8 Malignant disease
Approach to the patient with cancer
Symptoms
Patients can present in a number of ways:
• Tumour site-specific symptoms, e.g. breast lump, hoarse voice of laryngeal carcinoma, post-menopausal bleeding typically seen with endometrial carcinoma, or progressive dysphagia of oesophageal carcinoma.
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 |
Investigations
These should be aimed at confirming the presence of malignancy and assessing the extent of spread (i.e. staging the tumour). Although tumours may have a characteristic radiological appearance, biopsy with histology should always be performed, as the prognosis and treatments of different cancers vary greatly. Different tumours are staged in different ways. The most commonly used staging system for solid tumours is the TNM (tumour, node, metastases) system, which is updated every few years (Box 8.6, p. 269).
Cancer treatment
• Aims of treatment. The patient and the other medical teams should be clear about the intention of treatment. This enables patients to be realistic and to have the opportunity to organize aspects of their life and obtain the appropriate support. Often, the intention of treatment may be palliative but the prognosis can vary from months to years dependent on tumour type.
• Types of treatment
• Adjuvant treatment. Adjuvant treatment is given after complete surgical removal of a tumour. The risk of micrometastases is sufficiently high for therapy in the form of systemic treatment (chemotherapy, hormone therapy, targeted agents), radiotherapy or chemoradiation to be offered to reduce the risk of recurrent disease. These patients have no clinically detectable metastatic disease.
• Neoadjuvant treatment. Chemotherapy and/or radiotherapy are given to downstage a tumour before surgery.
• Measuring response to treatment (Box 8.1)
• Objective response to treatment. This is measured radiologically using re-evaluation criteria in solid tumour (RECIST).
• Subjective response to treatment. This is used mostly in palliative treatments to assess whether a patient perceives an improvement in symptoms. Measures of quality of life enable an assessment of the benefit of treatment compared to the side-effects.
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
Administration of radiotherapy
• External beam radiotherapy is the most commonly used form of radiotherapy. Treatment is with beams of ionizing radiation produced from a source external to the patient, most commonly a linear accelerator. Techniques are continually evolving to maximize dose to abnormal tissue while attempting to reduce dose to normal surrounding structures, e.g. conformal radiotherapy or intensity-modulated radiotherapy (IMRT). Brachytherapy is where the radiotherapy sources are placed within or close to the target volume, e.g. intracavitary (gynaecological, lung or oesophageal cancers), interstitial (tongue, floor of mouth, breast) or tumour surface (eye, skin).
• Systemic radionuclides are commonly used in oncology for diagnostic and therapeutic purposes. Therapeutic applications involve administering the radiopharmaceutical with the intent of selectively destroying diseased tissue, e.g. the radio-labelled tracer 131iodine or 99technetium is used in the treatment of benign thyroid disease and in follicular or papillary carcinoma of the thyroid after surgery.
Radiotherapy regimes
• Chemoradiation (e.g. cervical cancer, anal cancer, oesophageal cancer and tumours of the head and neck).
• Accelerated radiotherapy (e.g. squamous cell tumours of head and neck, non-small cell lung cancers).
• Palliative radiotherapy. For palliative treatments, a shorter course with a larger dose per fraction is used (Box 8.2).
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 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.
| 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
• 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.
Never give vinca alkaloid drugs intrathecally.Available chemotherapeutic drugs
• 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.
• 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.
• 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.
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.
| 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
• History and physical examination should be performed to help elucidate the source of infection, paying particular attention to indwelling lines.
• 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).
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.
Allogeneic stem cell transplantation
• Non-myelo-ablative allogeneic stem cell transplantation/’reduced-intensity’ transplantation. In this form of transplantation the conditioning regime is not myelo-ablative but still has an immunomodulatory effect, produced by drugs such as fludarabine. The principle is that the anticancer effect of the allogeneic stem cells will still be present without the complications of a conventional transplant, particularly the severity of graft versus host disease (GVHD).
Transplant complications
• Infections. The severe myelosuppression of the conditioning treatment renders the patient susceptible to a wide variety of potentially fatal infections with bacterial (Gram-negative and positive), viral (herpes simplex, herpes zoster, cytomegalovirus (CMV)), fungal (Aspergillus) and atypical organisms. Nearly all patients experience fever and require broad-spectrum antibiotics during this neutropenic period; GCSF is usually given, starting the day after transplant until neutrophil recovery. Despite recovery of their blood counts, patients who have undergone autologous transplantation do not recover full immune function for 3–6 months. Patients who have undergone allogeneic transplantation are affected, in addition to severe myelosuppression, by immune dysfunction that persists until their GVHD resolves. These patients are particularly susceptible to CMV disease secondary to reactivation. On testing positive for CMV, patients are treated with ganciclovir or foscarnet.
• Graft versus host disease (GVHD). This is secondary to the immune reaction of the donor cells against the normal host organs and affects 30–50% of allogeneic transplant recipients. GVHD is classified as being acute if it occurs in the first 100 days post transplant and chronic if it occurs after 100 days.
• Veno-occlusive disease usually presents in the first 2 weeks following allogeneic transplantation; it occurs in < 5% of patients. It is characterized by the triad of hepatomegaly, jaundice and ascites. Diagnosis is largely clinical but may be supported by hepatic Doppler US. Treatment is primarily supportive and thrombolysis is rarely used.
Principles of endocrine therapy
Breast cancer (p. 270)
• Anti-oestrogens. Oestrogen is the main hormone involved in the development of breast cancer and exerts its effects through the oestrogen receptor (ER), a ligand-activated nuclear transcription factor.
• Tamoxifen acts as a competitive antagonist of the ER and so inhibits the growth of breast tumours. Its exact mechanism of action is complex, since it also has partial agonist effects, which are tissue-dependent. As a result, long-term administration is associated with an increased risk of uterine cancer and thromboembolism, but not with vaginal atrophy or osteoporosis. The usual dose is 20 mg daily.
• Fulvestrant is a new type of anti-oestrogen with a different mechanism of action to tamoxifen; it acts as a pure ER antagonist and, as a result, reduces the risk of cross-resistance to treatment. In addition, it down-regulates the cellular levels of ER, which results in a reduction in progesterone receptor (PgR) expression.
• Aromatase inhibitors. These include anastrozole 1 mg daily, letrozole 2.5 mg daily and exemestane 25 mg daily. In post-menopausal women residual oestrogen production is solely from non-glandular sources, in particular subcutaneous fat. Therefore, aromatase inhibitors should not be used in pre-menopausal women unless ovarian suppression has occurred. Aromatase inhibitors suppress oestrogen levels in these women by inhibiting or inactivating aromatase, the enzyme responsible for the synthesis of oestrogens from androgenic substrates; as a result the drugs have no partial agonist activity
• Gonadorelin analogues (gonadotrophin-releasing hormone (GnRH) agonists, e.g. goserelin). These exert their effect by binding to hypothalamic GnRH receptors in the pituitary, with the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These peptides are not released from their binding sites and receptor down-regulation occurs with suppression of LH release and FSH release and so oestrogen synthesis. The role of GnRH agonists in pre-menopausal women is controversial, with some trials demonstrating equivalence of GnRH administration when compared to older-style chemotherapy regimens. For pre-menopausal women with ER and/or PgR-positive metastatic or locally advanced breast cancer, ovarian ablation can be considered to facilitate the use of aromatase inhibitors. This may be in the form of oophorectomy, radiotherapy, or the use of GnRH agonists alone.
