Toxicity of high-activity 111In-Octreotide therapy in patients with disseminated neuroendocrine tumours

Disseminated neuroendocrine tumours are difficult to treat and are generally not responsive to radiotherapy or chemotherapy. Nuclear medicine techniques using a radiolabelled somatostatin analogue, 111In-Octreotide, have been used for the diagnosis of neuroendocrine tumours. It has been suggested that high activities of such an agent may have a therapeutic effect. The aims of this study were to assess toxicity and to determine if there had been evidence of efficacy. Eight patients with known disseminated neuroendocrine tumours were enrolled in the study; six had carcinoid tumours, one had a medullary cell carcinoma of the thyroid and one patient had a malignant gastrinoma. Between 1.3 and 4.6 GBq of 111In-Octreotide were administered to each patient for up to five administrations over 12 months. A total of 23 administrations were given. Tests of vital signs, renal, liver and endocrine function as well as haematological markers were taken before and after treatment. The treatment was well tolerated with only one patient suffering from a sensation of flushing during the infusion but no changes in vital sings. There was a transient (up to 48 h) drop in circulating lymphocytes in four patients and platelets in two patients; no supportive therapy was needed. One patient with severe renal impairment had a slight reduction in glomerular filtration rate. We conclude that high-activity 111In-Octreotide is well tolerated with low toxicity and can be considered for use in patients with disseminated neuroendocrine tumours. Further work is now being performed to assess efficacy.     

Long-term efficacy of high-activity 111in-pentetreotide therapy in patients with disseminated neuroendocrine tumors.

High-activity (111)In-pentetreotide has been used to treat patients with disseminated neuroendocrine tumors. There is, however, little information related to the efficacy of this agent beyond the normal 6-mo assessment period. Before we can assume that such treatment would be beneficial to patients with neuroendocrine tumors the outcome of the patients over a longer time course should be determined. METHODS: The case records of 16 patients who had received high activities of (111)In-pentetreotide (with cumulative activities as high as 36.6 GBq) over a 2.5-y period, from January 1, 1997, to June 30, 2000, were reviewed. There were 8 female and 8 male patients (age range, 32-76 y): 10 patients had carcinoid, 2 had medullary cell carcinoma of the thyroid, and 1 each had a gastrinoma, glucagonoma, fibrolamellar cancer, and malignant histiocytoma. The minimum number of treatments received was 1 in 2 patients (with activities of 3.1 and 7 GBq); the maximum was 10 treatments (total, 36.6 GBq). Treatment was given using an infusion pump and was repeated at 4- to 12-wk intervals (mean number of treatments per patient, 6). Response to therapy was determined by changes in the size of the tumor on CT using the response evaluation criteria in solid tumors. Toxicity was measured using blood and urine tests of renal, hepatic, thyroid, and bone marrow function. The mean and median time from the last treatment to progression of disease and death (if applicable) was also calculated. RESULTS: No significant or long-lasting toxicity was encountered. At 6 mo after the patient's last treatment, 5 patients (30%) had disease progression, 2 had complete responses, and 3 had partial responses. Twelve months after their last treatment, 9 patients (56%) had disease progression, and, at 18 mo, 11 patients (69%) had disease progression. The mean progression-free survival was 12.25 mo (median, 9 mo). For those who survived 6 mo after their last treatment, the mean survival was 15.75 mo (median, 16 mo). At the 6-mo assessment point, there had been 3 deaths (19%): 1 death was not related to cancer. At 12 mo, there was 1 additional cancer death. At 18 mo, there were 3 additional deaths (1 was not related to the patient's carcinoid tumor but was due to a second coexistent cancer). By the end of the 18-mo assessment period, 7 patients (44%) had died. The mean time interval between disease progression and death was 5 mo. CONCLUSION: In patients treated with high-activity (111)In-pentreotide, 70% had some benefit for at least 6 mo after the end of treatment; however, 31% of patients will have sustained benefit at 18 mo from this treatment. This was obtained without significant toxicity.     

