Oxford Handbook of Clinical Medicine (9 edn)
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Oncology and palliative care: Contents
Cancer therapies 528
Radiotherapy 530
Tumour markers 534
Palliative care:
Relevant pages for specific cancers:
Anal (p633)
Breast (p604)
cns (p502)
Colorectal (p618)
Liver (p270)
Lung (p170)
Mesothelioma (p192)
Melanoma/skin cancers (p598)
men (p215)
Myeloma (p362)
Pancreas (p276)
Testicular (p652)
Thyroid (p602)
Upper gi (p620)
Nothing ever really matters, we might think, on gazing into the heavens, and spotting a few exploding galaxies or dying suns. But if we lead a more or less insignificant life we might rather like to matter. Dame Cicely Saunders (who combined nursing, social work and medicine, as well as founding the first hospice) matters to us because she never stopped telling her patients “You matter because you are you. You matter to the last moment of your life.” Was she right? We are better doctors if we believe her.
Consciously and continually strive to make your patients feel that they matter. Then you will realize that you matter too—and the exploding galaxies and dying suns will, for a moment, be eclipsed.
We thank Professor Max Watson, our Specialist Reader, and James Sewell, our Junior Reader, for their contribution to this chapter.
Oncology and palliative care: Overview
Relevant pages in other chapters:
Communicating about cancer
Include your patient in all decision-making processes. Many patients (not just the young and well informed) will appreciate this, and the giving of information and the sharing of decisions is known to reduce treatment morbidity. So, even when this is physically exhausting (the same ground may need covering many times) it is definitely worth spending this time. A huge amount is forgotten or fails to register initially, so videos and written information are important. Be sure to question, in an open way, about use of alternative therapies, which can indicate psychosocial distress and is frequently a sign of undisclosed worry of recurrence. Ask about this and through good communication and the promotion of autonomy, your patient’s fear-driven wish to try dangerous or untried therapies may be trumped by a spirit of rational optimism.
Looking after people with cancerNo rules guarantee success, but getting to know your patient, making an agreed management plan, and seeking out the right expert for each stage of treatment all need to be central activities in oncology. The patient will bring worries from all aspects of their family, work and social life. Communication is central to resolving these issues and the personal attributes of the doctor as a physician are key. Remember, it is never too early to start palliative care (with other treatments) and that quality of life is of the utmost importance.
Allowing negative feelings, eg fear or anger (anger can anaesthetize pain).
Counselling, eg with a breast cancer nurse in preparation for mastectomy.
Cognitive behavioural therapy reduces psychological morbidity associated with cancer treatments. See ohcs p370.
Group therapy (ohcs p376) reduces pain, mood disturbance and the frequency of maladaptive coping strategies.
Set the environment up carefully. Choose a quiet place where you will not be disturbed. Make sure family are present if wanted. Be sure of your facts.
Find out what the patient already knows or surmises (often a great deal). This may change rapidly, and different perceptions may all be relevant.
Ascertain how much the person wants to know. You can be surprisingly direct. “If anything were amiss, would you want to know all the details?”
Give some warning—“There is some bad news for us to address”. Offer small amounts of information at a time, as this can soften the impact.
Share information about diagnosis and treatments. Specifically list supporting people (eg nurses) and institutions (eg hospices). Break information down into manageable chunks and check understanding for each. Ask “Is there anything else you want me to explain?” Don’t hesitate to go over the same ground repeatedly. Allow denial: don’t force the pace, give them time.
Listen to any concerns raised; encourage the airing of feelings and empathize.
Summarize, make a plan and offer availability. Record details of the conversation in the notes (including the language used).
Follow through. Leave the patient with the strong impression that come what may, you are with them, and that this unwritten contract will not be broken.
Oncology and genetics
Genetic changes drive the pathogenesis of cancer. These changes occur most commonly as acquired events, but they may be inherited as germline mutations causing a cancer predisposition syndrome.
Familial breast/ovarian cancer
Familial prostate cancer
Familial colorectal cancer
∼20% of those with colorectal cancer have a family history of the disease. An individual’s relative risk (rr) of colorectal cancer is related to the degree of family history—refer to a genetic clinic if:
Two affected 1st–degree relatives aged <70 (rr ≈ 5);
One affected 1st-degree relative aged <45yrs at diagnosis (rr ≈ 3);
3 close relatives affected with average age at onset <60yrs (rr ≈ 2);
Familial adenomatous polyposis (below);
Potential family history of hnpcc (below).
Familial adenomatous polyposis is due to germline mutations in the apc gene (5q). Offspring are at 50% risk of being a gene carrier, and gene penetrance approaches 100% for colorectal cancer by 50yrs old. Once diagnosed, total colectomy prevents the inevitable development of carcinoma.
Peutz–Jeghers syndrome (p722) has a 10–20% lifetime risk of colorectal cancer, and is due to germline mutations in stk11, a serine threonine kinase (locus: 19p14).
Hereditary non-polyposis colorectal cancer (hnpcc) entails familial aggregation of colorectal cancer (hnpcc 1) ± cancer of uterus, ovary, stomach, renal pelvis, small gut, or pancreas (hnpcc 2) with mutations in 1 of 5 dna mismatch repair genes. Suspect a family history if ≥3 affected relatives (one 1st–degree), from 2 successive generations, of whom one was affected <50yrs old. Inheritance is autosomal dominant (incomplete penetrance). Genetic testing may be indicated. Lifetime risk of colorectal cancer for relatives who carry a mutation is 60%, and women with a mutation have a 40% lifetime risk of endometrial cancer. There is no consensus on prophylactic surgery/most centres use colonoscopic surveillance.
