Category Archives: Medical oncology

Palliative medicine and symptom control

Palliative medicine may be defined as the active, total care of patients whose disease is no longer responsive to curative treatment. The goal of this care is to achieve the best quality of life for patients and their families by controlling physical symptoms and psychological, social and spiritual problems.
Many symptoms suffered by such patients have a complex aetiology in which the physical component may be overlaid by psychosocial issues which require considerable input from a multidisciplinary team of professionals to resolve. Palliative care for the family unit accepts that death is a normal process which will neither be hastened nor postponed, and provides a support system for the family in bereavement. The first step in providing care is often to deal with physical symptoms.

Pain

Pain is the most feared symptom, although only twothirds of cancer patients suffer significant pain throughout the course of their disease. The principles of pain relief are careful assessment and diagnosis of the cause of the pain, use of analgesics according to the analgesic ladder and regular review of the effectiveness of the prescription.

The analgesic ladder, adopted by the Cancer Pain Relief Programme from the World Health Organization, groups drugs into three main classes:

1 Non-opioids, e.g. non-steroidal anti-inflammatory drugs including aspirin and paracetamol
2 Weak opioids, e.g. codeine and dextropropoxyphene or combinations of codeine with paracetamol
3 Strong opioids, e.g. morphine and diamorphine The ladder states that should optimum use of a drug, e.g. paracetamol 1 g 6-hourly, not result in satisfactory pain relief, the prescription should be increased to a weak opioid. If codeine 60 mg 4-hourly is not sufficient to control pain, the patient will require a strong opioid.

Strong opioid drugs

Morphine is the drug of choice and it should be given regularly by mouth. The dose can be tailored to the individual patient’s needs by the addition of ‘as required’ doses; morphine has no ceiling of analgesic effect. A suitable starting dose of morphine is lO mg 4-hourly, with a reduction to 5 mg if the patient is elderly or frail. Patients with renal failure may receive morphine in single doses, but should be carefully observed for the return of pain in order to determine the rate of excretion of morphine metabolites. If the lO mg dose does not last for 4 hours, a 50% increase in the dose should be made, i.e., 10, 15, 20, 30, 45, 60, 90, 120, 180 mg, until satisfactory pain control is achieved.
Once the patient’s 24 hour morphine requirement has been established, the prescription may be converted to a controlled-release preparation, e.g. MST. 20 mg morphine elixir 4-hourly = 120 mg in 24 hours = 60 mg MST twice daily If the patient is unable to take oral medication because of nausea or vomiting, gastrointestinal obstruction or altering levels of consciousness, the opiate should be given rectally or parenterally. In cancer patients in whom longer term treatment is required, continuous subcutaneous infusion is preferred. Diamorphine is used in this situation, because of its greater solubility. By subcutaneous or intramuscular injection diamorphine is about twice as potent as morphine. The conversion from oral morphine may be calculated:

30 mg morphine 4-hourly = 180 mg over 24 hours = 90 mg diamorphine over 24 hours
SIDE-EFFECTS. Constipation caused by opioid drugs is almost universal. The prescription of a stimulant laxative such as co-danthrusate 1-3 capsules at night should be mandatory at the same time as morphine is started. Nausea or vomiting can occur in up to 60% of patients started on morphine. However, for those who have worked up the analgesic ladder and who have no other cause for vomiting, the prescription of an ‘as required’ antiemetic is usually sufficient.

Confusion, nightmares and hallucinations occur in a small percentage of patients. Tolerance to these symptoms does not develop and a change of treatment is usually required.

Other drugs

Not all pains are clinically opioid responsive and in these situations the addition of co-analgesic drugs will result in improved analgesia. Non-steroidal anti-inflammatory drugs are used for bone pain in addition to an analgesic drug. Published studies have most frequently used naproxen (500 mg twice daily) but there is no clear evidence of anyone drug being superior in effect.

Neuropathic pains are generally only marginally improved by opiates. Several classes of drug have been found to be helpful. In cases of constant burning dysaesthesiae, the tricyclic antidepressants, usually amitriptyline, are helpful. Amitriptyline 25 mg at night increasing incrementally to 75-100 mg is usually sufficient (unlike the doses required for mood elevation) and a response, if achieved, can be expected in about 1 week.

nticonvulsant

drugs are useful in the management of lancinating, neuropathic pains. Carbamazepine starting at a dose of 100 mg twice daily is most commonly used, but recent interest has turned to sodium valproate 300 mg twice daily which may cause fewer adverse side-effects. In addition to drugs many other techniques, such as radiotherapy, anaesthesia and neurosurgery, are employed for the treatment of specific pains. Other physical symptoms Anorexia, malaise and weakness are among the most frequently troublesome symptoms. Current research suggests that endogenously produced cytokines, e.g. tumour necrosis factor, are mediators of the anorexia/cachexia syndrome. The approach to therapy at present depends simply on the adequate treatment of associated symptoms such as pain, nausea and psychological factors as well as attention to nutrition and the judicious use of steroids. ausea and vomiting occur in up to two-thirds of cancer patients in the last 2 months of life. The approach to treatment should be similar to that required for pain. It may, however, be more difficult to reach a diagnosis on the cause of the symptom and a somewhat empirical approach to treatment is used. In order to ensure adequate absorption of an antiemetic, parenteral administration for the first 24 hours can be helpful.

Antiemetics are classified according to their pharmacoical effects on neurotransmitters. A gastrokinetic dopamine antagonist such as metoclopramide 10 mg 6-8 hourly would be helpful in vomiting related to upper gastroointestinal tract stasis or to liver metastases. As it increases peristalsis in the upper bowel, metoclopramide should be avoided in cases of intestinal obstruction. Centrally acting antiemetics such as the anticholinergic phenothiazine cyclizine 50 mg 8-hourly or the dopamineantagonist butyrophenone haloperidol 1.5 mg 8-hourly would be the drug of choice in vomiting due to metabolic disturbance or drugs.

Bowel obstruction

Active medical management of malignant bowel obstruction includes the relief of intestinal colic using antispasmodics such as hyoscine butylbromide 60-80 mg daily; treating continuous pain with diamorphine; and vomiting, especially if nausea is a problem, with a centrallyacting emetic, e.g. cyclizine 150 mg daily or haloperidol 5- 10 mg daily.

Patients are allowed to drink and eat low-residue diets which are mostly absorbed in the proximal gastrointestinal tract. It is usually possible, with adequate mouth care, to prevent a sensation of thirst and parenteral fluids are not required. A few patients with intractable vomiting due to a high intestinal block may benefit from nasogastric aspiration.

Respiratory symptoms

Respiratory symptoms cause great distress to patients. Management is based on an accurate diagnosis of the cause and active treatment of all potentially reversible situations. Pleural and pericardial effusions should be drained, infections treated and symptomatic anaemic patients transfused. Sensations of breathlessness and a cycle of respiratory panic may be partially relieved by the prescription of diazepam 2 mg at’ night. Regular doses of short-acting morphine 5-20 mg 4-hourly are also helpful, as there may be morphine receptors within the lung. Nebulization of a morphine solution will reduce the sensation of breathlessness in a proportion of patients. Persistent unproductive cough is a very troublesome symptom. Opiates, codeine, methadone or morphine elixir are helpful as antitussive agents. Nebulized local anaesthetic can be helpful.

