Review Article Recent Trends in Radionuclide Imaging and Targeted Radionuclide Therapy of Neuroendocrine Tumours

Transcription

1 Review Article Recent Trends in Radionuclide Imaging and Targeted Radionuclide Therapy of Neuroendocrine Tumours G Gnanasegaran, N Kapse, J R Buscombe Dept of Nuclear Medicine, Guy s and St. Thomas Hospital NHS Trust, London, UK Dept of Nuclear Medicine, St Mary s Hospital NHS Trust Dept of Nuclear Medicine, Royal Free Hospital IJNM, 20(3): 55-66, 2005 Neuroendocrine tumours are a rare type of cancer that can arise in different parts of the body. These tumours are derived from neoplastic proliferation of cells of the diffuse neuroendocrine system and constitute approximately 2% of all malignant tumours of the gastrointestinal system. NETs can express neuroamine uptake mechanisms and somatostatin receptors or both. 123 I-mIBG and In-pentetreotide(octreoscan) are the commonly used radiopharmaceuticals for imaging. Once localized using 123 I-mIBG or octreoscan, these tumours can be successfully targeted with radiolabelled mibg or somatostatin analogues. This review focuses on recent advances and trends in both imaging and treatment of these tumours using nuclear medicine techniques. Introduction Cancer diagnosis is one of the clinical dilemmas every physician faces in spite of advances in diagnostic modalities. Most techniques have good sensitivity but very few have similar levels of specificity. In general, the smaller the tumour at the time of diagnosis, the better the prognosis. Accurate early detection of the tumour gives us a chance to plan and treat appropriately. Neuroendocrine tumours (NETs) are rare, slowgrowing tumours derived from neural crest cells. Common types of NETs include carcinoids, other pancreatic endocrine tumours, melanomas, phaeochromocytomas and medullary thyroid carcinomas. Carcinoids are malignant tumours derived from neoplastic proliferation of cells of the diffuse neuroendocrine system [1]. The estimated incidence is 1.5 per 100,000 of the population [2]. Carcinoid tumours are the most common neuroendocrine tumours in the gastrointestinal tract, with between 10% and 30% gastric in origin [2]. Carcinoids are commonly classified as foregut, midgut, or hindgut according to their embryological origin [3,4]. Typically, carcinoids arise from Kulchitsky or enterochromaffin cells. They often present as diagnostic dilemmas due to obscure or non-specific symptomatology. The ability of carcinoid tumours to cause clinical symptoms by secretion of hormones or biogenic amines is best recognised in the form of the carcinoid syndrome. Although generally slow growing, a significant proportion demonstrates aggressive tumour growth and may be difficult Correspondence to : Dr. J R Buscombe MD Dept of Nuclear Medicine Royal Free Hospital, London, UK j.buscombe@medsch.ucl.ac.uk to manage [4]. In spite of many diagnostic and therapeutic options available, careful patient selection and a multidisciplinary approach, is perhaps the most important criterion in prolonging survival [4,5]. Neuroendocrine tumours offer a new diagnostic and therapeutic challenge. There is great variability in the detection rate of the primary carcinoid tumours, which is often dependent on its location. These patients can be evaluated by both conventional imaging studies, such as computed tomography (CT)/magnetic resonance imaging (MRI), and functional imaging using nuclear medicine scintigraphy. Nuclear medicine imaging of neuroendocrine tumours Different tracers have been proposed in nuclear medicine to visualize neuroendocrine tumours and these modalities are based on different mechanisms of cellular uptake [Table1]. Table 1: Radiopharmaceuticals used in imaging NETs 131/ 123 I-metaiodobenzylguanidine (mibg) In-pentetreotide (octreoscan) In-octreotate In-lanreotide Tc(V) DMSA Tc- depreotide scintigraphy (NEOTECT) Tc-MDP Bone scan (complimentary in bone metastases only) Tc-Vapreotide (RC-160) SPECT/CT 18 F-FDG PET imaging 11 C-5HTP 68 Ga-DOTATOC 55

2 G Gnanasegaran et al The most widely used radiopharmaceutical is Iodinemetaiodobenzylguanidine ( 123 I-mIBG) and Inpentetreotide(octreoscan). 123 mibg and In-pentetreotide have made a tremendous impact in management of neuroendocrine tumours. The overall sensitivity of octreoscan in localising neuroendocrine tumours is high. The highest success rates were observed in detecting glucagonomas (100 %), vipomas (88 %), gastrinomas (73 %), non-functioning islet cell tumours (82 %) and carcinoids (87 %)[4,6-8][Fig1]. Scintigraphy with In-pentetreotide in general detects more metastatic lesions than with 123 I-mIBG in patients with neuroendocrine tumours. On occasion, scintigraphy with 123 I-mIBG demonstrates lesions not evident with In-pentetreotide. In several neuroendocrine tumour types, inclusion of octreoscan in localising and staging is beneficial and effective in terms of cost, patient management and quality of life [Table2&3] [4,6-8] Targeted radionuclide therapy for neuroendocrine tumours Meta-iodobenzylguanidine (mibg) therapy: Metaiodobenzylguanidine is a meta isomer of the guanethidine derivative iodobenzylguanidine. Radiolabeled mibg is commonly used in the diagnosis and treatment of tumours from neural crest origin. The sensitivity and specificity of radiolabelled mibg in detecting phaeochromocytoma is quite high. However, the rate of detection is relatively lower in carcinoid tumours [9,10]. Radiolabelled mibg therapy is used Figure 1 : Octreoscan showing multiple somatostatin receptor positive tumours in the liver and bones. in patients with phaeochromocytoma, paragangliomas, neuroblastomas and carcinoids [Table 4-6]. Several doses may be required to obtain an objective response and the treatment should not be repeated less than 4-6 weeks. In patients with