The planned population consists of adults with high-risk prostate cancer and no detectable metastasis on PSMA PET/CT imaging. To meet the study’s high-risk definition, patients must have at least two of three specified features: a Gleason score of at least 8, T3 or T4 disease, or a prostate-specific antigen concentration of at least 20 ng/mL. Investigators plan to enroll 700 patients over three years. Randomization will use a 2 × 2 factorial design, with participants assigned in equal proportions to four groups. All groups will receive androgen deprivation therapy and prostate and pelvic nodal radiotherapy, described in the abstract as standard treatment.

Arm A will receive standard treatment alone. Arm B will receive standard treatment plus darolutamide, Arm C will receive standard treatment plus a prostate stereotactic body radiotherapy boost, and Arm D will receive standard treatment plus both the radiotherapy boost and darolutamide. Randomization will be stratified according to the number of high-risk factors, either two or three; the presence or absence of a dominant intraprostatic lesion, classified as PI-RADS 5 or not; and the treatment center. The protocol is registered as 2023-509787-15-00 in the EU Clinical Trials Register and NCT06625970 on ClinicalTrials.gov.

The primary endpoint is metastasis-free survival. The protocol specifies a targeted hazard ratio of 0.65, with 170 events required to provide 80% power at a two-sided significance level of 5%. Planned secondary endpoints are clinical progression-free survival, biochemical progression-free survival, time to local relapse, overall survival, prostate cancer-specific survival, acute and long-term toxicity, and quality of life. These are prespecified analytical targets and do not represent observed benefits. The abstract provides no results on metastasis-free survival, adverse effects, quality of life, or any other outcome, and the study’s open-label design and international multicenter scope do not themselves establish treatment effectiveness. PEACE 7 is intended to assess the contributions of darolutamide and dose escalation with a stereotactic radiotherapy boost within the stated population and treatment regimen; conclusions about safety or efficacy must await the trial’s findings.

Subject of Research: A factorial phase III protocol evaluating darolutamide and stereotactic radiotherapy in high-risk localized prostate cancer

Article Title: Randomized phase III trial with a factorial design assessing the efficacy and safety of darolutamide and stereotactic dose-escalated radiotherapy in patients with high-risk localized prostate cancer: the PEACE 7 (GETUG-AFU 45) study protocol

Article References: Crehange, G., Blanchard, P., Foulon, S., La, C., Demogeot, N., Martin, J., Léger, C., Guirao, J., & Fizazi, K. (2026). Randomized phase III trial with a factorial design assessing the efficacy and safety of darolutamide and stereotactic dose-escalated radiotherapy in patients with high-risk localized prostate cancer: the PEACE 7 (GETUG-AFU 45) study protocol. BMC Cancer. https://doi.org/10.1186/s12885-026-16802-9

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16802-9

Keywords: PEACE 7, prostate cancer, phase III trial, study protocol, darolutamide, stereotactic radiotherapy, androgen deprivation therapy, metastasis-free survival, randomized trial, prostate radiotherapy, Randomized, phase

The core of Demircan’s critique rests on a principle familiar to every epidemiologist: treatment effect and treatment selection are two very different things. When patients are not randomized, the group that receives one therapy is often systematically different from the group that receives another, and any difference in outcomes may reflect those baseline differences rather than the therapy itself. In the study under scrutiny, patients who underwent microsurgical resection had greater baseline motor impairment than those allocated to stereotactic radiotherapy. That detail matters enormously, because a patient who enters treatment with a weakened arm or leg has far more room to demonstrate measurable improvement than a patient whose motor function is already intact. Improvement in the surgical cohort and stability in the radiotherapy cohort may therefore describe the same underlying quality of care, even though the numbers appear to favor one arm over the other.

This asymmetry in scoring is more than a statistical quirk. Functional outcome scales typically capture change from baseline, so a patient who regains the ability to walk after tumor decompression registers a dramatic gain, while a patient who never lost the ability to walk and remains unchanged after focused radiation registers only stability. Yet clinically, preserving intact neurological function is precisely the goal of treating a metastasis in eloquent motor cortex without opening the brain. Demircan points out that categorizing preserved near-intact function after stereotactic radiotherapy as mere stability understates what is, for those patients, a meaningful and desirable result. The apparent superiority of surgery may, in part, be an artifact of the yardstick rather than a genuine therapeutic advantage.

