A transient increase in tumor volume was observed after the first cycle, which may have represented delayed treatment effect or pseudoprogression secondary to vasogenic edema. Subsequently, the tumor volume decreased by 7% and remained stable with minimal change in volume throughout the remainder of treatment. Over the 4 cycles (8 months) of treatment, the tumor volume increased only 16% during ¹⁷⁷Lu-dotatate therapy in comparison to the rapid increase of 169% during the 8 months prior to ¹⁷⁷Lu-dotatate initiation. However, the tumor resumed its previous rapid growth after therapy cessation.

The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi ¹⁷⁷Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 μIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to ¹⁷⁷Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of ¹⁷⁷Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi ¹⁷⁷Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 μIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to ¹⁷⁷Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of ¹⁷⁷Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi ¹⁷⁷Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 μIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to ¹⁷⁷Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of ¹⁷⁷Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi ¹⁷⁷Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 μIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to ¹⁷⁷Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of ¹⁷⁷Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi ¹⁷⁷Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 μIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to ¹⁷⁷Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of ¹⁷⁷Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

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.

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.

Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10⁹/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (γGT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis.

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.

Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first ¹⁷⁷Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score ≥ 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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 objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done.

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four ¹⁷⁷Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9).

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.

A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [¹⁷⁷Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [¹⁷⁷Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated.

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

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.

Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort.

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.

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.

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

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.

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.

In all patients, the value of troponin I was in normal range. In all patients, the median values of serum troponin I before and after treatment were 0.2 ± 0.02 (range: 0.00-0.42) and 0.28 ± 0.02 (range: 0.00-0.46) ng/ml, respectively (p > 0.05). In the prostate cancer patients, the median values of serum troponin I before and after treatment were 0.26 ± 0.04 (0.04-0.42) and 0.30 ± 0.04 (0.00-0.41) ng/ml, respectively (p > 0.05). In the NET patients, the median values of serum troponin I before and after treatment were 0.18 ± 0.03 (0.00-0.42) and 0.17 ± 0.03 (0.00-0.46) ng/ml, respectively (p > 0.05).

On follow-up for a second PRRT cycle, there was a complete symptomatic response. Follow-up scans showed a significant decrease in the size of the sinonasal mass (˜1.9 0.8 cm vs. 7.0 4.6 5.0 cm at baseline), with a significant decrease in the size of the left cervical level II lymph node (1.5 1.1 cm vs. 2.2 1.3 cm at baseline) and complete resolution of the right hilar lymph node.

PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease.

PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease.

PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease.

PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease.

Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10⁹/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (γGT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis.

The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade ≥3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade ≥3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A ≥ 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade ≥3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade ≥2 thrombocytopenia (P = 0.831). Grade ≥3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122).

Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade ≥3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade ≥3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A ≥ 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade ≥3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade ≥2 thrombocytopenia (P = 0.831). Grade ≥3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122).

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Radiation absorbed doses (mean ± standard deviation) were obtained as 0.29 ± 0.12 mGy/MBq for kidneys, 0.30 ± 0.18 mGy/MBq for liver, 0.63 ± 0.37 mGy/MBq for spleen, 0.019 ± 0.001 mGy/MBq for bone marrow and 3.85 ± 1.74 mGy/MBq for tumours in the case group and they were 0.31± 0.26, 0.24 ± 0.14, 0.64 ± 0.42, 0.017 ± 0.016, 5.6 ± 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group.

Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10⁹/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (γGT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis.

Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10⁹/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (γGT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first ¹⁷⁷Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%).

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort.

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.

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four ¹⁷⁷Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score ≥ 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity.

In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 ± 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months).

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.

Fourteen patients (female = 11, male = 3) with progressive meningiomas (WHO 1 = 3, 2 = 10, 3 = 1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with ¹⁷⁷Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE uptake (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI).

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 efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

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 efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

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).

We present a 26-year-old man who started with pelvic pain and after a biopsy of a retro-rectal mass observed in a magnetic resonance was diagnosed with an advanced neuroendocrine tumour. After progression to lanreotide, everolimus and sunitinib, treatment with ¹⁷⁷Lu-DOTATATE was initiated, achieving an excellent response with a progression free survival (PFS) of 38 months.

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

At the end of the 4 cycles, fatigue, chest pain and dyspnea resolved, and episodes of tachyarrhythmia disappeared. The dosage of metoprolol and prazocin was considerably reduced, decreasing respectively from 125 mg to 50 mg and 2 mg to 1 mg TID. The chromogranin A decreased from 585 to 205 ng/mL and the serum norepinephrine decreased from 104 to 37 nmol/L after 4 cycles.

Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

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.

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

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.

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.

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first ¹⁷⁷Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%).

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.

Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four ¹⁷⁷Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9).

Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort.

In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 ± 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months).

Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score ≥ 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity.

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.

According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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.

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of ¹⁷⁷Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68).

Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of ¹⁷⁷Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following ¹⁷⁷Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months).

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 objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

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 efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating ¹⁷⁷Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after ¹⁷⁷LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of ¹⁷⁷Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months.

As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [¹⁷⁷Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of ¹⁷⁷Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [¹⁷⁷Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [¹⁷⁷Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [¹⁷⁷Lu]Lu-DOTATATE (p < 0.0001).

As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [¹⁷⁷Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of ¹⁷⁷Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [¹⁷⁷Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [¹⁷⁷Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [¹⁷⁷Lu]Lu-DOTATATE (p < 0.0001).

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).

Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [¹⁷⁷Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [¹⁷⁷Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [¹⁷⁷Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [¹⁷⁷Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [¹⁷⁷Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [¹⁷⁷Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes.

Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [¹⁷⁷Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [¹⁷⁷Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [¹⁷⁷Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [¹⁷⁷Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [¹⁷⁷Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [¹⁷⁷Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes.

Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [¹⁷⁷Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [¹⁷⁷Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable.

As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [¹⁷⁷Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of ¹⁷⁷Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [¹⁷⁷Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [¹⁷⁷Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [¹⁷⁷Lu]Lu-DOTATATE (p < 0.0001).

As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [¹⁷⁷Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of ¹⁷⁷Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [¹⁷⁷Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [¹⁷⁷Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [¹⁷⁷Lu]Lu-DOTATATE (p < 0.0001).

Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [¹⁷⁷Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [¹⁷⁷Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable.

The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [¹⁷⁷Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [¹⁷⁷Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [¹⁷⁷Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [¹⁷⁷Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [¹⁷⁷Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [¹⁷⁷Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes.

A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [¹⁷⁷Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [¹⁷⁷Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated.

Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [¹⁷⁷Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [¹⁷⁷Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [¹⁷⁷Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [¹⁷⁷Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [¹⁷⁷Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [¹⁷⁷Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes.

At the end of the 4 cycles, fatigue, chest pain and dyspnea resolved, and episodes of tachyarrhythmia disappeared. The dosage of metoprolol and prazocin was considerably reduced, decreasing respectively from 125 mg to 50 mg and 2 mg to 1 mg TID. The chromogranin A decreased from 585 to 205 ng/mL and the serum norepinephrine decreased from 104 to 37 nmol/L after 4 cycles.

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.

The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%).

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.