EXPERIMENTAL AND THERAPEUTIC MEDICINE 27: 225, 2024

Current clinical application of lutetium‑177

in solid tumors (Review)
TINGTING NIU1,2*, MI FAN1,2*, BINWEI LIN1, FENG GAO1, BANGXIAN TAN2 and XIAOBO DU1

1
Department of Oncology, Mianyang Central Hospital, Mianyang, Sichuan 621000; 2Department of Oncology,
Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China

Received July 23, 2023; Accepted January 24, 2024

DOI: 10.3892/etm.2024.12514

Abstract. Radionuclide‑based therapy represents a novel 1. Introduction

treatment regimen for tumors. Among these therapies, lute‑
tium‑177 (177 Lu) has gained significant attention due to its The number of total novel cancer cases globally is expected to
stability and safety, as well as its ability to emit both γ and β reach 28.4 million by 2040, which represents a 47% increase
rays, allowing for both imaging with single photon emission compared with 2020 (1). The increase is expected to be higher
computed tomography and tumor treatment. As a result, 177Lu in developing countries (64‑95%) compared with developed
can be used for both diagnosis and treatment for diseases countries (32‑56%) based on demographic changes (1). On the
such as prostatic and gastric cancer. Therefore, based on the basis of existing chemotherapy, radiotherapy, immunization,
available data, the present review provides a brief overview targeting and other therapies, novel diagnosis and treatment
of the clinical applications of 177 Lu‑targeted radionuclide methods require investigation. Due to its advantages of inte‑
therapy in metastatic prostate cancer, neuroendocrine grated diagnosis and treatment, targeted radionuclide therapy
tumors and other types of solid tumors, and highlights the has become a new strategy to further improve the prognosis
current therapeutic effect, reduction in damage to normal of cancer.
tissues and future research directions, including the devel‑ Targeted radionuclide therapy (TRT) involves labeling
opment of new nuclides and the application of more nuclides radionuclides on biomolecules with a specific binding ability,
in different tumors. In the future, such treatments could be which allows the biomolecule to bind to specific tumor targets,
used in more tumors. and thus the radionuclide is concentrated at the tumor site (2).
The α or β particles emitted by radionuclides can then irradiate
the tumor tissues specifically and ionize biological effects
Contents (low linear energy transfer), resulting in cell senescence and
death within the irradiation range (3). This achieves thera‑
1. Introduction peutic results with minimal effects on the surrounding normal
2. Basic characteristics of radionuclide 177Lu tissues. By combining the advantages of targeted therapy and
3. Application of 177Lu in prostate cancer brachytherapy, TRT provides novel methods for the diagnosis
4. Application of 177Lu in neuroendocrine tumors (NETs) and treatment of tumors. Based on current data, the present
5. Clinical application of 177Lu in other diseases review briefly introduced the use of different 177Lu drugs in
6. Present problems and future research directions treating several tumors, as well as the issues presented by the
7. Conclusions use of these drugs and future research directions.

2. Basic characteristics of radionuclide 177Lu

177
Lu belongs to the lanthanide metal group (4) and can emit
β ‑rays with a maximum energy of 0.49 MeV and with a
half‑life of 6.7 days (5). β‑rays are mostly used for treatment
Correspondence to: Professor Xiaobo Du, Department of of diseases such as prostate cancer, and the energy released by
Oncology, Mianyang Central Hospital, 12 Changjiaxiang, Mianyang,
the β‑particle rays of 177Lu has an average range of 670 µm in
Sichuan 621000, P.R. China
E‑mail: duxiaobo2005@126.com soft tissue, significantly reducing the damage caused by radio‑
nuclides to nearby healthy cells. In addition, 177Lu can emit two
*
Contributed equally characteristic γ‑rays (208 and 113 keV), which can be used as
a signal source for single‑photon emission computed tomog‑
Key words: lutetium‑177, prostate cancer, neuroendocrine tumor, raphy or positron emission tomography (PET) (6). These are
targeted radionuclide therapy, solid tumors mostly used for imaging and dosimetric analysis; for example,
177
Lu‑prostate‑specific membrane antigen (PSMA)‑image
and treat (I&T) PET/computed tomography (CT) is used for
2 NIU et al: CLINICAL APPLICATION OF 177LU IN SOLID TUMORS