Prostate cancer (p. 276)
• GnRH agonists. The gonadorelin analogues, leuprorelin acetate and goserelin acetate, are administered SC as a monthly or 3-monthly depot preparation. As in breast cancer, these drugs exert their effects by suppression of LH and FSH release and also testicular androgen synthesis. Since these agents initially cause a transient rise in testosterone, their use should be covered with an anti-androgen. Anti-androgens are typically administered 2 weeks before and after the first GnRH agonist injection. Side-effects of GnRH agonists are similar to those of surgical castration and include loss of libido, impotence, hot flushes, gynaecomastia, mood disturbance, osteoporosis, metabolic syndrome and anaemia.
• Anti-androgens, such as bicalutamide and flutamide, work by competitively blocking the androgen receptor. In addition to their use in preventing tumour flare when initiating GnRH agonist therapy, they are also employed along with GnRH agonists in patients who develop disease progression despite medical castration. Side-effects are similar to those of GnRH agonists.
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.
Table 8.4 Targeted therapies (cytokine modulation) used in cancer treatment
| Drug | Target | Malignancy |
|---|---|---|
| Cetuximab | Anti-EGFR | Colorectal cancer Head and neck |
| Bevacizumab | Anti-VEGF | Colorectal cancer |
| Rituximab | Anti-CD20 | Non-Hodgkin’s lymphoma |
| Alemtuzamab | Anti-CD52 | Chronic lymphocytic leukaemia |
| Trastuzumab | Anti-Her2 | Breast cancer |
| Imatinib | Tyrosine kinase inhibitor | Chronic myeloid leukaemia Gastrointestinal stromal tumours |
| Gefitinib | Tyrosine kinase inhibitor EGFR |
Non-small cell lung cancer |
| Erlotinib | Tyrosine kinase inhibitor | Non-small cell lung cancer Bronchoalveolar cancer |
| Dasatinib | Tyrosine kinase inhibitor | Chronic myeloid leukaemia |
| Sorafenib | Tyrosine kinase inhibitor | Renal cell cancer |
| Sunitinib | Tyrosine kinase inhibitor | Renal cell cancer |
| Nilotinib | Tyrosine kinase inhibitor | Chronic myeloid leukaemia |
| Bortezomib | Proteosome inhibitor | Myeloma |
| Panitumumab | EGFR | Metastatic colorectal cancer |
| Bexarotene | Retinoid X receptor agonist | Cutaneous T-cell lymphoma |
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
• Intracellular signal inhibitors. Most of these TK inhibitors are small molecules and they compete with the ATP binding pocket of the catalytic domain of oncogenic TKs. They are administered orally and are often used in combination with chemotherapy drugs or radiotherapy. Patients can develop resistance to treatment and the agents are often only active in subgroups of patients. Imatinib is a TK inhibitor that specifically inhibits the fusion oncoprotein BCR-ABL. Further examples of TK inhibitors are listed in Table 8.4. Many other molecules with a role in inhibiting proteins involved in cancer cell signalling are under development. Examples include farnesyl transferase inhibitors, which inhibit ras proteins, drugs that target the proteosome, inhibitors of the platelet-derived growth factor receptor, and drugs that inhibit matrix metalloproteinase.
Immunotherapeutic agents
• Interleukin(IL)-2 (aldesleukin) is a cytokine used to activate T-cell responses, and the recombinant protein is often given in conjunction with interferon (IFN)-α, a B-cell activator. It is usually given by SC injection and is used in renal cell carcinoma and melanoma. High-dose IV IL-2 is now rarely used due to its acute toxicity, which may lead to the capillary leak syndrome with pulmonary oedema and hypotension.
• Interferons are naturally occurring cytokines that function by stimulating humoral and cell-mediated immune responses that can produce an anti-tumour effect. They also have antiproliferative activity in some tumours.
• Tumour vaccines may be used to activate the patient’s immune system, using autologous and allogeneic tumour cells. A number of vaccine approaches have been investigated, including whole-tumour cell lysates, oncogenic peptides, genetically engineered antigen-presenting cells and solubilized cell surface antigens.
Common solid tumour management
Lung cancer
• Non-small cell carcinomas are staged according to the TNM system (Box 8.6) and have 5-year survival rates of < 6% overall.
• Small cell lung cancers are staged according to whether the disease is limited (tumour can be encompassed in a radical radiotherapy portal) or extensive (tumour is more extensive than limited-stage disease), and have a median survival of 12–24 months.
Treatment of non-small cell lung cancer
• Surgery in the form of lobectomy is curative in patients with operable non-small cell lung cancer. Any stage below and including IIIa is potentially operable, and should be discussed with a cardiothoracic surgeon at an MDT meeting. The patient needs to have sufficient pulmonary reserve and to be fit for surgery to be considered for this form of radical treatment.
• Radical radiotherapy is used for patients who are not suitable for surgery (usually due to co-morbidity) whose tumours can be encompassed in a radical radiotherapy field. Patients require an FEV1 > 1.5 L and a transfer factor of > 50% to be considered for radical radiotherapy. Various methods have been used to improve the outcome. Sequential chemotherapy (platinum-based), followed by radiotherapy and concurrent chemoradiation, has demonstrated improvements over conventionally fractionated radiotherapy alone, although there is a preponderance of patients with locally advanced tumours in these trials.
• Chemotherapy with platinum-containing regimens can be given in patients being treated with radical intent. Neo-adjuvant chemotherapy prior to surgery is currently being used in trials. Trials comparing surgery with surgery plus chemotherapy demonstrate a 13% reduction in risk of death and absolute benefit of 5% at 5 years. Pemetrexed is also used for maintenance therapy. Erlotinib (Table 8.4) is also used for locally advanced or metastatic disease after failure of chemotherapy.
• Palliative treatment
• Chemotherapy with platinum-containing regimens is used in patients with good performance status. Better response rates with increased 1-year survival and better palliation are seen when compared to best supportive care. Typical chemotherapy regimens include a platinum agent (cisplatin or carboplatin) with either gemcitabine, vinorelbine or paclitaxel. Second-line chemotherapeutic agents in use include docetaxel and pemetrexed.
• Palliative radiotherapy to the lung is used in any patient who is not suitable for radical radiotherapy. High-dose palliative regimens are used for patients who are fit but not suitable for radical radiotherapy, with variable results. Other fractionation regimens provide significant palliative benefit for patients with dyspnoea, haemoptysis or pain.
• Targeted treatments with TK inhibitors, such as erlotinib or gefitinib, are used (in patients with EGFR gene mutations) when chemotherapy regimens have been exhausted or a patient is not fit for them. A response rate of 19–33% was seen in a subgroup of patients who were female, were of Asian origin and have broncho-alveolar tumours. Gefitinib can also be used as initial treatment for pulmonary adenocarcinoma.
Breast cancer
Investigations
• Women should first be investigated by triple assessment. This comprises clinical examination, radiology (typically mammography and US but MRI if indicated) and fine needle aspiration cytology or core biopsy of the breast lump. The triple assessment is carried out in a dedicated one-stop clinic.
Prognosis
In early breast cancer the prognosis can be predicted from the factors listed above, and the survival probability and benefit from adjuvant therapy by using the website www.adjuvantonline.com. The 10-year survival can vary from > 90% for small, low-grade, node-negative tumours to < 20% for large, high-grade tumours with more than three nodes involved, if no adjuvant treatment is given.