metastatic pheochromocytoma treatment options are relatively few. Loh et al in their extensive review of the literature in 116 patients with malignant pheochromocytoma reported an initial symptomatic improvement in 76% of patients, tumour responses in 30%, and hormonal responses in 45%[11]. Various other groups have also reported an overall tumour response in more than 50% of the patients [12-18]. Unlike patients with metastatic catecholamine-secreting tumours, experience with 131 I-mIBG for carcinoid tumours is limited. In the treatment of metastatic carcinoid tumours in 98 patients Safford et al, reported symptomatic response in 72 patients (74%), a hormone response was measured in 52 patients (53%), and a radiographic response was assessed in 75 patients (77%) [19,20][Fig2a&2b]. The worldwide cumulative experience reported an objective tumour response in approximately 30% of patients and a symptomatic response in 50% [21-23]. Radiolabeled Somatostatin analogue therapy Somatostatin receptors are found on most tumours, such as carcinoids, paragangliomas, phaeochromocytomas, medullary thyroid cancers and endocrine pancreatic tumours [24-26]. These receptors play an important role in radionuclide therapy. The basis for somatostatin receptor therapy is the overexpression of these receptors [27]. Five types of somatostatin receptors have been identified so far [sstr1-5] and all bind to somatostatin-14 and somatostatin-28 with high affinity [28-30]. Somatostatin and its analogues act via the G-protein coupled receptors [31-35]. Various types of somatostatin analogues, such as octreotide, lanreotide and octreotate are currently available [36,37]. Octreotide was the first somatostatin analogue to be used after labelling with indium ( In) and currently it is also labelled with Yttrium ( Y) and 177 Lutetium ( 177 Lu). The recent introduction of the metal chelator tetraazacyclododecane tetra acetic acid (DOTA) has considerably improved the stability of somatostatin radioconjugates and made it possible to use a variety of radionuclides, such as Y, which delivers higher-energy Table 2 : Nuclear medicine imaging in NETs Localise primary tumours and detect sites of metastatic disease (staging and restaging) Predict the response to therapy as a prognostic parameter Select patients for radionuclide therapy Monitor the effects of surgery, radiotherapy or chemotherapy Detect relapse or progression of disease (follow-up of patients with known disease) 56

3 Tc-MDP Used for the detection of bone metastases. Bone scan is complementary Indian Journal of Nuclear Medicine, Vol. 20, No. 3, September I-mIBG NETs also express active amine precursor uptake-1 mechanisms. >% sensitivity for diagnosing adrenomedullary tumours % sensitive for detecting other NETs Somatostatin receptor NETs display somatostatin receptor scintigraphy (octreoscan) Octreoscan is a sensitive and specific technique Octreoscan Preferentially binds to somatostatin receptors 2 and 5 with high affinity In-pentetreotide Binds to receptor 3 with moderate affinity NEOSPECT Tc-depreotide is a peptide analogue of a somatostatin preferentially binds to Tc-depreotide somatostatin receptors 2, 3, and 5. Tc-Vapreotide Tc(V) DMSA Table 3 : Summary of Nuclear Medicine Imaging Modalities Tc-depreotide is convenient, accurate and cost effective characterization of pulmonary nodules. Somatostatin analogue Enhanced binding affinity to somatostatin receptors subtype 4 Important alternative to octreoscan Commonly used in medullary carcinoma of thyroid The role of Tc (V) DMSA is diminishing. 18 F-FDG (PET) 18F-FDG usually does not show sufficient uptake in well-differentiated tumours. 18 F-FDG is appears to be useful in detecting rare poorly differentiated neuroendocrine tumours 11 C-5HTP(PET) Detection rate is significantly higher compared to both computer tomography and somatostatin receptor scintigraphy. 68 Ga-DOTATOC Higher specific binding to SSTR 2 Labelling of the ligand with 68 Ga is easy Radiolabelled mibg therapy Specific: 123/131mIBG positive tumours a) Inoperable/ malignant phaeochromocytoma b) Inoperable/ malignant paraganglioma c) Inoperable/ malignant carcinoid tumour d) Stage III / IV neuroblastoma e) Inoperable/malignant medullary thyroid cancer General criteria: Stable haematology and biochemistry Haemoglobin (Hb) >100 g/l White blood cells (WBC) >3.0_109/l Platelets>100_109/l Urea<10 mmol/l Creatinine<160 _mol/l Glomerular filtration rate (GFR)>40ml/min Table 4 : Indications of targeted radionuclide therapy Radiolabelled somatostatin analogue therapy Specific: In-pentetreotide positive tumours a) Inoperable sympathoadrenal system tumours (phaeochromocytoma, neuroblastoma and paraganglioma) b) Inoperable functioning gastroenteropancreatic tumours (GEP) (carcinoid, gastrinoma,insulinoma, glucagonoma, VIPoma, etc.)inoperable medullary thyroid carcinoma c) Neuroendocrine tumour (NET) of unknown origin. General criteria: Stable haematology and biochemistry Haemoglobin (Hb) >100 g/l White blood cells (WBC) >3.0_109/l Platelets>100_109/l Urea<10 mmol/l Creatinine<160 _mol/l Glomerular filtration rate (GFR)>40ml/min 57

