Peptide Receptor Radionuclide Therapy with Indigenous

Am J Nucl Med Mol Imaging 2020;10(4):178-211 www.ajnmmi.us /ISSN:2160-8407/ajnmmi0115339

Review Article One decade of ‘Bench-to-Bedside’ peptide receptor radionuclide therapy with indigenous [177Lu]Lu-DOTATATE obtained through ‘Direct’ neutron activation route: lessons learnt including practice evolution in an Indian setting

Sandip Basu1,2, Sudipta Chakraborty2,3, Rahul V Parghane1,2, Kamaldeep2,4, Rohit Ranade1,2, Pradeep Thapa1,2, Ramesh V Asopa1,2, Geeta Sonawane1,2, Swapna Nabar1,2, Hemant Shimpi1,2, Ashok Chandak1,2, Vimalnath KV3, Vikas Ostwal2,5, Anant Ramaswamy2,5, Manish Bhandare2,6, Vikram Chaudhari2,6, Shailesh V Shrikhande2,6, Bhawna Sirohi5,7, Ashutosh Dash2,3, Sharmila Banerjee1,2

1Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Parel, Mumbai, India; 2Homi Bhabha National Institute, Mumbai, India; 3Radiopharmaceuticals Division, BARC, Mumbai, India; 4Health Physics Division, Bhabha Atomic Research Centre, Mumbai, India; 5Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India; 6Department of Surgical Oncology, Gastrointestinal and Hepato- Pancreato-Biliary Service, Tata Memorial Hospital, Mumbai, India; 7Apollo Proton Cancer Centre, Chennai, India Received May 30, 2020; Accepted August 14, 2020; Epub August 25, 2020; Published August 30, 2020

Abstract: The present treatise chronicles one decade of experience pertaining to clinical PRRT services in a large- volume tertiary cancer care centre in India delivering over 4,000 therapies, an exemplar of successful PRRT programme employing indigenous 177Lutetium production and resources. For the purpose of systematic discussion, we have sub-divided the communication into 3 specific parts: (a) Radiopharmaceutical aspects that describes 177Lu- tetium production through ‘Direct’ Neutron Activation Route and the subsequent radiolabeling procedures, (b) The specific clinical nuances and finer learning points (apart from the routine standard procedure) based upon clinical experience and how it has undergone practice evolution in our setting and (c) Dosimetry results with this indigenous product and radiation safety/health physics aspects involved in PRRT services. Initiated in 2010 at our centre, the PRRT programme is a perfect example of affordable quality health care delivery, with indigenous production of the radionuclide (177Lu) in the reactor and subsequent radiolabeling of the radiopharmaceutical ([177Lu]Lu-DOTATATE) at the hospital radiopharmacy unit of the centre, which enabled catering to the needs of a large number of patients of progressive, metastatic and advanced Neuroendocrine Neoplasms (NENs) and related malignancies.

Keywords: Neuroendocrine neoplasms (NENs), neuroendocrine tumor, peptide receptor radionuclide (PRRT), somatostatin receptor (SSTR), [177Lu]Lu-DOTATATE, [90Y]Y-DOTATATE, Direct’ neutron activation route, 177Lutetium, chemo-PRRT, duo-PRRT

Introduction majority and partial response in a sizeable fraction of patients. The somatostatin receptor The somatostatin receptor (SSTR)-targeted th- subtype 2 (SSTR2), a member of the G-protein eranostics integrates [99mTc]Tc/[111In]In/[68Ga] coupled somatostatin receptor family (SSTR Ga-labelled diagnostic SPECT or PET imaging 1-5) is the principal target for PRRT, in view of and [177Lu]Lu/[90Y]Y-labelled therapeutic radio- its predominance in the NENs. The therapy is pharmaceuticals for ‘Peptide Receptor Radi- accomplished through intravenously adminis- onuclide Therapy’ (PRRT), that has seen rapidly tered unsealed radiopharmaceutical, the most increasing applications for metastatic or adv- common across the world being [177Lu]Lu- anced and progressive neuroendocrine neo- DOTATATE (DOTATATE = DOTA0-(Tyr3)-octreotate) 177 plasms (NENs), and gratifying cumulative clini- [ Lu: Eβ(max) = 0.497 MeV; maximum tissue cal experience for disease stabilization in range ~2.5 mm], while [90Y]Y-DOTATATE or PRRT with [177Lu]Lu-DOTATATE: a decade of experience

products of natural lutetium and ytterbium targets along with the nuclear decay characteristics of the product radionuclides are given in Table 1.

The indirect route of production offers two distinct advan- tages over the direct route, (i) it provides NCA 177Lu (theoretical specific activity 4.1 TBq/mg, 110.9 Ci/mg), which in turn leads to higher specific activity of the radiolabeled peptide (ii) 177Lu produced from indirect route is practically free from any radionuclide contaminant, provided a robust radiochemical separation strategy is Figure 1. Alternate routes for production of 177Lu in Nuclear Reactor. adapted to separate 177Lu from radionuclides of ytterbium. Dif- DOTATOC is the other beta emitting therapeutic ferent approaches have been successfully uti- alternative, in which the harder beta energy lized in the separation of clinical grade NCA 90 177 [ Y: Eβ(max) = 2.28 MeV] and longer range of Lu from bulk quantity of neutron irradiated 90Y (maximum tissue range ~11 mm) makes it ytterbium target [8-11]. Although, NCA 177Lu is more suitable for larger and heterogeneous available from commercial sources, the abso- tumors (albeit also accounting for its more lute need of a complex radiochemical separa- nephrotoxicity), while [177Lu]Lu-DOTATATE is tion procedure to isolate 177Lu of requisite puri- more efficacious for smaller tumors. ty is challenging and expensive. It can be shown by theoretical calculation that irradiation of 1 Radiopharmaceutical aspects: the 177Lutetium mg of 99% enriched (in 176Yb) Yb O target at a revolution 2 3 thermal neutron flux of 5×1014 n/cm2.s will produce only ~3.2 GBq (~87 mCi) of 177Lu. Production of 177Lu suitable for formulation of 177 0 3 177 [ Lu]Lu-DOTA -Tyr -octreotate ([ Lu]Lu- In contrast to any other medically useful radio- DOTATATE) for PRRT nuclides, direct (n, γ) route can be utilized for large-scale production of 177Lu in nuclear reac- Two alternative routes are available for produc- tors, having medium to high thermal neutron tion of 177Lu with adequate specific activity flux (1.0×1014 n.cm-2.s-1 or higher), using en- required for its utility in PRRT, as shown in 176 Figure 1. The first is the “direct” route which riched lutetium target (80% or more in Lu), involves the thermal neutron activation of high- with specific activity adequate for preparing ly enriched (in 176Lu) lutetium target [176Lu(n, receptor-specific therapeutic radiopharmaceu- γ)177Lu] in research reactors with medium to ticals. This is possible due to the following two 176 high thermal neutron flux [1-7]. The second reasons, (i) Lu has very high thermal neutron route or the “indirect” route is based on neu- capture cross section (σ = 2090 b, I0 = 1087 b) 177 tron irradiation of highly enriched (in 176Yb) yt- for formation of Lu and also that (ii) the neu- terbium targets leading to the formation of no- tron capture cross section of 176Lu does not fol- carrier-added (NCA) 177Lu from the β- decay of low 1/v law and there is a strong resonance 177 very close to the thermal region [12]. Con- the short-lived activation product Yb (T1/2 = 1.9 h) [3, 8-10]. The post-irradition radiochemi- sequently, it is possible to produce 177Lu of spe- cal processing in the former case involves sim- cific activity of more than 20 Ci/mg (740 GBq/ ple dissolution of the irradiated target, whereas mg) in a medium flux reactor. The most signifi- the latter route involves elaborate procedure to cant advantage of direct route over the indirect separate 177Lu from ytterbium targets as well route is the simplicity of post-irradiation chemi- as its radionuclides. The neutron activation cal treatment procedure, which makes it much

179 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Table 1. Neutron activation products of natural lutetium and ytterbium targets along with the nuclear decay characteristics of the product radionuclides Target Activation Target element % Abundance σ (barns) Mode of decay T Decay product isotope product 1/2 Lu 175Lu 97.41 16.7 176mLu β-, γ 3.66 h 176Hf 6.6 176Lu β-, γ 4×1010 y 176Hf 176Lu 2.59 2.8 177mLu β-, γ & IT 160.4 d 177Hf (78.6%) 177Lu (21.4%) 2090 177Lu β-, γ 6.65 d 177Hf Yb 168Yb 0.13 2300 169Yb EC 32.02 d 169Tm 170Yb 3.04 9.9 171Yb Stable 171Yb 14.28 58.3 172Yb Stable 172Yb 21.83 1.3 173Yb Stable 173Yb 16.13 15.5 174Yb Stable 174Yb 31.83 63 175Yb β-, γ 4.18 d 175Lu 176Yb 12.76 2.85 177Yb β-, γ 1.9 h 177Lu

achievable specific activity while keeping the contamination from 177mLu to a minimum [1, 3, 5, 8, 13].