The second major concern involves what statisticians call informative crossover, and here the numbers are striking. Of the 41 patients initially allocated to stereotactic radiotherapy, 17 ultimately required salvage surgery, either because their tumors progressed or because they developed a new neurological deficit despite irradiation. That is a crossover rate of roughly 41 percent, and all of those patients were excluded from the comparative radiotherapy cohort. What remains in the analyzed group is, by construction, the subset of patients for whom radiotherapy succeeded. This is a form of survivorship bias built directly into the study design: the radiotherapy arm is pre-selected for good outcomes, while the failures are silently transferred out of view. Any comparison between the trimmed radiotherapy cohort and the surgical cohort will therefore flatter radiotherapy less than an intention-to-treat analysis would, or, depending on how the comparison is framed, obscure the clinically important fact that a substantial minority of radiotherapy patients fared poorly and needed rescue operations.

Demircan emphasizes that this 41 percent crossover does double duty. It simultaneously selects the analyzed radiotherapy cohort for patients in whom the treatment worked, and it identifies a subgroup with genuinely poor outcomes after initial radiotherapy, patients who progressed or deteriorated neurologically and required surgery anyway. For clinicians counseling a patient, that subgroup is not a footnote; it is central to the decision. A patient with a metastasis in the motor cortex wants to know not only the average outcome of each strategy but also the risk that the first choice will fail and leave them worse off. When more than four in ten patients initially assigned to radiotherapy end up needing surgery, the effective comparison is no longer surgery versus radiotherapy but surgery versus radiotherapy followed, in many cases, by surgery after all.

A third layer of complexity concerns what the surgical arm actually received. Postoperative radiotherapy was administered to 95 percent of surgically treated patients with available data. This means the study did not compare surgery alone with radiotherapy alone; it compared a multimodality package, microsurgical resection followed by adjuvant irradiation, against definitive stereotactic radiotherapy. The distinction is far from academic. Landmark randomized trials, including the phase 3 studies by Mahajan and colleagues and Brown and colleagues published in Lancet Oncology in 2017, established that postoperative stereotactic radiosurgery reduces local recurrence after resection but carries its own considerations regarding toxicity and cognitive outcomes. Attributing the combined strategy’s results to surgery alone would misrepresent the intervention patients actually underwent and could mislead centers that lack the full multidisciplinary apparatus the combined approach presumes.

Compounding all of this, the extent of resection was not reported. In neurosurgical oncology, the degree to which a tumor is removed is one of the strongest determinants of local control, particularly when adjuvant radiation is planned. A gross-total resection followed by cavity radiosurgery behaves very differently biologically from a subtotal decompression, both in terms of residual tumor cells and in the dose constraints that nearby motor pathways impose on the radiation plan. Without knowing how complete the resections were, readers cannot disentangle how much of the local control in the surgical arm came from the operation itself and how much from the postoperative irradiation that nearly all of those patients received. Demircan argues that this missing variable further complicates any interpretation of the study’s local control data and its functional outcomes.

None of this means the study is without value. Demircan is explicit that the findings do support microsurgical resection for appropriately selected patients, particularly those with large, symptomatic lesions that require rapid decompression. When a tumor is exerting mass effect on motor pathways and a patient is losing function hour by hour, focused radiation cannot act quickly enough, and surgical relief is the only option that restores room for the brain to recover. The critique is narrower and more precise: the data do not establish that surgery produces better functional outcomes than stereotactic radiotherapy once treatment selection is properly accounted for. Those are two very different claims, and conflating them could push clinical practice toward aggressive intervention in patients who would do just as well, with less risk, under a radiation-first strategy.

