Radiopharmaceuticals - Board Review Summary

Last reviewed and updated: August 2026. This field changes quickly; verify label language against current prescribing information before clinical use.

PART I - FOUNDATIONS: THERANOSTICS, ISOTOPES, AND CURRENT LANDSCAPE

What changed in 2026:

Pluvicto is now approved in hormone-sensitive disease. On July 31, 2026 the FDA approved Lu-177 PSMA-617 in combination with an ARPI for PSMA-positive metastatic androgen pathway modulation-naive/sensitive prostate cancer, based on PSMAddition. No prior taxane or ARPI failure is required for this indication.
New disease-state nomenclature. PCWG4 replaces castration-based terms with androgen pathway modulation terms, and the FDA used that language in the July 2026 approval. See the box below.
Azedra is off the US market. Approved 2018, production discontinued 2024. Belzutifan is now the FDA-approved systemic option for PPGL.
New survival data: final OS for PSMAfore, mature OS for TheraP, OS for ENZA-P, and final OS for PEACE-3.

Nomenclature: PCWG4 (know both sets of terms). PCWG4 recommends abandoning "castration-sensitive" and "castration-resistant" in favor of terms built on androgen pathway modulation (APM), which covers ADT and ARPIs rather than testosterone alone.

APMN = APM-naive. APMS = APM-sensitive. Together APMN/S replaces HSPC and CSPC.
APMR = APM-resistant, replacing CRPC and HRPC.
The rationale is that "naive" does not presuppose an outcome the way "sensitive" did, and that modern androgen-axis drugs are mechanistic rather than purely endocrinologic.
Boards and journals are in transition. This page uses the PCWG4 term with the legacy term in parentheses on first use in each section.

Core Management Paradigm

Question	Board-style answer	Why it matters
Is there a target?	Use target-specific imaging before therapy: PSMA PET for Lu-PSMA, SSTR imaging for Lu-DOTATATE, iobenguane avidity for I-131 MIBG.	No target means no useful radiopharmaceutical for that pathway.
Is there target-negative disease?	Look for discordant biology such as FDG-positive / PSMA-negative progression or rapidly growing target-negative lesions.	Target-negative disease is one of the most important reasons RPT fails.
Is the patient safe for treatment?	Check marrow, renal, hepatic, hydration, prior EBRT, prior chemo, and diffuse marrow tumor burden.	Most serious toxicities are predictable from reserve and organ dose.
Is there an urgent local problem?	Cord compression, unstable bone, focal neurologic deficit, obstruction, bleeding, or a dominant painful lesion usually needs surgery and/or EBRT first.	Systemic target therapy is not a substitute for urgent local control.
Is this approved-use or trial-frontier?	Separate current standards from moving-frontier work such as UpFrontPSMA, LUNAR, and alpha-emitter strategies. Note that PSMAddition moved from frontier to label in July 2026.	Boards often test the difference between "promising" and "standard," and that line moves.

Core Definition

Targeted radionuclide therapy delivers radiation systemically through a radiolabeled molecule, peptide, antibody, particle, or microparticle that naturally accumulates in, or is designed to target, tumor. The central board principle is that the therapeutic effect comes from absorbed radiation dose, not from the carrier molecule itself.

Theranostics

Radiopharmaceuticals fit a theranostic model: the same target can be used for diagnosis, treatment selection, dosimetry, response assessment, and therapy. This is the conceptual shift to memorize: imaging is not just staging; it can select, guide, and evaluate systemic radiation therapy.

Alpha vs Beta vs Beta-Auger Emitters

Property	Alpha emitters	Beta emitters	Dual beta-Auger (next-gen)
Examples	Ac-225, Th-227, Pb-212, Ra-223	I-131, Y-90, Lu-177, Sr-89, Sm-153	Tb-161
Physics advantage	High LET, dense double-strand DNA damage, less dependence on oxygenation	Cross-fire effect and broader dose deposition	Beta plus abundant Auger / conversion electrons deliver concentrated nm-μm radiation
Path-length advantage	Very short path length, often cell-scale	Millimeter-scale path length, useful for heterogeneous uptake	Theoretical edge against micrometastases and single cells
Imaging	Difficult; Ac-225 daughters give limited gamma for quantitative work	Varies by nuclide. Y-90 and Sr-89 are pure beta; I-131, Lu-177, and Sm-153 have imageable gammas. Y-90 can still be imaged by bremsstrahlung SPECT or internal pair-production PET.	Gamma emission comparable to Lu-177, so post-therapy imaging is feasible
Key drawback	Dose heterogeneity, daughter-decay toxicity, difficult imaging and dosimetry	Lower LET and more normal-tissue spill than alpha emitters	First-in-human only; long-term toxicity profile not yet established

Classic distractor: Sm-153 is not a pure beta emitter. It has a 103 keV gamma that permits post-therapy imaging. Sr-89 is the pure beta agent in that pair.

Major Clinical Agents to Know

Agent	Main disease	Particle / decay	Target / mechanism	Board takeaway
I-131 sodium iodide	Differentiated thyroid cancer	Beta emitter with gamma emission	Elemental iodine uptake through NIS	Historic proof that systemic targeted RT can improve survival.
Y-90 microspheres	HCC and selected liver-dominant disease	Pure beta emitter	Intra-arterial radioembolization	Locoregional radiopharma; dosimetry and arterial mapping are central.
High-specific-activity I-131 MIBG (Azedra) Discontinued	PPGL	Beta emitter with gamma emission	Norepinephrine-transporter targeting; carrier-poor, ~2,500 mCi/mg	FDA-approved 2018, production discontinued 2024. Still testable as the clean example of theranostic selection, dosimetric dosing, and thyroid blockade.
Conventional (low-specific-activity) I-131 MIBG	High-risk / relapsed neuroblastoma	Beta emitter with gamma emission	Same NET target, but large mass of unlabeled carrier MIBG	Different product from Azedra. Never FDA-approved for therapy; delivered under IND / expanded access at roughly 10-20 US centers. Weight-based dosing, not the Azedra dosimetric scheme.
Radium-223	Bone-metastatic mAPMR	Alpha emitter	Bone-seeking calcium mimetic	Improves OS in symptomatic bone-metastatic disease without known visceral metastases.
Lu-177 DOTATATE	SSTR-positive GEP-NET	Beta emitter with gamma emission	Radiolabeled somatostatin analog	Core PRRT platform for SSTR-positive GEP-NETs; also used off-label for SSTR-positive PPGL.
Lu-177 PSMA-617	PSMA-positive prostate cancer	Beta emitter with gamma emission	PSMA-targeted radioligand therapy	As of July 2026, approved across the metastatic spectrum: APM-resistant and APM-naive/sensitive disease.
Lu-177 PSMA-I&T (PNT2002)	PSMA-positive prostate cancer (investigational in US)	Beta emitter with gamma emission	Alternative PSMA ligand chelate	Agent used in LUNAR and SPLASH. Do not assume PSMA-617 data transfer directly.
Ac-225 PSMA	PSMA-positive mAPMR (investigational)	Alpha emitter	PSMA-targeted alpha therapy (TAT)	Effective post-Lu-177 progression; xerostomia is dose-limiting.
Tb-161 PSMA	PSMA-positive mAPMR (investigational)	Beta-Auger emitter	PSMA-targeted beta plus Auger therapy	First-in-human signals favorable activity and tolerability; theoretical advantage against micrometastases.