In India, the clinical grade 177Lu used in PRRT is indigenously produced following the direct route, by irradiation of enriched lutetium oxide target (~82% enriched in 176Lu) at a thermal neutron flux of 1.6×1014 n.cm-2.s-1 at Dhruva research reactor, Bhabha Atomic Research Centre (BARC), Mumbai. The irradiated target is dissolved in 0.01 M ultrapure HCl solution in an aseptic environment to obtain sterile, pyrogen 177 free, [ Lu]LuCl3 solution as the radiopharma- Figure 2. Theoretical yield 177Lu as a function of ir- ceutical precursor. radiation time at the irradiation position in Dhruva research reactor in India (ф = ~1.6×1014 n.cm-2.s-1, The theoretical yield of 177Lu ‘A’ (in Bq) pro- k = 1.75). duced via 176Lu(n, γ)177Lu at the end of irradiation is calculated using the formula: less technologically demanding as well as vzm vz Nk01 - 1 kt - mvz t cost-effective compared to the other route. A = ee- ` + 2 j [1] Moreover, there is absolutely no impediment mz+ ^vv21- kh6 @ towards scaling up the production as per its 176 Where, where, N0 = number of Lu atoms used clinical requirement. On the contrary, the major 177 concern in the large-scale clinical utilization of as target (at t = 0), λ = decay constant of Lu -1 177Lu produced via the direct route, is the pres- (in s ), σ = thermal neutron capture cross sec- 176 ence of the co-produced 177mLu, with a long T tion of Lu at the neutron velocity of 2200 1/2 -1 of 160.4 days (Table 1), which creates problem m.s (2090 b), σ’ = thermal neutron capture 177 in the disposal of radioactive wastes arising cross section of Lu at the neutron velocity of from the treatment of large number of patients 2200 m.s-1 (1000 b), φ = thermal neutron flux beside the additional radiation dose burden to of the reactor (in n.cm-2.s-1), t = time of irradia- the patients. A careful optimization of the dura- tion and ‘k’ is so called k-factor, the value of ‘k’ tion of irradiation depending on the available is reported to be between 1.5-2.5 [7]. This thermal neutron flux of the reactor is essential expression of the yield of 177Lu is based on the in the direct route to obtain 177Lu in the highest assumption that the neutron flux is highly ther-

180 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

which do not lead to the formation of 177Lu by (n, γ) process. Based on Equation 2, the specific activity of 177Lu has been found to be 1.25 tim- es higher compared to the yield of 177Lu, when irradiations of Lu targets (~82% enriched 176Lu) were carried out in Dhruva at a thermal neutron flux of 1.6×1014 n.cm-2.s-1 for 14 d. This enhancement of specific activity is an added advantage for 177Lu towards its utilization in receptor specific therapeutic radiopharmaceuticals. Practically, the specific activity of 177Lu has been found to be 900 ± 78 GBq/mg (24.3 ± 2.1 Ci/mg) (averaged over

177 300 batches). Figure 3. Typical gamma-ray spectrum of [ Lu]LuCl3 used for the formulation of [177Lu]Lu-DOTATATE. The impurity burden of 177mLu in 177Lu produced in our case malized and there is practically no contribution was found be ~0.015% of 177Lu activity produce of epithermal neutrons towards 177Lu forma- at end of irradiation (EOI) and ~0.02% of 177Lu tion. Based on Equation 1, the variation of theo- activity produced at 48 h post-EOI, when 177Lu retical yield of 177Lu as a function of irradiation is generally used in the clinic. A typical gamma 177 time at the irradiation position in Dhruva (where ray spectrum of [ Lu]LuCl3 used for formula- k = 1.75) is shown in Figure 2. It is evident for tion of [177Lu]LuDOTATATE is shown in Figure 3, the figure that the yield is maximum (~21 Ci/mg which confirms very high radionuclidic purity of Lu) when irradiation is carried out for 13-14 of the radiopharmaceutical precursor. This days. Hence, Lu targets are irradiated for 2 implies that for each patient administered weeks for production of 177Lu in India. Also, it is with 7.4 GBq dose of 177Lu-labeled-S-analogue very interesting to note that, in case of 177Lu, peptide, the administered dose of 177mLu is there is a mismatch between the theoretically ~1.48 MBq (40 μCi). The presence of 177mLu at calculated specific activity and that actually this level is not a matter of serious con- obtained l from its yield per unit mass of the cern from the point of view of radiation dose target irradiated. This is due to the significant burden to the patients. However, the use of burn up of target during the irradiation for which each GBq of 177Lu will lead to the accumulation the actual mass of lutetium present in the sys- of ~200 kBq of radioactive waste of 177mLu to be tem, post irradiation is significantly reduced disposed by following delay and decay compared to the initial mass of the target irradi- approach. ated. Using the burn-up correction, the actual specific activity S (Bq/mol) of 177Lu can be Formulation of [177Lu]Lu-DOTATATE for clinical expressed as: use

A 177 S = The therapy doses of [ Lu]Lu-DOTATATE radio- --vzkt vz1 k vzkt - mv+ z t ++11- ` 2 j pharmaceutical are formulated mainly in hospi- nn0 ce ee m ^mz+ ^vv21- khh 6 @ tal radiopharmacy prior to clinical use following [2] a protocol optimized after extensive radiochemical studies. Moderate specific activity 177 where, n0 is the number of moles of the target [ Lu]LuCl3 produced (20-24 Ci/mg) indige- isotope 176Lu at the start of irradiation and n is nously by direct neutron activation route is the number of moles of other lutetium isotopes used for the formulation. The general protocol

181 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 4. Schema of General protocol for the synthesis of [177Lu]Lu-DOTATATE. followed for the synthesis of the radiopharma- (TMH). More than 4,000 therapies have been ceutical is presented schematically in Figure 4. successfully administered with [177Lu]Lu-DOTA- During the last decade more than 400 batches TATE in around 1000 patients, and has involved of the [177Lu]Lu-DOTATATE were synthesized patients of (i) Gastroenteropancreatic NENs (10-15 therapeutic doses in each batch) with (GEP-NENs), (ii) Metastatic NEN with unknown >95% radiochemical purity, as confirmed by primary (CUP-NEN) (iii) Bronchopulmonary, Me- radio-HPLC (Figure 5). The specific activity of diastinal and Thymic NENs, (iv) Medullary thy- the formulation varied from 1.0 mCi/µg (53.1 roid carcinoma (MTC), (v) non-[131I]I-MIBG con- GBq/µmol) to 1.2 mCi/µg (63.8 GBq/µmol) of centrating metastatic Paraganglioma & Pheo- DOTATATE. The specifications of the radiophar- chromocytomas, and (vi) other miscellaneous maceutical formulation are summarized in tumors (non-iodine concentrating metastasis Table 2. of differentiated thyroid carcinoma or TENIS, metastatic Merkel Cell carcinoma, Meningioma, PRRT: clinical services recurrent/inoperable Phosphaturic Mesenchy- The PRRT clinical services was initiated at the mal Tumor and sinonasal neuroendocrine carci- Radiation Medicine Centre (RMC) -Tata Me- noma) (Table 3; Figure 6). The PRRT with [90Y] morial Hospital (TMH) premises in 2010, by the Y-DOTATATE is relatively new addition that has joint efforts of Radiation Medicine Centre (RM- started from September 2019 as a part of duo- C), BARC (Bhabha Atomic Research Centre) and PRRT protocol, which is at its optimization GI services of the Tata Memorial Hospital phase at present (detailed later). The important

182 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 5. Typical HPLC radio-chromatogram of [177Lu]Lu-DOTATATE formulation. HPLC was carried out using a dual pump HPLC unit with a C-18 reversed phase HiQ-Sil (5 μM, 25 cm×0.46 cm) column. The elution was monitored both by detecting UV signals at 270 nm as well as by radioactivity signal using NaI(Tl) detector. Gradient elution with Water (A) and acetonitrile (B) mixtures with 0.1% trifluoroacetic acid were used as the mobile phase (0-5 min 90% A, 5-15 min 90% A to 10% A, 15-20 min 10% A, 20-25 min 10% A to 90% A, 25-30 min 90% A). Flow rate was maintained at 1 mL.min-1.

Table 2. Specifications of 177[ Lu]Lu-DOTATATE therapy dose (~7.4 GBq, 200 and have shared our mCi) formulation perspectives on these Parameter Specification themes or issues. Appearance Clear pale yellow solution without any suspended particulate The clinical efficacy pH ~4.5 of 177Lu obtained Volume ~1.0 mL through “Direct” route Radionuclidic purity >99.95% as a therapeutic Radiochemical purity >95.0% radiopharmaceuti- Sterility Sterile formulation cal: results in major Apyrogenicity Pyrogen content <25 IU/mL malignancies

As mentioned before, Table 3. Spectrum of Malignancies treated by PRRT with 177Lu-DOTATATE two alternative strate- and their relative distribution gies are available for 177 Patients characteristics Number of Patients production of Lu with adequate specific 177Lu-DOTATATE PRRT 1000 90 activity required for Y-DOTATATE PRRT 11 its utility in PRRT. The Site of primary disease for 1000 pts first is the so called Gastroenteropancreatic NENs (GEP-NENs) 781 “direct” route which Metastatic NEN with unknown primary (CUP-NEN) 87 results in the produc- Lung NENs 30 tion of carrier-added Mediastinal/thymus NENs 27 177Lu. The second rou- Medullary Thyroid carcinoma (MTC) 50 te or the “indirect” rou- Pheochromocytomas and Paraganglioma (PCC/PGL) 15 te is based on neu- Miscellaneous 10 tron irradiation of highly enriched (in 176Yb) ytterbium targets lea- milestones in our clinical PRRT programme has ding to the formation of no-carrier-added (NCA) been depicted in Figure 7. Under this sections, 177Lu from the β- decay of the short-lived activa- 177 we have elaborated upon the learning points tion product Yb (T1/2 = 1.9 h).

