Article

Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate

February 2005
Journal of Nuclear Medicine 46 Suppl 1(1):83S-91S

February 2005
46 Suppl 1(1):83S-91S

Source
PubMed

Authors:

Roelf Valkema

Erasmus MC

Stanislas Pauwels

Université Catholique de Louvain - UCLouvain

Larry Kvols

Moffitt Cancer Center

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The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr(3)-octreotide ((90)Y-DOTATOC) or (177)Lu-DOTA(0),Tyr(3)-octreotate ((177)Lu-DOTATATE). Twenty-eight patients with metastasized neuroendocrine tumors received 1-5 cycles of (90)Y-DOTATOC, leading to renal radiation doses of 5.9-26.9 Gy per cycle and a total of 18.3-38.7 Gy. Median follow-up was 2.9 y (range, 1.5-5.4 y), with a median of 16 measurements (range, 5-53) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 3-7 cycles of (177)Lu-DOTATATE, leading to renal radiation doses of 1.8-7.8 Gy per cycle and a total of 7.3-26.7 Gy. Median follow-up was 2.4 y (range, 1.7-4.0 y), with a median of 10 (range, 6-27) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year. The median decline in CLR was 7.3% per y in patients treated with (90)Y-DOTATOC and 3.8% per y in patients treated with (177)Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT. This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.

Peptide radiopharmaceuticals for targeted diagnosis & therapy of human tumors

Chapter

Jan 2022

The overexpression of G-protein coupled receptors (GPCRs) on the cell membrane of cancer cells provides the opportunity to direct radionuclides specifically on cancer lesions by means of suitably designed peptide carriers. Depending upon the nuclear properties of the radionuclide, diagnosis or therapy—“theranostics”—may be applied in an integrated patient-adopted approach. Thus, diagnostic imaging will indicate patients eligible for radionuclide therapy that follows next and is also essential for dosimetry, therapy planning as well as for assessing therapeutic efficacy and disease progress. This integrated approach has been elegantly illustrated by the advent of theranostic somatostatin radiopeptide pairs in the management of patients with neuroendocrine tumors expressing somatostatin receptors. Likewise, radioligands have been developed for theranostics of prostate and breast cancer (overexpressing gastrin-releasing peptide receptors), medullary thyroid carcinoma (via cholecystokinin subtype 2 receptors), pancreatic cancer (via neurotensin subtype 1 receptors) and other cancer types, always aiming at personalized patient treatments. Recent breakthroughs in the development of peptide radiopharmaceuticals include for example a shift from receptor-agonist to receptor-antagonist radioligands. Antagonists are by definition less prone than agonists to elicit adverse reactions after intravenous injection in human given that they do not activate their cognate receptor after binding. Unexpectedly, radioantagonists have exhibited higher tumor targeting and superior pharmacokinetics in animal models and in human compared with radioagonists. Further approaches recently reported to enhance tumor targeting have to do with either the administration of peptidase inhibitors, improving in vivo stability and hence maximizing the supply of intact radiopeptides to tumor sites, or with the application of other biochemical tools, triggering upregulation of receptor-target expression on cancer cells. Multi-functional or multi-targeting peptides have been dynamically entering the field of cancer diagnosis, whereas adjuvant therapeutic schemes comprising GPCR-targeted radionuclide therapy have been showing convincing improvement of therapeutic indexes compared with monotherapies. In the chapter that follows, the aforementioned advances, the present status and future perspectives in the field of peptide radiopharmaceuticals are briefly reviewed and commented.

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies

Article

Full-text available

Feb 2022

Simple Summary Tumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper. Abstract Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.

Dosing Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity

Article

Full-text available

Dec 2021
EUR J NUCL MED MOL I

Purpose The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of ²²⁵Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. Methods ²²⁵Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up ⁶⁸Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). Results Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq ²²⁵Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous β-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with β-therapy studies. Conclusion Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60–80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of ²²⁵Ac-DOTATOC.

Radiological and Clinical Efficacy of Intra-Arterial 90Y-DOTATATE in Patients with Unresectable, Progressive, Liver Dominant Neuroendocrine Neoplasms

Article

Full-text available

Apr 2021

This study was performed to determine if intra-arterial (i.a.) administration of 90Y DOTATATE can provide an effective and safe alternative to the accepted standard for i.v. of peptide receptor radionuclide therapy (PRRT) in liver-dominant metastases of gastrointestinal pancreatic neuroendocrine neoplasm (GEP-NEN). A single site, prospective, preliminary case series study included 39 patients with histologically proven liver-dominant NEN. PRRT in the form of 1.15GBq 90Y DOTATATE was given selectively into the liver via radiological catheterization of the hepatic artery, up to four times. The endpoint was radiological response (RECIST). Secondary endpoints assessed clinical well-being post-treatment, progression-free survival (PFS), overall survival (OS), and toxicity. Partial response (PR) was noted in 13% of subjects six weeks post-therapy, increasing to 24% at six months and dropping to 13% at 36 months. Disease progression (DP) was not seen at six weeks, was 5% at six months, and 47% at 36 months. Clinical response based on PS seen in 74% of patients at six weeks, 69% at six months, and 39% at 36 months had PFS and OS, respectively, of 22.7 months and 38.2 months. There was no difference in OS/PFS between those with RECIST PR and SD. One patient had significant toxicity (3%). Use of i.a. PRRT appears to be safe and effective in treating patients with liver-dominant NEN. In addition, the best OS (51 vs. 22 months) was seen when i.a. was used as an upfront treatment of bulky GEP-NEN liver metastases and not after i.v. 90Y DOTATATE. The use of i.a. 90Y DOTATATE PRRT appears to be safe and effective in treating patients with liver-dominant NEN.

Advances in Radioligand Theranostics in Oncology

Article

Mar 2024
MOL DIAGN THER

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors

Article

Full-text available

Nov 2023
EUR J NUCL MED MOL I

Purpose The lead-203 (²⁰³Pb)/lead-212 (²¹²Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that ²¹²Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr³-octreotide (TOC)-based radiopharmaceuticals. Methods New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of ²⁰³Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the ²⁰³Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in ²¹²Pb therapy studies. Results The lead radiopeptide drug conjugate (RPDC) — [²⁰³Pb]Pb-PSC-PEG2-TOC — significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [²⁰³Pb]Pb-DOTA⁰-Tyr³-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [²¹²Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [²¹²Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. Conclusion Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic

Article

Full-text available

Mar 2023

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177 Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroen-docrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225 Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225 Ac, its physical and radiochemical properties, as well as the place of 225 Ac-DOTATOC and 225 Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

ACR-ACNM-ASTRO-SNMMI Practice Parameter for Lutetium-177 (Lu-177) DOTATATE Therapy

Article

Full-text available

Jun 2022
CLIN NUCL MED

Objectives: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients. Methods: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging. Results: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients. Conclusions: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE.

ACR-ACNM-ASTRO-SNMMI Practice Parameter for Lutetium-177 (Lu-177) DOTATATE Therapy

Article

Full-text available

May 2022
AM J CLIN ONCOL-CANC

Safety of peptide receptor radionuclide therapy with 177 Lutetium DOTATATE in neuroendocrine tumour patients with chronic kidney disease

Article

Feb 2022

Purpose: To assess efficacy and safety of 177Lu-DOTATATE in patients with neuroendocrine tumours (NETs) with reduced renal function i.e., eGFR below 60 ml/min/1.73 m2. Methods: A single-centre retrospective analysis was performed in 33 patients with eGFR less than 60 ml/min/1.73 m2. Of these 33 patients, 26 patients had chronic kidney disease (CKD) stage 3a (eGFR between 45-60 ml/min/1.73 m2) and 7 patients had CKD stage 3b (eGFR between 30-45 ml/min/1.73 m2). Renal toxicity and temporal changes in eGFR were recorded. Association of potential risk factors and any kidney function deterioration (>10% reduction of eGFR) was evaluated. Survival, radiological response assessment and quality of life data was collected. Results: The incidence of permanent grade 3/4 nephrotoxicity was 3% (single patient with grade 4 nephrotoxicity). The mean annual reduction of eGFR estimated at 2.5%. Permanent decline of >10% eGFR of any grade was recorded in 45% of patients (n = 15). Nine patients moved into higher CKD categories (eight patients who moved from CKD 3a to CKD 3b and one patient who moved from CKD3b to CKD 5). No significant relationship was found between renal risk factors and permanent reduction of renal function. Grade 3/4 bone marrow toxicity was observed in 9% of patients. The estimated median progression-free survival (PFS) was 42 months and median overall survival (OS) was 47 months. At the end of the treatment, the radiological assessment showed partial response in 33%, stable disease in 55%, and progressive disease in 12%. There was an improvement in global quality of life and endocrine score (EORTC QLQ-GI-NET21) (p value: 0.046 and 0.041 respectively). Conclusion: 177Lu-DOTATATE appears to be generally well-tolerated in patients with pre-existing CKD stage 3 with a low incidence of permanent major nephrotoxicity. 177Lu-DOTATATE appears to have a good therapeutic effect; with most patients reporting improvement in quality of life.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs

Article

Full-text available

Jan 2022
thno

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a "theranostic pair" imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.

