Peptide Receptor Radionuclide Therapy Treatment Research Articles

Treatment and Long-Term Safety Outcomes of Peptide Receptor Radionuclide Therapy for Metastatic Neuroendocrine Tumours: An Asian Experience

Purpose: Peptide receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NETs). It has been shown to be effective and well tolerated in patients with metastatic NETs in several centres in the USA, Europe, and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods: One hundred and seven (107) patients with metastatic NETs who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST 1.1 and qualitative analysis were examined. The overall and progression-free survival curves were also evaluated. Results: The median progression-free survival was 49 months. Response assessment after completion of treatment showed that 33 (37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression-free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion: Our results show that PRRT is safe and effective in the treatment of metastatic NET in the Asian population. There was a significant difference in the progression-free survival curves between low-grade and high-grade NET and in the progression-free and overall survival comparing the number of cycles received.

Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles.

Currently, the most used peptide receptor radionuclide therapy (PRRT) regimen for neuroendocrine tumors comprises 4 treatment cycles, and there is not enough large-scale data to support the safety of more individualized extended PRRT. This study aims to evaluate the therapeutic effectiveness and potential nephrotoxicity related to PRRT using more than four treatment cycles. In this retrospective analysis, we included patients who had received at least four PRRT cycles and had available follow-up data. We analyzed renal function indicators before and after multiple treatments, comparing nephrotoxicity in patients receiving four cycles ("standard") with those receiving more than four ("extended treatment"). Nephrotoxicity was assessed via creatinine levels and CTCAE creatinine grades. Treatment effectiveness was gauged using Kaplan-Meier survival analysis, focusing on overall survival and disease-specific survival (DSS). Statistical analyses were performed using SPSS version 26 (IBM), R 4.2.3, and GraphPad Prism 9.0.0. Statistical significance was defined as a P-value of less than 0.05. Our study cohort consisted of 281 patients in the standard group and 356 in the extended treatment group. No significant differences in baseline characteristics or renal function were noted between the two groups pre-treatment. Mean post-treatment creatinine levels did not significantly differ between the standard (89.30 ± 51.19μmol/L) and extended treatment groups (93.20 ± 55.98μmol/L; P = 0.364). Similarly, there was no statistical significance between the CTCAE creatinine grades of the two groups (P = 0.448). Adverse renal events were observed in 0.4% of patients in the standard group and 1.1% in the extended treatment group. After a median follow-up time of 88.3months, we found that median overall survival was significantly higher in the extended treatment group (72.8months) compared to the standard treatment group (52.8months). A Cox regression analysis further supported these findings, indicating a better prognosis for the extended treatment group in terms of overall survival (HR: 0.580, P < 0.001) and DSS (HR: 0.599, P < 0.001). Our findings suggest that extending PRRT treatment beyond the standard four cycles may be a safe and effective therapeutic strategy for NET patients. This approach could be particularly beneficial for patients experiencing disease recurrence or progression following standard treatment.

Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) has shown favorable results in neuroendocrine tumors (NETs). Long-term safety and efficacy data for 177 Lu-octreotate PRRT, particularly in combination with chemotherapy, is lacking. The authors conducted a retrospective review of the long-term toxicity and survival outcomes of 104 patients with advanced NETs treated on 4 phase 2 clinical trials with Lutetium-177-octreotate (177 Lu-octreotate) PRRT, mostly in combination with chemotherapy. Median follow-up was 68 months, which represents the longest follow-up study of 177 Lu-octreotate PRRT for NETs to date. Median progression-free survival (PFS) was 37 months, and median overall survival (OS) was 71 months. Five- and 10-year OS were 62% and 29%, and 5- and 10-year PFS were 36% and 21%, respectively, demonstrating 177 Lu-octreotate can provide durable responses. PRRT was well tolerated with 1.9% of patients developing chronic renal impairment and 1% of patients developing long-term thrombocytopenia. Interestingly, there was a relatively high rate of myelodysplasia (MDS)/leukemia (6.7%), possibly attributable to the longer follow-up (with all except 1 case occurring more than 4 years after PRRT treatment) or to the addition of concurrent chemotherapy. Lutetium-177-Octreotate PRRT remains an efficacious and well tolerated treatment in long-term follow-up. For clinicians deciding on the timing of PRRT for individual patients, the 6.7% long-term risk of MDS/leukemia needs to be balanced against the 21% PFS at 10 years.

