Metastatic disease

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Metastatic disease

• Dr Andrew Potter
• Registrar, Department of Radiation Oncology
• Royal Adelaide Hospital

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Metastases

• Tumour implants discontinuous with the primary
  tumour
• Always marks a tumour as malignant
• Benign neoplasms never, ever, ever, ever, ever,
  ever metastasise

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Metastases

• With few exceptions, all malignancies can
  metastasise
• Metasases from gliomas and basal cell carcinomas
  of the skin are rare.

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Metastases

• 30 of all newly-diagnosed solid cancers present
  with metastases
• Excluding skin cancers other than melanoma
• Metastatic disease strongly reduces the chance of
  cure
• Preventing distant spread is a great challenge in
  cancer research and treatment

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The basement membrane

• Squamous cell carcinoma in situ
• Invasive squamous cell carcinoma

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Metastatic cascade
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Mechanisms of spread

• Direct extension
• Lymphatic spread
• Haematogenous spread

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Direct extension

• Seeding of body cavities or surfaces may occur
  when a tumour penetrates into a natural open
  field
• Most commonly involves peritoneal cavity
• Any space may be involved
• Eg. Pleural, pericardial, subarachnoid spaces
• Characteristic of ovarian cancers
• Widespread peritoneal seeding
• Appendiceal carcinomas (rare)
• Fills peritoneum with pseudomyxoma peritonei

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Omental cake
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Lymphatic spread

• Most common pathway for spread for carcinomas
• No functional lymphatics within tumours - rely on
  adjacent lymphatic channels
• Pattern of lymph node involvement follows natural
  routes of lymphatic drainage

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Pelvic lymphangiogram
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Lymphovascular invasion
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Skip metastases

• Numerous venous-lymphatic anastomoses or
• Where inflammation (or RT) has obliterated
  lymphatics
• Occasionally local lymph nodes are bypassed but
  disease appears in distant nodes

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Sentinel nodes

• The first node in a regional lymphatic basin that
  receives lymph flow from a primary tumour
• Sentinel nodes identified by injection of dyes
  and/or radiolabelled tracers
• Identified nodes can then be biopsied to help
  predict likelihood of further lymphatic spread
• Important technique in breast and colon cancers,
  melanoma and some other situations

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Lymphoscintigram
Injection site
Sentinel node
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Regional lymph nodes

• Regional nodes may be effective barriers to
  further dissemination (or at least for a time)
• Cells arrested within nodes may be destroyed by
  immunological responses
• This may also result in localised hyperplasia
  (enlargement)
• Enlarged nodes are not necessarily indicative of
  disseminated disease

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Haematogenous spread

• Typical of sarcomas, also seen in carcinomas
• Veins are thin-walled vessels and more easily
  invaded than arteries
• Pulmonary tumours have ready access to arterial
  vessels
• Blood-borne tumour cells follow normal patterns
  of venous drainage from the primary site
• Liver and lungs most commonly involved
• All portal (GIT) blood drains via liver, all
  caval blood flows to lungs

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Haematogenous spread

• Tumours arising in close proximity to vertebral
  column often metastasise via paravertebral venous
  plexus
• Frequent vertebral metastases from thyroid and
  prostate carcinomas

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Aims of management

• Treat local symptoms
• Delay progression of systemic disease in patients
  who are otherwise well
• Disease-free survival
• Progression-free survival
• Overall survival
• Cure ?

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Brain metastases

• Common, far outnumbering primary brain tumours
• Up to 15 of cancer patients have brain
  metastases, up to 55 for melanoma
• Exact incidence unknown but probably increasing
• Better cancer treatment longer survival
• Earlier brain screening
• Modern imaging

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Brain metastases - incidence

• Varies according to primary site
• Lung - 18-64
• Breast - 2-21
• Colo-rectal - 2-12
• Melanoma - 4-16
• Renal - 1-8
• Thyroid - 1-10
• Prostate, skin, oropharyngeal - rarely
• Overall incidence 6-24

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Brain metastases

• Median time from diagnosis to identification of
  brain metastases is 12 months
• 2-3 years for melanoma, breast, renal cell,
  gynaecological cancers

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Brain metastases

• Access to brain is governed by blood-brain-barrier
  
• Brain mets may occur in several positions
• Meninges/leptomeninges
• Brain parenchyma (more common)
• 80 in cerebrum, mostly in grey-white matter
  interface
• 15 in cerebellum
• 5 in brainstem
• Result of haematogenous spread
• Median survival 1-2 months if untreated

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Brain metastases - presentation

• Headache - 24-53
• Focal weakness - 16-40
• Altered mental state - 24-31
• Seizures - 15-16
• Ataxia - 9-20
• Asymptomatic in up to 10
• Onset of symptoms days to weeks

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Brain metastases - diagnosis

• History and clinical examination
• CT the mainstay of imaging
• MRI
• Important if thought to have single metastasis
• More sensitive in distinguishing metastases from
  other lesions

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Brain metastases - imaging

• Well circumscribed
• Often at grey-white matter interface
• Do not infiltrate surrounding tissue
• vasogenic oedema

