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The blood-brain barrier's tight junctions and efflux pumps keep antibodies, antibody-drug conjugates and most kinase inhibitors out of the brain, so glioblastoma treatment has barely changed since 2005 and brain metastases, which develop in about a fifth of adults with cancer, are usually left to radiotherapy alone.
The blood-brain barrier excludes most large molecules, and small ones that are actively pumped back out, by tight junctions and efflux transporters, so antibodies, ADCs and a large share of 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.
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 has no treatment that reliably controls it. 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.
Lung cancer spreads to the brain more than any other common cancer, and the newest drugs seem to stop it happening. Almost no trial is designed to prove that, so the claim stays a footnote.
Interleukin-12 is an immune-stimulating cytokine that caused severe toxicity when injected into the bloodstream in the 1990s and was abandoned. An oncolytic herpes or adenovirus carrying the interleukin-12 gene under a drug-inducible promoter makes it only inside the tumour, keeping exposure local; trials include recurrent glioblastoma.
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.
Nearly half of women with metastatic triple-negative breast cancer develop brain metastases and survive under five months after the diagnosis, yet the trials that set the standard mostly exclude active brain disease. Requiring a brain metastasis cohort in every phase 3, with intracranial response as an endpoint, would answer whether the new drugs reach the brain.
Brain tumours release little DNA into blood because of the blood-brain barrier. Sonobiopsy briefly opens the barrier with focused ultrasound and microbubbles, raising circulating tumour DNA severalfold so a blood sample can replace repeat surgical biopsy for diagnosis and resistance monitoring in glioma and brain metastases.
The brain imports iron through the transferrin receptor. Antibody shuttle domains that bind that receptor raise brain exposure roughly ten to fifty-fold in primates and are already used in clinical Alzheimer's antibodies; the same engineering could carry antibody-drug conjugates or T-cell engagers to brain metastases.
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.
The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free.
One bottleneck page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One bottleneck page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
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.
First-line ALK treatment moved to a drug designed for the brain, and brain metastasis prevention became an explicit design goal rather than a hoped-for side effect. ALK-positive lung cancer is now among the longest-surviving metastatic solid tumours.
The trial that made ALK testing worth doing. It is also the clearest case in oncology of a drug finding its disease after the fact: crizotinib entered the clinic as a MET inhibitor and became an ALK drug because somebody checked.
The 13.3-month median is the pre-immunotherapy, pre-antibody-drug conjugate benchmark against which first-line trials now reporting medians near two years are measured; the brain metastasis rate is why trials that exclude active brain disease leave the question unanswered.
Shares EF-14, Robot-placed catheters and live imaging for drug infusion into brain tumours, EORTC 26981 / NCIC CE.3 (Stupp trial), Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Shares INDIGO, EORTC 26981 / NCIC CE.3 (Stupp trial), INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma, MGMT promoter methylation.
Shares Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases, Trials that include, and report, brain metastases in triple-negative breast cancer, Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission, Measure brain metastasis prevention as a primary endpoint, not as a secondary one.
Shares DESTINY-Breast12, HER2CLIMB, HER2-positive brain metastases, Focused-ultrasound blood-brain barrier opening.
Shares Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases, Trials that include, and report, brain metastases in triple-negative breast cancer, HER2CLIMB, Tucatinib.
Shares Insightec, Sunnybrook Odette Cancer Centre, Focused-ultrasound blood-brain barrier opening, Tumour treating fields (TTFields).
Shares A standard platform to get drugs into the brain: focused ultrasound plus shuttle-engineered therapeutics, Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases, Deliver CAR-T cells straight into the fluid around the brain, Trials that include, and report, brain metastases in triple-negative breast cancer.
Shares Robot-placed catheters and live imaging for drug infusion into brain tumours, EORTC 26981 / NCIC CE.3 (Stupp trial), Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma, Temozolomide.