STEP 3: Diagnosis, staging, and treatment planning

Step 3 outlines the process for confirming the diagnosis and stage of cancer and for planning subsequent treatment. The guiding principle is that interaction between appropriate multidisciplinary team members should determine the treatment plan.

The treatment team, after taking a thorough medical history and making a thorough medical examination of the patient, should undertake the following investigations under the guidance of a specialist.

  • Biochemical markers – measurement of serum chromogranin A may be appropriate. Specific hormonal assessment will be depend on symptomology of the primary NET.
  • Anatomical (e.g. CT, MRI) and functional imaging (68Ga-DOTATATE PET/CT, 18F-FDG PET) as indicated.
  • Biopsy – histopathological diagnosis (grade and differentiation). Biopsies should be reviewed by a pathologist with experience in NETs.

All diagnostic investigations should be completed within two weeks of the initial specialist appointment.

Hereditary susceptibility should be considered in any patient with a NET. The risk of a heritable cause is particularly high for people with medullary thyroid cancer, phaeochromocytoma and paraganglioma, for whom genetic counselling and testing should be routinely performed.

MEN-1 should be considered in those with a gastrinoma or multifocal gastroenteropancreatic neuroendocrine cancer (GEP-NET) at any age; patients with a GEP-NET before age 40 years; and patients with a bronchial or thymic NET at any age.

In MEN, approximately 10–15 per cent of all pNETs are associated with MEN-1, and up to 80 per cent of patients with MEN-1 will develop pNETs (O’Shea & Druce 2017).

For the exact tumours related to each MEN subtype, refer to section 1.3.

Other potential genetic causes include mutations in VHL, SDHA/B/C/D, fumarate hydratase and TMEM127 – refer to section 1.3 for more information.

Other rare genetic causes of phaeochromocytoma and paraganglioma include KIF1B, MDH2, GOT2, DLST and SLC25A11.

Anyone diagnosed with cancer should have a detailed personal and family cancer history taken. Consult relevant guidelines to determine if referral to a familial cancer service is appropriate.

A familial cancer service assessment can determine if genetic testing is appropriate. Genetic testing is likely to be offered when there is at least a 10 per cent chance of finding a causative ‘gene error’ (pathogenic gene variant; previously called a mutation). Usually testing begins with a variant search in a person who has had cancer (a diagnostic genetic test). If a pathogenic gene variant is identified, variant-specific testing is available to relatives to see if they have or have not inherited the familial gene variant (predictive genetic testing).

Medicare funds some genetic tests via a Medicare Benefits Schedule (MBS) item number but most are not. Depending on the personal and family history, the relevant state health system may fund public sector genetic testing.

Pre-test counselling and informed consent is required before any genetic testing. In some states the treating team can offer ‘mainstream’ diagnostic genetic testing, after which referral is made to a familial cancer service if a pathogenic gene variant is identified. The familial cancer service can provide risk management advice, facilitate family risk notification and arrange predictive genetic testing for the family.

Visit the Centre for Genetics Education website for basic information about cancer in a family.

For detailed information and referral guidelines for NETs risk assessment and consideration of genetic testing, see When should genetic testing be performed in patients with neuroendocrine tumours.

Find more information on MEN-1 genetic testing, risk management and lifetime risk.

For more information on MEN-2, visit the eviQ website.

The succinate dehydrogenase (SDH) complex genes are a family of genes (SDHA, SDHB, SDHC, SDHD and SDHAF2). For more information visit the eviQ website.

Pharmacogenetics describes how individual genetic differences can lead to differences in the way certain medicines interact with the body. These interactions can affect the effectiveness of medications and any side effects. Applying pharmacogenetics to treatment planning may help patients to be prescribed the most appropriate treatment at the optimal dose from the beginning
of treatment (NHMRC 2013).

Grading and staging is a critical element in treatment planning and should be clearly documented in the patient’s medical record.

The pathological biopsy should be reported or reviewed by a pathologist with expertise in NETs. NETs are graded pathologically based on the mitotic count (expressed as mitoses per 2mm2), the Ki-67 proliferative index and the presence of necrosis. Different cut-offs of Ki-67 index and mitotic rate are used to grade tumours of different sites, and for some sites the presence of necrosis increases the grade.