Best Practices for the Coordinated Care of Patients With Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy.

Neuroendocrine tumors (NETs) are rare, diverse malignancies; approximately two thirds originate in the gastrointestinal tract and pancreas and are known as gastroenteropancreatic NET. Most cases are diagnosed in the advanced or metastatic setting and overexpress somatostatin receptors. Recommended first-line treatment is somatostatin analogs; however, disease progression is common. [177Lu]Lu-DOTA-TATE is a radiolabeled peptide receptor radionuclide therapy (PRRT) indicated for the treatment of adult patients with somatostatin receptor-positive foregut, midgut, and hindgut gastroenteropancreatic NETs and progression on first-line somatostatin analogs. Many primary oncology practices may lack the staff, expertise, and infrastructure to treat patients with PRRT and primary oncologists may therefore refer their patients to a NET specialist at a tertiary center for treatment. Given the amount of organization required, PRRT treatment may seem to be complex; however, this process will be managed by a care coordinator who acts as a consistent point of contact for primary physicians regarding the care of their patients and ensures blood tests and scans are scheduled. In this article, we share our opinions, procedures, workflow, best practice, and roles and responsibilities when caring for patients receiving [177Lu]Lu-DOTA-TATE and focus on the role of the primary oncologist before, during, and after PRRT treatment.

Challenges in Von Hippel-Lindau's disease: PRRT in patients on hemodialysis.

SummaryVon Hippel–Lindau’s disease (VHL) is a hereditary tumor syndrome characterized by its prototype lesions, hemangioblastomas, and renal cell carcinomas. Treatment for renal cell carcinomas can ultimately result in long-term dialysis. Pancreatic neuroendocrine tumors (pNET) can also occur in the course of the disease. Currently, peptide receptor radionuclide therapy (PRRT) is the standard treatment for progressive neuroendocrine tumors. However, little is known about treatment with PRRT in patients on dialysis, an infrequent presentation in patients with VHL. We present a 72-year-old man with VHL on hemodialysis and a progressive pNET. He received four cycles of PRRT with a reduced dose. Only mild thrombopenia was seen during treatments. The patient died 9 months after the last PRRT because of acute bleeding in a hemangioblastoma. Hemodialysis is not a limiting factor for PRRT treatment and it should be considered as it seems a safe short-term treatment option for this specific group.Learning pointsVon Hippel–Lindau disease (VHL) is a complex disease in which former interventions can limit optimal treatment for following VHL-related tumors later in life.Metastasized pancreatic neuroendocrine tumors occur as part of VHL disease.Peptide receptor radionuclide therapy seems a safe short-term treatment option in patients on hemodialysis.

Haematotoxicity during peptide receptor radionuclide therapy: Baseline parameters differences and effect on patient's therapy course.

BackgroundMainly severe (CTCAE grade 3–4) haematotoxicity during peptide receptor radionuclide therapy (PRRT) is reported in literature due to major clinical impact, however moderate (CTCAE grade 2) haematotoxicity is common and could affect therapy management. The aim of this study was to evaluate the haematotoxicity course during PRRT and to compare baseline parameters between haematotoxicity grades.MethodsIn this retrospective study, 100 patients with a neuroendocrine tumour treated with PRRT were included. Patients were treated with an aimed number of four cycles with 7.4 GBq [177Lu]Lu-DOTA-TATE administered every 10 weeks. Haematological assessment was performed at baseline and frequently up to 10 weeks after the fourth cycle. The lowest haematological value was graded according to CTCAE v5.0, and patients were classified using the highest observed grade. Differences in baseline parameters, including [68Ga]Ga-DOTA-TATE positive tumour volume, were evaluated between CTCAE grades.ResultsFour cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0–1 in 54/100 patients, grade 2 in 38/100 and grade 3–4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0–1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed.ConclusionsThe incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values.

Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT

Simple SummarySmall intestinal neuroendocrine tumors (SI-NETs) are slow growing tumors expressing somatostatin receptors (SSTR), which are targeted in diagnostic and therapeutic methods. A fairly new treatment that targets SSTR2 is peptide receptor radionuclide therapy (PRRT), which prolongs survival for patients with metastasized NETs. However, the treatment is costly, and the effect is variable. Therefore, finding predictors for treatment response is warranted. The aim of this retrospective study was to immunohistochemically analyze the SSTR2 expression in SI-NETs, using a previously constructed tissue microarray, and to investigate if a high SSTR2 expression was correlated to overall survival (OS). Among 42 patients that had received PRRT, 10 had at least one tumor with low SSTR2 expression. The patients were grouped according to the SSTR2 expression (“High SSTR2” and “Low SSTR2”) in previously resected tumors. In contrast to the hypothesis of the study, patients with low SSTR2 expression had significantly longer OS after PRRT, compared with patients with high SSTR2 expression. Hence, the study suggests that low SSTR2 expression in resected tumors should not exclude SI-NET patients from receiving PRRT.(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of 177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in 177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT.

The Safety and Efficacy of the Repeated PRRT with [90Y]Y/[177Lu]Lu-DOTATATE in Patients with NET.

Purpose The peptide receptor radionuclide therapy (PRRT) is a treatment option for patients with disseminated, inoperable G1 and G2 neuroendocrine tumours (NETs). The study aims to evaluate the safety, efficacy, and progression-free survival (PFS) of patients after retreatment (R-PRRT) and re-retreatment (RR-PRRT) with tandem isotopes [90Y]Y/[177Lu]Lu-DOTATATE. Material and Methods. Out of 99 treated patients with G1 and G2 NETs, 26 were included in the study and treated with the repeated PRRT (with 5 undergoing the re-repeated PRRT treatment) after an initial positive response to four PRRT cycles and later progression of the disease. [68Ga]Ga-DOTATATE PET/CT and CT/MRI procedures were performed before and after the treatment. Patients were treated with [90Y]Y/[177Lu]Lu-DOTATATE (1 : 1) with mixed amino acid infusion for kidney protection. Toxicity was evaluated using the CTCAE 3.0 criteria. Results The median follow-up was 88 months (the range: 42–164). The median cumulative administered activity was 22.2 GBq (the range: 17.8–30.7 GBq). Myelodysplastic syndrome occurred in one patient (3.8%), and grade 4 renal toxicity was also detected in one patient (3.8%). No other cases of grade 3 or 4 bone marrow and renal toxicity were observed. The median PFS rate was 31 months after the PRRT and 23 months following the R-PRRT. The OS rate from the diagnosis (OS-d) was 109 months and from the start of the PRRT (OS-t)-92.4 months. During the restaging, 3–6 months after the PRRT, PR, SD, and PD were observed in 19.2%, 80.8%, and 0% of the patients, respectively. After the R-PRRT, PR, SD, and PD were observed in 50%, 42.3%, and 7.7% of the patients, respectively. Conclusions The repeated therapy with [90Y]Y/[177Lu]Lu-DOTATATE is safe and effective for patients with disseminated, inoperable G1 and G2 neuroendocrine tumours.

Cell-Free DNA and Clinical Characteristics in Patients with Small Intestinal or Pancreatic Neuroendocrine Tumors

Introduction: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low-grade small intestinal NET ­(siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA. Materials and Methods: We included 70 NET patients, siNET (n = 50) and pNET (n = 20). Plasma cfDNA levels were determined by droplet digital PCR for the beta-2-microglobulin gene every 6 months during a period of 3 years, including in a subgroup of 19 patients during peptide receptor radionuclide therapy (PRRT) therapy. Results: cfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p < 0.0001). ­cfDNA levels did not predict overall survival (crude hazard ratio [HR] 0.95 [0.57–1.58], p = 0.837, adjusted for smoking status HR 0.77 [0.51–1.17], p = 0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p = 0.66). cfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p = 0.029). Discussion/Conclusion: cfDNA levels are higher in NET patients than in healthy controls; however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.

Could the skewness and kurtosis texture parameters of lesions obtained from pretreatment Ga-68 DOTA-TATE PET/CT images predict receptor radionuclide therapy response in patients with gastroenteropancreatic neuroendocrine tumors?