pre‑ and post‑treatment imaging in patients with metastatic achieve significant PSA reduction and tumor remission in
prostate cancer (6,7). patients with mCRPC (16,17).
To evaluate the predictive effect after treatment, a trial
3. Application of 177Lu in prostate cancer involving 301 patients demonstrated that the extent of bone
metastases and their changes were potential markers for
The latest global cancer data results released by the World predicting treatment outcomes in patients with mCRPC (18).
Health Organization shows that the number of new cases of A previous single‑arm phase I study of 177 Lu‑PSMA‑I&T
prostate cancer in 2020 was 1.41 million, ranking it second neoadjuvant therapy in high‑risk prostate cancer before
most common amongst all new tumors and the number of radical prostatectomy included 14 patients with high‑crit‑
prostate cancer‑associated mortalities in men was 380,000, ical‑limited‑stage prostate cancer, defined as PSA >20 ng/ml,
making it the fifth most fatal cancer in men (1). In recent biopsy Gleason score ≥8, or clinical T stage ≥3a, who tested
years, the prevalence of metastatic castration‑resistant positive for PSMA between December 2019 and December
prostate cancer (mCRPC) has been increasing, and its 2021 (19). Furthermore, two or three doses of 177Lu‑PSMA‑I&T
prognosis is generally poor (8). The expression of PSMA in (7.4 GBq) were administered at 2‑week intervals, and surgery
prostate cancer is higher compared with that in other tissues, (including lymph node dissection) was performed 4 weeks
including prostatic epithelial cells, the small intestine and after the final dose. The main adverse reactions of this treat‑
salivary glands (9), and is 1,000 times higher compared with ment were the incidence of perioperative complications and
the lowest expression level in the kidney and small intes‑ organ functional toxicity, including bleeding, infection, pneu‑
tine (10). Therefore, precise targeted therapy with PSMA has monia and pulmonary embolism. After two doses, the PSA
emerged as a novel therapeutic method, resulting in a decline level was reduced by 17%, and after three doses it was reduced
in prostate specific antigen (PSA) levels and an increase in by 34%. No severe intraoperative complications were observed
overall survival (11,12). in 13 patients (one patient did not undergo surgery due to heart
problems), while four (30%) patients developed postoperative
Prostate cancer and 177Lu‑PSMA‑I&T. 1,4,7,10‑tetraazacy‑ complications (including pneumonia, pulmonary embolism,
clododececane‑1‑(gluta r ic acid)‑ 4,7,10 ‑tr iaceticacid urinary leakage and urinary tract infection) (19).
(DOTAGA) is a small PSMA inhibitor molecule labeled with Preliminary studies have demonstrated that neoadjuvant
177
Lu known as 177Lu‑PSMA‑I&T. In 2015, internal radiation therapy with 177Lu‑PSMA‑I&T followed by surgery is safe;
therapy using 177Lu‑PSMA‑I&T was reported to be effective however, further data should be obtained from long‑term
and safe in two patients with metastatic prostate cancer, with follow‑up (19). These findings suggest that patients treated
no detectable side effects (13). In a study by Barna et al (14), with 177Lu‑PSMA‑I&T show decreased PSA levels and fewer
177
Lu‑PSMA‑I&T was used to treat mCRPC with a mean serious adverse events, contributing to tumor remission (16‑18).
injection activity of 7,416±218 MBq. Follow‑up imaging using
Ga‑PSMA PET/CT was used to determine individual tumor Prostate cancer and 177 Lu‑PSMA‑617. 177 Lu‑PSMA‑617
molecular volume. The volume of 63 individual tumors in is a small molecule inhibitor labeled with 177 Lu using
bone, lymph nodes and liver tissues were observed to decrease 1,4,7,10‑tetraazacyclododecane‑1,4,7,10‑tetraacetic acid
by 32.3, 84.7 and 72.9% on average, respectively (14). In a (DOTA) as a chelating agent (20,21). In March, 2022, the U.S.
trial of 49 patients with mCRPC who received at least three Food and Drug Administration (FDA) approved the adminis‑
cycles of 177Lu‑PSMA‑I&T (6.0 GBq), no grade III/IV adverse tration of 177Lu‑PSMA‑617 for the treatment of adult patients
events were reported, indicating low nephrotoxicity or hema‑ with mCRPC, making it the first targeted radioligand therapy
totoxicity, according to the Common Terminology Criteria for to be approved by the FDA (22).
Adverse Events (CTCAE v5.0) (15). In a meta‑analysis, Kim and Kim (23) included 10 studies
Another prospective single‑arm trial included 40 patients involving 455 patients with mCRPC. The analysis showed
diagnosed with mCRPC who received 86 cycles of that 177Lu‑PSMA‑617 therapy resulted in a combined PSA
177
Lu‑PSMA‑I&T at a dose of 3.70‑14.43 GBq per cycle from reduction rate of 68.00% [95% confidence interval (CI),
December 2019 to September 2021, with a median follow‑up 63.55‑72.22%] and with PSA levels reduced by >50% in 34.45%
of 8 months (16). The findings revealed that six patients (15%) of patients (95% CI, 30.14‑38.97%). In phase II, single‑arm,
developed mild reversible dry mouth, and 28 patients (70%) single‑center trials by Violet et al (24) and Hofman et al (25),
developed grade 1‑4 bone marrow dysfunction (anemia, 177
Lu‑PSMA‑617 radionuclide therapy had a high response
thrombocytopenia and leukopenia) during follow‑up (toxici‑ rate, low toxicity and decreased pain in patients with metastatic
ties were assessed following the CTCAE v5.0). Serum PSA castration‑tolerant prostate cancer who progressed following
is the most significant marker for evaluating therapeutic conventional therapy (including taxane‑based chemotherapy
biochemical response. PSA levels were obtained every and second‑generation antiandrogen therapy). The FDA
4 weeks before and after treatment. A reduction of ≥30% from authorized 177Lu‑PSMA‑617 as a prostate cancer treatment in
baseline is considered a partial response, a >25% increase in March 2022 based on a phase III experiment conducted by
PSA above baseline is defined as disease progression, and PSA Sartor et al (26).
levels with changes between <‑30% and <+25% are considered An international, open‑label, Phase III clinical trial
disease stabilization. PSA levels were assessed after treatment involving 84 centers (52 centers in North America and 32 in
and accompanied by partial remission in 25 patients (62.5%), Europe) was conducted (26). Patients were randomly assigned
stable disease in five patients (12.5%) and progression in ten in a 2:1 ratio to receive either 177Lu‑PSMA‑617 (injection of
patients (25%). Trials have shown that 177Lu‑PSMA‑I&T can 7.4 GBq once every 6 weeks, lasting 4‑6 cycles) plus standard
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 27: 225, 2024 3