Other critical elements in the pathological reporting of NETs are:

  • tumour site and size
  • multifocality
  • lymphovascular and perineural invasion
  • extent of local invasion
  • surgical margins
  • nodal status
  • presence of background disease.

In addition to mitotic count, Ki-67 index and the reporting of tumour necrosis (subject to site), which are considered mandatory in all NETs, other ancillary tests that may be useful in selected circumstances include (Perren et al. 2017):

  • DAXX/ATRX immunohistochemistry (loss favours pancreatic origin)
  • p53/pRb immunohistochemistry (p53 mutation and loss of RB1 favours NEC over NET)
  • SSTR2 (may be used to predict positivity on 68Ga-DOTATATE PET/CT scans)
  • MGMT immunohistochemistry or promoter methylation (potential predictor of response to temozolomide)
  • immunohistochemistry for pancreatic hormone expression in context of a clinical hormonal syndrome (e.g. insulin and glucagon)
  • SDHB immunohistochemistry (loss of expression makes syndromic disease due to germline mutation of one of the SDH genes highly likely).

See figure 4 (below) for classification of neuroendocrine tumour with corresponding imaging features and treatment options.

* GaTate: 68Ga-DOTATATE PET/CT; a specialised Gallium 68-dotatate tracer is injected and binds to somatostatin receptors on the cell surface of neuroendocrine cells (I-Med Radiology Network 2020). The presence of these receptors enables appropriate treatment choice.

* FDG: 18F-FDG PET/CT: The most common radiotracer is F-18 fluorodeoxyglucose (FDG), a molecule similar to glucose. Cancer cells are more metabolically active and may absorb glucose at a higher rate. 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) avidity in NETs has been associated with higher grade disease (Chan et al. 2020).

The presence of active uptake of 18F-FDG PET/CT enables appropriate treatment choice.
Source: Hofman & Hicks 2012

Classifying NETs into one of the 4 stages is site-specific and should be in the form of the tumour, nodes and metastases (TNM) system – refer to the 8th edition of the American Joint Committee on Cancer’s Staging Manual.

Staging for NETs may involve these tests:

  • CT scan
  • MRI
  • 18F-FDG PET/CT
  • 18F-DOPA (for metastatic MTC, and for certain phaeochromocytomas)
  • I-123-MIBG or I-131 MIBG imaging (for phaeochromocytomas and paragangliomas) – choice of imaging depends on availability and local preference.

Note: Phaeochromocytomas/paragangliomas should never be biopsied

More information

Visit the Cancer Institute New South Wales website for information about understanding the stages of cancer.

Patient performance status is a central factor in cancer care and should be clearly documented in the patient’s medical record.

Performance status should be measured and recorded using an established scale such as the Karnofsky scale or the Eastern Cooperative Oncology Group (ECOG) scale. The ECOG scale is the most used scale for NETs.

A number of factors should be considered at this stage:

  • the patient’s overall condition, life expectancy, personal preferences and decision-making capacity
  • discussing the multidisciplinary team approach to care with the patient
  • appropriate and timely referral to an MDM
  • pregnancy and fertility
  • support with travel and accommodation
  • teleconferencing or videoconferencing as required

The multidisciplinary team should meet to discuss newly diagnosed patients before definitive treatment so that a treatment plan can be recommended. Patients should be presented at an appropriate NET multidisciplinary meeting, with all appropriate investigation results, within four weeks of diagnosis to develop the patient’s management plan. The level of discussion may vary, depending on the patient’s clinical and supportive care factors. Some patients with non-complex cancers may not be discussed by a multidisciplinary team; instead the team may have treatment plan protocols that will be applied if the patient’s case (cancer) meets the criteria. If patients are not discussed at an MDM, they should at least be named on the agenda for noting.

The proposed treatment must be recorded in the patient’s medical record and should be recorded in an MDM database where one exists.

Teams may agree on standard treatment protocols for non-complex care, facilitating patient review (by exception) and associated data capture.

Results of all relevant tests and access to images should be available for the MDM. Information about the patient’s concerns, preferences and social and cultural circumstances should also be available.