The Dependence of Renal 68Ga[Ga]-DOTATOC Uptake on Kidney Function and Its Relevance for Peptide Receptor Radionuclide Therapy with 177Lu[Lu]-DOTATOC

Article

Full-text available

Jul 2021

Background: In addition to its SSTR-specific binding in tumors and healthy tissues, DOTATOC analogues accumulate in kidney parenchyma. Renal tracer uptake might be a surrogate of kidney function or dysfunction. This study aimed to evaluate if kidney function can be estimated from 68Ga[Ga]-DOTATOC uptake in PET/CT and its impact on the nephrotoxicity of 177Lu[Lu]-DOTATOC PRRT. Methods: Two cohorts of patients (A: 128 diagnostic patients; B: 32 PRRT patients) were evaluated retrospectively. SUV values of the kidneys, physiologically SSTR-expressing organs and in background compartments were assessed. Kidney function was calculated as eGFR by CKD-EPI creatinine equation. Pearson's correlation coefficients and treatment-induced changes of uptake and kidney function were assessed and compared. Results: Kidney function and renal DOTATOC uptake showed a significant inverse correlation (R2 = 0.037; p = 0.029). Evaluated models of PET/CT measurements were not able to predict kidney function sufficiently. The uptake of other organs did not depend on eGFR. While the renal uptake increased after PRRT (p < 0.001), the kidney function did not change significantly (p = 0.382). Neither low pre-therapeutic eGFR nor high pre-therapeutic kidney uptake were risk factors of PRRT-induced deterioration in kidney function. Conclusion: The relevance of kidney function for renal 68Ga[Ga]-DOTATOC uptake is limited. The nephrotoxicity of 177Lu[Lu]-DOTATOC PRRT might be low and cannot be reliably predicted by pre-therapeutic measurements.

The state of PRRT and its sequencing amongst current therapeutic options for gastroenteropancreatic neuroendocrine tumors

Article

Mar 2021
NEUROENDOCRINOLOGY

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs, however, this may change with emerging data to suggest PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogues, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Optimization of the number of post-therapeutic planar imaging time points for the most reliable organ and tumour dosimetry in peptide receptor radionuclide therapy

Article

May 2024

177Lu-DOTATATE therapy is an effective treatment strategy for the treatment of neuroendocrine tumours. However, it could cause severe side effects in major critical organs. Therefore, individual dosimetry is essential for the safety and treatment of patients. Multiple imaging time points (4–6 time points) post administration of radioactivity can be used to obtain the best fit for dosimetric calculations, however, this is a tedious and time-consuming process. In this study, we aimed to reduce the number of imaging time points to three and optimized them for less cumbersome organ dosimetry. In this retrospective study, the images from 40 patients with neuroendocrine tumors were analysed. Sequential planar whole-body scans were acquired at five time points (0.5, 4, 24, 72/96 and 160 h) post administration of 177Lu-DOTATATE, which was considered the standard data set for dosimetry. Subsequently, seven subsets of three different time points (T1-0.5,4,24 h; T2-4,24,72/96 h; T3-0.5,4,160 h; T4-4,24,160 h; T5- 24,72/96,160 h; T6- 4,72/96,160 h; T7-0.5,4,72/96 h) were generated using standard data set. For each of these, normalized cumulative activity (NCA) and absorbed dose (AD) for kidneys, liver, spleen, lung, and tumours were estimated using Dosimetry Toolkit (GE Healthcare, Chicago, IL) and OLINDA EXM v.2 software respectively. The best three correlation coefficients of AD (mGy/MBq) of the standard data set with subsets were 0.74 (T2), 0.71(T6), 0.94 (T7) respectively for kidneys; 0.80(T3), 0.64(T6), 0.77(T7) respectively for spleen; 0.99(T3), 0.98(T6), 0.99(T7) respectively for liver; 0.63(T3), 0.62(T4), 0.75(T7) for lung and 0.92(T3), 0.90(T6), 0.96(T7) for tumours respectively. It was demonstrated that organ dosimetry with three-time point imaging can be as accurate as standard imaging when the imaging three time points are chosen optimally. The imaging subset of T7 (0.5, 4 and 72/96 h) produced the best results for organs and tumour lesions compared to other subsets.

Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000–2020

Article

Full-text available

Mar 2024

Simple Summary Pancreatic neuroendocrine tumors are a rare and heterogenous group of neoplasms. Surgical resection is the only curative option. However, there has been an increase in palliative medical options. The aim of this retrospective study was to investigate responses for the most commonly used medical treatments in 192 patients. The current results support the effectiveness of somatostatin analogues in low-grade tumors and showed that it might also be used in patients with Ki-67 ≥ 10%. Treatment with streptozocin and 5-floururacil as first-line treatment showed good efficacy for G2 disease. Due to good efficacy and generally good tolerability PRRT might be considered as first-line treatment for NET G2. The results confirmed poor prognosis in high-grade tumors treated with carboplatin/etoposide or temozolomide. The current results provide valuable knowledge as current treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Abstract Background: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Aim: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Methods: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Results: Median OS was 36 (95% CI: 26–46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9–9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1–7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). Conclusion: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

Long-term Nephrotoxicity after PRRT: Myth or Reality

Article

Full-text available

Jan 2024
thno

Rationale: The kidneys are commonly considered as the potential dose-limiting organ for peptide receptor radionuclide therapy (PRRT), making the risk of nephrotoxicity a primary concern. This retrospective analysis with prospective documentation and long-term follow-up aims to assess the risk of nephrotoxicity after PRRT in a large cohort of patients with neuroendocrine neoplasms (NENs) treated at our institution over the past 18 years. Methods: A total of 1361 NEN patients treated with 1-10 cycles of ¹⁷⁷Lu-DOTA-TOC/-NOC/-TATE, ⁹⁰Y-DOTA-TOC/-NOC/-TATE, DUO-PRRT (sequential administration of ⁹⁰Y- and ¹⁷⁷Lu-), or TANDEM-PRRT (combination of ⁹⁰Y- and ¹⁷⁷Lu- on the same day concomitantly) were included in this analysis. All parameters were prospectively documented in a structured database comprising over 250 items per patient and retrospectively analyzed. Kidney function, including serum creatinine, blood urea nitrogen, cGFR, and electrolytes, was evaluated before each PRRT cycle and during follow-up. Restaging was regularly performed at 6-month intervals until death. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0). Results: Between 2000 and 2018, a total of 5409 cycles of PRRT were administered to 1361 NEN patients. Follow-up after complete treatment was available for 1281 patients receiving 4709 cycles of PRRT, with a median follow-up time of 69.2 months (interquartile range, 32.8-110.5 months) and a maximum follow-up time of 175 months. Baseline creatinine levels were normal in 1039/1281 (81.1%) subjects, while grade 1 (G1) renal insufficiency was present in 221/1281 (17.3%) prior to PRRT. G2 was present in 19/1281 (1.5%), and G3 in 2/1281 (0.2%). After treatment, the proportion of G3/G4 grade patients only increased from 0.2% to 0.7%. Mean creatinine levels increased from a baseline of 0.90 ± 0.30 to 1.01 ± 0.57 mg/L (80.0 ± 26.7 to 89.4 ± 50.8 μmol/L) after treatment. In our main analysis cohort of 1244 patients (4576 cycles), 200 patients experienced an increase in CTCAE creatinine grade. Age, number of treatment cycles, type of radionuclides, and length of follow-up time were the main factors affecting CTCAE creatinine grading after treatment. When comparing the subgroups treated with different radionuclides, the risk of nephrotoxicity after ⁹⁰Y treatment alone and the ⁹⁰Y/¹⁷⁷Lu combination group was higher than after ¹⁷⁷Lu treatment alone. In the ⁹⁰Y treatment subgroup, the two significant risk factors for an increased CTCAE creatinine grade were identified to be age (≥60) and a long follow-up time. Conclusions: This retrospective analysis with prospective documentation in a large cohort of 1281 NEN patients receiving 4709 cycles of PRRT co-administered with renal protection, treated through the individualized approach at a single institution over 18 years, did not reveal any evidence of long-term PRRT-related renal toxicity. The results of our study suggest that with the use of proper renal protection, nephrotoxicity due to PRRT is more likely a myth than a reality.

Comparison of MIRDcalc and OLINDA EXM 2.0 organ-absorbed dose results for radionuclide therapy patientsComparison of MIRDcalc and OLINDA EXM 2.0 organ-absorbed dose results for radionuclide therapy patients

Conference Paper

Jan 2022

Long-Term Nephrotoxicity of 177 Lu-PSMA Radioligand Therapy

Article

Oct 2023

β-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Dosimetry in Lu-177-DOTATATE peptide receptor radionuclide therapy: a systematic review

Article

Sep 2023

Purpose: 177Lu- labelled somatostatin analog DOTATATE is an excellent vector for systemic radiation therapy in NETs. However, this treatment can affect organ functions or impact the quality of life of the patient, due to collateral irradiation of normal body organs. Here we conducted a comprehensive systematic review on organ and tumour dosimetry in 177Lu-DOTATATE therapy. Design: In this review, published peer-reviewed articles on organ dosimetry in patients following PRRT using 177Lu-DOTATATE have been included. All the articles were screened for inclusion based on the title and abstract of the study. PubMed, Publons and DOAJ were used as search engines to conduct a systematic search in the database. Articles were categorized into three groups: (1) Clinical studies describing the technical parameter and method of dosimetry in 177Lu-DOTATATE therapy or (2) Organ dosimetry in 177Lu-DOTATATE treatment or (3) Tumour dosimetry in 177Lu- DOTATATE treatment. Result: In total, 694 studies were retrieved from database searching on NET and PRRT and 43 original articles on 177Lu-DOTATATE dosimetry were included in this review. The median absorbed dose per unit of administered activity for kidneys, spleen, liver, bone marrow and tumour were 0.64 (0.47–0.90 Gy/GBq), 1.23 (0.53–1.59 Gy/GBq), 0.54 (0.23–0.62 Gy/GBq), 0.04 (0.02–0.06 Gy/GBq) and 4.6 (3.09–9.47 Gy/GBq), respectively. Conclusion: According to the present dosimetric review, 177Lu-DOTATATE PRRT appears to be a safe and reliable treatment option for advanced GEP-NETs. From the dosimetric point of view, kidneys are theoretically the major organs at risk in 177Lu-DOTATATE treatment. The optimization of the number of treatment cycles beyond the prescribed limit of four and the maximum administered activity in each cycle must be determined by individual patient dosimetry in order to reduce the risk of organ toxicities whilst maximizing therapeutic efficacy.