Current Standard vs Trial Frontier

Agent	Current practical standard / label anchor	Moving-frontier signal
Xofigo / Ra-223	mAPMR (mCRPC) with symptomatic bone metastases and no known visceral metastatic disease; 55 kBq/kg q4wk x6. The US label still describes monotherapy and does not include an ARPI-combination indication.	PEACE-3 final OS supports enzalutamide + Ra-223 with mandatory bone-protective therapy, but this remains an evidence-supported, non-labeled combination in the US.
Lutathera / Lu-177 DOTATATE	Adult and pediatric age ≥12 with SSTR-positive GEP-NET; 7.4 GBq q8wk x4. NCCN category 1 for progressive, octreotide-refractory GI NETs with intact SSTR expression.	NETTER-2 moves PRRT into first-line treatment for higher grade well-differentiated GEP-NET. ITM-11 (Lu-177 edotreotide) has an accepted NDA with a PDUFA date of August 28, 2026, supported by COMPETE, with COMPOSE in well-differentiated high-grade disease.
Pluvicto / Lu-177 PSMA-617 Updated	Two labeled indications. (1) PSMA-positive mAPMR (mCRPC) after ARPI therapy, either post-taxane or when appropriate to delay taxane. (2) Since July 31, 2026: PSMA-positive mAPMN/S (mHSPC) in combination with an ARPI, with no requirement for prior taxane or ARPI failure. Both require PSMA PET selection with Locametz or another approved agent; 7.4 GBq q6wk x6.	UpFrontPSMA and LUNAR push further into earlier and oligometastatic disease. SPLASH and ECLIPSE test Lu-177 PSMA-I&T. WARMTH Act (Ac-225) and VIOLET-161Tb push isotope physics.
Azedra / high-specific-activity I-131 MIBG Discontinued	No longer commercially available. Approved July 2018 for iobenguane-scan-positive unresectable, locally advanced, or metastatic PPGL in patients ≥12. Manufacturing was discontinued in 2024 for lack of commercial demand, with final doses produced to let existing patients finish. Payers no longer authorize new starts.	Still worth knowing as the theranostic archetype. The practical replacements are belzutifan (FDA-approved May 2025 for PPGL ≥12, first oral therapy for the indication) and Lu-177 DOTATATE off-label for SSTR-positive PPGL, which NCCN supports at category 2A.
Y-90 microspheres	Liver-directed radioembolization for selected HCC and liver-dominant tumors after mapping angiography and lung-shunt assessment.	Modern Y-90 is increasingly dosimetry-driven rather than empiric activity driven.

Classic Platform Quick Hits

Platform	Selection / workflow	High-yield toxicity or safety point
Differentiated thyroid I-131	NIS-dependent iodine avidity; used after thyroidectomy in selected intermediate/high-risk disease and for iodine-avid metastatic disease.	Pregnancy and breastfeeding are contraindicated. Counsel on sialadenitis and xerostomia, nasolacrimal duct stenosis and epiphora, marrow suppression, gonadal effects, secondary malignancy including leukemia, and radiation isolation.
High-specific-activity I-131 MIBG (Azedra) Discontinued	Required iobenguane scan-positive PPGL; dosimetric dose preceded therapeutic dosing.	Thyroid blockade was mandatory; monitor marrow, blood pressure, renal function, hypothyroidism, and pneumonitis. Rare MDS/AML.
Conventional I-131 MIBG / pediatric NB	MIBG avidity occurs in roughly 90% of neuroblastomas. I-123 MIBG is the diagnostic agent of choice; conventional I-131 MIBG is therapeutic in selected high-risk or relapsed settings, given under IND or expanded access rather than on label. Typical activity 5-18 mCi/kg, with stored stem cells required at ≥12 mCi/kg.	Know the Curie-score concept and that persistent MIBG-avid metastatic sites can drive local RT decisions. Myelosuppression is dose-limiting and often needs autologous stem cell rescue.
MIBG imaging in PPGL	Largely superseded by Ga-68 DOTATATE PET, which outperforms MIBG scintigraphy for metastatic and SDHx-related disease. F-18 FDG remains useful for aggressive or SDHB-mutated tumors.	A negative MIBG scan no longer rules out a targetable radiopharmaceutical option, because SSTR-directed therapy may still apply.
Y-90 radioembolization	Mapping angiography, extrahepatic-flow prevention, lung-shunt evaluation, and liver/tumor dose planning are core steps.	Watch for GI ulceration, radiation pneumonitis, biliary injury, and radioembolization-induced liver disease.
Sr-89 / Sm-153 bone palliation	Older bone-seeking agents for painful osteoblastic metastases. Sr-89 is a pure beta emitter (half-life about 50.5 days); Sm-153 EDTMP emits beta plus a 103 keV gamma (half-life about 46.3 hours) that allows post-therapy imaging.	Pain palliation without the OS signal that distinguishes Ra-223. Both are supply-limited or effectively unavailable in the US, so treat them as concept questions rather than practical options.

PART II - RADIUM-223

Indication and Practical Identity

Radium-223 dichloride is a bone-seeking alpha-emitting calcium mimetic approved for APM-resistant (castration-resistant) prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. It is not simply a pain drug: in the right bone-metastatic population, it improves survival and delays skeletal events.

ALSYMPCA

ALSYMPCA randomized 921 men with mAPMR (mCRPC), castrate testosterone, and at least 2 bone metastases to 6 injections of Ra-223 every 4 weeks vs placebo. The historical activity was reported as 50 kBq/kg; the current label-equivalent dose is 55 kBq/kg after NIST calibration standardization. Median OS improved from 11.3 to 14.9 months, median time to first skeletal event improved from 9.8 to 15.6 months, and time to alkaline phosphatase rise improved from 3.8 to 7.4 months. The study was stopped early for efficacy.

Radium-223 Management Paradigm

Clinical question	Board-style answer
Best candidate	mAPMR with symptomatic bone metastases, adequate marrow reserve, and no known visceral metastases.
Soft-tissue / visceral disease	Do not expect Ra-223 to control visceral disease; choose systemic therapy or focal RT as appropriate.
Bone health	Use bone-protective agents when combining with androgen-axis therapy; dental evaluation can be a practical bottleneck.
Response assessment	PSA and bone scan can mislead; alkaline phosphatase and symptom/skeletal-event trajectory are more informative, but imperfect.
Local symptom flare or impending event	Use EBRT or surgery for focal instability, cord compression, or dominant pain; Ra-223 is systemic bone-targeted treatment.

What to Monitor

Parameter	Practical point
Main toxicity concern	Marrow suppression; check CBC before each dose.
Common non-hematologic issues	Nausea, vomiting, constipation, diarrhea, peripheral edema; drug is cleared through liver/bile so stool is radioactive.
Pretreatment counts	ANC ≥1.5 x 10^9/L, platelets ≥100 x 10^9/L, Hgb ≥10 g/dL for first dose.
Subsequent-dose counts	ANC ≥1.0 x 10^9/L, platelets ≥50 x 10^9/L, Hgb ≥8 g/dL.
Hepatic labs	Typical threshold: bilirubin ≤1.5 x ULN and AST/ALT ≤2.5 x ULN.