The multidisciplinary team requires administrative support in developing the agenda for the meeting, for collating patient information and to ensure appropriate expertise around the table to create an effective treatment plan for the patient. The MDM has a chair and multiple lead clinicians. Each patient case will be presented by a lead clinician (usually someone who has seen the patient before the MDM). In public hospital settings, the registrar or clinical fellow may take this role. A member of the team records the outcomes of the discussion and treatment plan in the patient history and ensures these details are communicated to the patient’s general practitioner. The team should consider the patient’s values, beliefs and cultural needs as appropriate to ensure the treatment plan is in line with these.

The multidisciplinary team should be composed of the core disciplines that are integral to providing good care. Team membership should reflect both clinical and supportive care aspects of care. Pathology and radiology expertise are essential.

See Appendix E for a list of team members who may be included in the multidisciplinary team for NETs.

Core members of the multidisciplinary team are expected to attend most MDMs either in person or remotely via virtual mechanisms. Additional expertise or specialist services may be required for some patients. An Aboriginal and Torres Strait Islander cultural expert should be considered for all patients who identify as Aboriginal or Torres Strait Islander.

The general practitioner who made the referral is responsible for the patient until care is passed to another practitioner who is directly involved in planning the patient’s care.

The general practitioner may play a number of roles in all stages of the cancer pathway including diagnosis, referral, treatment, shared follow-up care, post-treatment surveillance, coordination and continuity of care, as well as managing existing health issues and providing information and support to the patient, their family and carer.

A nominated contact person from the multidisciplinary team may be assigned responsibility for coordinating care in this phase. Care coordinators are responsible for ensuring there is continuity throughout the care process and coordination of all necessary care for a particular phase (COSA 2015). The care coordinator may change over the course of the pathway.

The lead clinician is responsible for overseeing the activity of the team and for implementing treatment within the multidisciplinary setting.

Patients should be encouraged to participate in research or clinical trials where available and appropriate.

For more information visit the Cancer Australia website.

Cancer prehabilitation uses a multidisciplinary approach combining exercise, nutrition and psychological strategies to prepare patients for the challenges of cancer treatment such as surgery, systemic therapy and radiation therapy. Team members may include anaesthetists, oncologists, surgeons, haematologists, clinical psychologists, exercise physiologists, physiotherapists and dietitians, among others.

Patient performance status is a central factor in cancer care and should be frequently assessed. All patients should be screened for malnutrition using a validated tool, such as the Malnutrition Screening Tool (MST). The lead clinician may refer obese or malnourished patients to a dietitian preoperatively or before other treatments begin.

Patients who currently smoke should be encouraged to stop smoking before receiving treatment. This should include an offer of referral to Quitline in addition to smoking cessation pharmacotherapy if clinically appropriate.

Evidence indicates that patients who respond well to prehabilitation may have fewer complications after treatment. For example, those who were exercising before diagnosis and patients who use prehabilitation before starting treatment may improve their physical or psychological outcomes, or both, and this helps patients to function at a higher level throughout their cancer treatment (Cormie et al. 2017; Silver 2015).

For patients with NETs, including low-grade NETs, who will initially undergo close observation in a ‘watch and wait’ approach, the multidisciplinary team should consider these specific prehabilitation assessments and interventions for treatment-related complications or major side effects:

  • conducting a physical and psychological assessment to establish a baseline function level
  • identifying impairments and providing targeted interventions to improve the patient’s function level (Silver & Baima 2013)
  • reviewing the patient’s medication to ensure optimisation and to improve adherence to medicine used for comorbid conditions
  • referral to a psycho-oncology service to improve the patient’s knowledge and motivation towards healthy self-care behaviours and to emotionally regulate throughout the course of the disease and treatments.

Rehabilitation programs have considerable potential to enhance physical function while undergoing cancer treatment.

Cancer and cancer treatment may cause fertility problems. This will depend on the age of the patient, the type of cancer and the treatment received.

Infertility can range from difficulty having a child to the inability to have a child. Infertility after treatment may be temporary, lasting months to years, or permanent (AYA Cancer Fertility Preservation Guidance Working Group 2014).