In our study, tumor heterogeneity was evaluated using the parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT to assess therapy responses of lesions in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) treated with peptide receptor radionuclide therapy (PRRT). We retrospectively studied the texture analysis with relatively simple first-order parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT from 22 patients (eight females, 14 males; with a mean age: 54 ± 11 years) with GEP NETs who were treated with 2-6 therapy cycles of Lu-177 DOTA-TATE. A total of 326 lesions of 22 patients were evaluated in terms of treatment response by Ga-68 DOTA-TATE PET/CT examination performed before and after treatment. Receiver-operating characteristic (ROC) curves were generated to assess skewness and kurtosis to discriminate between responder and nonresponder lesions. A total of 326 lesions of 22 patients were evaluated and 137 lesions responded partially or completely to the treatment, 189 lesions did not respond to treatment, remained stable or progressed. The skewness and kurtosis values of the lesions which did not respond to the PRRT were significantly higher than those with response to PRRT treatment (P < 0.001 and P = 0.004, respectively). However, ROC curves provided a moderate area under the curve value for skewness and a relatively low value for kurtosis (0.619 and 0.518, respectively). Texture analysis using skewness and kurtosis of the lesions on pretreatment Ga-68 DOTA-TATE PET/CT was able to predict their responsiveness to PRRT.

SUN-914 Peptide Receptor Radionuclide Therapy for an Inoperable Small Cell Neuroendocrine Tumor in the Philippines

Background: Peptide Receptor Radionuclide Therapy treatment for neuroendocrine tumors is a well-tolerated treatment option for patients not amenable to receiving chemotherapy and radiotherapy. Clinical Case: A 42-year-old female was evaluated by a cardiologist for complaints of new onset recurrent throat discomfort, chest pain and palpitations. Two-Dimensional echo showed a large extra-cardiac mass compressing the main pulmonary artery. Chest CT with contrast reveal a 5.8 x 6.0 x 7.2 cm enhancing lobulated anterior mediastinal mass. Attempts to excise the mass failed due to the proximity to major blood vessels. Biopsy revealed a Carcinoid Tumor that was Chromogranin A positive but was asymptomatic for carcinoid syndrome. Everolimus treatment was given but was halted due to stomatitis. The patient remained fully functional. Re-evaluation of the mass with FDG PET show an increase in tumor size. Biopsy tissue re-testing showed small cell neuroendocrine carcinoma. Urine 5-hydroxyindoleacetic acid, plasma 5-hydroxyindoleacetic acid, and serum Chromogranin A were normal. A 68Ga-DOTATATE PET/CT scan reveal a slight increase in the mass that was intensely DOTATATE-avid. Two sessions of Peptide Receptor Radionuclide Therapy (PRRT) Lutetium-177 DOTATATE given at an 8-month interval were given. SPECT/CT re-evaluation showed good response and no evidence of metastases. A 68Ga-DOTA-octreotate PET-CT scan was done and showed good response to treatment. According to treatment guidelines, small cell neuroendocrine carcinoma that are non-resectable are treated with radiotherapy plus chemotherapy. But since the patient is fully functional and has minimal symptoms, other means of treatment such as PRRT may be well suited due to good tolerability and good treatment outcomes. Conclusion: PRRT is a promising treatment for NETs that is well tolerated giving better functionality and quality of life for patients opting not to undergo chemotherapy and radiotherapy. Reference: Cadiot, G. (2019). French and European Neuroendocrine Tumor Society consensus guidelines. Annales d’Endocrinologie, 80(3), p.174.

Non-Invasive Imaging Methodologies for Assessment of Radiation Damage to Bone Marrow and Kidneys from Peptide Receptor Radionuclide Therapy

Background/Aims: Peptide receptor radionuclide therapy (PRRT) is becoming clinical routine for management of neuroendocrine tumours. The number of PRRT cycles is correlated with treatment effect but theoretically limited by off-target radiation damage to kidneys and bone marrow. New imaging biomarkers for assessment of PRRT tissue damage would enable evaluation of novel renal and bone marrow protective agents, as well as personalised PRRT treatment regiments. Methods: Mice treated with [¹⁷⁷Lu]Lu-DOTA-TATE PRRT or vehicle were examined at baseline and following treatment with [¹⁸F]fluorothymidine (FLT) positron emission tomography (PET) and technetium-99m-mercapto-acetyl-tri-glycine ([^99mTc]Tc-Mag3) single-photon emission tomography (SPECT) to assess dynamic changes in bone marrow proliferation and renal function, respectively. Results: Bone marrow proliferation as assessed by [¹⁸F]FLT was decreased 2 days after PRRT treatment, but not vehicle, compared to baseline (target-to-background ratio [TBR_max] baseline:1.69 ± 0.29 vs. TBR_max PRRT: 0.91 ± 0.02, p < 0.01). Renal function as assessed by [^99mTc]Tc-Mag3 SPECT was similarly decreased 2 days following PRRT compared to vehicle (fractional uptake rate [FUR] vehicle: 0.030 ± 0.014 s^–1 vs. FUR PRRT: 0.0051 ± 0.0028 s^–1, p < 0.01). Conclusion: [¹⁸F]FLT PET and [^99mTc]Tc-Mag3 SPECT are promising techniques for assessing bone marrow and renal injury from [¹⁷⁷Lu]Lu-DOTA-TATE PRRT and may potentially improve patient management by allowing evaluation of protective interventions as well as enabling personalised PRRT treatments.

