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.

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.

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

Administration of chemotherapy drugs

• Chemotherapy drug doses are calculated on the basis of body surface area (BSA).

• Drug dosage may be modified during the course of treatment due to side-effects such as bone marrow suppression, stomatitis, renal insufficiency, hepatotoxicity and diarrhoea.

• Cytotoxic drugs are most commonly administered intravenously and should only be given by qualified personnel. IV administration may be via peripheral venous access or, in those who require repeated cycles of treatment, via indwelling venous catheter devices, such as Hickman, Groshong and peripherally inserted central catheter (PICC) lines. N.B. Veins of the antecubital fossa and wrist should be avoided.

• Vesicant cytotoxic drugs include doxorubicin, epirubicin, vincristine, vinblastine, vinorelbine, mitoxantrone, paclitaxel and 5-fluorouracil (5-FU). Care is taken to prevent extravasation and phlebitis. Free flow of fluid to the vein and adequate flashback of blood in the cannula are mandatory before administration. Dexrazoxane 1 g/m² IV daily for 2 days can be used for anthracycline extravasation as soon as possible.

• Only trained personnel should administer intrathecal chemotherapy. It is used in meningeal carcinomatosis or as CNS prophylaxis, in certain patients with lymphoma, haematological malignancies and choriocarcinoma. Cytotoxic drugs that may be given intrathecally include methotrexate, cytarabine and hydrocortisone. N.B. Never give vinca alkaloid drugs intrathecally.

Available chemotherapeutic drugs

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

• DNA-damaging agents

• Alkylating agents (e.g. chlorambucil, cyclophosphamide, ifosfamide and nitrosoureas, e.g. carmustine, lomustine, busulfan). These contain an alkyl group and so act by forming covalent bonds with cellular DNA, RNA and protein molecules. Alkylation of DNA leads to cross-linking of DNA strands and deactivation of repair processes, which in turn causes single-strand breaks. These actions interfere with cellular synthesis of DNA and culminate in cell death. Cytotoxicity is cell cycle-non-specific.

• Non-classical alkylating agents. Platinum compounds (e.g. cisplatin, carboplatin, oxaliplatin) cause inter-strand cross-links on the DNA helix and so block DNA replication. Dacarbazine (DTIC) is a purine analogue, which, following metabolism, acts in a similar manner to alkylating agents. Temozolomide is structurally related to dacarbazine.

• 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.

• Methotrexate is a folic acid antagonist. It binds to the enzyme dihydrofolate reductase and so blocks the conversion of folic acid to folinic acid. This results in the inhibition of thymidine and purine synthesis and so arrests RNA and DNA synthesis. When high doses of methotrexate are administered, folinic acid ‘rescue’ is given afterwards to protect normal tissues from prolonged exposure to methotrexate.

• 6-Mercaptopurine (6-MP) is a purine antagonist.

• Arabinosides include cytarabine (Ara-c), which acts by interfering with pyrimidine synthesis. A liposomal formulation of cytarabine is now available for intrathecal use in lymphomatous meningitis. Gemcitabine is another pyrimidine antimetabolite and fludarabine is an adenosine analogue.

• 5-Fluorouracil (5-FU) blocks the enzyme thymidylate synthase, which is essential for pyrimidine synthesis and so inhibits DNA synthesis. Folinic acid is a cofactor necessary for thymidylate synthase and so is often given along with 5-FU to potentiate its cytotoxic effects. Tegafur is a prodrug of 5-FU and is used in combination with uracil.

• Capecitabine is an orally administered prodrug of 5-FU, which is converted in tumours to 5-FU through the intermediate doxifluridine. It has been shown to be of similar efficacy as the combination of 5-FU and folinic acid.

• Pemetrexed inhibits folate-dependent enzymes, including thymidylate transferase.

