNA repair enzymes. 45% of the dose is excreted in the urine, 30% within 72 hours.

TOXICITY. (1) Anorexia, nausea, and vomiting (common). (2) Leucopenia is dose-limiting, and is maximal 21 days after treatment. (3) Alopecia (almost always). (4) Hypersensitivity to the detergents used in formulation (rare).

MONOAMINE OXIDASE INHIBITORS (''MAOIs') These antimetabolites cause DNA to fragment. As with all MAOIs, drug interactions may be a problem, especially with anaesthetic agents, alcohol, phenothiazines, sympathomimetic drugs, and foods high in tyramine (fish and cheese).

PROCARBAZINE [s7](''Natulen') INDICATIONS. Hodgkin's disease.

ADMINISTRATION. Orally as 50 mg capsules.

DOSE. Orally, 100 mg/m['2], maximum 200 mg, in courses of 14 to 21 days. Decrease the dose with hepatic, renal, or bone marrow dysfunction. Synergistic to CNS depression and ethanol. Procarbazine is an MAOI, so observe the drug interactions above.

ACTION. Rapidly absorbed by mouth. Plasma half-life 10 minutes. Concentrates initially in the liver, enters the CSF readily. Demethylated in the liver to produce CO[,2]. 45 to 70% excreted in the urine as metabolites in the first 24 hours.

TOXICITY. (1) Nausea and vomiting are frequent, and may be dose-limiting. Tolerance usually develops. (2) Leucopenia, thrombocytopenia, and anaemia are not common and may be delayed for several weeks. (3) Peripheral neuropathy is uncommon. Lethargy, drowsiness, and depression. Hyperexcitability, nervousness, and convulsions (uncommon). (4) Myalgia and arthralgia. (5) Dermatitis and hyperpigmetation (uncommon).

DIFFICULTIES [s8]WITH CYTOTOXIC DRUGS MYELOSUPPRESSION The patient's haemoglobin must be above 90 g/l before you start. Transfuse him if necessary. Measure it between courses, and if necessary transfuse him again.

In the instructions which follow ''leucocytes' means cells of the myeloid (granulocyte) series only, that is the total white cells, minus the lymphocytes. Monitor these by doing the total and differential white counts regularly and making the necessary calculation.

He is likely to bleed if his platelet count falls below 20,000[gm]l, and is almost certain to do so if it falls below 10,000[gm]l. You will not be able to give him a platelet rich concentrate, but your laboratory should be able to count his platelets.

The advice which follows is considered by some contributors to be overcautious. It concerns myelosuppression only; for infection see later.

No toxicity leucocytes[mt]4000 [gm]l, platelets [mt]100,000 [gm]l[md]give 100% of the standard dose.

Grade One toxicity leucocytes 2500 to 4000 [gm]l, platelets 80,000 to 100,000 [gm]l[md]give 100% of the standard dose of vincristine and 50% of the other drugs.

Grade Two toxicity leucocytes [lt]2500 [gm]l, platelets [lt]80,000 [gm]l[md]stop all drugs, wait until signs of toxicity Grade One return, and then dose as above.

Drugs are more effective at the full dose, so it is better to delay the next dose (provided the delay is not more than 2 weeks), rather than give 50% of the dose.

CAUTION ! (1) If his leucocyte count is [lt]1000 [gm]l Gram negative septicaemia is a danger. He may be so immunosuppressed that he shows few signs of it. Treat him as if he had septicaemia, as described below. (2) If petechial bleeding occurs and/or his platelet count is [lt]25,000 [gm]l, give 2 units of fresh blood. (3) Watch particularly for bone marrow depression when giving the alkylating agents, also 5-FU, actinomycin D, and adriamycin. It is unlikely with vincristine, methotrexate, or procarbazine.

INFECTION [s7]FOLLOWING CYTOXIC DRUGS He should have been free of infection when you started (see above), so any infections which do appear should be new ones.

If the temperature of a patient on cytotoxic drugs rises over 38[de]C for more than 12 hours, or his leucocyte count falls below 1000 [gm]l, start vigorous antibiotic therapy. Gram-negative septicaemia may be difficult to diagnose in an ill and immunocompromised patient, and is often an opportunistic infection. Stop cytotoxic drugs and don't restart them until his septicaemia is cured.