Evaluation of Using Small Volume of Interest Regions for Clinical Kidney Dosimetry in 177Lu-DOTATATE Treatments

Preprint

Full-text available

May 2023

Introduction: A small volume of interest (SV) method has been proposed and used to obtain time-effective kidney dosimetry protocols for ¹⁷⁷Lu-DOTATATE treatments. However, SV methods show only modest precision and accuracy compared to the whole-kidney parenchyma (WKP) segmentation approach. Here we aim to evaluate the influence of patient-specific partial volume effect corrections on kidney dosimetry calculations based on the WKP method, to perform a comparative analysis between the WKP and SV methods, and to determine how the use of multiple SVs affected the accuracy of clinical kidney dosimetry. Methods: We obtained SPECT/CT of 18 patients at 24, 48, and 168 hours after injection of ¹⁷⁷Lu-DOTATATE (7.3–7.8 GBq). The SPECTs were corrected for attenuation, scatter, and collimator detector response with Monte Carlo-based OSEM reconstruction (ASCC-SPECT) and post-filtered with a 0- to 12-mm Gaussian filter, or were only attenuation corrected with a Hann post-filter (AC-SPECT) as described in the first application of the SV method. Kidney dosimetry based on the manually segmented WKP was used as the golden standard. Recovery coefficients (RCs) for each WKP were determined by Monte Carlo simulations, and RCs for SVs were determined relative to the WKP method. Kidney absorbed doses were estimated based on measured activity concentrations fitted using the mono-exponential function. Uncertainties were measured for kidney dosimetry calculated based on the SV method with 1–5 VOIs with sizes of 4 mL (SV4), 2 mL (SV2), and 0.6 mL (SV0.6). Results: The mean RCs of the WKP volumes (31–243 mL) in non-filtered ASCC-SPECT and AC-SPECT were 0.85 (0.73–0.90) and 0.62 (0.46–0.51), respectively. The uncertainty in the kidney dosimetry calculation based on one SV4 on each SPECT data-point was 10.4%, and decreased as the number of VOIs was increased from 1 to 5. With the SV2 method, using a mean of 5 VOIs per kidney parenchyma, the uncertainty decreased to 6.3%. The uncertainty of the WKP method was 5.5%. Conclusion: Kidney dosimetry based on RC-corrected multiple SVs located on representative uptake regions in the kidney parenchyma is a fast approach that can provide satisfactory accuracy as compared to a single SV method.

Safety and Therapeutic Optimization of Lutetium-177 Based Radiopharmaceuticals

Article

Full-text available

Apr 2023

Peptide receptor radionuclide therapy (PRRT) using Lutetium-177 (177Lu) based radiopharmaceuticals has emerged as a therapeutic area in the field of nuclear medicine and oncology, allowing for personalized medicine. Since the first market authorization in 2018 of [¹⁷⁷Lu]Lu-DOTATATE (Lutathera®) targeting somatostatin receptor type 2 in the treatment of gastroenteropancreatic neuroendocrine tumors, intensive research has led to transfer innovative 177Lu containing pharmaceuticals to the clinic. Recently, a second market authorization in the field was obtained for [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto®) in the treatment of prostate cancer. The efficacy of 177Lu radiopharmaceuticals are now quite well-reported and data on the safety and management of patients are needed. This review will focus on several clinically tested and reported tailored approaches to enhance the risk–benefit trade-off of radioligand therapy. The aim is to help clinicians and nuclear medicine staff set up safe and optimized procedures using the approved 177Lu based radiopharmaceuticals.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based Lu-DOTATATE treatment of NET patients

Article

Full-text available

Sep 2022
EUR J NUCL MED MOL I

Purpose Radionuclide therapy with ¹⁷⁷Lu-DOTATATE is well established for patients with advanced somatostatin receptor–positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized ¹⁷⁷Lu-DOTATATE for which the number of cycles varied based on renal dosimetry. Methods Patients were eligible if they had a progressive, somatostatin receptor–positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of ¹⁷⁷Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0). Results Ninety-six patients who had received a median of 5 cycles (range 1–9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1–2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3–4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3–4 renal toxicity. Conclusion Individualized treatment with ¹⁷⁷Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials. Trial registration EudraCT 2011–000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078

Early Complications of Radioisotope Therapy with Lutetium-177 and Yttrium-90 in Patients with Neuroendocrine Neoplasms—A Preliminary Study

Article

Full-text available

Feb 2022

Neuroendocrine neoplasms (NENs) constitute a heterogenous group of tumors originating from neuroendocrine cells scattered throughout the body. Peptide Receptor Radionuclide Therapy (PRRT) is a treatment of choice of unresectable metastasized progressive and well-differentiated NENs. The aim of the study was to assess early bone marrow and kidney injury after administration of Lutetium-177 or Lutetium-177 combined with Yttrium-90. Thirty-one patients received treatment with [177Lu]Lu-DOTATATE with the activity of 7.4 GBq. Eleven patients received tandem treatment with [90Y]Y-DOTATATE with the activity of 1.85 GBq + [177Lu]Lu-DOTATATE with the activity of 1.85 GBq. After PRRT a significant decrease in leukocyte, neutrophil, and lymphocyte counts was noted. Tandem treatment demonstrated a more marked decrease in white blood cell count compared to Lutetium-177 therapy only. Conversely, no significant influence on glomerular filtration was found in this assessment. However, PRRT triggered acute renal tubule dysfunction, regardless of the treatment type. Regarding the acute complications, PRRT appeared to be a safe modality in the treatment of patients with NEN.

Treatment of Neuroendocrine Neoplasms with Radiolabeled Peptides—Where Are We Now

Article

Full-text available

Feb 2022

Simple Summary Neuroendocrine neoplasms (NENs) are a rare and diverse group of malignancies which are rising in incidence. Several treatments have been devised for unresectable or metastatic tumors, including peptide receptor radionuclide therapy (PRRT). PRRT specifically targets cells that express high levels of somatostatin receptors, such as well-or moderately differentiated NENs, to enable precise delivery. This article highlights the journey of PRRT from inception to the present day, where it is now integral in clinical practice guidelines worldwide. It also provides an overview of NENs and a history of somatostatin receptor imaging, which facilitates the selection of patients for PRRT. Practical considerations relating to appropriate use, treatment administration and side-effects are discussed, and perspectives on future directions to boost efficacy are detailed. Abstract Peptide receptor radionuclide therapy (PRRT) has been one of the most successful and exciting examples of theranostics in nuclear medicine in recent decades and is now firmly embedded in many treatment algorithms for unresectable or metastatic neuroendocrine neoplasms (NENs) worldwide. It is widely considered to be an effective treatment for well- or moderately differentiated neoplasms, which express high levels of somatostatin receptors that can be selectively targeted. This review article outlines the scientific basis of PRRT in treatment of NENs and describes its discovery dating back to the early 1990s. Early treatments utilizing Indium-111, a γ-emitter, showed promise in reduction in tumor size and improvement in biochemistry, but were also met with high radiation doses and myelotoxic and nephrotoxic effects. Subsequently, stable conjugation of DOTA-peptides with β-emitting radionuclides, such as Yttrium-90 and Lutetium-177, served as a breakthrough for PRRT and studies highlighted their potential in eliciting progression-free survival and quality of life benefits. This article will also elaborate on the key trials which paved the way for its approval and will discuss therapeutic considerations, such as patient selection and administration technique, to optimize its use.

Nephrotoxicity after radionuclide therapies

Article

Jan 2022

Radioligand therapies have opened new treatment avenues for cancer patients. They offer precise tumor targeting with a favorable efficacy-to-toxicity profile. Specifically, the kidneys, once regarded as the critical organ for radiation toxicity, also show excellent tolerance to radiation doses as high as 50–60 Gy in selected cases. However, the number of nephrons that form the structural and functional units of the kidney is determined before birth and is fixed. Thus, loss of nephrons secondary to any injury may lead to an irreversible decline in renal function over time. Our primary understanding of radiation-induced nephropathy is derived from the effects of external beam radiation on the renal tissue. With the growing adoption of radionuclide therapies, considerable evidence has been gained with regard to the occurrence of renal toxicity and its associated risk factors. In this review, we discuss the radionuclide therapies associated with the risk of nephrotoxicity, the present understanding of the factors and mechanisms that contribute to renal injury, and the current and potential methods for preventing, identifying, and managing nephrotoxicity, specifically acute onset nephropathies.

