Hemangioblastoma treatments are currently the greatest unmet medical need in VHL. This compartment gets a small fraction of the research time and funding. The project exists to bring that into balance.
We have made extraordinary progress on kidney cancer in VHL. Yet brain and spine hemangioblastomas, and the fear of deficits from multiple procedures, have always been at the forefront for patients. This page lays out the evidence: where the research goes, what the kidney received over thirty-four years and what the brain and spine did not, what the attribution of death now shows, and what a lifetime of CNS operations actually costs the people who undergo them.
The same queries, run on the same day, against the same three public databases, for renal cell carcinoma and for hemangioblastoma.
| Measure | Kidney | Hemangioblastoma | Ratio |
|---|---|---|---|
| Interventional drug trials ever registered | 1,654 | 10 | 165 : 1 |
| All interventional trials ever registered | 2,218 | 13 | 171 : 1 |
| Published clinical trials (PubMed, publication type) | 2,257 | 25 | 90 : 1 |
| Publications, all time | 56,077 | 2,878 | 19 : 1 |
| Publications, 2024–2026 | 9,197 | 310 | 30 : 1 |
| NIH funding, FY2024–25 combined | $151.0M | $1.4M | 107 : 1 |
| NIH projects ever titled “hemangioblastoma” | 33–34 / yr | 0 | — |
| Industry trials ever listing it as a condition | — | 1 | — |
The publication gap is widening, not closing. All-time 19:1, last decade 27:1, last three years 30:1. And the trial gap is far worse than the publication gap: hemangioblastoma is described about twenty times less often than kidney cancer, but trialed about ninety times less often.
In 1990, the natural history of VHL was described in 152 patients. Median actuarial survival was 49 years, and the paper’s closing sentence named “renal cell carcinoma the leading cause of death.”[11] That was the correct diagnosis of the problem, and the field acted on it.
Over the thirty-four years since the first approved agent, the kidney compartment received sixteen approved drugs across twenty-four regimens, nephron-sparing surgery, percutaneous cryoablation and thermal ablation, a validated intervention threshold, and transplantation as a backstop.[4] Two more regimens arrived in 2026 alone. In one year, the kidney gained twice as many approved regimens as the brain and spine have in all of history.
The 3 cm rule deserves specific credit. In 181 VHL patients followed a mean of 58 months, not one of the 108 whose largest renal tumor stayed under 3 cm developed a metastasis; above 3 cm, 27% did.[12] That single threshold converted renal VHL into a surveillance problem with a planned, repeatable intervention at a known trigger, and the organ tolerates it. In one series, fifty patients underwent seventy-one operations with a mean of 14.7 tumors removed per kidney, and none required renal replacement therapy.[13] It is one of the most effective guidelines in any hereditary cancer syndrome, and for most people with VHL it holds.
It worked. In the contemporary cohort, renal cell carcinoma is no longer a statistically significant predictor of overall survival (HR 1.55, 95% CI 0.75–3.23, p=0.24).[6] That is one of the quiet successes of modern medicine, and the people in this field built it.
Hemangioblastoma of the brain and spine received, in the same thirty-four years, one drug. It is now the leading cause of death in this disease, and an independent predictor of mortality where renal cell carcinoma is not. There is no 3 cm rule for the brain: no threshold, no repeatable intervention, and no backstop if the organ fails.
“The main cause of death is still CNS hemangioblastomas and hence improved treatment options are essential.” Binderup et al., J Med Genet 2017 — the Danish national cohort: every known VHL family in Denmark, genotype-confirmed, with a non-VHL sibling control arm.[14]
| Cause of death — contemporary cohort, n=336, 12,966 person-years | Deaths | Share | Independent predictor of survival |
|---|---|---|---|
| CNS hemangioblastoma | 45 | 66.2% | Yes — HR 2.43, p=0.001 |
| Renal cell carcinoma | 20 | 29.4% | No — HR 1.55, p=0.24 |
“Such discrepancy can partially [be] explained by… targeted therapy, minimally invasive surgery and active surveillance for RCCs… On the other hand, the pharmacological and surgical treatment for CHB are required to be further improved.” Zhou et al., 2019[6] — the shift is attributed by the authors to investment in the kidney, and they name the corollary themselves.