It is proposed that six alterations in cell physiology collectively dictate malignant growth:
Autonomy from growth signals;
Insensitivity to growth inhibitory signals;
Evasion of programmed cell death (apoptosis);
Unlimited replication potential;
Recruitment and proliferation of blood vessels (angiogenesis);
Mutations in normal genes involved in pathways associated with cell growth, differentiation, and death contribute to carcinogenesis. These mutations may result in a ‘gain of function’ (oncogenes) or ‘loss of function’ (tumour suppressor genes).
Oncogenes are mutated genes that increase activity in the absence of a relevant signal. For example, ras is a protein involved in signal transduction as part of a tiered cascade of molecular interactions. It is mutated in ∼30% of human cancers. Oncogenes behave in a dominant manner, therefore mutation to one allele results in continuous unchecked activation. Oncogene mutations occur most often as somatic events in sporadic tumours, or during the progression to malignancy in those with a predisposition gene. They are rarely inherited.
Tumour suppressor genes act as inhibitors of cellular growth. Suppression of pro-malignant processes are therefore lost in mutated genes. Unlike oncogenes, mutations to both alleles must occur before cellular effects are evident—usually as separate somatic events, but in the case of predisposition genes, the first ‘hit’ is inherited and the second may occur somatically. Thus the same gene can be involved in both inherited and sporadic tumours and explains why tumours occur at an earlier age and more than once in familial cancers. p53 is a tumour suppressor gene mutated in ∼50% of human cancers. Loss of function results in increased mutation, angiogenesis and tumour growth.
Most cancers arise from multiple mutations. This is perhaps best represented in the stepwise accumulation of cellular mutations in the pathogenesis of colorectal cancer, where virtually all carcinomas develop from adenomatous polyps (fig 1). It is thought to be the accumulation of mutations rather than the order that is critical to developing colorectal cancer.
Other familial cancer syndromes:
Oncological emergencies
A patient who becomes acutely unwell can often be made more comfortable with simple measures, but some problems require specific treatment.
Febrile neutropenic patients
Immediate treatment saves lives. See p346.
Spinal cord compression
Causes:
Typically extradural metastases. Other causes: extension of tumour from a vertebral body, direct extension of the tumour, or crush fracture.
Signs and symptoms:
Back pain, weakness or sensory loss with a root distribution (or a sensory level), bowel and bladder dysfunction. Have a low threshold for investigating patients with known cancer, who present with new or worsening back pain (especially thoracic or cervical) and any deterioration in mobility or sensation.
Investigations:
Urgent mri of the whole spine.
Management:
Superior vena cava (svc) obstruction with airway compromise
Causes:
Malignancy accounts for >90% of svc obstruction, ¾ of which are from lung cancer. Rare causes: mediastinal enlargement (eg germ cell tumour), thymus malignancy, mediastinal lymphadenopathy (eg lymphoma), thrombotic disorders (eg Behçet’s or nephrotic syndromes), thrombus around an iv central line, hamartoma.
Signs and symptoms:
Dyspnoea, orthop-noea, plethora/cyanosis, swollen face and arm, cough, headache and engorged veins.
Pemberton’s test:
Lifting the arms over the head for >1min causes facial plethora/cyanosis, jvp↑ (non-pulsatile), and inspiratory stridor.
Investigations:
Urgent contrast enhanced ct.
Management:
Malignancy associated hypercalcaemia
Affects 10–20% of patients with cancer, and 40% of those with myeloma. It is a very poor prognostic sign with 75% of patients dead within 3 months of starting hypocalcaemic treatment.
Causes:
Lytic bone mets, myeloma, production of osteoclast activating factor or pth-like hormones by the tumour.
Symptoms:
Lethargy, anorexia, nausea, polydipsia, polyuria, constipation, dehydration, confusion, weakness. Most obvious with corrected serum Ca2+ >3mmol/L (but >2.6mmol/L may be enough in some patients). Acute management involves rehydration followed by iv bisphosphonate (or calcitonin if resistant) See p691 for treatment of acute hypercalcaemia. Maintenance therapy with iv bisphosphonates is often required. The best treatment is control of underlying malignancy.
Raised intracranial pressure
(see also p840). Due to either a primary cns tumour or metastatic disease.
Signs and symptoms:
Headache (often worse in the morning, when coughing or bending over), nausea, vomiting, papilloedema, fits, focal neurological signs.
Investigations:
Urgent ct/mri is important to diagnose an expanding mass, cystic degeneration, haemorrhage within a tumour, cerebral oedema, or hydrocephalus due to tumour or blocked shunt, since the management of these scenarios can be very different.
Treatment:
Tumour lysis syndrome
Get advice today—eg from a neurosurgeon, or, where appointed, from your metastatic spinal cord compression co-ordinator. He or she will want to know:
Why you think it is urgent—eg back pain disturbing sleep (p544), radicular pain, local spinal tenderness with weak legs, sphincter disturbance, or a sensory level.
Has a tissue diagnosis of cancer been made?
Is the patient too frail for specialist treatment?
How is the compression progressing? If paraplegic for >24h, you may be too late.
How long is the patient likely to live? Is it >3 months? Urgent radiotherapy may have a role. If longer, spinal reconstruction with a bone graft may be appropriate. Vertebral body reinforcement is one option for pain. Laminectomy alone should only be done for isolated epidural tumours or neural arch metastases.
What is the fluid status (over-hydration is a danger)?
Has dvt prophylaxis been considered (p580)?
Have bisphosphonates (p696) been started? (Needed in all those with vertebral involvement from myeloma or breast cancer—they help pain and stability.)
Has the option of palliative radiotherapy been considered?