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centre looked into 50 patients with histopathologically confirmed metastatic/inoperable GEP-NETs (M:F 33:17, age: 26-71 years) who had undergone at least three cycles of PRRT with [177Lu]Lu-DOTATATE [19]. Symptomatic response was documented in more than 90% of patients in terms of improvement in health-related quality of life, the disease control rate (stable disease and partial response by scan) was observed in ~80% of cases. One point of note in this study was that (a) high pre- 177 Figure 6. Pie Chart of Spectrum of Malignancies treated by PRRT with [ Lu] therapy FDG SUVmax values Lu-DOTATATE and their relative distribution. were associated with increased chances of treatment refracto- In India, more than 90% of the PRRT proce- riness (disease control rate 52.94% versus dures (nearly all government centres and major- 96.97% in patients with absence of FDG ity of the private centres) are undertaken using uptake) and (b) symptomatic improvement was 177Lu obtained via the first pathway indigenous- observed in most cases irrespective of tumor ly in the research reactor. There has been Ki-67 index (Table 5A and 5B). In a recent anal- some debate on the efficacy of 177Lu produced ysis of a total of 468 patients with proven GEP- through the direct route. At our Centre, we have NEN who underwent from 2 to 7 cycles (at the obtained gratifying response with the indige- interval of 10-12 weeks) of intravenous [177Lu] nous product in large number of patients with Lu-DOTATATE PRRT at our centre, the overall clinical results similar to that is reported with clinical results are further depicted partial the product from the ‘indirect’ route (two clini- response by PERCIST and RECIST 1.1 of 25% cal examples depicted in Figures 8-11) in the and 27% and stable disease of 57% and 60% literature [14-18]. There was excellent concor- respectively. The PFS at 7 yrs was 71.1% and dance of the ranges in tumor absorbed doses OS was 79.4%. A total of 39 (8%) patients died (estimated in metastatic NET patients during 177 out of 468 patients at 7 years (unpublished different PRRT cycles) with indigenous [ Lu] work; personal communication). The PRRT pro- Lu-DOTATATE and that by the 177Lu produced cedures were well-tolerated with minimal neph- through ‘indirect’ route (a comparative table of rotoxicity (grade 1: 3.5%, grade 2, grade 3 and the tumor absorbed doses with the reported grade 4: <1% each) and hematotoxicity primar- studies and our own experience has been illus- trated in Figure 11; Table 4). Herein we present ily of grade 1 (1.7%), grade 2 and grade 3, 0.2% the comparative data with contemporary litera- each and no grade 4 hematotoxicity (Figures 8 ture in the 3 most common malignancies wh- and 9). ere the [177Lu]Lu-DOTATATE PRRT has been employed in our services viz. (i) Metastatic In a short series of metastatic NETs (both Advanced and Progressive Gastroenteropa- GEP-NEN and pulmonary NENs) with extensive ncreatic Neuroendocrine Tumors, (ii) Metasta- bone marrow involvement at diagnosis, the tic Advanced Pulmonary and Mediastinal majority (four out of five patients, i.e. 80%) of Neuroendocrine Tumors, and (iii) Metastatic the patients had excellent symptomatic Medullary Carcinoma of thyroid. response with at least stabilization of the disease at a follow-up period of 10-27 months Metastatic advanced and progressive gas- [20]. The single patient who had a progres- troenteropancreatic neuroendocrine tumors: sive disease also had a good symptomatic An interim analysis during 2014-2015 at our response in the initial 6 months from the

184 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 7. The important milestones in the Clinical PRRT Services and Practice Evolution in our set-up.

Figure 8. Post-PRRT complete response (CR) in a known patient of grade I (Ki-67 index = 1%) pancreatic NET with multiple hepatic metastases. The baseline [68Ga]Ga-DOTATATE scan (A) showed intensely SSTR avid multiple liver lesions and pancreatic tail lesion. Patient received 3 cycles of [177Lu]Lu-DOTATATE PRRT (cumulative dose of 550 mCi/20.35 GBq). The [177Lu]Lu-DOTATATE post-therapy scan (B) showed good concentration of tracer in liver lesions and pancreatic lesion. Following 3 cycles of PRRT, follow-up [68Ga]Ga-DOTATATE scan (C) showed complete resolution of liver lesions and pancreatic lesion suggestive of CR. first dose of PRRT. Despite the extensive bone rovement of health related quality of life in marrow involvement, no hematological toxi- patients with extensive metastatic disease city was observed (only one patient showed (Figure 12). Grade I anaemia), suggesting that PRRT was well-tolerated by this particular subgroup. We A large body of literature and guidelines exist have obtained gratifying response and imp- today demonstrating efficacy of 177 [ Lu]Lu-

185 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 9. Post-PRRT partial response (PR) in a case of grade II pancreatic NET (Ki-67 index = 5%) with liver metastases. Pre-PRRT [68Ga]Ga-DOTATATE PET-CT (A) showed intensely tracer avid pancreatic lesion measuring 8×7 cm and few metastatic liver lesions. The patient received 5 cycles of PRRT with [177Lu]Lu-DOTATATE (cumulative dose: 800 mCi/29.6 GBq). Post-PRRT, [68Ga]Ga-DOTATATE scan (B) showed reduction in size of pancreatic lesion (4×3.7 cm) and liver lesions suggestive of partial response to PRRT.

Figure 10. (A) 53 year old female, diagnosed as a case of atypical carcinoid of lung (MiB1 index of 6-10%), MiB-1 index of 6-10%. Multiple SSTR positive lesions in liver, both lungs, multiple rib & right sided pelvis, received 3 cycles of chemotherapy with cisplatin and etoposide with progression of disease. Excellent partial response was observed in the [68Ga]Ga-DOTATATE PET-CT (A). The patient had a FDG negative disease at baseline (B). She reported a dramatic decrease in symptoms including decrease in abdominal pain and frequency of diarrhea. Also reported weight gain and overall improvement in general condition and health related quality of life.

DOTATATE in metastatic GEP-NENs [22-29]. analysis of 22 studies (1758 patients) esti- Wang et al in a systematic review and meta- mated an overall CR+PR of 35.0% and

186 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 11. Illustration of comparison of tumor absorbed doses in different therapy cycle and a comparative table of the tumor absorbed doses with the reported studies and our own experience with indigenous [177Lu]Lu-DOTATATE, demonstrating excellent concordance (Table 4).

Table 4. Comparisons of tumor absorbed doses with literature data Literature Absorbed dose per unit activity (Gy/GBq) Ulrike Garske et al EJNMMI 201815 2.8-5 Ezgi Ilan et al JNM 201516 1.35-45.95 Christiane W. et al Cancer Biother. & Radiopharm. 200717 3.0-15.1 Michael Garkavij et al Cancer, 201018 0.1-20 Our experience 1.15-20.5

Table 5A. PRRT response in total 50 GEP-NETs 443 patients, were 29 and 63 months respec- on Symptomatic and PET-CT imaging [19] tively. Thus, the clinical results with the indige- 18F-FDG/68Ga-DOTATATE nously produced 177Lu has been in agreement Response Symptomatic PET/CT imaging with what has been reported in the literature responders (Table 6) [29]. Yes (PR+SD) 96% 82% No (PD) 4% 18% Metastatic advanced pulmonary and mediastinal neuroendocrine tumors: Metastatic pulmonary and mediastinal neuroendocrine tumors CR+PR+SD of 83% (on RECIST 1.1) [26]. form the next tumor group that is considered Another systematic meta-analysis of 15 stud- for the [177Lu]Lu-DOTATATE peptide receptor ies by Zhang et al reported a CR+PR of 27.58% radionuclide therapy [PRRT] in our setting. In on RECIST 1.1 and CR+PR+SD of 79.14% on an initial analysis in metastatic/advanced pul- RECIST 1.1 [27]. The PFS and OS were not esti- monary (NETs) in 19 patients, symptomatic mated in both of these meta-analyses. Ezzidin response following PRRT was observed in 79%. et al [28] in their study of 74 patients with a A total of 63% were finally characterized as median follow-up of 47 months, had document- responders and 37% were overall non-res- ed a PFS and OS of 26 months and 55 months ponders to PRRT based upon predefined respectively, while that by Brabander et al in 3-scale response evaluation criteria. All 7

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Table 5B. PRRT response in GEP-NETs with respect to SSTR-based and [18F]F-FDG PET/CT imaging findings [19] [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT finding → Discordance (SSTR>FDG Concordance (SSTR≤FDG PRRT response ↓ avid lesions, n = 33) avid lesions, n = 17) Yes (n = 41, 82%) 32/33 (96.97%) 9/17 (52.94%) No (n = 9, 18%) 1/33 (3.03%) 8/17 (47.06%)

Figure 12. A 35 year old female, diagnosed patient of duodenal NET (MiB1 labeling index 20%) with liver metastasis (involving left lobe) and history of radiofrequency ablation of the liver metastasis and external radiotherapy six months previously, was referred for exploring the feasibility of PRRT. Despite such extensive disease, the patient started working at 4 years. (A) [99mTc]Tc-HYNIC-TOC SSTR Imaging and (C) [177Lu]Lu-DOTATATE post therapy scan showing tracer uptake in residual primary tumor in duodenum (dotted arrow) and liver lesion (thin solid arrow) with fairly large area of photopenia suggesting necrosis. Diffuse uptake over axial and appendicular skeleton (with interspersed areas of focal uptake, particularly in left parietal bone) and intense bilateral uptake in breast nodules (thick solid arrows) indicate metastases from NET. (B) [18F]F-FDG PET/CT demonstrating relatively intense uptake in duodenal primary tumor (dotted arrow), intense uptake bilaterally in metastatic breast nodules (solid arrows), low- grade [18F]F-FDG uptake in liver lesion, and no uptake in bone marrow. (Reproduced with permission21).

