Malignant disease

Published on 02/03/2015 by admin

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Last modified 02/03/2015

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8 Malignant disease

Approach to the patient with cancer

All efforts should be made to obtain a histological diagnosis of malignancy before anticancer treatment is commenced. A combination of clinical examination, imaging and biochemical tests is subsequently used to assess response to treatment.

Performance status

This is a measurement of a patient’s overall functional status. It helps to predict how a treatment will be tolerated and also response to treatment. Performance status is commonly measured using the Eastern Cooperative Oncology Group scale (Table 8.1) or the Karnofsky scale.

Table 8.1 Eastern Cooperative Oncology Group (ECOG) performance status scale

Status Description
0 Asymptomatic, fully active and able to carry out all pre-disease performance without restrictions
1 Symptomatic, fully ambulatory but restricted in physically strenuous activity, able to carry out performance of light or sedentary nature e.g. light housework, office work
2 Symptomatic, ambulatory and capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours; in bed < 50% of day
3 Symptomatic, capable of only limited self-care, confined to bed or chair > 50% of waking hours, but not bedridden
4 Completely disabled, cannot carry out any self-care. Totally bedridden

Cancer treatment

Treatment may be in the form of surgery, systemic treatment (chemotherapy, hormonal treatment or targeted agents), radiotherapy or a combination of these. Surgery offers the best chance of cure in many cancers. However, this must be balanced against the potential loss of function and cosmesis.

Measuring response to treatment (Box 8.1)

Box 8.1 Definitions of response (RECIST)

• Complete response Complete disappearance of all detectable disease
• Partial response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters
• Stable disease Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
• Progressive disease At least a 20% increase in the sum of diameters of target lesions, or the appearance of new lesions

Principles of radiation treatment

Radiation is delivered to tissues by a variety of methods with the aim of causing cell death. The biological effect is achieved by X-rays causing direct or indirect damage to DNA.

The unit of absorbed dose is the Gray (Gy), which is equivalent to 1 joule absorbed per kilogram (1 J/kg) of absorbing tissue. Radiation dose is described by three factors: total dose in Gy, number of fractions, and duration of treatment (e.g. 50 Gy/25 Gy/5 weeks indicates that the total dose of 50 Gy is being given in 25 doses over 5 weeks) The effect of radiotherapy is also dependent on the volume irradiated and the radiosensitivity of the tumour and surrounding tissues.

Radiotherapy regimes

There are various radiotherapy regimes that can be used with curative or palliative intent, depending on the tumour and stage:

Side-effects are shown in Box 8.3.

Box 8.3 Potential side-effects of radiotherapy

Acute (during and up to 90 days)

• Skin Erythema, hair loss, dry desquamation, moist desquamation
• Gastrointestinal tract Nausea, anorexia, mucositis, oesophagitis, diarrhoea, proctitis
• Genitourinary tract Cystitis, urinary frequency, nocturia, urgency

Late (after 90 days)

• Skin Pigmentation, telangiectasia, atrophy
• Bone Necrosis, sarcoma
• Mouth Xerostomia, osteoradionecrosis
• Bowel Diarrhoea, stenosis, fistula
• Bladder Fibrosis, fistula
• Vagina Stenosis
• Lung Fibrosis
• Heart Pericardial reactions, cardiomyopathy
• CNS Myelopathy
• Reproductive Infertility, premature menopause, impotence

Principles of chemotherapy

Chemotherapy drugs are preferentially toxic to rapidly dividing cells but have a less marked effect on non-proliferating cells. They target cancer cells at various stages of the cell cycle, e.g. ‘phase-specific’ (preference for a given phase) or ‘cycle-specific’ agents.

Chemotherapy drugs are commonly given in combination (Table 8.2); the rationale for this is two-fold. Firstly, if drugs with differing mechanisms of action are used, which act at differing stages of the cell cycle, this can maximize the number and types of cancer cells killed. In addition, some drug combinations may have synergistic effects. Secondly, the simultaneous use of multiple drugs reduces the risk of drug resistance developing and the survival chances of the tumour.