The path forward, according to the correspondence, lies in how future studies are designed and reported. Outcomes should be tracked from the initial treatment allocation all the way through salvage therapy, so that the true cost of each starting strategy, including its failure rate, is visible rather than hidden by cohort trimming. Analyses should incorporate the variables that actually drive decisions and outcomes in this population: lesion volume, baseline neurological status, involvement of the corticospinal tract as mapped by diffusion tensor imaging and navigated transcranial magnetic stimulation, the extent of resection achieved, the burden of systemic disease, and the urgency of decompression. Advanced imaging and tractography techniques, already being used to spare motor structures in adjuvant radiotherapy planning, offer a way to individualize these decisions with far greater anatomical precision than was possible a decade ago.

For patients and clinicians, the takeaway is a familiar lesson in modern oncology delivered in an unfamiliar setting. Observational comparisons, however carefully assembled, are hostage to the forces that determine who receives which treatment. In motor cortex metastases, those forces, performance status, motor function, tumor size, and disease burden, are precisely the factors that also shape functional outcomes, making confounding especially potent. The study by Kraus and colleagues adds real evidence that surgery can serve selected patients well, and the correspondence by Demircan sharpens that evidence into something clinically usable: a reminder that preserved function after radiation is a success worth counting, that crossover is a result worth reporting, and that the question is not simply which treatment works, but which treatment works for which patient, under which circumstances, measured from the moment the first decision is made.

Subject of Research: Interpreting functional outcomes and treatment selection bias in managing brain metastases of the primary motor cortex

Article Title: Treatment selection or treatment effect? Interpreting functional outcomes in motor cortex metastases

Article References: Demircan, V. (2026). Treatment selection or treatment effect? Interpreting functional outcomes in motor cortex metastases. Journal of Neuro-Oncology, 179(2), Article 72. https://doi.org/10.1007/s11060-026-05787-x

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05787-x

Keywords: brain metastases, motor cortex, microsurgical resection, stereotactic radiotherapy, treatment selection bias, functional outcomes, crossover, postoperative radiotherapy, extent of resection, corticospinal tract, neuro-oncology, salvage surgery

The research, led by Cristian Udovicich and senior author Arjun Sahgal, focused on a technique the team calls salvage conventionally fractionated Gamma Knife stereotactic radiotherapy, abbreviated SFGK. Unlike single-session stereotactic radiosurgery, which delivers one concentrated blast of radiation, conventional fractionation spreads the treatment over many small daily doses, in this case most often 50.4 Gy delivered in 28 fractions. The approach exploits a fundamental principle of radiobiology: dividing a dose into smaller increments spares normal tissue far more than it spares the tumor, because healthy cells are better at repairing sublethal radiation damage between treatments than many tumor cells are.

Between 2019 and 2024, twenty-six consecutive patients harboring forty-four recurrent tumors underwent the salvage procedure. The overwhelming majority of these lesions, thirty-four in total or roughly three-quarters of the cohort, were meningiomas, the tumors that arise from the meninges, the protective membranes enveloping the brain and spinal cord. Most of these meningiomas were not benign; twenty-eight of the thirty-four were classified as World Health Organization Grade 2, an atypical form known for its stubborn tendency to recur even after surgery and radiation. The remaining patients carried other primary non-glial tumors, a category that excludes the gliomas and glioblastomas that originate from brain support cells and dominate much of the neuro-oncology literature.

What makes the study remarkable is the sheer amount of radiation these patients had already received. The median interval between the original radiotherapy course and the salvage treatment was 50.4 months, meaning most patients had enjoyed roughly four years of disease control before their tumors returned. Once SFGK was delivered, the median cumulative prescription dose, calculated using the EQD2 metric, which converts any radiation schedule into the biologically equivalent dose of 2 Gy per fraction, reached a staggering 102.7 Gy for patients who had undergone one prior course. For context, that figure approaches the tolerance limits of normal brain tissue, a territory where most radiation oncologists fear to tread.

The investigators were acutely aware of this danger, and the study’s dosimetry reflects a deliberate balancing act. The median EQD2 dose accumulated by normal brain tissue was 99.2 Gy, uncomfortably close to the tumor dose itself. This proximity underscores why conventional fractionation was chosen: by stretching 50.4 Gy across 28 sessions, the technique spreads out the biological burden on healthy tissue and allows gradual repair, while the precision of the Gamma Knife Icon platform, which integrates cone-beam CT imaging for frameless stereotactic guidance, ensures the radiation conforms tightly to each lesion. Earlier work by the same group, published in the Journal of Neurosurgery in 2023, had reported the first evidence that fractionated Gamma Knife reirradiation was feasible; the new study extends that signal with a larger cohort and formal survival statistics.

The results exceeded what many in the field would have predicted for such heavily irradiated tissue. Local progression-free survival, the study’s primary endpoint, stood at 91.0 percent at twelve months and 75.1 percent at twenty-four months across all patients. For the meningioma subgroup specifically, the corresponding figures were 90.6 percent and 74.1 percent. Overall survival was even more striking: 96.2 percent of patients were alive at one year and 83.2 percent at two years. In a population whose tumors had already defied surgery and a full course of radiation, these numbers represent a meaningful extension of disease control, particularly for atypical meningiomas, which historically carry poor outcomes at recurrence.

Safety data, often the Achilles heel of reirradiation studies, proved encouraging. Only two patients, or 6.9 percent of the cohort, developed Grade 3 radionecrosis, the dreaded condition in which irradiated brain tissue dies and swells, sometimes requiring surgery or corticosteroid therapy. A single patient, 3.4 percent, experienced Grade 3 progressive intracranial hemorrhage. Crucially, no Grade 4 or Grade 5 events, the most severe toxicity categories, were observed at all. With a median follow-up of 18.1 months, the authors acknowledge that late toxicities can take years to fully declare themselves, but the early safety profile appears acceptable given the extraordinarily high cumulative doses involved.

The study arrives at a moment when options for recurrent meningioma are desperately limited. Surgery at recurrence is often incomplete because these tumors adhere to critical vessels and nerves, and drug development has struggled; even recent trials of radioligand therapies such as lutetium-177 DOTATATE, tested prospectively in surgery- and radiation-refractory meningioma, remain experimental. Alternative reirradiation approaches using proton beams or carbon ions have shown promise but demand infrastructure unavailable to most patients. Fractionated Gamma Knife, by contrast, leverages equipment already installed in major cancer centers worldwide, making SFGK a potentially scalable salvage strategy.

The Toronto team’s work also fits into a broader movement in radiation oncology to formalize the once-forbidden practice of reirradiation. Recent prospective studies have established conventionally fractionated dose constraints for reirradiating primary brain tumors in adults, and the American Radium Society has published appropriate use criteria for retreatment in head and neck cancers. The Sunnybrook experience now provides some of the strongest evidence yet that primary brain tumors, specifically, can tolerate a second radical course when delivered with stereotactic precision and fractionation. A related report in 2025 documented even a third course of radical-intent conformal radiation in selected patients, suggesting the ceiling on cumulative dose may be higher than traditionally assumed when treatments are spaced and planned carefully.

For the patients whose atypical meningiomas had returned after years of remission, the study offers something that has long been in short supply: a well-tolerated option that meaningfully delays progression. The authors caution that their findings come from a retrospective single-institution series of twenty-six patients, and that longer follow-up will be needed to confirm durability and capture late toxicity. Yet the central conclusion stands on firm ground within those limits. Delivered in conventionally fractionated form on a modern frameless Gamma Knife platform, salvage reirradiation is feasible, achieves durable local control, and produces few serious adverse events, even when cumulative doses approach one hundred grays. For a field where recurrent, previously irradiated tumors have often meant palliative care alone, that is a result worth celebrating.

Subject of Research: Salvage fractionated Gamma Knife reirradiation for recurrent primary non-glial brain tumors

Article Title: Reirradiation outcomes following salvage conventionally fractionated Gamma Knife stereotactic radiotherapy (SFGK) to recurrent primary non-glial brain tumors

Article References: Udovicich, C., Tseng, C.-L., Detsky, J., Chen, H., Dinakaran, D., Soliman, H., Zeng, K. L., Ruschin, M., Yeboah, C., Holden, L., Atenafu, E. G., & Sahgal, A. (2026). Reirradiation outcomes following salvage conventionally fractionated Gamma Knife stereotactic radiotherapy (SFGK) to recurrent primary non-glial brain tumors. Journal of Neuro-Oncology, 179(3), Article 88. https://doi.org/10.1007/s11060-026-05757-3