The therapeutic value of SST-A octreotide alone or with adjuvant treatment in patients with advanced medullary thyroid carcinoma and positive (111)In-octreotide scan

Medullary thyroid carcinoma (MTC) as a neuroendocrine tumour arising from C cells of the thyroid gland secrets hormonal peptides; among them, calcitonine (CT) and carcino-embryonic antigen (CEA). These two peptides are used for the diagnosis and treatment response of MTC cases. In patients with advanced MTC, scintigraphy by [(111)In-DTPA-d-phe1]-octreotide is able to detect somatostatin receptors (SSTR) and thus identify regional lymph nodes and/or distal metastases. In this article, we have studied the use of [(111)In-DTPA-d-phe1]-octreotide in the treatment of patients with advanced MTC, and a positive octreotide scan. Twenty-two patients were studied, 16 with persistent MTC and six with relapsed MTC. All patients' tumours were detected by [(111)In-DTPA-d-phe1]-octreotide-scan to be SSTR positive. All patients were treated with the somatostatin analog (SST-A) octreotide, for 3-21 months. Nine patients were treated only with SST-A (Group A). The remaining 13 patients (Group B) received adjuvant treatment as follows: six patients received chemotherapy (Ch), five patients received both Ch and external radiotherapy (eRT) and two patients received only eRT. Results were as follows: Group B patients as compared to Group A patients had about the same objective and biological response. Patients of Group B had relatively better subjective response (less diarrheas and abdominal cramps) versus Group A patients, although this finding was not significant. Group B patients had a longer mean survival time after treatment as compared to Group A patients: 39 months (with a range of 4-72 months) versus 20 months (with a range of 3-60 months) respectively, (P<0.05). Also Group B patients had longer than Group A patients mean total survival time - measured from the start of the disease: 138 (18-270) versus 97 (13-235) months respectively (P<0.05). Based on the above findings, it is the opinion of the authors that patients with advanced MTC and SSTR tumor expression in vivo as indicated by [(111)In-DTPA-d-phe1]-octreotide scanning, when submitted to treatment with SST-A octreotide and adjuvant Ch and/or eRT treatment may have a better treatment response than if submitted to treatment with SST-A octreotide alone. More cases are being studied by us at the present.     

Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours

Purpose

The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with ¹⁷⁷Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2).

Methods

We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with ¹⁷⁷Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial ^99mTc-DTPA clearance measurements.

Results

The median follow-up period was 58 months (range 4 – 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 – 42) and 53 months (95 % CI 46 – 60), respectively. A G1 proliferation status was associated with longer PFS (p?=?0.04) and OS (p?=?0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, p?=?0.007), a high hepatic tumour burden (≥25 % liver volume, p?=?0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p?=?0.035).

Conclusion

The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient’s performance status, tumour burden and baseline plasma NSE level.     

Outcome and toxicity of salvage therapy with <Superscript>177</Superscript>Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours

Purpose

We assessed the outcome and toxicity of salvage therapy (repeat treatment) with ¹⁷⁷Lu-octreotate and high cumulative activities in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET).

Methods

We retrospectively analysed a consecutive cohort of 33 patients with metastatic GEP-NET who underwent salvage peptide receptor radionuclide therapy (PRRT) in our institution. All patients had progressive NET prior to salvage treatment and had shown an initial response to PRRT. The mean cumulative activity was 44.3 GBq (30.0–83.7 GBq). Radiographic response was assessed using CT and/or MRI according to modified SWOG criteria. Toxicity was evaluated using laboratory data, including complete blood counts and renal function tests using CTCAE 3.0. Survival analysis was performed with the Kaplan-Meier curve method and a significance level at p?<?0.05.