Psychological symptoms

Communication with all patients and their families is a basic tenet of care, but is particularly important in the stressful situations which surround fatal disease. Basic skills include allowing time for the patient to talk, using language which is appropriate to the circumstances, being prepared to repeat information and being aware that both patients and their families often receive bad news by blocking or denying it. It is important to remember that it is not always necessary to have an answer or a solution to every problem that is presented, but that considerable support may be given by sympathetic listening. Care of cancer patients should be designed to allow them to spend as much time as possible at home. Effective liaison between the hospital and the primary health care team is essential to ensure total care. It is especially important to avoid misinterpretation of information regarding treatment and prognosis that may be given. Approximately 60% of cancer patients will die in general hospital wards under the care of the physician or surgeon who first diagnosed their tumour. Anxiety or depression will be present in up to half of these patients. Caring for this group of patients requires detailed attention to alleviating physical symptoms and establishing a secure environment for the patient and their family to obtain information and support.

The practice of palliative medicine has traditionally been confined to patients with cancer although some services now cover HIV and AIDS and some of the rapidly fatal neurological diseases. These are all conditions in which the clinical situation is changing rapidly and where difficult symptoms exist. There are undoubtedly patients with non-malignant disease who would benefit from a similar multidisciplinary approach to their care. The patient- orientated principles of palliative medicine can however be usefully applied throughout medical practice.

Further reading

Armitage J (1993) Treatment of non-Hodgkin’s lymphoma. New England Journal of Medicine 328, 1023. Doyle D, Hanks G & MacDonald N (1993) Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press.

Rohatiner AZS & Lister TA (1990) The treatment of acute myelogenous leukaemia. In: Henderson ES & Lister TA (es) Leukaemia. Philadelphia: WB Saunders. Rohatiner AZS & Lister TA (1993) The challenge of acute myelogenous leukaemia. British Journal of Haematology 85, 641-645. Urba WJ & Longo DL (1992) Hodgkin’s disease. New England Journal of Medicine 326, 678. Yarbro JW (ed) Seminars In Oncology. Orlando: Grune & Stratton.

Solid tumours

The treatment of solid tumours involves the combined use of surgery, radiotherapy and chemotherapy. In the earlier stages surgery alone may be curative in many solid tumours, but may fail because of inadequate local excision with residual microscopic disease or because of disseminated micro metastases present at the time of diagnosis. Radiotherapy, similarly, is a local treatment which can often be used after surgery to reduce the chance of local recurrence. Good examples of this are breast cancer, where the use of surgery plus radiotherapy makes it possible to carry out breast-conserving surgery, and in rectal cancer, where local relapse in the pelvis can be reduced by the addition of radiotherapy. In some solid tumours, like early laryngeal cancer, radiotherapy can be used on its own with curative intent. It also has an important role in palliative treatment.

Chemotherapy is systemic treatment which can reach any part of the body with an adequate blood supply and is therefore normally used to treat disseminated cancer. Only a minority of metastatic solid cancers can routinely be cured with chemotherapy. These include testicular cancer, choriocarcinoma and childhood solid tumours. In other advanced solid tumours, chemotherapy may cure a small minority but it is usually given with the intention of prolonging life and relieving symptoms. In this situation it may be used to reduce the volume of the tumour without any realistic hope of eradicating disease. When chemotherapy is used without prospect of cure it is essential that care is taken choosing drugs with the least sideeffects. The development of new less toxic chemotherapeutic drugs and more effective antiemetics have done much to reduce the side-effects of chemotherapy. Chemotherapy is increasingly being used in patients who have had surgical clearance of their primary tumour but are at high risk of relapse from metastatic disease at distant sites. When used in this situation as adjuvant chemotherapy, there is a much greater chance of eradicating the tumour than when chemotherapy is given at the time of clinical relapse.

Breast cancer

Breast cancer is the commonest cancer in women. Although surgical removal of the primary tumour is usually possible, most women will eventually relapse with metastatic disease.

Adjuvant therapy

Adjuvant therapy immediately following surgery has reduced the number of women dying from breast cancer by about 25%. A meta-analysis of all randomized trials of adjuvant therapy in breast cancer has shown conclusively that adjuvant chemotherapy, most commonly cyclophosphamide, methotrexate and 5-fluorouracil, for 6 months reduces the death rate by about 25% in premenopausal node-positive women. Adjuvant tamoxifen given for 2-5 years reduces death from breast cancer by a similar amount in postmenopausal patients. Trials to improve these results further are in progress.

Advanced disease

Patients with established metastatic disease are treated with hormonal therapy or chemotherapy. Women who have high levels of oestrogen receptors in their tumour have a greater chance of responding to hormonal treatments. In addition certain clinical features can predict the likelihood of responding to hormonal manipulations.

1 More likely to respond to hormonal treatment
(a) Receptor positive
(b) Long interval from initial surgery to time of relapse
(c) Metastatic disease in bone and soft tissue

2 Less likely to respond to hormonal treatments
(a) Receptor negative
(b) Short interval from initial surgery to relapse
(c) Liver metastases or lymphangitis carcinomatosa

Endocrine therapy is usually tried first in those patients who have characteristics suggesting they are likely to respond. Useful remissions can be obtained for years and many elderly patients may live a normal life expectancy despite still having residual breast cancer. A range of hormonal manipulations are available:

1 Premenopausal
(a) Cessation of ovarian function
(i) Oophorectomy
(ii) Radiation-induced ovarian ablation
(iii) LHRH analogue with down-regulation of the pituitary
(b) Anti-oestrogen-tamoxifen
(c) Progesterone

2 Postmenopausal
(a) Tamoxifen
(b) Progesterone
(c) Aromatase inhibitors, e.g. aminoglutethamide

In patients who are unlikely to respond to hormonal treatment or who fail therapy with hormones, chemotherapy is used. If chosen carefully chemotherapy can provide good quality palliation and prolongation of life. The most common regimens used include:

• CMF (cyclophosphamide, methotrexate, 5-fluorouracil)
• MMM (mitozantrone, methotrexate and mitomycin C
• Doxorubicin and cyclophosphamide
The first two regimens are often very well tolerated and cause little in the way of nausea and vomiting and do not usually cause hair loss. Single agent mitozantrone is often used in elderly unfit patients and is usually well tolerated.

Lung cancer

This is the commonest cancer in males, and second commonest cancer in females after breast cancer. It is also the most preventable cancer as over 90% is directly related to cigarette smoking. For practical purposes lung cancer can be divided into small-cell lung cancer, comprising about 20%, and non-small-cell lung cancer, comprising 80%. In non-small-cell lung cancer surgery should be considered in all cases although only one-quarter of patients will be operable and only one-quarter of them will be cured. Radiotherapy may provide useful palliation in inoperable patients and very good symptom relief in metastatic disease. Chemotherapy is still experimental in non-small-cell lung cancer and its role is not yet established. In small-cell lung cancer the disease has almost always disseminated by the time of diagnosis and surgery is thus inappropriate. As opposed to non-small-celliung cancer, this tumour is very chemosensitive and radiosensitive and the majority of patients will respond to combination chemotherapy (e.g. mitomycin, ifosfamide and cisplatin) with good relief of symptoms and modest prolongation of life. A small proportion of limited small-cell lung cancer patients will be cured. In patients with extensive disease, who are incurable, single agent etoposide orally or intravenously is a possible alternative to combination chemotherapy. As in non-small-cell lung cancer, radiotherapy can provide very useful palliative relief.