protocol‑approved treatment (177 Lu‑PSMA‑617 group) or at any of the tested dose levels. Grade 4 neutropenia without
standard treatment only (e.g., abiraterone and enzalutamide) fever was found in eight patients (53.5%). Subsequently,
(control group). Among the 831 patients with metastatic two patients (13.3%) developed thrombocytopenia, and no
castration‑tolerant prostate cancer treated with at least one grade ≥3 non‑hematological toxicity was observed. A PSA
androgen receptor pathway inhibitor and one or two taxane decrease of >50% after treatment with 177Lu‑J591 was seen in
receptor inhibitors, 581 were included in the analysis set. 11 patients (73.3%). The results suggest that a single 177Lu‑J591
177
Lu‑PSMA‑617 + standard therapy significantly extended fractionated course in combination with docetaxel is a viable
imaging‑based progression‑free survival (PFS) time compared option for patients with mCRPC (33). A review of the various
with standard therapy (median, 8.7 vs. 3.4 months; hazard ratio phase I and II trials of 177Lu‑J591 in metastatic prostate cancer
for progression or death, 0.40; 99.2% CI, 0.29‑0.57; P<0.001) showed improved OS, and in almost all cases, myelosuppres‑
and OS (median, 15.3 vs. 11.3 months; hazard ratio for death, sion is tolerable and reversible (31). While 177Lu‑J591 may be
0.62; 95% CI, 0.52‑0.74; P<0.001). The most frequent adverse considered a potential treatment option, the effectiveness of its
reactions in the 177 Lu‑PSMA‑617 group were fatigue, dry combination with docetaxel still requires additional research
mouth and nausea; however, these events were usually grade and clinical trials to establish its efficacy and safety.
1 or 2 (Response Evaluation Criteria in Solid Tumors, version
1.1) (27) and had little impact on the quality of life. Prostate cancer and [177Lu] Ludotadipep. Ludotadipep is
a new PSMA inhibitor tagged with 177Lu, which contains a
177
Lu‑PSMA‑I&T vs. 177Lu‑PSMA‑617. The distinction between 4‑iodophenyl butanoic group that can bind to albumin and
the two PSMA‑targeting medications, 177Lu‑PSMA‑617 and prolong circulation time and boost absorption in tumors. A
177
Lu‑PSMA‑I&T, lies in the chelating agents they use. A prospective study from Korea evaluated the efficacy of 177Lu
study with 110 patients with mCRPC from two locations Ludotadipep in patients with 18F‑PSMA‑PET/CT‑positive
(University Hospital Würzburg and University Hospital mCRPC. From November 2020 to March 2022, a total of
Bonn), including 55 who received 177Lu‑PSMA‑I&T and 55 30 patients were enrolled for single dose of 177Lu Ludotadipep
who received 177Lu‑PSMA‑617, revealed no significant differ‑ radiopharmaceutical therapy (34). Patients were divided into
ences in the harmful effects of the two at a dose of roughly five groups (n=6) and given an increasing dose of 1.9, 2.8, 3.7,
6.0 GBq per 8 weeks. Survival with 177Lu‑PSMA‑I&T and 4.6 and 5.6 GBq for each group. In this study, 29 patients who
177
Lu‑PSMA‑617 was comparable with a median OS time of received 177Lu Ludotadipep (one patient found to deviate from
12.0 vs. 13.0 months, respectively, with no serious grade III/IV the inclusion criteria after enrollment), 36 treatment‑emergent
toxicity (28). In another study that assessed the safety, biolog‑ adverse events (58.6%) and four adverse drug reactions (10.3%)
ical distribution and dosiology in 138 patients, 51 individuals were observed. Overall 16 (66.7%) of the 24 participants with
were administered 177 Lu‑PSMA‑I&T at 6.1±1.0 GBq and complete 12‑week follow‑up data showed a reduction in PSA
87 patients received 177Lu‑PSMA 617 at 6.5±1.1 GBq (one levels, and nine (37.5%) of those subjects showed a PSA
injection). The mean dose of 177Lu‑PSMA‑617 was higher decline of ≥50%. At the 12th week after receiving a single
compared with 177Lu‑PSMA‑I&T (0.04 vs. 0.03 Gy/GBq), and dosage of 177Lu Ludotadipep, five of the 24 patients (20.8%)
the systemic half‑life of 177Lu‑PSMA‑I&T (35 h) was shorter displayed disease progression (a ≥25% increase in PSA levels
compared with that of 177lu‑PSMA‑617 (42 h). Of all the healthy from the baseline), suggesting that 177Lu Ludotadipep may be
organs, the lacrimal glands had the highest mean absorbed a promising new treatment for mCRPC (34).
tumor dose of 177Lu‑PSMA‑I&T and 177Lu‑PSMA‑617 (5.8
vs. 5.9 Gy/GBq), but patients tolerated the therapy without 4. Application of 177Lu in neuroendocrine tumors (NETs)
any acute side effects (29). A study that further evaluated the
difference in efficacy between 177Lu‑PSMA‑617 plus standard NETs are rare, heterogeneous tumors that originate from cells
therapy (hormone therapy, bisphosphonates and radiotherapy) of the diffuse endocrine system (35). Approximately two‑thirds
and 177Lu‑PSMA‑617 alone showed that combined therapy of NETs occur in the gastrointestinal and pancreatic systems,
extended the duration of pain exacerbation compared with including the stomach, small intestine, colon, appendix, rectum
177
Lu‑PSMA‑617 alone (30). It is hoped that future studies can and pancreas. The most common NET subtype is the gastro‑
include the combined use of nuclides with other drugs (such as intestinal pancreatic NET (GEP‑NET) (36). An analysis of
targeted drugs and chemotherapy drugs), and it is hoped that United States cancer data showed that the incidence of gastro‑
new progress and breakthroughs can be made in the treatment intestinal neuroendocrine tumors has continuously increased
of mCRPC through combination therapy. each decade from 1977 to 2016 (37). Currently, surgery is
the primary therapeutic method for GEP‑NETs because most
Prostate cancer and 177Lu‑J591. J591 is a deimmunizing GEP‑NETs are inert. In addition, severe cases are treated with
monoclonal antibody that binds to PSMA and has internal‑ radiochemotherapy, molecularly targeted medicine.
ized properties (internalization of a putative ligand) (31,32). Most pancreatic and GEP‑NETs express somatostatin
Participants received 75 mg/m docetaxel once every 21 days receptor (SSTR)2 and 5, these receptors can be chelated to a
for 2 cycles, with two progressive increments of ‘Lu‑1591’ β‑emitting radioisotope 177Lu for therapy. The new approach
at cycle 3 (1.48 GBq/m2, up to 2.96 GBq/m2). Docetaxel was for treating advanced NETs is peptide receptor radionuclide
administered in cycle 3 (half of the Lu‑J591 dose 2 to 3 days therapy (38).
before docetaxel and the other half of the dose 2 weeks after Somatostatin is a peptide with a potent and broad antise‑
docetaxel), with the fourth cycle of docetaxel given 6‑9 weeks cretory action. SSTRs which belong to the G protein‑coupled
after the third cycle. No dose‑limiting toxicity was observed receptor family, are widely distributed in various tissues of
4 NIU et al: CLINICAL APPLICATION OF 177LU IN SOLID TUMORS