4 G Gnanasegaran et al 2a 2b Figure 2a and b : Pre and post therapy mibg images show reduction/resolution in a neck lesion from a phaeochromocytoma. Multiple liver metastases are also noted. Table 5 : General information and protocol for radionuclide therapy [13] 1. Patients should have a biopsy proven, inoperable NETs 2. Prior documentation of radionuclide positive tumours by quantitative tracer scans 3. Drugs interfering with the uptake and/or retention should be withdrawn 4. Patients should receive adequate (written and verbal) information about the procedure 5. Written consent must be obtained from the patient. 6. Patients and careers should receive specific instruction/information in radiation safety precautions. 7. Double check the patient by name, patient number, date of birth (Ideally 2 persons should check) 8. During administration: Vital signs monitoring is essential, and prophylactic anti emetics may be needed (ondansetron is the anti-emetic of choice). 9. Patient instruction and Precautions:Patients should be advised to observe rigorous hygiene in order to avoid contamination. Double toilet flush and hand wash is recommended after urination.incontinent patients should be catheterised prior administration. 10. Set up radiation protection procedures and appropriate signage on the door 11. Check trolley and staff for contamination 12. Return the waste to the hot lab in nuclear medicine for disposal 13. Post therapy imaging if feasible 14. Follow up: Weekly blood count for at least 6 weeks post therapy 15. Tumour response assessment: using conventional radiological or radionuclide methods or clinical criteria radiation, for receptor-targeted radionuclide therapy. The tumour response rate depends on multiple factors such as: type of radiolabelled somatostatin, tumour type, tumour burden and tumour size. Prior to the treatment, a radiotracer study is performed with In-octreotide or In-lanreotide to assess the receptor status. Various dose regimes have been reported and strategies are still evolving. There is currently no strict protocol/consensus available in any of the nuclear medicine society guidelines (Table 6&7). Clinical efficacies of radionuclide somatostatin analogue therapies: In-DTPA-octreotide (auger emitter): In addition to gamma photons, In also emits auger electrons, which are useful in therapy [38-40]. In-octreotide is internalised by the NET cell and lies in close proximity to DNA [41]; therefore, if given in sufficient activities, In-octreotide could have a therapeutic effect. Early results by Valkemma et al [42] in their 40 evaluable patients, reported stable disease or minor response in 53% (21 patients) and progressive disease status in 47% (19 patients) [42] (Table 8). In this study patients received multiple doses (1 to 22 cycles) and doses ranged from GBq. Six patients received doses greater than 100 GBq and three of these patients developed myelodysplastic syndrome and acute myeloid leukaemia. However, these patients were treated with interferons and chemotherapy previously [42]. In the remaining patients who received less than 100GBq mild and transient haematological side effects were observed. Only five patients were reported to have grade I renal toxicity, which was based on their serum creatinine values. Many research groups have used multiple doses of In-DTPA-octreotide, up to 160 GBq, to treat patients with somatostatin receptor positive tumours [43,44]. The overall therapeutic effects included partial and 58

5 Indian Journal of Nuclear Medicine, Vol. 20, No. 3, September 2005 Table 6: Infusion protocols for various radionuclide therapies 131 I-mIBG therapy Oral potassium iodate or potassium iodide commencing one day prior to mibg therapy and continued for up to 3 days post therapy. Drugs interfering with the uptake and/or retention of [ 131 I] MIBG should be withdrawn (1 to 2 weeks prior to treatment). Usual administered activities range between 3.7 and 11.2 GBq ( mci). Administered by slow intravenous infusion [45 minutes 4hours] via an indwelling cannula or central venous line using a lead-shielded infusion system. Reducing or temporarily stopping the 131 I-mIBG infusions usually manages unstable hypertension. Radionuclide somatostatin analogue therapy Y-DOTATOC: 500ml of Hartman (Hepa 8% amino acid) solution is given 30 minutes before injecting the radiolabeled (Y-DOTATOC) somatostatain analogue. After intravenous injection of Y-DOTATOC, an additional dose of 1500ml of amino acids is infused over a period of 3-3 1/2 hours. Y-LANREOTIDE: 1.2 GBq infused over about 30 minutes 4-6 weeks apart. After care check renal and BM function every 2 weeks (normally get GP to do this and send results in until 8 weeks after last treatment).can give second set of treatment with a 6 month break maximum is 6 treatments. Y-OCTREOTATE: Start amino acids infusion (1 litre Viamin 18 or similar) at a rate of 1litre per 4 hours or slower if vomiting occurs give 8mg oral odansetron and wait for 30 minutes.3-4gbq of Y- octreotate is infused over minutes, Continue amino acids till finished. Treatment can be repeated at 6-8 week period for 3 treatments only and no further treatments is currently recommended. minor remissions in a few patients and, mostly, stabilization of previously progressive tumours. In a series of patients, Buscombe et al reported that 31% of the patients had an objective response from the treatment of their disease with high-activity In-octreotide, and 44% had a period of tumour stability, with no growth in tumour size for at least 6 months after the end of treatment. This study concluded at least 70% of patients showed some benefit from the treatment [45]. ( Y-DOTA-Tyr 3 )-Octreotide (beta emmiter): Y-DOTATOC University Hospital, Basel phase I/II study: Initial results of phase II study reported by Waldherr et al are encouraging [46,47]. They treated patients with 4 intravenous injections of a total of 6,000 MBq/m 2 Y-DOTATOC, administered at intervals of 6 weeks, all patients having received renal protection through co-infusion of amino acid infusion. The overall response rate was 24%. In the later phase of the trial the patients were treated with higher doses of Y- DOTATOC (7.4 GBq/m 2 in 4 equal injections at intervals of 6 weeks, with renal protection using Hartmann-HEPA 8%) [46,47]. An objective response was observed in 23% of the patients (WHO criteria), complete remission in 5%, partial remission in 18%, stable disease in 69%, and progressive