Local treatment
• Surgery. The type of surgery (wide local excision, mastectomy with or without reconstruction) is dictated by the tumour size and position, and patient preference. Surgical staging of the axilla is also performed by a sentinel lymph node sampling, in which a blue tracer, with or without a radiotracer, is injected around the tumour bed. The lymph node(s) (sentinel node) that picks up the dye or tracer is/are excised. If no lymph node metastases are identified in the histological sample, the patient can be spared the morbidity of a full axillary nodal dissection.
• Radiotherapy is indicated in all patients following breast-conserving surgery. It is also used following mastectomy in women who are at high risk of locally recurrent disease (large tumour, multifocal disease, skin involvement, more than four nodes involved). If an adequate surgical procedure to the axilla has been performed in women who are found to have positive lymph nodes, radiotherapy to the axilla can be avoided; otherwise the risk of lymphoedema significantly increases. In women who are node-positive (usually three or more nodes), radiotherapy to the supraclavicular fossa is offered in addition.
• Adjuvant systemic treatment
• Targeted treatments This is indicated in women with hormone receptor-positive disease. Aromatase inhibitors are increasingly being used in post-menopausal women as first-line therapy in all but good-prognosis tumours. They can be used either alone for 5 years or sequentially with tamoxifen. Tamoxifen has a different side-effect profile to aromatase inhibitors. There is an increased risk of endometrial proliferation (and consequent malignancy), as well as thromboembolic problems with tamoxifen. The main side-effects of aromatase inhibitors are musculoskeletal, such as joint aches and reduction in bone density. Endocrine treatment should be given after completion of chemotherapy in a sequential manner.
• Chemotherapy. The decision as to whether to offer adjuvant chemotherapy is based on an individual woman’s risk of relapse. The consequent benefit of chemotherapy is therefore proportional to her risk of relapse. Optimal treatment regimes of combination chemotherapy include an anthracycline. A taxane is often added in node-positive women. The choice of combination offered depends on individual risk, co-morbidity and the toxicity profile of the combination. Trastuzumab is also given if a patient is confirmed as being Her2-positive. Currently, standard practice is to give trastuzumab for 1 year in total but trials are ongoing to define the optimal duration. The main side-effect is reversible cardiotoxicity and trastuzumab is therefore not given concurrently with anthracyclines. During treatment, patients should undergo 3-monthly echos to monitor left ventricular function.
Treatment of metastatic breast cancer
• Endocrine treatment. Women who are oestrogen and progesterone receptor-positive are more likely to respond to endocrine manipulation. The choice of hormonal treatment is dependent on what was used in the adjuvant setting and the period since hormonal treatment was last used. Endocrine treatment is usually tried first in women who do not have immediately life-threatening disease. Remission of up to 2 years is seen and, on progression, alternate hormonal treatments can be used.
• Chemotherapy. This is used for patients with visceral metastases or rapidly progressive disease, or when all other treatment options are exhausted. Chemotherapy can provide good palliation and prolongation of survival. The choice of chemotherapy regimen is dependent on previously used regimes, Her2 status, fitness for treatment, and bone marrow and liver function.
Gastrointestinal cancers
Colorectal carcinoma
• Surgical resection. Surgery is the primary treatment modality for colonic cancer and removal of the primary tumour is possible in 90% of cases. The surgical procedure used is dependent on the tumour site and usually involves a right or left hemicolectomy or sigmoid colectomy. In patients with metastatic disease, palliative bowel surgery is recommended if there is evidence of bowel obstruction, significant luminal narrowing, and bleeding from the tumour. With rectal tumours, unlike in colon cancer, the ability to obtain wide resection margins may be limited by the bony pelvis and local recurrences are a greater problem (see below).
• Adjuvant treatment for colonic tumours: stage III disease. Despite adequate surgical resection, the 5-year survival in patients with stage III tumours is only 30–60%. Clinical failure is predominantly the result of clinical progression from previously undetected micrometastases. Studies have investigated the optimal treatment duration and established that 6–8 months of adjuvant treatment appears to be the most effective. Two treatment regimes are commonly used:
• Planned adjuvant treatment should commence within 6–8 weeks of primary resection. In patients with temporary stomas, stoma reversal can be performed prior to starting adjuvant treatment. Patients with low resections may find retaining the stoma helpful with regard to the control of chemotherapy-related diarrhoea. Chemotherapy may commence 2 weeks after an uncomplicated stoma reversal.
• Adjuvant treatment for colonic tumours: stage II disease. Chemotherapy is used e.g. in individuals with T4 tumours, poorly differentiated tumours, evidence of perforation, or lymphovascular or neural invasion, and those who may have been inadequately staged as a result of suboptimal lymph node examination (< 13 nodes in the surgical specimen). Other prognostic markers, such microsatellite instability and 18q loss of heterozygosity, may play a future role in patient selection.
• Rectal tumours
• Total mesorectal excision (TME). TME is used to remove the entire package of mesorectal tissue surrounding the cancer when a local trans-anal operation is inappropriate because of the extent of disease. A low rectal anastomosis is often possible; if not, abdomino-perineal excision can be performed but requires a permanent colostomy. TME combined with pre-operative radiotherapy reduces local recurrence rates in rectal cancer but has not been found to have a significant effect on survival. Post-operative 5-FU-based chemotherapy can be used in high-risk patients (lymph node-positive disease). If, on MRI, the circumferential margin appears involved or if the tumour is low within the rectum, long-course chemo-radiotherapy is given adjuvantly, followed by surgical resection 6 weeks later.
• Isolated colorectal metastates. Around 10–25% of patients present with metastatic disease isolated to the liver or develop liver disease as a recurrence after primary resection. Patients are eligible for hepatic resection if complete resection of the metastasis is possible with tumour-free margins and if the functioning hepatic volume post resection is adequate. In a subgroup of patients in whom the predicted remaining functional hepatic volume is small, pre-operative selective embolization of the portal vein branches can be used, since it induces hypertrophy of the liver and so increases the functional hepatic volume. ‘Down-staging’ of liver metastases with neo-adjuvant chemotherapy is also used in those with potentially resectable lesions. Neo-adjuvant chemotherapy with oxaliplatin and 5-FU is usually administered for 12–24 weeks dependent on response, and once surgery is deemed possible, it is scheduled for 3–4 weeks after chemotherapy is completed. The addition of cetuximab (for patients with wild-type k-ras gene) or bevacizumab (a humanized antibody against VEGF) to the chemotherapy regime may increase the number of patients suitable for resection and improve outcomes. Alternative options for isolated liver or lung metastases include local tumour ablation (such as radiofrequency ablation or regional hepatic intra-arterial chemotherapy or chemoembolization).
• Widespread metastatic colorectal tumours. Fluoropyrimidines (e.g. 5-FU, capecitabine) as single agents, or more commonly in combination with either irinotecan or oxaliplatin, have become first-line therapy. When given to unselected patients in addition to combination chemotherapy, panitumumab (antibody specific to the EGFR and cetuximab (antibody against the EGFR) have been associated with worse toxicity and progression-free survival. However, they have been shown to be of benefit to those with the non-mutated (wild-type) k-ras gene.
Oesophageal cancer
• Patients with potentially resectable tumours should receive neo-adjuvant chemotherapy with cisplatin and 5-FU for two cycles, prior to planned resection. This has been found to improve median survival by 3 months and 2-year survival by 11% (from 34 to 43%).