• DNA repair inhibitors

• Cytotoxic antibiotics bind to DNA by intercalating adjoining nucleotide pairs on the same DNA strand and inhibit DNA repair. They are cell cycle non-phase-specific. Anthracycline antibiotics (e.g. doxorubicin) have a cumulative toxicity to the myocardium, which can result in cardiomyopathy.

• Epipodophyllotoxins (e.g. topoisomerase I inhibitors, e.g. irinotecan, topotecan; topoisomerase II inhibitors, e.g. etoposide, tenoposide) act on the topoisomerase enzymes that regulate the 3-D structure of DNA by unwinding coiled double-stranded DNA. These drugs therefore indirectly cause the formation of single and double DNA strand breaks and have maximal effect late in S or G2 phases of the cell cycle.

• Anti-tubilin agents

• Vinca alkaloids (e.g. vincristine, vinblastine) act by binding to tubulin and inhibiting microtubule formation, thereby preventing cell division. Due to their neurotoxicity they should never be given intrathecally.

• Taxanes (e.g. paclitaxel, docetaxel) bind to tubulin dimers and prevent their assembly to microtubules.

Side-effects of treatment

• Nausea and vomiting are common side-effects of chemotherapy treatment, which can be prevented in up to 75% of patients with modern antiemetics. These symptoms may occur acutely (during the 24 hours following administration) or may be delayed (more than 24 hours after treatment and possibly lasting up to a week). The degree of emetogenicity is dependent on the drug and its dose (Box 8.4). Combination chemotherapy may also have greater emetogenicity than the sum of the single agents used alone. A stepped approach to antiemetic treatment depending on emetogenicity of the drug is used (Table 8.3). If the selected antiemetic regime is not sufficient, lorazepam 1–2 mg oral/sublingual (particularly useful in anticipatory nausea and vomiting), oral haloperidol and cyclizine IV/SC/oral can be used.

• Alopecia (hair loss) is particularly troublesome with agents such as cyclophosphamide, doxorubicin, etoposide, bleomycin and paclitaxel. It usually begins 1–2 weeks following chemotherapy and becomes maximal 1–2 months later. Regrowth usually occurs shortly after treatment ends. Scalp cooling is sometimes used to reduce hair loss when the drug used has a short half-life, e.g. doxorubicin.

• Bone marrow suppression is a common side-effect of many cytotoxic agents and is a dose-related phenomenon. It most commonly occurs 7–14 days following chemotherapy; however, some drugs can cause delayed myelosuppression (21–35 days after treatment), such as chlorambucil, carboplatin, nitrosoureas and melphalan.

• Anaemia is managed with red cell transfusions or with recombinant erythropoietin. Patients are commonly transfused if they are symptomatic and if their haemoglobin is < 6–8 g/dL.

• Thrombocytopenia (< 10–20 × 10⁹/L) is treated with platelet transfusions to prevent spontaneous haemorrhage from occurring.

• Neutropenic patients are at high risk of fungal and bacterial infections, especially Gram-negative infections from enteric bowel flora. In addition, those patients with indwelling lines are at risk of infection with Gram-positive organisms. Neutropenic patients with a temperature > 38°C and < 0.5 × 10⁹ neutrophils should be treated immediately with broad-spectrum antibiotics until microbiological results are available, and should be closely monitored (Box 8.5). The use of colony-stimulating haematopoietic growth factors, such as granulocyte colony stimulating factor (GCSF) 5 mg/kg SC daily or pegfilgrastim 6 mg as a single dose 24 hours post-chemotherapy, can reduce the duration of neutropenia in patients on highly myelosuppressive chemotherapy regimes.