the body and are classified into five subtypes (SSTR1‑5) (39). NETs and 177Lu‑DOTA‑JR11 (177Lu‑OPS201). 177Lu‑OPS201
SSTR2 is associated with gastrointestinal neuroendocrine is a novel somatostatin antagonist with high affinity for
system (40). SSTR2 (47). In situ testing in a SSTR2‑positive neuroen‑
docrine model in mice reveals that 177Lu‑OPS201 causes a
NETs and 177Lu‑1, 4, 7, 10‑tetraazacyclododecane‑1, 4, 7, greater decrease in living tumor tissue, a significant delay
10‑tetraacetic acid‑D‑phenylalanine 1‑tyrosine 3‑threo‑ in tumor growth and increased toxicity compared with
nine 8‑octreotide (177 Lu‑DOTA‑TATE) also known as 177
Lu‑DOTATOC (an SSTR agonist that primarily targets
DOTA‑octreotate. 177Lu‑DOTA‑TATE is a labeled precursor SSTR2). Likewise, the use of the 177 Lu‑OPS201 has been
of DOTA‑modified octreotide. Octreotide is a somatostatin shown to increase tumor uptake of agonist 177Lu‑DOTA‑TATE
analogue that is used to control NET progression (41). in vitro (47); however, it has not been validated at clinical trial
A 177Lu‑labeled SSTR agonist has been used to treat soma‑ stage. According to a recent in vitro study, 177Lu‑OPS201 has
tostatin receptor positive GEP‑NETs (42). The FDA approved a high affinity, and 177Lu‑OPS201 has at least four times more
the first radiopharmaceutical for the treatment of GET on receptor‑binding sites compared with 177Lu‑DOTA‑TATE. In
January 26, 2018. conclusion, 177Lu‑OPS201 has demonstrated faster binding,
An open, randomized, phase III clinical trial (NETTER‑1) slower dissociation and a longer cell retention period compared
enrolled 231 patients with locally advanced or metastatic, with 177Lu‑DOTA‑TATE (48).
well‑differentiated, somatostatin receptor‑positive midgut
neuroendocrine tumors. Patients were randomly assigned 5. Clinical application of 177Lu in other diseases
(1:1) to receive intravenous 177 Lu‑DOTA‑TATE 7.4 GBq +
intramuscular long‑acting octreotide (30 mg every 8 weeks) Fibroblast activating protein (FAP) overexpression in
(experimental group) or high‑dose long‑acting octreotide cancer and 177Lu‑FAP‑2286. FAP is expressed in a number
(60 mg every 4 weeks) (control group). According to the of malignancies. 177 Lu‑FAP‑2286 is a FAP‑binding cyclic
NETTER‑1 trial, which was reported on July 24, 2016, the peptide consisting of seven amino acids, of which two cysteine
estimated rate of PFS at 20 months was 65.2% (95% CI, residues pass through an aromatic partial ring that is linked to
50.0‑76.8%) in the experimental group and 10.8% (95% CI, the DOTA chelating agent (49). FAP‑2287 (a murine surrogate
3.5‑23.0%) in the control group. The response rate (complete for FAP‑2286) is well targeted for 177Lu targeted radionuclide
plus partial) in the experimental group was 18%, whereas therapy, rapidly accumulates in tissues and persists in tumors
it was only 3% in the control group (P<0.001). Preliminary for a long time (50).
findings show that using 177 Lu‑DOTA‑TATE markedly A trial has been performed that involved 11 patients with
increases the PFS (43). In a 2021 follow‑up analysis the advanced pancreatic, breast, rectal and ovarian cancers receiving
median OS for the experimental group was 48.0 months 177
Lu‑FAP‑2286. The results showed that the dosage of admin‑
(95% CI, 37.4‑55.2 months), while the control group OS istration of 177Lu‑FAP‑2286 (5.8±2.0 GBq; range, 2.4‑9.9 GBq)
was 36.3 months (95% CI, 25.9‑51.7 months). The OS of the was well tolerated, and no adverse or clinically detectable
experimental group did not improve significantly compared pharmacological effects were found or reported in any patient.
with that of the control group, and there was no statistically The systemic effective dose was 0.07±0.02 Gy/GBq (range,
significant difference in OS. However, in absolute terms, 0.04‑0.1 Gy/GBq). The mean absorbed doses in kidney and red
there was a difference of 11.7 months in the median OS bone marrow were 1.0±0.6 Gy/GBq (range, 0.4‑2.0 Gy/GBq)
between 177 Lu‑DOTA‑TATE and octreotide alone groups. and 0.05±0.02 Gy/GBq (range, 0.03‑0.09 Gy/GBq), respec‑
In the experimental group, 111 patients (3%) experienced tively. No grade 4 adverse events were observed; however,
serious adverse events related to treatment that were grade grade 3 adverse reactions occurred in three patients, including
3 or worse. During the 100 months of follow‑up, 2% of one pancytopenia, one leukopenia and one pain response.
patients developed myelodysplastic syndrome, yet no other 177
Lu‑FAP‑2286 is widely used in adenocarcinoma and is well
experimental group patients experienced renal impairment tolerated with few side effects (51). These results indicate that
that was grade 3 or worse. Although the OS was not statisti‑ 177
Lu‑FAP‑2286 has encouraging clinical data and deserves
cally significant, the results showed that the 11.7 monthly further exploration.
difference in the median OS between 177 Lu‑DOTA‑TATE
treatment and high‑dose long‑acting octreotide treatment Meningioma and 177Lu‑DOTA‑TATE. At present, there is no
alone may be considered clinically relevant (44). evidence‑based systemic treatment for patients with progres‑
A study compared PFS and OS in 177Lu‑DOTA‑TATE and sive meningioma who are unable to receive surgery or external
patients with advanced and unresectable gastrointestinal neuro‑ radiotherapy. External radiation therapy was given to 15 patients
endocrine tumors treated with everolimus and sunitinib (45). with meningioma, all of whom had received radiotherapy and
In comparison to everolimus, sunitinib and best supportive 14 of whom had surgery and then received 177Lu‑DOTA‑TATE
care, the results of the primary analysis demonstrated that (7.5‑29.6 GBq). 177Lu‑DOTA‑TATE was administered with a
177
Lu‑DOTA‑TATE may be a more effective therapy choice. In maximum activity of 7.4 GBq per cycle with a maximum of
a study evaluating the efficacy and safety of 177Lu‑DOTA‑TATE 4 cycles. In this cohort, the interval between the cycles was
in 30 patients with NET and extensive bone metastases, radio‑ a median of 9 weeks (range, 6‑14 weeks). Subsequently, six
logical evaluation at the end of treatment showed partial response patients (40%) were stable following treatment. The median
in five patients, stable disease in 20 patients, and progressive PFS of the whole cohort was 7.8 months, with a 6‑month PFS
radiological disease in three patients. Clinical progress was rate of 60%. The median OS was 13.6 months, with a 12‑month
observed in another two patients (46). OS rate of 60%. Prior to therapy, their average monthly tumor
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 27: 225, 2024 5