Staging systems are used to describe the extent to which a cancer has spread when first diagnosed. This is vital to determine the most appropriate treatment and to assess prognosis. It also provides a common language for doctors to communicate. Note that the stage of a cancer does not change, even if the cancer progresses or recurs. Most solid organ cancers are staged using the tnm system1, which is based on the extent of tumour (t), the extent of spread to lymph nodes (n), and the presence of metastases (m). Each cancer using the tnm system has its own classification—some use additional values and more detailed subcategories to those listed below:
Tx | Primary tumour cannot be assessed | Nx | Nodes cannot be assessed |
T0 | No evidence of primary tumour | N0 | No node involvement |
Tis | Carcinoma in situ | N1–3 | Regional node metastases |
T1–4 | Size and/or extent of primary tumour | M0 | No distant spread |
(1=small tumour with minimal invasion; 4=large tumour with extensive invasion) | M1 | Distant metastases |
Tx | Primary tumour cannot be assessed | Nx | Nodes cannot be assessed |
T0 | No evidence of primary tumour | N0 | No node involvement |
Tis | Carcinoma in situ | N1–3 | Regional node metastases |
T1–4 | Size and/or extent of primary tumour | M0 | No distant spread |
(1=small tumour with minimal invasion; 4=large tumour with extensive invasion) | M1 | Distant metastases |
A number of prefixes may also be used: c refers to clinical stage (based on information gained prior to surgery, eg from imaging or biopsy); p is the stage given after pathological examination; y refers to assessment of stage after neoadjuvant therapy; r is used if a tumour is re-staged after a disease-free interval; a indicates stage determined at autopsy.
A colorectal cancer staged as pT2 pN1b M0 describes a tumour staged after pathological examination that invades the muscularis propria of the bowel and has metastases in 2–3 regional lymph nodes, with no evidence of distant metastases. For specific tnm staging see p171 (lung cancer); p604 (breast cancer); p621 (oesophageal cancer); p649 (bladder cancer). Some cancers may also have alternative staging systems such as Duke’s classification for colorectal cancer (p619) or the figo system used in gynaecological malignancies.
The tnm stage may be combined to assign an overall ‘Stage’. In some cancers this may also require non–anatomical factors, such as the histological Gleason score in prostate cancer (p647), or the presence of serum tumour markers in testicular cancer. Stage 0 refers to carcinoma in situ; Stages i–iii describe local, locally advanced and regional disease; Stage iv indicates distant metastatic disease.
Cancer therapies
Cancer affects 30% of the population; 20% die from it. Management requires a multidisciplinary team, and communication is vital. Most patients wish to have some part in decision-making at the various stages of their treatment, and to be informed of their options. The majority will undergo a variety of therapies during the treatment of their cancer and your job may be to orchestrate these. Include the patient in the decision-making process (p522).
Surgery
Has a number of roles:
Surgical biopsy may be required to provide tissue for histological diagnosis.
Staging may be undertaken laparoscopically.
Surgery is often performed with curative intent and is the mainstay of treatment (and principal hope of cure) in most patients with solid tumours. It may be the only treatment required in early gi tumours, soft tissue sarcomas, and gynaecological tumours, but best results are often achieved when used in combination with radiotherapy or chemotherapy.
Palliative surgery may be required in advanced disease, eg surgical debulking of large tumours or stabilization of pathological fractures.
Occasionally surgery may be used prophylactically, eg in brca/fap (p524).
Radiotherapy
Uses ionizing radiation to kill tumour cells. See p530.
Chemotherapy
Cytotoxics should be given under expert guidance by people trained in their administration. Drugs are given with a variety of intents, often in combination: Neoadjuvant—to shrink tumours prior to surgery and thus reduce the need for major surgery (eg mastectomy). There is also a rationale that considers early control of micro-metastasis. Primary therapy—as the sole treatment, eg for haematological malignancies. Adjuvant—to reduce the chance of relapse after primary surgery in, eg breast and bowel cancers. Palliative—to provide relief from symptomatic metastatic disease and possibly to prolong survival.
Important classes of drugs include:
Alkylating agents: Antiproliferative drugs that bind via alkyl groups to dna, eg cyclophosphamide, chlorambucil, busulfan.
Antimetabolites: Interfere with normal cellular metabolism of nucleic acids, eg methotrexate, 5-fluorouracil.
Vinca alkaloids: ‘Spindle poisons’ which target mechanisms of cell division, eg vincristine, vinblastine.
Antitumour antibiotics: Vary in action (depending on type), eg dactinomycin, doxorubicin, mitomycin.
Monoclonal antibodies: Inhibit a specific targeted process, such as angiogenesis, (eg bevacizumab for renal cell carcinoma), or epidermal growth factor receptors (eg panitumumab and cetuximab). nb: over-expression of epidermal growth factor receptors correlates with poor prognosis in many cancers.
Others: eg etoposide, taxanes, platinum compounds.
Side-effects
depend on the types of drugs used, and include:
Alopecia: Can have a profound impact on self esteem and quality of life.
Neutropenia: Most commonly seen 10–14d after chemotherapy (but can occur within 7d for taxanes). Neutropenic sepsis requires immediate attention (p346).
Principles of combination chemotherapy:
Combination therapy has important advantages over single-agent use. It increases tumour cell kill, leading to improved overall response. It offers a broader range of drug activiy against resistant tumour cells and it prevents or slows the development of new drug-resistant cells. Each drug should have:
Single-agent activity in that tumour type (preferentially including drugs that induce complete remission)
A different mechanism of activity—ideally with additive or synergystic cytotoxic effect
Non-overlapping toxicitiy—to maximize the benefit of full therapeutic doses
Action on a different part of the cell cycle
Extensive application in many cancers.