Gastrointestinal cancer

urgery is the primary treatment for gastrointestinal cancer with radiotherapy sometimes being used after surgery o prevent local relapse. Chemotherapy is playing an increasingly important role.

OESOPHAGEAL CANCER

In early-stage squamous cell carcinoma of the oesophagus surgery is the treatment of choice. In patients who are imuperable radiotherapy is given as primary treatment. More recently it has been shown that chemotherapy, comprising 5-fluorouracil and cisplatin, given concurdy rently with radiotherapy improves the cure rate and is now part of standard therapy.

STRIC CANCER AND COLONIC CANCER

Adjuvant therapy

Adjuvant therapy has not yet been shown to be useful in ‘gastric cancer. In contrast, in Dukes’ Band C colon canthe can the use of adjuvant chemotherapy following surgery has reduced the number of people relapsing and dying with metastatic disease by about one-third.

 Advanced disease

“In advanced metastatic gastric and colonic cancer relativly mild chemotherapy can provide good quality palliation and mprovement in quality and quantity of life in some patients. Chemotherapy is based on 5-fluorouracil and cisplatinum in gastric cancer and 5-fluorouracil and folinic acid in colonic cancer. With the appropriate support these regimens are usually very well tolerated. Ovarian cancer Surgery plays a major role in the treatment of ovarian cancer in all stages. In patients where the disease is confined to the ovary, the surgery can be curative, sometimes without the need for further therapy. In patients with more advanced disease, with spread throughout the pelvis and abdomen, surgery still has a role in improving response and survival from chemotherapy. It has been shown that the response to chemotherapy is much enhanced if the tumour is debulked to leave only small amounts of metastatic disease. The most important drugs used to treat ovarian cancer are cisplatinum and its analogue carboplatin, which is associated with less sideeffects. More recently taxol, from the bark of the Western Yew, has been shown to have substantial activity in carcinoma of the ovary.

Testicular cancer

This is the commonest cancer in young men 15-35 but comprises only 1-2% of all cancers. There are two histological types, seminomas and teratomas.

Seminomas

Seminomas are the least common of these tumours and are very radiosensitive. These can almost always be cured with surgery and radiotherapy to the para-aortic lymph nodes. When there is more widespread disease chemotherapy cures the majority of patients.

Teratomas

This disease often presents with para-aortic and pulmonary metastases. It is very rapidly growing and most patients have a raised o-fetoprotein or 13 human chorionic gonadotrophin (I3-HCG) in the peripheral blood which can be used as tumour markers to follow the response of the disease to treatment. Chemotherapy is the treatment of choice once the disease has spread and radiotherapy has very little role. The great majority of patients can be cured with chemotherapy. The major drugs used include cisplatinum, etoposide, bleomycin and ifosfamide.Management of patients with cancer of an unknown primary site Approximately 5% of all cancers present with no obvious primary site. The aim of investigation and searching for a primary is to identify turn ours that are likely to respond to treatment, and to be able to provide the most appropriate palliative care. It is also important to avoid expensive and unnecessary diagnostic procedures. The most important initial distinction is between well-differentiated and poorly differentiated carcinomas because a subset of poorly differentiated carcinomas may be extremely responsive to chemotherapy and may occasionally be cured.

Well-differentiated adenocarcinoma

The most important primaries to exclude are those that respond well to the treatment. In females breast cancer should always be considered especially if they have axillary lymphadenopathy. Even in the absence of a clinically palpable mass in the breast mammography will sometimes detect an unsuspected primary.
Ovarian cancer and thyroid cancer may also respond well to therapy and should be excluded. In men prostatic carcinoma and thyroid cancer similarly should always be considered.
With improvements in the palliative chemotherapy of advanced gastric and colonic carcinoma, younger fitter patients should also be considered for investigations of the upper and lower gastrointestinal tract to exclude these tumours.

Poorly differentiated carcinomas

In addition to the above investigations, in patients with poorly differentiated carcinomas detailed immunoperoxidase tumour staining is very important as a subgroup of these patients will turn out to have lymphoma, germ cell tumours or neuroendocrine tumours which may all be very responsive to chemotherapy.
Patients under the age of 50, particularly those with peripheral lymphadenopathy or lymph nodes in the mediastinum and retroperitoneum, may have highly responsive tumours that respond well to teratoma-type cisplatin-based chemotherapy. There are a high proportion of complete responders and a minority will achieve long-term remission.

Waldenstrom’s macroglobulinaemia

An illness most often seen in elderly men, the clinical features may be more like those oflymphoma, i.e. peripherallymph node enlargement and symptoms due to bone marrow infiltration, or symptoms of hyperviscosity may predominate.

CLINICAL FEATURES

• General malaise and weight loss
• Lymph node enlargement
• Symptoms of hyperviscosity (headaches, visual disturbance)
• Symptoms of anaemia
• A bleeding tendency

INVESTIGATION

BLOOD COUNT:
Hb normal or low
WBC normal or low
Platelets normal or low
ESR usually raised
BLOOD FILM usually shows rouleaux formation
BONEMARROWASPIRATEusually shows infiltration with Iymphoplasmacytoid cells
PROTEIN ELECTROPHORESIS shows an IgM paraprotem

TREATMENT

Alkylating agents and, in younger patients, more intensive doxorubicin-containing regimens produce meaningful responses but recurrence is inevitable. In patients in whom hyperviscosity is the main problem, regular plasmapheresis can be helpful. Death results from progressive bone marrow infiltration and infection.

Monoclonal gammopathy of undetermined significance (MGUS)

This is characteristically seen in older people; a paraprotein is found in the blood but the level is low «2g litre “). Patients may be quite asymptomatic and the paraprotein detected as a result of investigations for some quite different reason. The blood count is usually normal and there is no renal impairment or bone destruction. In such patients, no specific treatment is required but they should be followed up regularly in case they later develop lymphoma or myeloma.

The paraproteinaemias

Multiple myeloma

Myeloma is part of a spectrum of diseases characterized by the presence of a paraprotein in the serum that can be demonstrated as a monoclonal, dark-staining band on protein electrophoresis. The paraprotein is produced by abnormal, proliferating plasma cells that produce, most often, IgG or IgA and rarely IgD. The paraproteinaemia may be associated with excretion of light chains in the urine, which are either K or A; the excess light chains have for many years been known as Bence-lones protein.

CLINICAL FEATURES

Myeloma is a disease of the elderly, the median age at presentation being 60 years. It is a complex illness which represents the interrelationship between:

BONE DESTRUCTION causing fractures, vertebral collapse (which can cause spinal cord compression) and hypercalcaemia.
BONE MARROW INFILTRATION resulting in anaemia, neutropenia and thrombocytopenia, together with production of an abnormal protein which may (rarely) result in symptoms of hyperviscosity.
RENAL IMPAIRMENT due to a complex combination of factors, i.e. deposition of light chains, hypercalcaemia, hyperuricaemia and, usually in patients who have had the disease for some time, deposition of amyloid. All of this is further complicated by a reduction in the normal immunoglobulin levels contributing to the tendency for patients with myeloma to have recurrent infections.

PROGNOSIS

Severe anaemia and renal failure at presentation used to be the two main factors associated with a very poor prognosis, with 50% of patients dying within 9 months. The availability of renal dialysis has reduced the impact of renal failure. In patients without these features at presentation, the median survival with treatment is of the order of 2 years.