disease in 8%. Table 7 : Summary of targeted therapy with radiolabeled somatostatin analogues RadioPharmaceuticals Indium- Pentetreotide Yttrium- pentetreotide Yttrium-lanreotide 177 Lutitiumoctreotate Type of radiation Auger electrons High -energy ß- High -energy ß- Low -energy ß- emitter (>1mm) emitter (>1mm) and γ (<200µm) Half-life (t 1/2 ) 67 hours 64 hours 64 hours hours Chelator DTPA DOTA DOTA DOTA Dose Up to 5GBq/cycle 1 to 4.4 GBq/cycle 1.2 GBq/cycle GBq/cycle Amino acid co-infusion NO YES NO YES Imaging Yes Brehmsstrahlung Brehmsstrahlung Yes imaging if feasible imaging if feasible Receptor affinity SS receptor 2 /5 with high, SS receptor 2 /5 with high, SS receptors 2, 3, 4, Octreotate has 9 3 with moderate affinity 3 with moderate affinity and 5 with high and fold higher and does not bind to and does not bind to receptor 1 with lower affinities for the 1 and 4. 1 and 4. affinity SS receptor 2. 59

6 G Gnanasegaran et al Table 8: Clinical efficacies of various radiolabeled somatostatin analogues therapy [OR-objective response, CR-complete remission, PR-partial remission/response, SD- stable disease, PD-progressive disease in 8%. MR-minor remission/response, MDS-myelodysplastic syndrome, AML- acute myeloid leukaemia] Study Results Side effects In-DTPA-octreotide SD or MR in 53% and progressive 3 patients developed MDS and AML. In the Valkemma et al disease status in 47% remaining patients mild and transient haematological side effects were observed. In-DTPA-octreotide OR in 31%, SD in 44% (6 month). No evidence of significant treatment- Buscombe et al 70% of patients showed some associated toxicity. 1 patient had transient benefit from the treatment flushing, 1 patient abdominal cramps after administration of the In-pentetreotide ( Y-DOTA-Tyr 3 )-Octreotide OR in 23%, CR in 5%, PR in 18%, Renal toxicity, thrombocytopenia and liver Waldherr et al SD in 69%, PD in 8%. An overall 63% toxicity were reported in some patients. clinical benefit in terms of clinical Nausea and vomiting were observed in symptoms was obtained. patients treated with amino acids Y-DOTA-Tyr 3 )-Octreotide CR in 5%, PR in 22%, SD in 49%, 48% patients experienced nauseas and phase I/II study PD in 20% and 4% of the vomiting (grade I-II gastrointestinal toxicity). Pagenelli et al patients were not evaluable 3 patients developed grade III haematological toxicity. Transient drop in lymphocytes was also noted. ( Y-DOTA-Tyr 3 )-Octreotide PR in 3, MR in 7, SD in 19 patients, 3 patients had grade 2 renal toxicity; (Novartis sponsored) phase I study PD in 9 patients In total Haematological toxicity was also reported in Valkemma et al 47% showed symptomatic 6(5 had previous chemotherapy). 6 patients improvement developed grade 3 leukopenia and one developed MDS 2 years after therapy Y-DOTA-lanreotide SD in 41% regressive tumour No severe acute or chronic haematological (MAURITIUS) disease in 14% toxicity, change in renal or liver function Virgolini et al Y-DOTA-lanreotide PR in 54% and SD in 46%(5 months). 6 patients had grade 1 and 2 haematological (MAURITIUS) However, 15 patients died with a toxicity and no renal toxicity Buscombe et al mean survival of 5 months. 46% of the patients were reported to have benefited by this treatment 177 Lu-TATE [ DOTA O -Tyr 3 ]- CR in 3, PR in 32, MR in 24, SD in 44 1 patient had renal insufficiency and octreotate and PD in 22 patients 1 patient developed hepatorenal syndrome Kwekkeboom et al An overall 63% clinical benefit in terms of clinical symptoms was obtained. These promising tumour responses after therapy are essentially similar to those found in other Y- DOTATOC studies, despite differences in therapy regimens [48]. European institute of oncology (EIO), Milan- phase I/II study: In the phase I study Pagenelli et al included 40 patients to access the maximum tolerable dose per cycle [48-50]. The patients were divided into eight groups and co-infusion of amino acid infusion (arginine and lysine) was used immediately before and after administration of the radionuclide. The patients were treated with two doses of Y-DOTATOC with activity increasing by 0.37 GBq per group (starting dose was 2.96 GBq), after co-infusion with lysinearginine based amino acids. Overall 48% patients experienced nausea and vomiting (grade I-II gastrointestinal toxicity)[48-50]. No adverse reaction was reported in patients treated with Y-DOTOTOC up to 5.5GBq/cycle. In seven patients receiving 5.18GBq, three patients developed grade III haematological toxicity and in view of these observations, 5.18GBq was reported to the maximum tolerable activity per cycle [48-50]. In patients followed up to 3-30 months no 60

7 Indian Journal of Nuclear Medicine, Vol. 20, No. 3, September 2005 permanent renal toxicity has been reported [48-50]. In both phase I/II study, patients with heterogeneous group of neuroendocrine tumours were studied. Complete response (CR) was reported in 5% of the patients, partial response (PR) in 22%, stable disease in 49%, progressive disease in 20% and 4% of the patients were not evaluable (NE)[48-50]. [ Y-SMT-487/ Octreother], Novartis sponsored phase I study: The aim of this study was to define a maximum tolerable dose (single and cumulative dose) while limiting the kidney dose to 27Gy [51,52]. Dosimetric evaluation was performed with 86 Y-DOTATOC. 