review article one decade of ‘bench-to-bedside’ peptide ... · volume tertiary cancer care...

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

Review ArticleOne 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 pro-gramme 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

The somatostatin receptor (SSTR)-targeted theranostics integrates [99mTc]Tc/[111In]In/[68Ga]Ga-labelled diagnostic SPECT or PET imaging and [177Lu]Lu/[90Y]Y-labelled therapeutic radio-pharmaceuticals for ‘Peptide Receptor Radi- onuclide Therapy’ (PRRT), that has seen rapidly increasing applications for metastatic or advanced and progressive neuroendocrine neo-plasms (NENs), and gratifying cumulative clini-cal experience for disease stabilization in

majority and partial response in a sizeable frac-tion of patients. The somatostatin receptor subtype 2 (SSTR2), a member of the G-protein coupled somatostatin receptor family (SSTR 1-5) is the principal target for PRRT, in view of its predominance in the NENs. The therapy is accomplished through intravenously adminis-tered unsealed radiopharmaceutical, the most common across the world being [177Lu]Lu- DOTATATE (DOTATATE = DOTA0-(Tyr3)-octreotate) [177Lu: Eβ(max) = 0.497 MeV; maximum tissue range ~2.5 mm], while [90Y]Y-DOTATATE or

http://www.ajnmmi.us

PRRT with [177Lu]Lu-DOTATATE: a decade of experience

179 Am J Nucl Med Mol Imaging 2020;10(4):178-211

DOTATOC is the other beta emitting therapeutic alternative, in which the harder beta energy [90Y: Eβ(max) = 2.28 MeV] and longer range of 90Y (maximum tissue range ~11 mm) makes it more suitable for larger and heterogeneous tumors (albeit also accounting for its more nephrotoxicity), while [177Lu]Lu-DOTATATE is more efficacious for smaller tumors.

Radiopharmaceutical aspects: the 177Lutetium revolution

Production of 177Lu suitable for formulation of [177Lu]Lu-DOTA0-Tyr3-octreotate ([177Lu]Lu- DOTATATE) for PRRT

Two alternative routes are available for produc-tion of 177Lu with adequate specific activity required for its utility in PRRT, as shown in Figure 1. The first is the “direct” route which involves the thermal neutron activation of high-ly enriched (in 176Lu) lutetium target [176Lu(n, γ)177Lu] in research reactors with medium to high thermal neutron flux [1-7]. The second route or the “indirect” route is based on neu-tron irradiation of highly enriched (in 176Yb) ytterbium targets leading to the formation of no-carrier-added (NCA) 177Lu from the β- decay of the short-lived activation product 177Yb (T1/2 = 1.9 h) [3, 8-10]. The post-irradition radiochemi-cal processing in the former case involves sim-ple dissolution of the irradiated target, whereas the latter route involves elaborate procedure to separate 177Lu from ytterbium targets as well as its radionuclides. The neutron activation

ferent approaches have been successfully uti-lized in the separation of clinical grade NCA 177Lu from bulk quantity of neutron irradiated ytterbium target [8-11]. Although, NCA 177Lu is available from commercial sources, the abso-lute need of a complex radiochemical separa-tion procedure to isolate 177Lu of requisite puri-ty is challenging and expensive. It can be shown by theoretical calculation that irradiation of 1 mg of 99% enriched (in 176Yb) Yb2O3 target at a thermal neutron flux of 5×1014 n/cm2.s will pro-duce only ~3.2 GBq (~87 mCi) of 177Lu.

In contrast to any other medically useful radio-nuclides, direct (n, γ) route can be utilized for large-scale production of 177Lu in nuclear reac-tors, having medium to high thermal neutron flux (1.0×1014 n.cm-2.s-1 or higher), using enriched lutetium target (80% or more in 176Lu), with specific activity adequate for preparing receptor-specific therapeutic radiopharmaceu-ticals. This is possible due to the following two reasons, (i) 176Lu has very high thermal neutron capture cross section (σ = 2090 b, I0 = 1087 b) for formation of 177Lu and also that (ii) the neu-tron capture cross section of 176Lu does not fol-low 1/v law and there is a strong resonance very close to the thermal region [12]. Con- sequently, it is possible to produce 177Lu of spe-cific activity of more than 20 Ci/mg (740 GBq/mg) in a medium flux reactor. The most signifi-cant advantage of direct route over the indirect route is the simplicity of post-irradiation chemi-cal treatment procedure, which makes it much

Figure 1. Alternate routes for production of 177Lu in Nuclear Reactor.

products of natural lutetium and ytterbium targets along with the nuclear decay charac-teristics of the product radio-nuclides are given in Table 1.

The indirect route of produc-tion 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 radiochemi-cal separation strategy is adapted to separate 177Lu from radionuclides of ytterbium. Dif-



less technologically demanding as well as cost-effective compared to the other route. Moreover, there is absolutely no impediment towards scaling up the production as per its clinical requirement. On the contrary, the major concern in the large-scale clinical utilization of 177Lu produced via the direct route, is the pres-ence of the co-produced 177mLu, with a long T1/2 of 160.4 days (Table 1), which creates problem in the disposal of radioactive wastes arising from the treatment of large number of patients beside the additional radiation dose burden to the patients. A careful optimization of the dura-tion of irradiation depending on the available thermal neutron flux of the reactor is essential in the direct route to obtain 177Lu in the highest

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 free, [177Lu]LuCl3 solution as the radiopharma-ceutical precursor.

The theoretical yield of 177Lu ‘A’ (in Bq) pro-duced via 176Lu(n, γ)177Lu at the end of irradia-tion is calculated using the formula:

Ak

N ke e

2 1

0 1 k t t1 2=+ -

-m z v v

v z m - - +v z m v z

^`

hj6 @ [1]

Where, where, N0 = number of 176Lu atoms used as target (at t = 0), λ = decay constant of 177Lu (in s-1), σ = thermal neutron capture cross sec-tion of 176Lu at the neutron velocity of 2200 m.s-1 (2090 b), σ’ = thermal neutron capture cross section of 177Lu at the neutron velocity of 2200 m.s-1 (1000 b), φ = thermal neutron flux of the reactor (in n.cm-2.s-1), t = time of irradia-tion and ‘k’ is so called k-factor, the value of ‘k’ is reported to be between 1.5-2.5 [7]. This expression of the yield of 177Lu is based on the assumption that the neutron flux is highly ther-

Table 1. Neutron activation products of natural lutetium and ytterbium targets along with the nuclear decay characteristics of the product radionuclides

Target element Target isotope % Abundance σ (barns) Activation

product Mode of decay T1/2 Decay product

Lu 175Lu 97.41 16.7 176mLu β-, γ 3.66 h 176Hf6.6 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 177HfYb 168Yb 0.13 2300 169Yb EC 32.02 d 169Tm

170Yb 3.04 9.9 171Yb Stable171Yb 14.28 58.3 172Yb Stable172Yb 21.83 1.3 173Yb Stable173Yb 16.13 15.5 174Yb Stable174Yb 31.83 63 175Yb β-, γ 4.18 d 175Lu176Yb 12.76 2.85 177Yb β-, γ 1.9 h 177Lu

Figure 2. Theoretical yield 177Lu as a function of ir-radiation time at the irradiation position in Dhruva research reactor in India (ф = ~1.6×1014 n.cm-2.s-1, k = 1.75).



malized and there is practically no contribution of epithermal neutrons towards 177Lu forma-tion. Based on Equation 1, the variation of theo-retical yield of 177Lu as a function of irradiation time at the irradiation position in Dhruva (where k = 1.75) is shown in Figure 2. It is evident for the figure that the yield is maximum (~21 Ci/mg of Lu) when irradiation is carried out for 13-14 days. Hence, Lu targets are irradiated for 2 weeks for production of 177Lu in India. Also, it is very interesting to note that, in case of 177Lu, there is a mismatch between the theoretically calculated specific activity and that actually obtained l from its yield per unit mass of the target irradiated. This is due to the significant burn up of target during the irradiation for which the actual mass of lutetium present in the sys-tem, post irradiation is significantly reduced compared to the initial mass of the target irradi-ated. Using the burn-up correction, the actual specific activity S (Bq/mol) of 177Lu can be expressed as:

S

n n ek

ke e

A

0

2 1

1k t k t t1 1 2

=

+ ++ -

-m z v v

v z- - - +v z v z m v z

^^c `

hh mj6 @

[2]

where, n0 is the number of moles of the target isotope 176Lu at the start of irradiation and n is the number of moles of other lutetium isotopes

was found be ~0.015% of 177Lu activity produce at end of irradiation (EOI) and ~0.02% of 177Lu activity produced at 48 h post-EOI, when 177Lu is generally used in the clinic. A typical gamma ray spectrum of [177Lu]LuCl3 used for formula-tion of [177Lu]LuDOTATATE is shown in Figure 3, which confirms very high radionuclidic purity of the radiopharmaceutical precursor. This implies that for each patient administered with 7.4 GBq dose of 177Lu-labeled-S-analogue peptide, the administered dose of 177mLu is ~1.48 MBq (40 μCi). The presence of 177mLu at this level is not a matter of serious concern from the point of view of radiation dose burden to the patients. However, the use of each GBq of 177Lu will lead to the accumulation of ~200 kBq of radioactive waste of 177mLu to be disposed by following delay and decay approach.

Formulation of [177Lu]Lu-DOTATATE for clinical use

The therapy doses of [177Lu]Lu-DOTATATE radio-pharmaceutical are formulated mainly in hospi-tal radiopharmacy prior to clinical use following a protocol optimized after extensive radio-chemical studies. Moderate specific activity [177Lu]LuCl3 produced (20-24 Ci/mg) indige-nously by direct neutron activation route is used for the formulation. The general protocol

Figure 3. Typical gamma-ray spectrum of [177Lu]LuCl3 used for the formula-tion of [177Lu]Lu-DOTATATE.

which do not lead to the formation of 177Lu by (n, γ) pro-cess. 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 radiopharmaceuti-cals. Practically, the specific activity of 177Lu has been found to be 900 ± 78 GBq/mg (24.3 ± 2.1 Ci/mg) (averaged over 300 batches).

The impurity burden of 177mLu in 177Lu produced in our case



followed for the synthesis of the radiopharma-ceutical is presented schematically in Figure 4. During the last decade more than 400 batches of the [177Lu]Lu-DOTATATE were synthesized (10-15 therapeutic doses in each batch) with >95% radiochemical purity, as confirmed by radio-HPLC (Figure 5). The specific activity of the formulation varied from 1.0 mCi/µg (53.1 GBq/µmol) to 1.2 mCi/µg (63.8 GBq/µmol) of DOTATATE. The specifications of the radiophar-maceutical formulation are summarized in Table 2.

PRRT: clinical services

The PRRT clinical services was initiated at the Radiation Medicine Centre (RMC) -Tata Me- morial Hospital (TMH) premises in 2010, by the joint efforts of Radiation Medicine Centre (RM- C), BARC (Bhabha Atomic Research Centre) and GI services of the Tata Memorial Hospital

(TMH). More than 4,000 therapies have been successfully administered with [177Lu]Lu-DOTA- TATE in around 1000 patients, and has involved patients of (i) Gastroenteropancreatic NENs (GEP-NENs), (ii) Metastatic NEN with unknown primary (CUP-NEN) (iii) Bronchopulmonary, Me- diastinal and Thymic NENs, (iv) Medullary thy-roid carcinoma (MTC), (v) non-[131I]I-MIBG con-centrating metastatic Paraganglioma & Pheo- chromocytomas, and (vi) other miscellaneous tumors (non-iodine concentrating metastasis of differentiated thyroid carcinoma or TENIS, metastatic Merkel Cell carcinoma, Meningioma, recurrent/inoperable Phosphaturic Mesenchy- mal Tumor and sinonasal neuroendocrine carci-noma) (Table 3; Figure 6). The PRRT with [90Y]Y-DOTATATE is relatively new addition that has started from September 2019 as a part of duo-PRRT protocol, which is at its optimization phase at present (detailed later). The important

Figure 4. Schema of General protocol for the synthesis of [177Lu]Lu-DOTATATE.



milestones in our clinical PRRT programme has been depicted in Figure 7. Under this sections, we have elaborated upon the learning points

ding to the formation of no-carrier-added (NCA) 177Lu from the β- decay of the short-lived activa-tion product 177Yb (T1/2 = 1.9 h).

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 [177Lu]Lu-DOTATATE therapy dose (~7.4 GBq, 200 mCi) formulationParameter SpecificationAppearance Clear pale yellow solution without any suspended particulatepH ~4.5Volume ~1.0 mLRadionuclidic purity >99.95%Radiochemical purity >95.0%Sterility Sterile formulationApyrogenicity Pyrogen content <25 IU/mL

Table 3. Spectrum of Malignancies treated by PRRT with 177Lu-DOTATATE and their relative distributionPatients characteristics Number of Patients177Lu-DOTATATE PRRT 100090Y-DOTATATE PRRT 11Site of primary disease for 1000 pts Gastroenteropancreatic NENs (GEP-NENs) 781 Metastatic NEN with unknown primary (CUP-NEN) 87 Lung NENs 30 Mediastinal/thymus NENs 27 Medullary Thyroid carcinoma (MTC) 50 Pheochromocytomas and Paraganglioma (PCC/PGL) 15 Miscellaneous 10

and have shared our perspectives on these themes or issues.

The clinical efficacy of 177Lu obtained through “Direct” route as a therapeutic radiopharmaceuti-cal: results in major malignancies

As mentioned before, two alternative strate-gies are available for production of 177Lu with adequate specific activity required for its utility in PRRT. The first is the so called “direct” route which results in the produc-tion of carrier-added 177Lu. The second route or the “indirect” route is based on neu-tron irradiation of highly enriched (in 176Yb) ytterbium targets lea-



In India, more than 90% of the PRRT proce-dures (nearly all government centres and major-ity of the private centres) are undertaken using 177Lu obtained via the first pathway indigenous-ly in the research reactor. There has been some debate on the efficacy of 177Lu produced through the direct route. At our Centre, we have obtained gratifying response with the indige-nous product in large number of patients with clinical results similar to that is reported with the product from the ‘indirect’ route (two clini-cal examples depicted in Figures 8-11) in the literature [14-18]. There was excellent concor-dance of the ranges in tumor absorbed doses (estimated in metastatic NET patients during different PRRT cycles) with indigenous [177Lu]Lu-DOTATATE and that by the 177Lu produced through ‘indirect’ route (a comparative table of the tumor absorbed doses with the reported studies and our own experience has been illus-trated in Figure 11; Table 4). Herein we present the comparative data with contemporary litera-ture in the 3 most common malignancies where the [177Lu]Lu-DOTATATE PRRT has been employed in our services viz. (i) Metastatic Advanced and Progressive Gastroenteropa- ncreatic Neuroendocrine Tumors, (ii) Metasta- tic Advanced Pulmonary and Mediastinal Neuroendocrine Tumors, and (iii) Metastatic Medullary Carcinoma of thyroid.