growth rate (TGR) was 4.6% for the surface and 14.8% for the

Table I. Recruiting clinical trials of 177Lu targeted radionuclide therapy for tumors expressing SSTR and PSMA (except neuroendocrine tumor and prostate cancer) in the past 5 years.

SSTR2, somatostatin receptor subtype 2; PSMA, prostate‑specific membrane antigen; NPC, metastatic nasopharyngeal cancer; ORR, overall response rate; PFS, progression free survival; DLTs, number
Assess the response
Primary outcome
volume. The surface and volume were scanned and determined
by magnetic resonance imaging. The TGR decreased to 3.1%

Tumor uptake
AEs/efficacy
of treatment.
in surface (P=0.016) and 5.0% in volume (P=0.013) per month
after treatment. The results suggest that 177Lu‑DOTA‑TATE
can control tumor growth (52).

DLTs
ORR

of participants with dose limiting toxicities; AEs, adverse events; NCT, national clinical trial; I.V, intravenous; PFS, progression‑free survival; N/A, not applicable; I&T, image and treat.
PFS

PFS

PFS
Metastatic salivary gland cancer and 177Lu‑PSMA‑617. PSMA
is expressed on tumor cells or in the tumor neovasculature in
salivary gland carcinoma, particularly in certain subtypes

Administration
such as salivary gland and salivary duct carcinomas (53,54).

Route
There have been cases of salivary gland malignancies that

I.V
I.V

I.V

I.V
I.V
I.V
I.V

I.V

show significant uptake in 68Ga‑PSMA‑11 PET‑CT (55‑57).
Therefore, in view of the encouraging results of patients
treated for CRPC, the potential use of 177Lu‑PSMA‑617 to treat
metastatic salivary gland cancer has been assessed.
In a retrospective study by Klein Nulent et al (58), six

Neuroendocrine tumors
Recurrent breast cancer
patients were treated with 177 Lu‑PSMA‑617. This cohort
included four adenoid cystic carcinomas, one adenocarcinoma

Endoradiotherapy
Application
(not otherwise specified) and one acinic cell carcinoma. A total

Metastatic NPC

Neuroblastoma

Glioblastoma
of four patients reported instant reduction of tumor‑related

Meningioma
symptoms; the most common improvement was a reduction

Glioma
in pain, followed by a reduction in fatigue. Two individuals
demonstrated a radiological response, indicating either stable
disease or a partial remission. All treatment‑related clinical
and hematological adverse events were graded using the
CTCAE standard version 5.0. This study demonstrated that

Lu‑177/Ga‑68
palliative 177Lu‑PSMA‑617 for salivary gland cancer is safe
Isotope

and generally well tolerated.

Lu‑177
Lu‑177

Lu‑177

Lu‑177
Lu‑177
Lu‑177
A 56‑year‑old man with progressive metastatic salivary

Ga‑68
cancer who received treatment every 6 weeks and was first
evaluated after four courses (cumulative activity of 24.3 GBq
177
Lu‑PSSMA‑617) showed stable disease on imaging
according to Positron Emission tomography Response Criteria
Tyr3‑Octreotate

In Solid Tumor (PERCIST) criteria (59).

