A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of ¹⁷⁷Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively

A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of ¹⁷⁷Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively

After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (P = 0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with ≥2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer-Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 ± 33.3 points (P = 0.11).

A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of ¹⁷⁷Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively

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).

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).

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).

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

The 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.

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

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

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

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).

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).

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.

CgA is a marker used in the diagnosis of NETs. Pre-treatment CgA levels were measured in 25 patients. Of the 25 patients, 6 (24.0%), 13 (52.0%), and 6 (24.0%) patients had pretreatment CgA blood level less than 95ng/mL, between 95 and 1000ng/mL, and greater than 1000ng/mL, respectively. After all 4 PRRT cycles were completed; CgA levels were measured in 3 patients. Two (66.7%) patients had post-treatment CgA between 95 and 1000 ng/mL while 1 (33.3%) patient had levels above 1000 ng/mL.

CgA is a marker used in the diagnosis of NETs. Pre-treatment CgA levels were measured in 25 patients. Of the 25 patients, 6 (24.0%), 13 (52.0%), and 6 (24.0%) patients had pretreatment CgA blood level less than 95ng/mL, between 95 and 1000ng/mL, and greater than 1000ng/mL, respectively. After all 4 PRRT cycles were completed; CgA levels were measured in 3 patients. Two (66.7%) patients had post-treatment CgA between 95 and 1000 ng/mL while 1 (33.3%) patient had levels above 1000 ng/mL.

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.

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.

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).

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%).

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).

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).

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).

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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).

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.

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.

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).

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.

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.

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 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).

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.

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

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

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

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 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.

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).

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.

After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (P = 0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with ≥2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer-Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 ± 33.3 points (P = 0.11).

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.

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.

In total, 61 RNT cycles were evaluated in 34 patients with age of 65 ± 2.83 (median ± SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05).

In total, 61 RNT cycles were evaluated in 34 patients with age of 65 ± 2.83 (median ± SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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.

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.

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.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

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

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

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min.

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of ¹⁷⁷Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively

AE was recorded in 13 patients out of the entire 35 patients treated with PRRT. A grade 5 AE was reported in 2 patients (15.4%) and grade 3 AEs were reported in 5 patients (38.5%). Of the 5 grade 3 AE patients, 1 patient developed ascites, pleural effusion, and acute kidney injury; the second patient developed hematoma at the injection site and pain in the lower extremities; the third patient had shortness of breath, cough, and hemoptysis; the fourth patient had nausea, vomiting, and deep vein thrombosis; and the fifth patient developed obstructive jaundice. All 5 grade 3 AE patients were hospitalized and treated. One patient (7.7%) with a grade 2 AE developed an upper respiratory infection and required antibiotics. Five patients (38.5%) with grade 1 AEs had nausea, vomiting, abdominal pain, and/or diarrhea. No patients developed a grade 4 AE.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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

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.

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

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

AE was recorded in 13 patients out of the entire 35 patients treated with PRRT. A grade 5 AE was reported in 2 patients (15.4%) and grade 3 AEs were reported in 5 patients (38.5%). Of the 5 grade 3 AE patients, 1 patient developed ascites, pleural effusion, and acute kidney injury; the second patient developed hematoma at the injection site and pain in the lower extremities; the third patient had shortness of breath, cough, and hemoptysis; the fourth patient had nausea, vomiting, and deep vein thrombosis; and the fifth patient developed obstructive jaundice. All 5 grade 3 AE patients were hospitalized and treated. One patient (7.7%) with a grade 2 AE developed an upper respiratory infection and required antibiotics. Five patients (38.5%) with grade 1 AEs had nausea, vomiting, abdominal pain, and/or diarrhea. No patients developed a grade 4 AE.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred.

There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles.

Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with ¹⁷⁷Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients).

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.

Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min.

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.