Purpose
In this study, we aim to evaluate the efficacy and safety of
225
AC-DOTATATE targeted alpha therapy in advanced-stage paragangliomas (PGLs).
Methods
Nine (6 males and 3 females) consecutive ...patients with histologically proven PGLs were treated with
225
Ac-DOTATATE targeted alpha therapy (TAT) and concomitant radiosensitizer, capecitabine, at 8-weekly intervals up to a cumulative activity of ~ 74 MBq. The primary endpoint included evaluating therapy response and disease control rate (DCR) using the RECIST 1.1 criteria. Additional secondary endpoints comprised clinical response assessment using EORTC QLQ-H&N35 questionnaire, Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group performance status (ECOG), analgesic score (AS), dose alterations of anti-hypertensive drugs (anti-HTN), and the safety and side-effect profile evaluation as per CTCAE criteria version 5.0.
Results
Following
225
Ac-DOTATATE treatment, morphological response revealed partial response in 50%, stable disease in 37.5%, and disease progression in 12.5%, with a DCR of 87.5%. Similarly, the symptomatic response was remarkable, and anti-HTN drugs were stopped in 25% and reduced in 37.5%. Another significant finding in our study revealed a morphologic DCR of 66.6% (2/3) in patients who failed previous lutetium-177 peptide receptor radionuclide therapy (
177
Lu-PRRT). Regarding the KPS, ECOG, and AS performance scores, a notable improvement was observed post-
225
Ac-DOTATATE treatment. The QLQ-H&N35 symptom scores evaluated in seven H&N PGL patients showed significant improvement in all aspects. No improvement in sexual function was noted (
P
= 0.3559). Despite the significant reduction in the analgesic score post-treatment (
P
= 0.0031), the QLQ-H&N35 revealed only marginal significance concerning the intake of pain killers (
P
= 0.1723). No grade III/IV hematological, renal, and hepatological toxicities were noted.
Conclusion
The evidence from this study suggests
225
Ac-DOTATATE therapy is effective and safe in the treatment of advanced-stage PGLs and also reports a clear benefit even in patient’s refractory to the previous
177
Lu-PRRT.
Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), though uncommon, presents a considerable therapeutic challenge with poor long-term outcomes. Currently, tyrosine kinase inhibitors are ...the mainstay of treatment for advanced RAIR-DTC patients. However, these agents are associated with a multitude of adverse events with resultant deterioration in the quality-of-life of the patients. Targeted theranostic approaches with radiolabelled integrin binders and fibroblast activation protein- (FAP)-inhibitors seem to have a promising role in the management of such patients. This mini-review focuses on these novel theranostic strategies in RAIR-DTC, with emphasis on recent advances, existing challenges, and future directions.
Purpose
68
GaGa-labeled fibroblast activation protein inhibitors (
68
GaGa-FAPi) have shown promising preclinical and clinical results in PET imaging. The present study aimed to evaluate the ...biodistribution, pharmacokinetics, and dosimetry of
68
GaGa-DOTA.SA.FAPi, another modified FAPi tracer, and performed a head-to-head comparison with
18
FF-FDG PET/CT scans in patients with various cancers.
Methods
In this prospective study, patients underwent both
18
FF-FDG and
68
GaGa-DOTA.SA.FAPi PET/CT scans 60 min post-injection (p.i.). Dosimetry studies were conducted in three patients using
68
GaGa-DOTA.SA.FAPi serial time-point imaging. The absorbed dose was calculated using OLINDA/EXM 2.2 software. Quantification of the uptake of the tracers was assessed using standardized uptake values corrected for lean body mass (SUL).
Results
Fifty-four patients (mean age; 48.4 years) with 14 types of cancers involving 37% breast, 24% lung, 7.4% head and neck (H&N), and remaining 31.6% patients with other histologies were evaluated prospectively. Physiological uptake of
68
GaGa-DOTA.SA.FAPi was observed in the liver, kidneys, pancreas, heart contents, and to a lesser extent in the lacrimals, oral mucosa, salivary glands, and thyroid glands. Uptake in the target lesions on
68
GaGa-DOTA.SA.FAPi scan was initiated at 10 min, and no additional lesions were detected in the delayed acquisition time points. The pancreas was the organ with the highest absorbed dose (5.46E-02 mSv/MBq). While the patient-based comparison between the radiotracers revealed complete concordance in the detection of primary, pleural thickening, bone and liver metastases, and second primary malignancy, discordant findings were observed in the detection of lymph node (7.5%), lung nodules (5.6%), and brain metastases (2%). According to the site of primary disease, patients with H&N cancers demonstrated the highest SULpeak and average (avg) values on
68
GaGa-DOTA.SA-FAPi which was similar to the values of
18
FF-FDG (SULpeak: 15.4 vs. 14.2; P-0.680) (SULavg: 8.3 vs. 7.9; P-0.783). The lowest uptake was observed in lung cancers with both the radiotracers (SULpeak: 5.8 vs. 7.4; P-0.238) (SULavg: 4.9 vs. 5.3; P-0.313). A significantly higher SULpeak and SULavg for brain metastases to normal brain parenchyma ratios were observed on
68
GaGa-DOTA.SA.FAPi in contrast to the
18
FF-FDG values {SULpeak: median: 59.3 (IQR: 33.5–130.8) versus 1.5 (1–2.3); P-0.028}. Except for brain metastases, comparable SULpeak and average values were noted between the radiotracers in all other regions of metastases with no significant difference.
Conclusion
68
GaGa-DOTA.SA.FAPi is a promising alternative among the FAPI class of molecules and performed well as compared to standard-of-care radiotracer
18
FF-FDG in the diagnosis of various cancers.
Skeletal metastases in differentiated thyroid cancer (DTC) patients are associated with poor prognosis. The objective was to determine the maximum I-131 cumulative activity that could be safely ...administered without compromising efficacy. The secondary objective was to identify other prognostic factors affecting survival outcomes. This was a retrospective cohort study done at a tertiary-care institution comprising of data from January 1990-June 2020. 489 DTC patients having skeletal metastases with greater than or equal to12 months follow-up were included. Ninety-six percent of patients had thyroidectomy followed by radioiodine therapy for skeletal metastases. All patients were on oral suppressive levothyroxine tablets. External beam radiotherapy (EBRT) and oral tyrosine kinase inhibitors were used whenever indicated. The main outcome measures were overall survival (OS), progression-free survival (PFS), and adverse-events. There were 347 (71%) females and 324 (66%) had follicular carcinoma thyroid. Median follow-up was 78 (interquartile range, IQR: 37-153) months. 333 patients (68%) received less than or equal to37GBq I-131 cumulative activity (group 1) and 156 patients (32%) received >37GBq cumulative RAI activity (group 2). Overall median OS and PFS were 74 (95% confidence interval (CI): 62.2-85.8) and 48 (95%CI: 40.5-55.4) months, respectively. The 5-, 10-, 15- and 20-year estimated overall survival probabilities were 55.7%, 28.4%, 14% and 8.3%, respectively. On multivariate analysis, age(<55years) (p37GBq (p<0.001) and EBRT(p = 0.001) were favourably associated with OS; no factors were significantly associated with PFS. The median OS for groups 1 & 2 were 51 versus 90 months (p37GBq resulted in more adverse events (2.4%), particularly bone marrow suppression (3.5%). For better survival outcomes, cumulative I-131 activity upto 37GBq could be administered with acceptable toxicity to DTC patients with skeletal metastases.
Background
177
LuLu-DOTA-ZOL has shown promising results from the dosimetry and preclinical aspects, but data on its role in the clinical efficacy are limited. The objective of this study is to ...evaluate the efficacy and safety of
177
LuLu-DOTA-ZOL as a bone pain palliation agent in patients experiencing pain due to skeletal metastases from various cancers.
Methods
In total, 40 patients experiencing bone pain due to skeletal metastases were enrolled in this study. The patients were treated with a mean cumulative dose of 2.1 ± 0.6 GBq (1.3–2.7 GBq)
177
LuLu-DOTA-ZOL in a median follow-up duration of 10 months (IQR 8–14 months). The primary outcome endpoint was response assessment according to the visual analogue score (VAS). Secondary endpoints included analgesic score (AS), global pain assessment score, Eastern Cooperative Oncology Group Assessment performance status (ECOG), Karnofsky performance status, overall survival, and safety assessment by the National Cancer Institute’s Common Toxicity Criteria V5.0.