Metastatic advanced and progressive gastroenteropancreatic neuroendocrine tumors: An interim analysis during 2014-2015 at our

riness (disease control rate 52.94% versus 96.97% in patients with absence of FDG uptake) and (b) symptomatic improvement was observed in most cases irrespective of tumor Ki-67 index (Table 5A and 5B). In a recent anal-ysis of a total of 468 patients with proven GEP-NEN who underwent from 2 to 7 cycles (at the interval of 10-12 weeks) of intravenous [177Lu]Lu-DOTATATE PRRT at our centre, the overall clinical results are further depicted partial response by PERCIST and RECIST 1.1 of 25% and 27% and stable disease of 57% and 60% respectively. The PFS at 7 yrs was 71.1% and OS was 79.4%. A total of 39 (8%) patients died out of 468 patients at 7 years (unpublished work; personal communication). The PRRT pro-cedures were well-tolerated with minimal neph-rotoxicity (grade 1: 3.5%, grade 2, grade 3 and grade 4: <1% each) and hematotoxicity primar-ily of grade 1 (1.7%), grade 2 and grade 3, 0.2% each and no grade 4 hematotoxicity (Figures 8 and 9).

In a short series of metastatic NETs (both GEP-NEN and pulmonary NENs) with extensive bone marrow involvement at diagnosis, the majority (four out of five patients, i.e. 80%) of the patients had excellent symptomatic response with at least stabilization of the dis-ease at a follow-up period of 10-27 months [20]. The single patient who had a progressive disease also had a good symptomatic response in the initial 6 months from the

Figure 6. Pie Chart of Spectrum of Malignancies treated by PRRT with [177Lu]Lu-DOTATATE and their relative distribution.

centre looked into 50 patients with histopathologically con-firmed metastatic/inoperable GEP-NETs (M:F 33:17, age: 26-71 years) who had under-gone 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-relat-ed 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-therapy FDG SUVmax values were associated with increased chances of treatment refracto-



first dose of PRRT. Despite the extensive bone marrow involvement, no hematological toxicity was observed (only one patient showed Grade I anaemia), suggesting that PRRT was well-tolerated by this particular subgroup. We have obtained gratifying response and imp-

rovement of health related quality of life in patients with extensive metastatic disease (Figure 12).

A large body of literature and guidelines exist today demonstrating efficacy of [177Lu]Lu-

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 resolu-tion of liver lesions and pancreatic lesion suggestive of CR.



DOTATATE in metastatic GEP-NENs [22-29]. Wang et al in a systematic review and meta-

analysis of 22 studies (1758 patients) estimated an overall CR+PR of 35.0% and

Figure 9. Post-PRRT partial response (PR) in a case of grade II pancreatic NET (Ki-67 index = 5%) with liver metasta-ses. 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 in-dex 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.



CR+PR+SD of 83% (on RECIST 1.1) [26]. Another systematic meta-analysis of 15 stud-ies by Zhang et al reported a CR+PR of 27.58% on RECIST 1.1 and CR+PR+SD of 79.14% on RECIST 1.1 [27]. The PFS and OS were not esti-mated in both of these meta-analyses. Ezzidin et al [28] in their study of 74 patients with a median follow-up of 47 months, had document-ed a PFS and OS of 26 months and 55 months respectively, while that by Brabander et al in

443 patients, were 29 and 63 months respec-tively. Thus, the clinical results with the indige-nously produced 177Lu has been in agreement with what has been reported in the literature (Table 6) [29].

Metastatic advanced pulmonary and mediasti-nal neuroendocrine tumors: Metastatic pulmo-nary and mediastinal neuroendocrine tumors form the next tumor group that is considered for the [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy [PRRT] in our setting. In an initial analysis in metastatic/advanced pul-monary (NETs) in 19 patients, symptomatic response following PRRT was observed in 79%. A total of 63% were finally characterized as responders and 37% were overall non-responders to PRRT based upon predefined 3-scale response evaluation criteria. All 7

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 dataLiterature Absorbed dose per unit activity (Gy/GBq)Ulrike Garske et al EJNMMI 201815 2.8-5Ezgi Ilan et al JNM 201516 1.35-45.95Christiane W. et al Cancer Biother. & Radiopharm. 200717 3.0-15.1Michael Garkavij et al Cancer, 201018 0.1-20Our experience 1.15-20.5

Table 5A. PRRT response in total 50 GEP-NETs on Symptomatic and PET-CT imaging [19]

Response Symptomatic18F-FDG/68Ga-DOTATATE

PET/CT imaging responders

Yes (PR+SD) 96% 82%No (PD) 4% 18%



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 →PRRT response ↓

Discordance (SSTR>FDG avid lesions, n = 33)

Concordance (SSTR≤FDG 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 metasta-sis (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).