Radiation Safety Pearls

Ra-223 has a half-life of about 11.4 days. After administration, blood, urine, and stool are radioactive, with stool the most practical issue.
Counsel on gloves for contaminated fluids/laundry, closed-lid toilet flushing, separate washing of stained clothes, and airport radiation sensor detection. There are generally no major routine contact restrictions, but avoid prolonged close contact such as holding a small child in the lap for long periods. No routine post-treatment imaging is used.

ERA-223 and PEACE-3

Trial	Schema	Main result	Takeaway
ERA-223	Abiraterone/prednisone +/- Ra-223	No improvement in symptomatic skeletal EFS; fractures 29% vs 11%.	Do not give abiraterone and Ra-223 concurrently. This warning is in the current Xofigo label.
PEACE-3 Final OS	Enzalutamide +/- Ra-223 in first-line bone-metastatic mAPMR; asymptomatic or mildly symptomatic, no visceral disease; bone-protective agent mandatory after ERA-223.	Primary rPFS 19.4 vs 16.4 mo, HR 0.69 (0.54-0.87). Final analysis (58 months, 317 deaths): OS 38.2 vs 32.6 mo, HR 0.76 (0.60-0.96), p=0.0096; rPFS confirmed at 19.2 vs 16.4 mo, HR 0.71.	Real OS benefit, but with three caveats worth memorizing. See the box below.

PEACE-3 caveats, all board-testable:

The OS curves cross at roughly 18 months. Hazards are non-proportional, and further time-dependent analyses are planned. Early benefit is not uniform.
Age interaction. HR 0.66 in patients under 75 versus 1.01 at 75 and older, significant at the 10% two-sided level.
Toxicity increases. Grade ≥3 TEAEs rose from 57.6% to 69.3%, and treatment-related grade ≥3 from 18.8% to 28.9%, most commonly hypertension.
Bone-protective agents are not optional. After the ERA-223 fracture signal they became mandatory, which cut combination-arm fractures from about 53% to 14%.
Numbers you may see elsewhere. The interim OS analysis reported 42.3 vs 35.0 months, HR 0.69. The ASCO GU 2026 abstract reported HR 0.75 with a one-sided logrank p of 0.0078. Cite the Annals of Oncology final analysis.
Not a US labeled combination. Xofigo labeling still describes CRPC with symptomatic bone metastases and no known visceral disease, states that safety and efficacy with agents other than GnRH analogues are not established, and warns specifically against combination with abiraterone/prednisone. Describe enzalutamide + Ra-223 as evidence-supported but off-label.

PART III - LU-177 DOTATATE

Indication and Mechanism

Lu-177 DOTATATE is a beta-emitting radiolabeled somatostatin analog indicated for adult and pediatric patients age ≥12 with SSTR-positive GEP-NETs, including foregut, midgut, and hindgut NETs. It binds somatostatin receptors, is internalized, and then delivers beta radiation to the tumor and nearby cells; the accompanying gamma emission also enables post-therapy imaging and dosimetry. Lu-177 DOTATATE is the only NCCN category 1 recommendation for progressive, octreotide-refractory GI NETs with intact SSTR expression on Ga-68 DOTATATE imaging.

Pediatric approval detail: the April 2024 extension to patients 12 and older was based on PK, dosimetry, and safety from NETTER-P plus extrapolation from NETTER-1. NETTER-P included a PPGL cohort, but the approved indication is GEP-NET only. PPGL use remains off-label with NCCN category 2A support, which matters now that Azedra is gone.

Management Paradigm + Dose Anchors

Decision point	Practical answer
Required imaging	Confirm SSTR-positive disease on SSTR imaging; SSTR-negative or poorly differentiated NEC biology should push away from PRRT.
Classic standard setting	Progressive well-differentiated SSTR-positive midgut NET after somatostatin analog therapy: NETTER-1.
Earlier-line setting	Newly diagnosed advanced well-differentiated higher grade 2 or grade 3 GEP-NET with SSTR expression: NETTER-2.
Standard course	7.4 GBq q8 weeks x4, with octreotide LAR 30 mg after each treatment dose.
Renal protection	Lysine/arginine amino acid infusion plus antiemetics; nausea often comes from the amino acids rather than the radioligand itself.
On the horizon	ITM-11 (Lu-177 edotreotide), a second PRRT agent, has an accepted NDA with a PDUFA date of August 28, 2026, supported by positive COMPETE results in grade 1-2 GEP-NET, with COMPOSE running in well-differentiated high-grade disease.

NETTER-1

NETTER-1 randomized 229 patients with advanced, well-differentiated, progressive SSTR-positive midgut NETs to Lu-177 DOTATATE 7.4 GBq every 8 weeks x4 plus octreotide LAR 30 mg vs high-dose octreotide LAR 60 mg every 4 weeks. PFS HR was 0.18, 20-month PFS was 65.2% vs 10.8%, and ORR was 18% vs 3%. Median OS was 48.0 vs 36.3 months, not statistically significant but clinically favorable. This established Lutathera as a standard PRRT platform.

NETTER-2

NETTER-2 moved PRRT earlier. In 226 patients with newly diagnosed advanced SSTR-positive, well-differentiated, higher grade 2-3 GEP-NETs, Lu-177 DOTATATE 7.4 GBq every 8 weeks x4 plus octreotide LAR 30 mg significantly improved median PFS from 8.5 to 22.8 months (HR 0.276) and improved ORR from 9.3% to 43.0%. This is the first phase III trial showing first-line radioligand benefit in a metastatic solid tumor setting.

NETTER-1 vs NETTER-2

Feature	NETTER-1	NETTER-2
Tumor group	Midgut NET only	All GEP-NETs
Grade	Grade 1-2	Higher grade 2 and well-differentiated grade 3
Line of therapy	Post-SSA progression	First line
PFS HR	0.18	0.276
ORR	18%	43%

Administration Pearl

Standard course is 4 doses every 8 weeks.
L-lysine / L-arginine amino acid infusion starts 30 minutes before therapy and continues during and for at least 3 hours after to help protect kidneys. Long-acting octreotide 30 mg IM is typically given 4-24 hours after each Lutathera dose and then continued on schedule. Avoid long-acting SSA within about 4 weeks before therapy when feasible; short-acting octreotide can be used for symptoms but is usually stopped 24 hours before treatment.

Toxicity / Monitoring Pearls

Issue	What to remember
Marrow	Check CBC before each cycle; prior chemotherapy, diffuse marrow disease, and prior large-field RT increase cytopenia risk.
Kidney	Renal dose is why amino acids matter; monitor creatinine / clearance and hydrate.
Liver	Monitor LFTs, especially with bulky liver disease or prior liver-directed therapy.
Hormonal syndrome	Carcinoid crisis is uncommon but board-testable; coordinate somatostatin analog management.
Late risks	MDS / AML are rare but real long-term risks after PRRT.

PART IV - LU-177 PSMA-617 AND RELATED PSMA-RLT STRATEGIES

Current Pluvicto Paradigm

Pluvicto is Lu-177 PSMA-617 / lutetium Lu 177 vipivotide tetraxetan, a beta-emitting PSMA-targeted radioligand. As of July 31, 2026 it is approved across the PSMA-positive metastatic spectrum:

mAPMR (mCRPC) after ARPI therapy, in patients who have either already received taxane or are considered appropriate to delay it. This bridges VISION (post-taxane) and PSMAfore (taxane-naive).
mAPMN/S (mHSPC) in combination with an ARPI, based on PSMAddition. Prior taxane or ARPI failure is not required.

