Metastatic disease and palliative care

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14

Metastatic disease and palliative care

Introduction

Metastatic spread is defined as spread of breast cancer beyond the breast and ipsilateral axillary and/or internal mammary lymph nodes. With current therapies, metastatic disease is incurable and treatment is, by definition, palliative. Such patients may, however, benefit considerably from treatment. The principles and practice of treatment include a combination of active disease management, active symptom management, and appropriate support for patient and family. A more detailed review of the evidence is provided in the National Institute of Health and Clinical Excellence (NICE) guideline.1

Historically, palliative care and terminal care were one and the same. However, modern palliative care includes symptom and supportive care for patients ‘upstream’ in their illness. As cancer advances, patients’ symptom burden increases, and they need the best of symptom control as well as the best of cancer treatment. All surgeons should be able to provide high-quality basic palliative care for their patients, and specialist palliative care staff should be available to support staff to manage the most complex and persisting problems.

A frequent dilemma is how much and how intensively to both treat and provide care aimed at comfort. The issues faced by staff working at this interface between intensive palliative surgical (or medical) treatment and intensive symptom control are demanding and complex.

Presentation and prognosis

A minority of breast cancer patients (< 10%) present initially with metastatic disease.2 Most metastatic patients, however, present months or years after their primary treatment (surgery and appropriate adjuvant therapy). The natural history of breast cancer can be very long – patients still die from breast cancer 20 years and more after their initial treatment.3

Most patients present with symptoms of metastatic disease between follow-up visits;4 screening asymptomatic patients is not worthwhile.5,6 The common sites of metastatic spread are listed in Table 14.1; among other sites is the peritoneum, to which infiltrating lobular carcinoma, in particular, can spread and cause non-specific abdominal symptoms and/or obstruction.

Table 14.1

Symptoms commonly associated with metastatic spread to different organs

Site Common symptoms
Pleura Dyspnoea (due to effusion)
Bone Pain
Pathological fracture
Nausea and thirst (due to associated hypercalcaemia)
Lung Dyspnoea
Cough (dry cough is often seen with lymphangitis carcinomatosa)
Liver Fatigue
Nausea
Anorexia
Pain over liver
Brain Headache (often worse first thing in the morning)
Unilateral weakness
Unsteady gait

Staging

All patients presenting with locally advanced, inoperable or locally recurrent breast cancer should undergo a series of investigations to stage their disease adequately. In addition, patients presenting with metastatic disease at one site (e.g. bone) should have investigations to assess the extent of spread to other organs. The principal sites of spread are the thorax, bone and liver. Thus, tests to assess the extent of spread and organ function include a full blood count, clinical chemistry (urea and electrolytes, bone chemistry and liver function tests), tumour markers (carcinoembryonic antigen and carbohydrate antigen 15-3, which can be useful to assess response7), bone scintigram and computed tomography (CT) scan of thorax abdomen and pelvis. Alternatives are a liver ultrasound or magnetic resonance imaging (MRI). Increased long bone activity identified on bone scintigraphy should be further assessed by plain X-ray, supplemented by MRI if necessary, to assess degree of destruction and risk of pathological fracture. The brain should be assessed (CT or MRI) if the patient has symptoms suggestive of intracranial metastases. Urgent MRI of the whole spine is required if the patient has symptoms of spinal cord compression.

Clinicians need to understand the limitations of these investigations. Although bone scintigraphy is more sensitive than plain X-ray, it will not detect all bone metastases. If a patient has persistent bony symptoms and a negative bone scan (or negative in the symptomatic area) then an MRI should be requested, since it is more sensitive than bone scintigraphy. Discrete liver metastases are well visualised by most techniques, but diffuse infiltration may not be apparent on liver ultrasound. Positron emission tomography (PET)-CT cam be useful8 in resolving whether lymph nodes or isolated lesions seen in the lung or liver are indeed metastases (albeit infected or inflammatory conditions can also be positive on fluorodeoxyglucose PET).

Treatment

Management is palliative and the aim of treatment is to give the patient the best quality of life with the minimum of side-effects. Successful management of symptoms will tend to prolong survival, but the emphasis of treatment is on the quality of the life lived rather than its length. Patients need to understand from their clinician the nature of their illness and the aims of treatment before discussing treatment options, likely side-effects and potential benefits.

Broadly speaking, systemic therapies control breast cancer and specific therapies control specific symptoms. The two are not mutually exclusive and most patients will need both.

Systemic therapy

In general, a durable response to systemic therapy offers the best quality of life (see guidance in Fig. 14.1).