Table 6. Meta-analysis and literature reports of response and survival of PRRT in metastatic GEP-NETs

Name/author of the study No of studies/ patients analyzed

Radionuclide used for PRRT

Follow up period after PRRT

Response on anatomical or molecular PFS OS

Wang LF et al26 Systematic meta-analysis 22 studies (1758 patients) 177Lu and 90Y-DOTATATE Review article 35.0% = CR+PR on RECIST 1.183% = CR+PR+SD on RECIST 1.1

Not evaluated Not evaluated

Zhang J et al27 Systematic meta-analysis 15 studies 177Lu and 90Y-DOTATATE Review article 27.58% = CR+PR on RECIST 1.179.14% = CR+PR+SD on RECIST

1.1

Not evaluated Not evaluated

Ezzidin et al28 74 177Lu-DOTATATE 47 months (me-dian follow up)

36.5% PR, 17.6% MR, 35.1% SD, and 10.8% PD

26 mo 55 mo

Brabander et al29 443 177Lu-DOTATATE Not mentioned SD-36% 29 mo 63 mo



non-responders had moderate to intense FDG-avid primary lung lesion and 5 had FDG- avid metastatic liver disease (SUVmax >5) (Table 7). The median OS was 40 months [30]. The results obtained were well-commensurate with two studies reported in literature on 177Lu-octreotate in metastatic pulmonary neu-roendocrine tumors, where the progressive dis-ease reported were 32% and 30%, one in pure metastatic pulmonary NET scenario [31] and the other in a combined analysis of patients with gastroenteropancreatic and bronchial neuroendocrine tumors [29]. In the study by Sabet et al, the DCR was 67% (PR = 27%, SD = 41% and CR 0%) matches well with the res- ponder group of 63% in our preliminary analysis [30, 31]. Response evaluation to PRRT in 30 patients of metastatic pulmonary NETs over last 10 years shows a PD of 31% on RE- CIST 1.1 and 47% on PERCIST & biochemical parameters (unpublished work; personal com-munication). Thus, the DCR (SD+PR+CR) by RECIST 1.1 was 69% and by PERCIST & bio-chemical parameters was 53% (Table 8; Figures 10 and 13).

With regard to mediastinal NETs, twenty-seven patients with histopathologically and radio- logically proven metastatic or advanced mediastinal NET, who had undergone [177Lu]Lu-DOTATATE PRRT, metabolic PET-CT response evaluation demonstrated partial metabolic response in 33.3%, metabolically stable dis-ease was seen in 18.5%, while 44.4% of the patients showed metabolic disease progres-

and longer PFS showed significant association [32]. There is relatively sparse clinical study data in the literature till date on [177Lu]Lu-DOTATATE PRRT in metastatic mediastinal/thymic NETs, which are primarily reported as case reports.

We have to mention here that for both meta-static pulmonary and mediastinal NENs, in addition to the aggressive biology of this tumor group, PRRT has been usually considered at an advanced state following chemotherapy failure which we believe could be partly responsible for its relatively inferior outcome compared to the GEP-NENs.

Metastatic medullary carcinoma of thyroid (MTC): [68Ga]Ga-DOTATATE positive metastatic MTC forms the 3rd most common indication for PRRT in our set-up. In a total of 43 somatosta-tin receptor-positive metastatic MTC patients treated with [177Lu]Lu-DOTATATE PRRT [33], 61% were responders and 39% were nonre-sponders based upon PERCIST criteria, while with RECIST 1.1 criteria 62% were responders and 38% were non-responders (Figure 15). Significant association between responses to PRRT was observed with following prognostic variables: (a) size of lesions (<2 cm) and (b) FDG uptake in lesions (SUVmax of <5). PRRT was well tolerated in all patients without any major grade 3 or 4 toxicity. The median OS was 26 months and the median PFS 24 months. There are much smaller series that have been pub-lished in this domain and more results may be awaited for comparison with the indigenous [177Lu]Lu-DOTATATE (Table 10) [34, 35].

