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.

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 response ⁷), 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 useful ⁸ 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).

Figure 14.1 Outline of systemic therapy. Oestrogen receptor positive (ER + ve) includes all ER-positive and/or progesterone receptor-positive patients. ER-positive patients with lymphangitis carcinomatosa or liver metastases would normally be considered for chemotherapy in preference to hormone therapy.

Most patients with oestrogen receptor (ER)-positive tumours will be initially treated with hormone therapy: it is generally less toxic than chemotherapy, responses are of longer duration and there is no evidence that patients with ER-positive metastatic disease do better with chemotherapy first.⁹

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, Beatson ¹⁰ 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

Response to ovarian ablation is improved if tamoxifen is added.¹¹

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.

AIs are more effective ¹⁶ 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.

Figure 14.2 Progression-free survival on the basis of local assessment of radiographic studies. Reproduced from N Engl J Med 2012; 366(6): 520–9.

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