Used for precise staging in areas occult to ct (eg marrow, cns). See p748.
Used for staging/follow-up of prostate, breast, and lung cancer.
Used for localizing active disease in breast cancer and thyroid (eg if not iodine-avid). Like bone scans, it uses technetium (99mTc).
Used to localize viable tissue, eg in brain tumours.
Used for staging and follow-up in lymphoma.
Used to demonstrate cancers with somatostatin receptors (eg pancreas, medullary thyroid, neuroblastoma, and carcinoid tumours).
99mTc-labelled tumour antibodies are used in staging by detecting tumour antigen, eg in lung, colon, and prostate cancer.
2-[18f] fluoro-2-deoxy-d-glucose positron emission tomography detects high rates of aerobic metabolism, eg in lung, colon, breast, and testis.
Used to localize noradrenaline production, eg phaeochromocytoma. mibg = meta-iodobenzylguanidine.
Do not use an iv line for cytotoxic drugs if there is any doubt about its patency. Extravasation of vesicant agents can cause severe tissue necrosis. Suspect if there is pain, burning or swelling at the infusion site.
Beau’s lines (fig 1) are horizontal depressions in the nail plate that run parallel to the moon-shaped portion of the nail bed. They result from a sudden interruption of nail keratin synthesis and may be due to local infection or trauma, systemic illness or from medication (see p32). Each line in this photo coincided with a round of chemotherapy for breast cancer. The patient was triumphant at having survived it all (just).
Beau’s lines
Radiotherapy
Radiotherapy is used in >50% of cancer patients. It uses ionizing radiation to produce free radicals which damage dna. Normal cells are better at repairing this damage than cancer cells, so are able to recover before the next dose (or fraction) of treatment.
Radical treatment
is given with curative intent. The total doses given range from 40–70 gray (Gy) in 15–35 daily fractions. Some regimens involve giving several smaller fractions a day with a gap of 6–8h. Combined chemoradiation is used in some sites, eg anus and oesophagus, to increase response rates.
Palliation
Early reactions
occur within 8 weeks of treatment.
Tiredness: Common after radical treatments. It can last weeks to months.
Skin reactions: These vary from erythema to dry desquamation to moist desquamation to ulceration. On completing treatment, use moisturizers.
Mucositis: All patients receiving head and neck treatment should have a dental check-up before therapy. Avoid smoking, alcohol, and spicy foods. Antiseptic mouthwashes may help. Aspirin gargle and other soluble analgesics are helpful. Treat oral thrush, eg with Nystatin oral solution (1mL swill and swallow every 6h) ± fluconazole 50mg/24h po.
Diarrhoea: Usually after abdominal or pelvic treatments. Maintain good hydration. Avoid high-fibre bulking agents; try loperamide 2mg po after each loose stool (max 16mg/24h).
Dysphagia: Following thoracic treatments.
Cystitis: After pelvic treatments. Drink plenty of fluids. Use nsaids.
Bone marrow suppression: More likely after chemotherapy unless large areas are being irradiated. Usually reversible.
Late reactions
occur months or years after treatment.
cns: Somnolence, 6–12wks after brain radiotherapy. Treat with steroids. Spinal cord myelopathy—progressive weakness. mri is needed to exclude cord compression. Brachial plexopathy—numb, weak, and painful arm after axillary radiotherapy. Reduced iq can occur in children receiving brain irradiation if <6yrs old.
Lung: Pneumonitis may occur 6–12wks after thoracic treatment, eg with dry cough ± dyspnoea. Treat with prednisolone 40mg od, reducing over 6wks.
gu: Urinary frequency: small fibrosed bladder after pelvic treatments. Fertility: pelvic radiotherapy (and cytotoxics) may ↓ fertility, so consider ova or sperm storage. This is a complex area: get expert help. See box 2. In premature female menopause or reduced testosterone, replace hormones. Vaginal stenosis and dyspareunia. Erectile dysfunction can occur several years after pelvic radiotherapy.
Others: Panhypopituitarism following radical treatment involving pituitary fossa. Children need hormones checking regularly as growth hormone may be required. Hypothyroidism—neck treatments, eg for Hodgkin’s lymphoma. Secondary cancers, eg sarcomas, usually wait 10 or more years before appearing, as do Cataracts.
Conventional external beam radiotherapy (ebrt) is the most common form of treatment and delivers beams of ionizing radiation to the patient from an external linear accelerator.
Stereotactic radiotherapy is a highly accurate form of ebrt used to target small lesions with great precision—most frequently in treating intracranial conditions. It is often referred to by the manufacturer’s name, eg Gamma Knife®, Truebeam®.
Brachytherapy involves a radiation source being placed within or close to a tumour, allowing high local radiation dose to a small tumour. Implants may be placed within a cavity (eg uterus) or interstitially (eg prostate or breast).
Radioisotope therapy uses tumour-seeking radionuclides to target specific tissues. For example,131I (radioiodine) to ablate remaining thyroid tissue after thyroidectomy for thyroid cancer. mibg (p529) is used to treat neural crest tumours.
Fertility issues in cancer patientsPlan with patients before treatment and get expert help.
Do not write him off as infertile—testicular sperm extraction (tese) with icsi can yield normal pregnancies.For ethical issues see ohcs p293.
Urgent referral in possible malignancy43
Diagnosis of cancer on clinical grounds alone can be difficult; however, a variety of clinical scenarios and symptoms should alert you to the possible presence of malignancy and prompt urgent referral to the appropriate specialist. The list below is by no means exhaustive but covers the commonest presentations.
Lung
Immediate admission if there are signs of superior vena caval obstruction (p526) or stridor;
Urgently (within 2 weeks) if persistent haemoptysis (smokers or non-smokers over 40);
Suggestive cxr (pleural effusion, slowly resolving consolidation);
Normal cxr but high suspicion;
History of asbestos exposure and recent chest pain or dyspnoea;
Upper gastrointestinal
Urgent referral should be regardless of H. pylori status if there is dyspepsia plus any one of chronic gi bleeding, dysphagia, progressive unintentional weight loss, persistent vomiting, iron-deficiency anaemia, epigastric mass, or suspicious barium meal result. Also:
Isolated dysphagia;
Unexplained upper abdominal pain and weight loss, with or without back pain;
Upper abdominal mass without dyspepsia;
Obstructive jaundice;
Consider referral in vomiting or iron deficiency anaemia with weight loss, or in dyspepsia with Barrett’s oesophagus, dysplasia, atrophic gastritis or old (>20yrs ago) peptic ulcer surgery. For endoscopy: those over 55 with persistent unexplained recent onset dyspepsia.
Lower gastrointestinal
If there are equivocal symptoms and you are not anxious, it is reasonable to watch and wait. Do pr examination and fbc in all.
Over 40 with pr bleeding and bowel habit change (more loose/frequent >6 weeks);
Any age with a right lower abdominal mass likely to be bowel;
Palpable rectal mass;
Men or non-menstruating women with unexplained iron-deficiency anaemia and Hb less than 11 or 10 respectively. High-risk groups: Ulcerative colitis; it is unproven whether a family history of colon cancer assists decisions in symptomatic patients (p524).
Breast
Discrete, hard lump with fixation;
Over 30 with a discrete lump persisting after a period or presenting post-menopause;
Under 30 with an enlarging lump, fixed and hard lump, or family history;
Previous breast cancer with a new lump or suspicious symptoms;
Unilateral eczematous skin or nipple change unresponsive to topical treatment;
Recent nipple distortion;
Spontaneous bloody unilateral nipple discharge;
Men over 50 with a unilateral firm subareolar mass;
Consider referral if under 30 with a lump or persistent breast pain.
Gynaecology
Examination suggestive of cervical cancer (don’t wait for a smear test);
Postmenopausal bleeding in non-hrt patients or those on hrt after 6 weeks cessation;
Vulval lump or bleeding;
Consider in persistent intermenstrual bleeding. Ultrasound: any abdominal or pelvic mass not gi or urological in origin. Do pelvic and abdominal examinations, with speculum as appropriate.
Urology
Hard irregular prostate (refer with psa result);
Normal prostate but raised psa (p534) and urinary symptoms;
Painless macroscopic haematuria at any age;
Over 40 with persistent or recurrent uti and haematuria;
Over 50 with unexplained microscopic haematuria;
Any abdominal mass arising from the urinary tract;
Swelling or mass in the body of the testis;
Ulceration or mass in the penis.
Central nervous system
New onset cranial nerve palsy or unilateral sensorineural deafness (p468);
Recent-onset headaches with features of raised intracranial pressure (eg vomiting, drowsiness, posture-related headache, pulse-synchronous tinnitus; p468) or other cns symptoms;
A new and different unexplained headache of progressive severity;
Recent-onset seizures;
Consider in rapid progression of subacute focal deficit, unexplained cognitive impairment, or personality change with features indicative of a tumour.
Haematological
p346;
Thyroid
p602;
Skin
p598.
Is the energy we expend in speeding up referrals paying off?On the good side, establishing clear referral responsibilities forces everyone to look at what they are doing—and this has facilitated many care pathways.
Paired surgeons and physicians (eg upper gi surgeon and gastroenterologist)
Radiologists
Oncologists
Histopathologists
Palliative care physicians
Specialist care nurses
Meeting administrators
This expert forum aims to provide the most up-to-date and relevant options for treatment individualized for each patient. However, despite everyone’s best efforts, there can still remain an inherent uncertainty as to what is exactly the best treatment for the patient—something which in the end may only be known to the patient him- or herself when given the options.
Tumour markers50
Tumour markers are specific molecules (usually glycoproteins) that may be found in higher concentrations in the serum and other tissues in patients with certain cancers (see table p535). They are rarely sufficiently specific to be diagnostic and do not replace biopsy for establishing a diagnosis. Many tumour markers are raised in several cancers and may also be raised in benign conditions. Normal levels do not exclude malignancy or disease recurrence.