• The use of neo-adjuvant chemoradiation is controversial. Although a 25% complete pathological response rate can be seen, a survival advantage has not been consistently demonstrated.
• In patients with inoperable non-metastatic lesions, radical chemoradiation (with cisplatin and 5-FU) should be used. The concurrent use of chemotherapy has been found to improve median survival by 5 months (from 9 to 14 months) and to be associated with a 5-year survival of 26%, versus 0% when compared to radiotherapy alone.
• Disease that is not suitable for radical treatment can be palliated in a number of ways. For dysphagia, placement of an oesophageal stent or palliative radiotherapy (or brachytherapy) can improve symptoms. Bleeding may be palliated by endoscopic laser treatment or radiotherapy. Palliative chemotherapy with epirubicin, cisplatin or oxaliplatin and 5-FU or capecitabine (ECF/EOX/ECX) can be used, and this provides a median 2-year survival of 14% and median survival of 9 months (as compared to 3–4 months with best supportive care).
Gastric cancer
• Surgery can be curative in the rare patient who presents with early-stage disease. However, fewer than 5% of patients present with such disease (T1N0 or T2N1). The type of surgery is dependent on the position of the tumour. The extent of lymphadenectomy varies.
• Adjuvant chemoradiation with 5-FU and folinic acid has been shown to improve survival significantly. Median survival was 36 months for the adjuvant chemoradiation group, as compared to 27 months for the group undergoing surgery alone. This research has been criticized for a possible over-estimation of benefit due to inadequate surgical staging. Patients have to be extremely fit to receive this treatment, as it is associated with significant gastrointestinal morbidity.
Gynecological malignancy
Epithelial ovarian cancer
• Surgery has a major role in the treatment of ovarian cancer. It should involve a mid-line incision, total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph node sampling, omentectomy, peritoneal biopsies and washings, thorough inspection of the sub-diaphragmatic areas and removal of all the gross disease.
• Platinum-based chemotherapy regimes (with taxane for advanced disease) are given adjuvantly if the disease is early-stage but poorly differentiated, or if it is more advanced.
• Treatment at relapse depends on the time from end of completion of the last treatment. Patients may well be re-challenged with a platinum-based regimen, typically if relapse is after > 6 months. Other chemotherapy agents used at relapse include paclitaxel, oral etoposide, liposomal doxorubicin or topotecan.
Endometrial cancer
• Adjuvant radiotherapy (external beam and vault brachytherapy) is offered if the risk of nodal metastases is high, based on the pathology.
Cervical cancer
• Wertheim’s hysterectomy or chemoradiation is the ideal treatment. If there is lymph node disease, deep infiltration of the tumour or disease stage ≥ IB2, surgery should be avoided and the patient should be offered chemoradiation.
weeks, with intracavitary treatment given to boost the dose to the cervix.Genitourinary malignancies
Prostate cancer
• Treatment for localized disease
• Radical prostatectomy involves the removal of the prostatic urethra and seminal vesicles, with lymph node dissection. Nerve-sparing procedures have reduced the incidence of erectile dysfunction.
• Conformal external beam radiotherapy has generally replaced conventional external beam irradiation, as the surrounding normal tissue receives less radiation. Intensity-modulated radiotherapy (IMRT) is increasingly used for prostate cancer, as this has the advantage of being able to shape the radiotherapy beam, enabling a higher radiation dose to be given to the tumour but even lower doses to be received by surrounding tissue. Brachytherapy can involve the placement of either radioactive pellets into the prostate gland (for low-risk tumours) or temporary guidewire needles to facilitate high-dose rate treatment in locally advanced disease.
• Treatment for metastatic disease
• Gonadorelin analogues or surgical castration. Gonadorelin analogues (GnRH), e.g. leuprorelin or goserelin, which shut down the pituitary–gonadal axis, are given. Around 85% of patients are effectively palliated using hormonal therapy, with a median response of 18–24 months. Anti-androgens such as flutamide and bicalutamide act by competing with dihydroxytestosterone at the receptor level, and are always used when initiating GnRH therapy to prevent tumour flare.
• Second-line treatments. Despite continued androgen suppression most patients will develop progressive disease, with a median survival of 7–12 months.
• Maximal androgen blockade (MAB) is achieved by the addition of an anti-androgen to GnRH treatment, and is used once there is evidence of progression on GnRH analogue alone.
• Hormone withdrawal may be therapeutic in ~30% of patients who progress while receiving anti-androgen treatment, since anti-androgens may paradoxically stimulate the androgen receptor in these tumours.
• Other second-line hormonal therapies may also be of palliative benefit such as low-dose corticosteroids and diethylstilbestrol.
• Radiotherapy to bone metastases can provide excellent local pain relief in up to 75% of patients and in those with multiple painful bony sites; bone-seeking β-emitting isotopes may be useful. Studies have also demonstrated a reduced skeletal-related event rate using zoledronate, though currently it is not NICE-approved.
Bladder cancer
• Superficial tumours. Treatment is with cytoscopic resection and regular cytoscopic follow-up, since up to 70% of tumours recur. In patients with a high risk of recurrence, adjuvant intravesical chemotherapy utilizing mitomycin-C or doxorubicin, or intravesical immunotherapy utilizing bacillus Calmette–Guérin (BCG) is used.
• Muscle-invasive disease. Surgery in the form of a radical cystectomy with bilateral pelvic lymphadenectomy and/or radical radiotherapy is performed. The use of platinum-based neo-adjuvant chemotherapy has been shown to give a modest survival benefit. For high-risk patients with T3–T4 and/or N+ M0 disease, the 5-year survival after radical treatment is only 25–35%.
• Metastatic disease. MVAC (mitomycin, vincristine, doxorubicin, cisplatin) is associated with clinical responses in 50% of patients. The median survival with this combination is only 13 months, however, and is associated with moderate toxicity — particularly febrile neutropenia and mucositis. Gemcitabine and cisplatin (GC) are comparable to MVAC. In addition, GC has a more favourable side-effect profile and is easier to administer.
Testicular germ cell tumours
• Inguinal orchidectomy. This is performed prior to any further treatment, except in patients with life-threatening metastatic disease, who are treated with up-front chemotherapy.
• Adjuvant treatments for stage I seminomas. Seminomas are highly sensitive to chemotherapy and radiotherapy; as a result the cure rate in these patients is almost 100%. There are currently three treatment strategies for these patients:
• Adjuvant radiotherapy is the most frequently used. There is a 15–20% risk of relapse after surgical treatment and adjuvant radiotherapy reduces this figure to 3–4%.
• Surveillance policy with administration of chemotherapy or irradiation on relapse is also used. This involves regular follow-up and CT scanning to detect and treat early relapse. This approach takes into account the fact that 80% of patients do not need adjuvant radiation therapy, which is not without side-effects. Since relapses can occur up to 10 years after orchidectomy, follow-up is prolonged.
• Adjuvant treatments for stage IIA/B seminomas. Abdominal radiotherapy is the standard approach for these patients, with relapse-free survival at 6 years of 95% for stage IIA and 89% for stage IIB.
• Adjuvant treatments for non-seminomas. In stage I disease, vascular invasion of the primary tumour increases the rate of recurrence from 14–22% to 43%. Patients with vascular invasion are offered adjuvant chemotherapy with two cycles of BEP (bleomycin, etoposide, cisplatin). In patients with a low risk of relapse a surveillance policy is adopted.