Value of Peptide Receptor Radionuclide Therapy as Neoadjuvant Treatment in the Management of Primary Inoperable Neuroendocrine Tumors

Article

Full-text available

Nov 2021

Introduction Neuroendocrine neoplasms including neuroendocrine tumors (NETs) are often diagnosed as primary disseminated or inoperable. In those cases, systemic extensive therapy is necessary, but radical treatment is unlikely. As described in the literature, in some selected cases, peptide receptor radionuclide therapy (PRRT) may be used as a first-line/neoadjuvant therapy that allows further successful surgery. Such treatment may enable a reduction of total tumor burden or allow a radical treatment which improves the final outcomes. Aim This study aims to assess whether neoadjuvant PRRT could be a treatment option for patients with initially unresectable NETs. Methods Among the group of 114 patients treated with PRRT between the years 2005 and 2020, in 32 cases, it was the first-line therapy, mainly due to massive disease burden at the time of diagnosis. Among them, nine patients received PRRT as the first-line treatment due to the primary inoperable tumors with the intention of preoperative reduction of the tumor size in order to allow for a surgical treatment. Results Neoadjuvant PRRT enabled surgery in four out of nine (45%) patients. Finally, in two out of four cases, the goal (radical surgery) has been achieved. Conclusion PRRT may be considered not only as a palliative but also as a neoadjuvant therapy in advanced, somatostatin-positive NETs that were initially inoperable.

Prophylactic Peripheral Blood Stem Cell Collection in Patients with Extensive Bone-Marrow Infiltration of Neuroendocrine Tumours Prior to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE

Article

Full-text available

Oct 2021

Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.

Review 90 Y/ 177 Lu-DOTATOC: From Preclinical Studies to Application in Humans

Article

Full-text available

Sep 2021

The PRRT (Peptide Receptor Radionuclide Therapy) is a promising modality treatment for patients with inoperable or metastatic neuroendocrine tumors (NETs). Progression-free survival (PFS) and overall survival (OS) of these patients are favorably comparable with standard therapies. The protagonist in this type of therapy is a somatostatin-modified peptide fragment ([Tyr3] octreotide), equipped with a specific chelating system (DOTA) capable of creating a stable bond with β-emitting radionuclides, such as yttrium-90 and lutetium-177. In this review, covering twenty five years of literature, we describe the characteristics and performances of the two most used therapeutic radiopharmaceuticals for the NETs radio-treatment: [ 90 Y]Y-DOTATOC and [ 177 Lu]Lu-DOTATOC taking this opportunity to retrace the most significant results that have determined their success, promoting them from preclinical studies to application in humans.

Efficacy and safety of peptide receptor radionuclide therapy in advanced radioiodine-refractory differentiated thyroid cancer and metastatic medullary thyroid cancer: a systematic review

Article

Full-text available

May 2021
BMC CANCER

Background It has been shown that a subgroup of patients with differentiated thyroid cancer (DTC) and medullary thyroid carcinoma (MTC) would progress to advanced stages of thyroid cancer. Therefore, the present study was done to systematically review available evidence in order to investigate efficacy and safety of peptide receptor radionuclide therapy (PRRT) in the patients with advanced radioiodine refractory differentiated thyroid cancer (RR-DTC) and metastatic MTC. Methods For this purpose, relevant studies investigated safety and efficacy of PRRT in the patients with advanced RR-DTC and metastatic MTC were identified by searching Medline (Pubmed, Ovid, and Ebsco), Scopus, Embase, Web of Science, and Cochrane Library databases (from database inception to March 24, 2021). The review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Searching was done independently by two investigators. Two researchers independently extracted the data and any disagreement was adjudicated by consensus. Quality of the studies was assessed using the tool of case reports/series in systematic reviews. Results 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. Conclusion Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events. Trial registration PROSPERO registration number: CRD42019125245.

Activity quantification and dosimetry in radiopharmaceutical therapy with reference to 177Lutetium

Article

Full-text available

Mar 2024

Radiopharmaceutical therapy has been widely adopted owing primarily to the development of novel radiopharmaceuticals. To fully utilize the potential of these RPTs in the era of precision medicine, therapy must be optimized to the patient's tumor characteristics. The vastly disparate dosimetry methodologies need to be harmonized as the first step towards this. Multiple factors play a crucial role in the shift from empirical activity administration to patient-specific dosimetry-based administrations from RPT. Factors such as variable responses seen in patients with presumably similar clinical characteristics underscore the need to standardize and validate dosimetry calculations. These efforts combined with ongoing initiatives to streamline the dosimetry process facilitate the implementation of radiomolecular precision oncology. However, various challenges hinder the widespread adoption of personalized dosimetry-based activity administration, particularly when compared to the more convenient and resource-efficient approach of empiric activity administration. This review outlines the fundamental principles, procedures, and methodologies related to image activity quantification and dosimetry with a specific focus on ¹⁷⁷ Lutetium-based radiopharmaceuticals.

Safety and efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors: A single center experience

Article

Full-text available

May 2024
PLOS ONE

Peptide receptor radionucleotide therapy (PRRT) with ¹⁷⁷Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with ¹⁷⁷Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. ¹⁷⁷Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3–20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.

Terbium “Sisters”: More Than just a “Swiss Army Knife”

Chapter

Full-text available

Jan 2024

The concept of radiotheragnotics is employed at many nuclear medicine entities worldwide, where ⁶⁸ Ga and ¹⁷⁷ Lu are the most commonly used radiometals for PET imaging and radionuclide therapy, respectively. The application of radionuclides of the same element (i.e., radioisotopes) would enable the preparation of chemically identical radiopharmaceuticals for both imaging and therapy. At the Paul Scherrer Institute, the realization of this concept has been a major research focus over the last decade. Among several interesting metals, terbium is of particular relevance. It comprises four radioisotopes suitable for nuclear medicine purposes, including imaging using single photon emission computed tomography (SPECT; terbium-155) and positron emission tomography (PET; terbium-152), respectively, as well as targeted radionuclide therapy using α-particles (terbium-149) and β¯-particles (terbium-161). This chapter presents the birth of the terbium “sisters” at PSI and briefly summarizes the most important achievements obtained with each of the four sisters. Future perspectives and challenges with regard to clinical translation of the “terbium sister concept” are presented and discussed.

978-3-030-97220-2

Chapter

Full-text available

Jul 2023

Nuriye Ozlem Kucuk

Peptide Receptor Radionuclide Therapy

Article

Full-text available

Oct 2022

The concept of using a targeting molecule labeled with a diagnostic radionuclide for using PET or SPECT imaging with the potential to demonstrate that tumoricidal radiation can be delivered to tumoral sites by administration of the same or a similar targeting molecule labeled with a therapeutic radionuclide is named “theranostics”. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (SSAs) is a well-established second/third-line theranostic treatment for somatostatin receptor-positive well-differentiated (neuro-)endocrine neoplasms (NENs). PRRT with 177Lu-DOTATATE was approved by the regulatory authorities in 2017 & 2018 for selected patients with low-grade well-differentiated gastroenteropancreatic (GEP) NENs. It improves progression-free survival as well as quality of life of GEP NEN patients. Favorable symptomatic and biochemical responses using PRRT with 177Lu-DOTATATE have also been reported in patients with functioning metastatic GEP NENs like metastatic insulinomas, VIPomas, glucagonomas, gastrinomas and patients with carcinoid syndrome. This therapy might also become a valuable therapeutic option for inoperable low grade bronchopulmonary (BP) NENs, inoperable, or progressive pheochromocytomas and paragangliomas and medullary thyroid carcinomas. First-line PRRT with 177Lu-DOTATATE and combinations of this therapy with cytotoxic drugs are currently under investigation. New radiolabeled somatostatin receptor ligands include SSAs coupled with alpha radiation emitting radionuclides and somatostatin receptor antagonists coupled with radionuclides.

Neuroendocrine Tumors: Therapy with Radiolabeled Peptides

Chapter

Oct 2022

Treatment of neuroendocrine tumors (NETs) is typically multidisciplinary and should be individualized according to the tumor histology, lesion extent, patient performance status, and symptoms. Surgery is the only potentially curative option. NET liver metastases are typically hypervascular, and chemoembolization or bland embolization of the hepatic artery, performed mechanically by microspheres or chemically with cytotoxic agents, can lead to significant necrosis. Medical therapy is directed at the control of symptoms and/or reducing tumor growth. Strategies range from the use of bioactive agents (somatostatin analogues or interferon) to conventional chemotherapy. PRRT uses radiolabeled somatostatin analogue peptides to treat unresectable or metastasized NETs. The therapeutic strategy of PRRT has been utilized for more than two decades and is accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP, bronchopulmonary, and other NETs. PRRT with either 90Y-DOTATOC or 177Lu-DOTATATE is generally extremely well tolerated, with modest toxicity to the target organs, such as the kidneys and bone marrow. The chapter illustrates the efficacy and safety features of these compounds.

Association between fibrosis markers and kidney function following peptide receptor radionuclide therapy in patients with neuroendocrine tumours

Article

Sep 2022

Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the 51Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman's rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61-73). Median time from last PRRT to inclusion was 8 months (IQR: 3-20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = -0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.

Radionuclide Therapy in Malignant Thyroid Diseases: Medullary Thyroid Cancer

Chapter

Aug 2022

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells that produce calcitonin (Ct). It constitutes 2–5% of all thyroid malignancies. It can be seen in sporadic form or hereditary form as a component of multiple neuroendocrine neoplasia (MEN) type 2. Its prognosis is poor compared to differentiated thyroid cancers. At the time of diagnosis, 35–50% of MTC patients are diagnosed with regional metastasis; 13–15% are diagnosed with distant metastasis to organs such as lungs, bones, and liver [1, 2]. According to SEER data, 10-year survival in gland-limited MTCs is approximately 95.6%, and overall survival in patients with regional disease is 75.5% [1]. The 10-year survival rate of those with distant metastasis at the time of diagnosis is approximately 20% [1, 2].