Both indications require PSMA PET selection using Locametz or another approved PSMA PET product. Dose is 7.4 GBq q6wk x6.

PSMA-RLT Patient Selection

Selection step	Why it matters
PSMA PET positivity	Required for treatment selection; approved PSMA PET products are used to confirm target expression.
Discordant disease check	FDG-positive / PSMA-negative or clinically aggressive target-negative disease predicts poor RLT control and may need another strategy.
Marrow reserve	Diffuse bone metastases, prior taxane, prior Ra-223, prior EBRT, and low baseline counts increase cytopenia risk.
Renal / salivary toxicity	Hydration and frequent voiding reduce bladder dose; dry mouth and renal lab changes are practical toxicities.
Focal progression	Heterogeneous oligoprogression can be treated with EBRT/SBRT while continuing or sequencing RLT in selected cases.

NCCN / VISION Exclusion Criteria: 177Lu-PSMA-617 is not recommended in patients with dominant PSMA-negative lesions. A lesion is considered PSMA-negative if its uptake is ≤ liver background and it meets size criteria: solid organ metastases ≥ 1.0 cm or lymph nodes ≥ 2.5 cm in short axis. FDG-avid/PSMA-negative mismatch lesions suggest an aggressive variant biology that predicts poor response, often making alternatives like cabazitaxel more appropriate.

The hardest evidence for this comes from TheraP screen failures: among 61 men excluded before randomization for low PSMA expression or PSMA/FDG discordance, restricted mean survival to 36 months was only 11.0 months, versus about 19 months in both randomized arms. Selection imaging identifies a genuinely worse-prognosis population.

VISION: Post-Taxane mAPMR

VISION randomized 831 patients with PSMA-positive mAPMR (mCRPC) who had progressed after ARPI and taxane therapy to Lu-177 PSMA-617 7.4 GBq every 6 weeks x6 plus SOC vs SOC alone. Median OS improved from 11.3 to 15.3 months, and image-based PFS improved from 3.4 to 8.7 months. Grade 3+ toxicity was higher (53% vs 38%), but QOL was not adversely affected.

PSMAfore: Taxane-Naive mAPMR Final OS added

PSMAfore randomized 468 patients (234 per arm) with PSMA-positive mAPMR who had progressed once on a prior ARPI, comparing Lu-177 PSMA-617 7.4 GBq every 6 weeks x6 against a change of ARPI. Crossover was permitted after centrally confirmed radiographic progression.

In the prespecified primary rPFS analysis, which is also the analysis reflected in current labeling, median rPFS improved from 5.55 to 9.30 months (HR 0.41, 95% CI 0.29-0.56).

In the final OS analysis, median OS was 24.5 vs 23.1 months (HR 0.91, 95% CI 0.72-1.14, p=0.20) by ITT, so there was no statistically significant survival advantage. Interpretation is complicated by crossover: 141 of 234 patients (60.3%) in the ARPI-change arm crossed over, representing 75.4% of those with centrally confirmed progression.

PSMAfore numbers you will see in three different forms. Label the analysis whenever you quote it.

Primary rPFS analysis: 9.30 vs 5.55 months, HR 0.41 (0.29-0.56). Use this one by default.
Second interim (ESMO): 12.02 vs 5.59 months, HR 0.43.
Third data cutoff (peer-reviewed primary report): 11.60 vs 5.59 months, HR 0.49 (0.39-0.61).
Crossover adjustment cuts both ways. The IPCW-adjusted OS HR was 0.59 (0.38-0.91), but the RPSFT-adjusted HR was 0.84 and not significant, and the common-treatment assumption was likely not met. Do not quote 0.59 as if it were the result; the ITT HR of 0.91 is the result.
Counterintuitive safety finding: exposure-adjusted grade ≥3 and serious adverse events were higher with ARPI change than with Lu-PSMA-617. Dry mouth and anemia were more common with Lu-PSMA-617.

Lu-PSMA Hematologic Dose Modification

Hematologic toxicity from Lu-177 PSMA-617 is cumulative, predictable, and manageable with proactive monitoring and dose modification.

20% dose reduction for grade 2-3 thrombocytopenia or grade 3-4 anemia/neutropenia.
Treatment delays up to 4 weeks for count recovery are acceptable.
Plan for 6 total cycles with flexibility based on count recovery, tumor response, and patient-specific factors.
Higher risk in patients with diffuse marrow disease, prior taxane, prior Ra-223, or prior wide-field RT.

TheraP and ENZA-P Survival data added

Trial	Design	Main result	Takeaway
TheraP	Phase II, n=200, post-docetaxel mAPMR; cabazitaxel vs Lu-PSMA-617. Dual-tracer PSMA/FDG PET selection.	PSA response 66% vs 37%; RECIST response 49% vs 24%; PFS HR 0.63; grade 3-4 AEs 33% vs 53%. Mature OS showed no difference: 36-month RMST 19.1 vs 19.6 months, difference -0.5 (95% CI -3.7 to 2.7), p=0.77; median OS 16.4 vs 19.4 months, HR 0.97.	Better response, better tolerability, better patient-reported outcomes, but no evidence of an OS difference versus cabazitaxel. Subsequent crossover was substantial: 32% of the Lu-PSMA arm later received cabazitaxel and 20% of the cabazitaxel arm later received Lu-PSMA.
ENZA-P	Phase II, n=162, first-line mAPMR with no prior docetaxel or ARPI for metastatic castration-resistant disease and at least 2 risk factors for early progression on enzalutamide. Enzalutamide +/- adaptive-dose Lu-PSMA-617 guided by PSMA PET and PSA response.	PSA-PFS 13 vs 7.8 months; grade 3+ toxicity similar. OS: 34 vs 26 months, HR 0.55 (0.36-0.84), p=0.0053, at 34 months median follow-up. Deterioration-free survival favored the combination for physical function and overall QOL.	The strongest randomized signal for combining PSMA-RLT with an ARPI, and it drove the phase III combination strategy. Note 38% of the control arm received Lu-PSMA off trial afterward, and this is a phase II.