• Mucositis is commonly seen with drugs such as methotrexate, 5-FU and high-dose melphalan, and reflects drug-induced mucosal sloughing. It can also be due to candidiasis secondary to the myelosuppressive effects of chemotherapy. If radiotherapy is administered simultaneously, mucositis can be more severe due to reduction in salivary secretions. Since the mouth is a potential portal for entry of enteric organisms, good oral hygiene is imperative in all cancer patients. Mucositis is best prevented using antiseptic mouthwashes such as chlorhexidine gluconate every 6 hours, along with prophylactic nystatin suspension or amphotericin lozenges. If mucositis is severe, IV fluid may be needed along with SC diamorphine for pain relief and sucralfate suspension orally. If there are any ulcers suggestive of herpes simplex virus infection, aciclovir should be prescribed. Palifermin, a human keratinocyte growth factor, is also helpful.

• Cardiotoxicity has been associated with anthracyclines such as doxorubicin and daunorubicin. It is dose-related, and can be avoided by restricting the cumulative dose of doxorubicin to 450 mg/m². Unfortunately, once cardiomyopathy has developed, it is not reversible.

• Renal toxicity in the form of acute tubular necrosis can occur with agents such as cisplatin, methotrexate and ifosfamide. Renal function should be monitored during treatment and the patient should be adequately hydrated.

• Neurotoxicity occurs mainly with vincristine, vinblastine, taxanes and cisplatin (but less so with carboplatin). It is dose-related and cumulative. These drugs cause a peripheral sensory neuropathy and the dose should be reduced or the drug omitted before development of significant symptoms, as the neuropathy may potentially be permanent. Rarely, the plant alkaloids can lead to autonomic nerve dysfunction, which can in turn cause gastrointestinal aperistalsis. High doses of cisplatin can also cause ototoxicity, resulting in high-tone hearing loss and tinnitus. A dose-dependent encephalopathy can occur with ifosfamide; it can be reversed with 50 mg methylene blue in 2% solution by slow IV injection.

• Sterility in males and females can be caused by a number of drugs, such as alkylating agents, vinblastine and procarbazine. In males, storage of sperm should be offered in all patients treated with curative intent. In females, oocysts can be fertilized and cryopreserved.

• Secondary malignancies are one of the long-term complications of treatment since chemotherapeutic drugs have mutagenic potential. Acute leukaemia is the most common secondary malignancy and occurs 6–10 years after initial treatment. Solid tumours and lymphomas tend to occur more than 15 years after initial treatment and there is no time limit on the duration of risk. Drugs such as the epipodophyllotoxins and alkylating agents are particularly implicated in this complication.

• Tumour lysis syndrome can occur with chemosensitive tumours with rapid doubling times, as the result of a large cell kill following chemotherapy/steroid treatment. The sudden release of large amounts of intracellular contents into the bloodstream can lead to acute tubular necrosis. This is particularly associated with Burkitt’s lymphoma, high-grade non-Hodgkin’s lymphoma, lymphoblastic lymphoma and acute leukaemia. Patients are especially at risk if they have bulky disease, high uric acid levels and high levels of LDH prior to treatment. Tumour lysis syndrome comprises hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia, and can lead to acute kidney injury, cardiac arrhythmias and tetany. At-risk patients should be treated prophylactically with allopurinol 300–600 mg orally or 200 mg IV, starting at least 24 hours prior to chemotherapy treatment and continued for the duration of chemotherapy treatment. Patients should be adequately hydrated, with IV fluids commenced prior to treatment and a fluid intake of at least 3 L daily maintained through chemotherapy treatment. Rasburicase 0.2 mg/kg/day for 5–7 days, starting on day 1 of chemotherapy treatment, is used if the patient is at very high risk or if significant tumour lysis develops despite prophylactic measures. U&E, urate, PO₄ and calcium must be monitored 6-hourly post chemotherapy and the renal dialysis used early if prophylactic measures prove unsuccessful.