Exceptions are patients with lymphangitis carcinomatosa or extensive liver metastases – hormone-induced response rates at both these sites are low, and one may not be able to wait 6–8 weeks for a response, hence chemotherapy is indicated. Endocrine therapy is ineffective in ER-negative breast cancer. If patients respond well to either endocrine or chemotherapy, then they may respond to second-line agents on relapse.

Endocrine therapy

Premenopausal women

In 1896, Beatson10 demonstrated the endocrine sensitivity of breast cancer for the first time, by undertaking surgical oophorectomy for advanced breast cancer. Current therapy (Table 14.2) aims to either decrease levels of circulating oestrogen (ovarian ablation) or block its effect on the oestrogen receptor (anti-oestrogens). Ovarian ablation can be performed either by surgical removal (usually laparoscopically), by a short course of radiotherapy to the pelvis (infrequent – because of gastrointestinal side-effects), or the use of a luteinising hormone-releasing hormone (LH-RH) agonist, e.g. goserelin. The latter is given by monthly injection into the anterior abdominal wall and is reversible; thus, if there is no tumour response, the patient’s periods can be restored and menopausal symptoms abolished. Tamoxifen is a partial oestrogen agonist but its effects on breast cancer cells are to antagonise oestrogen. It is effective in both pre- and postmenopausal women.

Table 14.2

Endocrine agents used in breast cancer

Class of agent Examples Main side-effects
Ovarian ablation Surgical oophorectomy
Radiation menopause
LH-RH agonists
Menopausal symptoms
Anti-oestrogens Tamoxifen
Fulvestrant
Menopausal symptoms
Thrombo-embolism
Aromatase inhibitors Anastrozole
Letrozole
Exemestane
Menopausal symptoms
Arthralgia
Osteoporosis
Progestagens Megesterol acetate Weight gain
Increased appetite
Thrombo-embolism
Glucocorticoid suppression

Aromatase inhibitors (AIs; see next section) work in postmenopausal but not in premenopausal women. Particular caution should be taken with women who have chemotherapy-induced amenorrhoea, as they may still have some ovarian function, making AIs ineffective.12 In premenopausal women, a combination of LH-RH agonist plus AI has shown responses.13

Progestagens (e.g. megesterol acetate, medroxyprogesterone) at high dose have been used for many years, for their anti-oestrogenic action. Their main side-effects are significant weight gain and increased risk of thromboembolic disease. Suppression of glucocorticoid production has been reported,14 so patients may need hydrocortisone to cover physiological stress (e.g. pinning of pathological fractures, infections, etc.).

Thus, first-line therapy would be tamoxifen ± ovarian ablation, with an AI/LH-RH agonist as second line and progestagens as third line. Choice will, however, be influenced by prior adjuvant therapy, though if it is > 1 year since the last endocrine therapy (e.g. tamoxifen), it may be worth retrying it.

Postmenopausal patients

Ovarian ablation has no role. Oestrogen in postmenopausal women is produced by conversion of androstenedione to oestrone by aromatase,15 mostly in peripheral fat but also in liver, normal breast tissue and some breast cancers. Aromatase inhibitors (Table 14.2) reduce circulating oestrogen to nearly immeasurable levels.

There are two types of AI: non-steroidal (anastrozole and letrozole) and steroidal (exemestane). Their side-effects are, however, similar (Table 14.2), implying that these are due to their reduction of circulating oestrogen.

image

AIs are more effective16 than tamoxifen (appropriate second-line agent) and progestagens (third line).

Fulvestrant is a pure oestrogen antagonist, as unlike tamoxifen it has no agonist action. It binds to, blocks and degrades the oestrogen receptor. Clinical trials in postmenopausal women have shown it to be as active as anastrozole.17 It is given monthly by intramuscular injection – a potential advantage where oral compliance is a problem. Studies with higher doses, 500 mg instead of the standard 250 mg dose, have shown that these higher doses appear effective.

Adding biological agents such as mTOR (mammalian target of rapamycin) inhibitors to endocrine agents such as tamoxifen or aromatase inhibitors appears to increase response rate, duration of response and even overall survival (Fig. 14.2). Studies with these agents are continuing, although as yet they are not used outside clinical trials.

Chemotherapy

Chemotherapy is used to treat ER-negative breast cancer, ER-positive breast cancer that is no longer sensitive to endocrine agents, and advanced ER-positive visceral disease. The main classes of drugs and their side-effects are listed in Table 14.3. These drugs are toxic and should only be prescribed by clinicians (usually oncologists) experienced in their use.