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Table 6. Meta-analysis and literature reports of response and survival of PRRT in metastatic GEP-NETs No of studies/ Radionuclide used Follow up period Response on anatomical or Name/author of the study PFS OS patients analyzed for PRRT after PRRT molecular Wang LF et al26 Systematic meta-analysis 22 studies (1758 patients) 177Lu and 90Y-DOTATATE Review article 35.0% = CR+PR on RECIST 1.1 Not evaluated Not evaluated 83% = CR+PR+SD on RECIST 1.1 Zhang J et al27 Systematic meta-analysis 15 studies 177Lu and 90Y-DOTATATE Review article 27.58% = CR+PR on RECIST 1.1 Not evaluated Not evaluated 79.14% = CR+PR+SD on RECIST 1.1 Ezzidin et al28 74 177Lu-DOTATATE 47 months (me- 36.5% PR, 17.6% MR, 35.1% SD, 26 mo 55 mo dian follow up) and 10.8% PD Brabander et al29 443 177Lu-DOTATATE Not mentioned SD-36% 29 mo 63 mo

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Table 7. Response evaluation to PRRT in 19 pulmonary NET patients [30] Response Symptomatic evaluation Biochemical evaluation PERCIST* RECIST 1.1** Complete response 42% 7% 5% 5% Partial Response 26% 15% 10% 5% Minor response 20% 20% Stable disease 12% 31% 18% 37% Progressive disease 20% 47% 47% 33% PERCIST*=PET response criteria in solid tumors. RECIST 1.1**=Response Evaluation Criteria In Solid Tumors.

Table 8. Response evaluation to PRRT in 30 patients sion (Table 9; Figure 14). The median PFS of metastatic pulmonary NETs over last 10 years and OS were 36 months and 66 months Response Symptomatic Biochemical RECIST 1.1 PERCIST respectively. Significant level of associa- CR 42% 7% 4% 5% tion of PFS was observed with surgical intervention, higher cumulative PRRT PR 26% 15% 8% 12% dose, metabolic response, smaller sized SD 12% 31% 57% 36% primary lesion, and low lesional FDG PD 20% 47% 31% 47% uptake; with respect to the OS, higher cumulative PRRT dose, low FDG uptake non-responders had moderate to intense FDG- and longer PFS showed significant association avid primary lung lesion and 5 had FDG- [32]. There is relatively sparse clinical study avid metastatic liver disease (SUVmax >5) data in the literature till date on [177Lu] (Table 7). The median OS was 40 months [30]. Lu-DOTATATE PRRT in metastatic mediastinal/ The results obtained were well-commensurate thymic NETs, which are primarily reported as with two studies reported in literature on case reports. 177Lu-octreotate in metastatic pulmonary neu- We have to mention here that for both meta- roendocrine tumors, where the progressive dis- static pulmonary and mediastinal NENs, in ease reported were 32% and 30%, one in addition to the aggressive biology of this tumor pure metastatic pulmonary NET scenario [31] group, PRRT has been usually considered at an and the other in a combined analysis of patients advanced state following chemotherapy failure with gastroenteropancreatic and bronchial which we believe could be partly responsible neuroendocrine tumors [29]. In the study by for its relatively inferior outcome compared to Sabet et al, the DCR was 67% (PR = 27%, SD = the GEP-NENs. 41% and CR 0%) matches well with the res- ponder group of 63% in our preliminary anal- Metastatic medullary carcinoma of thyroid 68 ysis [30, 31]. Response evaluation to PRRT in (MTC): [ Ga]Ga-DOTATATE positive metastatic rd 30 patients of metastatic pulmonary NETs MTC forms the 3 most common indication for over last 10 years shows a PD of 31% on RE- PRRT in our set-up. In a total of 43 somatosta- CIST 1.1 and 47% on PERCIST & biochemical tin receptor-positive metastatic MTC patients treated with [177Lu]Lu-DOTATATE PRRT [33], parameters (unpublished work; personal com- 61% were responders and 39% were nonre- munication). Thus, the DCR (SD+PR+CR) by sponders based upon PERCIST criteria, while RECIST 1.1 was 69% and by PERCIST & bio- with RECIST 1.1 criteria 62% were responders chemical parameters was 53% (Table 8; and 38% were non-responders (Figure 15). Figures 10 and 13). Significant association between responses to PRRT was observed with following prognostic With regard to mediastinal NETs, twenty-seven variables: (a) size of lesions (<2 cm) and (b) FDG patients with histopathologically and radio- uptake in lesions (SUVmax of <5). PRRT was logically proven metastatic or advanced me- well tolerated in all patients without any major diastinal NET, who had undergone [177Lu] grade 3 or 4 toxicity. The median OS was 26 Lu-DOTATATE PRRT, metabolic PET-CT response months and the median PFS 24 months. There evaluation demonstrated partial metabolic are much smaller series that have been pub- response in 33.3%, metabolically stable dis- lished in this domain and more results may be ease was seen in 18.5%, while 44.4% of the awaited for comparison with the indigenous patients showed metabolic disease progres- [177Lu]Lu-DOTATATE (Table 10) [34, 35].

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Figure 13. A. Patient of Pulmonary NET with hepatic metastases, presenting with profound anorexia and weight loss over previous 2 months. The baseline [68Ga]Ga-DOTATATE (a) and FDG PET-CT in May 2016 show tracer avid left lung mass and multiple liver lesions with minimal to absent FDG uptake in the lesions (b). The patient received 5 cycles of PRRT from June 2016 to Dec 2017 (750 mCi/27.75 GBq). B. In 2018, the patient was asymptomatic with decrease in serum CgA level and [68Ga]Ga-DOTATATE PET-CT showed no changes in size, number of lesions or tracer uptake in the primary left lung lesion and metastatic liver lesions, with increase in necrotic changes in liver and lung lesions-suggesting disease stabilization in this case.

Table 9. Response evaluation results of Medi- Dual tracer PET-CT in individualizing treatment astinal NETs to [177Lu]Lu-DOTATATE PRRT [32] regimen in NENs: a valuable adjunct alongwith Response Symptomatic Metabolic Anatomical tumor Ki-67/MIB-1 index in assessing tumor CR 37% 3.7% 0% biology PR 25.9% 33.3% 22.2% While the tumor Ki-67/MIB-1 labeling index SD 14.8% 18.5% 25.9% forms an integral part of assessment of meta- PD 22.2% 44.4% 51.9% static NENs, dual tracer PET-CT molecular

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Figure 14. 177Lu-DOTATATE PRRT in disease stabilization of Thymic NET. The patient was diagnosed case of MEN 1, with thymic NET (Mib-1 index = 15%), pituitary adenoma and parathyroid adenoma. He was operated for pituitary adenoma, parathyroid adenoma and inoperable for thymic NET. He was evaluated for PRRT in view of inoperable and metastatic disease. [68Ga]Ga-DOTATATE and FDG-PET/CT showed SSTR and FDG avid enlarged mediastinal lesions (A), patient received 2 cycles of PRRT (B), the follow-up [68Ga]Ga-DOTATATE and FDG PET/CT in Dec 2017 (C) demonstrates stable disease.

Figure 15. Metastatic MTC treated with [177Lu]Lu-DOTATATE PRRT. Diagnosed case of MTC with past history of total thyroidectomy and bilateral selective neck dissection presents with follow-up serum calcitonin of 6271 pg/ml and CT abdomen showing metastatic liver lesions. Baseline [68Ga]Ga-DOTATATE PET-CT (A) showed intensely SSTR avid (Krenning score = 4) bilobar liver lesions (SUVmax 25) and bony metastasis in right acetabulum (SUVmax 23). Subsequently, the patient received 2 cycles of PRRT (300 mCi). 177Lu-DOTATATE post therapy scan (B) showed good

192 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience concentration of tracer in liver and skeletal lesions. Post-PRRT [68Ga]Ga-DOTATATE PET-CT (C) showed reduction in SSTR uptake in liver lesions (SUVmax 16) and right acetabulum bony lesion (SUVmax 13) with significant reduction serum calcitonin level from 6271 to 2167 pg/ml, suggestive of favorable response to PRRT.