Surgeons will say, correctly, that a hemangioblastoma operation is usually survived with function preserved, and the published rates support them. Most deterioration recorded at discharge resolves by three to six months,[15,16] and in the largest prospective VHL cohort, 225 patients over a mean 6.9 years, only 4% sustained a lasting drop in performance status attributed to operative morbidity.[10]
That is not where the burden is. The burden is what accumulates across a lifetime of them.
In the Japanese national registry of 168 operated spinal hemangioblastomas, 101 sporadic (non-hereditary) and 67 VHL with mean follow-up of 53.6 months, sporadic patients improved significantly between discharge and six months. The VHL patients did not improve at all, and then tended to decline. At final follow-up, 22.4% of the VHL patients required assistance to walk or used a wheelchair, against 4.0% of the sporadic patients. The reason sits in the same table: 70.1% of the VHL patients had already had brain tumor surgery, against 1.0% of the sporadic group.[17]
“In VHL disease, short-term functional prognosis is expected to be adequate if there is no history of CNS tumor surgery, but thereafter the risk of functional deterioration increases with each surgery because of the tendency for new lesions to appear in the CNS.” Takeshima et al., Neurospine 2023 — Neurospinal Society of Japan, 58 centers, nationwide.[17]
| Function permanently impaired | Patients | Mean age at surgery, that organ |
|---|---|---|
| Central nervous system — sensory or motor | 34 (26.5%) | 27.8 years |
| Vision | 21 (16.4%) | — |
| Hearing | 16 (12.5%) | — |
| Kidney — requiring dialysis | 2 (1.5%) | 36.5 years |
The deficits that remain are also the ones the field measures least. At follow-up in a five-center European spinal series, residual sensory deficit was present in 60.8%, gait disturbance in 37.3% and motor deficit in 25.5%, while the McCormick grade distribution, the standard outcome measure for these operations, barely moved — 83.4% grade I–II before surgery, 90.2% at follow-up.[19] After upper-cervical myelotomy, permanent sensory and gait dysfunction reached 43% with the McCormick grade again showing no significant change.[20] The scale the field grades this surgery on is not sensitive to what patients actually lose: numbness, position sense, balance, continence, and pain that outlasts the operation by years.
The patient-reported data, such as it is, shows a dose–response. Across 220 people with VHL in five countries, EQ-5D health state fell from 0.825 in those who had never had surgery, to 0.803 after one, to 0.705 after two or more. Among those who could recall their most recent operation, 51.8% said it worsened their fatigue, 51.2% their mental health, and 45.2% their ability to go about daily life.[21] That survey was funded by the manufacturer of the one approved drug, and its instruments are not validated in VHL; we cite it because it is the only data of its kind that exists in this disease.
Nobody has ever measured the cumulative deficit burden across a VHL patient’s lifetime of CNS operations. That absence is itself the argument.
The foundational goal of the Rath Family Foundation’s hemangioblastoma research is to help people with VHL minimize lifetime surgical procedures. That is the primary outcome variable the project measures against and funds for. CNS hemangioblastoma causes two thirds of VHL deaths; the disability it leaves behind is counted above; and the patients themselves have said what they want.
When asked, 47.3% of VHL patients named reducing the number of surgeries as their top treatment goal, and 73% said they would take a pill that might delay surgery.[21] Roughly half of these tumors never grow and only about 6% ever become symptomatic,[10] so a model that can certify “watch, do not cut” prevents surgeries directly, without a new drug. The one published procedure-rate figure in this disease, a fall from 0.35 to 0.08 procedures per patient-year on belzutifan in a real-world cohort (Al Abbas 2026, PMID 42610708), has never been reproduced prospectively or reported with a confidence interval. Surgery-free survival has never been used as a VHL endpoint.
Building that endpoint, and the natural-history model behind it, is Track I of the research agenda.