| Frequently used tumour markers 50 | ||||
|---|---|---|---|---|
| Tumour marker | Relevant cancer | Use | Associated cancers | Associated benign conditions |
Other cancers and benign conditions in which the same tumour marker may be raised (not comprehensive) | ||||
Alpha-fetoprotein (αfp) | Germ cell/testicular | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Colorectal; gastric; hepatobillary; lung | Cirrhosis; pregnancy; neural tube defects |
Hepatocellular | ||||
Calcitonin | Medullary thyroid | Diagnosis, monitoring treatment & detecting recurrence | None known | C-cell hyperplasia |
Cancer antigen (ca) 125 | Ovarian | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Breast; cervical; endometrial; hepatocellular; lung; non-Hodgkin’s lymphoma; pancreatic; medullary thyroid carcinoma; peritoneal; uterine | Many: Liver disease; cystic fibrosis; pancreatitis; urinary retention; diabetes; heart failure; pregnancy; sle; sarcoid; ra; diverticulitis; ibs; endometriosis; fibroids |
ca 19-9 | Pancreatic | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Colorectal; gastric; hepatocellular; oesophageal; ovarian | Acute cholangitis; cholestasis; pancreatitis; diabetes; ibs; jaundice |
ca 15-3 | Breast | Monitoring treatment & detecting recurrence | Hepatocellular; pancreatic | Cirrhosis; benign breast disease; in normal health |
Carcinoembryonic antigen (cea) | Colorectal | Prognosis, monitoring treatment & detecting recurrence | Breast; gastric; lung; mesothelioma; oesophageal; pancreatic | Smoking; chronic liver disease; chronic kidney disease; diverticulitis; jaundice |
Human chorionic gonadotrophin (β-hcg) | Germ cell/testicular | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Lung | Pregnancy |
Gestational trophoblastic | ||||
Paraproteins | B cell proliferative disorders (eg myeloma) | Diagnosis, monitoring treatment & detecting recurrence | None known | None known |
Thyroglobulin | Thyroid (follicular/papillary) | Monitoring treatment & detecting recurrence | None known | None known |
| Frequently used tumour markers 50 | ||||
|---|---|---|---|---|
| Tumour marker | Relevant cancer | Use | Associated cancers | Associated benign conditions |
Other cancers and benign conditions in which the same tumour marker may be raised (not comprehensive) | ||||
Alpha-fetoprotein (αfp) | Germ cell/testicular | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Colorectal; gastric; hepatobillary; lung | Cirrhosis; pregnancy; neural tube defects |
Hepatocellular | ||||
Calcitonin | Medullary thyroid | Diagnosis, monitoring treatment & detecting recurrence | None known | C-cell hyperplasia |
Cancer antigen (ca) 125 | Ovarian | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Breast; cervical; endometrial; hepatocellular; lung; non-Hodgkin’s lymphoma; pancreatic; medullary thyroid carcinoma; peritoneal; uterine | Many: Liver disease; cystic fibrosis; pancreatitis; urinary retention; diabetes; heart failure; pregnancy; sle; sarcoid; ra; diverticulitis; ibs; endometriosis; fibroids |
ca 19-9 | Pancreatic | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Colorectal; gastric; hepatocellular; oesophageal; ovarian | Acute cholangitis; cholestasis; pancreatitis; diabetes; ibs; jaundice |
ca 15-3 | Breast | Monitoring treatment & detecting recurrence | Hepatocellular; pancreatic | Cirrhosis; benign breast disease; in normal health |
Carcinoembryonic antigen (cea) | Colorectal | Prognosis, monitoring treatment & detecting recurrence | Breast; gastric; lung; mesothelioma; oesophageal; pancreatic | Smoking; chronic liver disease; chronic kidney disease; diverticulitis; jaundice |
Human chorionic gonadotrophin (β-hcg) | Germ cell/testicular | Diagnosis, prognosis, monitoring treatment & detecting recurrence | Lung | Pregnancy |
Gestational trophoblastic | ||||
Paraproteins | B cell proliferative disorders (eg myeloma) | Diagnosis, monitoring treatment & detecting recurrence | None known | None known |
Thyroglobulin | Thyroid (follicular/papillary) | Monitoring treatment & detecting recurrence | None known | None known |
The main value of tumour markers is in monitoring the course of an illness, determining the effectiveness of treatment and in detecting cancer recurrence. Screening of asymptomatic populations to detect early cancer has yet to consistently demonstrate a survival benefit (trials for psa are conflicting and for ca 125 ongoing).
As well as being a marker of prostate cancer, psa is (unfortunately) raised in benign prostatic hyperplasia. See p647 for advising men who ask for a psa test. 25% of large benign prostates give psa up to 10 ng/mL. psa may also be raised if:
Black Africans
Taller men
Recent ejaculation (avoid for 24h prior to measurement)
Recent rectal examination (usually insignificant
)
Prostatitis
| Age (yrs) | psa cut-off values ng/mL |
|---|---|
50–59 | ≥ 3.0 |
60–69 | ≥ 4.0 |
70 and over | ≥ 5.0 |
| Age (yrs) | psa cut-off values ng/mL |
|---|---|
50–59 | ≥ 3.0 |
60–69 | ≥ 4.0 |
70 and over | ≥ 5.0 |
psa ng/mL | psa will be ∼50% lower after 6 months on 5α reductase inhibitors (see p644) | |
Benign prostatic hyperplasia | <4 in 91% 4–10 in 8% >10 in 1% | |
Prostate carcinoma | <4 in 15% 4–10 in 20% >10 in 65% |
psa ng/mL | psa will be ∼50% lower after 6 months on 5α reductase inhibitors (see p644) | |
Benign prostatic hyperplasia | <4 in 91% 4–10 in 8% >10 in 1% | |
Prostate carcinoma | <4 in 15% 4–10 in 20% >10 in 65% |
The above is a guide; reference ranges and populations vary. More specific assays, such as free psa/total psa index and psa density, are also available, which may partly solve these problems. It is shown to illustrate the common problem of interpreting a psa of ∼8—and as a warning against casual requests for psas in the (vain) hope of simple answers. nb: psa should be ‘undetectable’ after radical prostatectomy—refer to a urologist if >0.04ng/mL.
Antineuronal antibody associated paraneoplastic syndromes are rare, fascinating non-metastatic manifestations of malignancy mediated by hormones, cytokines or antibodies. They are triggered by an altered immune system response to a neoplasm and their importance is that they often pre-date symptoms associated with the cancer itself. They are worth knowing about: if you do, you will occasionally save a life by making a rather clever double diagnosis, eg of an odd eyelid rash (dermatomyositis p554) and of its associated cancer (eg colon cancer); examples are given in ohcs p589.
Palliative care: principles and symptom relief
Palliative care is the medicine of palliating (relieving) symptoms. Though this most often applies in the later stages of a malignancy, it does not necessarily have to— something that doctors and patients all too often forget.
Take time to find out exactly what is troubling a patient and approach problems holistically. Remember, each person comes with a set of emotions, preconceptions and a family already attached. Most hospitals now have a dedicated palliative care team for help and advice. See also p7.