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05757-3

Keywords: Gamma Knife, reirradiation, meningioma, brain tumors, stereotactic radiotherapy, radiation necrosis, local control, radionecrosis, WHO Grade 2 meningioma, fractionated stereotactic radiotherapy, salvage therapy, neuro-oncology

Researchers at Tampere University Hospital set out to answer a question that had not been addressed before: whether temporal muscle thickness, or TMT, measured on ordinary computed tomography scans, could predict survival in patients aged 70 or older who received brain radiotherapy for metastatic cancer. The question matters because prognostication in this population is exceptionally difficult and exceptionally important. Brain metastases affect an estimated 10 to 40 percent of patients with solid tumors, and population studies place the incidence between 8.3 and 14.3 per 100,000 people, a figure that almost certainly underestimates the true burden because not all cases are registered. Median survival across the field ranges from as little as two months to 21 months depending on the primary cancer, and for patients over 65, Surveillance, Epidemiology, and End Results data indicate a median survival of four months or less for nearly all common malignancies, including breast, colorectal, esophageal, renal, and lung cancer and melanoma.

Accurate prognostic tools would allow clinicians to tailor treatment intensity intelligently. Patients with a favorable outlook might benefit from more aggressive interventions, while those expected to survive only weeks could be spared the burdens of hospitalization, repeated radiotherapy sessions, or chemotherapy in the final weeks of life, interventions that may degrade quality of life without meaningfully extending it. Honest prognostic information also underpins shared decision-making, giving patients and families a realistic basis on which to weigh intensive treatment against palliative care. The Tampere team reasoned that if a simple measurement already embedded in the treatment-planning scan could sharpen these predictions, it would be a genuinely useful clinical instrument.

The study, published in Cancer Reports, took the form of a retrospective cohort analysis of consecutive patients aged 70 years or older who underwent brain radiotherapy, with or without prior surgical resection, for brain metastases between 2014 and 2022. From the hospital’s electronic radiotherapy database, 249 patients met the inclusion criteria: 136 men with a mean age of 76.0 years and 113 women with a mean age of 76.4 years. Lung cancer dominated the cohort, accounting for 113 patients or 45.4 percent, followed by breast cancer with 29 patients and melanoma with 27. Most participants, 226 in total, received radiotherapy alone, split between whole-brain radiotherapy, given to 151 patients, and stereotactic radiotherapy, delivered to 98, while 23 patients underwent surgical resection followed by postoperative radiation.

Measuring the temporalis muscle requires surprising methodological care. A single observer, blinded to patient outcomes, assessed TMT on each patient’s first radiotherapy planning head CT, or on a diagnostic CT performed within the preceding month. The measurement plane had to be oriented parallel to the falx cerebri, the membrane dividing the brain’s hemispheres, and tangential to the floor of the middle cranial fossa, with the image windowed to a narrow setting of 80 Hounsfield units width and 40 length to sharpen the muscle’s boundaries. On the first axial slice above the bony orbit, a tangent line was drawn from the muscle’s anterior attachment to the skull, and thickness was recorded at the muscle’s thickest point perpendicular to that line, deliberately excluding fat, fascia, and blood vessels. The average of left and right measurements was used in the analyses. To confirm the technique’s reliability, a second observer independently measured a random sub-cohort of 19 patients, and the agreement between readers was excellent, with an intraclass correlation coefficient of 0.942 for single measurements and 0.970 for averages—figures indicating that the measurement itself is robust and reproducible.

Because men naturally have thicker temporal muscles than women, the researchers derived sex-specific thresholds for low TMT by maximizing Youden’s index, a statistical measure balancing sensitivity and specificity, for three-month survival. The resulting cut-offs were 4.3 millimeters for men, with 46.7 percent sensitivity and 74.6 percent specificity, and 3.975 millimeters for women, with 64.6 percent sensitivity and 49.2 percent specificity. These thresholds are notably lower than those reported in earlier studies of younger patients, a difference the authors attribute to the advanced age of their cohort, in which temporal muscle wasting is already widespread. By these criteria, 35.3 percent of the men and 56.6 percent of the women had low temporal muscle thickness.