• Treatment of patients with advanced disease
• BEP is the gold standard chemotherapy treatment; 3–4 cycles are given, depending on prognostic stratification. Following chemotherapy treatment residual masses may remain despite normalization of tumour markers.
Renal cell cancer (RCC)
• Treatment of localized disease. Laparoscopic radical nephro-ureterectomy is the primary treatment, unless bilateral tumours are present or the contralateral kidney functions poorly, in which case a partial nephrectomy may be considered. Most patients with localized disease treated surgically achieve complete disease control with local recurrence rates of less than 2–3%. At present, no adjuvant treatments are routinely used, even in high-risk patients.
• Treatment of metastatic RCC. In patients with isolated metastases suitable for curative resection, nephrectomy followed by metastectomy prolongs survival.
• Systemic treatment of advanced disease. Cytotoxic chemotherapy has virtually no activity in RCC.
• IFN-α results in response rates of around 15% with a median survival benefit of 2 months, and is being superseded by new drugs (below), especially since increasing evidence shows that patients with intermediate and poor-prognosis disease derive no benefit from this form of treatment.
• Immunotherapy with high-dose IV IL-2 has overall survival rates similar to IFN-α treatment; however, in a small fraction of patients (7%) sustained remissions occur. The treatment is associated with considerable toxicity, secondary to a capillary leak syndrome, and studies have reported 4% of deaths to be treatment-related. Attempts are being made to identify which patients are most likely to derive benefit from this form of treatment.
• Sunitinib, a TK inhibitor, has been shown to improve clinical outcomes in RCTs. It is now routinely used as a first-line agent.
• Sorafenib targets the Raf/MEK/ERK pathway, which has been implicated in RCC. It acts by inhibiting Raf kinase and in addition has an anti-angiogenesis effect by targeting the receptor TKs, VEGF receptor 2 and platelet-derived growth factor receptor (PDGFR). Phase II and III studies of sorafenib in patients with advanced refractory RCC have demonstrated significantly prolonged progression-free survival. It is used in patients who have progressed following cytokine therapy.
• Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), which is downstream of the phosphoinositide 3-kinase and Akt pathways, and is regulated by the PTEN (phosphatase and tensin homologue) tumour suppressor gene. It therefore acts by inhibiting both angiogenesis and tumour cell proliferation. It has been shown to increase overall survival as a first-line agent in patients with poor-prognosis disease. Everolimus, an orally administered mTOR inhibitor, has been shown to increase progression-free survival in patients who have progressed after treatment with at least one anti-VEGF therapy.
Hodgkin’s lymphoma
| • lymphocyte-predominant (LP) |
| • nodular sclerosing (NS) |
| • mixed cellularity (MC) |
| • lymphocyte-depleted (LD). |
Treatment
• Early-stage disease (I–IIA or B). The standard care for these patients is a combination of short-duration (2–4 cycles) chemotherapy, using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by involved field radiation (20–30 Gy). This regimen provides 10-year overall survival rates of about 95%, and reduces the risk of secondary malignancies and cardiotoxicity, when compared with alkylating agent-based regimes.
• Advanced-stage disease (III–IVA or B; I–IIB with bulky disease). The treatment of choice for these patients is combination chemotherapy with or without adjuvant radiotherapy.
• The ‘gold standard’ combination regimen is ABVD given monthly for a total of 6–8 cycles, followed by involved field radiotherapy to all patients who presented initially with mediastinal bulk disease and to those with partial remission following chemotherapy. This approach is curative in ~50–60% of patients.
• Primary progressive and relapsed disease. Between 5 and 10% of patients with Hodgkin’s lymphoma experience primary treatment failure and 30% of initial responders relapse. Treatment options for these patients depend on the initial treatment used and, in the case of patients with relapsed disease, on the length of remission following first-line treatment.
• In patients who relapse after initial radiotherapy for early-stage disease, conventional chemotherapy is the treatment of choice.
• In patients with primary refractory disease and in those who relapse < 12 months following initial treatment, second remissions are often achieved using non-cross-resistant chemotherapy regimes, the majority of which contain etoposide and an alkylating agent. It is conventional to consolidate remission in this group when possible with high-dose therapy (BEAM (carmustine, etoposide, cytarabine, melphalan) or CBV (cyclophosphamide, carmustine, etoposide)) and peripheral blood cell progenitor rescue (PBPCR). Registry data suggest that this may be curative in up to 50%, although follow-up does not extend beyond 15 years.
Late complications of treatment
• Patients cured of Hodgkin’s lymphoma are at an increased risk of developing secondary tumours, particularly acute myeloblastic leukaemia.
• Patients who have received mantle radiotherapy are at increased risk of developing lung tumours, especially if they smoke, and breast cancer.
Non-Hodgkin’s lymphoma (NHL)
Indolent B-cell non-Hodgkin’s lymphoma
• Follicular lymphoma (FL). Although most patients present with minimal symptoms apart from lymphadenopathy, the disease is often disseminated and bone marrow involvement common. It is a remitting and recurring disease with a clinical course of a median of 10 years, during which there will be around three episodes of relapse. Chemotherapy has no major impact on survival and the disease outcome is independent of how early treatment is initiated. Death is secondary to either resistant disease or transformation to diffuse large B-cell lymphoma.
• Localized disease (stage I and II) is seen in < 15%. Radiotherapy is the standard treatment and may result in long-term disease-free survival in a sizeable proportion of cases.
• Disseminated disease with minimal symptoms follows a watch-and-wait period after diagnosis until the patient becomes symptomatic (B symptoms) or develops signs of advanced disease (organ impairment, i.e. bone marrow failure, bulky disease (lymph node mass > 10 cm), radiological progression documented on two scans 3 months apart). In this situation a repeat biopsy should be performed in case there has been histological transformation to large-B-cell lymphoma.
Intermediate and high-grade lymphoma
• The gold standard treatment is the cyclical R-CHOP regime (rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone). In patients with early-stage disease with good prognostic features, 60–70% are cured with either 6 cycles of treatment or 3 cycles followed by involved field radiotherapy. In patients with more extensive disease, 6–8 cycles are usually given and the cure fraction is around 45%.
• First-line treatment failure has a very poor prognosis and despite second-line therapy < 10% of patients will achieve long-term disease-free survival.
Burkitt’s lymphoma
• Treatment. Typical chemotherapy regimens are CODOX-M/IVAC (cytarabine (intrathecal), vincristine, doxorubicin, methotrexate (IV-high-dose and intrathecal)/(ifosfamide, etoposide, cytarabine, methotrexate (intrathecal)). Up to 6 cycles of treatment are given at monthly intervals. The likelihood of tumour lysis syndrome correlates with tumour burden; as a result, adequate hydration and monitoring are essential. Rasburicase is a major advance (p. 263). The reported complete remission rate is high — 70–90%, depending on age, with very few recurrences after 1 year.
Primary extranodal lymphoma
• Primary cerebral lymphoma is an aggressive disease with a poor prognosis. Standard treatment is with radiotherapy and corticosteroids; despite this, median time to progression is less than a year. An alternative approach is high-dose methotrexate chemotherapy, with whole-brain radiotherapy reserved for disease recurrence.
• Primary gastric MALT lymphoma (extranodal marginal zone B-cell) is commonly associated with Helicobacter pylori infection. Generally these tumours are indolent; systemic spread and constitutional ‘B’ symptoms are uncommon. Treatment is with H. pylori eradication therapy (antibiotics and proton pump inhibitor), followed by endoscopic surveillance, and this results in complete tumour regression in 70–80% of patients. With disease progression, a further course of eradication therapy is recommended; other options include irradiation or alkylating agent therapy.