Table 10. PRRT response evaluation in MTC patients and also those with Ki-67 LI between in four categories [33] 20-30%: Wide variation in tumor behav- Response Symptomatic Biochemical RECIST 1.1 PERCIST iour at both of the above regions of Ki-67 index, where the relative uptake of [68Ga] CR 19% 11% 0% 0% Ga-DOTATATE and FDG becomes particu- PR 28% 30% 4% 10% larly useful for deciding on the therapy on SD 4% 10% 58% 51% an individualized basis. Having observed PD 49% 49% 38% 39% this early-on, we have adopted the practice routinely in our Institute. imaging findings (somatostatin receptor based The observation made over years have been [68Ga]Ga-DOTATATE and tumor glucose metabo- recently reflected by the WHO 2017 NEN grad- lism with FDG) has developed into a valuable ing. Amongst the grade 3 NENs, there is now adjunct for personalizing the treatment regi- increasing recognition of a ‘well differentiated men in this group of patients (Figure 15). Sev- NEN composed of cells showing minimal to eral studies in the early years including ours moderate atypia, lacking necrosis and expre- had observed that tumors with low or negligible ssing general markers of neuroendocrine dif- FDG uptake respond well to somatostatin tar- ferentiation (diffuse and intense synaptophy- geted therapy, while those with high FDG sin and chromogranin A)’ which contrasts to the uptake demonstrates refractoriness to PRRT ‘poorly differentiated NEN is composed of high- alone [19, 37]. The relative uptake of [68Ga] ly atypical small or large cells expressing faint Ga-DOTATATE and FDG enables assessment of neuroendocrine differentiation markers’. Hen- the dynamic tumor biology of NENs on a con- ce, two different subsets within the grade 3 tinuous scale and is utilized for clinical decision NENs are now recognized by the recent WHO making and personalizing the treatment strate- 2017 NEN classification, distinguishing well dif- gies [38]; depending upon the dual tracer PET- ferentiated grade 3 neuroendocrine tumours CT findings, the patients are subdivided into 3 (NET G3) from poorly differentiated grade 3 classical subgroups: (i) Tumors with low Ki-67 neuroendocrine carcinomas (NEC G3), which is an important step from management view- index, are usually positive on SSTR imaging points. with low/absent FDG uptake: they are candidates for SSA and PRRT, (ii) Tumors with high Dual tracer PET-CT findings of the relative trac- Ki-67 index, are usually negative on SSTR er accumulation in tumor lesions based upon based imaging and shows high uptake on FDG- somatostatin receptor expression (by [68Ga]Ga- PET/CT: are candidates for chemotherapy DOTATATE/NOC PET-CT) and tumor glycolysis (CAPTEM if the Ki-67<55% or platinum based (by FDG-PET/CT), can potentially aid in deci- chemotherapy if the Ki-67>55%) (Figure 16). phering the aforementioned tumor characteris- (iii) Tumors demonstrating both high [68Ga] tics, and differentiating NET G3 from NEC G3. A Ga-DOTATATE and 18F-FDG uptake on dual trac- high [68Ga]Ga-DOTATATE/NOC with low/absent er PET/CT form the intermediate grey zone and FDG uptake would be more consistent with the intermediate Ki-67 index, wherein a combined diagnosis of G3-NEC. approach of PRRT plus chemotherapy is employed (Figures 17-19) [36, 38, 39]. (ii) Discordance between Ki-67/MIB-1 and the dual tracer PET-CT findings: Though the stan- The specific areas where this manoeuvre dard findings on dual tracer PET-CT is charac- becomes particularly useful for clinical decision teristic and remains in agreement with the making are: reported Ki-67/MIB-1 labeling index, the outli- ers or exceptions are not uncommon in day-to- (i) The tumor biology in tumors with intermedi- day practice. Herein two considerations need ate level of Ki-67 labeling index (e.g. 10-20%) to be made: (a) Ki-67/MIB-1 labeling index from

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Figure 16. Dual tracer PET-CT as valuable adjunct in personalizing treatment regimen in metastatic NENs (Repro- duced with permission from Basu et al36). a single lesion and single-site biopsy could be crine neoplasms (GEP-NENs) that are (ii) pro- fraught with its inability to assess the tumor gressive on Synthetic Somatostatin Analo- biology as a whole on a continuous scale and gues (SSAs) and demonstrate high grade (b) even in the same individual, interlesional uptake (Krenning score 3 or 4 on semi-quanti- heterogeneity can exist, thus one biopsy speci- tative scale) on SSTR based [68Ga]Ga-DOTATOC/ men may not be representative of all lesions, TATE PET-CT or [99mTc]Tc-HYNIC-TOC SPECT-CT. which could be better portrayed by the molecu- (iii) Symptomatic functioning NENs, who are lar PET-CT imaging (Images of case examples: resistant to the long-acting SSAs (octreotide/ Figures 20, 21). In our set-up the findings in the lanreotide) form another group where PRRT is PET-CT imaging forms an important parameter usually considered. Beyond the aforemen- and given equivalent important to the Ki-67 tioned indications, the clinical applications of index for clinical decision-making of therapies PRRT has been widened substantially over the in metastatic NENs, if not more. recent years, and can be subdivided into two PRRT beyond classical indication of GEP-NENs: groups: (A) extended indications within GEP- expanding the boundaries of SSTR based NENs and (B) applications in tumors beyond Theranostics GEP-NENs.

The classical standard indications for PRRT has Extended indications within GEP-NENs: The fol- been (i) metastatic and unresectable advanced lowing two groups of GEP-NEN patients are now grade I or II gastroenteropancreatic neuroendo- frequently considered for PRRT with 177Lu-

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Figure 17. [68Ga]Ga-DOTATATE and [18F]F-FDG PET-CT in a patient of CUP-NET with Ki-67 index = 2% showing matched histopathology and dual tracer molecular PET-CT imaging finding with minimal FDG and avid [68Ga]Ga-DOTATATE uptake.

Figure 18. A known case of NEC with unknown primary site. Pre- senting with complaints of abdominal pain and cough, the biopsy from abdominal lesions showed metastatic carcinoma with neuroendocrine differentiation and posi- tivity for CK7, synaptophysin and negativity for chromogranin and p40. Ki-67 index was 80-90%. The patient did not receive any treatment before the molecular imaging. [18F]F-FDG PET-CT scan (A) showed intensely FDG avid multiple liver lesions, lung nodules, skeletal lesions and mesenteric deposits with no uptake in above- mentioned lesions on [68Ga]Ga- DOTATATE PET-CT (B). The patient is NOT a suitable case for PRRT.

DOTATATE and increasingly be- coming clinical routine: (iv) In NENs with MIB-1 index between 20 and 30%, a sizeable fraction of patients demonstrate high uptake on [68Ga]Ga- DOTATATE PET-CT, where PRRT can be successfully employed [40]. Amongst this subgroup, a fraction of patients do show

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centrating metastatic Paraga- nglioma & Pheochromocyto- ma (Figure 22); (d) Non-iodine concentrating metastasis of differentiated thyroid carcinoma (TENIS: only 15-20% of this patient subgroup demonstrates enough uptake to justi- fy PRRT)**, [41]; (e) Other tumors with neuroendocrine tumor differentiation/character- ization: metastatic Merkel Cell carcinoma, Meningioma and recurrent/inoperable Phosph- aturic Mesenchymal Tumor, Re- current Metastatic Sinonasal Neuroendocrine Carcinoma, Recurrent metastatic large cell neuroendocrine carcinoma (LC- NEC) of larynx (Figure 23) [42-46].

‘**’ represent clinical indications where PRRT has been considered even though there Figure 19. Dual tracer PET finding matched with that predicted by HPR. was a lesser degree of uptake Pancreatic NET with liver lesions, Ki-67 index = 15%, showing high uptake (Krenning score 2) on SSTR 68 on both [ Ga]Ga-DOTATATE (A) and FDG (B) PET-CT. The patient is a typical based scanning, in view of the case for consideration for combined chemo-PRRT. fact that alternative experi- mental therapies were either high uptake of FDG additionally, wherein we potentially toxic, only modest efficacious or advocate combined chemo-PRRT (the regimen expensive. The aforementioned list of PRRT employed in our set-up is detailed later). The indications is partly adapted with newer addi- ESMO clinical practice guidelines for GEP-NENs tions from Basu et al46). advocates PRRT upto Ki-67 of 30%. The role of [99mTc]Tc-HYNIC-TOC SPECT/SPECT- (v) While usually PRRT is considered in patients CT as decision making scan in the absence of 68 with disease progression on cold somatostatin [ Ga]Ga-DOTATOC/NOC/TATE PET-CT analogues, there has been increasing adoption The diagnostic modality of choice for SSTR of this treatment modality upfront at diagnosis based imaging is [68Ga]Ga-DOTATOC/NOC/TATE in patients with widely metastatic disease on PET-CT, which has been proven superior to whole body diagnostic SSTR based study, the other conventional diagnostic modalities where the disease is already ‘progressed’ in- including the other whole body functional imag- volving multiple sites. ing (such as [111In]In-octreotide or [99mTc] Tc-HYNIC-TOC SPECT-CT), in view of its superior Tumors beyond Gastroenteropancreatic NENs resolution and ability for quantification. (GEP-NENs): Over the years, we have now acquired fair amount of experience in various However, in the absence of PET-CT or 68Ge/68Ga ‘beyond GEP-NENs’ indications, wherein 177Lu- generator, the mandatory requirements for DOTATATE PRRT provide good disease stabiliza- [68Ga]Ga-DOTATOC/NOC/TATE PET-CT, a factor tion in substantial fraction of patients. These to be considered in several peripheral centres include: (a) metastatic/inoperable Bronchopu- in developing nations, [99mTc]Tc-HYNIC-TOC pla- lmonary and Mediastinal/Thymic NENs, [30, nar and SPECT-CT gamma camera based imag- 32]; (b) metastatic/inoperable Medullary thy- ing can do reasonably well for decision making roid carcinoma** [33]; (c) Non-131I-MIBG con- of PRRT in patients with large volume disease.

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Figure 20. Discordance between Ki-67 and dual tracer PET-CT findings in a patient of metastatic NET of unknown primary site, liver biopsy reported as metastatic NET with Ki-67 index = 22%. [68Ga]Ga-DOTATATE PET-CT (A) showed intensely SSTR avid multiple liver and wide spreads skeletal lesions. [18F]F-FDG PET-CT (B) showed mild FDG uptake in liver lesions and faint FDG uptake in skeletal lesions.

Figure 21. Discordance between Ki-67 and dual tracer PET-CT findings in a patient of pancreatic NET with pancreatic mass involving the body and tail with splenic and colonic infiltration. HPR:NET with Ki-67:1-2%. However, shows low grade SSTR based 68Ga-DOTATATE uptake (left panel) but high on FDG (right panel) PET-CT.