Pain
See p538.
Nausea and vomiting
Causes include chemotherapy, constipation, gi obstruction, drugs, severe pain, cough, oral thrush, infection and uraemia.
Management:
Oral agents:
Constipation
Very common se with opiates, and better prevented than treated. May also be due to ↑Ca2+ or dehydration. Use bisacodyl 5mg at night, or combine a stimulant with a softener (co-danthramer 5–10mL nocte). Macrogols 2–4 sachets/12h are useful in resistance. Try glycerol suppositories or an enema if oral therapy fails.
Breathlessness
Mouthcare
Treat any candida infection or other underlying cause. Simple measures such as chewing ice chips, pineapple chunks (release proteolytic enzymes) or gum should be tried. Good oral hygiene with mouth washes, chorhexidine and saliva substitutes, such as Biotene Oralbalance® gel, can help.
Pruritus
(itching) See p26.
Venepuncture problems
Repeated venepuncture with the attendant risk of painful extravasation and phlebitis may be avoided by insertion of a single or multilumen skin-tunnelled catheter (eg a Hickman line) into a major central vein (eg subclavian or internal jugular) using a strict aseptic technique. Patients can look after their own lines at home, and give their own drugs. Problems include: infection, blockage (flush with 0.9% saline or dilute heparin, eg every week), axillary, subclavian, or superior vena cava thrombosis/obstruction, and line slippage.
The last days and weeks of life
Once a decision has been made that a patient is entering the very final days of their illness, comfort should be the main concern. Think about stopping observations, unnecessary blood tests and medications (such as those for long-term prophylaxis). Prescribe ‘as required’ subcutaneous end of life drugs before they are needed (see box 2). Start a syringe driver if any of these are being given regularly. Ensure that a ‘do not attempt resuscitation’ order has been made and clearly documented (usually by a senior doctor). Personalised end-of-life care plans should be made, which focus on control of symptoms, comfort and cessation of unnecessary interventions. Consider whether transfer to a hospice may be appropriate. If going home is a priority, it can be arranged at very short notice.
Syringe drivers allow a continuous subcutaneous infusion of drugs when the oral route is no longer feasible and avoids repeated cannulation attempts. Several drugs can be administered subcutaneously to palliate a number of symptoms:
| Indication | Drug | Subcutaneous dose | Comment |
|---|---|---|---|
Pain | Diamorphine | Start 10–20mg/24h If converting from oral morphine divide total 24h dose by 3 (see p539). | If using regular breakthrough doses, ↑ daily dose by total breakthrough dose required. |
Agitation | Midazolam | 20–100mg/24h | |
Nausea and vomiting | Cyclizine | 150mg/24h | |
Haloperidol | 1.5–10mg/24h | ||
Respiratory secretions | Hyoscine hydrobromide1 | 0.6–2.4mg/24h | |
Glycopyrronium | 0.6–1.2mg/24h | ||
Bowel colic | Hyoscine butylbromide1 | 20–120mg/24h |
| Indication | Drug | Subcutaneous dose | Comment |
|---|---|---|---|
Pain | Diamorphine | Start 10–20mg/24h If converting from oral morphine divide total 24h dose by 3 (see p539). | If using regular breakthrough doses, ↑ daily dose by total breakthrough dose required. |
Agitation | Midazolam | 20–100mg/24h | |
Nausea and vomiting | Cyclizine | 150mg/24h | |
Haloperidol | 1.5–10mg/24h | ||
Respiratory secretions | Hyoscine hydrobromide1 | 0.6–2.4mg/24h | |
Glycopyrronium | 0.6–1.2mg/24h | ||
Bowel colic | Hyoscine butylbromide1 | 20–120mg/24h |
Do not confuse the vastly different doses for hyoscine hydrobromide and hyoscine butylbromide!
Prescribe the following prn subcutaneous medications for all dying patients before they are needed, in anticipation of any symptoms. Also write them up for any patients on syringe drivers who may require breakthrough doses.
| Indication | Drug | Subcutaneous dose | Comment |
|---|---|---|---|
Pain | Diamorphine | 2.5–5mg/3–4h | Breakthrough dose = 1/6th of total 24h dose. |
Agitation | Midazolam | 2.5mg–5mg/4h | |
Nausea and vomiting | Haloperidol | 1–2.5mg/8h | |
Respiratory secretions | Hyoscine hydrobromide1 | 0.4mg/8h |
| Indication | Drug | Subcutaneous dose | Comment |
|---|---|---|---|
Pain | Diamorphine | 2.5–5mg/3–4h | Breakthrough dose = 1/6th of total 24h dose. |
Agitation | Midazolam | 2.5mg–5mg/4h | |
Nausea and vomiting | Haloperidol | 1–2.5mg/8h | |
Respiratory secretions | Hyoscine hydrobromide1 | 0.4mg/8h |
(alphabetically listed)
Colestyramine 4g/6h po (1h after other drugs) may help itch with jaundice.
Dexamethasone 8mg iv stat relieves symptoms of svc or bronchial obstruction, and lymphangitis carcinomatosa. 4mg/24h po may stimulate appetite, reduce ↑icp headache, or induce (in some patients) a satisfactory sense of euphoria (short-term benefits must be balanced against side-effects).
Fluconazole 50mg/24h po for candida.
Haloperidol 0.5–5mg/24h po helps agitation, hallucinations, and vomiting.
Hyoscine hydrobromide 0.4–0.6mg/8h sc or 0.3mg sublingual: vomiting from upper gi obstruction or noisy bronchial rattles.