DOTA‑TATE
DOTATATE

Ga‑PSMA
Edotreotide
PSMA I&T
Vector

Lutathera
DOTA0‑
Dotatate

Metastatic thyroid cancer and 177Lu‑DOTA‑TATE/177Lu‑P

SMA‑617I. A number of studies have shown that PSMA is
expressed in thyroid cancer, and significant uptake can be
68

observed with 68Ga‑PSMA‑11 PET‑CT (60‑63). Therefore,

177
Lu‑PSMA‑617 has been used to treat metastatic thyroid
PSMA

PSMA

cancer. Assadi and Ahmadzadehfar (64) treated a patient

Target

SSTR
SSTR

SSTR

SSTR
SSTR
SSTR

with progressing thyroid cancer and neck and lung metas‑

tases with 177 Lu‑PSMA. The patient previously received
25.9 GBq 131Iodine and sorafenib for 6 months, and radio‑
ligand therapy targeting the somatostatin receptor using
Phase

N/A
III

Lu‑DOTA‑TATE. As the patient exhibited persistent

II
II

II

II
II

177
I

disease progression and severe breathing difficulties, the

patient was then treated with 7.4 GBq 177Lu‑PSMA‑617. With
whole‑body SPE‑CT imaging, there was a higher level of
Starting date

2022‑09‑01

2021‑05‑19

2023‑03‑28

2022‑05‑10
2019‑05‑15
2022‑01‑17

whole‑body imaging with 177Lu‑PSMA‑617 compared with

2023‑01

2023‑07

receiving 177Lu‑DOTA‑TATE, suggesting that treatment with

177
Lu‑PSMA‑617 is potentially more effective compared with
177
Lu‑DOTA‑TATE for the treatment of this patient. However,
the patient died unexpectedly of cardiac arrest two weeks
after treatment.
NCT04529044
NCT05198479

NCT04903899

NCT05644080
NCT05918302
NCT05109728
NCT03971461
NCT05214820

I n a n additiona l st udy, two patients received

177
Lu‑PSMA‑617 therapy for thyroid carcinoma. One patient
showed disease progression on imaging 1 month later, the
other patient showed partial, temporary response of lung and
NCT
 6

Table II. New targets of clinical trials of 177Lu targeted radionuclide therapy for solid tumors in the past 5 years.

Administration
NCT Starting date Phase Target Vector Isotope Application route Primary outcome

NCT05623891 2022‑12 I ED‑B B5‑IgG4 Lu‑177 Solid Tumors I.V Tissue distribution/
Dosimetry/AEs
NCT05815394 2023‑03‑03 I NY108 DOTA Lu‑177 Prostate cancer I.V Tissue distribution/AEs
NCT04786847 2022‑01‑30 I PSMA TLX591 Lu‑177 MPC I.V AEs
NCT05723640 2023‑05‑10 I FAP LNC1004 Lu‑177 Solid tumor I.V DLTs/safety/MDT
NCT05410821 2022‑06‑15 I FAP DOTA‑EB‑FAPI Lu‑177 Thyroid cancer I.V Safety/tolerability/MDT
NCT05603559 2023‑01‑01 I PSMA P17‑087/088 Lu‑177 mCRPC I.V Dosimetry/AEs
NCT05013086 2021‑10‑01 I Integrin αvβ3 AB‑3PRGD2 Lu‑177 NSCLC I.V Standardized uptake value
NCT05130255 2022‑11‑17 I GD2 DOTA Lu‑177 Solid tumors I.V DLTs
NCT04997317 2021‑04‑21 I SSTR2 satoreotide Lu‑177 Meningiomas I.V Therapeutic index/safety
NCT03872778 2019‑07‑24 I/II GRPR NeoB Lu‑177 Solid tumor I.V DLTs/MDT
NCT04665947 2020‑12‑18 I ABM‑5G DOTA Lu‑177 Pancreatic cancer I.V DLTs/RP2D
NCT05706129 2023‑03‑14 I/II DPI‑4452 DOTA Lu‑177/Ga‑68 Solid tumors I.V TEAEs/DLTs/ORR
NCT05868174 2023‑05‑23 I CAIX Peposertib Lu‑177 Solid tumors I.V DLTs/safety
NCT05432193 2022‑07‑13 I FAP PNT6555 Lu‑177 Solid tumors I.V AEs
NCT04711135 2022‑08‑31 II SSTR Lutetium Lu‑177 GEP‑NETs I.V Absorbed radiation
doses/AEs
NCT04647526 2021‑02‑25 III PSMA PNT2002 Lu‑177 mCRPC I.V rPFS
NCT04469127 2023‑01‑30 I/II αvβ3 DOTA Lu‑177 Breast cancer I.V Safety and tolerability
NCT05533242 2023‑06 I 6A10 DOTA Lu‑177 Glioblastoma I.V MDT/safety
NCT05178693 2022‑04‑25 I SSTR ASTX727 Lu‑177 NETs I.V To determine whether
NIU et al: CLINICAL APPLICATION OF 177LU IN SOLID TUMORS

pre‑treatment with
ASTX727 results in
re‑expression of SSTR2

PSMA, prostate‑specific membrane antigen; FAP, fibroblast activation protein; SSTR2, somatostatin receptor subtype 2; GRPR, gastrin‑releasing peptide receptor; CAIX, carbonic anhydrase IX; MPC,
metastatic prostate cancer; mCRPC, metastatic castration‑resistant prostate cancer; NSCLC, non‑small cell lung cancer; GEP‑NETs, gastroenteropancreatic neuroendocrine tumors; I.V, intravenous; AEs,
adverse events; DLTs, number of participants with dose limiting toxicities; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose; TEAEs, treatment emergent adverse events; ORR, overall
response rate; rPFS, radiographic progression‑free survival; NCT, national clinical trial.
Table III. Ongoing clinical trials of 177Lu targeted radionuclide therapy combined with other solid tumor treatments in the past 5 years.