Radionuclide Therapy in Neuroendocrine Tumors

Chapter

Aug 2022

Neuroendocrine tumors (NET) are considered rare malignancies and their incidence is reported as 2–5/100,000 in various sources [1, 2]. In a comprehensive epidemiology study conducted by Yao et al. in 2004 by examining the US Surveillance, Epidemiology and End Results records (SEER database), the NET incidence was found to be 5.25/100,000. However, in this study, the rate of increase in the NET incidence was found to be higher than the rate of increase in general malignancy and the incidence was found to have increased from 1.9 to 5.25 out of 100,000 in the last 30 years. More importantly, its prevalence at publication date (2004) was found to be 103,312 (35/100,000) for the United States due to its relatively longer survival [3]. According to these results, the prevalence of NET, which is considered to be rare, is higher than the total prevalence of gastric and pancreatic cancers for 2004 with the effect of relatively long survival times [3]. Increased awareness of NET among clinicians is thought to have an effect on the increase in the incidence of NET overtime in addition to the recently used advanced imaging methods and diagnostic examinations [1, 4].

Side effects of radiopeptide therapy for neuroendocrine tumors

Chapter

Jan 2022

Flavio Forrer

Somatostatin receptor targeting with radiolabeled peptides for imaging and therapy of neuroendocrine tumors has gained increasing relevance over the last two decades. Imaging with radiopeptides is used for diagnosis, staging, re-staging and follow-up of these tumors. Beside this, imaging is important to select patients for radiopeptide-therapy. For therapy somatostatin analogs labeled with the β-emitters ⁹⁰Y and in particular ¹⁷⁷Lu are widely used. The most widely used compounds are ¹⁷⁷Lu-DOTATATE ([¹⁷⁷Lu-DOTA⁰,Tyr³,Thr⁸]-octreotide or [¹⁷⁷Lu-DOTA⁰,Tyr³]-octreotate) and ¹⁷⁷Lu-DOTATOC ([¹⁷⁷Lu-DOTA⁰,Tyr³]-octreotide). As the compound can be used in diagnosis (labeled with the PET-radionuclide ⁶⁸Ga) and therapy these compounds constitute ideal theranostic pairs. ¹⁷⁷Lu-DOTATATE was the first radiopeptide for therapy that received FDA-approval in January 2018. The approval was based on the NETTER-1 study which compared ¹⁷⁷Lu-DOTATATE therapy with high-dose long-acting octreotide in a prospective, randomized setting. The study showed that the median progression free survival (PFS) was 8.5 months in the high-dose long-acting octreotide arm while it was not reached in the ¹⁷⁷Lu-DOTATATE arm while side effects were tolerable and mostly mild. The most common adverse effects included lymphopenia, increased liver enzymes, nausea, hyperglycemia, and hypokalemia. With a median follow-up of 24 months, myelodysplastic syndrome was reported in 2.7% of patients receiving ¹⁷⁷Lu-DOTATATE. Kidney toxicity—a major concern in radiopeptide therapy—was not observed. All patients received amino acid solution as a renal protectant. Nowadays radiopeptide therapy with radiolabeled somatostatin analogs is an established, safe and effective treatment for metastatic well differentiated (G1 and G2) neuroendocrine tumors. The treatment is implemented in the widely accepted ENETS consensus guidelines of 2016.

Dosimetry in radionuclide therapy: the clinical role of measuring radiation dose

Article

Feb 2022
LANCET ONCOL

Radionuclide therapy is a rapidly expanding oncological treatment method. Overwhelmingly, the application of radionuclide therapy in clinical practice relies on fixed or empirical dosing strategies. In principle, the application of dosimetry promises to improve patient outcomes by tailoring administered radionuclide therapy activities to each patient's unique tumour burden and tumour uptake. However, robust prospective data are scarce due to few prospective randomised clinical trials investigating the use of dosimetry in radionuclide therapy. In this Review, we describe the role of dosimetry as it has been applied historically and in modern clinical practice and its potential future applications. We further emphasise areas of future growth and a potential pathway to optimised personalised activity modulation of radionuclide therapy

Dosimetry-Guided Radiopharmaceutical Therapy

Article

Dec 2021

SPECT/CT for Dosimetry

Chapter

Jan 2022

This chapter reviews the clinical applications of SPECT/CT in dosimetry. After introducing the benefits of SPECT/CT versus planar imaging and the challenges inherent to dosimetry assessment, dose–response and dose–toxicity studies are reviewed. Recent breakthroughs in individualized radionuclide therapy planning resulting in significant patient outcome improvements are discussed, especially in the context of international recommendations and rules, and the persistent lobbying of some nuclear medicine boards to prevent their use. New developments in Compton cameras allowing fast SPECT for alpha emitter are presented.

Accuracy of Two Dosimetry Software Programs for 177Lu Radiopharmaceutical Therapy Using Voxel-Based Patient-Specific Phantoms

Article

Jan 2021

Purpose: Virtual dosimetry using voxel-based patient-specific phantoms and Monte Carlo (MC) simulations offer the advantage of having a gold standard against which absorbed doses may be benchmarked to establish the dosimetry accuracy. Furthermore, these reference values assist in investigating the accuracy of the absorbed dose methodologies from different software programs. Therefore, this study aimed to compare the accuracy of the absorbed doses computed using LundADose and OLINDA/EXM 1.0. Methods: The accuracy was based on 177Lu-DOTATATE distributions of three voxel-based phantoms. SPECT projection images were simulated for 1, 24, 96, and 168 h post-administration and reconstructed with LundADose using 3D OS-EM reconstruction. Mono-exponential curves were fitted to the bio-kinetic data for the kidneys, liver, spleen, and tumours resulting in SPECT time-integrated activity (SPECT-TIA). The SPECT-TIA were used to compute mean absorbed doses using LundADose (LND-DSPECT) and OLINDA (OLINDA-DSPECT) for the organs. Pre-defined true activity images, were used to obtain TRUE-TIA and, together with full MC simulations, computed the true doses (MC-DTrue). The dosimetry accuracy was assessed by comparing LND-DSPECT and OLINDA-DSPECT to MC-DTrue. Results: Overall, the results presented an overestimation of the mean absorbed dose by LND-DSPECT compared to the MC-DTrue with a dosimetry accuracy ≤6.6%. This was attributed to spill-out activity from the reconstructed LND-DSPECT, resulting in a higher dose contribution than the MC-DTrue. There was a general underestimation (

Combination of terbium‑161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Article

Full-text available

Mar 2022
EUR J NUCL MED MOL I

Purpose The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the ¹⁶¹Tb- and ¹⁷⁷Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [¹⁶¹Tb]Tb-DOTA-LM3 was 102-fold more potent than [¹⁷⁷Lu]Lu-DOTA-LM3; however, ¹⁶¹Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their ¹⁷⁷Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [¹⁶¹Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [¹⁷⁷Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [¹⁶¹Tb]Tb-DOTA-LM3 may outperform the clinically employed [¹⁷⁷Lu]Lu-DOTATOC for the treatment of patients with NENs.

Systemic Radiopharmaceutical Therapy of Pheochromocytoma and Paraganglioma

Article

Sep 2021

Whereas benign pheochromocytomas and paragangliomas are often successfully cured by surgical resection, treatment of metastatic disease can be challenging in terms of both disease control and symptom control. Fortunately, several options are available, including chemotherapy, radiation therapy, and surgical debulking. Radiolabeled metaiodobenzylguanidine (MIBG) and somatostatin receptor imaging have laid the groundwork for use of these radiopharmaceuticals as theranostic agents. 131I-MIBG therapy of neuroendocrine tumors has a long history, and the recent approval of high-specific-activity 131I-MIBG for metastatic or inoperable pheochromocytoma or paraganglioma by the U.S. Food and Drug Administration has resulted in general availability of, and renewed interest in, this treatment. Although reports of peptide receptor radionuclide therapy of pheochromocytoma and paraganglioma with 90Y- or 177Lu-DOTA conjugated somatostatin analogs have appeared in the literature, the approval of 177Lu-DOTATATE in the United States and Europe, together with National Comprehensive Cancer Network guidelines suggesting its use in patients with metastatic or inoperable pheochromocytoma and paraganglioma, has resulted in renewed interest. These agents have shown evidence of efficacy as palliative treatments in patients with metastatic or inoperable pheochromocytoma or paraganglioma. In this continuing medical education article, we discuss the therapy of pheochromocytoma and paraganglioma with 131I-MIBG and 90Y- or 177Lu-DOTA-somatostatin analogs.

Renal and Red Marrow Dosimetry in Peptide Receptor Radionuclide Therapy: 20 Years of History and Ahead

Article

Full-text available

Aug 2021
INT J MOL SCI

The development of dosimetry and studies in peptide receptor radionuclide therapy (PRRT) over the past two decades are reviewed. Differences in kidney and bone marrow toxicity reported between 90Y, 177Lu and external beam radiotherapy (EBRT) are discussed with regard to the physical properties of these beta emitter radionuclides. The impact of these properties on the response to small and large tumors is also considered. Capacities of the imaging modalities to assess the dosimetry to target tissues are evaluated. Studies published in the past two years that confirm a red marrow uptake in 177Lu-DOTATATE therapy, as already observed 20 years ago in 86Y-DOTATOC PET studies, are analyzed in light of the recent developments in the transferrin transport mechanism. The review enlightens the importance (i) of using state-of-the-art imaging modalities, (ii) of individualizing the activity to be injected with regard to the huge tissue uptake variability observed between patients, (iii) of challenging the currently used but inappropriate blood-based red marrow dosimetry and (iv) of considering individual tandem therapy. Last, a smart individually optimized tandem therapy taking benefit of the bi-orthogonal toxicity-response pattern of 177Lu-DOTATATE and of 90Y-DOTATOC is proposed.