• Primary cutaneous lymphoma is usually of T-cell origin and includes the Sézary syndrome and mycosis fungoides. It is often multi-focal and other organs are usually involved late in the pathogenesis of the disease. Local treatment with topical steroids, topical nitrogen mustard and radiotherapy are used, along with immune-modulating photopheresis, PUVA photochemotherapy and oral retinoids.
Management of leukaemia
Acute leukaemia
• Supportive treatment in the acute setting and during the course of the illness. If the patient is acutely unwell with signs of septic shock or is acutely haemorrhaging, cardiovascular and respiratory resuscitation should be implemented. Sepsis should be managed according to local neutropenic sepsis guidelines (Box 8.5). Leucopheresis may be required if the peripheral blast count is high or there are signs of leucostasis. Patients may require packed red cell transfusions, if anaemic, and platelet transfusions to prevent bleeding (platelet count < 10 × 109/L in the uninfected patient or < 20 × 109/L in the infected patient) or to control bleeding. In order to prevent infections, patients, relatives and staff should be educated about hand washing and isolation facilities. Selected antibiotics, antifungals and antiviral agents may be started prophylactically and good mouth care is obligatory.
• Specific treatment. Treatment depends on the leukaemic subtype, prognostic factors, and the patient’s age and co-morbidity. Since potentially curative treatment for ‘low-risk good-prognosis’ leukaemia carries considerable morbidity and potential mortality and that for ‘high-risk’ leukaemia even more, it is essential that the ‘risk–benefit’ ratio be clearly addressed with patients. Curative therapy involves intensive chemotherapy treatment and admission to hospital for up to a month in the first instance, with subsequent shorter admissions over a period of up to 6 months. Palliative treatment includes palliative chemotherapy along with supportive measures as discussed above.
Acute myeloid leukaemia (AML)
• Treatment
• Patients under the age of 60 years are usually treated with curative intent; the approach used is based on the cytogenetic pattern, which determines a patient’s ‘risk’. The first stage is induction chemotherapy, which usually consists of 3 days of an anthracycline (e.g. daunorubicin or idarubicin) and 7 days of cytarabine, with treatment of CNS leukaemia using either intrathecal cytarabine or methotrexate. Remission rates of 70–80% are achieved. Once remission is achieved, consolidative treatment is required to reduce the undetectable burden of leukaemic cells, so that cure is possible. In young adults with favourable cytogenetics (e.g. t(8:21) or inv(16)), high-dose cytarabine is generally used. For high-risk patients, allogeneic stem cell transplantation provides the best chance of cure. For the remainder, treatment options include intensive chemotherapy, high-dose treatment with autologous stem cell rescue or sibling-matched allogeneic transplant. Using this approach, ~50% of those entering complete remission are cured (~30% overall).
• Patients over the age of 60 years have a poor prognosis. They represent over half of patients and the choice of initial treatment is much more contentious. For the majority, treatment is palliative. Options range from supportive care to low-dose chemotherapy (low-dose cytarabine or hydroxyurea), investigational agents as part of a clinical trial and high-dose chemotherapy (anthracycline or mitoxantrone and cytarabine).
• Acute promyelocytic leukaemia (APML). This AML subtype is uncommon and is typically associated with a coagulopathy, which is due to the release of thromboplastin by the promyelocytes. It is characterized by a translocation, t(15;17), which results in the production of a fusion protein, PML-RARα. These patients are treated with all-trans retinoic acid (ATRA) and an anthracycline in induction, with ATRA/anthracycline–based post-remission therapy and a year of ATRA maintenance. Complete remissions and molecular remissions occur in at least 80% of younger patients. At least 60% of patients can expect to be cured.
Acute lymphoblastic leukaemia (ALL)
• Treatment. Although specific treatment approaches differ according to subtype and risk, the overall strategy is based upon remission induction therapy, followed by intensification (consolidation) therapy and continuation treatment to eliminate residual leukaemia.
• Remission induction commonly includes dexamethasone, vincristine, an anthracycline antibiotic (doxorubicin) and asparaginase or cyclophosphamide given in two phases. For patients with Philadelphia chromosome (ph)-positive ALL, imatinib is generally incorporated into their treatment.
• Choice of consolidation therapy, once patients are in remission, is determined by the individual risk of recurrence. Allogeneic transplantation benefits certain very high-risk paediatric and adult patients, such as those with BCR-ABL-positive ALL (Philadelphia chromosome-positive) or those with a poor initial response to treatment.
• Maintenance treatment is continued for 2 years and in most cases consists of oral methotrexate administered weekly and daily mercaptopurine. To prevent CNS recurrence, prophylactic intrathecal chemotherapy is given as soon as the blasts are cleared from the peripheral blood and, depending on risk, may be continued for 2 years. Intrathecal methotrexate or cytarabine and hydrocortisone are used. Cranial irradiation is reserved for patients at very high risk or who have known CNS involvement. An alternative is high-dose systemic methotrexate with intrathecal methotrexate.
• Prognosis for childhood ALL is now excellent, with 5-year survival rates of 70–83% and cure rates of ~80%. The experience with adult ALL has been much less satisfactory, with reported cure rates of < 40%, despite the use of allogeneic transplantation in high-risk patients. As with AML, recurrences occur within the first 3 years and the outcome is extremely poor.
Chronic leukaemia
Chronic myeloid leukaemia (CML)
CML is a clonal malignant myeloproliferative disorder, which originates from an early haematopoietic progenitor cell. The progeny of this stem cell proliferates over a period of months to years and when the leukaemia is diagnosed the peripheral blood white cell count is characteristically raised with granulocytes at all stages of development. CML accounts for 14% of all leukaemias and its peak incidence is at 40–60 years. It very rarely occurs in children. CML is characterized cytogenetically by a balanced translocation between chromosomes 9 and 22, t(9;22)(q23;q11.2). The resultant chromosome is known as the Philadelphia chromosome (ph) and gives rise to a chimeric gene, BCR-ABL. This in turn translates into a fusion protein product with increased TK activity, which plays a pivotal role in the pathophysiology of CML.
• Treatment
• Chronic phase. Imatinib is an orally administered agent that specifically inhibits the BCR-ABL tyrosine kinase, which is found in CML. It is first-line treatment for patients with chronic-phase disease, and has replaced IFN-α in this setting. Imatinib has been shown to induce haematological response rates of > 95%, and complete cytogenetic responses of around 80%. Imatinib treatment is generally well tolerated. Adverse effects include oedema, rash, nausea, diarrhoea and muscle cramps. Patients receiving imatinib are monitored using a mixture of peripheral blood counts, cytogenetic analysis and real-time quantitative PCR (RQ-PCR) for BCR-ABL mRNA. Resistance to imatinib does occur and may develop through several mechanisms, the most common of which is reactivation of BCR-ABL kinase activity by either point mutation or gene amplification. In patients who have a suboptimal response to imatinib or who develop secondary resistance, second-generation tyrosine kinase inhibitors (TKIs), such as dasatinib or nilotinib, may be used. Imatinib dose escalation may be an alternative strategy for restoring responsiveness; however, its effect is unusually short-lived. Allogeneic stem cell transplantation (SCT) is commonly used in patients younger than 60 years of age who have incomplete cytogenetic responses to imatinib therapy and have suitable donors. In patients without suitable donors who are not suitable candidates for transplantation or are unable to take second-generations TKIs due to problems with QT prolongation, IFN, cytarabine plus hydroxyurea can be used. In patients who have had a good response to imatinib and have an HLA-matched donor, the decision is more difficult, since long-term survival data regarding imatinib treatment are not yet available. One option is to offer transplantation to patients at low risk of treatment-related death (young patients with sibling donors) and to reserve transplantation in higher-risk patients for when they show signs of disease progression. Since the graft versus leukaemia effect plays a role in SCT, reduced-intensity conditioning allogeneic transplantation may represent an improvement in the immunotherapeutic approach to CML. Initial reports have demonstrated high response rates with this approach but longer follow-up is needed.