60 patients were analysed in the study, of which 47 patients were analysed [51,52]. Single cycle doses up to 200mCi/m 2 were given in 16 patients. The remaining 31 patients received escalating doses of 25, 50, 75 and 100mCi/ m 2 two to four weeks. All the patients had amino-acid coinfusion. The tumour response was calculated in 38 patients who were treated with maximum dose. Three patients showed partial response (PR), 7 patients showed MR, 19 patients showed SD and in 9 patients showed disease progression. In total 47% showed symptomatic improvement [51,52]. Y-DOTA-lanreotide (MAURITIUS) (beta emitter): The structure of DOTA-lanreotide is different from DOTAoctreotide. The C-terminus DOTA-lanreotide has a ThrNH 2 and at the N-terminus, D-phe is replaced by a D-2 naphthylalanine [53,54]. This modification in the structure is reported to lower the kidney dose and co-infusion of amino acid is not required. However, dose to bone marrow, wholebody, liver and intestine is higher. Y-DOTA-lanreotide is a universal Somatostatin (SST) receptor subtype ligand that binds all the five-somatostatin receptor types, which could be used to treat various tumour types [53,54]. Y-DOTAlanreotide binds with high affinity to somatostatin receptors 2,3 and 5 and intermediate affinity for receptor 1[53-55]. In the MAURITIUS (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a European Study) trial cumulative treatment doses of up to 8.5GBq Y-DOTAlanreotide were given as short-term intravenous infusion. Results in 154 patients indicate stable tumour disease in 41% (63 of 154) of patients and regressive tumour disease in 14% (22 of 154) of tumour patients with different tumour entities expressing Somatostatin receptors [55]. In another study, Buscombe et al treated 28 patients with advanced somatostatin receptor positive tumours with cumulative treatment doses up to 5.5 GBq. The response was assessed with CT/MRI and the RECIST [56,57] criteria at 3 months post treatment. 54% (15 patients) showed partial response (PD) and in 46%(13 patients) stabilization of disease was seen up to 5 months, however 15 patients died with a mean survival of 5 months. 177 Lu-TATE [DOTA O -Tyr 3 ]-octreotate (beta and gamma emitter): 177 Lu-DOTATATE is recently developed peptide and has been used for the treatment of neuroendocrine tumours [58,59]. This agent seems to show the highest tumour uptake of all tested octreotide analogues so far, not only in rats but also in patients with neuroendocrine tumours [60]. The somatostatin analog [DOTA 0,Tyr 3 ]octreotate has a ninefold higher affinity for the somatostatin receptor subtype 2 compared with [DOTA 0,Tyr 3 ]octreotide in vitro [58-60]. 177 Lu would be optimal for small tumours and post therapy imaging is also feasible. In a preliminary report Kwekkeboom et al, found a complete and partial response in 38% of their first 35 patients treated with 177 Lu-octreotate[59]. In a more recent update of this treatment in 131 patients with GEP tumours with somatostatin receptor-positive tumours with up to a cumulative dose of 22.2 to 29.6 GBq (600 to 800 mci) of 177 Luoctreotate. Complete remission was noted in three patients, partial remission in 32 patients, minor response in 24 patients, stable disease in 44 patients and progressive disease in 22 patients [61]. Combination therapy with Y-labeled and 177 Lu somatostatin analogues: Clinical trials using Y-labelled and 177 Lu somatostatin analogues have demonstrated the benefits of these compounds in targeted radionuclide therapy [62]. These radiolabeled analogues differ in their physical properties (half-life, energy type and path length [62][Table 9]. In patients with large/bulky, poorly vascularised and heterogeneous tumours, treatment with Y-labelled compounds is preferable. However, in patients with smaller tumours, therapy with 177 Lu somatostatin analogs is preferable. Combination of these two compounds could improve the clinical therapeutic outcome in patients treated with radiolabeled somatostatin analogs Though this combination formula seems to be interesting, further clinical results are awaited [62]. The same authors are also considering another interesting option of repeated administration of these compounds, such as initial administration with Y-labeled anologues for larger tumours, followed by 177 Lu analogues to treat smaller residual tumour [62]. Yttrium/Brehmsstrahlung imaging: The value of radionuclide therapy is largely determined by the predictability of the patterns of biodistribution of the radiopharmaceutical. Yttrium ( Y), a pure beta-emitter is an attractive option for targeted radionuclide therapy. The beta particles emitted from Y interact with the tissue to produce brehmsstrahlung radiation. Imaging Y could be relevant for the assessment/monitoring of the therapeutic plan and outcome. Conventional gamma photon imaging methods cannot be easily applied to imaging of Y-bremsstrahlung because of its continuous energy spectrum [63]. However, Gnanasegaran et al have successfully imaged patients treated with Y-lanreotide followed by whole-body brehmsstrahlung imaging 24 hours later [64-65]. All the images were acquired using the gamma camera, fitted with 61

8 G Gnanasegaran et al Table 9 : Difference between Y&177Lu analogs [62] Y-anologs Pure, high-energy beta (β) emitter (2.27MeV) Half life 2.7 days (64 hours) Maximum range is 12 mm Shorter half life leads to increased dose Higher energies and longer particle range, leads to more radioactivity in tumour cell per peptide. Better cross fire through the tumour, which is useful in large/bulky tumours and heterogeneous distribution of receptor Possibility of large absorbed doses to the adjacent tissue, especially when the tumours are close to critical organs and normal tissues may receive large absorbed doses. Less suitable for smaller tumours, because they will not be able to absorb all electrons emitted high-energy collimators, with a 75 kev photopeak and 50% windows [64-65]. In view of the limited resolution of the brehmsstrahlung imaging it was not possible to identify all tumour sites and total tumour uptake was therefore not calculated. However, localisation of the radioloabelled Figure 3 : Post therapy brehmsstrahlung image showing good localisation in a patient who