Circulating Biochemical Markers of Gastro-Entero-Pancreatic (GEP) Neuroendocrine Neoplasms (NENs)

Chapter

Full-text available

Jul 2021

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms which represent a true challenge for clinicians. Their incidence and prevalence have been increasing over the past years partly due to increased awareness and improvements in instrumental diagnostic techniques so that a growing number of clinicians are facing this disease. Management of NEN represents a clinical challenge because of its late presentation, scarcity of standardized guidelines, and limitations in imaging modalities and biomarkers to guide management. The beginning of the diagnostic process of NENs is often based on the measurement of circulating markers, before planning expensive and invasive diagnostic tests; however up to 60–80% of NENs are metastatic at diagnosis, which highlights the frequent failure to identify symptoms or to establish a biochemical diagnosis. Classical available markers, which can be divided into general and specific biomarkers, often lack sensitivity and/or specificity and need to be interpreted in the diagnostic process. Therefore, it is very important to know the advantages and limitations of these diagnostic tools. On the other hand, new biomarkers are emerging in the scenario of molecular diagnostics. This chapter aims to review the different characteristics of the available biomarkers, exposing the strengths and limitations of each, for their best clinical use.

Radioreceptor Therapy

Chapter

Jul 2021

Peptide receptor radionuclide therapy (PRRT) is an effective therapy for patients with inoperable or metastasized NETs, usually well tolerated. Acute and chronic side effects are generally mild. Combining PRRT with synergistic drugs may result in additive effects, through several mechanisms such as increased tumor perfusion, SSTR upregulation, and radiosensitization. In recent years, great interest has been shown in PRRT with alpha particle-emitting radionuclides (Bismuth-213 or Actinium-225) and in PRRT agents based on SSTR antagonists.

Complications and Side Effects on the Course of Liver Radio-Infusions with 111In-Octreotide

Chapter

May 2021

Radioactive peptide transhepatic arterial infusion is an effective tool for the treatment of small (less than 20 mm) liver neuroendocrine metastatic tumors and micro-metastases. Adequate use of this therapy requires knowledge and a multidisciplinary cooperation to obtain optimal results and avoid treatment specific complications. A great deal of research has been undertaken to understand the angiographic, technical, and safety aspects concerning liver radionuclide-infusion after selective catheterization of the hepatic artery. Peptide receptor radionuclide therapy (PRRT) is generally well tolerated. The extremely rare complications reported after PRRT with 111In-octreotide include acute gastrointestinal side effects occurring within 24 h and subacute hematological toxicity 4–8 weeks after treatment. Another extremely rare side effect reported, not for 111In but for 90Y- and 177Lu-labeled peptides, is “carcinoid crisis” during the infusion or within the first 24 h following it. Delayed side effects, e.g., renal toxicity, liver toxicity, leukemia, and myelodysplastic syndrome, occur in a tiny percentage.

Activity Concentration Estimation in Automated Kidney Segmentation Based on Convolution Neural Network Method for 177LU–SPECT/CT Kidney Dosimetry

Article

Jun 2021

For 177Lu-DOTATATE treatments, dosimetry based on manual kidney segmentation from computed tomography (CT) is accurate but time consuming and might be affected by misregistration between CT and SPECT images. This study develops a convolution neural network (CNN) for automated kidney segmentation that accurately aligns CT segmented volume of interest (VOI) to the kidneys in SPECT images. The CNN was trained with SPECT/CT images performed over the abdominal area of 137 patients treated with 177Lu-DOTATATE. Activity concentrations in automated and manual segmentations were strongly correlated for both kidneys (r > 0.96, p < 0.01) in the testing cohort (n = 20). The Bland–Altman analyses demonstrated higher accuracy for the CNN segmentation compared to the manual segmented kidneys without VOI adjustment. The CNN demonstrated a potential for accurate kidney segmentation. The CNN was a fast and robust approach for assessment of activity concentrations in SPECT images, and performed equally well as the manual segmentation method.

Cockcroft DW, Gault MHPrediction of creatine clearance from serum creatinine. Nephron 16: 31-41

Article

Full-text available

Feb 1976

A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.

Amino acid infusion blocks renal tubular uptake of an indium-labeled somatostatin analogue

Article

Full-text available

Jul 1993

The Indium-labelled somatostatin analogue pentetreotide has been successfully developed for imaging of somatostatin receptor positive tumours. However there is significant renal tubular uptake of the radiolabelled peptide, which can obscure upper abdominal tumours and would preclude its use for targeted radiotherapy. The aim of this study was to determine whether amino acid infusion, which has been shown to block renal tubular peptide reabsorption, diminishes renal parenchymal uptake of this radiolabelled analogue. Eight patients being scanned with the 111In-labelled somatostatin analogue, pentetreotide, for localisation of gastroenteropancreatic tumours received an infusion of synthetic amino acids. The ratio of isotope uptake in kidney to that in spleen was assessed, and compared to the ratio for matched control patients, to determine if amino acid infusion reduced renal parenchymal uptake of the radiopharmaceutical. The amount of isotope in the urine was determined to ensure that any effect of the amino acid infusion was unrelated to changes in clearance. Infusion of amino acids significantly reduced renal parenchymal uptake of isotope at 4 h. There was a non-significant increase in urinary clearance of isotope over the 4 h, consistent with reduced reuptake and a lack of effect on glomerular filtration rate. This technique, by preventing renal damage, may allow the use of this somatostatin analogue for local radiotherapy, and could be of wider value in blocking tubular re-uptake of potentially nephrotoxic agents, such as radiolabelled Fab fragments. Images Figure 1

Radiation nephropathy after radiotherapy in metastatic medullary thyroid carcinoma

Article

Full-text available

Jun 2001

Rationale and Objectives: Numerous experimental models are used to investigate the effectiveness of thrombectomy devices. We aimed to study the systematic effects of different in vitro thrombus models on the results of experimental thrombectomy and examined how thrombi formed in vitro and ex vivo differ. Methods: Three variables involved in human in vitro thrombogen-esis were investigated: spontaneous or thrombin-induced clotting, age (1 or 5 days old), and storage temperature (4°C or 21°C). The fibrin content of in vitro and fresh or old ex vivo thrombi was measured by histologic studies. Ten experiments were performed with each of 8 different in vitro thrombus types using (1) ultrasound thrombolysis, (2) Oasis thrombectomy, (3) Amplatz thrombectomy, and (4) Straub-Rotarex catheters. Thrombus weight was measured after standardized treatment. Results: The fibrin content was markedly lower in all in vitro than in fresh and old ex vivo thrombi. In vitro thrombus type had no impact on the effectiveness of ultrasound thrombolysis and Amplatz thrombectomy. Thrombogenesis type affected Oasis and Straub-Rotarex catheter use. Storage temperature had a systematic impact on the outcome of Oasis thrombectomies. Conclusion: The fibrin content of in vitro thrombi differs substantially from that of fresh and old ex vivo human thrombi. Experimental conditions may systematically impact experimental evaluation of thrombectomy procedures. In vitro thrombi with thrombin-induced thrombogenesis should be favored for use in thrombectomy experiments.

The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study

Article

Full-text available

Aug 2001

The aim of this phase II study was to evaluate the tumour response of neuroendocrine tumours to targeted irradiation with the radiolabelled somatostatin analogue 90Y-DOTATOC. In addition, the palliative effect of 90Y-DOTATOC treatment on the malignant carcinoid syndrome and tumour-associated pain was investigated. Forty-one patients (mean age 53 years) with neuroendocrine gastroenteropancreatic and bronchial tumours were included. Eighty-two percent of the patients had therapy resistant and progressive disease. The treatment consisted of four intravenous injections of a total of 6000 MBq/m2 90Y-DOTATOC, administered at intervals of six weeks. The overall response rate was 24%. For endocrine pancreatic tumours it was 36%. Complete remissions (CR) were found in 2% (1 of 41), partial remissions (PR) in 22% (9 of 41), minor response in 12% (5 of 41), stable disease (SD) in 49% (20 of 41) and progressive disease (PD) in 15% (6 of 41). The median follow up was 15 months (range 1 month to 36 months). The median duration of response has not been reached at 26 months. The two-year survival time was 76 +/- 16%. Eighty-three percent of the patients suffering from the malignant carcinoid syndrome achieved a significant reduction of symptoms. The treatment was well tolerated. A reduction of pain score was observed in all patients (5 of 41) with morphine dependent tumour-associated pain. Side effects included grade III (NCIGC) pancytopenia in 5%, and vomiting shortly after injection in 23%. No grade III-IV renal toxicity was observed. Targeted radiotherapy with 90Y-DOTATOC is a novel, well-tolerated treatment for neuroendocrine tumours with a remarkable objective response rate, survival time, and symptomatic response.

Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: A phase I study

Article

Full-text available

Mar 2003

The aim of this study was to determine the maximum tolerated dose of (90)Y-DOTATOC per cycle administered in association with amino acid solution as kidney protection in patients with somatostatin receptor-positive tumours. Forty patients in eight groups received two cycles of (90)Y-DOTATOC, with activity increased by 0.37 GBq per group, starting at 2.96 and terminating at 5.55 GBq. All patients received lysine +/- arginine infusion immediately before and after therapy. Forty-eight percent developed acute grade I-II gastrointestinal toxicity (nausea and vomiting) after amino acid infusion whereas no acute adverse reactions occurred after (90)Y-DOTATOC injection up to 5.55 GBq/cycle. Grade III haematological toxicity occurred in three of seven (43%) patients receiving 5.18 GBq, which was defined as the maximum tolerable activity per cycle. Objective therapeutic responses occurred. Five GBq per cycle is the recommended dosage of (90)Y-DOTATOC when amino acids are given to protect the kidneys. Although no patients developed acute kidney toxicity, delayed kidney toxicity remains a major concern, limiting the cumulative dose to ~25 Gy. The way forward with this treatment would seem to be to identify more effective renal protective agents, in order to be able to increase the cumulative injectable activity and hence tumour dose.

Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [Lu-177-DOTA(0),Tyr(3)]octreotate

Article

Full-text available

Apr 2003

Medical treatment and chemotherapy are seldom successful in achieving objective tumour reduction in patients with metastatic neuroendocrine tumours. Treatment with the radiolabelled somatostatin analogue [(90)Y-DOTA(0),Tyr(3)]octreotide may result in partial remissions in 10-25% of patients. The newer analogue [DOTA(0),Tyr(3)]octreotate (octreotate) has a ninefold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA(0),Tyr(3)]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide (177)Lu, it has proved very successful in achieving tumour regression in animal models. The effects of (177)Lu-octreotate therapy were studied in 35 patients with neuroendocrine gastro-entero-pancreatic (GEP) tumours who underwent follow-up for 3-6 months after receiving their final dose. Patients were treated with doses of 100, 150 or 200 mCi (177)Lu-octreotate, to a final cumulative dose of 600-800 mCi, with treatment intervals of 6-9 weeks. Nausea and vomiting within the first 24 h after administration were present in 30% and 14% of the administrations, respectively. WHO toxicity grade 3 anaemia, leucocytopenia and thrombocytopenia occurred after 0%, 1% and 1% of the administrations, respectively. Serum creatinine and creatinine clearance did not change significantly. The effects of the therapy on tumour size were evaluable in 34 patients. Three months after the final administration, complete remission was found in one patient (3%), partial remission in 12 (35%), stable disease in 14 (41%) and progressive disease in seven (21%), including three patients who died during the treatment period. Tumour response was positively correlated with a high uptake on the octreoscan, limited hepatic tumour mass and a high Karnofsky Performance Score. Because of the limited efficacy of alternative therapies, many physicians currently adopt an expectant attitude when dealing with patients with metastatic GEP tumours. However, in view of the high success rate of therapy with (177)Lu-octreotate and the absence of serious side-effects, we advocate its use in patients with GEP tumours without waiting for tumour progression.

Chronic renal failure

Article

Jan 2004

R.G. Luke

Is radiation nephropathy caused by yttrium-90? Reply

Article

Mar 2002

The lady who had a remote history of ovarian malignancy and developed thrombotic microangiopathy

Article

Mar 2000
NEPHROL DIAL TRANSPL

Solange Moll

[ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate: comparison with [ 111 In-DTPA 0 ]octreotide in patients

Article

Sep 2001

The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0,Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177Lu-octreotate expressed as a percentage of the injected dose was comparable with that after 111In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177Lu-octreotate, was comparable to that after 111In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.

Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide

Article

Apr 2001

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type-1 (AT1) receptor antagonist

Article

Mar 1998
RADIOTHER ONCOL

Previous studies showed that progression of established radiation nephropathy could be delayed by continuous treatment with high doses of captopril, an angiotensin-converting-enzyme (ACE) inhibitor. The current studies were designed to determine whether a lower dose or a shorter treatment with captopril would be effective and whether an angiotensin II type-1 (AT1) receptor antagonist (AII blocker) would be effective. In the captopril studies, rats were given renal irradiation at doses sufficient to produce radiation nephropathy. Six months after irradiation, animals were stratified by azotemia and assigned to no treatment, continuous high- or low-dose captopril, or 6 weeks of high-dose captopril. Captopril was given in drinking water at 62.5 mg/l (low dose) or 500 mg/l (high dose). The AII blocker study had a similar design, except that the nephropathy was the result of total body irradiation and bone marrow transplantation and the treatments were no treatment or continuous treatment with an AII blocker, L-158,809 (20 mg/l in drinking water). Animals were followed for 1 year with periodic studies of renal function. Survival and renal function were significantly enhanced by all treatments. Continuous captopril treatment was more effective than the 6-week course of treatment, but there was no difference in effectiveness between the high and low doses of captopril. In continuous therapy, captopril and the AII blocker had roughly equivalent efficacy. Both the ACE inhibitor and the AII blocker were effective treatments for established radiation nephropathy. The best results with the ACE inhibitor required continuous therapy, but could be achieved with a low dose of the drug.

Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy

Article

May 1998

Angiotensin-converting enzyme (ACE) inhibitors are effective in the prophylaxis of radiation-induced renal and lung injury. Studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than blocking AII synthesis with ACE inhibitors, would also be effective. Rats received total body irradiation (TBI) followed by bone marrow transplantation (BMT), and were randomized to: an ACE inhibitor (captopril); an AII type 1 (AT1) receptor antagonist (L-158,809); or no treatment. Drug therapy began 9 days prior to BMT and continued for the duration of the study. Analysis of renal function, histopathology and animal survival showed that the AII blocker was more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. Further studies have shown that the AII blocker is as effective as captopril in the treatment of established radiation nephropathy, and that the AII blocker is at least as effective as captopril in the prophylaxis of lung injury induced by chemo-radiation therapy. These studies indicate that blockage of the AT1 receptor by itself is sufficient for the treatment of radiation-induced renal and lung injury, hence the renin-angiotensin system is fundamentally involved in the pathogenesis of these injuries. These studies provide further evidence that there is more to late radiation injuries than delayed mitotic cell death.

Biokinetics and dosimetry in patients administered with 111In-DOTA-Tyr3-octreotide: Implications for internal radiotherapy with 90Y-DOTATOC

Article

Sep 1999
Eur J Nucl Med

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe(1)-Tyr(3)-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with (90)Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 microg), labelled with 150-185 MBq of (111)In. Blood and urine samples were collected throughout the duration of the study (0-2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3-4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ micromol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for (111)In-DOTATOC in blood was 0.9+/-0.4 h. The injected activity excreted in the urine in the first 24 h was 73%+/-11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2+/-1.8 h in spleen, 1.7+/-1.2 h in kidneys, 2.4+/-1.9 h in liver, 1.5+/-0.3 h in urinary bladder and 9. 4+/-5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03-6.50 h). Based on our findings, the predicted absorbed doses for (90)Y-DOTATOC would be 7.6+/-6.3 (spleen), 3.3+/-2.2 (kidneys), 0.7+/-0.6 (liver), 2.2+/-0.3 (bladder), 0.03+/-0.01 (red marrow) and 10.1 (range: 1.4-31.0) (tumour) mGy/MBq. These results indicate that high activities of (90)Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the desired therapeutic response desired would be obtained.

Yttrium-90 DOTATOC: first clinical results

Article

Nov 1999
Eur J Nucl Med

In a pilot study, DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), which can be labelled with the beta-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of (90)Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of (90)Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120+/-1347 MBq/m(2)) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of > or = 3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity < or = grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of < or = 7400 MBq/m(2). Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m(2) and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. (90)Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment - at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during (90)Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing.

The lady who had a remote history of ovarian malignancy and developed thrombotic microangiopathy

Article

Apr 2000

OctreoTherTM: Ongoing Early Clinical Development of a Somatostatin-Receptor-Targeted Radionuclide Antineoplastic Therapy

Article

Feb 2000

OctreoTher ((90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide, a.k.a. (90)Y-SMT 487) consists of a somatostatin peptide analogue (Tyr(3)-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle x 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using [90Y]-DOTA-D-Phe1Tyr3-octreotide: A pilot study

Article

Jul 2001
NUCL MED COMMUN

Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.

Radiation nephropathy caused by yttrium 90

Article

Oct 2001

End-stage renal disease after treatment with 90Y-DOTATOC

Article

Nov 2001
Eur J Nucl Med

DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), a newly developed somatostatin analogue which can be stably labelled with the beta-emitter yttrium-90, can be used for receptor-mediated internal radiotherapy. A 78-year-old woman suffering from a carcinoid of the small intestine with multiple metastases in the liver as well as mesenteric and supraclavicular lymph node metastases was treated with this therapy after the disease had progressed under other chemotherapy options employed years previously. The patient received four single doses of 90Y-DOTATOC at 6-week intervals, yielding a cumulative dose of 9,620 MBq (5,659 MBq/m2). Restaging revealed stable metastatic disease. Serum creatinine and urea nitrogen levels were within the normal range prior to starting and during DOTATOC therapy. However, 15 months after cessation of DOTATOC therapy, a progressive deterioration of renal function occurred, leading to end-stage renal disease. Urinalysis revealed a slight proteinuria of 700 mg/day without haematuria, leucocyturia or casts. There was no obvious risk factor for chronic renal insufficiency except DOTATOC therapy. However, it was not feasible to use kidney biopsy to prove the presence of radiation-induced nephritis. Intermittent haemodialysis was started as the creatinine clearance declined to below 10 ml/min. Diuresis was not affected. The presented case shows delayed renal insufficiency after a relatively low cumulative dose of 90Y-DOTATOC (5,659 MBq/m2). This serious adverse event indicates that further studies are needed to evaluate which dose of 90Y-DOTATOC, under which renal protection regimen, will provide optimal management, balancing risks and benefits.

