Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response

Vaughan, Emily; Machta, Joseph; Walker, Martin; Toumpanakis, Christos; Caplin, Martyn; Navalkissoor, Shaunak

doi:10.1259/bjr.20180041

Cited by 52 publications

(56 citation statements)

References 17 publications

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“…It is described that after the initial 4 cycles of PRRT the majority of patients will present with stable disease, but will eventually show disease progression 5 , 39 . Patients that present with progressive disease after at least a year and that have responded well to the initial PRRT cycles are eligible for additional cycles of PRRT as it has been shown that retreatment is beneficial in terms of PFS and is often well tolerated 32 , 40 . A prerequisite for (re)treatment is the presence of positive lesions by [ 68 Ga]Ga-DOTA-TATE on a positron-emission-tomography (PET) scan, indicating SST 2 positive tumors 40 , 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Patients that present with progressive disease after at least a year and that have responded well to the initial PRRT cycles are eligible for additional cycles of PRRT as it has been shown that retreatment is beneficial in terms of PFS and is often well tolerated 32 , 40 . A prerequisite for (re)treatment is the presence of positive lesions by [ 68 Ga]Ga-DOTA-TATE on a positron-emission-tomography (PET) scan, indicating SST 2 positive tumors 40 , 41 . However, information about the SST 2 expression of single tumor cells within these lesions and their uptake of the radioligand before and after treatment is often unknown.…”

Section: Discussionmentioning

confidence: 99%

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Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Feijtel¹,

Doeswijk²,

Verkaik³

et al. 2021

Theranostics

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Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with lutetium-177 is targeted to NET cells by binding to the somatostatin receptor subtype 2 (SST 2 ). During radioactive decay, DNA damage is induced, leading to NET cell death. Although the therapy proves to be effective, mortality rates remain high. To appropriately select more optimal treatment strategies, it is essential to first better understand the radiobiological responses of tumor cells to PRRT. Methods: We analyzed PRRT induced radiobiological responses in SST 2 expressing cells and xenografted mice using SPECT/MRI scanning and histological and molecular analyses. We measured [ 177 Lu]Lu-DOTA-TATE uptake and performed analyses to visualize induction of DNA damage, cell death and other cellular characteristics. Results: The highest accumulation of radioactivity was measured in the tumor and kidneys. PRRT induced DNA damage signaling and repair in a time-dependent manner. We observed intra-tumor heterogeneity of DNA damage and apoptosis, which was not attributed to proliferation or bioavailability. We found a strong correlation between high DNA damage levels and high SST 2 expression. PRRT elicited a different therapeutic response between models with different SST 2 expression levels. Heterogeneous SST 2 expression levels were also confirmed in patient NETs. Conclusion: Heterogeneous SST 2 expression levels within NETs cause differentially induced DNA damage levels, influence recurrent tumor phenotypes and impact the therapeutic response in different models and potentially in patients. Our results contribute to a better understanding of PRRT effects, which might impact future therapeutic outcome of NET patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Feijtel¹,

Doeswijk²,

Verkaik³

et al. 2021

Theranostics

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“…Overall, 21 (77.8%) of the 27 men and 9 (52.9%) of the 17 women died, which means that nearly one third of the treated patients were still alive more than 12 y after initial diagnosis of inoperable metastatic disease. Different studies report median overall survival ranging from 22 to 71 mo (4,(16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Twelve-Year Follow-up After Peptide Receptor Radionuclide Therapy

et al. 2018

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Peptide receptor radionuclide therapy (PRRT) has been used for more than twenty years as a systemic treatment approach in inoperable or metastatic somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to analyze the long-term outcome of PRRT with regard to the most commonly used radiopharmaceuticals, Y-DOTA-Tyr3-octreotide (Y-DOTA-TOC) and Lu-DOTA-Tyr3-octreotate (Lu-DOTA-TATE). This retrospective clinical study included a total of 44 consecutive patients (27 men) with advanced tumors and enhanced SSTR expression. Mean age at initial diagnosis was 60 years (SD 11.3, range 40 to 84 years). Median follow-up was 80 months. In the mean 5.3 ± 2.5 cycles were administered forLu-PRRT with mean activity of 27.2 ± 14.9 GBq per patient and 5.5 ± 2.6 cycles for Y-PRRT with mean activity of 14.7 ± 7.3 GBq. Overall, 378 cycles were administered (mean 8.6 ± 3.4 cycles per patient) with an overall cumulative activity of 1514.1 GBq. Median overall survival (OS) was 79 months. Twenty-one (77.8%) of the 27 men and nine (52.9%) of the 17 women had died 12 years after commencement of PRRT. Shortest duration of illness was eight months, longest 155 months. Severe side-effects (WHO Grades III and IV) are seen in nine of the 14 patients still alive. Chronic kidney disease in combination with anemia is the most common finding in the nine patients with severe side-effects. Very poor prognosis was found for those patients who showed progressive disease (PD) in comparison with patients with cumulative disease control after initial PRRT (log-rank, p<0.001), while women and patients with no more than two tumor sites seem to especially benefit from PRRT not reaching significance levels. PRRT is very encouraging in terms of long-term outcome. Thirty-two percent (14/44 patients) of the patients with metastatic or inoperable disease are still alive more than 12 years after the beginning of radionuclide therapy. Possible predictors for favourable outcome are initial response to PRRT, number of affected sites and female gender.

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“…Current evidence indicates that the kidneys can tolerate mean absorbed doses above the general dose limit of 23 Gy and that patients can receive more than the standard of 4 fractions of 7.4 GBq (3–5). Recent studies have also reported the use of retreatment for patients with progressed disease (6,7). If higher renal mean absorbed doses are accepted, higher total activity will be administered and bone marrow toxicity might become the dose-limiting factor.…”

mentioning

confidence: 99%

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During ¹⁷⁷Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases

et al. 2019

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This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose–response relationship during treatment with 177Lu-DOTATATE in patients with and without skeletal metastases. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of 177Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time–activity concentration curve for the low-uptake compartment. This time–activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of 177Lu-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. Results: Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12–0.33, 0.15–1.44, 0.19–1.71, 0.21–1.60, and 0.18–2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (rs) were −0.49 for the planar method, −0.61 for L4-SPECT, −0.63 for V-SPECT, −0.63 for L-SPECT, and −0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (rs = −0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (rs = −0.61 to −0.74). The mean bone marrow absorbed doses were 3%–69% higher for patients with skeletal metastases than for patients without. Conclusion: The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.

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Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response

Abstract: The majority of studies on PRRT have shown that it is effective as an initial treatment. This study with long-term follow-up demonstrates that PRRT is safe and effective retreatment option in patients that have progressed following initial PRRT course.

Cited by 52 publications

References 17 publications

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Twelve-Year Follow-up After Peptide Receptor Radionuclide Therapy

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During ¹⁷⁷Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases

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Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response

Abstract: The majority of studies on PRRT have shown that it is effective as an initial treatment. This study with long-term follow-up demonstrates that PRRT is safe and effective retreatment option in patients that have progressed following initial PRRT course.

Cited by 52 publications

References 17 publications

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Twelve-Year Follow-up After Peptide Receptor Radionuclide Therapy

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases

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Bone Marrow Absorbed Doses and Correlations with Hematologic Response During ¹⁷⁷Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases