Radioligand therapy has transformed the treatment landscape for metastatic castration-resistant prostate cancer, or mCRPC, a stage of disease in which tumors no longer respond to hormone deprivation. The approved therapy, lutetium-177 labeled PSMA-617, homes in on prostate-specific membrane antigen, a molecule abundantly displayed on the surface of prostate cancer cells, and delivers beta radiation directly to metastatic deposits. Clinical trials demonstrated improved survival and tolerability, leading to regulatory approval in both Europe and the United States. Yet not every patient responds, and resistance eventually emerges in many. This therapeutic gap has driven a search for alternative radionuclides capable of packing more lethal energy into tumor cells, and terbium-161 has quickly become one of the most compelling candidates.

The appeal of terbium-161 lies in its distinctive decay physics. It closely mimics lutetium-177 in the ways that matter for clinical logistics: nearly identical half-lives of 6.9 versus 6.6 days, similar mean beta particle energies of 154 versus 133 kiloelectronvolts, and gamma emissions suitable for post-treatment imaging and dosimetry. But terbium-161 also emits a far greater abundance of conversion electrons and low-energy Auger electrons. These particles travel less than 500 nanometers in tissue and deposit energy at a high linear energy transfer of 4 to 26 kiloelectronvolts per micrometer. In principle, this means intense, highly localized irradiation precisely where the radioligand binds, particularly damaging for microscopic tumor deposits and single tumor cells that beta particles from lutetium-177 may spare. Preclinical studies and simulation work have consistently suggested a dosimetric advantage for terbium-161, and an initial head-to-head comparison in six patients corroborated the theory.

What has been missing is rigorous dosimetry in a larger patient cohort. The new study addresses that gap by analyzing 15 men with mCRPC enrolled in a prospective therapeutic registry who received terbium-161 labeled PSMA-617, typically as a second-line radioligand option after prior therapy with lutetium-177 or actinium-225. Patients received a median of two treatment cycles with a mean administered activity of 6.0 plus or minus 1.3 gigabecquerels per cycle, for a cumulative mean activity of 12.3 plus or minus 4.6 gigabecquerels. The radiolabeling process, adapted from established lutetium-177 methodology, achieved radiochemical yields and purity consistently above 99 percent, and administered activities were individually tailored to each patient’s tumor burden, renal function, and blood counts.

Dosimetric assessment relied on a hybrid two-dimensional and three-dimensional imaging protocol. Planar whole-body scans were acquired at roughly 24, 48, and at least 69 hours after injection, supplemented by SPECT/CT imaging of the head and neck on day one and of the abdomen on day two. Using a 74.6 kiloelectronvolt photopeak window, scatter and attenuation corrections, partial-volume corrections derived from terbium-161 phantom measurements, and automated Bayesian volume segmentation, the physics team calculated absorbed doses with the OLINDA/EXM software following the internationally recognized MIRD schema. This combination of planar kinetics rescaled by quantitative SPECT values represents a methodologically sound middle ground between speed and accuracy, and it allowed the researchers to track 43 individual metastatic lesions alongside the kidneys, liver, parotid glands, and submandibular glands.

The organ dosimetry results place terbium-161 therapy squarely within the safety envelope established for lutetium-177. Kidneys received the highest mean absorbed dose at 0.70 plus or minus 0.41 gray per gigabecquerel, followed by the parotid glands at 0.40 plus or minus 0.20 and the submandibular glands at 0.36 plus or minus 0.14 gray per gigabecquerel, with the liver absorbing the least at 0.13 plus or minus 0.08 gray per gigabecquerel. Absorbed doses did not change significantly between the first and second treatment cycles, and no deterioration in renal toxicity was observed even in the two patients with the highest kidney doses, both of whom entered the study with pre-existing renal risk factors. The reported kidney dose range overlaps the published spectrum for lutetium-177 PSMA-617, which spans roughly 0.39 to 0.99 gray per gigabecquerel across major studies.

The tumor findings are where the therapy’s promise becomes most visible. Across 43 analyzed metastases, predominantly bone lesions, the mean absorbed tumor dose was 5.95 plus or minus 3.60 gray per gigabecquerel, with individual lesions ranging from 0.68 to 32.34 gray per gigabecquerel. Bone metastases absorbed 5.89 plus or minus 4.20 gray per gigabecquerel and lymph node metastases 5.46 plus or minus 2.97 gray per gigabecquerel, with lesions retaining the tracer for a mean effective half-life of 44 hours. These figures compare favorably with meta-analytic data for lutetium-177 PSMA ligands, which reported mean bone lesion doses of about 3.6 to 4.1 gray per gigabecquerel and soft-tissue doses of about 2.9 to 4.2 gray per gigabecquerel. Translated into therapeutic indices, the tumor-to-kidney ratio reached 10.55 plus or minus 8.32 and the tumor-to-parotid ratio 16.15 plus or minus 11.85, well above the kidney therapeutic indices of 3.6 to 5.3 previously published for lutetium-177-based approaches.

The study also probed the relationship between dose and response, finding a suggestive but statistically non-significant trend. Patients whose disease progressed biochemically tended to have received lower tumor absorbed doses, averaging 3.15 plus or minus 1.62 gray per gigabecquerel, than patients with stable disease at 5.81 plus or minus 2.64 or partial PSA remission at 6.52 plus or minus 3.27 gray per gigabecquerel, with a moderate correlation between tumor dose and PSA change. The authors attribute the lack of statistical significance to the small, heterogeneous, and heavily pretreated cohort rather than to any absence of a dose-response relationship, which earlier work in PSMA radioligand therapy has supported. Importantly, no severe adverse events or treatment discontinuations occurred in the cohort, reinforcing the emerging picture from the independent VIOLET phase 1/2 trial of terbium-161 PSMA-I&T that this radionuclide is safe and clinically active.

The investigators are careful to note the limitations: the cohort was small, all patients had undergone multiple prior radioligand therapy cycles that may have altered tracer kinetics, red marrow dosimetry was not feasible, and lesion selection was constrained by imaging criteria that could introduce bias. Nonetheless, as the largest terbium-161 PSMA dosimetry study published to date, the work provides a quantitative foundation for a therapy that could ultimately serve not only prostate cancer patients but also those receiving peptide receptor radionuclide therapy or FAP-targeted treatments. The favorable tumor-to-organ ratios reported here support continued clinical development, and the authors argue that individualized dosimetry will be central to future treatment planning, allowing clinicians to adapt activity prescriptions per patient to maximize tumor kill while protecting kidneys and salivary glands. Larger prospective trials will determine whether terbium-161’s physical advantages translate into a survival benefit, but the dosimetric arithmetic now clearly favors it.

Subject of Research: Organ and tumor dosimetry of terbium-161 PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer

Article Title: Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC

Article References: Schaefer-Schuler, A., Blickle, A., Ganz, S., Petto, S., Burgard, C., Speicher, T., Bastian, M. B., Maus, S., Bartholomä, M., Ezziddin, S., & Rosar, F. (2026). Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08171-z

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08171-z

Keywords: terbium-161, PSMA-617, radioligand therapy, dosimetry, prostate cancer, mCRPC, Auger electrons, SPECT/CT, tumor-to-organ ratio, nuclear medicine, theranostics, kidney dose

Radioligand therapy with 177Lu-PSMA-617 has transformed the treatment landscape for metastatic castration-resistant prostate cancer, a lethal stage of the disease in which roughly half of patients survive less than five years after their metastatic diagnosis. The therapy exploits prostate-specific membrane antigen, a protein abundantly displayed on the surface of prostate cancer cells and further upregulated as tumors become castration resistant. A ligand called PSMA-617 delivers the beta-emitting radioisotope lutetium-177 directly to tumor cells, irradiating metastases throughout the body while sparing much of the surrounding healthy tissue. Following the landmark phase III VISION trial, the approach gained approval from the United States Food and Drug Administration in March 2022 for PSMA-positive patients who had already received an androgen receptor pathway inhibitor and taxane chemotherapy.

Yet the therapy has an uncomfortable secret: only about half of eligible patients derive meaningful clinical benefit. Except for PSMA PET imaging criteria used to confirm that tumors carry the target molecule, clinicians currently lack validated biomarkers to identify who will respond and who will progress despite treatment. This gap matters both scientifically and economically. A recent cost-effectiveness analysis based on the VISION trial concluded that adding 177Lu-PSMA to standard care may only be cost-effective under specific clinical and economic assumptions, underscoring the urgency of better patient selection.

To address this problem, investigators at IRCCS Istituto Romagnolo per lo Studio dei Tumori in Meldola, Italy, enrolled 145 patients between April 2017 and October 2022 in a prospective observational biological study nested within a single-arm phase II trial of 177Lu-PSMA-617. Of these, 142 patients received at least one dose and were fully evaluable. Within seven days of the first infusion, the researchers collected baseline blood samples and measured a panel of routinely available laboratory markers, including hemoglobin, alkaline phosphatase, prostate-specific antigen, chromogranin A, neuron-specific enolase, and CEA, along with inflammatory ratios derived from the complete blood count. All patients received treatment in four cycles administered every eight to twelve weeks, using either a lower activity of 3.7 to 4.4 gigabecquerels or a higher activity of 5.5 gigabecquerels per cycle.