SYMPTOMS

• Bone pain, most commonly backache due to vertebral involvement
• Symptoms of anaemia
• Recurrent infections
• Symptoms of renal failure
• Symptoms of hypercalcaemia
• Rarely, symptoms of hyperviscosity and bleeding due to thrombocytopenia

INVESTIGATIONS

FULL BLOOD COUNT:
Hb normal or low
WCC normal or low
Platelets normal or low
ESR almost always high
BLOOD FILM – there may be rouleaux formation as a consequence of the paraprotein
UREA AND ELECTROLYTES – there may be evidence of renal failure
SERUM CALCIUM – normal or raised
SERUM ALKALINE PHOSPHATASE – usually normal
TOTAL PROTEIN – normal or raised
SERUM ALBUMIN – normal or low
PROTEIN ELECTROPHORESIS characteristically shows a monoclonal band
URIC ACID – normal or raised
SKELETAL SURVEY – characteristic lytic lesions, most easily seen in the skull
URINE – for assessment of light chain excretion
BONE MARROW ASPIRATE – shows characteristic infiltration by plasma cells

Myeloma affecting the skull.

Myeloma affecting the skull.

TREATMENT

General

Bone pain can be helped by radiotherapy. Pathological fractures may be prevented by prompt orthopaedic surgery with pinning of lytic bone lesions seen on the skeletal survey. Renal impairment requires urgent attention and patients may need to be considered for long-term peritoaeal dialysis or haemodialysis. Renal impairment is often a consequence of hypercalcaemia which requires correction with bisphosphonates (disodium etidronate:
i.v. infusion 7.5 mg kg:’ for 3 days) or hydration and systemic steroids if bisphosphonates are not available. Anaemia should be corrected and infection treated. Patients with spinal cord compression known to be due to myeloma are treated with dexamethasone, followed by radiotherapy to the lesion delineated by a myelogram. Hyperviscosity is treated by plasmapheresis, together with systemic therapy.

Multiple myeloma showing replacement

Multiple myeloma showing replacement

Specific

The use of alkylating agents, e.g. melphalan or cyclophosphamide, given in conjunction with prednisolone has increased the survival from 7 months to 2.5 years. Recently, more intensive doxorubicin-containing regimens have been used, and in selected patients high-dose melphalan with allogeneic or autologous BMT or PBPC rescue have been tried. Adjuvant IFN therapy following both standard chemotherapy and very intensive treatment involving allogeneic or autologous BMT is being evaluated.

Myeloablative therapy with bone marrow transplantation

High doses of chemotherapy, such as cyclophosphamide, and radiation both kill cells indiscriminately; myelosuppression is therefore the main dose-limiting toxicity. Thus, without a ‘transplant’ the person would die of bone marrow failure. The indications for this type of treatment are shown

A child with Burkitt, lymphoma

A child with Burkitt, lymphoma

Allogeneic BMT

The donor is usually an HLA-identical brother or sister. The patient (recipient) receives the myeloablative therapy (drugs or drugs plus total body irradiation [TBI]), over a period of several days. The donor supplies approximately 1 litre of bone marrow, aspirated from the posterior iliac crests, which is then given intravenously to the recipient, together with immunosuppressive drugs (e.g. steroids, cyclosporin) to prevent rejection and graft-versus- host disease (GVHD). The patient’s blood count usually recovers within 3-4 weeks.
Allogeneic BMT has a mortality of 25-40%, depending mainly on the person’s age; the main causes of death are infection (bacterial, fungal or viral, cytomegalovirus pneumonitis being the greatest problem) and GVHD. The latter is a syndrome that can occur to varying degrees, in which mature T lymphocytes in the donor marrow infiltrate the skin, gut and liver. Acute GVHD occurs in the first 3 months but may also run a chronic course. Patients who develop GVHD have a lower incidence of recurrent leukaemia than those who do not, e.g. the recipients of syngeneic (twin) transplants. Thus, not only does the ‘marrow ablative’ chemoradiotherapy have an antileukaemic effect, but T cells within the donor marrow appear to have an immunological role, the ‘graft vs. leukaemia’ effect, which itself correlates with the development of GVHD.

Possible indications for the use of myeloablative therapy.

Possible indications for the use of myeloablative therapy.

The use of allogeneic transplantation is primarily limited by donor availability; using a ‘matched unrelated donor’ increases the likelihood of GVHD, which, as mentioned above, is the major cause of mortality and longterm morbidity (chronic GVHD). T-cell depletion of the donor marrow has been attempted but this also removes the putative ‘graft vs. leukaemia’ effect, resulting in an increased risk of recurrence.

Autologous B M T

Using the patient’s own bone marrow is limited by the potential risk of reinfusing malignant cells. A remission is first induced; 1 litre of marrow is then aspirated from the patient’s iliac crests under general anaesthetic and (usually) cryopreserved. The myeloablative therapy is given and the thawed marrow reinfused intravenously, as with an allogeneic transplant. The time to blood count recovery after an autograft is usually somewhat longer than after an allograft. Methods to remove malignant cells, as well as methods to induce a ‘graft vs. leukaemia’ effect, are currently being investigated. The mortality is considerably lower than with allogeneic BMT (5-10%), GVHD not being a problem. Bacterial and fungal infection are the greatest risk; viral and fungal infections can continue to be a problem for up to 1 year afterwards due to a reversal of the normal T helper: suppressor cell ratio.

The use of peripheral blood

progenitor cells (PBPC) instead of autologous bone marrow to support myeloablative therapy It is possible, by using chemotherapy for ablation followed by the growth factor G-CSF (see p. 360), to stimulate haemopoietic progenitor cells in the marrow to proliferate, so that they can be collected from the peripheral blood. PBPC are increasingly being used instead of autologous bone marrow since, because they are more differentiated cells, the time to recovery of the blood count is only 2-3 weeks, with obvious advantages in both human and economic terms. PBPC have predominantly been used in patients with HD and NHL in an experimental setting.

Non-Hodgkin’s lymphoma (NHL)

The term non-Hodgkin’s lymphoma encompasses many different histological subtypes. The basic subdivision into high and low grade (Kiel classification) reflects the rate at which the cells are dividing. Ironically, high-grade lymphomas (those in which the cells are dividing quickly) are potentially curable, whereas low-grade lymphomas are generally considered to be incurable with conventional therapy, although patients may live for a number of years and respond to treatment several times. A further subdivision is made on the basis of B- or T-cell origin. Most NHLs are of B-cell phenotype although T-cell tumours are increasingly being recognized. Several different histological groupings have been suggested; the two most widely used at present are the Kiel classification and the ‘Working Formulation’. The latter (which looks much simpler) is not really a histological classification but an attempt to group together diseases which behave in a relatively similar way, to allow comparison between treatment results.

CLINICAL FEATURES

Most patients present with peripheral lymph node enlargement, with or without systemic symptoms. Patients with low-grade lymphoma often have bone marrow infiltration and may have symptoms of anaemia, recurrent infections or bleeding. In addition to peripheral lymphadenopathy, NHLs frequently also involve mediastinal, intra-abdominal and pelvic lymph nodes with resulting symptoms. In contrast, they may involve only an extranodal site, e.g. part of the gastrointestinal tract  24.

INVESTIGATIONS

FULL BLOOD COUNT AND ESR – anaemia; an elevated wee or thrombocytopenia would be suggestive of bone marrow infiltration.
UREA AND ELECTROLYTES – patients may, for example, have renal impairment as a consequence of ureteric obstruction, secondary to intra-abdominal or pelvic lymph node enlargement.
LIVER BIOCHEMISTRY may be abnormal if there is hepatic involvement.
CHEST X-RAY. CT SCANS of chest, abdomen and pelvis.
BONE MARROW ASPIRATE AND TREPHINE BIOPSY.
LYMPH NODE BIOPSY (or Trucut needle biopsy in the case of surgically inaccessible nodes) .