Because the thing that has repeatedly failed to transfer is precisely the brain. Sunitinib: 33% response in renal lesions, 0 of 21 in hemangioblastoma.[22] Pazopanib: 52% renal, 2 of 49 hemangioblastoma.[23] Sunitinib again, in VHL patients: 64% renal response, every CNS lesion stable.[24] Three cohorts, three drugs, one direction. The dissociation is the best-replicated fact in VHL therapeutics, and it is the reason a kidney-first strategy has not reached the brain.
No. It funds hemangioblastoma of the brain and spine. VHL is the reason those tumors occur, not the scope of the project. Work in renal cell carcinoma, pancreatic neuroendocrine tumor, pheochromocytoma or endolymphatic sac tumor is out of scope even when the researcher is a VHL researcher. Mechanistic groundwork done in kidney cells is welcome on one condition: show, with evidence, that the compound reaches a hemangioblastoma of the brain or spine at a therapeutic level, or set out a credible path to getting it there. A kidney-derived hypothesis is eligible. A kidney endpoint is not.
Because the approved drug already works there. In the ocular subgroup of its pivotal trial, all sixteen eyes with evaluable active retinal lesions were graded improved: 100% at a median thirty-seven months, with no new lesions and no ocular progression.[25] That is the result we want in the brain and do not have. Retinal disease is not finished business, but it is the one hemangioblastoma compartment where the existing drug performs as well as anyone could ask of it. The brain and spine are where it does not.
Partly, and more than most people realize. In the solid component of CNS lesions the response rate is 76%, which is better than its own renal response rate.[5] But it is one drug, taken indefinitely, with anemia in roughly nine patients in ten, and in its own pivotal trial at fifty months the most common reason for stopping it was the patient’s own decision to withdraw.[26] One drug is not a therapeutic area.
Surgery here is excellent and still not enough. In the most experienced center in the world, 98% of operations improved or stabilized symptoms and there were no radiographic recurrences, and the same 80 patients still required 126 craniotomies for cerebellar lesions alone.[16] The result is good; it just has to be done again, and again, and the patient does not come all the way back each time. A drug that keeps one operation from being necessary is worth more here than in any compartment where the operation is repeatable at low cost.
Anatomy, not technique. A hemangioblastoma is a highly vascular tumor embedded in non-regenerating eloquent tissue inside a closed bony compartment. There is no survivable thermal margin, no equivalent of losing some nephrons, and no equivalent of dialysis or transplant if the organ fails. In one series, ten patients received thirty-two separate renal ablation sessions treating fifty-seven tumors, with a mean eGFR loss of 5.5 mL/min over seven and a half years.[27] There is no CNS analogue to that at any price.
Market size, and it is nobody’s fault. Roughly 688,000 Americans are living with kidney cancer;[28] roughly 3,700 have VHL-associated CNS hemangioblastoma.[29] That is 187 to 1, and trial activity sits almost exactly on it. No company is behaving badly. But public funders sit at 107:1, tracking the commercial incentive rather than correcting for it, and philanthropy has no such excuse either. That is the whole argument for this project.
Total identifiable public funding for hemangioblastoma research, across all years, is about $2.4 million.[8] A commitment the size of a single kidney-cancer R01 would more than double the world’s funded research in this compartment. There is no crowded field to enter here. There is, as yet, barely a field.
Half of these tumors never grow, 72% of those that do grow do so in bursts, and only 6.3% ever become symptomatic. That is why the definitive natural-history study, 1,921 lesions over 15,819 lesion-years, concludes that “unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies.”[10]
Measuring benefit is the gate every drug in this compartment has to pass through, and it is still shut. Solving it is shared groundwork that no single company owns, it is unglamorous, and it is exactly what industry will not pay for. That is what makes it the right first use of philanthropic money, rather than a complaint about the field.
Numbered in order of first citation in the original overview. Notes beneath an entry record where a figure in the text is derived from, or differs slightly from, the source. Journal records were checked against PubMed and publisher pages on 12 October 2026.
Procedure-rate figure (0.35 to 0.08 procedures per patient-year) cited in “The outcome that matters”: Al Abbas et al., 2026, PMID 42610708. Treatment-goal and pill-preference figures (47.3%, 73%) are from Sundaram et al., 2025, reference 21.