Metronidazole 400mg/8h po mitigates anaerobic odours from tumours; so do charcoal dressings (Actisorb®).
Naproxen 250mg/8h with food: fevers caused by malignancy or bone pain from metastases (consider splinting joints if this fails).
Nerve blocks may lastingly relieve pleural or other resistant pains.
Sodium chloride nebulizers 5mL as needed, can aid persistent cough.
Spironolactone 100mg/12h po + bumetanide 1mg/24h po for ascites associated with portal hypertension (but not for ascites caused by abdominal malignancy, ie where serum-ascites albumin gradient <11g/L).
Palliative care: pain relief
(See also p7)
Pain
Assessment
Management
By the mouth—give orally wherever possible.
By the clock—give at fixed intervals to give continuous relief.
By the ladder—following the who stepwise approach (box).
For the individual—there are no standard doses for opiates, needs vary.
With attention to detail—inform, set times carefully, warn of side-effects.
Morphine
If the oral route is unavailable try morphine/diamorphine iv/sc (see box for conversions). If difficulty tolerating morphine/diamorphine, try oxycodone po/iv/sc/pr, starting at an equivalent dose. It is as effective as morphine and is a useful 2nd-line opioid with a different range of receptor activity. OxyNorm® is the oral liquid form. There are also fentanyl transdermal patches which should usually be started under specialist supervision (after opioid dose requirements have been established). Remove after 72h, and place a new patch at a different site. 45mg oral morphine/24h is approximately equivalent to a 12mcg/h fentanyl patch.Suppositories
for pain: try oxycodone 30mg pr (eg 30mg/8h ≈ 30mg morphine).
Syringe drivers
Unfounded fears:
Prescribing morphine and other controlled drugs:
Include the total quantity in both words and figures, and include the formulation (tablets, capsules, oral liquid, etc). On charts rewrite medications in full if doses change and always give the amount in milligrams, especially when using liquid preparations.
Morphine-resistant pain
Consider methadone or ketamine, and adjuvants such as nsaids, steroids, muscle relaxants or anxiolytics + seek expert help. If neuropathic pain is suspected, try amitriptyline (10–25mg on) or pregabalin (25–300mg/12h). Depression is common, and can amplify pain, so consider starting an ssri.
(See p576 for nnt)
Rung 1 | Non-opioid | Paracetamol; nsaids |
Rung 2 | Weak opioid | Codeine; dihydrocodeine; tramadol |
Rung 3 | Strong opioid | Morphine; diamorphine; hydromorphone; oxycodone; fentanyl; buprenorphine (± adjuvant analgesics) |
Rung 1 | Non-opioid | Paracetamol; nsaids |
Rung 2 | Weak opioid | Codeine; dihydrocodeine; tramadol |
Rung 3 | Strong opioid | Morphine; diamorphine; hydromorphone; oxycodone; fentanyl; buprenorphine (± adjuvant analgesics) |
| 24h dose (mg) | 4h dose (mg) | Relative potency to oral morphine | |
|---|---|---|---|
Morphine po | 30 | 5 | 1× |
Morphine iv | 15 | 2.5 | 2× |
Morphine sc | 15 | 2.5 | 2× |
Diamorphine iv | 12 | 2 | 3× |
Diamorphine sc | 12 | 2 | 3× |
Oxycodone po | 15 | 2.5 | 2× |
Oxycodone iv | 12 | 2 | 3× |
Oxycodone sc | 7.5–15 | 1.25–2.5 | 3× |
Alfentanil sc1 | 1 | — | 30× |
| 24h dose (mg) | 4h dose (mg) | Relative potency to oral morphine | |
|---|---|---|---|
Morphine po | 30 | 5 | 1× |
Morphine iv | 15 | 2.5 | 2× |
Morphine sc | 15 | 2.5 | 2× |
Diamorphine iv | 12 | 2 | 3× |
Diamorphine sc | 12 | 2 | 3× |
Oxycodone po | 15 | 2.5 | 2× |
Oxycodone iv | 12 | 2 | 3× |
Oxycodone sc | 7.5–15 | 1.25–2.5 | 3× |
Alfentanil sc1 | 1 | — | 30× |
Alfentanil can be used in patients with marked renal failure—discuss with the palliative care team first
To convert oral codeine, dihydrocodeine, or tramadol to oral morphine, divide the total daily dose by about 10.
Conversions are not exact; these tables are intended as a rough guide. The potency figures in particular can vary widely. If in doubt, use a dose below your estimate.
Total sedationWhy is there so much variation in cancer 5-yr survival rates? In breast cancer, 5-yr survival is 82% in England, 88% in Australia and 89% in Sweden. One reason is nhs inefficiency; another is cultural. If an English woman feels a lump she may say “I haven’t got time to be ill,” or “Let’s see if it goes away,” or “If this is how I’m going to die, so be it,” but others may say “I’d better get this sorted now.”
The tnm system was developed and is maintained by the American Joint Committee on Cancer (ajcc) and the International Union Against Cancer (uicc). Gynaecological malignancies use both the tnm and figo classifications for staging. Haematological malignancies and cns tumours do not use the tnm system.
Some recommend (on scant evidence) topical dimethylsulfoxide (dmso) and cooling after extravasation of anthracyclines or mitomycin, locally injected hyaluronidase if vinca alkaloids involved, and locally injected sodium thiosulfate (sodium hyposulfite) if chlormethine (mechlorethamine; mustine). nb all uses unlicensed.
Note there are no age specific reference ranges for men over 80 years. Nearly all will have a focus of cancer, which only needs to be diagnosed if likely to need palliative treatment.
Document that this is the patient’s wishes, each dose increase is proportionate and plans have been discussed with an experienced colleague; take into account gmc guidance.
