STEP 6: Managing refractory, relapsed, residual or progressive disease

Patients who present with recurrent, residual or metastatic disease should be managed by a multidisciplinary team and offered timely referral to appropriate physical, practical and emotional support.

Step 6 is concerned with managing recurrent or local residual and metastatic disease. The likelihood of recurrence depends on many factors usually related to the type of cancer, the stage of cancer at presentation and the effectiveness of treatment. Some cancers cannot be eradicated even with the best initial treatment. But controlling disease and disease-related symptoms is often possible, depending on the clinical situation.

Some patients will have metastatic disease on initial presentation. Others may present with symptoms of recurrent disease after a previous cancer diagnosis. Access to the best available therapies, including clinical trials, as well as treatment overseen by a multidisciplinary team, are crucial to achieving the best outcomes for anyone with metastatic disease.

Signs and symptoms will depend on the type of cancer initially diagnosed and the location of metastatic disease. They may be discovered by the patient or by surveillance in the post-treatment period. New symptoms or changes in symptoms may include (Cancer.Net 2019):

  • increase in facial flushing
  • increased diarrhoea
  • wheezing
  • heart problems such as palpitations, difficulty breathing, becoming easily tired
  • increased abdominal pain
  • bloating
  • bone pain.

In a suspected recurrence or progression, re-staging of relapsed or refractory disease should be performed with:

  • bloods
  • 24-hour urinary 5HIAA if carcinoid syndrome
  • contrast CT of chest/abdomen/pelvis or MRI
  • Ga-68-DOTATATE PET/CT (or similar)

Managing metastatic disease is complex and should therefore involve all the appropriate specialties in a multidisciplinary team including palliative care where appropriate. From the time of diagnosis, the team should offer patients appropriate psychosocial care, supportive care, advance care planning and symptom-related interventions as part of their routine care. The approach should be personalised to meet the patient’s individual needs, values and preferences. The full complement of supportive care measures as described throughout the optimal care pathway and in Appendices A, B and C should be offered to assist patients and their families and carers to cope. These measures should be updated as the patient’s circumstances change.

Survivorship care should be considered and offered at an early stage. Many people live with advanced cancer for many months or years. As survival is improving in many patients, survivorship issues should be considered as part of routine care. Health professionals should therefore be ready to change and adapt treatment strategies according to disease status, prior treatment tolerance and toxicities and the patient’s quality of life, in addition to the patient’s priorities and life plans.

If there is an indication that a patient’s cancer has returned or progressed, care should be provided under the guidance of a treating specialist. Each patient should be referred back to the original multidisciplinary team. The multidisciplinary team may include new members such as palliative care specialists.

Treatment will depend on the location, extent of recurrent or residual disease, previous management and the patient’s preferences.
In managing people with NETs, treatment may include these options (refer to Step 4 for further detail):

  • change in SSA – regimen and/or dose
  • PRRT
  • localised progression – consider liver-directed therapy and radiation therapy for bone metastasis
  • widespread and systemic recurrence – consider systemic therapy – chemotherapy, targeted therapies, immunotherapy (remains investigational)
  • pre-screen patient for any currently recruiting or imminent clinical trial
  • palliation.

The potential goals of treatment should be discussed, respecting the patient’s cultural values. Wherever possible, written information should be provided.

Encourage early referral to clinical trials or accepting an invitation to participate in research.

Carcinoid syndrome

When GEP-NETs metastasise, the most common site for metastatic tumours (‘secondaries’) is the liver. Other areas of spread can include the bones, the lungs and the lymphatic system. Many metastatic NETs can cause symptoms due to over-production of hormones. The most common is carcinoid syndrome, which can occur in approximately 10 per cent of patients and is caused when an excess of hormones such as serotonin, histamine and somatostatin are produced (NORD 2021). The symptoms of carcinoid syndrome vary and can often be highly individual.

Typical symptoms include (NECA 2020a):

  • flushing
  • diarrhoea
  • faecal urgency
  • wheezing
  • abdominal pain
  • pellagra (niacin deficiency). Although rare, pellagra presents as a rash, dark pigmentation on the skin, a swollen mouth and a bright red tongue.

Patients can experience vomiting and diarrhoea, headache, fatigue, depression, disorientation, confusion or memory loss.

Carcinoid crisis

Sometimes patients with functioning NETs may suffer a particularly severe episode of carcinoid syndrome triggered by stressors, general anaesthetic or treatments. Early recognition of a carcinoid crisis enables preventative measures. Symptoms include (NECA 2020a):

  • intense flushing
  • diarrhoea
  • abdominal pain
  • wheezing
  • palpitations
  • low or high blood pressure
  • altered mental state and, in extreme cases, coma.

Without treatment, the complications can be life-threatening, but if the patient is having any procedures the NET specialist should ensure the patient is comprehensively monitored and may give an infusion of an SSA (octreotide) as a preventative measure as per institutions policy.