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 of metastatic pulmonary NETs over last 10 yearsResponse Symptomatic Biochemical RECIST 1.1 PERCISTCR 42% 7% 4% 5%PR 26% 15% 8% 12%SD 12% 31% 57% 36%PD 20% 47% 31% 47%

sion (Table 9; Figure 14). The median PFS and OS were 36 months and 66 months respectively. Significant level of associa-tion of PFS was observed with surgical intervention, higher cumulative PRRT dose, metabolic response, smaller sized primary lesion, and low lesional FDG uptake; with respect to the OS, higher cumulative PRRT dose, low FDG uptake



Dual tracer PET-CT in individualizing treatment regimen in NENs: a valuable adjunct alongwith tumor Ki-67/MIB-1 index in assessing tumor biology

While the tumor Ki-67/MIB-1 labeling index forms an integral part of assessment of meta-static NENs, dual tracer PET-CT molecular

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-astinal NETs to [177Lu]Lu-DOTATATE PRRT [32]Response Symptomatic Metabolic AnatomicalCR 37% 3.7% 0%PR 25.9% 33.3% 22.2%SD 14.8% 18.5% 25.9%PD 22.2% 44.4% 51.9%



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 le-sions (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



Table 10. PRRT response evaluation in MTC patients in four categories [33]Response Symptomatic Biochemical RECIST 1.1 PERCISTCR 19% 11% 0% 0%PR 28% 30% 4% 10%SD 4% 10% 58% 51%PD 49% 49% 38% 39%

The observation made over years have been recently reflected by the WHO 2017 NEN grad-ing. Amongst the grade 3 NENs, there is now increasing recognition of a ‘well differentiated NEN composed of cells showing minimal to moderate atypia, lacking necrosis and expressing general markers of neuroendocrine dif-ferentiation (diffuse and intense synaptophy-sin and chromogranin A)’ which contrasts to the ‘poorly differentiated NEN is composed of high-ly atypical small or large cells expressing faint neuroendocrine differentiation markers’. Hen- ce, two different subsets within the grade 3 NENs are now recognized by the recent WHO 2017 NEN classification, distinguishing well dif-ferentiated grade 3 neuroendocrine tumours (NET G3) from poorly differentiated grade 3 neuroendocrine carcinomas (NEC G3), which is an important step from management view- points.

Dual tracer PET-CT findings of the relative trac-er accumulation in tumor lesions based upon somatostatin receptor expression (by [68Ga]Ga- DOTATATE/NOC PET-CT) and tumor glycolysis (by FDG-PET/CT), can potentially aid in deci-phering the aforementioned tumor characteris-tics, and differentiating NET G3 from NEC G3. A high [68Ga]Ga-DOTATATE/NOC with low/absent FDG uptake would be more consistent with the diagnosis of G3-NEC.

(ii) Discordance between Ki-67/MIB-1 and the dual tracer PET-CT findings: Though the stan-dard findings on dual tracer PET-CT is charac-teristic and remains in agreement with the reported Ki-67/MIB-1 labeling index, the outli-ers or exceptions are not uncommon in day-to-day practice. Herein two considerations need to be made: (a) Ki-67/MIB-1 labeling index from

imaging findings (somatostatin receptor based [68Ga]Ga-DOTATATE and tumor glucose metabo-lism with FDG) has developed into a valuable adjunct for personalizing the treatment regi-men in this group of patients (Figure 15). Sev- eral studies in the early years including ours had observed that tumors with low or negligible FDG uptake respond well to somatostatin tar-geted therapy, while those with high FDG uptake demonstrates refractoriness to PRRT alone [19, 37]. The relative uptake of [68Ga]Ga-DOTATATE and FDG enables assessment of the dynamic tumor biology of NENs on a con-tinuous scale and is utilized for clinical decision making and personalizing the treatment strate-gies [38]; depending upon the dual tracer PET-CT findings, the patients are subdivided into 3 classical subgroups: (i) Tumors with low Ki-67 index, are usually positive on SSTR imaging with low/absent FDG uptake: they are candi-dates for SSA and PRRT, (ii) Tumors with high Ki-67 index, are usually negative on SSTR based imaging and shows high uptake on FDG-PET/CT: are candidates for chemotherapy (CAPTEM if the Ki-67<55% or platinum based chemotherapy if the Ki-67>55%) (Figure 16). (iii) Tumors demonstrating both high [68Ga]Ga-DOTATATE and 18F-FDG uptake on dual trac-er PET/CT form the intermediate grey zone and intermediate Ki-67 index, wherein a combined approach of PRRT plus chemotherapy is employed (Figures 17-19) [36, 38, 39].

The specific areas where this manoeuvre becomes particularly useful for clinical decision making are:

(i) The tumor biology in tumors with intermedi-ate level of Ki-67 labeling index (e.g. 10-20%)

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.

and also those with Ki-67 LI between 20-30%: Wide variation in tumor behav-iour at both of the above regions of Ki-67 index, where the relative uptake of [68Ga]Ga-DOTATATE and FDG becomes particu-larly useful for deciding on the therapy on an individualized basis. Having observed this early-on, we have adopted the prac-tice routinely in our Institute.



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 fraught with its inability to assess the tumor biology as a whole on a continuous scale and (b) even in the same individual, interlesional heterogeneity can exist, thus one biopsy speci-men may not be representative of all lesions, which could be better portrayed by the molecu-lar PET-CT imaging (Images of case examples: Figures 20, 21). In our set-up the findings in the PET-CT imaging forms an important parameter and given equivalent important to the Ki-67 index for clinical decision-making of therapies in metastatic NENs, if not more.