Results
In total, 40 patients (15 males and 25 females) with a mean age of 46.6 ± 15.08 years (range 24–78 years) were treated with either 1 (
N
= 15) or 2 (
N
= 25) cycles of
177
LuLu-DOTA-ZOL. According to the VAS response assessment criteria, complete, partial, and minimal responses were observed in 11 (27.5%), 20 (50%), and 5 patients (12.5%), respectively with an overall response rate of 90%. Global pain assessment criteria revealed complete, partial, minimal, and no response in 2 (5%), 25 (62.5%), 9 (22.5%), and 4 (10%) patients, respectively. Twenty-eight patients died and the estimated median overall survival was 13 months (95% CI 10–14 months). A significant improvement was observed in the VAS, AS, and ECOG status when compared to baseline. None of the patients experienced grade III/IV haematological, kidney, or hepatotoxicity due to
177
LuLu-DOTA-ZOL therapy.
Conclusion
177
LuLu-DOTA-ZOL shows promising results and is an effective radiopharmaceutical in the treatment of bone pain due to skeletal metastases from various cancers.
Purpose
Recently, the new hybrid chelator DATA (6-amino-1,4-diazepine-triacetate) has been introduced, which has the advantage of high yield and radiolabelling of DATA-based octreotide derivative ...(TOC) at room temperature in contrast to tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) that needs 95 °C for effective labelling. However, the diagnostic potential of DATA-TOC has not been studied with other chelators in humans. The aim of this study was to compare the diagnostic efficacy of
68
GaGa-DATA-TOC with
68
GaGa-DOTA-NOC (which is the current standard for imaging neuroendocrine tumours (NET)) in patients of gastroenteropancreatic neuroendocrine tumours (GEP-NETs).
Methods
Fifty patients (thirty-one males and nineteen females) with biopsy-proven GEP-NETs were included in the study. Patients age ranged from 14 to 75 years (mean 46.11 years). All patients underwent two PET studies with
68
GaGa-DATA-TOC and
68
GaGa-DOTA-NOC. Images were evaluated visually and semi-quantitatively using maximum standardized uptake values (SUVmax) of tumour, mediastinum and liver. Tumour-to-liver (T/L) and tumour-to-mediastinum (T/M) SUVmax ratios were computed. For the purpose of comparison, patient-wise as well as lesion-wise analysis was carried out. The nonparametric-related samples Wilcoxon signed-rank test was used for comparison of the SUVmax values and ratios.
Results
On visual evaluation, the biodistribution and image quality of
68
GaGa-DATA-TOC was similar to
68
GaGa-DOTA-NOC. Physiological liver uptake was lower in
68
GaGa-DATA-TOC as compared with
68
GaGa-DOTA-NOC, 7.65 ± 5.37 vs 8.94 ± 5.95 (
p
= 0.009), respectively. On a patient-wise analysis, both
68
GaGa-DATA-TOC and
68
GaGa-DOTA-NOC were lesion-positive in the 44 patients (88%) and were negative in the 6 patients (12%). On a lesion-based analysis,
68
GaGa-DATA-TOC had 98.6% concordance with
68
GaGa-DOTA-NOC (232 out of 235 lesions detected). The target tumour SUVmax on
68
GaGa-DATA-TOC and
68
GaGa-DOTA-NOC were 36.63 ± 32.24 and 40.82 ± 36.89, respectively (
p
= 0.097). The T/L SUVmax ratios were not significantly different (5.99 ± 5.52 vs 5.67 ± 4.96,
p
= 0.77).
Conclusion
68
GaGa-DATA-TOC PET/CT imaging produced results that were comparable with
68
GaGa-DOTA-NOC. It, thus, has potential utility as an effective and safe alternative to
68
Ga-DOTA-NOC with the added benefit of ease, cost-effective and improved yield of instant kit-type synthesis.
Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as
GaGa-labelled FAPI-02, 04, 46, ...and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of
LuLu-DOTA.SA.FAPi, and
LuLu-DOTAGA.(SA.FAPi)
in patients with various cancers. The FAPi agents,
LuLu-DOTA.SA.FAPi and
LuLu-DOTAGA.(SA.FAPi)
, were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq)
LuLu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of
LuLu-DOTAGA.(SA.FAPi)
. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of
LuLu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of
LuLu-DOTAGA.(SA.FAPi)
involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the
LuLu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the
LuLu-DOTAGA.(SA.FAPi)
group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than
LuLu-DOTA.SA.FAPi (
< 0.011).