TREATMENT

Treatment will depend on the extent and distribution of disease as well as on histological subtype. Patients with stage I disease can be cured with radiotherapy alone (or radiotherapy plus chemotherapy); those with more extensive involvement require systemic therapy.

Updated Kiel classification of non-Hodgkin's lymphomas.

Updated Kiel classification of non-Hodgkin’s lymphomas.

Working Formulation for non-Hodgkin's lymphoma.

Working Formulation for non-Hodgkin’s
lymphoma.

Low-grade lymphomas

Follicular lymphoma

Repeated remissions can usually be achieved with relatively simple treatment, e.g. the allcylating agent chlorambucil. More intensive treatment has thus far not been shown to improve survival. The response rate at presentation, first and second recurrence is approximately 75%, with a median survival of 9 years. With such conventional therapy, the disease remains incurable, and new approaches such as IFN and the use of myeloablative therapy with allogeneic or autologous BMT are therefore being investigated. Low-grade B-cell diffuse lymphomas (generally either lymphoplasmacytoid or centrocytic) The majority of patients present with advanced disease, the bone marrow frequently being involved. In the small proportion of patients who present with localized disease, the site may be extranodal, most frequently the gastrointestinal tract. The prognosis for patients with low-grade B-cell diffuse lymphoma is worse than that of patients with equivalent stage follicular lymphoma, with a median survival of 3.5 years, fewer than 20% surviving more than 5 years.

Low-grade T-cell lymphoma

These tumours are less common than their B-cell counterparts and are part of a spectrum of disease known as ‘peripheral T-cell lymphomas’. Patients present with enlargement of a peripheral lymph node which, on biopsy and immunophenotyping, is found to be of T-cell origin. Remissions can be achieved with relatively simple treatment, e.g. chlorambucil, but are usually short-lived and therefore more intensive treatment is generally used. However, with current conventional treatment, recurrence is virtually inevitable.

High-grade lymphomas

High-grade lymphomas are more commonly of B-cell, rather than T-cell, origin. Some patients with localized (stage I disease) can be cured with local radiotherapy with or without chemotherapy, or chemotherapy alone. However, the majority present with more advanced disease, chemotherapy being usually given with curative intent. Achievement of a CR is a prerequisite for cure.

TREATMENT

Treatment usually comprises an anthracycline, e.g. doxorubicin given with cyclophosphamide, vincristine (oncovin) and prednisolone (CHOP). Variations on a theme of CHOP have since been tried but thus far none has been shown to be definitively superior in terms of survival. Three factors correlate with survival: advanced disease (stage III and IV), a high serum lactate dehydrogenase (LDH) and poor performance status (an estimate of the person’s general state of health) are all associated with a poor prognosis.
With modern combination chemotherapy, 60-70% of patients respond to treatment and about one-third overall are cured. The treatment is inevitably myelosuppressive and therefore, particularly in older patients, the main problem is potentially fatal infection as a consequence of neutropenia. Recurrent high-grade lymphoma has a grave prognosis. However, a proportion of patients who respond to further chemotherapy at recurrence can still be cured with myeloablative therapy supported by autologous BMT or peripheral blood progenitor cells.

Burkitt’s lymphoma

Burkitt’s lymphoma was first described by Dennis Burkitt in children in West Africa who presented with a specific syndrome comprising a lesion in the jaw, extranodal abdominal involvement and ovarian tumours. This specific type of lymphoma is found in areas of Africa where there is a high incidence of the Epstein Barr virus EBV) and in areas where malaria is common. Most patients have EBV antibodies in the serum. The tumour can be treated with both radiation and chemotherapy and associated with a chromosome change, most commonly.

The lymphomas

Lymphomas represent abnormal proliferations of different parts of the lymphoid system and are currently classified  on the basis of histological appearance into:

• Hodgkin’s disease
• Various subtypes of non-Hodgkin’s lymphoma

Hodgkin’s disease (HD)

With modern treatment (radiotherapy, chemotherapy or BOth), HD is now a potentially curable illness. The choice of treatment is determined largely by the distribution and extent of disease (i.e. the ‘stage’)

Staging classification of Hodgkin's disease

Staging classification of Hodgkin’s disease

CLINICAL FEATURES

Symptoms

• Painless lymph node enlargement (most often the cervical nodes). The majority of patients present with lymph node enlargement; the latter however in itself does not imply the diagnosis oflymphoma. The differential diagnosis of cervical lymph node enlargement is shown.
• ‘B’ symptoms: fever, drenching night sweats, weight loss of> 10% body weight.
• Other constitutional symptoms, e.g. pruritus, fatigue, anorexia and alcohol-induced pain at the site of enlarged lymph nodes.
• Symptoms due to involvement of other organs, e.g. lung, bone, liver.

Signs

• Peripheral lymph node enlargement
• Enlargement of the spleen/liver depending on stage

INVESTIGATIONS

BLOOD COUNT: normal or a normochromic, normocytic anaemia

Differential diagnosis of cervical lymph node enlargement.

Differential diagnosis of cervical lymph node enlargement.

Histological appearance of Hodgkin's disease

Histological appearance of Hodgkin’s disease

ERYTHROCYTE SEDIMENTATION RATE (ESR) USUally raised
LIVER BIOCHEMISTRY – abnormal if liver involved
URIC ACID – normal or raised
CHEST X-RAY – may show mediastinal (with or without lung involvement)
CT SCANS – may show involvement of intrathoracic, abdominal or pelvic lymph nodes
BONE MARROW ASPIRATE AND TREPHINE BIOPSY – may show involvement in patients with advanced disease
LYMPH NODE BIOPSY – required for a definitive diagnosis. Classically, Sternberg-Reed cells  are present together with a characteristic admixture of lymphocytes and histiocytes A typical chest X-ray and CT scan of the same patient are shown.

‘STAGING’

The ‘stage’ of disease, i.e. its extent and distribution, will influence the choice of treatment. There is currently debate as to the need for a ‘staging laparotomy’. The aim of the latter is to biopsy any intra-abdominal lymph nodes which appear enlarged and to perform a splenectomy, the spleen being notoriously difficult to demonstrate as being involved with lymphoma by any radiological technique.
The original Ann Arbor staging classification has been modified (see Table 7.12) to take into account the volume of lymph node masses and the use of modern imaging techniques such as CT scanning. The long-term outcome is closely related to stage.

(a) A chest X-ray and (b) a (T scan of a large mediastinal mass

(a) A chest X-ray and (b) a (T scan of a large mediastinal mass

TREATMENT

Treatment is virtually always given with curative intent and consists of radiotherapy, cyclical combination chemotherapy or both. The choice of treatment will depend predominantly on:
• Stage
• Involved sites
• ‘Bulk’ of lymph node masses
• Presence or absence of B symptoms

Stages IA and lIA

The majority of patients are treated with radiotherapy, provided that all the involved sites can be encompassed within a radiation field. Patients with a large ‘bulky’ mediastinal mass are usually given chemotherapy initially, since otherwise too much lung tissue would be irradiated with potential long-term lung damage. Such patients receive radiotherapy subsequently.

