Brain metastases from systemic cancers (secondary brain tumours) are 10 times more common than primary brain tumours, with lung cancer accounting for one-fifth of secondary tumours. This results from haematogenous spread and typically occur at the grey-white matter junction. The narrowing blood vessels in this region traps tumour emboli.¹

Survival with brain metastasis is poor at approximately 1.3 months with steroids alone² and three to six months with treatment.³ Many of the approved chemotherapy drugs in non-small cell lung cancer do not cross the blood-brain barrier. 

The most important factors which determine patient treatment options in this setting include: 

• Number and location of brain metastases
• Tumour histology and molecular characteristics
• Extracranial disease control 
• Patient performance. 

Surgical resection is recommended mainly for patients with a single brain metastasis in an accessible location, especially when the tumour size is large and causing a considerable mass effect, and in those with good performance status and in whom systemic disease is limited or absent.⁴

Adjuvant radiotherapy 

When surgery is possible, adjuvant radiotherapy (RT) is superior to surgery alone as demonstrated in randomised prospective studies. In one trial,⁵ patients who received surgery and adjuvant RT survived six months longer than patients who received radiation alone (median, 40 weeks versus 15 weeks; p < 0.01). This reduces the risk of local surgical site recurrence by 50-60% within the next six to 12 months. 

Early whole brain radiotherapy (WBRT) side effects include alopecia and fatigue. The late side effects are rarely experienced owing to limited survival. These include leukoencephalopathy and brain atrophy, leading to neurocognitive deterioration and dementia, radiation necrosis with symptoms related to the site of necrosis, normal pressure hydrocephalus causing cognitive, gait and bladder dysfunction, and cerebrovascular disease.

Fortunately, the patient in Case 1 did not experience any of these late side-effects. Factors favouring his extended survival include an early resected lung cancer diagnosis with no extracranial recurrence following adjuvant chemotherapy. Therefore, metastatectomy of this solitary readily accessible disease site was possible and experienced no surgical or RT toxicity.

Nowadays stereotactic radiosurgery (SRS) is an option and when possible is associated with less neurotoxicity WBRT. SRS is a focused ablative radiation treatment delivered with sub-millimetre precision to the tumour localised in three-dimensions (one to five fractions), in those with up to three brain metastases. 

Treatment advances

With the advances in next generation sequencing, lung cancer biopsies should be tested for the presence of actionable variants. The emergence of targeted drugs with oncogene addiction demonstrates far greater intracranial activity than previous treatment modalities in non-small cell lung cancers with brain metastases. The phase III ALEX trial of patients with metastatic anaplastic lymphoma kinase (ALK) disease identified a five-year overall survival (OS) with alectinib of 62.5%. This trial (n = 152) included 36 (24%) patients having baseline asymptomatic central nervous system metastasis. The median progression free survival (PFS) in this cohort was 25.4 months, including 38% PFS at four years.⁶ Median OS data is immature. 

Targeted drugs used in metastatic NSCLC patients harbouring an actionable variant, now have the potential to lead to survival for several years.

Ectopic ACTH (Cushing’s) syndrome 

Ectopic ACTH (Cushing’s) syndrome is defined as secretion of adrenocorticotropic hormone (ACTH) from outside the pituitary; small cell lung cancer is responsible for over 50% of cases.⁷ Following syndrome of inappropriate anti-diuretic hormone secretion (SIADH), it is the most common paraneoplastic syndrome caused by small cell lung cancer. 

Hyperpigmentation is attributed to excess ACTH secretion, a potent melanocortin receptor agonist which stimulates melanogenesis.⁸ Hyperpigmentation is marked in ectopic ACTH syndrome relative to Cushing’s disease (pituitary ACTH secretion) due to significantly greater concentrations of ACTH, and ACTH precursors, including pro-opiomelanocortin (POMC) and pro-ACTH in these often-aggressive ectopic tumours.⁸ 

Cushing’s syndrome is associated with significant mortality and morbidity due to its association with venous thrombosis, atypical infection, metabolic derangements and neuropsychiatric disturbances. If the source of cortisol excess is not amenable to surgical resection, for example due to multiple sites of metastases as highlighted in this case, rapid (medical) correction of the cortisol excess is necessitated.⁷

In Case 2, a combination of high dose metyrapone and hydrocortisone, maintained cortisol within target ranges to prevent an adrenal crisis for nine months despite recurrence of metastatic disease.

Metastatic small cell lung cancer is exquisitely sensitive to platinum-based regimens. However, disease recurrence within three months is deemed refractory or resistant with response to most treatments less than 10%. 

Recurrence after three months, have a modest improved response of approximately 25%.⁹ Second-line therapy may induce responses in 10-40% of patients, these are usually short-lived, and the median survival rarely exceeds six months.¹⁰ This remains a potential treatment option for our patient.