Monitoring Kidney Function in Neuroendocrine Tumor Patients Treated with (90)Y-DOTATOC: Associations with Risk Factors.

Peptide receptor radionuclide therapy (PRRT) is an established treatment for progressive neuroendocrine tumours with nephrotoxicity as the limiting factor. It is therefore important to monitor kidney function changes after PRRT treatment. We aimed to investigate kidney function by different methods and during a 4-hour and a 24-hour amino acid (AA) infusion protocol. We measured the Glomerular Filtration Rate (GFR) in 28 patients before and 3, 6, 12, and 18 months after (90)YDOTATOC therapy. We used standardized (51)Cr-EDTA plasma clearance (Cr-GFR) and estimated GFR (eGFR) by the simplified 4 variable Modification of Diet in Renal Disease based on serum creatinine values. Further, we determined GFR in 15 patients treated with a 4-hour infusion of AA compared to 13 patients with a 24-hour infusion at 3, 6, 12 and 18 months after therapy. Pre-existing risk factors associated with kidney failure were seen in 82% of the patients. We observed a significant reduction in Cr-GFR up to 12 months after PRRT (mean loss 27 ml/min/1.73 m(2) (32%)). The eGFR continuously overestimated the Cr-GFR with a bias of 8%. There was no significant difference between the two AA protocols, however, the 24-hour AA protocol tended to reduce mean Cr-GFR loss 12 months post therapy. Pre-existing risk factors for kidney failure were highly prevalent in this patient cohort, and kidney function after PRRT treatment is best monitored by (51)Cr-EDTA plasma clearance. Further, the use of a 24-hour AA kidney protection protocol seems to reduce the loss of kidney function in these patients.

Renal function affects absorbed dose to the kidneys and haematological toxicity during ¹⁷⁷Lu-DOTATATE treatment.

PurposePeptide receptor radionuclide therapy (PRRT) has become an important treatment option in the management of advanced neuroendocrine tumours. Long-lasting responses are reported for a majority of treated patients, with good tolerability and a favourable impact on quality of life. The treatment is usually limited by the cumulative absorbed dose to the kidneys, where the radiopharmaceutical is reabsorbed and retained, or by evident haematological toxicity. The aim of this study was to evaluate how renal function affects (1) absorbed dose to the kidneys, and (2) the development of haematological toxicity during PRRT treatment.MethodsThe study included 51 patients with an advanced neuroendocrine tumour who received 177Lu-DOTATATE treatment during 2006 – 2011 at Sahlgrenska University Hospital in Gothenburg. An average activity of 7.5 GBq (3.5 – 8.2 GBq) was given at intervals of 6 – 8 weeks on one to five occasions. Patient baseline characteristics according to renal and bone marrow function, tumour burden and medical history including prior treatment were recorded. Renal and bone marrow function were then monitored during treatment. Renal dosimetry was performed according to the conjugate view method, and the residence time for the radiopharmaceutical in the whole body was calculated.ResultsA significant correlation between inferior renal function before treatment and higher received renal absorbed dose per administered activity was found (p < 0.01). Patients with inferior renal function also experienced a higher grade of haematological toxicity during treatment (p = 0.01). The residence time of 177Lu in the whole body (range 0.89 – 3.0 days) was correlated with grade of haematological toxicity (p = 0.04) but not with renal absorbed dose (p = 0.53).ConclusionPatients with inferior renal function were exposed to higher renal absorbed dose per administered activity and developed a higher grade of haematological toxicity during 177Lu-DOTATATE treatment. The study confirms the tolerability of PRRT in patients with an advanced neuroendocrine tumour but indicates that patients with inferior renal function are at risk of being exposed to higher absorbed doses to normal tissue on treatment.