Stages lIB, IIWB, IVAlB

Most patients are treated with chemotherapy in the first instance, with subsequent radiotherapy to sites of ‘bulky’ disease to prevent local recurrence. (In practice, the latter applies mainly to patients with a large mediastinal mass at presentation as above.) The first effective chemotherapy for HD, a regimen comprising mustine, vincristine (oncovin), procarbazine and prednisolone (MOPP) was used until recently, when the combination ABVD (doxorubicin (previously known as Adriamycin), bleomycin, vinblastine and dacarbazine) was developed and added to MOPP, as alternating cycles.

Survival in Hodgkin's disease related to stage at presentation.

Survival in Hodgkin’s disease related to stage at
presentation.

Apart from the immediate side-effects of nausea, vomiting and hair loss, potential long-term side-effects, namely infertility and second malignancy, have caused concern. Current ‘MOPP-EVA’ so-called ‘HYBRID’ treatment programmes have therefore been designed to minimize these long-term effects, by reducing the amount of alkylating agent and adding drugs such as doxorubicin. The emphasis has been on using alternating, non-crossresistant drug combinations, given as cycles of treatment, e.g. every 4 weeks for about 6 months. Treatment can usually be given on an outpatient basis and most people are able to lead a normal life. The prognosis correlates closely with stage. However, survival of patients in whom recurrence occurs is inferior to that of those who remain in continuous remission.

RESISTANT DISEASE AND RECURRENCE

Failure to achieve an initial complete or almost complete response and early recurrence (within 1 year of remission being achieved) are both associated with a very poor prognosis. Similarly, patients who develop recurrent HD more than once will almost certainly die of HD eventually.
Hence, the use of myeloablative therapy with autologous bone marrow or peripheral blood progenitor cell support in these situations (see p.371). In contrast, patients who develop recurrent HD, e.g, within the abdomen, a few years after receiving radiotherapy for localized, supradiaphragmatic disease can be given combination chemotherapy, still with curative intent.

Survival courses of patients with Hodgkin's disease.

Survival courses of patients with Hodgkin’s disease.

TREATMENT AT RECURRENCE

Recurrence of ALL occurs most frequently in the bone marrow and is associated with a worse prognosis if it occurs during maintenance therapy. CNS recurrence, detected by the presence of leukaemic blast cells in the cerebrospinal fluid, is now less frequent since the regular use of CNS prophylaxis. Treatment comprises intrathecal drugs plus radiotherapy to the meninges surrounding the brain and spinal cord, followed by reinduction chemotherapy if the recurrence is limited to the CNS. Unfortunately, it often occurs in association with bone marrow recurrence, when induction of a second CR followed by myeloablative therapy with allogeneic or autologous BMT is the only potentially curative option.
Testicular recurrence is usually manifest by painless enlargement of one or both testicles. It can occur in isolation, shortly before, or concurrent with bone marrow recurrence. Treatment involves radiotherapy to the testes, followed by reinduction chemotherapy (for isolated testicular recurrence) or, if the marrow is also involved, the latter followed by myeloablative therapy with allogeneic or autologous BMT, provided a second remission can be achieved.

Chronic myeloid leukaemia

The majority of patients die within 5 years of diagnosis. The illness has a progressive clinical course which starts with a chronic phase of 3-4 years’ duration. This evolves into an accelerated phase which may be manifest by fever, weight loss, increasing splenomegaly, anaemia, thrombocythaemia and refractory leukocytosis with increasing numbers of blast cells. The duration of the accelerated phase is variable though blastic transformation usually supervenes within a few months. Unlike de novo acute leukaemia, the blastic phase of CML is characterized by the development of acute leukaemia which may be myeloid (60%), lymphoid (30%) or erythroid (10%) in origin. The blastic phase is generally refractory to treatment, the median survival being less than 6 months. Less frequently, CML transforms into myelofibrosis, death ensuing from bone marrow failure.

CLINICAL FEATURES

ymptoms

These are usually of insidious onset:
• Anaemia
• Sweating at night, fever, weight loss
• Abdominal discomfort due to splenic enlargement

Signs

• Anaemia
• plenomegaly

Philadelphia chromosome.

Philadelphia chromosome.

INVESTIGATION

BLOOD COUNT:
Hb low or normal.
WCC raised with characteristically the whole spectrum of myeloid precursors, including a few blast cells.
Platelet count low, normal or raised.
BONE MARROW ASPIRATE shows a hypercellular marrow with an increase in myeloid precursors. On cytogenetic analysis, the Ph chromosome t(9;22) is present in most patients.

TREATMENT

CONVENTIONAL TREATMENT – the aim is to relieve symptoms, keep the WCC under control and reduce the size of the spleen. Most patients are currently treated with hydroxyurea (or busulphan) given orally with allopurinol to prevent hyperuricaemia.
MYELOABLATIVE THERAPY SUPPORTED BY ALLOGENEIC BMT can be curative but the approach is limited by donor availability, the age of the patient, and the morbidity and mortality of the transplant procedure .
EXPERIMENTAL TREATMENT – trials involving IFN are currently in progress to determine whether this drug is any ‘better’ than the conventional treatment.
Chronic lymphocytic leukaemia

CLL is an incurable disease of older people, characterized by an uncontrolled proliferation and accumulation of mature B lymphocytes (although T-cell CLL does occur). The symptoms are a consequence of bone marrow failure, i.e. anaemia, infection and bleeding. A proportion of patients remain asymptomatic and never need any treatment, dying of an unrelated cause; in the remainder, the disease can usually be kept under control for 9-10 years, infection being the predominant cause of death.

RAI staging classification of chronic lymphoblastic leukaemia.

RAI staging classification of chronic lymphoblastic
leukaemia.

CLINICAL FEATURES

As mentioned above, some patients may be asymptomatic, the diagnosis being a chance finding on the basis of a blood count done for a quite different reason.

Symptoms

• Symptoms of anaemia ma develop rapidly in the context of haemolysis, which is usually precipitated by infection.
• Recurrent infections are due to neutropenia with or without reduced immunoglobulin levels.
• Painless lymph node enlargement.

Signs

Any combination of:
• Signs of anaemia
• Lymph node enlargement
• Enlarged liver and/or spleen

INVESTIGATIONS

BLOOD COUNT:
Hb low or normal WCC >15 x 109/litre of which at least 40% are lymphocytes.

Platelets low or normal

SERUM IMMUNOGLOBULINS low or normal COOMBS’ TEST positive if haemolysis is occurring Two different staging classifications are in use. They are useful because they correlate closely with prognosis. The median survival of patients with stage 0 (or stage A) CLL is 8 years as compared with 2 years for patients presenting with stages III or IV (or stage C) disease

Binet staging classification of chronic lymphoblastic leukaemia.

Binet staging classification of chronic lymphoblastic leukaemia.

TREATMENT

The disease may remain stable for several years. There is no advantage to starting treatment before there is a clinical indication, e.g. anaemia, recurrent infections, bleeding, ‘bulky’ lymphadenopathy or increasing splenomegaly. Chlorambucil is most often used. The purine analogues, fludarabine and 2-cWoroadenosine acetate, are being evaluated, interest lying in the fact that CR can be achieved although such remissions are rarely durable.

Hairy cell leukaemia (HCL)

A rare disease of late middle age, HCL represents again a clonal proliferation of abnormal B (or very rarely, T) cells which, as in CLL, accumulate in the bone marrow and spleen. The bizarre name relates to the appearance of the cells on a blood film where they have an irregular outline due to the presence of filament-like cytoplasmic projections.