In India, [99mTc]Tc-HYNIC-TOC is available for kit formulation method which played important role in the initial years of PRRT development at our set- up (Figures 24, 25) [47].

Patient preparation in specific clinical scenarios

Large volume functioning hepatic metastases: minimizing the incidence of ‘carcinoid cri- sis’: Overall, PRRT is a very well-tolerated procedure with minimal adverse effects, however, post-PRRT acute carcinoid syndrome (“carcinoid cri- sis”) is a rare but life-threatening risk that requires emergency

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Figure 22. Diagnosed patient of invasive paraganglioma of carotid body, Mib-1 index 10%, the patient underwent excision of right carotid body tumor in 2013 and received post-operative EBRT in 2013. Presented with bony pain and headache in 2016. Patient evaluated for PRRT, the [68Ga]Ga-DOTATATE (B) and FDG PET/CT (A) showed multiple skeletal lesions and lung nodules, following which the patient received 2 cycles of PRRT (C). In 2017 both [68Ga]Ga- DOTATATE (D) and FDG PET/CT show SSTR and FDG avid lesions with no change as compared to baseline-suggesting stable disease (SD) in metastatic paraganglioma with PRRT.

Figure 23. Observation of [68Ga]Ga-DOTATATE (A) avid metachronous Meningioma in a known patient of pancreatic NET (Ki-67 index = 4%) with metastatic liver lesions. Initially the patient underwent right hepatectomy and pancre- aticoduodenectomy in 2015. In subsequent years, he complained of abdominal pain, weakness and headache. 68Ga-DOTATATE PET-CT showed SSTR avid brain lesion (B, blue arrows), liver lesion (C), skeletal lesion (D), abdominal lymph nodal and lung lesions (E). Meningioma was confirmed on MRI of brain region. medical management. This is typically observed cyproheptadine on a regular basis 1 to 2 days in patients with large volume functioning hepat- before scheduled PRRT is also a helpful prac- ic metastases. In our experience, adequate tice (it exerts its action as a potent antagonist patient preparation is key to minimize the inci- of the 5-HT2 receptors). dences in these cases, which would involve short acting octreotide injections (subcutane- Protein deficiency, poor nutrition status and ous) till 1 day before of PRRT and initiate the generalized anasarca: enhancing the chances same next day following PRRT continuing for 2 of undertaking PRRT: This is a challenge to the weeks. Priming this subgroup of patients with attending physicians, more relevant to the

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Figure 24. Pancreatic NET with no metastatic disease showing concordance between [99mTc]Tc-HYNIC-TOC (A) and [68Ga]Ga-DOTATATE PET/CT (B).

Figure 25. Jejunal NET with metastatic disease in abdominal lymph nodes, liver and skeleton. [68Ga]Ga-DOTATATE PET-CT (B) has advantage in detecting small volume/tiny lesions as compared to [99mTc]Tc-HYNIC-TOC planar study (A). SPECT-CT enhances the lesion detectability. developing world, the protein deficiency being ease burden. Oral protein supplementation primarily due to poor nutritional status, gastro- along with octreotide therapy enhances the intestinal loss of protein and tryptophan and general condition and enables to administer hepatic dysfunction due to large hepatic dis- PRRT in the isolation ward.

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For malnourished patients with anasarca, un- of synthetic somatostatin analogues (SSA) and dergoing treatment, generally a high calorie & better control of the functioning disease. We high protein diet is recommended. In patients have some limited experience of managing with conditions like ascites and pedal edema, such patients with resistant disease, where the energy requirement varies between 25-40 [177Lu]Lu-DOTATATE helped in substantial reduc- kcals/kg/day but if the patient is underweight: tion of 5-HIAA levels and resulted in symptom- it would be 35-40 kcals/kg/day. The protein atic improvement and improved health related requirements is higher for these patients due quality of life (from NYHA grade III at baseline to to nutritional hypoalbunemia (1.2-2 g/kg/bw). NYHA grade I after 4-6 cycles), finally enabling Supplement amount depends on patient’s taking the patient for corrective valvular sur- present condition and food intake. The greater gery [48]. the decrease in food intake the higher the quantity of prescribed supplement. If the One concern on advocating PRRT in patients of patient is on oral diet, lesser quantity is pre- carcinoid heart disease has been the concern scribed like 100 gms a day or lesser but the of volume overload in patients with features of quantity is more if he is on tube feeds. cardiac insufficiency related to amino acid infusion and hence caution exerted in various Use of aprepitant as an additional antiemetic guidelines [24]. Our Institutional protocol of a during PRRT: Nausea and vomiting is a com- relatively prolonged mixed amino acid protocol mon occurrence during PRRT primarily related of 7.5-8 hours adopted during PRRT is particu- to the metabolic acidosis due to the amino acid larly helpful to address this concern, and can co-infusion used for nephroprotection, rather be recommended in this clinical setting of than the radiopharmaceutical. This could be CaHD to undertake this treatment uneventfully. Dexamethasone-ondansetron pre-treatment Furthermore, it needs to be mentioned that the on a regular basis, however, there remains a renal absorbed dose has been reported to be small fraction of patients who show refractory further reduced by prolonging the infusion time vomiting during or soon after the therapy which of the amino acid solution over 10 hours by up could be well managed with oral Aprepitant, an to a factor of 39% [24].

NK1 antagonist in the central and peripheral nervous system, the typical adult dose is 125 PRRT in neoadjuvant setting mg, 80 mg and 80 mg on days 1, 2, and 3 respectively. In a patient who develops refrac- [177Lu]Lu-DOTATATE PRRT shows modest suc- tory vomiting during the first cycle of PRRT, he is cess in the neoadjuvant setting, where the pri- considered for Aprepitant on a routine basis mary intent is reduction of the size of an initially from 2nd cycle onwards. unresectable primary GEP-NENs to bring to the point when it becomes operable. We follow a Carcinoid heart disease: can PRRT be poten- slightly different regimen in this context, where tially helpful in enhancing the chances of cor- a higher mean dose with shorter time interval is rective vulvular surgery?: Carcinoid Heart followed (i.e. 200 mCi at 8 weekly interval) com- Disease is seen in the setting of high volume pared to the metastatic setting, where the functioning disease, typically in patients with intent is primarily disease stabilization and pal- bulky hepatic involvement which is an impor- liative (mean of 150 mCi per cycle administered tant risk factor (Peak 5-HIAA forms a significant at 12 weekly intervals for 5 such cycles). We predictor of the disease progression) that leads have observed excellent tolerability of this regi- secretion of vasoactive substances (5-hydroxy- men in all patients without any major hemato- tryptamine, tachykinins, and prostaglandins) logic or renal toxicity. reaching the right side of the heart through hepatic veins and consequent deposition of In our initial experience, the inoperable disease fibrous tissue on the endocardial surfaces of became operable in around 26% of patients, the heart resulting in pathologenesis of carci- assessed in a population of 57 (Figure 26). This noid heart disease. Though the usual reported is similar to the published results, the success incidence is upto 70% within the subgroup of for operability is around one-third of treated patients with carcinoid syndrome, its incidence patients (~30%) [49, 50] (unpublished work; is now much reduced owing to widespread use personal communications). Another observa-

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Figure 26. Efficacy of PRRT in neoadjuvant setting. A 35 years old male, diagnosed case of pancreatic NET with Ki-67 of 1%. Baseline [68Ga]Ga-DOTATATE PET-CT scan (A) showed intensely SSTR avid (krenning score = 4) pancreatic head mass >180° contact with SMV (SUVmax 59, 5.6×4.0×7.2 cm) and SSTR avid peri-pancreatic lymph node (SUVmax 55, 3.4×2.6 cm). Subsequently, patient received 2 cycles of PRRT (400 mCi). 177Lu-DOTATATE post therapy scan (B) showed good concentration of tracer activity in pancreatic head mass and peri-pancreatic lymph node. Follow-up [68Ga]Ga-DOTATATE PET-CT scan (C) showed reduction in size and SSTR uptake of pancreatic head mass with <180° contact with SMV (SUVmax 34, 4.4×3.5×4.1 cm) and also reduction in SSTR uptake and size of peri-pancreatic lymph node (SUVmax 30, 2.3×1.7 cm), suggestive of favorable response to PRRT. tion in a sizeable fraction of patients that could therapy with capecitabine-temozolamide and be made with neoadjuvant PRRT is substantial [177Lu]Lu-DOTATATE PRRT) for these group of regression of liver disease, thereby facilitating patients. In chemo-PRRT protocol, 2 cycles of surgical removal of primary and residual liver CAPTEM chemotherapy is sandwiched between lesions. This has been also reported by investi- 2 PRRT cycles of [177Lu]Lu-DOTATATE. gators who have employed [90Y]Y-DOTATOC and [90Y]Y-DOTATATE in the neoadjuvant setting [51, The standard CAPTEM regimen comprises of 52]. oral capecitabine (CAP), 750 mg/m2 twice daily for 14 days (D1-D14) and oral temozolomide Sandwich Chemo-PRRT in patients with avid (TEM) 200 mg/m2 once daily for 5 days (D10- [68Ga]Ga-DOTATATE and [18F]F-FDG uptake on D14) followed by two weeks rest period and dual tracer PET-CT: its comparison with PRCRT another CAPTEM cycle given for total 28 days is From our initial years of experience with PRRT, followed by next cycle of PRRT at around 3 we had observed that these group of tumors months (Figure 27). In a population of 38 usually demonstrate aggressive biology, treat- patients with metastatic NENs with high uptake ment refractoriness to PRRT alone and in- on both 68Ga-DOTATATE and 18F-FDG dual tracer creased incidence of progressive disease and PET/CT, who were treated with this Chemo- mortality in due course. Since 2013, we had PRRT regimen, we found encouraging results adopted a combination approach (oral chemo- with partial response in around 45%, stable 201 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience

Figure 27. Protocol adopted for Sandwich Chemo-PRRT. disease in 39% and progressive disease in 16% Duo-PRRT with [90Y]Y-DOTATATE in combina- on RECIST 1.1 with an overall disease control tion with [177Lu]Lu-DOTATATE in large volume rate of 84% in this aggressive group of tumors lesions (unpublished work; personal communications) (Figure 28). The superior efficacy of 90 [ Y]Y-DOTATATE for large sized lesions and heterogeneous lesions Amongst the various combination regimen, results from higher beta-particle energy of 2.28 PRCRT using 177Lu-octreotate with concomitant MeV (mean energy of 0.94 MeV) of 90Y (maxi- 5-FU radiosensitizing infusional chemotherapy mum soft tissue range ~11 mm) compared to has been employed at other centres [53, 54] in 177 that of Lu [Eβ(max) = 0.497 MeV, maximum patients with FDG-avid NET. The dosage of soft tissue range ~2.5 mm]. 5-FU in PRCRT in this regimen has been (200 mg/m2/24 h), starting approximately 4 days With the availability of indigenous [90Y]Y-DOT- before the day of PRRT administration, and ATATE, 11 NET patients with large volume continued for 3 weeks in total and early discon- lesions have received [90Y]Y-DOTATATE PRRT tinuation in the event of hand-foot syndrome or (Figure 29). Post PRRT stable disease has been other acute toxicity. There was achievement of observed in all 11 patients in the limited period good partial response, with long progression- of time, on imaging response evaluation with free survival of 48 months in a cohort of 52 no major acute adverse effects. We are in the patients [54]. The other investigators have process of optimizing the duo-PRRT regimen at used (i) First 14 days of capecitabine 1500 our set-up (with different regimen for the meta- 2 mg/m and last 5 days of temozolomide 200 static and neoadjuvant settings), including opti- 2 mg/m commencing on the morning of PRRT mization of post-therapy Bremsstrahlung and 2 [55], (ii) oral capecitabine (1250 mg/m ) for 15 PET-CT imaging following [90Y]Y-DOTATATE treat- st consecutive days from the 1 day of PRRT [56], ment (Figures 29 and 30) [58, 59]. and (iii) oral capecitabine (500-1000 mg/m2) twice daily for 14 days (starting 1 day after the Radiation safety aspects in [177Lu]Lu-DOT- PRRT) and oral temozolomide (150-250 mg/ ATATE PRRT m2) once per day for 5 days (days 10-14 after the PRRT) [57], with varying partial response In our institute PRRT is administered as in- (from 9% to 70%) being documented [55-57]. patient therapy procedure. World-over, there is We believe that our aforementioned “sandwich some variation in this regard, while some coun- chemo-PRRT” regimen could be more user tries consider PRRT as an outpatient procedure friendly and easier to adopt in a busy clinical and some countries consider it as in-patient setting. procedure. To minimise the radiation doses of

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Figure 28. Efficacy of ‘Sandwich Chemo-PRRT’. A diagnosed case of pancreatic NET (Ki-67 index = 8%) with hepatic and ovarian metastatic disease. The baseline [68Ga]Ga-DOTATATE (A) and [18F]F-FDG PET-CT scans (B) in 2015 showed both SSTR and FDG avid multiple liver lesions, abdominal lymph nodes, bilateral adnexal lesions. The patient received sandwich Chemo-PRRT from 2015 to 2018. Post chemo-PRRT follow up [68Ga]Ga-DOTATATE and [18F] F-FDG PET-CT scans in 2018 showed significant reduction of SSTR and FDG uptake in liver lesions, abdominal lymph nodes and bilateral adnexal lesions suggestive of PR after sandwich Chemo-PRRT treatment regimen. staff, carers and general public each institute the limits set by the regulatory body are have their own radiation safety protocols. Our adhered. In our institute, all the liquid waste institute also have evolved elaborate radiation generated in isolation wards, including urine safety protocols, the salient points among them and faeces of NET patients are collected in are mentioned in this review. Prior to adminis- dual delay tank. Once activity levels decrease tration of the [177Lu]Lu-DOTATATE, patients and to discharge limits set by our national regulato- their relatives were provided with radiation ry body, discharges are let to municipal sewer- safety and hygiene practices instructions. age system. Patients were explained about their stay in spe- cial (isolation) ward, because this physical To establish the discharge criteria and ensure preparation of patients helps in minimizing the that public exposure is less than the limit set by radiation exposure and contamination of physi- national regulatory body radiation field from the cians, nursing staff, other staff members and patient’s body should be monitored. In litera- visitors. To avoid the spread of contamination, ture [60] it reported that the average exposure entry to the isolation ward is restricted. St- at one meter immediately after treatment is 19 andard operating procedures are mandated to ± 5 µSv/h (for mean administered activity 7.09 be followed by the physicians, radiation safety GBq) and at time of discharge (4-5 h) is 9.8 ± officers, radio-pharmacists and nursing staff, 3.1 µSv/h. In our experience we found that the during synthesis of [177Lu]Lu-DOTATATE, prepa- average exposure at one meter immediately ration of patient doses, administration of [177Lu] after treatment is 20.22 ± 3.21 µSv/h (for Lu-DOTATATE and discharge of patients from mean administered activity 7.4 GBq) and at isolation wards. Regular radiation surveys and time of discharge (18-20 h) is 7.05 ± 2.94 contamination checks are performed to ensure µSv/h (Table 11). The predictive effective dose

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data of lutetium kinetics in laboratory animals revealed that lutetium collects in tissue and organs (60% in bones, 2% in the liver and 0.5% in the kidneys). In addition, lutetium is reported to have biological half-life of 3500 days in bone and the liver and 10 days in the kidneys [62]. Hence most of the lutetium that enters the body accumulates in the bone over a period.

In-vivo kinetics of [177Lu]Lu-DOTATATE

After administration of [177Lu]Lu-DOTATATE intravenously to the NET patients, [177Lu]Lu- DOTATATE uptake is seen in the kidney, liver, spleen and metastatic sites within 2 hours. Most of the [177Lu]Lu-DOTATATE which in not absorbed in the body is quickly excreted out from the body in the urine. As per the literature reports [63], [177Lu]Lu-DOTATATE is primarily excreted in the urine, with a cumulative excretion of 44% with in 5 hours, 58% within 24 hours and 65% within 48 hours. In our experience of 24 hours urinary excretion studies, we found a cumulative excretion of 35% within 2 hours, 55% within 6 hours and 70% within 24 hours (results from ongoing 177Lu-DOTATATE dosimetry work). Sandstrom et al [64] studied in-vivo kinetics in patients administered with [177Lu]Lu-DOTATATE and reported that the clearance of [177Lu]Lu-DOTATATE is biphasic inside the NET patients. The effective half-life of fast component is 1.28 h (range 0.93-1.52 h) and slow component is 49.5 h (range 45.1-56.6 h). Figure 29. Treatment Protocol for “duo-PRRT” pro- During our studies, we also found that the clear- tocol for large volume disease (lesion size >5 cm) 177 in metastatic and advanced Neuroendocrine Neo- ance of Lu is biphasic inside the NET patients plasms (Reproduced with permission from Basu et with effective half-life of fast component is al42). 2.23+/-0.95 hours and slow component is 36.20+/-16.47 hours (Table 11) [66]. to the family members of NET patients is found ALARA principle for critical organs to be less than 0.15 mSv (Occupancy factor 0.5) [61]. Before discharging the patients from Bone marrow and kidneys are the critical the ward, once again all instruction of radiation organs in PRRT. Proximal tubular reabsorption safety and hygiene practices were provided in of the [177Lu]Lu-DOTATATE and subsequent written as well as verbal, so as to minimise the retention results in high radiation exposure to dose to family members and general public. the kidney. To reduce the high kidney retention 177 In vivo kinetics of lutetium and labelled radio- of [ Lu]Lu-DOTATATE, positively charged amino pharmaceuticals acids are co-infused to completely inhibit reabsorption of the [177Lu]Lu-DOTATATE in the kid- In vivo kinetics of lutetium ney. The co-administration of these amino acids reduces the kidney dose significantly in Till date there is no data available about the the range of 9% to 53% [67]. Renal absorbed kinetics of lutetium in human body. However, dose is further reduced by up to 39% by extend-

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Table 11. A comparison of Radiation Dosimetry and related parameters obtained with [177Lu]Lu-DOTATATE through direct neutron activation route with that of reported literature Parameters Types Our Study Literature Value References Dose Ratea (µSv/h) Immediately after dosage administration 3.92 ± 0.63 (2.69-5.61) 2.68-4.47 [60, 61, 72, 73] Per unit administered activity (µSv/h/GBq) At the time of Discharge 7.05 ± 2.94b 7.0 ± 3.0c 9.8 ± 3.1d In-vivo Kinetics (Hours) Fast component 2.23 ± 0.95e (0.82-4.90) 1.28-4.7 [64, 66, 72] Slow component 36.20 ± 16.47 (12.15-71.94) 49.5-87.2 Urinary Excretionsf (%) 0-2 Hours 35 [64, 73] 0-6 Hours 55 44-46 0-24 Hours 70 58 Dosimetry Estimates [Absorbed dosef (mGy/MBq)] Kidneys 0.72 ± 0.23 0.55-1.15 [65, 74-81] Bone marrow 0.041 ± 0.021 0.03-0.07 Total Body 0.071 ± 0.025 0.05-0.07 Tumors 8.83 ± 7.18 3.41-9.7 aDose rate at 1-meter distance from the surface of patient’s body. bDischarge time was 18-20 hours after dose administration. cDischarge time was 18 hours after dose administration. dDischarge time was 4-5 hours after dose administration. eDuring our study, we also found that the clearance of 177Lu follows bi-exponential decay in 83.33% NET patients and in 16.67% NET patients it follows mono-exponential decay. fResults from ongoing 177Lu-DOTATATE dosimetry work.