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Brain metastases - treatment

• Steroids
• Reduce peritumoural oedema
• Dexamethasone 16mg/day, tapering downwards based
  on clinical response
• Anti-seizure medications
• Used for patients presenting with or developing
  seizures during treatment
• Generally not started prophylactically

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Brain metastases - surgery

• Diagnostic craniotomy and biopsy can be useful if
  initial presentation with brain mets and no
  tissue diagnosis
• Improves local control and survival (assuming low
  volume of extra-cranial disease) compared to WBRT
  alone
• Relieves mass effect
• Lesion(s) must be resectable
• Patient must be fit for surgery

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Brain metastases - SRS

• Smaller metastases, up to 4cm
• High dose, small volume, single fraction
• Useful for small number of mets
• SRS vs surgery?
• Current trial at RAH for solitary brain mets

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Brain metastases - WBRT

• Mainstay of treatment
• Simple, quick, effective
• Symptomatic improvement in 60
• Median survival 3-6 months
• Dose and fractionation based on local and
  systemic disease load and patient factors
• 10Gy single fraction or 12Gy in 2
• 20Gy in 5 or 30Gy in 10
• Consider boosting?
• Adjuvant WBRT after surgery or SRS

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Brain metastases - chemotherapy

• Many agents do not cross the blood-brain barrier
• ? BBB compromised by tumour vessels
• Indications for chemotherapy
• Salvage after failing surgery RT
• Chemosensitive primary tumour
• Systemic metastases requiring chemotherapy
• Intrathecal chemotherapy for leptomeningeal
  disease

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Lung metastases

• Second most common site of metastases
• Solitary site of metastases in up to 20 of
  cancer patients
• Common site of failure in sarcomas (30-80)
• Median survival 12 months if unresected
• Lung metastases uncommonly seen in isolation for
  carcinomas
• Uncommonly occur as solitary lesions
• i.e. always look for more than one lung met

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Lung metastases - presentation

• Often asymptomatic
• Incidental finding on CXR or CT chest
• Airway compression/obstruction
• Dyspnoea
• Cough
• Haemoptysis
• Stridor
• Atelectasis/collapse
• Post-obstructive pneumonia
• Pain
• Invasion into pleura or chest wall

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Lung metastases - imaging

• CXR
• Often first indicator of lung metastases
• Lung nodules
• cannonball lesions
• Segmental collapse
• Mediastinal/hilar nodal disease
• Pleural effusion

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Lung metastases - imaging

• CT
• Most effective imaging technique
• Shows nodules lt5mm
• Rounded, well circumscribed lesions
• Nodal or parenchymal
• Can be difficult to distinguish from primary lung
  cancer

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Lung metastases - imaging

• PET
• Metastases often FDG-avid
• Useful in distinguishing tumour from other
  lesions, esp where CT inconclusive
• Important when deciding on radical vs palliative
  primary treatment

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Lung metastases - chemotherapy

• Preferential treatment for chemosensitive
  tumours, and for primaries that metastasise
  elsewhere
• Variety of agents
• Traditional cytotoxics
• Hormonal manipulation - eg. tamoxifen
• Molecular therapies - eg. Herceptin

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Lung metastases - radiotherapy

• Whole lung RT for micrometastases
• Significant risks - radiation pneumonitis
• No proven benefit
• Focal RT to symptomatic lesions
• May be used to control local symptoms
• Airway compression/obstruction, haemoptysis, pain

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Lung metastases - surgery

• Indications
• Metastatic disease limited to lung
• Primary neoplasm is definitively controlled
• Patient fit for lung resection
• Prognostic factors
• Age
• Disease-free interval
• Histology and grade of primary tumour
• Number of metastases resected

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Survival following metastatectomy
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Lung metastases - other management

• Fibre-optic bronchoscopy and laser resection of
  endobronchial lesions
• EBRT for durability
• Endobronchial stenting
• Endobronchial brachytherapy

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Liver metastases

• Common site of haematogenous metastases from GIT
  because of portal venous drainage
• Other primaries to metastasise to liver include
• Breast
• Lung (small cell and non-small cell)
• Melanoma
• Neuroendocrine tumours
• Prognosis generally poor, even with aggressive
  therapy

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Liver metastases - presentation

• May be asymptomatic
• Deranged liver function tests
• Incidental finding on imaging
• Jaundice
• Right upper quadrant pain
• Nausea and vomiting

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Liver metastases - imaging

• Ultrasound
• Inexpensive
• Simple
• Accessible
• Safe - no radiation

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Liver metastases - imaging

• CT
• Most commonly used modality
• Overall detection rate for liver mets from
  colo-rectal cancers around 85
• Rounded hypodense or enhancing lesions
• Small lesions may be difficult to characterise

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Liver metastases - imaging

• PET
• Useful in distinguishing malignant vs
  non-malignant lesions
• Identifies or excludes further metastases in 20
  of patients following conventional staging
  investigations