CLINICAL FEATURES

Symptoms

• Symptoms of anaemia
• Recurrent infections
• Abdominal discomfort due to splenic enlargement

Signs

• Signs of anaemia
• Palpable spleen

INVESTIGATIONS

BLOOD COUNT:
Hb usually low
WCC usually low (or raised with circulating ‘hairy cells’)

Platelets usually low

BONE MARROW shows increased cellularity with characteristic infiltration by ‘hairy’ cells

TREATMENT

The use of IFN  has revolutionized the management of patients with this illness. Although CR is rarely achieved, in the majority of cases the blood count reverts to normal obviating the need for regular blood transfusions and admissions to hospital with life-threatening infections. Such remissions are temporary but treatment can be given repeatedly. Two new drugs, deoxycoformycin and 2-chloroadenosine acetate (2- CDA), are of interest because CR is achieved much more frequently than with IFN.

Prolymphocytic leukaemia

Another rare B-cell disorder, often mistaken for CLL, prolymphocytic leukaemia, is characterized by bone marrow failure (anaemia, neutropenia and thrombocytopenia) and, as in HCL, splenomegaly. Treatment is generally with chlorambucil as for CLL, though splenectomy may be indicated and, again, fludarabine is being evaluated.

TREATMENT AT RECURRENCE

Second remissions are more difficult to achieve and are virtually never durable. The decision to treat a person at the time of recurrence will therefore (even more than at presentation) depend on the patient’s overall situation and his/her wishes. In younger patients, provided a second remission can be achieved, cure is still a possibility for a proportion, with the use of myeloablative therapy with allogeneic/autologous BMT. In older patients, the options lie between further intensive combination chemotherapy and keeping the person as well as possible for as long as possible, with supportive measures such as blood transfusions for anaemia, antibiotics for infection and the judicious use of palliative oral drugs that help to lower the circulating blast cell count.

Acute promyelocytic leukaemia

APML has a specific association with disseminated intravascular coagulation (DIC) . Patients may present with severe bleeding and this tends to increase when treatment is started as the leukaemic blast cells break down, leading to further consumption of clotting factors and platelets. Treatment consists of regular, twice daily, platelet transfusions and maintenance of the fibrinogen level with fresh frozen plasma. Provided remission can be achieved, patients with APML (which is associated with the chromosome translocation t(l5; 17» have a somewhat better prognosis overall than patients with other subtypes of AML. Ensuring that they survive this early period of DIC is therefore critical. It has recently been demonstrated that the use of a differentiating agent, all-trans-retinoic acid (ATRA), given orally can lead to the achievement of CR in some patients with APML. ATRA has a differentiating effect on leukaemic promyelocytes, both in vitro and in vivo. It does not appear to be effective in other subtypes of AML. Unfortunately such remissions do not last and need to be consolidated with conventional chemotherapy. The advantage is that patients receiving ATRA do not usually develop DIC, with a decrease in the risk of fatal haernorrhage.

Acute myelogenous leukaemia-c-overall survival over

Acute myelogenous leukaemia-c-overall survival over

FAB classification of acute lymphoblastic leukaemia.

FAB classification of acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia

Predominantly a disease of children, ALL is also potentially curable. Overall, 90% of children respond to treatment and 50-60% are cured. The results in adults are not as good, with only approximately 30% being cured. ALL is classified on the basis of the morphology of the leukaemic blast cells into subtypes Ll-L3.

There is also an ‘immunological’ classification which is continually evolving as more sophisticated techniques are developed for detecting the B- or T-cell origin of lymphoid cells.

TREATMENT

The principles of treatment are the same as for AML, the aim being to return the bone marrow to normal and the person to a normal state of health. The sequence of treatment is, however, somewhat different because ALL has a propensity for involvement of the central nervous system (CNS); thus treatment also includes prophylactic intrathecal drugs (methotrexate or cytosine arabinoside) with or without prophylactic cranial radiotherapy to the meninges. Most patients also receive oral maintenance therapy for 2-3 years. The sequence of treatment is shown.

Cyclical combination chemotherapy comprising vincristine, prednisolone and an anthracycline such as doxorubicin forms the basis of most treatment regimens. Other drugs such as r.-asparaginase, cyclophosphamide and/or cytosine arabinoside (also known as cytarabine) are also increasingly being used in patients (both adults and children) considered to be at high risk of recurrence.

Treatment regimen for acute lymphoblastic leukaemia. la

Treatment regimen for acute lymphoblastic leukaemia.

Immunological categories of acute lymphoblastic leukaemia.

Immunological categories of acute lymphoblastic leukaemia.

Although a proportion of adult patients are cured with the initial therapy, in the rest the disease recurs and ultimately proves fatal unless secondary remission can be achieved and further treatment involving BMT given, when a further 20-30% of patients will survive long term.

Haematological malignancy

Introduction

Leukaemia, lymphoma and myeloma constitute only a small proportion of all malignant diseases. They share common origins in the myeloproliferative and lymphoproliferative systems but are a heterogeneous group, with a natural history resulting in survival ranging from a few months to several years. Their importance lies in their responsiveness to both chemotherapy and radiotherapy, so that many patients with acute leukaemia, Hodgkin’s disease, and high grade non-Hodgkin’s lymphoma, can now be cured. However, the majority of patients with haematological malignancy still die as a consequence of the illness, it is therefore essential to explain the disease, its treatment and the chance of success to the patient and to the family.

LEUKAEMIA

Leukaemia is rare, with an annual overall incidence of 5 per 100000. Both subtypes of acute leukaemia can occur in all age groups but acute lymphoblastic leukaemia (ALL) is predominantly a disease of childhood, whereas acute myelogenous leukaemia (AML) is most frequently seen in older adults.

AETIOLOGY

In the majority of cases, the aetiology is unknown. Feline leukaemia virus has been shown to cause the disease in cats; there is, however, no evidence for a viral aetiology in humans apart from the association of a specific subtype of T-cell leukaemia, found predominantly in the Southern Island of Japan and the Caribbean, with the retrovirus HTLV-l. However, many people in the endemic areas have antibodies to the virus, implying past infection, but may never develop leukaemia.

Genetic factors

Many patients with acute leukaemia have a chromosomal abnormality. When complete remission (CR) is achieved, the chromosomal translocation/deletion often becomes undetectable, but returns at recurrence. Such a cytogenetic change usually implies a worse prognosis but not always: 99% of patients with acute promyelocytic leukaemia (APML) have the (15;17) translocation; the latter and the t(8;21) translocation in AML  in fact confer a better long-term prognosis once CR has been achieved.

The first non-random chromosomal abnormality to be described was the Ph chromosome which is associated in 95% of cases with chronic myeloid leukaemia (CML). The Ph chromosome is also found in some patients with ALL, the incidence in the latter increasing with age. The translocation is shown schematically. The Ph chromosome is an abnormal chromosome 22, resulting from a reciprocal translocation between part of the long arm of chromosome 22 and chromosome 9. The resulting karyotype is described as t(9;22)(q34;qll). The molecular consequences of the translocation have been defined as follows: the oncogene C-ABL) normally present on chromosome 9 is translocated to chromosome 22, where it comes into juxtaposition with a region of chromosome 22 named the ‘breakpoint cluster region’ (BCR). The translocation thus creates a hybrid transcription unit consisting of the 5′ end of the BCR gene and the C-ABL proto-oncogene. The new gene is capable of being expressed as a chimeric mRNA which has been identified in cells from patients with CML. When translated, this produces a fusion protein that has tyrosine kinase activity and enhanced phosphorylating activity compared to the normal C-ABL protein. The contribution of these molecular events to the disease process is at present unclear. The precise breakpoint differs in CML and Ph-positive ALL, leading to the production of two different tyrosine kinase proteins.