Early prediction of tumour response to PRRT

Summary[177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) in peptide receptor radionuclide therapy (PRRT) offers direct intra-therapeutic dosimetry. The aim of this study was to compare tumour and non-tumour parameters and assess intra-individual variations. Patients, methods: Retrospective analysis of 53 consecutive PRRT treatment cycles (mean activity of 7.53 ± 0.46 GBq 177Lu-octreotate, intended four cycles at intervals of 10–14 weeks, standard nephroprotection) in 27 GEP NET patients. Extended planar dosimetry with serial wholebody imaging on selected, non-superimposed tumour and non-tumour regions; liver (LM), bone (BM), and other (OM) metastases. The per-cycle variation was compared with posttreatment response (CT/MRI three months post-treatment, modified SWOG criteria). Results: Residence time in tumor lesions (133–147 h) exceeded that in kidneys (93 h). Tumour-to-kidney absorbed dose ratios ranged from 14 to 28 (LM, BM, OM). Intra-individual per-cycle dose variation was insignificant for kidneys, but significant for metastases (LM, BM, and OM; p &lt; 0.05). The mean per-cycle decrease of tumour absorbed dose (_D/A0[%]) was linked to morphologic response after PRRT. A mean decrease of &gt;20% was predictive of a partial or minor remission in all 11 evaluable patients, while absent significant dose reduction indicated stable or progressive disease in 4/5 patients. The dose decrease was unrelated to volume effects and also observed for BM. Conclusion: Besides confirmation of a favourable tumour-to-kidney parameter relation for 177Lu-octreotate, stepwise intra-lesional comparison seems to imply a prognostic impact of tumor dosimetry: The early per-cycle change _D/A0 between treatment cycles may predict the outcome after PRRT. Larger studies are needed to confirm this finding.

Secondary acute myeloid leukaemia after peptide receptor radionuclide therapy

Dear Editor, Peptide receptor radionuclide therapy (PRRT) with YDOTATOC or Lu-DOTATATE has demonstrated its efficacy in the treatment of neuroendocrineand somatostatin-receptor expressing tumours [1, 2]. Several clinical trials have confirmed that adverse effects are represented by possible renal impairment [3] and low but not absent haematological toxicity. We report on a patient who developed acute myeloid leukaemia (AML) following peptide receptor radionuclide therapy for a well-differentiated neuroendocrine carcinoma. He was a 50-year-old man with a past medical history of alcoholism, oesophagitis, arterial hypertension, thalassemia β-minor and deep venous thrombosis of left popliteal vein. He was also a heavy smoker. In November 2005 following repeated episodes of upper abdominal pain, he underwent a thoracic and abdominal CT-scan which showed a pancreatic lesion of 20 mm and another lesion in the Vater papilla of 30 mm in size. An Octreoscan® showed high uptake on the upper right renal pole and on the fifth and seventh hepatic segments. An oesophagoduodenoscopy revealed a duodenal neoformation of 20 mm. The ampullary lesion and peripancreatic lymph node were surgically removed in April 2006, and a fine needle biopsy of the liver was performed. Histology of the ampullary lesion showed a low-grade neuroendocrine carcinoma with extension to the duodenal submucosa, mucosa and focal angioinvasion. Immunohistochemistry was positive for chromogranin A, synaptophisin, neuron-specific enolase and for cytokeratins AE1–AE3 focally. Ki67 was expressed in less than 1% of nuclei. Insulin and glucagone himmunoistochemistry was negative. Histology of the lymph node demonstrated metastasis of the neuroendocrine carcinoma, whereas the liver biopsy showed necrosis without vital tumour cells. Between November 2005 and June 2007, the patient was closely monitored by repeated abdominal CT-scans. In October 2006 an Octreoscan® was repeated on the patient which showed a focal uptake in the pancreatic region. In June 2007, two new small suprarenal lesions were detected; the peri-pancreatic lesion was unchanged. On the basis of the neuroendocrine carcinoma and the increased uptake in receptor scintigraphy, the patient was started on PRRT. From June 2007 to February 2009, he received 6 cycles of PRRT with a cumulative activity of 20.16 GBq (545 mCi) of LuDOTATATE and 5.55 GBq (150 mCi) of Y-DOTATOC. A CT scan performed in October 2008 after 2 cycles of PRRT showed no increase in the size of peri-pancreatic and surrenalic lesions. This finding was confirmed by a subsequent CT-scan in January 2009. The patient completed his PRRT treatment in February 2009. A follow-up CT-scan performed in December 2009 documented that the disease was stable. In January 2010 pancytopenia was observed with Hb 9.1 g/dl, white cell count 6,400/μl, neutrophils 70% and platelets 157,000/μl. A bone marrow aspirate showed hypocellularity with trilineage dysplasia and blasts count <5%, suggestive of alcohol-induced myelodysplastic syndrome A. Piccin (*) : I. Pusceddu : S. Cortelazzo Haematology Department and Bone Marrow Transplant Unit, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy e-mail: apiccin@gmail.com