Table 14.3

Main cytotoxic chemotherapy drugs used in breast cancer

Group of drugs Examples Main side-effects*
Anthracyclines Doxorubicin
Epirubicin
Mouth ulcers
Cardiomyopathy
Alkylating agents Cyclophosphamide
Antimetabolites 5-Fluorouracil
(capcitabine)
Methotrexate
Coronary spasm
Hand–foot symdrome
Taxanes Docetaxel
Paclitaxel
Peripheral and autonomic neuropathy
Mouth ulcers
Vinca alkaloids Vinorelbine Peripheral neuropathy
Gemcitabine
Platinum Carboplatinum
Cis-platinum
Neuropathy
Renal failure

*Nearly all these drugs can cause fatigue, nausea, vomiting, myelosuppression, cessation of periods (premenopausal women) and alopecia, so they are not listed individually.

The drug groups with the highest activity are the anthracyclines and the taxanes. The major limitation to anthracycline use is cardiomyopathy – the risk increasing as cumulative dose increases. A course of anthracyclines cannot, therefore, usually be repeated. Taxanes are active and more effective than some other regimens.19 Capecitabine is an oral prodrug of 5-fluorouracil. It is metabolised into the active component in the liver and possibly in the tumour itself.

As more agents are used in the adjuvant (or neoadjuvant) setting, the use of other active drugs such as vinorelbine, gemcitabine and platinum agents in metastatic disease is likely to increase. Platinum salts may have particular activity in the treatment of patients with basal-type tumours20 and are currently being studied in clinical trials.

The choice of chemotherapy agents is influenced by prior therapy, the general health of the patient, and what agent is most likely to produce useful palliation with minimal side-effects.

Trastuzumab

A growth factor receptor gene, human epidermal growth factor (HER-2), is amplified in about 14% of breast cancers and is associated with a poorer prognosis.21 Trastuzumab is a humanised monoclonal antibody that targets the HER-2 receptor in patients whose tumours overexpress HER-2 as assessed by immunohistochemistry and/or fluorescence in situ hybridisation (FISH) testing.

Trastuzumab is generally well tolerated except for cardiac toxicity, so is not usually given concurrently with anthracyclines. It should be used with caution in patients with prior anthracycline exposure or significant cardiac disease; patients require cardiac monitoring by multiple-gated acquisition (MUGA) scan or echocardiogram.

With these provisos, trastuzumab can be used in HER-2-positive patients. It is generally given with a course of taxane chemotherapy and continued as a single agent whilst response is maintained. Response may last months and even years. Trastuzumab is a large molecule and does not pass the blood–brain barrier, so patients who respond may develop brain metastases as the sole site of active disease. The brain metastases should be treated actively (see later), trastuzumab continued and the patient may regain remission. Other drugs targeting HER-2-positive breast cancers including pertuzumab and T-DM1 are in clinical trials. Combination of pertuzumab and trastuzumab looks particularly promising in patients with metastatic breast cancer (Fig. 14.3).

Lapatinib inhibits the tyrosine kinases of HER-2 and has been shown to be active in combination with capecitabine in patients who have relapsed on trastuzumab.23

Assessment of response

The most important method of assessing benefit is whether the patient’s symptoms have improved. Nevertheless, symptoms can improve independently of systemic therapy (e.g. analgesics for pain). Thus, it is also important to assess response to systemic therapy objectively. Locally recurrent disease can be assessed by regular photography and compared with previous clinical photographs. Similarly, monitoring measurable lesions on CT provides objective evidence of response. Assessment of bony metastases can be difficult. Plain X-ray changes are slow to develop with response, and responding sclerotic lesions will show little change. Bone scintigraphy can be misleading; 3 months after starting therapy, there may be increased uptake at sites of disease (‘flare’) indicating response and this can be indistinguishable from progression. Changes in the levels of tumour markers at 3 months can predict response24 or individual lesions can be monitored by MRI.1

Control of symptoms

Despite the absence of evidence, staff, patients and families are often concerned that intensive symptom management prevents further palliative treatment of underlying cancer and that it inevitably causes sedation and may even hasten death. Uncontrolled symptoms affect quality of life and the ability of the patient to make considered treatment decisions, hence meticulous symptom control should be available as part of comprehensive cancer management.

Pain

Sixty-five per cent of patients with advanced cancer suffer pain.27 One-third of those with pain have one pain, another third have two different types of pain and the remaining third have three or more types of pain. Cancer-related nerve pain is common; 70–90% of pain responds to potent opioids if properly prescribed28 and the key to managing pain is careful assessment using a simple structured tool such as ‘NOPQRST’ (Box 14.1).