Case 1: Non-small cell lung cancer with brain metastases

A 53-year-old man, and a former smoker with a 25-pack-year history, attended his GP in 2005 with a two-month history of cough and increasing shortness of breath. He completed two courses of antimicrobials over the next month for a respiratory tract infection with no improvement in his symptoms. However, following an episode of haemoptysis, he was referred for a respiratory physician consultation. His past medical history included a triple vessel coronary artery bypass graft five years earlier and a hiatus hernia.

A chest x-ray identified a right lower lobe lesion. Subsequent work-up and staging – including endobronchial ultrasound (EBUS) with biopsy, positron emission tomography (PET) and computerised tomography (CT) of his thorax, abdomen and pelvis – identified an 8cm poorly differentiated squamous cell (non-small cell lung), lymph node negative cancer. A right lower lobectomy was completed with clear surgical margins. 

In accordance with the (then) tumour, node and metastasis (TNM) fifth edition classification, this was a stage IB (pT2N0) squamous cell carcinoma. 

As his tumour exceeded 4cm, he was treated with four cycles of adjuvant platinum doublet (cisplatin and vinorelbine) chemotherapy. This was well tolerated, and he remained on surveillance with CT scans. Almost eight months later, he developed frontal headaches and early morning nausea with intermittent vomiting. A CT scan of his brain (with contrast) identified a ring-enhancing right temporoparietal lesion with moderate oedema. He was commenced on dexamethasone which attenuated these symptoms. Subsequent magnetic resonance image (MRI) brain scan identified this as a solitary metastatic site. 

This lesion was resected in a neurosurgical cancer centre with histological conformation of a moderately differentiated metastatic squamous cell lung carcinoma. He completed adjuvant whole brain radiotherapy (WBRT) with 10 fractions/30Gy. 

This man remains on surveillance with no signs of local or distant recurrence 16 years after his initial lung cancer diagnosis.

Case 2: Metastatic small cell lung cancer

A 60-year-old man presented with a six-week history of a non-resolving cough, shortness of breath, profound fatigue, and unintentional weight loss. He was a former smoker with an 80-pack-year history. His medical history includes hepatic steatosis and alcohol excess (20 units/day).

A chest x-ray revealed a large, left mid-zone lesion, and biochemistry identified hypokalaemic hypochloraemic metabolic alkalosis. Despite intravenous and oral potassium replacement, his plasma potassium reached a maximum of 3.0mmol/l (range 3.5-5.1mmol/l). Subsequent investigations confirmed an 11cm left upper lobe bronchogenic small cell cancer (SCLC) with extension into the superior segment of the left lower lobe. The presence of distal pancreatic metastases was suspected with FDG-avidity on positron emission tomography (PET-CT) and subsequent MRI pancreas; though resolving pancreatitis was a differential based on endoscopic ultrasound (EUS) findings. Brain imaging is mandated in newly diagnosed extensive/metastatic small cell lung cancer and a solitary enhancing 9mm right frontal lobe metastasis was confirmed on MRI. As he had an asymptomatic single small brain metastasis, he proceeded with urgent chemotherapy for metastatic small cell lung cancer with platinum doublet carboplatin and etoposide.

The combination of hypokalaemia, metabolic alkalosis and SCLC prompted consideration of adrenocorticotropic hormone (ACTH) excess. A random morning cortisol was elevated at 1,125nmol/L with a corresponding ACTH of 188pg/ml (range 7.2 to 63.3pg/ml). A morning cortisol level post 1mg dexamethasone suppression test was 1,177nmol/L (Reference range < 50nmol/L). Given the clinical context and severity of hypokalemia, the decision was taken to postpone further endocrine tests and introduce a steroidogenesis inhibitor metyrapone. The dose was titrated to achieve a target cortisol < 300nmol/L and normalise urinary free cortisol. His cortisol levels on metyrapone were < 100nmol/L therefore hydrocortisone was introduced as part of a block and replace regimen two months after commencing metyrapone. Cortisol was assayed using mass spectrometry to eliminate cross-reactivity with 11-deoxycortisol which accumulates with metyrapone use.⁷

The patient presented to the emergency department following his fourth (six cycles planned) chemotherapy cycle with fatigue, diarrhoea, abdominal pain and reduced appetite. A physical examination disclosed rapidly developing generalised hyperpigmentation, particularly notable on mucous membranes and skin folds. There was diffuse muscle wasting and ongoing weight loss. A subsequent CT thorax, abdomen and pelvis identified a treatment response with a reduction in size of the primary lesion (now measuring 6cm) and resolution of pancreatic lesions with a stable cerebral lesion was confirmed on his CT brain scan.

He completed a total of six cycles of chemotherapy. His post treatment CT scan identified a stable (though reduced from initial scan) lung primary with new distal pancreatic and right interpolar (renal) metastases. His cerebral metastasis was stable and he now proceeded with WBRT. Following its completion, he was rechallenged with platinum doublet chemotherapy (more than three months after completing first-line chemotherapy) and remains on active treatment. He also remains under the care of the endocrine department.

References

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