Results

Radiographic responses consisted of complete response in 1 patient (3.0 %), partial response in 6 patients (18.2 %), minor response in 1 patient (3.0 %), stable disease in 14 patients (42.4 %), and progressive disease in 11 patients (33.3 %). Median progression-free survival (PFS) from the start of salvage therapy was 13 months (95 % CI 9–18) and patients with a history of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment (p?=?0.04). None of the patients developed severe nephrotoxicity (grade 3/4) or a myelodysplastic syndrome during follow-up. Relevant albeit reversible haematotoxicity (grade 3/4) occurred in 7 patients (21.2 %). The cumulative administered activity was not associated with an increased incidence of haematotoxicity.

Conclusion

PRRT with ¹⁷⁷Lu-octreotate in the re-treatment setting is safe and effective in patients with metastatic GEP-NET.

     

Report on short-term side effects of treatments with <Superscript>177</Superscript>Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours

Purpose Treatment with the radiolabelled somatostatin analogue ¹⁷⁷Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to ¹⁷⁷Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. Methods Seven patients were treated with 7.4 GBq ¹⁷⁷Lu-octreotate and capecitabine (1650 mg/m² per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. Results None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. Conclusions Treatment with the combination of ¹⁷⁷Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with ¹⁷⁷Lu-octreotate as single agent with regard to anti-tumour effects and side effects.     

Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours

Purpose

The prognostic value of FDG PET for neuroendocrine tumours (NETs) has been reported. In this study we evaluated the role of FDG PET in predicting response and progression-free survival (PFS) after ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced well-differentiated grade 1/2 NETs.

Methods

We retrospectively evaluated 52 patients with progressive advanced NETs overexpressing somatostatin receptors and treated with Lu-PRRT with a cumulative activity up to 27.7 GBq divided into five courses. According to WHO 2010/ENETS classification, patients were stratified into two groups: those with grade 1 tumour (Ki-67 index ≤2 %, 19 patients), and those with grade 2 tumour (Ki-67 index >3 % to <20 %, 33 patients). On the basis of the FDG PET scan, 33 patients were classified as PET-positive (PET+) and 19 as PET-negative (PET?).

Results

FDG PET was positive in 57 % of patients with grade 1 NET and in 66 % of patients with grade 2 NET, and the rates of disease control (DC, i.e. complete response + partial response + stable disease) in grade 1 and grade 2 patients were 95 % and 79 %, respectively (P?=?0.232). In PET? and PET+ patients, the DC rates were 100 % and 76 % (P?=?0.020) with a PFS of 32 and 20 months, respectively (P?=?0.033). Of the PET+ patients with grade 1 NET, 91 % showed disease control, whereas about one in three PET+ patients with grade 2 NET (32 %) progressed after Lu-PRRT (DC rate 68 %).

Conclusion

These results suggest that FDG PET evaluation is useful for predicting response to Lu-PRRT in patients with grade 1/2 advanced NETs. Notably, none of PET? patients had progressed at the first follow-up examination after Lu-PRRT. Grade 2 NET and PET+ (arbitrary SUV cutoff >2.5) were frequently associated with more aggressive disease. PET+ patients with grade 2 NET, 32 % of whom did not respond to Lu-PRRT monotherapy, might benefit from more intensive therapy protocols, such as the combination of chemotherapy and PRRT.     

Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour patients treated with targeted radiopeptide therapy

Purpose  

Administration of positively charged amino acids has been introduced to reduce the nephrotoxicity of targeted radiopeptide therapy (TRT). However, the amino acid solution may have side effects, including hyperkalaemia. The aim of this study was to evaluate the frequency and the magnitude of hyperkalaemia in neuroendocrine tumour (NET) patients undergoing TRT.     

177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients

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.     

Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177 Lu-DOTATOC therapy

Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. The average dose values per cycle were 3.41 ± 1.28 Gy (1.91–6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14–11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47–39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1–2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p =  < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation:  = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.     