Box 8.4 Emetogenicity of common cytotoxic agents

Low (+); incidence <30%

• Bleomycin

• Fludarabine

• Vinca alkaloids

• Chlorambucil

• Docetaxel

• Etoposide

• Melphalan (oral)

• Methotrexate ≤ 500 mg/m²

• Paclitaxel

• Mitoxantrone

• Topotecan

• Pemetrexed

• Mitomycin

• Gemcitabine

• Fluorouracil

Moderate (++); incidence 30–90%

• Cyclophosphamide < 1,500 mg/m

• Daunorubicin

• Doxorubicin

• Epirubicin

• Ifosfamide

• Cytarabine >1 g/m²

• Methotrexate > 500 mg/m² to < 2 g/m²

• Irinotecan

• Oxaliplatin

• Carboplatin

High (+++); incidence >90%

• Carmustine

• Cisplatin

• Cyclophosphamide ≥ 1,500 mg/m²

• Etoposide — high-dose

• Dacarbazine

• Dactinomycin

• Melphalan — high-dose

• Methotrexate ≥ 2 g/m²

Table 8.3 Antiemetic recommendations

Emeto-genicity	On days of chemotherapy	Days after chemotherapy
Low	No antiemetic required routinelyMetoclopramide 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 dailyDexamethasone 4–8 mg IV/oral daily	Metoclopramide or domperidone 20 mg 3 times daily for 3 days, then as requiredDexamethasone 4 mg twice daily for 2 days
High	Granisetron 1 mg IV/oral 1–2 times dailyDexamethasone 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 requiredDexamethasone 4 mg twice daily for 2–3 daysGranisetron 1 mg twice daily for 2 days

Box 8.5 Managing a febrile neutropenic patient

• The patient should be reviewed promptly and treatment initiated without delay (see Fig. 20.6).

• History and physical examination should be performed to help elucidate the source of infection, paying particular attention to indwelling lines.

• Resuscitation should be carried out with IV fluids to restore circulatory function.

• Cultures of blood (from indwelling lines and peripheral), urine, sputum, stool should be collected and a CXR performed.

• Empirical IV antibiotic should be started, e.g.:

– Ceftazidime 2 g — followed by 1 g 3 times daily— and gentamicin 5 mg/kg IV daily (reduce dose in renal impairment).

– Piperacillin with Tazobactam 4.5 g x 3 daily + Gentamycin is an alternative

– If the patient clinically deteriorates and/or temperature is still elevated after 48 hours, the antibiotics should be changed according to culture results or changed to increase Gram-positive and negative cover, e.g. imipenem 500 mg 4 times daily and vancomycin 1 g twice daily IV

– If the patient fails to respond to second-line antibiotic treatment, fungal infection should be looked for with high-resolution CT scan of the chest. Antifungal agents, such as liposomal amphotericin, caspofungin or voriconazole, may be considered

• Each time antibiotics are changed, blood and other cultures should be repeated and CXR performed.

• Febrile neutropenic patients should be closely monitored and nursed in modified reverse isolation.

• After 48 hours, if the patient has clinically improved, is afebrile and cultures are negative, antibiotics may be stopped and the patient observed closely.

Principles of endocrine therapy

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.

Selective targets (Table 8.4)

Monoclonal antibodies

• Trastuzumab is a monoclonal antibody directed against Her2/Nu (human epidermal growth factor receptor 2), a member of the EGFR family. As well as modifying the immune response, it acts as an anti-growth factor and so increases the apoptotic response to cytotoxics.

• Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), preventing activation of the VEGF receptor TK and its downstream pathway. It has demonstrated significant activity in combination with chemotherapy in colorectal, lung and ovarian cancer.

• Rituximab is a humanized monoclonal antibody directed against the B-cell-specific antigen CD20. It is used in patients with low- and high-grade CD20-positive non-Hodgkin’s lymphoma. It is given as an IV infusion and is usually administered weekly for 4 weeks. Side-effects: in patients with cardiovascular disease and those receiving cardiotoxic chemotherapy, exacerbation of arrhythmias and heart failure occur. Infusion-related side-effects are common and predominantly occur with the first dose. These include flu-like symptoms, nausea, flushing and, rarely, hypersensitivity reactions. Patients should therefore be given pre-medication with paracetamol and antihistamines; corticosteroids are also given.

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