LuLu-DOTAGA.(SA.FAPi)
had significantly longer median whole-body Te compared to that of
LuLu-DOTA.SA.FAPi 46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5);
-0.0167. The Te of tumor lesions was significantly higher for
LuLu-DOTAGA.(SA.FAPi)
compared to
LuLu-DOTA.SA.FAPi 86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5);
-0.0004. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the
LuLu-DOTA.SA.FAPi, and
LuLu-DOTAGA.(SA.FAPi)
groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with
LuLu-DOTAGA.(SA.FAPi)
compared to
LuLu-DOTA.SA.FAPi.
LuLu-DOTAGA.(SA.FAPi)
is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.
Purpose
To compare
131
I-therapy outcomes in high turnover and normal turnover Graves’ disease patients and predict optimal first
131
I activity for high turnover patients.
Methods
Retrospective ...cohort design (1:2) validated by propensity score analysis. Cohort 1, high turnover (2-h RAIU/24-h RAIU ≥ 1),
n
= 104, and cohort 2, normal turnover (ratio < 1),
n
= 208, patients were compared for post
131
I outcome. The cure was defined as a combined euthyroid and stable hypothyroid state following
131
I treatment. Logistic regression analysis was used for identifying prognostic factors. The propensity score was applied; 77 matched pairs (1:1 ratio) of high and normal turnover patients were selected as a validation set.
Results
First
131
I cure rates of 28% in high turnover and 66% in normal turnover groups (
p
= 0.001) were noted. The therapy cycles (median, 2 vs. 1) and cumulative
131
I activity (median, 15 vs. 7 mCi) were required to cure hyperthyroidism in cohort 1 and cohort 2, respectively. Age (> 44 years), higher grade of goitre, and 2-h RAIU (> 37%) were associated with
131
I therapy failure. The high turnover patients needed a factor of 1.5–2 times more
131
I activity to achieve a similar cure rate compared to the normal turnover patients. The first-dose cure rate was 31% vs. 60% by propensity score analysis (
n
= 154), no way different (28% vs.66%) from the whole group of 312 patients.
Conclusion
High turnover Graves’ disease patients, if administered standard
131
I activity, the outcomes shall be poor. To improve the success rate,
131
I activity should be increased by 1.5 to 2 times in the high turnover patients.
Summary
Objective
Distant metastases, although rare, account for maximum disease‐related mortality in differentiated thyroid cancer (DTC). Lungs and bones are the most frequent sites of metastases. ...We sought to identify the prognostic factors in adult DTC patients presenting with pulmonary metastases at initial diagnosis.
Design
Retrospective cohort study.
Patients
From the medical records of 4370 patients, 200 patients aged more than 21 years who were identified to have pulmonary metastases at the time of diagnosis were included in the analysis.
Results
The sites of metastases were lungs alone in 133 (67%) patients, and additional sites in remaining 67 (33%) patients were as follows: bones in 59, liver in 4, brain in 2 and both bone and liver in two patients. During the mean follow‐up of 61 months (range, 12–312 months), 76 patients achieved remission, 121 (60·5%) patients had biochemically and/or structurally persistent disease and three patients showed disease progression. Multivariate analysis revealed presence of macro‐nodular (chest X‐ray positive) pulmonary metastases and concomitant skeletal metastases as independent factors decreasing the likelihood of remission. Of the 76 patients with remission, 16 (21%) developed subsequent recurrence. Patient age >45 years and follicular histopathology were independently associated with greater hazards of developing recurrence.
Conclusion
This study suggests that the patients with macro‐nodular lung metastases and/or concomitant skeletal metastases have reduced odds of achieving remission. Moreover, significant number of patients recur even after complete remission with RAI treatment, hence strict surveillance is recommended especially in patients with age >45 years and/or with follicular histology of DTC.
PDF
![[177Lu]Lu-DOTA-ZOL bone pai...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2191-219X/small "[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results")