Moving Earlier: PSMAddition, UpFrontPSMA, and LUNAR

Trial	Population	Main result	Current interpretation
PSMAddition Now labeled	PSMA-positive mAPMN/S (mHSPC), phase III. Lu-PSMA-617 added to ADT + ARPI.	rPFS HR 0.72 (0.58-0.90) at primary analysis; 0.67 (0.55-0.82) on updated analysis. PSA nadir <0.2 at 48 weeks 87.4% vs 74.9%. OS trend HR 0.80 (0.63-1.01), not yet mature. Grade ≥3 AEs 50.7% vs 43.0%.	No longer frontier. This trial supported the July 31, 2026 FDA approval of Pluvicto with an ARPI in mAPMN/S. The open question is the final OS readout, which will determine whether this becomes a routine triplet component or a precision option for selected patients.
UpFrontPSMA	De novo high-volume mAPMN/S, phase II (n=130). Required PSMA-avid disease on Ga-68 PSMA-11 PET-CT with no major FDG-PSMA discordance.	Sequential Lu-PSMA 7.5 GBq x2 q6wk → docetaxel 75 mg/m² x6 q3wk vs docetaxel alone. Undetectable PSA at 48 weeks 41% vs 16% (OR 3.88). PSA-PFS HR 0.43; rPFS HR 0.45; ORR 66% vs 37%.	First randomized trial of Lu-PSMA in hormone-sensitive disease; only 2 cycles (not 6 as in VISION) added to standard docetaxel/ADT. Still investigational, and a different strategy from the now-approved PSMAddition regimen.
LUNAR	Oligorecurrent hormone-sensitive prostate cancer with 1-5 PSMA PET-positive lesions. Single-center UCLA, open-label phase II, n=92 (47 SBRT alone, 45 combination). Agent was Lu-177 PNT2002 6.8 GBq x2 neoadjuvant to SBRT, not Lu-PSMA-617.	PFS 17.6 vs 7.4 months, HR 0.37 (0.22-0.61), p<0.0001; hormone-therapy-free survival 24.3 vs 14.1 months. 98% of progression events were new lesions rather than in-field recurrence. No significant increase in toxicity.	Proof of concept that PSMA-RLT plus SBRT can address visible and occult disease together. Single-center phase II with a one-sided alpha of 0.1, so treat it as a future-direction study rather than a standard.

UpFrontPSMA dual-tracer pearl: the trial used both PSMA-PET and FDG-PET to select patients with high-volume PSMA-avid disease and no major discordance. FDG-positive / PSMA-negative disease identifies more aggressive, potentially neuroendocrine-differentiated tumors less likely to respond to PSMA-RLT. Dual-tracer imaging is increasingly important in patient selection across PSMA-RLT trials.

LUNAR pearl: this was the first randomized trial of PSMA-targeted radioligand therapy in hormone-sensitive oligorecurrent prostate cancer. The mechanistic message is in the failure pattern: almost every progression was a new lesion, not an in-field recurrence, so the benefit came from treating occult micrometastatic disease rather than improving local control.

Other PSMA Ligands: SPLASH and ECLIPSE

SPLASH was a phase III trial of Lu-177 PNT2002 (PSMA-I&T) versus ARPI change in mAPMR after progression on a prior ARPI. Median rPFS was 9.5 vs 6.0 months (HR 0.71, 0.55-0.92, p=0.0088) and median biochemical PFS was 7.0 vs 3.9 months (HR 0.58). There was no significant OS difference, with immature data and the same crossover problem seen in PSMAfore. ECLIPSE is a separate phase III of Lu-177 PSMA-I&T in post-ARPI, taxane-naive mAPMR.

Why this matters for boards: PSMA-617 and PSMA-I&T are different ligands with different biodistribution and dosimetry. LUNAR and SPLASH used PNT2002. Do not treat PSMA-RLT as a single interchangeable drug class.

Beyond Lu-177: Alpha and Beta-Auger Emitter Strategies

Trial / agent	Physics / mechanism	Key findings	Takeaway
WARMTH Act (Sathekge 2024) Ac-225-PSMA-617	Alpha emitter with 4 alpha particles in decay chain; RBE ~4.2x higher than Lu-177-PSMA. Effective even in oxygen-poor microenvironments.	Largest cohort: 488 patients, 7 international centers. Dose 8 MBq IV q8 weeks. Xerostomia is dose-limiting: 68% after 1 cycle, 100% after ≥8 cycles, though only 11 patients discontinued for xerostomia. Hematologic: any-grade anemia 81%, leukopenia 44%, thrombocytopenia 54%; grade ≥3 toxicity relatively low.	Effective post-Lu-177 progression but salivary gland toxicity remains the main limitation of PSMA-targeted alpha therapy (TAT).
VIOLET-161Tb (Buteau 2025) Tb-161-PSMA-I&T	Dual beta-Auger emitter. Half-life 6.89 days (similar to Lu-177's 6.65). Beta plus abundant Auger / conversion electrons deposit concentrated radiation over nm-μm distances, giving a theoretical edge against single cells and micrometastases.	First-in-human phase I/II (n=30, mAPMR post-taxane and ARPI). 7.4 GBq per cycle. No dose-limiting toxicities; only 7% grade 3-4 AEs. PSA50 70%, PSA90 40%; PSA-PFS 9.0 months; rPFS 11.1 months. Preclinical: 2.4x higher tumor-absorbed dose vs Lu-177-PSMA-617 with improved therapeutic index.	Encouraging early signal for next-generation isotope; uses logistics similar to Lu-177. Phase III data not yet available.

Retreatment / Sequencing

Retrospective studies such as RALU, REALITY, and extended-therapy series suggest that rechallenge or additional Lu-PSMA can be feasible in selected patients, with the main risks being myelosuppression and renal function decline. This remains individualized rather than a fixed standard. Lu-PSMA after Ra-223 can be feasible when marrow reserve allows. Sequencing of Lu-PSMA → Ac-225 after progression is an active area of investigation. With the July 2026 hormone-sensitive approval, a new and unanswered question is what to offer patients who progress after receiving PSMA-RLT in the APM-naive setting.

PART V - I-131 MIBG, Y-90, AND OLDER / SPECIALIZED PLATFORMS

I-131 MIBG: Two Different Products

The single most common error in this area is treating "I-131 MIBG" as one drug. There are two, and they differ in specific activity, regulatory status, dosing, and patient population.

High-specific-activity (carrier-poor) I-131 iobenguane, marketed as Azedra. Specific activity about 2,500 mCi/mg. FDA-approved July 2018 for PPGL in patients ≥12. Production discontinued in 2024.
Conventional low-specific-activity I-131 MIBG. Contains a large mass of unlabeled carrier MIBG. Never FDA-approved for therapy. Reached patients through an industry-sponsored IND and expanded access protocol, not through academic compounding pharmacies. Used chiefly for high-risk and relapsed neuroblastoma at roughly 10-20 US centers.
Separately, conventional I-131 MIBG was FDA-approved as an imaging agent in 1994, and I-123 MIBG (AdreView) in 2008. So "I-131 MIBG was never FDA-approved" is false as a blanket statement; the accurate claim is that the low-specific-activity therapeutic product was never approved.

Azedra: What to Know Now That It Is Gone Discontinued

Feature	Practical point
Availability	Discontinued. Approved 2018, manufacturing wound down in 2024 for lack of commercial demand, with remaining doses reserved so existing patients could finish. Payer policies no longer permit new starts.
Historical approved niche	Age ≥12 with iobenguane-scan-positive, unresectable, locally advanced, or metastatic PPGL requiring systemic anticancer therapy.
Workflow	Dosimetric dose first, then up to 2 therapeutic doses adjusted by dosimetry and weight, at least 90 days apart. This scheme is specific to Azedra and does not describe neuroblastoma dosing.
Therapeutic dose anchor	18,500 MBq if >62.5 kg, or 296 MBq/kg if ≤62.5 kg.
Thyroid blockade	Start inorganic iodine at least 24 hours before each dose and continue after treatment per protocol. Applies to both MIBG products.
Toxicities	Marrow suppression, hypertension, nausea/vomiting, fatigue, hypothyroidism, pneumonitis, and rare MDS/AML.