NCT Starting date Phase Target Combination treatment Application Primary outcome

NCT05340374 2022‑07‑14 I/II PSMA Cabazitaxel + 177Lu‑PSMA‑617 mCRPC DLTs/MTD/RP2D

NCT04525638 2020‑06‑29 II SSTR Nivolumab + 177Lu‑DOTATATE NENS ORR
NCT05766371 2023‑06‑30 II PSMA Pembrolizumab + 177Lu‑PSMA‑617 CRPC rPFS
NCT03874884 2019‑07‑09 I PSMA Olaparib + 177Lu‑PSMA‑617 mCRPC DLTs/MTD/RP2D
NCT05150236 2022‑04‑29 II PSMA Ipilimumab + Nivolumab + 177Lu‑PSMA‑617 mCRPC PSA‑PFS
225
NCT04886986 2021‑06‑30 I/II PSMA AC‑J591+ 177Lu‑PSMA‑I&T mCRPC DLTs/MTD
NCT05613894 2023‑06‑26 Ib PSMA Cabozantinib + 177Lu‑PSMA‑617 mCRPC DLTs
NCT05239533 2022‑02‑16 II Anti‑carbonic Nivolumab + 177Lu‑girentuximab Kidney cancer MTD/ORR
anhydrase IX
monoclonal antibody
NCT05868174 2023‑05‑23 I CAIX Peposertib + 177Lu‑TLX250 Solid tumors DLT/safety
NCT04720157 2021‑06‑09 III PSMA SoC + 177Lu‑PSMA‑617 mHSPC rPFS
NCT05663710 2023‑06‑30 II SSTR Cabozantinib + Nivolumab RCC Incidence of PFS
NCT04261855 2020‑10‑08 I/II SSTR Avelumab + 177Lu‑DOTATATE MCC PFS
223
NCT05383079 2022‑09‑13 I/II PSMA Ra + 177Lu‑PSMA‑I&T mCRPC DLTs/MTD/RP2D
NCT05724108 2023‑03‑15 II SSTR Triapine + 177Lu‑DOTATATE NENS ORR
NCT05249114 2022‑12‑28 I SSTR Cabozantinib + 177‑Lu‑DOTATATE NENS MTD PFS
NCT05687123 2023‑04‑28 I SSTR Sunitinib Malate + 177Lu‑DOTATATE Pancreatic NENS AEs
NCT04750954 2021‑06‑04 I SSTR Peposertib + 177Lu‑DOTATATE Pancreatic NENS RP2D
NCT05682443 2023‑07‑01 II PSMA ONC‑392 + 177Lu‑PSMA‑617 mCRPC rPFS
NCT05247905 2022‑03‑16 II SSTR Capecitabine + Temozolomide Pancreatic NENS PFS
EXPERIMENTAL AND THERAPEUTIC MEDICINE 27: 225, 2024

NCT04086485 2022‑10‑03 I/II SSTR Olaparib + 177Lu‑DOTATATE GEP‑NET MTD/ORR

NCT04614766 2022‑09‑30 I/II SSTR Lutathera + Azedra SPORE‑3 MTD/ORR

PSMA, prostate‑specific membrane antigen; CAIX, carbonic anhydrase IX; SSTR, somatostatin receptor subtype; SoC, standard of care; mCRPC, metastatic castration resistant prostate cancer; OPC,
oligometastatic prostate cancer; NENS, neuroendocrine neoplasms; CRPC, castration resistant prostate cancer; mHSPC, metastatic hormone sensitive prostate cancer; RCC, renal cell carcinoma; MCC,
Merkel cell carcinoma; GEP‑NET, gastroenteropancreatico neuroendocrine tumor; SPORE‑3, mid‑gut neuroendocrine tumors; DLTs, number of participants with dose limiting toxicities; MTD, maximum
tolerated dose; RP2D, recommended Phase 2 dose; PSA PFS, prostate‑specific antigen progression free survival at 1 year; bPFS, biochemical progression free survival; ORR, overall response rate; rPFS,
radiographic progression‑free survival; AEs, adverse events.
7
8 NIU et al: CLINICAL APPLICATION OF 177LU IN SOLID TUMORS