At a median follow-up of 44 months, the cohort experienced a median progression-free survival of 7.0 months and a median overall survival of 16.8 months, outcomes broadly consistent with the pivotal VISION and TheraP trials. In univariable analyses, elevated platelet-to-lymphocyte ratio, alkaline phosphatase, PSA, and CEA each predicted shorter progression-free survival, while low hemoglobin and high neutrophil-to-lymphocyte ratio, along with the same markers, predicted shorter overall survival. But when the researchers integrated all clinical characteristics and serum biomarkers into multivariable Cox regression models, only a handful of factors retained independent significance: prior docetaxel exposure, low hemoglobin, high PSA, and, critically, elevated CEA. High CEA independently predicted both shorter progression-free survival, with a p-value of 0.026, and shorter overall survival, with a p-value of 0.003.

The statistical rigor of the analysis strengthens the claim. Multicollinearity checks using variance inflation factors confirmed that no variable simply duplicated another, with all values below two. When CEA was added to a model containing established prognostic factors, the overall model fit improved significantly according to a likelihood-ratio test, and Harrell’s concordance index rose from 0.732 to 0.742. Although PSA alone discriminated outcomes better than CEA alone, with C-indices of 0.652 versus 0.598, combining the two markers pushed the C-index to 0.694, demonstrating that CEA carries prognostic information that PSA does not capture. Exploratory correlation analyses reinforced this independence: baseline CEA showed essentially no relationship with PSA levels and only a weak association with chromogranin A, while it did not correlate with bone disease burden measured on PSMA PET scans.

The biological story behind elevated CEA may be as compelling as the statistics. CEA is an oncofetal glycoprotein long used as a tumor marker in colorectal and other cancers, and previous work has linked it to aggressive disease biology in prostate cancer. In particular, elevated serum CEA in castration-resistant prostate cancer has been associated with liver metastases, markedly shorter survival, and distinctive circulating tumor DNA alterations. It has also been tied to aggressive variant prostate cancer, a molecularly distinct and treatment-resistant phenotype. Although a single-arm design without a control group prevents the authors from claiming that CEA specifically predicts benefit from 177Lu-PSMA rather than simply flagging inherently aggressive disease, the finding raises the hypothesis that high CEA identifies a biologically distinct subgroup with intrinsic resistance to PSMA-targeted radioligand therapy. Notably, baseline FDG PET was not mandatory in this cohort, so the researchers could not test whether CEA-elevated patients harbored FDG-positive, PSMA-low lesions typical of aggressive variants.

Other markers behaved as expected. Lower hemoglobin, likely reflecting chronic inflammation and extensive bone marrow involvement rather than a direct effect on treatment response, remained independently associated with shorter overall survival. Alkaline phosphatase, a proxy for skeletal tumor burden, also independently predicted overall survival, consistent with three prior studies and a recent meta-analysis. Inflammatory ratios lost much of their significance after adjustment, although platelet-to-lymphocyte ratio retained an association with progression-free survival. An intriguing exploratory interaction suggested that the prognostic impact of CEA may differ according to the administered radiation activity, but the authors caution that this post hoc finding is hypothesis-generating only, since dose was not randomly assigned and lower activities were reserved for frailer patients.

The study’s limitations temper, but do not erase, its promise. The administered activities were lower than the currently approved Pluvicto regimen of 7.4 gigabecquerels every six weeks, potentially limiting generalizability, and no metastatic biopsies were available to histologically confirm neuroendocrine differentiation among patients with elevated chromogranin A or neuron-specific enolase, markers of limited specificity that can rise in many benign and malignant conditions. External validation in cohorts treated with the approved dosing schedule will be essential before CEA enters routine risk stratification. Still, the vision is clear: if validated, a marker already present on virtually every hospital laboratory requisition could, at essentially no added cost, help clinicians identify patients facing aggressive, inherently resistant disease, guide them toward alternative or combination strategies, and reserve this costly radioligand therapy for those most likely to benefit. In the precision oncology era, the humble CEA blood draw may prove an unexpectedly powerful ally.

Subject of Research: Baseline serum carcinoembryonic antigen as an independent prognostic biomarker for survival outcomes in metastatic castration-resistant prostate cancer patients treated with 177Lu-PSMA radioligand therapy

Article Title: Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy

Article References: Giunta, E. F., Marini, I., Grassi, I., Nicolini, S., Foca, F., Celli, M., Caroli, P., Sarnelli, A., Brighi, N., Schepisi, G., Monti, M., De Giorgi, U., Lolli, C., & Sansovini, M. (2026). Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08173-x

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08173-x

Keywords: 177Lu-PSMA, prostate cancer, radioligand therapy, CEA, biomarker, metastatic castration-resistant prostate cancer, prognostic factors, PSMA, overall survival, progression-free survival, PSMA-617, serum tumor markers