• Accelerated phase. Imatinib treatment results in haematological responses in 82% of patients; cytogenetic responses, however, are only seen in 43%. Allogeneic transplantation in these patients has the potential for cure, though response rates are poor. Other options include autologous marrow transplantation to return the patient to a chronic phase, which in some cases is durable, α-interferon, high-dose cytarabine and hydroxyurea.
• Blast phase. Imatinib has demonstrated marked activity in patients with both myeloid and lymphoid blast crisis. Haematological responses of around 50% have been seen, with cytogenetic responses of 16%; however, 1-year survival with this approach is < 35%. Clinical trials are currently under way to evaluate the role of imatinib in combination with other drugs in this setting. Allogeneic SCT is successful in < 10% of patients, due to the high incidence of complications and risk of recurrence; nevertheless, in young patients with a suitable donor, it provides the only chance of a cure. Other treatment options include vincristine and prednisolone for patients with lymphoblastic transformation, or cytarabine and daunorubicin for patients with non-lymphoid blast crisis. Myeloid blast crisis is usually refractory to chemotherapy and these patients have a very poor prognosis.
Chronic lymphocytic leukaemia (CLL)
• Treatment is dependent on stage and cytogenetic marker status. Early-stage, good-prognosis disease is typically managed expectantly, since there is no survival benefit for immediate versus delayed therapy in these patients. Treatment is instigated in these patients when they develop signs of disease progression, such as anaemia, recurrent infections, splenic discomfort or doubling of the lymphocyte count in < 6 months. Treatment is also recommended for those with advanced-stage disease and certain patients with intermediate-stage disease.
• Chlorambucil with or without prednisolone achieves partial responses in 60–70% in previously untreated patients and successfully palliates the disease. Higher response rates have been seen with regimes combining anthracyclines and alkylating agents; however, these have considerably more toxicity and carry no survival advantage. Chlorambucil treatment is usually given for several months and then withheld until there is progression.
• Fludarabine is a purine analogue, and alone or in combination with an anthracycline-containing regime has been found to result in higher remission rates and longer progression-free survival, than chlorambucil, but no survival benefit. It is, however, more toxic, with higher rates of infection (neutropenic sepsis, herpes simplex, Pneumocystis), autoimmune haemolytic anaemia and persistent thrombocytopenia. The increased infection risk may persist for months to years after treatment with a purine analogue. Prophylaxis with co-trimoxazole for 6–12 months may therefore be given to prevent pneumocystic infection, and aciclovir prophylaxis to prevent herpes virus infection. According to NICE guidelines, fludarabine monotherapy should be offered as second-line treatment to patients who have failed first-line therapy with an alkylating agent.
• Rituximab added to chemotherapy combinations, such as fludarabine or pentostatin with cyclophosphamide, has recently been shown to result in significant improvements in response rates; long-term survival data are, however, awaited. Alemtuzumab (campath-1H), a monoclonal antibody directed at CD52, may be used as initial therapy in patients with a 17p deletion or as a second-line agent for those who have failed chlorambucil and fludarabine. Other treatments under evaluation include myelo-ablative chemotherapy with autologous PBSCR and allogeneic stem cell transplantation using myelo-ablative and non-myelo-ablative conditioning regimes.
• Treatment of disease complications
• Autoimmune haemolytic anaemia and/or thrombocytopenia can occur in patients with any stage of CLL and initial therapy should be with corticosteroids. If haemolysis is refractory or recurrent, splenectomy is used.
• Infection is common, especially in advanced disease, and includes organisms such as Pneumocystis jiroveci and Candida albicans. The early recognition of infections and institution of appropriate therapy are therefore critical in these patients. IV immunoglobulin can reduce the frequency of bacterial infections in patients with hypogammaglobulinaemia but is expensive and the long-term benefits are unproven.
Multiple myeloma
• This systemic malignancy peaks at 60–65 years of age and is characterized by the clonal proliferation and accumulation of malignant plasma cells in the bone marrow. These malignant plasma cells secrete paraprotein (M protein), mainly monoclonal intact IgG (55%), IgA (20%) and rarely IgD, and normal Ig production is impaired.
• Plasmacytomas (single lesions) may involve bone or soft tissue and about 25% of patients have a serum and/or urine M protein. They are treated with radiotherapy and should be closely followed up, as some will go on to develop classical myeloma.
• A minority of patients have a monoclonal gammopathy of unknown significance (MGUS). This is characterized by the presence of a monoclonal paraprotein of serum Ig in the absence of clinicopathological evidence of multiple myeloma. Around 25% of MGUS patients go on to develop myeloma over a 20–25-year period.
Diagnosis
Two out of three diagnostic features should be present:
A low β2 microglobulin and an albumin of about 35 g/L are of good prognostic value.
Treatment
• Response to treatment. A complete remission is attained once there is an absence of monoclonal paraprotein in serum and urine using immunofixation for a minimum of 6 weeks; < 5% plasma cells in the bone marrow aspirate and trephine; no increase in number and size of lytic bone lesions; and/or disappearance of soft-tissue plasmacytoma.
• Patients eligible for HD chemotherapy and PBSCR
• Induction therapy typically involves stem cell-sparing regimes such as cyclophosphamide, thalidomide and dexamethasone (CTD). Patients on thalidomide and dexamethasone are at increased risk of developing a DVT and antithromboembolic prophylaxis should be given. Around 50% of patients on thalidomide develop a sensory motor peripheral neuropathy. For those with primary refractory disease the combination of bortezomib (a proteasome inhibitor, which inhibits activation of NFκB and lowers IL-6 and VEGF levels), doxorubicin and dexamethasone (PAD) can be used. Following induction therapy peripheral blood stem cells are collected using either GCSF alone or with GCSF treatment during the recovery phase following high-dose cyclophosphamide treatment.
• Consolidation therapy using high-dose melphalan and PBSCR is then undertaken. Another approach is the use of two sequential episodes of high-dose treatment and PBSCR, known as a tandem transplant. Early reports suggest that this approach has a better overall and event-free survival. Since a graft versus myeloma effect has been clearly demonstrated, non-myelo-ablative allogeneic stem cell transplant strategies are also under investigation.
• Patients ineligible for HD chemotherapy and PBSCR. Treatment regimes include attenuated CTD (CTDa), melphalan, prednisolone and thalidomide (MPT) or the combination of cyclophosphamide and dexamethasone. Chemotherapy is continued until there is a stable level of M protein in serum and urine and no evidence of progression.
• Relapsed disease. On first relapse the combination of bortezomib and dexamethasone can be used; with a subsequent relapse the combination of oral lenalidomide (a derivative of glutamic acid structurally similar to thalidomide but with less toxicity) along with dexamethasone may be used. If patients have not previously received thalidomide, a thalidomide-containing regime such as CTD/CTDa or MPT is used.