NeuroEndocrine Cancer Australia provides a fact sheet named Carcinoid Crisis and Anaesthesia , and a wallet card for patients, which gives advice on treatment in the event of carcinoid crisis.

Carcinoid heart disease

Up to 20 per cent of patients with carcinoid syndrome present with carcinoid heart disease and, without treatment, can develop right heart failure (NECA 2020b). With SSAs, the progression of carcinoid heart disease is significantly slowed and other symptoms of heart failure may be managed with diuretics. Some patients with carcinoid heart disease may be suitable for cardiac surgery to replace the leaking valves (NECA 2020b). ECG and chest x-ray may provide clues to the diagnosis of carcinoid heart disease, but the most sensitive test is echocardiography of the heart. Echocardiography should be performed regularly to monitor the function of the heart in patients with functional neuroendocrine cancers (NECA 2020b). Urinary 5HIAA is a useful companion biomarker that measures serotonin excretion and also ProBNP (Grozinsky-Glasberg et al. 2015). While early valvular replacement can be complex, this should be managed in a specialist centre with experience in managing carcinoid valvular disease.

Advance care planning is important for all patients with a cancer diagnosis but especially those with advanced disease. Patients should be encouraged to think and talk about their healthcare values and preferences with family or carers, appoint a substitute decision-maker and consider developing an advance care directive to convey their preferences for future health care in the event they become unable to communicate their wishes (AGDH 2021).

More information

Refer to section 4.3 ‘More information’ for links to resources.

Refer patients and carers to Advance Care Planning Australia or to the Advance Care Planning National Phone Advisory Service on 1300 208 582.

Early referral to palliative care can improve the quality of life for people with cancer and in some cases may be associated with survival benefits (Haines 2011; Temel et al. 2010; Zimmermann et al. 2014). The treatment team should emphasise the value of palliative care in improving symptom management and quality of life to patients and their carers. Refer to section 4.3 for more detailed information.

The lead clinician should ensure timely and appropriate referral to palliative care services. Referral to palliative care services should be based on the patient’s need and potential for benefit, not prognosis.

More information

Refer to the end of section 4.3 ‘Palliative care’ for links to resources.

The treatment team should support the patient to participate in research and clinical trials where available and appropriate.

For more information visit the Cancer Australia website.

See validated screening tools mentioned in Principle 4 ‘Supportive care’.

A number of specific challenges and needs may arise at this time for patients:

  • assistance for dealing with emotional and psychological distress resulting from fear of death or dying, existential concerns, anticipatory grief, communicating wishes to loved ones, interpersonal problems and sexuality concerns
  • potential isolation from normal support networks, particularly for rural patients who are staying away from home for treatment
  • cognitive changes as a result of treatment and disease progression such as altered memory, attention and concentration (a patient may appoint someone to make medical, financial and legal decisions on their behalf – a substitute decision-maker – before and in case they experience cognitive decline)
  • management of physical symptoms including dietary issues (reduction in food intake and avoidance of food types due to symptoms)
  • decline in mobility or functional status as a result of recurrent disease and treatments (referral to physiotherapy or occupational therapy may be required)
  • coping with hair loss and changes in physical appearance (refer to the Look Good, Feel Better program – see ‘Resource list’)
  • appointing a substitute decision-maker and completing an advance care directive
  • financial issues as a result of disease recurrence such as gaining early access to superannuation and insurance
  • legal issues (completing a will, care of dependent children) and making an insurance, superannuation or social security claim on the basis of terminal illness or permanent disability.

Rehabilitation may be required at any point of the metastatic care pathway, from preparing for treatment through to palliative care. Issues that may need to be dealt with include managing cancer-related fatigue, improving physical endurance, achieving independence in daily tasks, returning to work and ongoing adjustment to cancer and its sequels.

Optimising nutrition (maintaining a healthy weight and food intake/diet) during and post-treatment is important to avoid further complications such as declining nutritional status (malnutrition), negative social impacts and reduced quality of life. Patients with a NET often change their diet due to NET symptoms and therefore require support and education to ensure they are meeting their dietary needs. Referral to a dietitian for assessment and nutrition support should be considered for symptomatic patients and those reporting weight loss or a change in their diet.

Exercise is a safe and effective intervention that improves the physical and emotional health and wellbeing of cancer patients. Exercise should be embedded as part of standard practice in cancer care and be viewed as an adjunct therapy that helps counteract the adverse effects of cancer and
its treatment.

The lead clinician should ensure there is adequate discussion with patients and carers about the diagnosis and recommended treatment, including treatment intent and possible outcomes, likely adverse effects, prognosis (refer to step 5) and the supportive care options available.

More information

Refer to Principle 6 ‘Communication’ for communication skills training programs and resources.