Systemic Options for PPGL After Azedra

Belzutifan (Welireg) was FDA-approved on May 14, 2025 for adult and pediatric patients 12 and older with locally advanced, unresectable, or metastatic PPGL, based on LITESPARK-015. It is the first oral therapy approved for the indication and is the practical successor to Azedra on the label.
Lu-177 DOTATATE is used off-label for SSTR-positive PPGL with NCCN category 2A support. Patient selection shifts from iobenguane avidity to SSTR expression on Ga-68 DOTATATE PET.
Conventional chemotherapy (CVD) and tyrosine kinase inhibitors remain in the algorithm.
Board framing: the theranostic target for PPGL has largely shifted from the norepinephrine transporter to the somatostatin receptor.

Y-90 Radioembolization

Y-90 radioembolization is not systemic RLT in the same way as Lu-PSMA or Lu-DOTATATE. It is catheter-directed liver RT that exploits hepatic arterial tumor supply. The board workflow is: mapping angiography, protect extrahepatic flow, Tc-99m MAA / lung-shunt assessment, activity and liver/tumor dosimetry, treatment delivery, then response/toxicity surveillance.

Y-90 concept	Board-review pearl
Tumor supply	HCC is often mostly arterial; normal liver gets substantial portal venous flow.
Physics	Y-90 is a pure beta emitter with half-life about 2.7 days and millimeter-to-centimeter beta range. Post-treatment imaging is still possible using bremsstrahlung SPECT or the small internal pair-production branch on PET.
Dosimetry	Modern Y-90 is increasingly personalized; DOSISPHERE-01 supports tumor-dose-driven planning in selected HCC.
Toxicity	GI ulceration from nontarget delivery, radiation pneumonitis from lung shunt, biliary injury, liver failure, and radioembolization-induced liver disease.
EBRT comparison	Y-90 is intra-arterial and lobar/segmental; EBRT is anatomy-based and often better for vascular invasion, nonarterial target geometry, or extrahepatic local problems.

Older Bone-Targeted Beta Emitters

Sr-89 and Sm-153 EDTMP are older bone-seeking agents used for painful multifocal osteoblastic metastases.

Sr-89 is a pure beta emitter, half-life about 50.5 days, calcium analog.
Sm-153 EDTMP emits beta plus a 103 keV gamma, half-life about 46.3 hours. The gamma permits post-therapy imaging, which is a favorite distractor when a question calls both agents "pure beta emitters."
Both palliate pain but carry no OS evidence comparable to Ra-223 in APM-resistant disease.
Use has declined sharply, and both are effectively unavailable or supply-limited in the US. Treat them as concept questions.

Lymphoma Radioimmunotherapy Quick Hit

Y-90 ibritumomab tiuxetan and historical I-131 tositumomab (withdrawn from the US market in 2014) are useful board-concept examples of antibody-based radioimmunotherapy in B-cell lymphoma. The practical modern takeaway is conceptual more than routine workflow: radioimmunotherapy can target CD20-positive lymphoma, but use has become uncommon.

PART VI - ACCESS, STAFFING, AND WHO SHOULD OWN RPT

Access Is a Major Clinical Problem

A major implementation priority is to expand access beyond academic centers. The geographic mismatch between where patients live and where RPT is available is a real clinical problem, and one of the main reasons radiation oncology should stay involved. The July 2026 hormone-sensitive Pluvicto approval roughly doubles the eligible population, which makes capacity, not evidence, the near-term rate-limiting step.

Radiation Oncology vs Nuclear Medicine

Group	Advantages	Limitations
Radiation Oncology	Community footprint, oncology referral relationships, ability to combine EBRT + RPT, dose-thinking culture, toxicity follow-up experience.	Often lacks PET/SPECT infrastructure, hot lab, radioactive bathroom, or AU-certified physicians.
Nuclear Medicine	Imaging expertise, theranostic infrastructure, direct radiopharma experience, diagnostic isotope familiarity.	Less community reach in many regions, often less longitudinal oncology toxicity management and insurance coordination, less experience with EBRT integration.

Program-Building Requirements

Minimal program ingredients:

Staffing: nuclear medicine technologist or trained RTT, nurse, APP support, financial counselor, coordinator, qualified medical physicist, and an Authorized User
Infrastructure: hot lab with dose calibrator and GM meter, dedicated administration room, RAM license, and a radioactive bathroom
Follow-up capability: lab monitoring, toxicity management, coordination with medical oncology, and transfusion support when needed

Why Radiation Oncology Belongs in the Workflow

The best framing is collaboration, not turf. Nuclear medicine often owns imaging infrastructure and radiopharmaceutical logistics; radiation oncology adds dose thinking, community access, toxicity follow-up, and the ability to combine RPT + EBRT for heterogeneous disease, urgent local problems, or consolidative treatment.

Practical Patient Counseling for Lu-PSMA-Type Therapy

The Pluvicto label uses tiered restrictions, not a single blanket duration. After each administration:

Increase oral fluid intake and void frequently to reduce bladder dose.
Limit close contact (less than 3 feet): household contacts 2 days; children and pregnant women 7 days.
Sleep in a separate bedroom from: household contacts 3 days; children 7 days; pregnant women 15 days.
Refrain from sexual activity for 7 days.
Use effective contraception during therapy and for 14 weeks after the last dose.
Toilet and hygiene precautions for the first 2 days: sit to urinate, flush toilet paper immediately, wash hands thoroughly, and wash soiled laundry separately.

Exam trap: a blanket "3 days of close contact restriction and 3 days in a separate bedroom" is wrong. Close contact for ordinary adults is 2 days, and the child and pregnancy tiers run substantially longer.

PART VII - DOSIMETRY: THE BIG UNRESOLVED FRONTIER

Why Dosimetry Matters

EBRT is prescribed to a point or volume dose.
RPT is usually prescribed like systemic therapy, by injected activity, body weight, or surface area.
That mismatch is the core reason dosimetry remains such a hot topic.

Arguments For and Against Patient-Specific Dosimetry

Potential advantage	Potential drawback
Tumor uptake is heterogeneous across lesions and across patients.	Treatment complexity increases substantially.
Normal tissue dose also varies by patient.	Cost rises for already expensive therapies.
Injected activity could theoretically be adapted to improve therapeutic ratio.	Current fixed-activity regimens already produce major clinical benefit.
Could optimize combination RPT + EBRT plans.	Prospective trials are still needed to prove that dosimetry changes outcomes.

General Workflow

The workflow is: SPECT/CT imaging - ROI contouring - time integration - dose calculation - dose evaluation.
Post-therapy quantitative SPECT/CT is often performed about 3-5 days after administration, with camera calibration required for quantitative dosimetry. A single time point around 84-106 hours can be a practical approximation in selected workflows.

Where Dosimetry Is Most Useful Today

Scenario	Why dosimetry can change management
Heterogeneous uptake / response	Identifies lesions that may need SBRT, systemic switch, or treatment intensification.
Retreatment or extended therapy	Helps judge cumulative kidney, marrow, salivary gland, or tumor absorbed dose before giving more cycles.
Y-90 liver therapy	Personalized liver/tumor dosimetry is already clinically influential and more mature than routine Lu-PSMA dosimetry.
RPT + EBRT integration	Allows the team to think about cumulative dose to marrow, kidney, bowel, salivary glands, and overlapping targets.
Earlier-line use	Patients treated in the APM-naive setting have longer expected survival and may receive more subsequent therapy, which raises the stakes on cumulative marrow and renal dose.
Fixed-activity standard regimens	Most approved RPT is still delivered by fixed activity or weight-based activity; prospective outcome-changing dosimetry trials remain needed.