Treatment of complications
• Skeletal involvement may include bone pain, which may require analgesic treatment. NSAIDs are particularly effective but some patients may require local radiotherapy. Bisphosphonates (clodronate/zoledronic acid) are specific inhibitors of osteoclast activity and are used as an adjunct to chemotherapy, in patients with lytic lesions or osteopenia. Long-term administration has been shown to reduce the progression of bone disease.
• Spinal cord compression due to myeloma is treated with dexamethasone followed by radiotherapy or with surgical decompression.
Oncological emergencies
Malignant hypercalcaemia
Malignant hypercalcaemia (see Box 15.3, p. 588) may complicate up to 10% of all cancers, especially breast, squamous cell carcinoma of lung and myeloma.
Palliative care and symptom control
Pain
Around 70% of cancer patients experience moderate to severe pain during the course of their disease, but with conventional analgesia this can be well controlled in most. The principles of good pain management include careful assessment of the nature and cause of the pain, instigation of analgesics according to the WHO analgesic ladder and regular review of the effectiveness of the drugs prescribed (Fig. 8.1). WHO has developed a three-step analgesic ladder for cancer pain relief. If patients complain of pain, they should be started on medication as recommended on the first step of the ladder and then moved up to subsequent steps until their pain is under control.
• Step 2. Weak opioid drugs — such as codeine, dextropropoxyphene, tramadol and combinations of codeine with paracetamol.
• Step 3. Strong opioid drugs — such as morphine, diamorphine, hydromorphone, oxycodone and transdermal fentanyl.
Strong opioid drugs
Morphine is the most commonly used strong opioid and is given by mouth. It is available as an oral solution or as an immediate-release tablet and is given regularly every 4 hours. When a patient commences morphine, a starting dose of 5–10 mg is commonly used; however, if it is replacing a stronger analgesic, a higher starting dose is necessary. If the patient’s pain is relieved by morphine but the relief is not sustained until the next dose, the dose is increased by 50% until the pain is controlled. Once the patient’s 24-hour morphine requirements have been established, this dose can be converted to a controlled-release preparation, which is then administered once or twice a day. For example:
• Side-effects
• Nausea and vomiting occur when morphine is initially prescribed but usually resolve after a few days. A centrally acting antiemetic may help relieve these symptoms.
Gastrointestinal symptoms
• Anorexia and cachexia are common symptoms in advanced cancer but may also occur during adjuvant or radical treatment regimes. The exact mechanisms in advanced malignancy are poorly understood, although the production of endogenous cytokines (tumour necrosis factor and interleukins) plays a role in the aetiology. There is no specific treatment at present but general management requires addressing associated symptoms. Progestogens (megestrol acetate) and steroids (low-dose dexamethasone, e.g. 2 mg once to twice daily) can be used judiciously in the terminal phase of life. It is essential to enlist the help of a dietitian when anorexia can be predicted as a problem caused by treatment (e.g. radical chemoradiation of the head and neck when mucositis causes significant pain; radiotherapy to regions involving small bowel; highly emetogenic chemotherapy regimes) so that nutritional support can be used early.
• Nausea and vomiting are frequently encountered and can be treatment- or disease-related. Two-thirds of patients in the terminal phase of their disease will encounter nausea and vomiting. The treatment approach should be similar to that used for pain. A detailed history and examination will help to elucidate a cause for the nausea or vomiting. It may be necessary to administer the antiemetics parenterally until vomiting has stopped, to ensure adequate absorption. As with analgesics, antiemetics are most effective if prescribed regularly (Table 8.5).
• Constipation in cancer patients is due to many factors, such as medications (i.e. analgesia), anorexia and dehydration, immobility, hypercalcaemia, abdominal/pelvic malignancy or spinal cord compression. Patients should be encouraged to mobilize and advised to improve their diet and fluid intake. A stimulant laxative (senna 2 tablets at night) and stool softener (sodium docusate 200 mg twice daily) should be routinely prescribed with opiate analgesics. Dantron 5–10 mL at night, alone or with poloxamer, is used in terminally ill patients requiring both a stimulant laxative and a stool softener. Methylnaltrexone 0.15 mg/kg SC is used for opioid-induced constipation. For patients who are faecally impacted, an arachis oil enema should be used at night to lubricate and soften faeces, prior to administration of a phosphate enema in the morning. In patients who have chronic constipation usually with extensive constipation visible on a plain abdominal X-ray, macrogols (osmotic laxatives), in a maximum dose of 8 sachets/day for 3 days, are being used for severe cases.
• Bowel obstruction is a common complication of advanced abdominal/pelvic malignancy. Most patients will be managed medically, although some will be suitable for surgical intervention. Medical management of bowel obstruction is dependent on the symptoms.
• If nausea and vomiting occur, centrally acting antiemetics should be prescribed (cyclizine up to 50 mg 3 times daily or haloperidol 5–10 mg/day).
• Intractable vomiting due to high intestinal block may be relieved by naso-gastric tube. Octreotide is used to reduce intestinal secretions and vomiting at doses of 300–600 mcg/day, so reducing the volume of naso-gastric aspirate or vomit.
| Cause | Antiemetic |
|---|---|
| Gastric stasis | Metoclopramide (10–20 mg 4 times daily) |
| Treatment-related (chemotherapy*, radiotherapy†) | Domperidone (20 mg 3 times daily), dexamethasone (4 mg twice daily), metoclopramide, ondansetron (8 mg twice daily), granisetron (1 mg twice daily), levomepromazine (3.175 mcg–25 mcg/24 hours) |
| Bowel obstruction | Cyclizine (50 mg 3 times daily), haloperidol (1.5 mg 1–2 times daily), levomepromazine (3.175 mcg–25 mcg/24 hours) |
* Different chemotherapy regimes are classed as being of low, moderate and high emetogenicity. The type, combination and duration of antiemetic will be given prophylactically according to regime.
† If radiotherapy-induced nausea is due to small bowel being irradiated, a 5HT3 antagonist is usually necessary.
Respiratory symptoms
Breathlessness can be a very distressing symptom in cancer patients and the underlying cause should be identified and treated if possible. Antibiotics may be used to treat respiratory infections, pleural and pericardial effusions may be drained and symptomatic anaemia transfused. Breathlessness at rest may be partly relieved by regular doses of oral morphine starting at 5 mg every 4 hours. If the breathlessness is associated with anxiety, diazepam 5–10 mg daily may also be of benefit. If there is significant bronchospasm or obstruction, corticosteroids are helpful. Excessive respiratory secretions occur frequently in the terminal stages of cancer and are sometimes referred to as the death rattle. For these patients SC infusion of hyoscine hydrobromide 0.6–2 mg/24 hours may be helpful.
Benson JR, et al. Early breast cancer. Lancet. 2009;373:1463-1479.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
Elwood PC, et al. Aspirin, salicylates and cancer. Lancet. 2009;373:1301-1309.
Guppy AE, Nathan PD, Rustin GJ. Epithelial ovarian cancer: a review of current management. Clin Oncol (R Coll Radiol). 2005;17(6):399-411.
Madoff RD. Rectal cancer: optimal treatments leads to optimal results. Lancet. 2009;373:811-820.
Sarssain C, et al. CNS complications of radiotherapy and chemotherapy-review. Lancet. 2009;374:1639-1651.