was treated with intra-arterial Y- lanreotide 177 Lu-analogs Medium energy β emitter (0.5MeV) with low-abundance gamma (γ) Half life 6.7days(160.8 hours) Maximum range is 2.1mm Smaller particle range and lower energy leads to better absorption in smaller tumours Lu emits γ radiation suitable for gamma camera scintigraphy Dosimetry can be performed Longer half-life makes transportation more convenient somatostatin analogues at the tumour sites was documented [64-65]. Radioembolization/ Intra-arterial Y-Lanreotide therapy: The results of intravenous radiolabelelled somatostatin analogue therapy led people to investigate the use intraarterial radionuclide therapy to get better tumour localisation of the radiolabeled somatostatin analogue. NETs show a particular predisposition for hepatic spread. Such metastases receive most of their blood supply from the hepatic artery. In patients with tumour/metastases that are primarily within the liver, it would seem logical to deliver the Y-DOTA-lanreotide directly to the liver metastasis by means of hepatic intraarterial infusion, with the goal of achieving higher intratumoral concentrations of Y-DOTA-lanreotide and providing more effective treatment. The technique involves identification and selective catheterisation of the relevant hepatic artery via a femoral artery puncture in the angiographic suite/ catheter lab. Once this has been identified 1.2 GBq of Y-lanreotide is infused in about 5 minutes using a 5 French catheter into the hepatic artery [57,66]. McStay et al have reported a partial response in three patients, stable disease in 12 and disease progression 4 patients. Clinical improvement was reported in 61%, with a reduction in biologic marker levels. The 1-year reported survival rate was 63% (median survival time, 15 months)[67]. Some groups are currently investigating the role of intraarterial radiolabeled micro spheres and results of these studies are awaited. Post therapy brehmsstrahlung imaging can be performed (if available) to assess/confirm localisation [Fig 3]. 62

9 Indian Journal of Nuclear Medicine, Vol. 20, No. 3, September 2005 Nuclear Medicine management of NETs Figure 5: Treatment algorithm for the treatment of neuroendocrine tumours biodistribution [68]. 68 Gallium a generator-produced positron-emitting isotope is reported to be a promising PET tracer for somatostatin receptor imaging [69]. DOTATOC radiolabeled with the positron emitting gallium can be used for more accurate PET-based quantitation of somatostatin receptors in NETs [70,71]. Labelling of the ligand with 68 Ga is easy to perform and generator production of the tracer may ensure its continuous availability. However, the short half-life of 68 Ga (T 1/2 =68.1 min) can be a limitation. 68 Ga-DOTATOC is also reported to have higher specific binding to SSTR 2 [72]. Further evaluation in a larger number of patients is awaited. Y-octreotate therapy: Use of Y-octreotate for the treatment of neuroendocrine tumours is currently under investigation and results are awaited [Fig 4]. 68 Ga-DOTATOC Positron emission tomography (PET) for imaging somatostatin receptor positive tumours is desirable because of its improved spatial resolution and ability to quantify Limitations Though many radionuclide peptides have reached the clinical/ treatment phase, more clinical data is needed to assess the therapeutic outcome to move higher up in the treatment algorithm. A major drawback is lack of general consensus between various groups regarding optimisation of treatment factors [Fig 5]. Various other factors also affect patient outcome [Table10]. In most radionuclide therapies, bone marrow toxicity is dose limiting. In Peptide receptor radionuclide therapy, the bone marrow remains at risk, but Figure 4 : Pre-therapy In-pentetreotide (OCTREOSCAN) scan showing multiple tumours in the liver (left) and Posttherapy brehmsstrahlung image show localisation of Y- octreotate in the tumour (right). Table 10 : Factors affecting radionuclide somatostatin analogue therapy [73] 1. Stability of radioligand 2. Density of SS receptors expressed 3. Type/number of SS receptors expressed 4. Affinity/down regulation/desensitization of radioligand for sst subtypes 5. Efficiency of receptor mediated internalization of radioligand 6. Trapping or retension or localization of radioisotopes within the tumour cell 7. Mass of the injected radiopharmaceutical 8. Homogenous /heterogeneous expression of SS receptors 9. Mutations in sst genes 10. Resistence due to absence of receptor subtype 63

10 G Gnanasegaran et al by using somatostatin analogs labelled with ß-emitters such as Y and 177 Lu, the radiosensitive kidney is the dose-limiting organ. Since there is no clear-cut method of accessing the risk to the kidneys, the toxicity and dose limits to the kidneys are complex. To reduce radiation exposure to the kidney, different groups have tested several regimens of amino acid co-infusion, but these solutions have some disadvantages, in particular their hyperosmolarity and their propensity to cause vomiting and metabolic changes. Conclusion Radionuclide imaging and targeted radionuclide therapies play a very important role in the diagnosis and management of NETs. The challenge of balancing benefits (clinical response to radionuclide therapy) and risks (renal radiotoxicity) is a significant one; careful assessment of biodistribution, dosimetry and toxicity is essential, preferably on an individualised basis. Finally every patient ideally should receive a tailor-made therapy based on his or her particular tumour biology profile. References 1. Gilligan, CJ, GP Lawton, LH Tang, AB West and IM Modlin (1995). Gastric carcinoid tumors: the biology and therapy of an enigmatic and controversial lesion. Am J Gastroentrol, Newton JN, Swerdlow AJ, dos Santos