PRRT beyond classical indication of GEP-NENs: expanding the boundaries of SSTR based Theranostics

The classical standard indications for PRRT has been (i) metastatic and unresectable advanced grade I or II gastroenteropancreatic neuroendo-

crine neoplasms (GEP-NENs) that are (ii) pro-gressive on Synthetic Somatostatin Analo- gues (SSAs) and demonstrate high grade uptake (Krenning score 3 or 4 on semi-quanti-tative scale) on SSTR based [68Ga]Ga-DOTATOC/TATE PET-CT or [99mTc]Tc-HYNIC-TOC SPECT-CT. (iii) Symptomatic functioning NENs, who are resistant to the long-acting SSAs (octreotide/lanreotide) form another group where PRRT is usually considered. Beyond the aforemen-tioned indications, the clinical applications of PRRT has been widened substantially over the recent years, and can be subdivided into two groups: (A) extended indications within GEP-NENs and (B) applications in tumors beyond GEP-NENs.

Extended indications within GEP-NENs: The fol-lowing two groups of GEP-NEN patients are now frequently considered for PRRT with 177Lu-



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

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 up-take.

Figure 18. A known case of NEC with unknown primary site. Pre-senting with complaints of abdom-inal pain and cough, the biopsy from abdominal lesions showed metastatic carcinoma with neuro-endocrine 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 treat-ment before the molecular imag-ing. [18F]F-FDG PET-CT scan (A) showed intensely FDG avid mul-tiple 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.



potentially toxic, only modest efficacious or expensive. The aforementioned list of PRRT indications is partly adapted with newer addi-tions from Basu et al46).

The role of [99mTc]Tc-HYNIC-TOC SPECT/SPECT-CT as decision making scan in the absence of [68Ga]Ga-DOTATOC/NOC/TATE PET-CT

The diagnostic modality of choice for SSTR based imaging is [68Ga]Ga-DOTATOC/NOC/TATE PET-CT, which has been proven superior to the other conventional diagnostic modalities including the other whole body functional imag-ing (such as [111In]In-octreotide or [99mTc]Tc-HYNIC-TOC SPECT-CT), in view of its superior resolution and ability for quantification.

However, in the absence of PET-CT or 68Ge/68Ga generator, the mandatory requirements for [68Ga]Ga-DOTATOC/NOC/TATE PET-CT, a factor to be considered in several peripheral centres in developing nations, [99mTc]Tc-HYNIC-TOC pla-nar and SPECT-CT gamma camera based imag-ing can do reasonably well for decision making of PRRT in patients with large volume disease.

high uptake of FDG additionally, wherein we advocate combined chemo-PRRT (the regimen employed in our set-up is detailed later). The ESMO clinical practice guidelines for GEP-NENs advocates PRRT upto Ki-67 of 30%.

(v) While usually PRRT is considered in patients with disease progression on cold somatostatin analogues, there has been increasing adoption of this treatment modality upfront at diagnosis in patients with widely metastatic disease on whole body diagnostic SSTR based study, where the disease is already ‘progressed’ involving multiple sites.

Tumors beyond Gastroenteropancreatic NENs (GEP-NENs): Over the years, we have now acquired fair amount of experience in various ‘beyond GEP-NENs’ indications, wherein 177Lu- DOTATATE PRRT provide good disease stabiliza-tion in substantial fraction of patients. These include: (a) metastatic/inoperable Bronchopu- lmonary and Mediastinal/Thymic NENs, [30, 32]; (b) metastatic/inoperable Medullary thy-roid carcinoma** [33]; (c) Non-131I-MIBG con-

Figure 19. Dual tracer PET finding matched with that predicted by HPR. Pancreatic NET with liver lesions, Ki-67 index = 15%, showing high uptake on both [68Ga]Ga-DOTATATE (A) and FDG (B) PET-CT. The patient is a typical case for consideration for combined chemo-PRRT.

centrating metastatic Paraga- nglioma & Pheochromocyto- ma (Figure 22); (d) Non-iodine concentrating metastasis of differentiated thyroid carcino-ma (TENIS: only 15-20% of this patient subgroup demon-strates 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 indica-tions where PRRT has been considered even though there was a lesser degree of uptake (Krenning score 2) on SSTR based scanning, in view of the fact that alternative experi-mental therapies were either



In India, [99mTc]Tc-HYNIC-TOC is available for kit formulation method which played impor-tant 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, how-ever, post-PRRT acute carci-noid syndrome (“carcinoid cri-sis”) is a rare but life-threatening risk that requires emergency

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 find-ings 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.



cyproheptadine on a regular basis 1 to 2 days before scheduled PRRT is also a helpful prac-tice (it exerts its action as a potent antagonist of the 5-HT2 receptors).