Peptide receptor radionuclide therapy with <Superscript>177</Superscript>Lu-octreotate in patients with foregut carcinoid tumours of bronchial,gastric and thymic origin

Purpose Foregut carcinoid tumours have a different embryological origin than other gastroenteropancreatic neuroendocrine tumours (GEP NETs). In the total group of GEP NETs (n = 131), treatment with ¹⁷⁷Lu-octreotate resulted in tumour remission in 47% of patients, with a median time to progression (TTP) of >36 months. As patients with foregut carcinoids may respond differently, we here present the effects of this treatment in a subgroup of patients with foregut carcinoids of bronchial, gastric or thymic origin. Methods Nine patients with bronchial, five with gastric and two with thymic carcinoids were treated. All patients had metastasised disease. The intended cumulative dose of ¹⁷⁷Lu-octreotate was 22.2–29.6 GBq. Southwest Oncology Group criteria were used for response evaluation. Results Bronchial carcinoids: Five patients had partial remission, one had minor response (MR, tumour size reduction: ≥25%, <50%), two had stable disease (SD) and one had progressive disease (PD). Median TTP was 31 months. Gastric carcinoids: One patient had complete remission, one had MR and two had SD, including one with PD at baseline. One patient developed PD. Thymic carcinoids: One patient had SD. In the other patient, disease remained progressive. All patients: Overall remission rate was 50%, including MR. Conclusion ¹⁷⁷Lu-octreotate treatment can be effective in patients with bronchial and gastric carcinoids. Its role in thymic carcinoids cannot be determined yet because of the limited number of patients. The overall remission rate of 50% in patients with the studied foregut carcinoids is comparable to that in the total group of GEP NETs.     

Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours

Purpose Somatostatin receptor scintigraphy with ¹¹¹In-DOTA-DPhe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) and ¹¹¹In-DOTA-lanreotide (¹¹¹In-DOTA-LAN) has been used for staging of neuroendocrine tumours (NETs). However, the comparative diagnostic value of these radioligands on a lesion basis has not yet been established. The aim of this study was to compare the diagnostic capacity of ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy in patients with NETs, evaluating whether significant differences exist in lesion imaging with these radioligands. Furthermore, dosimetric data were compared. Methods Forty-five patients with NETs were investigated with ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy. Scintigraphic results were compared with those of conventional imaging and/or surgery in each patient, and also ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in 20 patients. Results ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy were true positive in 42/45 (93%) and 39/45 (87%) patients, and imaged 74/91 (81%) and 73/91 (80%) tumour lesions, respectively. ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN detected liver metastases in 21 and 14 patients, mediastinal metastases in seven and 11 patients, and bone metastases in two and seven patients, respectively. These radioligands revealed lesions not seen by conventional imaging in seven and eight patients, respectively, or by ¹⁸F-FDG-PET in eight and seven patients, respectively. The estimated tumour absorbed doses for ⁹⁰Y-DOTA-TOC were higher than those for ⁹⁰Y-DOTA-LAN in 14 patients, whereas the opposite was true in 12 patients. Conclusion Both ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN are suitable for imaging tumour lesions in patients with NETs and can detect lesions that may not be seen by conventional imaging and ¹⁸F-FDG-PET. Compared with ¹¹¹In-DOTA-LAN, ¹¹¹In-DOTA-TOC has a superior diagnostic capacity for liver metastases, but a lower diagnostic capacity for metastatic lesions in mediastinum and bone.     

Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with <Superscript>177</Superscript>Lu-D OTATATE

Purpose

Lu-DOTATATE (Lu-PRRT) is a valid therapeutic option in differentiated pancreatic neuroendocrine tumors (P-NETs). FDG PET seems to be an important prognostic factor in P-NETs. We evaluated the efficacy of Lu-PRRT and the role of FDG PET in 60 patients with advanced P-NETs.

Methods

From March 2008 to June 2011, 60 consecutive patients with P-NETs were enrolled in the study. Follow-up lasted until March 2016. Eligible patients were treated with two different total cumulative activities (18.5 or 27.8 GBq in 5 cycles every 6–8 weeks), according to kidney and bone marrow parameters.