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Liver metastases - surgery

• Well established benefit of resection in
  colo-rectal and neuroendocrine tumours
• Overall 5-year survival after liver resection for
  colo-rectal metastases 26-40
• 5-year O/S variable for other histologies
• 20 for breast
• 70 for neuro-endocrine

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Liver metastases - chemotherapy

• Systemic chemotherapy/hormonal therapy
• Variable, depending on histology
• Intra-hepatic arterial chemotherapy
• Injection of chemotherapy agents into hepatic
  artery - focally high dose of drug, especially if
  highly extracted by liver

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Liver metastases - radiotherapy

• EBRT
• Uncommon procedure
• Temporary palliation of pain
• Especially capsule pain caused by expansion of
  liver and capsular stretch
• Dexamethasone cover
• Doses variable
• Eg. 10Gy in 2

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Liver metastases - radiotherapy

• Yttrium-90 spheres
• Small spheres of radioactive yttrium-90 injected
  into hepatic artery
• Typical activity 2-3GBq
• Physical half-life 2.7 days
• ? emitter up to 2.3 MeV energy
• Effective path length 5mm
• Dosimetry difficult to establish
• Risk of hepato-pulmonary shunting

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Bone metastases

• Cause of significant morbidity in cancer patients
• Most commonly breast (65-75) and prostate (70)
  primaries
• Lung, thyroid, renal carcinoma 30-40
• Most common metastatic site is the spine
• Important quality of life issue
• Mean survival variable
• 3 months with lung cancer
• 19 months with thyroid and breast cancer

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Bone metastases - presentation

• Pain
• Hypercalcaemia
• bones, stones, groans and moans
• Pathological fractures
• Spinal instability
• Spinal cord compression

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Bone metastases - imaging

• Plain X-rays
• Inexpensive, simple
• Useful in establishing bone integrity
• ?need for surgical fixation
• Lytic lesions
• Breast, lung, renal, thyroid
• Sclerotic lesions
• Prostate, sometimes breast

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Bone metastases - imaging

• Bone scintigraphy (bone scan)
• 99mTc
• 72-84 sensitive for occult bone metastases
• May not show lytic lesions well
• Useful for RT planning to correlate with
  structural (simulation) imaging

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Bone metastases - imaging

• CT
• Not routine
• Useful in determining extent of cortical
  destruction
• Can identify a target for biopsy if primary
  unknown

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Bone metastases - imaging

• MRI
• Not routine
• Gold standard for assessing spinal cord
  compression
• Clearly distinguished between normal and
  metastatic marrow

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Bone metastases - chemotherapy

• Cytotoxics and immunotherapies
• Agent(s) and response dependent on primary
  histology
• Overall response around 20-30
• Hormonal therapies
• 30-65 response for receptor-positive breast
  cancers
• Up to 80 response for prostate cancers

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Bone metastases - bisphosphonates

• Pyrophosphate analogues
• Bind to bone and inhibit osteoclastic bone
  resorption
• Effective in preventing skeletal events (eg.
  Fractures) in osteolytic metastases (such as
  breast cancer)
• Effective in treating hypercalcaemia of malignancy

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Bone metastases - surgery

• Indications
• Spinal cord compression
• Surgical decompression followed by RT
• Lytic lesions with significant cortical
  destruction (especially load-bearing long bones)
• Prophylactic internal fixation followed by RT
• Pathological fracture treatment, eg. fractured
  neck of femur

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Bone metastases - radiotherapy

• EBRT
• Mainstay of palliative treatment
• Provides some degree of pain relief in up to
  80-90 of cases, and total relief in 50-85
  (where disease is localised)
• Good evidence that single fractions (8Gy) are as
  effective for bone pain as fractionated treatment
  (20Gy in 5 or 30Gy in 10)
• Fractionated course may be superior where there
  is significant neuropathic pain or soft tissue
  component

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Bone metastases - radiotherapy

• Unsealed radionuclides
• Strontium-89, samarium-153
• Low-energy ? emitters injected intravenously
• Attached to bone-seeking carriers, incorporated
  into metabolically active (osteoblastic) bone
  metastases
• Results in localised irradiation and pain relief
• Indicated in widespread bony metastases from
  prostate or breast cancers
• Contra-indicated in incontinence, short life
  expectancy (lt6 months), poorly compliant patients
• Improvement in pain in up to 80 of cases at 6
  months

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Lymph node metastases

• Usually considered in primary management
• Also a common site for disease recurrence
• Lymphatic spread
• Role for surgical excision if localised
  recurrence
• eg. recurrent melanoma, SCC head and neck
• Improves local control (and in some cases
  survival)
• Chemotherapy and radiotherapy may offer effective
  palliation if symptomatic

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Summary

• Definition
• Mechanisms
• Direct extension
• Lymphatic spread
• Haematogenous spread
• Metastatic cascade

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Summary

• Specific sites
• Brain
• Lung
• Liver
• Bone
• Nodes
• Treatment modalities
• Medical - chemotherapy/hormones/immuno/other
• Surgical
• Radiotherapy