The brain: barrier and sanctuary
Most drugs cannot cross into the brain, so brain tumours and brain metastases lag every other site.
The blood-brain barrier excludes most large molecules and many small ones by tight junctions and active efflux, so antibodies, ADCs and many kinase inhibitors reach the brain at a fraction of plasma concentration. Glioblastoma median survival with the Stupp regimen has been about 15 months since 2005 and no drug since has meaningfully moved it; temozolomide, lomustine and tumour-treating fields remain the standard, with vorasidenib the first real advance in a decade for IDH-mutant low-grade glioma. Brain metastases develop in around a fifth of adults with cancer, are excluded or under-represented in most systemic-therapy trials, and are usually managed with radiotherapy alone. Newer agents (tucatinib, osimertinib, lorlatinib, trastuzumab deruxtecan) show that CNS activity is achievable when designed for; focused ultrasound, convection-enhanced delivery, intrathecal cell therapy and receptor-mediated transcytosis are the delivery technologies under test.
- Tight endothelial junctions and P-glycoprotein efflux exclude most antibodies, ADCs and many small molecules.
- Glioma cells infiltrate diffusely along white-matter tracts, so surgery and focal radiotherapy cannot remove them all.
- Patients with brain metastases are excluded from most trials, so CNS activity is rarely measured until after approval.
- Glioma is immunologically cold and the brain has limited lymphatic drainage, blunting immunotherapy.
- Tumour heterogeneity in glioblastoma is extreme and single-target agents (EGFRvIII vaccine) have failed.
- Insightec's MR-guided focused ultrasound transiently opens the blood-brain barrier and is in trials to deliver chemotherapy and antibodies to glioma.
- HER2CLIMB and DESTINY-Breast12 show that tucatinib and trastuzumab deruxtecan have meaningful activity against HER2-positive brain metastases, changing trial eligibility norms.
- INDIGO established vorasidenib for IDH-mutant grade 2 glioma, the first targeted therapy to delay progression in diffuse glioma.
- Intraventricular and locoregional CAR-T (IL13Ra2, GD2 for H3K27M diffuse midline glioma) at City of Hope and Stanford bypass the barrier entirely.
- Novocure's Optune tumour-treating fields device is approved for glioblastoma and is being tested in brain metastases and other sites.
- The FDA and ASCO-Friends of Cancer Research recommendations now call for inclusion of patients with treated or stable brain metastases in trials.
A small ultrasound device implanted in the skull can be switched on at each chemotherapy visit to briefly open the brain barrier, letting drugs in every cycle.
Most cancer drugs cannot cross into the brain. Combine ultrasound that briefly opens the barrier with drugs engineered to be carried across, and make this a standard platform for every brain tumour and brain metastasis.
Up to a fifth of people with advanced solid tumours have cancer in the brain and are usually barred from trials. Letting in those whose brain disease is treated, stable or symptom-free would widen trials and tell us whether drugs work in the brain.
Drugs that reach brain tissue may still fail to reach the fluid where cancer spreads along the linings. A lab model of that second barrier would let us screen for drugs that cross it.
Cancer spreading along the linings of the brain is almost untreatable. Injecting engineered immune cells directly into the brain fluid, through a small reservoir, reaches it.
The nerves at the top of the nose lead directly into the brain, bypassing the barrier. Nasal delivery of drugs, and even immune cells, has worked in animals.
New drugs that destroy cancer proteins are usually too big to enter the brain. Making much smaller versions could bring this approach to brain tumours.
Interleukin-12 is one of the most powerful immune stimulants but is too toxic to inject into the bloodstream. A virus can be engineered to make it only inside a tumour.
Engineered immune cells given by drip rarely reach brain tumours. Briefly opening the barrier with focused ultrasound at the right moment may let them in.
Some cancers reach the brain in up to a quarter of patients. Prevention trials could aim specifically at stopping that, instead of treating it once it has happened.
Fluid taken from the lower back contains DNA from brain tumours. Testing it can diagnose, monitor and detect resistance without brain surgery.
Whether a drug gets into the brain is measured early in development but rarely published. Making that number public would show which existing drugs could treat brain disease.
Pumping drugs slowly through fine tubes into a brain tumour can bypass the barrier, but the fluid often leaks away. Robotic placement and live scans would show where it actually goes.
One in five people with advanced cancer has brain spread, yet most trials refuse them. Requiring brain cohorts would give those patients evidence instead of guesswork.
A fifth of patients with solid tumours develop brain metastases and are usually excluded from trials. This would fund a programme that studies and treats them as a disease in their own right.
Brain tumours shed very little DNA into blood, so a sonobiopsy briefly opens the brain's barrier with focused ultrasound to release enough to read from a blood sample.
The brain has natural transport doors for iron. Attaching a key that fits those doors can smuggle large drug molecules in, a trick now working in Alzheimer's medicines.
Young adults with a grade 2 IDH-mutant glioma who have had surgery can now take a daily tablet that slows or reverses tumour growth and defers radiotherapy and chemotherapy, both of which carry long-term cognitive costs, by years. It confirms that the IDH mutation is a driver that can be targeted, not just a marker. Whether it improves survival or cognition over the long term, and whether it helps in higher-grade or previously treated tumours, is unknown.
For ALK-positive advanced lung cancer, lorlatinib as the first drug offers the possibility of many years without progression and strong protection against brain metastases. Alectinib and brigatinib remain alternatives with a gentler side-effect profile; the choice weighs lorlatinib's cognitive, metabolic and weight effects against its unmatched duration of control.
Anyone diagnosed with advanced lung cancer should have EGFR testing before treatment, because osimertinib as the first drug gives the longest disease control, protects the brain, and is well tolerated. Chemotherapy is not the first step for these patients. The remaining questions are whether to intensify upfront (adding chemotherapy or amivantamab) and how to treat resistance when it develops.
Patients with newly diagnosed glioblastoma who are fit and under about 70 receive six weeks of radiotherapy with daily temozolomide followed by six monthly cycles of temozolomide; this is still the backbone of treatment two decades later. Testing MGMT methylation identifies who benefits most and guides decisions in older patients. Median survival with the regimen remains only around 15-20 months, and no drug since has clearly improved on it, which is why glioblastoma is a priority for new approaches.