Results

Twenty-eight patients received a mean full activity (FA) of 25.9 GBq and 32 a mean reduced activity (RA) of 18.5 GBq. The disease control rate (DCR), defined as the sum of CR+PR+SD was 85.7 % in the FA group and 78.1 % in the RA group. Median progression-free survival (mPFS) was 53.4 months in the FA group and 21.7 months in the RA group (P?=?0.353). Median overall survival (mOS) was not reached (nr) in FA patients and was 63.8 months in the RA group (P?=?0.007). Fifty-five patients underwent an FDG PET scan before Lu-PRRT, 32 (58 %) showing an increased FDG uptake in tumor sites. mPFS was 21.1 months in FDG PET-positive patients and 68.7 months in the FDG PET-negative group (P?<?0.0002), regardless of the total activity administered.

Conclusion

Both FA and RA are active in patients undergoing Lu-PRRT. However, an FA of 27.8 GBq of Lu-PRRT prolongs PFS and OS compared to an RA of 18.5 GBq. Our results indicate that FDG PET is an independent prognostic factor in this patient setting.

     

Indium-111-labelled liposomes: dosimetry and tumour detection in patients with cancer

Neutral phospholipid vesicles (VesCan), which had been prepared for clinical use, were loaded with 37 MBq indium-111 and administered to seven patients with malignant tumours. The median lipid dose was 2.0 mg/kg. Sequential images showed rapid blood clearance at the early stage, with homogeneous uptake of ¹¹¹In-labelled VesCan (¹¹¹In-labelled V-liposomes) in the liver and spleen. Dosimetric estimates for these organs were 1.2 and 1.5 mGy/MBq, respectively, with a whole-body exposure dose of 0.076 mGy/MBq. Total renal excretion of ¹¹¹In was less than 10% of the injected dose, occurring mainly as ¹¹¹In-EDTA in three patients. Gamma camera images 24–48 h after administration revealed increased activity in the tumours of four patients. ¹¹¹In-labelled V-liposomes may enable the demonstration of the tumour site without toxicity and with radiation doses comparable to other radionuclide imaging techniques. Correspondence to: A. Kubo     

[177Lu-DOTA0,Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients

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.     

Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT)

Purpose

To review the response and outcomes of ¹⁷⁷Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT) in patients with neuroendocrine tumour (NET) expressing high levels of somatostatin receptors with uncontrolled symptoms or disease progression.

Methods

A total of 68 patients (39 men; 17 – 76 years of age) who had completed an induction course of at least three cycles of LuTate PRCRT between January 2006 and June 2010 were reviewed. Ten patients were treated for uncontrolled symptoms and 58 had disease progression despite conventional treatment. The majority had four induction LuTate cycles (median treatment duration 5 months and cumulative activity 31 GBq), and 63 patients had concomitant 5-FU radiosensitizing infusional chemotherapy. Factors predicting overall survival were assessed using the log-rank test and Cox proportional hazards regression.

Results

Of those treated for uncontrolled symptoms, 70 % received benefit maintained for at least 6 months after treatment. Among patients with progressive disease 68 % showed stabilization or regression on CT, 67 % on molecular imaging and 56 % biochemically up to 12 months after treatment; 32 patients died. Overall survival rates at 2 and 5 year were 72.1 % and 52.1 %, respectively. Median overall survival was not estimable at a median follow-up of 60 months (range 5 – 86 months). Nonpancreatic primary sites, dominant liver metastases, lesion size <5 cm and the use of 5-FU chemotherapy were statistically significantly associated with objective response. A disseminated pattern and a high disease burden (whole-body retention index) were associated with an increased risk of death. Objective biochemical, molecular imaging and CT responses were all associated with longer overall survival.

Conclusion

A high proportion of patients with progressive NET or uncontrolled symptoms received therapeutic benefit from LuTate with concomitant 5-FU chemotherapy. The achievement of objective biochemical, molecular or CT responses within 12 months was associated with improved overall survival. Patients with a primary pancreatic site and larger lesions (>5 cm) appeared to have lower objective response rates and may need a more aggressive treatment approach.