Peptide Receptor Radionuclide Therapy with 90Y-DOTATOC and 177Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland

Aim: Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this treatment option still needs clinical evaluation. Methods: In this study, we evaluated the PRRT treatment response of 69 Danish patients with NET mainly originating from the gastroenteropancreatic system. Fifty-six patients (81%) were referred for PRRT to the Department of Nuclear Medicine, University Hospital Basel, Switzerland, between 2004 and 2008 due to progression assessed by the referring physicians. However, when retrospectively evaluated, only 42 of the 69 patients (61%) had progression according to RECIST (Response Evaluation Criteria in Solid Tumors). Most patients were treated with ⁹⁰Y-DOTATOC. Results: Based on RECIST, a complete response was observed in 5 patients (7.4%), a partial response in 11 patients (16.2%) and stable disease in 42 patients (61.8%). Progressive disease after completed therapy was observed in 10 patients (14.7%). The median progression-free survival was 29 months (95% CI: 22–36 months). Pancreatic NET seemed to respond better to PRRT than small intestinal carcinoid tumors (p = 0.03). The overall frequency of serious adverse events was low. Conclusion: Implementation of PRRT in clinical routine has provided a valuable new therapeutic option for the treatment of advanced NET. We suggest that PRRT may advance from second- or third-line to first- or second-line therapy in inoperable/unresectable NET patients.

Update:Improvement Strategies for Peptide Receptor Scintigraphy and Radionuclide Therapy

Somatostatin receptor-targeting peptides are widely used for the imaging and therapy of neuroendocrine tumors. Peptide-receptor radionuclide therapy (PRRT) in neuroendocrine tumor patients with radiolabeled somatostatin analogs has resulted in symptomatic improvement, prolonged survival, and enhanced quality of life. The side-effects of PRRT are few and mostly mild, certainly when using kidney protective agents. If a more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasized or inoperable neuroendocrine gastroenteropancreatic tumors. Yet, much profit can be gained from improving the receptor-targeting strategies available and developing new strategies. This review presents an overview of several options to optimize receptor-targeted imaging and radionuclide therapy. These include the optimization of peptide analogs, increasing the number of receptors on the tumor site, and combining PRRT with other treatment strategies. The development of new peptide analogs with increased receptor-binding affinity and improved stability might lead to a higher accumulation of radioactivity inside tumor cells. Analogs of somatostatin have been widely studied. However, much profit can be gained in improving peptide analogs targeting other tumor-related receptors, including gastrin-releasing peptide (GRP) receptors, neurotensin (NT) receptors, cholecystokinin (CCK) receptors, and glucagon-like peptide-1 (GLP-1) receptors. Several peptide analogs targeting these receptors are well on their way to clinical utilization. The literature shows that it is possible to increase the receptor density on tumor cells by using different methods, which results in higher binding and internalization rates and thus a higher contrast during peptide-receptor scintigraphy. In PRRT treatment, this would enable the administration of higher therapeutic doses to tumors, which might lead to a higher cure rate in patients. Combinations of radionuclide therapy with other treatment modalities, such as chemotherapy or pretreatment with radiosensitizers, might increase the impact of the treatment. Further, the administration of higher dosages of radioactivity to the patient, enabled by combinations of PRRT with strategies reducing the radiation dose to healthy organs, will improve the outcome of tumor treatment. Also, targeting one or several tumor-specific receptors by using combinations of therapeutic agents, as well as by reducing nontarget uptake of radioactivity, will enlarge the therapeutic window of PRRT. Clinical studies will provide more insight in the effects of combining treatment strategies in cancer patients.