Table 8.2 Some common chemotherapy regimens

Malignancy Regimen Components
Hodgkin’s lymphoma ABVD Doxorubicin, bleomycin, vinblastine, dacarbazine
BEACOPP Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone
Non-Hodgkin’s lymphoma CHOP Cyclophosphamide, hydroxy-doxorubicin, vincristine, prednisolone
Breast cancer FEC 5-FU, epirubicin, cyclophosphamide
FEC-T 5-FU, epirubicin, cyclophosphamide followed by docetaxel
TAC Docetaxel, doxorubicin and cyclophosphamide
Lung cancer PE Cisplatin, etoposide
GC Gemcitabine, carboplatin
Stomach cancer ECF Epirubicin, cisplatin, 5-FU
Colorectal cancer FolFOx Oxaliplatin, 5-FU, folinic acid
OX Oxaliplatin, capecitabine

Administration of chemotherapy drugs

Available chemotherapeutic drugs

Cytotoxic drugs can be classified into the groups listed below according to their mechanism of action and chemistry.

DNA-damaging agents

Antimetabolites. These compounds disrupt nucleic acid synthesis by falsely substituting for purines and pyrimidines, and may combine with vital enzymes required for cell division. Maximal cytotoxicity is seen in the S phase of cell cycle.

Side-effects of treatment

Table 8.3 Antiemetic recommendations

Emeto-genicity On days of chemotherapy Days after chemotherapy
Low No antiemetic required routinely
Metoclopramide 10 mg 3 times daily or domperidone 20 mg 3 times daily if the patient experiences nausea and vomiting
 
Moderate Metoclopramide 20 mg IV oral 3 times daily or domperidone 20 mg oral 3 times daily
Dexamethasone 4–8 mg IV/oral daily
Metoclopramide or domperidone 20 mg 3 times daily for 3 days, then as required
Dexamethasone 4 mg twice daily for 2 days
High Granisetron 1 mg IV/oral 1–2 times daily
Dexamethasone 8–16 mg IV/oral daily (in 1 or 2 divided doses)
Metoclopramide or domperidone 20 mg 3 times daily for 3–5 days, then as required
Dexamethasone 4 mg twice daily for 2–3 days
Granisetron 1 mg twice daily for 2 days

Box 8.5 Managing a febrile neutropenic patient

Principles of high-dose therapy

In chemosensitive tumours, the administration of high doses of chemotherapy maximizes their cytotoxic effect, but their limiting effect is bone marrow toxicity and susceptibility to infections. Haematopoietic stem cells are often infused into the patient to shorten the neutropenic period, which may last 2–3 weeks. The patient is reverse barrier-nursed in isolation, preferably in a negative air pressure-ventilated room.

The source of stem cells may be autologous (from the patient or an identical twin), allogeneic (from a non-identical donor) or umbilical cord blood.

Allogeneic stem cell transplantation

In allogeneic transplantation a donor, ideally with fully matched major HLA antigens, e.g. siblings, acts as the stem cell source. Transplantation is highly toxic and the morbidity and mortality are related to the recipient’s age and the donor’s HLA compatibility. Transplant-related mortality for an HLA sibling-matched allograft is 15–30% but for volunteered unrelated donors can be as high as 45%. The first component of the transplant is myelo-ablative chemotherapy, often combined with total body irradiation (TBI). This has the dual effect of eradicating the malignancy and ablating the patient’s immune system, allowing the graft to ‘take’. A day following the conditioning treatment, the donor stem cells are then infused intravenously. It is thought that engraftment of the donor’s immune system, along with anti-tumour activity (graft versus tumour), is responsible for the increased efficacy of this approach. In order to prevent graft rejection, anti-T-cell antibodies or a combination of immunosuppressants such as ciclosporine, methotrexate or tacrolimus may be given. Unlike with solid organ transplants, lifelong immunosuppressants are not required; they are usually continued for around 6 months. Allogeneic transplants have been used successfully in acute and chronic leukaemias, along with myeloma.

Transplant complications

Common side-effects associated with myelo-ablative conditioning regimens are nausea and vomiting, mucositis, oesophagitis, gastritis, abdominal pain, diarrhoea and reversible alopecia.

Principles of endocrine therapy

Breast cancer (p. 270)

Principles of targeted treatments

The treatment of malignancy has been revolutionized by the advent of molecularly targeted treatments that inhibit the tyrosine kinase (TK) pathway. These treatments aim to exploit tumour-specific over-expression of epidermal growth factor receptors (EGFR), deranged and chaotic tumour vasculature and supporting extracellular matrix. Inhibition is achieved directly (using small molecules) or indirectly (using monoclonal antibodies). These treatments present an opportunity in the future to provide patient-specific treatment, reduce side-effect profiles and improve outcome.