What Early Outcome Data Suggest

Several Lu-PSMA studies show that whole-body tumor absorbed dose correlates with PSA response, and in newer series also with bPFS and OS. In one real-world implementation, about half of patients undergoing dosimetry had a management change, such as adding SBRT to heterogeneous progression, consolidating residual disease, switching therapy for poor uptake, or holding treatment when response was excellent.

Exam framing: dosimetry is one of the most plausible places where radiation oncology can add unique value to radiopharmaceutical programs, but it is not yet a universally proven standard-of-care requirement.

CROSS-CUTTING HIGH-YIELD POINTS

Nomenclature: PCWG4 replaces castration-based terms with APMN / APMS / APMR. APMN/S maps to HSPC and CSPC; APMR maps to CRPC. The FDA adopted this language in the July 2026 Pluvicto approval.
Theranostics integrates imaging, patient selection, dosimetry, response assessment, and therapy in one target-based workflow.
Therapeutic effect comes from absorbed dose, not from the carrier molecule.
Alpha emitters have high LET and short path length but problematic heterogeneity and harder dosimetry.
Beta emitters have lower LET but a cross-fire effect that helps with heterogeneous uptake.
Pure beta vs beta-plus-gamma: Y-90 and Sr-89 are pure beta. I-131, Lu-177, and Sm-153 (103 keV gamma) permit post-therapy imaging.
Beta-Auger emitters (Tb-161) combine beta plus concentrated nm-μm Auger dose, theoretically targeting micrometastases.
I-131 is the historical proof-of-principle that systemic targeted RT can improve survival.
Two different I-131 MIBG products: high-specific-activity Azedra (approved 2018, discontinued 2024) for PPGL, and conventional low-specific-activity MIBG (never approved for therapy, IND/expanded access) for neuroblastoma.
PPGL systemic therapy now: belzutifan is FDA-approved (May 2025, age ≥12), and Lu-177 DOTATATE is used off-label for SSTR-positive disease. The theranostic target has shifted from NET to SSTR.
Y-90 radioembolization is locoregional radiopharma; mapping angiography, lung-shunt assessment, and liver/tumor dosimetry are central.
Radium-223 improves OS in symptomatic bone-metastatic APM-resistant disease without known visceral metastases and is not just a palliative drug.
ALSYMPCA numbers to know: OS 14.9 vs 11.3 months; time to skeletal event 15.6 vs 9.8 months.
Current Ra-223 label dose: 55 kBq/kg q4wk x6; older ALSYMPCA descriptions used 50 kBq/kg.
ERA-223: do not combine abiraterone and Ra-223 concurrently because fractures increased and efficacy did not improve.
PEACE-3 final OS: enzalutamide + Ra-223 improved OS to 38.2 vs 32.6 months (HR 0.76, p=0.0096). Caveats: curves cross around 18 months, no benefit at age ≥75 (HR 1.01), more grade ≥3 toxicity, mandatory bone-protective agents, and this combination is not a US labeled indication.
Target expression is mandatory: no PSMA, SSTR, or MIBG avidity means no target for that radiopharmaceutical.
Discordant target-negative disease: 177Lu-PSMA-617 is excluded if PSMA-negative lesions (uptake ≤ liver) meet size criteria (solid organs ≥ 1.0 cm, lymph nodes ≥ 2.5 cm). Dual-tracer PSMA + FDG imaging helps identify these aggressive clones, and TheraP screen failures had an RMST of only 11.0 months.
Lu-177 DOTATATE is the only NCCN category 1 recommendation for progressive, octreotide-refractory GI NETs with intact SSTR expression. NETTER-1 is the classic progressive midgut dataset.
NETTER-2 moves RLT into the first-line setting for higher grade well-differentiated GEP-NETs.
ITM-11 (Lu-177 edotreotide) has a PDUFA date of August 28, 2026 and would be the second PRRT platform for GEP-NET.
Lu-177 DOTATATE administration pearl: give lysine/arginine amino acids beginning 30 minutes before and continuing for at least 3 hours after infusion.
VISION established Lu-PSMA-617 as an OS-improving therapy in post-taxane PSMA-positive mAPMR.
PSMAfore: primary rPFS 9.30 vs 5.55 months (HR 0.41). Final OS was negative by ITT: 24.5 vs 23.1 months, HR 0.91, p=0.20, with 60.3% crossover. IPCW-adjusted HR 0.59; RPSFT-adjusted HR 0.84 and not significant.
TheraP: better PSA response (66% vs 37%) and less grade 3-4 toxicity (33% vs 53%) than cabazitaxel, but no OS difference with mature follow-up (36-month RMST 19.1 vs 19.6 months, p=0.77).
ENZA-P: adaptive-dose Lu-PSMA-617 added to enzalutamide improved PSA-PFS (13 vs 7.8 months) and OS (34 vs 26 months, HR 0.55) in poor-risk first-line APM-resistant disease.
Lu-PSMA hematologic management: 20% dose reduction for grade 2-3 thrombocytopenia or grade 3-4 anemia/neutropenia; treatment delays up to 4 weeks for count recovery.
Current Pluvicto label concept: two indications. PSMA-positive mAPMR after ARPI (post-taxane or taxane-delaying), and, since July 31, 2026, PSMA-positive mAPMN/S in combination with an ARPI with no prior-therapy failure requirement.
PSMAddition supported that hormone-sensitive approval: rPFS HR 0.72 at primary analysis and 0.67 on update, with an immature OS trend of HR 0.80.
UpFrontPSMA is the first randomized trial of Lu-PSMA in hormone-sensitive disease; 2 cycles of Lu-PSMA before docetaxel improved undetectable-PSA rate from 16% to 41%.
LUNAR is the first randomized PSMA-RLT trial in oligorecurrent hormone-sensitive disease. Single-center phase II, n=92, agent was Lu-177 PNT2002, and 98% of progressions were new lesions rather than in-field failures.
SPLASH and ECLIPSE test Lu-177 PSMA-I&T (PNT2002), a different ligand from PSMA-617. SPLASH rPFS was 9.5 vs 6.0 months (HR 0.71) with no significant OS difference.
WARMTH Act: largest Ac-225-PSMA cohort (n=488); active post-Lu-177 progression but xerostomia is dose-limiting (68% after 1 cycle, 100% after ≥8 cycles).
VIOLET-161Tb: first-in-human Tb-161-PSMA-I&T phase I/II; favorable PSA50 70% / rPFS 11.1 months with low grade 3-4 AEs.
Pluvicto counseling is tiered: close contact 2 days for adults and 7 days for children and pregnant women; separate bedroom 3 / 7 / 15 days respectively; no sexual activity for 7 days; contraception for 14 weeks after the last dose.
Radiation oncology has a real role in improving access to RPT, especially in the community and in combining RPT with EBRT.
Program needs include an AU, hot lab, radioactive bathroom, trained technologists, physics support, and strong coordination infrastructure.
Dosimetry is promising but not fully validated; it may personalize activity selection and EBRT integration, but prospective trials are still needed.