Silva IM et al (1994)). The epidemiology of carcinoid tumours in England and Scotland. British Journal of Cancer 70, Sjoblom SM (1988) Clinical presentation and prognosis of gastrointestinal carcinoid tumours. Scand J Gastroenterol; 23: Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF & Burroughs AK (1998). Carcinoid tumour. Lancet 352, Helena R. Balon, Stanley J. Goldsmith, Barry A et al.procedure Guideline for Somatostatin ReceptorScintigraphy with In- Pentetreotide. J Nucl Med : McStay MK, Caplin ME. (2002) Carcinoid tumour. Minerva Med 93: Zimmer T, Ziegler K, Liehr RM, Stolzel U, RieckenEO, Wiedenmann B(1993). Endosonography of neuroendocrine tumours of the stomach, duodenum, and pancreas.ann N Y Acad Sci 1994; 733: Acta Radiol, 34(5): Oberg K. Carcinoid Tumors (1998): Current Concepts in Diagnosis and Treatment. Oncologist 3(5), Sisson JC, Shapiro B, Beierwaltes WH et al (1984). Radiopharmaceutical treatment of malignant pheochromocytoma. J Nucl Med 25(2): Hoefnagel CA, Voute PA, de Kraker J, Marcuse HR (1987). Radionuclide diagnosis and therapy of neural crest tumors using iodine-131 metaiodobenzylguanidine. J Nucl Med 28(3): Loh KC, Fitzgerald PA, Matthay KK, Yeo PP & Price DC (1997). The treatment of malignant pheochromocytoma with iodine- 131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. Journal of Endocrinological Investigation 20, Bomanji JB, Wong W, Gaze MN et al (2003). Treatment of neuroendocrine tumours in adults with 131I-MIBG therapy. Clinical Oncology (Royal College of Radiologists) 15, Guidelines for 131 I - meta Iodo Benzylguanidine Therapy (2002) (EANM Radionuclide Therapy Committee guidelines), 14. Hoefnagel CA, Lewington VJ. (2004) MIBG therapy. In: P. J. Ell, S S Gambhir (eds) Nuclear Medicine in Clinical Diagnosis and Treatment Vol.1, pp Churchill Livingstone, New York. 15. Troncone L & Rufini V (1997). 131I-MIBG therapy of neural crest Tumours. Anticancer Research 17, Mukherjee JJ, Kaltsas GA, Islam N (2001) Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)Imetaiodobenzylguanidine [(131)I-mIBG]. Clinical Endocrinology 55, Kaltsas G, Mukherjee JJ, Foley R, Britton K & Grossman A (2003). Treatment of metastatic pheochromocytoma and paraganglioma with 131I-meta-iodobenzylguanidine (MIBG). Endocrinologist 13, Ackery DM, Troncone L (1991). Session on the role of [131I]metaiodobenzylguanidine in the treatment of malignant phaeochromocytoma. Chairmen s report. J Nucl Biol Med , Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB (2004). Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours European Journal of Endocrinology 151, Safford SD, Coleman RE, Gockerman JP (2004). Iodine-131 metaiodobenzylguanidine treatment for metastatic carcinoid. Results in 98 patients. Cancer 101, Hoefnagel CA (1994). Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. Eur J Nucl Med ; 21, Hoefnagel CA, Delprat CC & Valdes Olmos RA (1991). Role of [131I]metaiodobenzylguanidine therapy in medullary thyroid carcinoma. Journal of Nuclear and Biological Medicine 35, Castellani MR, Alessi A, Savelli G, Bombardieri E(2004).The role of radionuclide therapy in medullary thyroid cancer. Tumori 89, Virgolini I, Pangerl T, Bischof C, Smith-Jones P, Peck- Radosavljevic M (1997) Somatostatin receptor subtype expression in human tissues: a prediction for diagnosis and treatment of Cancer. Eur J Clin Invest 27: Reubi JC, Kvols L, Krenning E & Lamberts SW (19). Distribution of somatostatin receptors in normal and tumor tissue. Metabolism39, Reubi JC, Laissue J, Krenning E & Lamberts SW (1992). Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications. Journal of Steroid Biochemistry and Molecular Biology 43, Faiss S, Scherubl H, Riecken EO, Wiedenmann B (1996). Drug therapy in metastatic neuroendocrine tumors of the gastroenteropancreatic system. Recent Results Cancer Res 142, Bruns C, Raulf F, Hoyer D, Schloos J, Luebbert H & Weckbecker G (1996).Binding properties of somatostatin receptor subtypes. Metabolism: Clinical and Experimental 45, Patel YC (1997). Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest 20,

11 Indian Journal of Nuclear Medicine, Vol. 20, No. 3, September Reubi JC, Laissue J, Waser B, et al (1994). Expression of somatostatin receptors in normal, inflamed and neoplastic human gastrointestinal tissues. Ann NY Acad Sci 733, Lamberts SWJ, Krenning EP, Reubi JC (1991). The role of somatostatin and its analogs in the diagnosis and treatment of tumours. Endocrinol Rev 12, Reubi JC, Lamberts SW, Maurer R(1988). Somatostatin receptors in normal and tumoral tissue. Horm Res 29, Reubi JC, Kvols LK, Waser B, et al (19): Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 50, Papotti M, Macri L, Bussolati G, Reubi JC (1989). Correlative study on neuro-endocrine differentiation and presence of somatostatin receptors in breast carcinomas. Int J Cancer 43, Hofland LJ, van Hagen PM, Lamberts SW (1999). Functional role of somatostatin receptors in neuroendocrine and immune cells. Ann Med 31, Hofland LJ & Lamberts SW (1997). Somatostatin analogs and receptors. Diagnostic and therapeutic applications. Cancer Treatment and Research 89, Lamberts SW, van der Lely AJ, de Herder WW & Hofland LJ (1996). Somatostatin analogs: future directions. Metabolism 45, Macke HR, Brand J M (2004). Receptor targeted radiopeptide therapy. In: P. J. Ell, S S Gambhir (eds) Nuclear Medicine in Clinical Diagnosis and Treatment, Vol. 1 pp Churchill Livingstone, New York. 39. de jong M, Bakker W H,Krenning P et al, (1997). Yttrium- and indium- labelling, receptor binding and biodistribution of [DOTA 0 ], D-Phe1, Tyr3]octreotide, a promosing somatostatin analogue for radionuclide therapy. Eur J Nucl Med 24; Heppeler A, Froidevaux S, Macke H R et al, (1999) Radiometallabelled macrocyclic chelator-derivatised somatostatin anlogue with