The survival picture in the cohort was stark. Median overall survival was just 90 days, or roughly three months, and by the one-year mark 86.7 percent of the patients had died. Patients with normal TMT did live somewhat longer on average than those with low TMT, with a median of 103 days versus 75 days, and in univariate analyses low TMT was significantly associated with worse survival at three months, with a hazard ratio of 1.54, and at six months, with a hazard ratio of 1.41. At one month and twelve months, no association reached statistical significance. But the crucial test came when the researchers adjusted their models for other clinical variables: age, body mass index, surgical treatment, and type of radiotherapy. Once these factors were accounted for, the relationship between TMT and survival evaporated entirely at every time horizon, with the adjusted three-month hazard ratio falling to 1.40 and losing significance.

What did predict survival, independently, were other clinical variables. Receiving whole-brain radiotherapy rather than stereotactic radiotherapy carried a substantially higher risk of death at every time point, with an adjusted hazard ratio of 5.98 for one-month survival and approximately 2.3 at the longer horizons. This likely reflects treatment selection rather than harm: whole-brain radiotherapy is generally reserved for patients with multiple metastases and poorer prognosis, while stereotactic techniques are favored for those with limited, more favorable disease. Similarly, patients who did not undergo surgical resection had markedly higher mortality across all time frames, since surgery is typically offered only to younger patients with solitary lesions and better expected outcomes. Higher body mass index was protective for one-month survival, with a hazard ratio of 0.31, and advancing age independently worsened six- and twelve-month survival. The authors are candid that these patterns largely mirror the realities of clinical decision-making.

The contrast with previous research is instructive. Of six earlier studies evaluating TMT in patients with brain metastases, three found that low thickness predicted shorter survival, while others found no association once confounders were considered. Crucially, those studies examined patients on average more than a decade younger, with median survival extending from three to eleven months, and several included only surgically treated patients. The Tampere cohort, by contrast, was older, sicker, and predominantly managed with radiotherapy alone. The researchers also tested whether TMT predicted survival within their largest tumor subgroup, the 113 lung cancer patients, and found no significant association at any time point, which discouraged further subgroup analyses. Additional limitations deserve mention: performance status, number of brain lesions, intracranial tumor volume, extracranial disease status, and systemic therapy were not incorporated into the models, and the derived sex-specific cut-offs may risk overfitting, making external replication essential.

The study’s conclusion is refreshingly direct: temporal muscle thickness should not be regarded as a prognostic factor in patients aged 70 or older with brain metastases treated with radiotherapy. The finding is a valuable corrective to a growing enthusiasm for imaging-derived body-composition markers, reminding clinicians and researchers that a measurement can be technically reliable, easily obtained, and biologically plausible yet still fail to add independent predictive value in the population that matters. In very old, profoundly ill patients whose median survival is measured in weeks, disease aggressiveness and treatment selection appear to overwhelm any signal carried by skeletal muscle reserves. For this vulnerable group, prognostic conversations must continue to rest on established clinical variables, while the search for better tools goes on.

Subject of Research: Temporal muscle thickness as a prognostic marker for survival in older patients with brain metastases treated with radiotherapy

Article Title: Association Between Temporal Muscle Thickness and Survival in Older Patients With Brain Metastases Undergoing Radiation Therapy

Article References: Pikkarainen, L., Korhonen, T. K., Tolonen, A., Pesonen, E. K., Hernandez, N., Skyttä, T., & Arponen, O. (2026). Association Between Temporal Muscle Thickness and Survival in Older Patients With Brain Metastases Undergoing Radiation Therapy. Cancer Reports, 9(9), Article e70671. https://doi.org/10.1002/cnr2.70671

Image Credits: AI Generated

DOI: 10.1002/cnr2.70671

Keywords: temporal muscle thickness, brain metastases, radiotherapy, survival, sarcopenia, cachexia, prognostication, computed tomography, whole-brain radiotherapy, stereotactic radiotherapy, older patients, Cancer Reports