Analgesic requirements are likely to increase as illness advances.

Other strong opioids are used when the transdermal route is preferred or the patient has unacceptable side-effects with morphine.

Non-oral routes (e.g. by a subcutaneous syringe driver) are preferable when nausea and vomiting are present and do not mean that the patient is dying, merely that an alternative route to deliver medication is needed – for example, a patient with pain who is vomiting due to hypercalcaemia and constipation. Morphine (10 mg given by intermittent intravenous boluses) may lead to erratic pain control and sleepiness, which can be avoided by using lower doses by subcutaneous infusion, until the situation has resolved and oral medications are appropriate.

Common concerns over opioid analgesics: Whilst morphine is the drug of first choice, side-effects or inadequate pain relief may limit benefit in 10–30% of patients. Switching opioids may reduce side-effects (Box 14.2) but if the pain is not opioid sensitive and toxicity is not a problem, switching from one to the other alone will not solve uncontrolled pain.30

Pain flares: Transient flares of severe pain are common and may be due to end of dose failure, a spontaneous worsening of pain or incident pain. The first two usually respond to an increased 24-hour dose of opioid.

image

Incident pain occurs in two-thirds of patients with pain31 and is common in patients with bone metastases. It is the result of an intervention such as weight bearing, coughing or moving.

Analgesia sufficient to manage an incident pain peak may cause toxicity in relation to background pain; therefore, a fast, short-acting rescue analgesic such as transmucosal or intranasal fentanyl may be more effective than breakthrough oral morphine.

Liver capsule pain from liver metastases usually responds to dexamethasone 4–12 mg p.o. daily or, for speed and if pain is associated with nausea or vomiting, 12 mg over 24 hours by subcutaneous syringe driver for a few days until symptoms have resolved. The dose should then be reduced to the smallest effective oral maintenance dose.

Neuropathic pain: Patients often find it difficult to describe accurately nerve pain that typically has burning, shooting, stabbing, knife-like or tingling character and patients frequently accompany their description by rubbing the dermatome where the pain is felt. It has a distressing quality, which may not be adequately reflected in a simple 0–10 scale; hence a simple neuropathic pain screening tool has been recently developed.32 It is critical to recognise neuropathic pain, and to diagnose the underlying pathology, as it usually represents new and potentially treatable metastatic disease.

Neuropathic pain responds to opioids in approximately one-third of patients, but the remaining two-thirds may be difficult to manage. Nerve root involvement is most likely to result from brachial plexus involvement or epidural disease as a result of vertebral metastases and subsequent bony collapse. Drugs used primarily for reasons other than analgesia may help,33,34 such as low doses of antidepressants (amitriptyline or nortriptyline35), anticonvulsants (gabapentin, pregabalin36) or specific N-methyl-D-aspartate antagonists (ketamine37). Methadone (specialist use only) is helpful when pain consists of a mixture of neuropathic and non-neuropathic pain, but there is insufficient published evidence on its use in cancer-induced pain.38 Finally, interventional procedures – cordotomy (unilateral nerve root pain) or epidural followed by an intrathecal implant – may be considered following consultation with the local pain or anaesthetic service.

Bisphosphonates: Bisphosphonates inhibit osteoclast activity, leading to decreased bone absorption.

image

There is good evidence42,43 that regular treatment with bisphosphonates for 6 months or longer reduces ‘skeletal morbidity’, namely reduction in pathological fractures, need for palliative radiotherapy and hypercalcaemia.

The drugs used are most commonly the third-generation drugs zoledronate and ibandronate. Zoledronate is given intravenously every 4 weeks (or 3-weekly with chemotherapy); ibandronate can be given orally (on an empty stomach 1 hour before food). They are usually reasonably well tolerated but can cause flu-like symptoms, gastrointestinal disturbance and rarely osteonecrosis of the jaw.44 They should be given with caution in patients with renal impairment. Intravenous bisphosphonates can also reduce pain in patients with widespread bony metastases.45 A monoclonal antibody against rank ligand, denosumab, looks promising and is at least as effective as zoledronate and can be administered by subcutaneous injection.

Effusions: Pleural spread is common, especially on the ipsilateral side. The patient usually presents with dyspnoea, and drainage with pleurodesis (using talc47) gives good symptomatic relief. Ascites is less common than pleural spread and is managed by repeated percutaneous drainage.