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Figure 30. Post [90Y]Y-DOTATATE whole body planar bremsstralung image (A) and post [90Y]Y-DOTATATE regional PET- CT scan (B) in a known case of large sized pancreatic NET with liver metastatic disease (Ki-67 index = 1%), who had stable disease to [177Lu]Lu-DOTATATE PRRT, showing good tracer uptake in primary pancreatic and metastatic liver lesions. ing the infusion time of the amino acids solution absorbed dose per unit cumulative activity tion over 10 h, and up to 65% by extending the and τ is the residence time/disintegrations cor- protection over 2 days after radiopeptide ad- responding to the total number of decays occur- ministration, thereby covering the renal excre- ring in the organ divided by A0. For individual- tion phase more efficiently [68, 69]. ized patient dosimetry the values of S-factor rescaled according to the mass of the patient Internal dosimetry organ. Once the integral activities in the organs of interest are determined using mathematical The absorbed dose estimation of normal models, absorbed doses are generally calcu- organs and tumour/metastatic lesions provides lated using dedicated software programs such the means for optimizing the dose administra- as OLINDA/EXM 1.0 or its newer version tion of radio-peptide in PRRT, thereby full thera- OLINDA 2.2.0. For obtaining the integral activi- peutic window can be achieved with limited ties in the organs of interest input data include radiation-induced side effects to normal or- data from blood, urine, and whole-body scans gans, particularly the kidney and bone marrow, at different time intervals sufficiently covering which are considered as dose limiting organs in decay of fast and slow component of the radio- PRRT. The MIRD (Medical Internal Radiation isotope after PRRT. The planar images are use- Dose) scheme provides reference techniques ful to derive biokinetics over time, while SPECT for internal dosimetry. PRRT dose estimates in and SPECT/CT fused images, although requir- organs are generally calculated using the MIRD ing more time to acquire, provide insight into scheme, with the basic formula [70]: organ-specific three-dimensional activity distri- Ď = Ã×S = A × τ × S bution. In our experience the radiation absorbed 0 dose (mGy/MBq) to the kidney, spleen, liver, Where Ď is the Mean absorbed dose to target bone marrow, whole body and tumour are 0.69 organ from a uniformly distributed activity in ± 0.23, 0.93 ± 0.58, 0.13 ± 0.06, 0.04 ± 0.02, source organ, Ã is the Cumulative activity in the 0.06 ± 0.02 and 4.91 ± 3.73 respectively (Table source organ, S is the ‘S’ factor, it is the radia- 11, results from ongoing 177Lu-DOTATATE do-

206 Am J Nucl Med Mol Imaging 2020;10(4):178-211 PRRT with [177Lu]Lu-DOTATATE: a decade of experience simetry work), which are comparable with that [2] Das T and Pillai MR. Options to meet the future reported in the literature [68]. global demand of radionuclides for radionuclide therapy. Nucl Med Biol 2013; 40: 23-32. Conclusion [3] Banerjee S, Pillai MR and Knapp FF. Lute- tium-177 therapeutic radiopharmaceuticals: Thus in this treatise, the multifaceted aspects linking chemistry, radiochemistry, and practi- of PRRT were discussed (encompassing the cal applications. Chem Rev 2015; 115: 2934- radiopharmaceutical aspects, clinical PRRT 2974. services, radiation safety and dosimetry involv- [4] Cutler CS, Hennkens HM, Sisay N, Huclier- ing [177Lu]Lu-DOTATATE PRRT obtained from Markai S and Jurisson SS. Radiometals for indigenous resources), with clinical practice combined imaging and therapy. Chem Rev points and lessons learnt over last 10 years 2013; 113: 858-883. [5] Chakraborty S, Vimalnath KV, Lohar SP, Shetty from the experience of a large volume PRRT PS and Dash A. On the practical aspects of centre in India. The specific areas of clinical large-scale production of 177Lu for peptide re- challenges such as combination regimen for ceptor radionuclide therapy using direct neu- FDG avid lesions and duo-PRRT for large sized tron activation of 176Lu in a medium flux -re tumors were emphasized. The role of alpha search reactor: the Indian experience. J therapy with [225Ac]Ac-DOTATATE is evolving at Radioanal Nucl Chem 2014; 302: 233-242. this point and its place in the practice needs to [6] Mikolajczak R, Parus JL, Pawlak D, Zakrzewska be defined. The practical and unclear issues E, Michalak W and Sasinowsk I. Reactor produced 177Lu of specific activity and purity suit- were discussed with examples and reference able for medical applications. J Radioanal Nucl drawn from the published literature in each Chem 2003; 257: 53-57. domain, to provide the readers an in-depth [7] Dvorakova Z, Henkelmann R, Lin X, Türler A holistic overview of this subject. and Gerstenberg H. Production of 177Lu at the new research reactor FRM-II: irradiation yield Acknowledgements of 176Lu(n,gamma)177Lu. Appl Radiat Isotope 2008; 66: 147-151. The authors sincerely acknowledge the staff [8] Chakravarty R, Das T, Dash A and Venkatesh members of Reactor Group, Bhabha Atomic M. An electro-amalgamation approach to iso- Research Centre for their valuable role in regu- late no-carrier-added 177Lu from neutron irradi- lar operation and maintenance of Dhruva re- ated Yb for biomedical applications. Nucl Med search reactor, which was utilized for produc- Biol 2010; 37: 811-820. [9] Mirzadeh S, Du M, Beets AL and Knapp FF Jr. tion of 177Lutetium throughout last decade. Method for preparing high specific activity 177Lu. United States Patent 2004; 6716353. One decade of ‘Bench-to-Bedside’ Peptide [10] Lebedev NA, Novgorodov AF, Misiak R, Brock- Receptor Radionuclide Therapy with indigenous mann J and Roesch F. Radiochemical separa- [177Lu]Lu-DOTATATE obtained through ‘Direct’ tion of no-carrier-added 177Lu as produced via Neutron Activation Route: Lessons learnt in- the 176Yb(n, γ)177Yb→177Lu process. Appl Radiat cluding Practice Evolution in an Indian Setting. Isotope 2000; 53: 421-425. [11] Bilewicz A, Zuchowska K and Bartos B. Separa- 176 Disclosure of conflict of interest tion of Yb as YbSO4 from Yb target for production of 177Lu via the 176Yb(n, γ)177Yb→177Lu None. process. J Radioanal Nucl Chem 2009; 280: 167-169. Address correspondence to: Dr. Sandip Basu, Ra- [12] Atlas of neutron capture cross sections (1997). IAEA Nuclear Data Section, Vienna. diation Medicine Centre (BARC), Tata Memorial [13] Zhernosekov KP, Perego RC, Dvorakova Z, Hen- Hospital Annexe, Jerbai Wadia Road, Parel, Mumbai kelmann R and Türler A. Target burn-up cor- 400012, India. Tel: 91-22-24149428; Fax: 91-22- rected specific activity of 177Lu produced via 24157098; E-mail: [email protected] 176Lu(n, gamma) 177Lu nuclear reactions. Appl Radiat Isotope 2008; 66: 1218-1220. References [14] Basu S, Parghane R, Ranade R, Thapa P, Ra- maswamy A, Ostwal V, Sirohi B, Panda D and [1] Pillai MR, Chakraborty S, Das T, Venkatesh M Shrikhande SV. Peptide receptor radionuclide and Ramamoorthy N. Production logistics of therapy in the management of neuroendocrine 177Lu for radionuclide therapy. Appl Radiat Isot tumors (Neoplasms)*: fundamentals and sa- 2003; 59: 109-118. lient clinical practice points for medical oncolo-

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din S. Efficacy of peptide receptor radionuclide ized model. Nucl Med Commun 2015; 36: therapy with 177Lu-octreotate in metastatic pul- 766-774. monary neuroendocrine tumors: a dual-centre [40] Basu S. Should grade of tracer uptake on so- analysis. Am J Nucl Med Mol Imaging 2017; 7: matostatin receptor-targeted imaging be the 74-83. major determinant and break the barrier of [32] Adnan A, Kudachi S, Ramesh S, Prabhash K histopathologic criteria for determining the and Basu S. Metastatic or locally advanced suitability of Peptide receptor radionuclide mediastinal neuroendocrine tumours: out- therapy? J Nucl Med 2013; 54: 2018-9. come with 177Lu-DOTATATE-based peptide re- [41] Jois B, Asopa R and Basu S. Somatostatin receptor radionuclide therapy and assessment ceptor imaging in non-(131)I-avid metastatic of prognostic factors. 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Gratifying clinical experience with an indig- their implications for treatment decisions and enously formulated single-vial lyophilized HYN- outcome pertaining to peptide receptor radio- IC-TOC kit at the radiopharmaceutical division nuclide therapy in patients with advanced neu- of BARC: a pivotal boost for building up a pep- roendocrine tumour: developing a personal- tide receptor radionuclide therapy programme

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