liver metastases (65). Side effects were not mentioned in either breast cancer, metastatic nasopharyngeal carcinoma, neuro‑
of these two case reports of thyroid carcinoma. blastoma, glioblastoma and glioma, NETs of the lung and
thymus for SSTR‑expressing tumors and upper metastatic
Advanced renal cell cancer and 177 Lu‑cG250. Previous gastric cancer for PSMA‑expressing tumors.
studies have shown that carbonic anhydrase IX is almost Likewise, future research should focus on the develop‑
universally expressed (>90%) in metastatic clear cell renal ment of more 177Lu TRT targets in solid tumors. In the past
cell carcinoma (ccRCC), and its expression in healthy tissues 5 years, the ongoing clinical trials of new targets for 177Lu TRT
has been extensively evaluated, but is limited to gastroin‑ have included fibronectin ED‑B, NY108, TLX591, LNC1004,
testinal mucosa and gastrointestinal associated structures, 3PRGD2 and GD2 (Table II).
with much lower expression levels compared with those Lastly, the use of 177Lu TRT in combination with other treat‑
in ccRCC (66,67). Thus, 177 Lu‑girentuximab (cG250) was ments should be explored. For example, in a preclinical model
used to treat ccRCC. Diagnostic Indium111‑cG250 imaging (murine model), 177Lu‑FAP‑2287 enhanced anti‑PD‑1‑mediated
confirmed cG250 accumulation in 23 patients with progressive tumor growth inhibition by modulating the tumor microenviron‑
ccRCC metastases (68). In this phase I study, patients received ment and increasing the recruitment of tumor‑infiltrating CD8+
a high‑activity dose of 177Lu‑cG250. At 3 months after the T cells (50). Another study showed that concurrent rather than
initial treatment, 74% of patients had stable illness (evaluated sequential blockade of the PD‑1/PD‑L1 axis combined with 177Lu
by PERCIST), and one patient had a partial response that TRT improves OS and long‑term tumor control (73). The study
persisted for 9 months. Mean growth of target tumor lesions of the metabolism principle of nuclide in the body can further
was reduced from 40.4% in the 3 months before treatment to clarify the treatment method in the future to improve the survival
5.5% 3 months after the first treatment cycle. There were no period. A Phase I study of the 177Lu‑DOTA0‑Tyr3‑Octreotate
significant non‑hematological adverse effects noted (68). combination with nivolumab was well tolerated and showed
Additionally, in a phase II study, 14 patients with ccRCC signs of antitumor activity for patients with neuroendocrine
were treated with 177Lu‑cG250, of which eight patients had tumors of the lung (74). In the past 5 years, the number of ongoing
stable disease and one had partial regression. The treatment clinical trials of 177Lu TRT combined with other treatments for
was generally well tolerated (69). solid tumors has increased. A list of the current trials is shown in
Table III. The results of these clinical trials will likely improve
Metastatic bone tumors and 177 Lu‑EDTMP. A study by the current options for 177Lu TRT treatments.
Elboga et al (70) found that 177Lu‑ethylenediamine tetramethyle
nephosphonic acid (EDTMP) effectively relieved pain caused 7. Conclusions
by bone metastases in patients with breast or prostate cancer.
Of the 75 patients treated with 177Lu‑EDTMP, 59 responded 177
Lu TRT have been successfully applied in patients with
positively, while 16 did not. The pain score was analyzed, NETs or metastatic prostate cancer, resulting in prolonged
and patients who responded had markedly lower pain scores PFS, OS and improved quality of life with tolerable toxici‑
after each radiopharmaceutical treatment. A meta‑analysis ties. However, 177Lu TRT are rarely used to treat other solid
involving 172 patients revealed that 177 Lu‑EDTMP had a tumors and clinical efficacies need to be improved. The use of
significant effect on relieving bone pain, suggesting that this 177
Lu‑DOTA‑TATE and 177Lu‑PSMA‑617 should be expanded
agent could be a good choice when other pain‑relieving radio‑ to various diseases, and more new targets for 177Lu TRT should
pharmaceuticals are not available (71). be researched and developed. Lastly, 177Lu TRT in combina‑
Currently, it is proposed that a 177Lu‑EDTMP rapid kit be tion with other treatments provide further treatment options
developed based on its success in palliative treatment, which, for solid tumors.
if successfully implemented, could greatly reduce pain in
terminal cancer patients (72). Acknowledgements

6. Present problems and future research directions Not applicable.

At present, the main problem with 177Lu TRT is the limited Funding
variety of drugs used in clinical practice, and the need for
further improvement in clinical efficacy. 177 Lu TRT is a This work was financially supported by the NHC Key
promising treatment method for solid tumors, but currently Laboratory of Nuclear Technology Medical Transformation,
only 177 Lu‑DOTA‑TATE and 177 Lu‑PSMA‑617 have been Mianyang Central Hospital (grant nos. 2022HYX001 and
approved treatment for NETs and prostate cancer, respectively. 2022HYX0015).
Moreover, the response rate of 177Lu TRT for mCRPC was
from 32.3 to 68%, and 177Lu‑DOTA‑TATE for neuroendocrine Availability of data and materials
tumors was only 18%.
Future research on 177Lu TRT should focus on expanding Not applicable.
the application of 177Lu‑DOTA‑TATE and 177Lu‑PSMA‑617
to other diseases that express PSMA or SSTR. There are Authors' contributions
currently ongoing clinical trials assessing the activity of
177
Lu‑DOTA‑TATE and 177 Lu‑PSMA‑617 on SSTR and TN and MF drafted the manuscript. BL, FG and BT partici‑
PSMA‑expressing tumors as listed in Table I. This includes pated in the data review and collection for the study. XD
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 27: 225, 2024 9

conceived the study and reviewed and edited the manuscript. 16. Bu T, Zhang L, Yu F, Yao X, Wu W, Zhang P, Shi L, Zang S,
Meng Q, Ni Y, et al: 177Lu‑PSMA‑I&T radioligand therapy
All authors read and approved the final version of the manu‑ for treating metastatic castration‑resistant prostate cancer: A
script. Data authentication is not applicable. single‑centre study in East Asians. Front Oncol 12: 835956,
2022.
17. Emmett L, John N, Pathmanandavel S, Counter W, Ayers M,
Ethics approval and consent to participate Sharma S, Agrawal S, Poole A, Hovey E, Pranavan G, et al:
Patient outcomes following a response biomarker‑guided
Not applicable. approach to treatment using 177Lu‑PSMA‑I&T in men with
metastatic castrate‑resistant prostate cancer (Re‑SPECT). Ther
Adv Med Oncol 15: 17588359231156392, 2023.
Patient consent for publication 18. Karimzadeh A, Heck M, Tauber R, Knorr K, Haller B,
D'Alessandria C, Weber WA, Eiber M and Rauscher I:
Not applicable.
177
Lu‑PSMA‑I&T for treatment of metastatic castration‑resistant
prostate cancer: Prognostic value of scintigraphic and clinical
biomarkers. J Nucl Med 64: 402‑409, 2023.
Competing interests 19. Golan S, Frumer M, Zohar Y, Rosenbaum E, Yakimov M,
Kedar D, Margel D, Baniel J, Steinmetz AP, Groshar D, et al:
Neoadjuvant 177Lu‑PSMA‑I&T radionuclide treatment in patients
The authors declare that they have no competing interests. with high‑risk prostate cancer before radical prostatectomy:
A single‑arm phase 1 trial. Eur Urol Oncol 6: 151‑159, 2023.
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