superb tumour targeting peoperties and potential for receptor-mediated internal radiotherapy.chem A Eur J 5; Stolz B, Weckbecker G, Smith-Jones PM, Albert R, Raulf F, Bruns C (1998). The somatostatin recptor targeted radiotherapeutic [Y-DTPA-Dphe1, Tyr3]octreotide(Y-SMT 487) eradicates experimental rat pancreatic CA Tumours.Eur J Nucl Med 25; Valkema R, de Jong M, Bakker WH, et al (2002). Phase I study of peptide receptor radionuclide therapy with [In-DTPA] octreotide: the Rotterdam experience.seminars in Nuclear Medicine 32, Kwekkeboom D, Krenning EP, de Jong M (2000). Peptide receptor imaging and therapy.j Nucl Med 41, Anthony LB,Woltering EA, Espenan GD, Cronin MD, Maloney TJ & McCarthy KE (2002). Indium--pentetreotide prolongs survival in gastroenteropancreatic malignancies. Seminars in Nuclear Medicine 32, Buscombe JR, Caplin ME & Hilson AJ (2003). Long-term efficacy of highactivity In-pentetreotide therapy in patients with disseminated neuroendocrine tumors. Journal of Nuclear Medicine 44, Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J (2001). The clinical value of [Y-DOTA]-D-Phe1-Tyr3- octreotide (Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol 12, Waldherr C, Pless M, Maecke HR, et al (2002). Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq Y- DOTATOC. J Nucl Med 43, Bodei L, Cremonesi M, Zoboli S et al (2003) Receptor mediated radiotherapy with Y-DOTATOC in association with amino acid infusion ; a phase I study. Eur J Nucl Med 30, Paganelli G, Zoboli S, Cremonesi M, Macke HR, Chinol M (1999). Receptor-mediated radionuclide therapy with Y-DOTA-D- Phe1-Tyr3-Octreotide: preliminary report in cancer patients. Cancer Biother Radiopharm 14, Chinol M, Bodei L, Cremonesi M, Paganelli G (2002).Receptormediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group.Semin Nucl Med 32, Valkema R, Jamar F, Bakker WH, et al (2001). Safety and efficacy of [Y--DOTA, Tyr(3)]octreotide (Y--SMT487; OCTREOTHER TM ) peptide receptor radionuclide therapy (PRRT): preliminary results of a phase-1 study Eur J Nucl Med 28 : 1025P. 52. Valkemma R, Jamar F, Jonard P et al (2000). Targeted radiotherapy with Y-DOTA-Tyr3-octreotide (Y- SMT487;Octreother TM), a phase I study. J Nucl Med 41(Suppl), P. 53. Giusti M, Ciccarelli E, Dallabonzana D (1997) Clinical results of long term slow release lanreotide treatment of acromegaly. Eur J Clin Invest 27: Smith-Jones PM, Bischof C, Leimer M et al (1999). DOTA- Lanreotide: A Novel Somatostatin Analog fortumor Diagnosis and Therapy,Endocrinolgy 140, Virgolini I, Britton K, Buscombe J, Moncayo R, Paganelli G, Riva P (2002) In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin Nucl Med 3, Buscombe J R, Caplin ME, Bouvier C (2002 ) Treating somatostatin receptor positive tumours with Y-lanreotide J Nuc Med 43,34p 57. Buscombe J R, Caplin ME,Piggot K et al (2002). Physical and pharmacological targeting: Hitting neuroendocrine tumours with double whammy use of Y-lanreotide given intra-arterioly J Nuc Med 43, 316p 58. Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL et al. [177Lu-DOTAOTyr3]octreotate: comparison with [In-DTPAo]octreotide in patients. European Journal of Nuclear Medicine Kwekkeboom DJ, Bakker WH, Kam BL, et al (2003) Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu- DOTA 0,Tyr 3 ]octreotate. Eur J Nucl Med Mol Imaging 30, Reubi JC, Schar JC, Waser B, et al (2000) Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 27, Kwekkeboom DJ, Teunissen JJ, Bakker WH Bakkerey et al (2005) Radiolabeled somatostatin analog [177Lu- DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 23, de Jong M, Breeman WA, Valkema R, Bernard BF, Krenning EP (2005) Combination radionuclide therapy using 177Lu- and Ylabeled somatostatin analogs. J Nucl Med 46, 13S-7S 63. Shen S, DeNardo GL, Yuan A, DeNardo DA, DeNardo SJ (1994). Planar gamma camera imaging and quantitation of yttrium- bremsstrahlung. J Nucl Med 35, Gnanasegaran G, Buscombe JR (2005). Can In- Pentetreotide Predict the Bio-distribution of Y-Lanreotide? WJNM 4, Gopinath G, Buscombe JR, Heath G, Hilson A J W (2002). Biodistribution of Y- lanreotide and In- octreotide- Are they different? Nucl Med Com. 23; 4;

12 G Gnanasegaran et al 66. Gnanasegaran G, Buscombe JR, O Rourke E, Caplin ME, Purfield D, Hilson AJW (2005) Brehmsstrahlung imaging after intraarterial Y-lanreotide-radionuclide therapy for carcinoid liver metastases, Nucl Med Com, 26, McStay MK, Maudgil D, Williams M, Tibballs JM, Watkinson AF, Caplin ME, Buscombe JR. (2005)Large-Volume Liver Metastases from Neuroendocrine Tumors: Hepatic Intraarterial Y-DOTA- Lanreotide as Effective Palliative Therapy. Radiology.;237(2): Henze M, Schuhmacher J, Hipp P, Kowalski J, Becker DW, Doll J, Macke HR, Hofmann M, Debus J, Haberkorn U(2001).PET imaging of somatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-octreotide: first results in patients with meningiomas. J Nucl Med. ;42(7): Kowalski J, Henze M, Schuhmacher J, Macke HR, Hofmann M, Haberkorn U.( 2003), Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)- Octreotide in comparison to [In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol. 5(1): Henze M, Schuhmacher J, Hipp P, Kowalski J D, Becker DW, Doll J, Maecke H R, Hofmann M, Debus J Haberkorn U ( 2001). PET imaging of somatostatin receptors using 68 Ga- DOTA 0 -D Phe 1 -Tyr 3 -Octreotide (DOTATOC): first results in patients with meningiomas. J. Nucl. Med 42, Ugur O, Kothari PJ, Finn RD, Zanzonico P, Ruan S, Guenther I, Maecke HR, Larson SM.. (2002)Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors.nucl Med Biol;29(2): Karl H. Bohuslavizki.(2001) Somatostatin Receptor Imaging: Current Status and Future Perspectives, J. Nucl. Med 42: Hofland LJ, Lamberts SW, (2003).The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance Endocrine Reviews 24,