Between the Scylla and Charybdis of peptide radionuclide therapy: Hitting the tumor and saving the kidney

Article

Nov 2001
Eur J Nucl Med

Is radiation nephropathy caused by yttrium-90?

Article

Apr 2002

Nephrotoxicity versus anti-tumour efficacy in radiopeptide therapy: Facts and myths about the Scylla and Charybdis [2]

Article

Mar 2002

Receptor-mediated radiotherapy with 90Y-DOTA-DPhe1-Tyr3-octreotide: The experience of the European Institute of Oncology Group

Article

May 2002
SEMIN NUCL MED

High concentrations of subtype 2 somatostatin tumor receptors (sst(2)) are expressed in numerous tumors, enabling primary and metastatic masses to be localized by scintigraphy after injecting (111)In-labeled somatostatin analogue octreotide. In addition to neuroendocrine tumors, somatostatin receptors have been identified on cancers of the central nervous system, breast, lung, and lymphatic tissue, and the use of radionuclide-labeled somatostatin analogues appeared promising for therapy as well as for diagnosis of such malignancies. The somatostatin analogue [DOTA-(D)Phe(1)-Tyr(3)] octreotide (DOTATOC) possesses favorable characteristics for its potential therapeutic use in that it shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3), high hydrophilicity, stable and facile labeling with (111)In and (90)Y. We began to investigate the potential therapeutic applications of (90)Y DOTATOC in 1997 by performing a thorough dosimetric study in 18 patients who were administered (111)In DOTATOC to estimate the absorbed doses during(90)Y-DOTATOC therapy. Then, we moved on and treated an overall number of 256 patients, mostly recruited in 2 distinct protocols with and without the administration of kidney protecting agents, with (90)Y DOTATOC. No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The MTD per cycle was defined as 5.18 GBq. Objective therapeutic responses were documented in more than 20% of patients in terms of partial and complete responses. The present article reports in details our clinical experience (still ongoing) and outcomes with the use of (90)Y DOTATOC.

Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies *

Article

May 2002
SEMIN NUCL MED

Somatostatin and its analogues bind to somatostatin receptors (sst) 1 through 5 that are overexpressed in neuroendocrine neoplasms such as gastroenteropancreatic (GEP) malignancies. After ligand-receptor binding, a fraction of the ligand-receptor complexes internalize. This internalization process is an effective means of delivering cytotoxic radiolabeled somatostatin analogues, especially those emitting short-range decay particles such as Auger electrons, to the neoplastic cell nucleus. Indium-111-pentetreotide, an sst 2 preferring somatostatin analogue with gamma and Auger electron decay characteristics, is commonly used for the scintigraphic evaluation and management of neuroendocrine cancer patients. This clinical trial was performed to determine the effectiveness and tolerability of therapeutic doses of (111)In-pentetreotide in patients with GEP tumors. GEP tumor patients who had failed all forms of conventional therapy, with worsening of tumor-related signs and symptoms and/or radiographically documented progressive disease, an expected survival less than 6 months, and sst positivity as determined by the uptake on a 6.0 mCi (111)In-pentetreotide scan (OctreoScan; Mallinckrodt Medical, Inc, St. Louis, MO), were treated with at least 2 monthly 180-mCi intravenous injections of (111)In-pentetreotide. Baseline clinical assessments, serum chemistries, and plasma pancreastatin levels were measured and repeated before each (111)In-pentetreotide treatment. From February 1997 to February 1998, 27 GEP (24 carcinoid neoplasms with carcinoid syndrome and 3 pancreatic islet cells) patients were accrued, with 26 patients evaluable for clinical and radiographic responses, 21 patients evaluable for biochemical assessments, and 27 patients evaluable for survival analysis and safety. Toxicity was evaluated by using standard National Cancer Institute (NCI) Common Toxicity Criteria guidelines. Clinical benefit occurred in 16 (62%) patients. Pancreastatin levels decreased by 50% or more in 81% of the patients. Objective partial radiographic responses occurred in 2 (8%) patients, and significant tumor necrosis (defined by 20 Hounsfield units or greater decrease from baseline) developed in 7 (27%) patients. The following transient Grades 3/4 NCI Common Toxicity Criteria side effects were observed, respectively: leukocyte: 1/1; platelets: 0/2; hemoglobin: 3/0; bilirubin: 1/3; creatinine: 1/0; neurologic: 1/0. Myeloproliferative disease and/or myelodysplastic syndrome have not been observed in the 6 patients followed-up for 48+ months. The median survival was 18 months (range, 3-54+ mo). Two doses (180 mCi) of (111)In-pentetreotide are safe, well-tolerated, and improve symptoms in 62% of patients, decrease hormonal markers in 81% of patients, decrease Hounsfield units on computed tomography (CT) scans in 27% of patients, with 8% partial radiographic responses and increased expected survival in GEP cancer patients with somatostatin receptor-expressing tumors. The maximal tolerated dose of (111)In-pentetreotide and the optimal dosing schedules remain under investigation.

Kidney failure after treatment with Y-90-DOTATOC

Article

Apr 2002

Facts and myths about radiopeptide therapy: Scylla, Charybdis and Sibyl

Article

Sep 2002

Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine

Article

Jan 2003

As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique in analysing somatostatin receptor-receptor positive lesions such as neuroendocrine tumours, a logical next step is peptide receptor radionuclide therapy (PRRT). Initial studies on PRRT were performed with high doses of [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other somatostatin analogues have been used for this purpose. However, the dose delivered to the kidney is a major dose-limiting factor. Amino acid solutions have previously been used to reduce renal uptake of radioactivity, but these solutions have some disadvantages, i.e. their hyperosmolarity and their propensity to cause vomiting and metabolic changes. In this study we tested various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide PRRT in order to assess their safety and their capacity to inhibit the renal uptake of radioactivity. Patients served as their own non-infused control. Renal radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%, P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or 2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels rose significantly. Maximal potassium levels were within the toxic range (6.3, 6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic analysis did not reveal significant changes in any of the patients. Vomiting occurred in 50% of patients infused with AA, but in only 6% of patients receiving no amino acid infusion (controls) and 9% of patients receiving LysArg. We conclude that co-infusion of Lys75 or LysArg results in a significant inhibition of renal radioactivity in PRRT, allowing higher treatment doses and thus resulting in higher tumour radiation doses. Because Lys75 produced serious hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective in offering renal protection in PRRT and is safe.

Successful treatment of radiation nephropathy with angiotensin II blockade

Article

Feb 2003
INT J RADIAT ONCOL

The aim of this report is to document the successful treatment of radiation nephropathy. Clinical case report with statistical analysis of evolution of kidney function. A case of radiation nephropathy was found in a kidney transplant recipient whose kidney transplant had been irradiated with 750 cGy 23 years previously. Use of the angiotensin II blocker, losartan, was associated with significant stabilization of the kidney function. Radiation nephropathy can be successfully treated. Other normal-tissue radiation injuries may also be treatable.

90 Y-DOTATOC and nephrotoxicity

Article

Dec 2002

86Y-DOTA0-D-Phe1-Tyr3-octreotide (SMT487) - A phase 1 clinical study: Pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion

Article

May 2003

The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly ( P<0.05) reduced (86)Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3+/-1.3 vs 4.4+/-1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1+/-0.4 vs 1.7+/-0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of (90)Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.

Receptor radionuclide therapy with 90Y-[DOTA] 0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours

Article

Aug 2004

Somatostatin receptors are over-expressed in many tumours, mainly of neuroendocrine origin, thus enabling treatment with somatostatin analogues. Almost a decade of clinical experience of receptor radionuclide therapy with the analogue (90)Y-[DOTA](0)-Tyr(3)-octreotide [(90)Y-DOTATOC] has now been obtained at a few centres of excellence. This review reports on the present state of the art of receptor radionuclide therapy and discusses new perspectives.

Renal Toxicity after Radionuclide Therapy

Article

Jun 2004

During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.

Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours

Article

Nov 2004

For the internal radiotherapy of neuroendocrine tumours, the somatostatin analogue DOTATOC labelled with 90Y is frequently used [90Y-DOTA-Phe1-Tyr3)-octreotide (SMT487-OctreoTher)]. Radiation exposure to the kidneys is critical in this therapy as it may result in renal failure. The aim of this study was to compare cumulative organ and tumour doses based upon dosimetric data acquired with the chemically identical 86Y-DOTA-Phe1-Tyr3-octreotide (considered as the gold standard) and the commercially available 111In-pentetreotide. The cumulative organ and tumour doses for the therapeutic administration of 13.32 GBq 90Y-DOTA-Phe1-Tyr3-octreotide (three cycles, each of 4.44 GBq) were estimated based on the MIRD concept (MIRDOSE 3.1 and IMEDOSE). Patients with a cumulative kidney dose exceeding 27 Gy had to be excluded from subsequent therapy with 90Y-DOTA-Phe1-Tyr3-octreotide, in accordance with the directives of the German radiation protection authorities. The range of doses (mGy/MBq 90Y-DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumour masses was 0.6-2.8, 1.5-4.2, 0.3-1.3 and 2.1-29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively, versus 1.3-3.0, 1.8-4.4, 0.2-0.8 and 1.4-19.7 (111In-pentetreotide), with wide inter-subject variability. Despite renal protection with amino acid infusions, estimated cumulative kidney doses in two patients exceeded 27 Gy. Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumour-free liver was underestimated. However, both dosimetric approaches detected the two patients with an exceptionally high radiation burden to the kidneys that carried a potential risk of renal failure following radionuclide therapy.

Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate

Abstract

No full-text available

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