CONSOLIDATED AGENT / PHYSICS / ADMINISTRATION TABLE

Agent / isotope	Particle / decay	Half-life / range	Target / disease	Dose / schedule anchor
I-131 sodium iodide	Beta emitter with gamma emission	Half-life about 8 days; beta path roughly 2 mm	NIS / differentiated thyroid cancer	Activity individualized by risk, remnant, metastases, and practice pattern.
Y-90 microspheres	Pure beta emitter	Half-life about 2.7 days; mean beta range a few mm, max about 1 cm	Intra-arterial liver-directed therapy for selected HCC / liver-dominant disease	Activity planned by mapping angiography, lung-shunt assessment, and liver / tumor dosimetry.
High-specific-activity I-131 MIBG (Azedra) Discontinued	Beta emitter with gamma emission	I-131 half-life about 8 days	Norepinephrine transporter / iobenguane-avid PPGL	Dosimetry first; therapy 18,500 MBq if >62.5 kg or 296 MBq/kg if ≤62.5 kg, up to 2 doses at least 90 days apart. Not commercially available.
Conventional I-131 MIBG	Beta emitter with gamma emission	I-131 half-life about 8 days	Norepinephrine transporter / high-risk or relapsed neuroblastoma	Weight-based 5-18 mCi/kg under IND or expanded access; stored stem cells required at ≥12 mCi/kg. Never FDA-approved for therapy.
Radium-223 / Xofigo	Alpha emitter	Half-life about 11.4 days; very short alpha path length	Calcium mimetic / osteoblastic bone metastases in mAPMR without known visceral disease	Current label: 55 kBq/kg q4wk x6; historical ALSYMPCA reporting used 50 kBq/kg.
Lu-177 DOTATATE / Lutathera	Beta emitter with gamma emission	Half-life about 6.7 days; beta range about 1-2 mm	SSTR-positive GEP-NET (age ≥12); off-label SSTR-positive PPGL	7.4 GBq q8wk x4; amino acids start 30 min before and continue for at least 3 h after.
Lu-177 PSMA-617 / Pluvicto	Beta emitter with gamma emission	Half-life about 6.7 days; beta range about 1-2 mm	PSMA-positive mAPMR after ARPI, and mAPMN/S with an ARPI since July 2026	7.4 GBq / 200 mCi q6wk x6 in both settings.
Lu-177 PSMA / UpFrontPSMA regimen	Beta emitter with gamma emission	Lu-177 half-life about 6.7 days	De novo high-volume mAPMN/S, sequential strategy	Investigational: 7.5 GBq q6wk x2 → docetaxel 75 mg/m² q3wk x6 + ADT.
Lu-177 PSMA-I&T / PNT2002 (LUNAR, SPLASH)	Beta emitter with gamma emission	Lu-177 half-life about 6.7 days	PSMA-positive oligorecurrent hormone-sensitive disease (LUNAR); post-ARPI mAPMR (SPLASH)	Investigational in the US. LUNAR: 6.8 GBq x2 about 8 weeks apart before SBRT.
Ac-225-PSMA-617	Alpha emitter; 4 alpha particles in decay chain; RBE ~4.2x vs Lu-177	Ac-225 half-life about 10 days; very short alpha path	PSMA-positive mAPMR (investigational)	8 MBq IV q8wk in WARMTH Act; xerostomia dose-limiting.
Tb-161-PSMA-I&T	Beta-Auger dual emitter	Half-life about 6.89 days; beta plus concentrated nm-μm Auger	PSMA-positive mAPMR (investigational)	7.4 GBq in VIOLET phase I/II; higher activity cohort planned.
Sr-89	Pure beta emitter	Half-life about 50.5 days	Calcium analog / painful osteoblastic bone metastases	Palliation only; no OS signal. Supply-limited in the US.
Sm-153 EDTMP	Beta emitter with imageable 103 keV gamma	Half-life about 46.3 hours	Phosphonate bone-seeking / painful osteoblastic bone metastases	Palliation only; no OS signal. Supply-limited in the US.

KEY LANDMARK TRIALS (memorize)

Trial / anchor	Disease / setting	One-line takeaway
ALSYMPCA	Symptomatic bone-metastatic APM-resistant disease without known visceral metastases	Radium-223 improves OS and delays skeletal events.
ERA-223	APM-resistant prostate cancer	Abiraterone + Ra-223 increased fractures and did not help efficacy.
PEACE-3	First-line APM-resistant disease with bone metastases	Enzalutamide + Ra-223 improves rPFS and final OS (38.2 vs 32.6 mo, HR 0.76), but curves cross, benefit is absent at age ≥75, bone protection is mandatory, and the combination is not US-labeled.
NETTER-1	Progressive SSTR-positive midgut NET	Established Lu-177 DOTATATE as standard PRRT therapy; NCCN cat 1.
NETTER-2	First-line higher grade GEP-NET	Moved Lu-177 DOTATATE into the first-line setting with major PFS and ORR gains.
VISION	Post-taxane PSMA-positive mAPMR	Lu-177 PSMA-617 improves OS and PFS.
PSMAfore	Taxane-naive APM-resistant disease	Pluvicto beats ARPI switch for rPFS (HR 0.41) and supports taxane-delay use, but final OS was neutral by ITT (HR 0.91) with 60% crossover.
TheraP	APM-resistant disease, cabazitaxel comparison	Lu-PSMA improves PSA response and lowers severe toxicity, but mature OS showed no difference.
ENZA-P	Poor-risk first-line APM-resistant disease	Adaptive Lu-PSMA + enzalutamide improves PSA-PFS and OS (34 vs 26 mo, HR 0.55).
PSMAddition	PSMA-positive mAPMN/S	Phase III basis for the July 2026 FDA approval of Pluvicto plus ARPI in hormone-sensitive disease; OS still immature.
UpFrontPSMA	De novo high-volume mAPMN/S	First randomized Lu-PSMA + docetaxel vs docetaxel trial; 2 cycles of Lu-PSMA tripled undetectable-PSA rate at 48 weeks.
LUNAR	Oligorecurrent hormone-sensitive prostate cancer	First randomized PSMA-RLT trial in early oligometastatic disease; single-center phase II using Lu-177 PNT2002.
SPLASH / ECLIPSE	Lu-177 PSMA-I&T in post-ARPI APM-resistant disease	A second PSMA ligand with positive rPFS (9.5 vs 6.0 mo) but no significant OS difference so far.
WARMTH Act	Ac-225-PSMA-617 in APM-resistant disease	Largest cohort (n=488) of PSMA-targeted alpha therapy; effective but xerostomia is dose-limiting.
VIOLET-161Tb	Tb-161-PSMA-I&T in APM-resistant disease	First-in-human dual beta-Auger RLT; favorable activity and tolerability.
Azedra pivotal experience	Iobenguane-avid PPGL	Established high-specific-activity I-131 MIBG as a systemic option, though the product was discontinued in 2024.
LITESPARK-015	Locally advanced, unresectable, or metastatic PPGL	Supported the May 2025 approval of belzutifan, the first oral therapy for PPGL.
DOSISPHERE-01 / LEGACY	HCC Y-90 radioembolization	Support modern personalized Y-90 dosimetry and high local-control liver-directed therapy.
RALU / REALITY / extended Lu-PSMA series	Retreatment / rechallenge	Retreatment may be feasible, but evidence remains retrospective.
Violet / Fitzpatrick / Grkovski	Lu-PSMA dosimetry	Whole-body tumor absorbed dose correlates with response and outcomes.