Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

Both 90Y-DOTATOC and ¹⁷⁷Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, ¹⁷⁷Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

Both 90Y-DOTATOC and ¹⁷⁷Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, ¹⁷⁷Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

Both 90Y-DOTATOC and ¹⁷⁷Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, ¹⁷⁷Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq ¹⁷⁷Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or ¹⁷⁷Lu-DOTATATE.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

Both 90Y-DOTATOC and ¹⁷⁷Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, ¹⁷⁷Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

There was no statistically significant heterogeneity among the ¹⁷⁷Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for ¹⁷⁷Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between ¹⁷⁷Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (¹⁷⁷Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1).

This case report is a good example of the efficacy and safety of salvage therapy with ¹⁷⁷Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, ¹⁷⁷Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used.

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with ¹⁷⁷Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported.

Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with ¹⁷⁷Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or ¹⁷⁷Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively.

In detail, we report pooled data on 149 ¹⁷⁷Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with ¹⁷⁷Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3.