Patients need to be advised about and potentially referred for discussion about fertility preservation before starting treatment and need advice about contraception before, during and after treatment. Patients and their family should be aware of the ongoing costs involved in optimising fertility. Fertility management may apply in both men and women. Fertility preservation options are different for men and women and the need for ongoing contraception applies to both men and women.

The potential for impaired fertility should be discussed and reinforced at different time points as appropriate throughout the diagnosis, treatment, surveillance and survivorship phases of care. These ongoing discussions will enable the patient and, if applicable, the family to make informed decisions.

All discussions should be documented in the patient’s medical record.

More information

See the Cancer Council website for more information.

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

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

  • assistance for dealing with psychological and emotional distress while adjusting to the diagnosis; treatment phobias; existential concerns; stress; difficulties making treatment decisions; anxiety or depression or both; psychosexual issues such as potential loss of fertility and premature menopause; history of sexual abuse; and interpersonal problems
  • strong emotions such as anger at the medical community for the delays and misunderstanding of the diagnosis, confusion, fear and hopelessness about what the future holds
  • management of physical symptoms such as pain and fatigue (Australian Adult Cancer Pain Management Guideline Working Party 2019)
  • malnutrition or undernutrition, identified using a validated nutrition screening tool such as the MST (note that many patients with a high BMI [obese patients] may also be malnourished [WHO 2018])
  • referral to a dietitian for management of dietary needs and management of symptoms such as abdominal pain, diarrhoea and flushing – patients may benefit from using a food and symptom diary.
  • explaining the role of diagnostic tools such as PET scans and funding
  • support for families or carers who are distressed with the patient’s cancer diagnosis
  • support for families/relatives who may be distressed after learning of a genetically linked cancer diagnosis
  • specific spiritual needs that may benefit from the involvement of pastoral/spiritual care.

Additionally, palliative care may be required at this stage.

For more information on supportive care and needs that may arise for different population groups, see Appendices A, B and C.

In discussion with the patient, the lead clinician should undertake the following:

  • establish if the patient has a regular or preferred general practitioner and if the patient does not have one, then encourage them to find one
  • provide written information appropriate to the health literacy of the patient about the diagnosis and treatment to the patient and carer and refer the patient to the Guide to best cancer care (consumer optimal care pathway) for NETs, as well as to relevant websites and support groups such as NeuroEndocrine Cancer Australia NET Nurse support line 1300 287 363 or support online
  • provide a treatment care plan including contact details for the treating team and information on when to call the hospital
  • refer the patient to the NeuroEndocrine Cancer Australia Treatment and wellness plan
  • discuss a timeframe for diagnosis and treatment with the patient and carer
  • discuss the benefits of multidisciplinary care and gain the patient’s consent before presenting their case at an MDM
  • provide brief advice and refer to Quitline (13 7848) for behavioural intervention if the patient currently smokes (or has recently quit), and prescribe smoking cessation pharmacotherapy, if clinically appropriate
  • recommend an ‘integrated approach’ throughout treatment regarding nutrition, exercise and minimal or no alcohol consumption among other considerations
  • communicate the benefits of continued engagement with primary care during treatment for managing comorbid disease, health promotion, care coordination and holistic care
  • where appropriate, review fertility needs with the patient and refer for specialist fertility management (including fertility preservation, contraception, management during pregnancy and of future pregnancies)
  • be open to and encourage discussion about the diagnosis, prognosis (if the patient wishes to know) and survivorship and palliative care while
  • clarifying the patient’s preferences and needs, personal and cultural beliefs and expectations, and their ability to comprehend the communication
  • encourage the patient to participate in advance care planning including considering appointing one or more substitute decision-makers and completing an advance care directive to clearly document their treatment preferences. Each state and territory has different terminology and legislation surrounding advance care directives and substitute decision-makers.

The lead clinician has these communication responsibilities:

  • involving the general practitioner from the point of diagnosis
  • ensuring regular and timely communication with the general practitioner about the diagnosis, treatment plan and recommendations from MDMs and inviting them to participate in MDMs (consider using virtual mechanisms)
  • supporting the role of general practice both during and after treatment
  • discussing shared or team care arrangements with general practitioners or regional cancer specialists, or both, together with the patient.

More information

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