Environmental factors

1 Chemicals, e.g. benzene compounds used in industry.
2 Drugs, e.g. cytotoxic agents such as chlorambucil and procarbazine.
3 Radiation-the evidence for radiation causing leukaemia comes from three sources:
(a) The atomic bombs exploded in Hiroshima and Nagasaki resulted in an increased incidence of both AML and, in particular, CML in people living in surrounding areas. There is therefore concern about the population living round Chernobyl.
(b) In the past, patients with ankylosing spondylitis were treated with radiotherapy, leading to an increased incidence of secondary AML.
(c) A small proportion of patients with Hodgkin’s disease receiving (usually) both chemotherapy and radiotherapy will develop secondary AML. Unlike de novo AML which is potentially curable, AML developing in relation to previous cytotoxic chemotherapy is nearly always resistant to treatment.

CLASSIFICATION

Leukaemia can be divided on the basis of the speed of evolution of the disease into acute or chronic. Each of these is then further subdivided into myeloid or lymphoid, according to the cell type involved, hence the terms:

 • Acute myelogenous leukaemia
• Acute lymphoblastic leukaemia
• Chronic myeloid leukaemia
• Chronic lymphocytic leukaemia

ACUTE LEUKAEMIA (AML and ALL)

CLINICAL FEATURES

The symptoms of acute leukaemia are a consequence of bone marrow failure:
• Symptoms of anaemia, e.g. tiredness, weakness, shortness of breath on exertion
• Repeated infections, e.g. sore throat, pneumonia
• Bruising and/or bleeding
• Occasionally, lymph node enlargement and/or symptoms relating to enlargement of the liver and spleen There may be few or no signs; commonly patients have:
• Signs of anaemia
• Bruises, petechial haemorrhages, purpura, fundal haemorrhages
• Signs of infection
• Sometimes peripheral lymphadenopathy and/or hepatosplenomegaly

INVESTIGATIONS

The definitive diagnosis is made on the peripheral blood film and a bone marrow aspirate. Additional investigations such as cytogenetic analysis and immunophenotyping of the leukaemic blast cells are not mandatory but can be helpful. If the patient has a fever, blood cultures and a chest X-ray are essential.

BLOOD COUNT

A low haemoglobin (Hb).
White cell count (WCC) usually raised, but can be decreased or normal.

Platelets usually reduced.
PERIPHERAL BLOOD FILM shows characteristic leukaemic blast cells.
BONE MARROW ASPIRATE usually shows increased cellularity with a high percentage of abnormal lymphoid or myeloid blast cells.

MANAGEMENT  GENERAL

The decision to treat a patient with curative intent will depend on the person’s age, their general state of health, the point in the course of the illness (presentation or recurrence), and the person’s wishes. The use of intensive combination chemotherapy may, for example, be entirely inappropriate at the time of recurrence in an older person.

The diagnosis, its implications, the treatment options and the likely outcome of such treatment, together with its side-effects, need to be explained to the patient and to the family. People often find it difficult to assimilate all of this information on one occasion; it is therefore essential to give them the opportunity to ask questions, particularly as circumstances change. Before starting treatment, the following need to be considered:

CORRECTION OF ANAEMIA AND THROMBOCYTOPENIA by administration of blood and platelets.
TREATMENT OF INFECTION with intravenous antibiotics.
LEUKAEMIC BLAST CELLS can infiltrate the brain and the lungs resulting in coma and respiratory failure respectively. If the blast cell count in the peripheral blood is very high (>100 x 109/litre) the patient may need leucophoresis (i.e. blood is collected from a vein and centrifuged so as to remove some of the leukaemic cells; the red cells and plasma are then returned to the patient via another vein). Leucophoresis can be life saving; an alternative is to use high doses of the drug hydroxyurea.
ADMINISTRATION OF ALLOPURINOL, a xanthine oxidase inhibitor to treat and prevent hyperuricaemia. In certain types of leukaemia where the rate of cell division is very fast, e.g. B-ALL, T-ALL, patients may develop the ‘tumour lysis’ syndrome when chemotherapy is given. The latter is characterized by hypercalcaemia and high serum levels of phosphate and potassium resulting from a high rate of cellular breakdown. This is a potentially life-threatening situation and difficult to treat once it has happened. It can usually be prevented by making sure that chemotherapy is not given whilst the uric acid level is high, by giving intravenous fluids before starting chemotherapy and monitoring the relevant biochemical parameters at regular intervals. Patients may require haemodialysis to correct the metabolic imbalance. Specific treatment programmes for the different subtypes of leukaemia will be mentioned only briefly since treatment regimens are evolving. Good ‘supportive care’ in terms of antibiotics and blood products is as important as the specific combination of drugs used; patients with acute leukaemia should therefore be treated in specialist centres where the medical and nursing staff are familiar with the management of neutropenia and thrombocytopenia.

Patients need to be informed of what is going on as the situation changes.

Acute myelogenous leukaemia

AML is a potentially curable disease. The aim of treatment is to restore the bone marrow to normal and the patient to a normal state of health, i.e. complete remission (CR). AML is classified on the basis of the morphological appearance of the bone marrow into seven subtypes, FAB M1-M7, which differ depending on the predominant cell type involved.

TREATMENT

Treatment has traditionally been regarded in two parts:
remission/induction and postremission/consolidation therapy. The rationale for going on with treatment beyond the point of CR is based on data from an experimental mouse model (L1210 leukaemia) and from children with ALL in whom it has been calculated that, at the time of presentation, the number of leukaemic blast cells is of the order of 1012 or 1013.At the point of CR, i.e. when there is no morphologically detectable leukaemia, there are still 108 or 109 leukaemic blast cells present. It is therefore not surprising that if no postremission therapy is given, the majority of patients develop recurrent leukaemia.

Remission/induction therapy usually includes an anthracycline drug such as daunorubicin or doxorubicin, given in conjunction with cytosine arabinoside. The first cycle of treatment is given in hospital; the patient needs to stay for about 4 weeks due to the risk of infection and bleeding consequent upon neutropenia and thrombocytopenia. Subsequent cycles of treatment are given as much as possible on an outpatient basis. There is much debate as to the best postremission therapy. Alternatives include:

• Further cycles of chemotherapy which is the same as that given to induce remission
• Chemotherapy different from that given to induce remission
• Myeloablative therapy with allogeneic/autologous bone marrow transplantation (BMT).
With modern combination chemotherapy, approximately -0% of younger people (aged <60 years) would be expected to return to normal health. However, within 1- 3 years, the disease will recur in at least 60% of the latter, the remainder almost certainly having been cured. In general, treatment has become more intensive over the last _0 years with a concomitant improvement in overall suviral. Survival curves for patients treated at St Bartholomew’s Hospital during three consecutive time periods are shown.

Following recurrence, it is possible to give further treatment in an attempt to induce secondary remission but such remissions are rarely durable, hence the use of very intensive treatment involving BMT.

FAB classification of acute myelogenous leukaemia.

FAB classification of acute myelogenous leukaemia.