If you are not able to isolate the organism and give him more specific treatment, give him: (1) Ampicillin and metronidazole (2.9). Or, gentamicin 1.5 mg/kg 8-hourly (expensive) and metronidazole (2.9). (2) If he does not respond, to one of these in 48 hours, give him chloramphenicol and metronidazole. (3) If he still does not respond, and particularly if his blood pressure falls, add a broad-spectrum penicillin to the gentamicin and metronidazole he is already receiving.

Fig. 32-2 THE EFFECT OF VARYING THE INTERVAL between courses of treatment, at the same dosage, on the size of a tumour cell population. The stages in a patient's clinical condition are the same as in the previous figure. In 1, the interval between courses allows his symptoms to return, but is short enough to maintain an essentially steady state. In 1a, the intervals are rather longer, and after the second course treatment fails to relieve his symptoms. In 2, the second course is begun before the return of symptoms, and the 5th is begun when there are no clinical or radiological signs of disease, although the tumour can be shown by special tests. In 3, the intervals between courses are short enough to reduce the tumour cell population considerably. From the Oxford Textbook of Medicine.

OTHER TOXIC EFFECTS [s7]FOLLOWING CYTOXIC DRUGS Beware of impaired renal function with drugs excreted mainly in the urine[md]cyclophosphamide, melphalan, busulphan, and procarbazine. Don't give these if his renal function is much impaired (blood urea [mt]17 mmol/l). If it is between 7 and 17 mmol/l (40 and 100 mg/dl) reduce the dose. Methotrexate is particularly contraindicated if his renal function is impaired. If his consumption of animal protein is low, even a blood urea of 5 to 7 mmol/l suggests renal impairment. Renal toxicity is less likely if you make sure he is well-hydrated, and is drinking 3 or 4 litres a day. If his blood urea is normal, for his diet, after a period of hydration, give normal doses. Otherwise, reduce the dose as follows.

If his consumption of animal protein is low, give [2/3] the dose if his blood urea is 6 to 9 mmol/l. Give half the dose if it is 9 to 17 mmol/l. Give none if it is over 17 mmol/l. If he has been receiving methotrexate, he will need folinic acid rescue to be extended for a further 24 hours.

CAUTION ! (1) If he has impaired renal function, avoid nephrotoxic drugs. (2) Monitor the renal function of all patients, by testing their urine for protein, and measuring their blood urea, at least weekly at first.

If he has liver disease: (1) Don't give drugs which are metabolized in the liver, or give them in a reduced dose (cyclophosphamide and the other alkylating agents). (2) Give drugs which are excreted in the bile in reduced dose (vincristine, adriamycin, 5 FU). (3) Avoid drugs which are metabolized to more active compounds (5FU). They will be less effective, and toxic effects will be more likely. If you have to use them, give them in reduced doses.

If he suffers from serious nausea and vomiting, so that his fluid balance is compromised, delay or reduce the dose, to 50% (nitrogen mustard, 5FU, actinomycin D, and procarbazone). Also give him antiemetics (see above).

If he has stomatitis or diarrhoea delay or reduce the dose (5FU, methotrexate, procarbazine).

If he suffers from the cardiac side-effects of doxorubicin (''Adriamycin'), stop it.

If he has a mild sensory neuropathy, (common with vincristine) there is no need to limit the dose.

If he has a severe neuropathy (not uncommon with vincristine), stop the drug. It usually reverses spontaneously 4 to 6 months after the last dose. If it is not severe, and there are no other useful drugs, consider giving half the dose. A sensory neuropathy (''pins and needles' proceeding to numbness) usually preceeds the motor one. Use his power to dorsiflex his ankle to monitor neuropathy. Any weakness indicates serious neurotoxicity; stop the drug.

If he has convulsions, severe lethargy, or depression (procarbazine), stop the drug.

HIS VEINS ARE NOW HIS MOST PRECIOUS POSsESSION LYMPHOMAS, BLASTOMAS AND SARCOMAS