Nausea, vomiting and retching: These are common, distressing symptoms and are reported in 50–60% of patients suffering from advanced cancer. Numerous neurotransmitters and receptor types are involved; thus, anti-emetics are mainly neurotransmitter blockers (Table 14.4).48

Table 14.4

Management of nausea/vomiting due to cancer or its treatment

Anti-emetic
Metabolic, e.g. hypercalcaemia
Drug/toxin induced, e.g. opioid
Haloperidol 1.5 mg nocte/b.d.
Levomepromazine 6 mg tab nocte
Haloperidol 1.5 mg nocte/b.d.
Levomepromazine 6 mg nocte
Chemotherapy Ondansetron
Dexamethasone
Radiotherapy Ondansetron
Raised intracranial pressure (cerebral metastases, brain stem or meningeal disease) Cyclizine 50 mg t.d.s. or 150 mg/24 h s.c.
Dexamethasone 4–16 mg in morning
Bowel obstruction
(if surgery inappropriate)
Cyclizine 50 mg p.o. t.d.s./150 mg/24 h s.c.
Hyoscine butyl bromide 40–100 mg/24 h s.c.
Octreotide 300–1000 mg/24 h s.c.
Ondansetron 8–24 mg/24 h p.o., i.v., s.c.
Gastric stasis/outlet obstruction Metochlopramide or domperidone 10–20 mg q.d.s. or
Metochlopramide 30–100 mg/24 s.c.
Vestibular disease (base skull tumour) Cyclizine 50 mg p.o. t.d.s.
Levomepromazine 6 mg p.o.
Haloperidol 1.5 mg b.d.
Trial dexamethasone

Constipation: Constipation is present in half of all patients with advanced cancer. It causes pain, distension, anorexia, nausea, malaise and embarrassment, and diagnostic confusion if it results in ‘overflow’ diarrhoea. Contributory factors include opioid use, reduced fluid and fibre intake, and reduced mobility. A recent Cochrane systematic review49 concluded that all laxatives assessed were ineffective for a significant proportion of patients, and some patients required multiple ‘rescue’ laxatives. Patients on opiates should be routinely prescribed a stimulant and a softener. Methylnaltrexone is a novel treatment for opioid-induced constipation.50

Overall care of the patient approaching death

On approaching the terminal phase, patient and clinicians need to recognise that active treatment becomes less appropriate, although active symptom palliation remains paramount. The primary care team and the hospital specialists involved in the care of the patient will often have known the patient for some considerable time and have some knowledge of the family circumstances. But if the patient does not understand the reality of their situation, then important issues may not have been discussed. For example, the young single mother will need to address the future care of her children, an older woman the care of a frail elderly spouse.

Patients may have survived many relapses over the years, and they and their families may believe that they will recover from the current episode. Clinical staff need to recognise a patient’s likely prognosis – is she ill with very advanced metastatic breast cancer and is she perhaps dying?

What does the patient understand? Although clinical prediction of survival is a useful independent predictor for survival, it tends to be over-optimistic and for many patients it will be inaccurate. Broadly speaking, when deterioration in health is noted over months, survival is likely to be months, when it has been over weeks, survival is likely weeks and when it has been over days, survival is likely to be days.

In advanced malignancy, symptoms rather than test results may be more useful in predicting survival. Patients with low performance status (Palliative or Karnofsky Performance Scales) have a poorer survival, although higher performance status does not necessarily predict for longer survival. Certain symptoms such as nausea, breathlessness and weakness have independent value as prognostic factors. Combining clinical prediction with other factors to produce a prognostic score (Table 14.5) gives simple and clinically more accurate useful bedside prognostic information.51

Recognition and communication that the patient may be dying

‘The physician does and does not want to pronounce a death sentence and the patient does and does not want to hear it’

The patient and family value communication of information and support that will come from a variety of sources (e.g. doctors, specialist and general nurses, palliative care staff) at different times and stages.

Patients, families and professionals need to understand that death is a possibility before they can discuss management options. Several consultations may need to take place over a few days as people psychologically edit what they are told.

Communication in difficult situations is difficult, and easy for professionals to avoid. Some patients prefer not to discuss these matters, as do some professionals. Both patients and professionals may collude to limit such discussions.52

There is usually more agreement about the most appropriate approach when a patient is actively dying, i.e. the last few days or hours, and the use of care pathways53 may be helpful in ensuring that all pre-emptive medications for distress, pain, etc. are prescribed and that the goals of care are clear to the patient, family and staff. Requests for transfer to hospice are common during this time, even when the patient is comfortable and their needs are being met. Other patients may wish to be at home and many specialist palliative care services can help with a swift, supported discharge.

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