Protein deficiency, poor nutrition status and generalized anasarca: enhancing the chances of undertaking PRRT: This is a challenge to the attending physicians, more relevant to the

medical management. This is typically observed in patients with large volume functioning hepat-ic metastases. In our experience, adequate patient preparation is key to minimize the inci-dences in these cases, which would involve short acting octreotide injections (subcutane-ous) till 1 day before of PRRT and initiate the same next day following PRRT continuing for 2 weeks. Priming this subgroup of patients with

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.



ease burden. Oral protein supplementation along with octreotide therapy enhances the general condition and enables to administer PRRT in the isolation ward.

developing world, the protein deficiency being primarily due to poor nutritional status, gastro-intestinal loss of protein and tryptophan and hepatic dysfunction due to large hepatic dis-

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.



of synthetic somatostatin analogues (SSA) and better control of the functioning disease. We have some limited experience of managing such patients with resistant disease, where [177Lu]Lu-DOTATATE helped in substantial reduc-tion of 5-HIAA levels and resulted in symptom-atic improvement and improved health related quality of life (from NYHA grade III at baseline to NYHA grade I after 4-6 cycles), finally enabling taking the patient for corrective valvular sur-gery [48].

One concern on advocating PRRT in patients of carcinoid heart disease has been the concern of volume overload in patients with features of cardiac insufficiency related to amino acid infu-sion and hence caution exerted in various guidelines [24]. Our Institutional protocol of a relatively prolonged mixed amino acid protocol of 7.5-8 hours adopted during PRRT is particu-larly helpful to address this concern, and can be recommended in this clinical setting of CaHD to undertake this treatment uneventfully. Furthermore, it needs to be mentioned that the renal absorbed dose has been reported to be further reduced by prolonging the infusion time of the amino acid solution over 10 hours by up to a factor of 39% [24].

PRRT in neoadjuvant setting

[177Lu]Lu-DOTATATE PRRT shows modest suc-cess in the neoadjuvant setting, where the pri-mary intent is reduction of the size of an initially unresectable primary GEP-NENs to bring to the point when it becomes operable. We follow a slightly different regimen in this context, where a higher mean dose with shorter time interval is followed (i.e. 200 mCi at 8 weekly interval) com-pared to the metastatic setting, where the intent is primarily disease stabilization and pal-liative (mean of 150 mCi per cycle administered at 12 weekly intervals for 5 such cycles). We have observed excellent tolerability of this regi-men in all patients without any major hemato-logic or renal toxicity.

In our initial experience, the inoperable disease became operable in around 26% of patients, assessed in a population of 57 (Figure 26). This is similar to the published results, the success for operability is around one-third of treated patients (~30%) [49, 50] (unpublished work; personal communications). Another observa-

For malnourished patients with anasarca, undergoing treatment, generally a high calorie & high protein diet is recommended. In patients with conditions like ascites and pedal edema, the energy requirement varies between 25-40 kcals/kg/day but if the patient is underweight: it would be 35-40 kcals/kg/day. The protein requirements is higher for these patients due to nutritional hypoalbunemia (1.2-2 g/kg/bw). Supplement amount depends on patient’s present condition and food intake. The greater the decrease in food intake the higher the quantity of prescribed supplement. If the patient is on oral diet, lesser quantity is pre-scribed like 100 gms a day or lesser but the quantity is more if he is on tube feeds.

Use of aprepitant as an additional antiemetic during PRRT: Nausea and vomiting is a com-mon occurrence during PRRT primarily related to the metabolic acidosis due to the amino acid co-infusion used for nephroprotection, rather than the radiopharmaceutical. This could be Dexamethasone-ondansetron pre-treatment on a regular basis, however, there remains a small fraction of patients who show refractory vomiting during or soon after the therapy which could be well managed with oral Aprepitant, an NK1 antagonist in the central and peripheral nervous system, the typical adult dose is 125 mg, 80 mg and 80 mg on days 1, 2, and 3 respectively. In a patient who develops refractory vomiting during the first cycle of PRRT, he is considered for Aprepitant on a routine basis from 2nd cycle onwards.

Carcinoid heart disease: can PRRT be poten-tially helpful in enhancing the chances of cor-rective vulvular surgery?: Carcinoid Heart Disease is seen in the setting of high volume functioning disease, typically in patients with bulky hepatic involvement which is an impor-tant risk factor (Peak 5-HIAA forms a significant predictor of the disease progression) that leads secretion of vasoactive substances (5-hydroxy-tryptamine, tachykinins, and prostaglandins) reaching the right side of the heart through hepatic veins and consequent deposition of fibrous tissue on the endocardial surfaces of the heart resulting in pathologenesis of carci-noid heart disease. Though the usual reported incidence is upto 70% within the subgroup of patients with carcinoid syndrome, its incidence is now much reduced owing to widespread use



therapy with capecitabine-temozolamide and [177Lu]Lu-DOTATATE PRRT) for these group of patients. In chemo-PRRT protocol, 2 cycles of CAPTEM chemotherapy is sandwiched between 2 PRRT cycles of [177Lu]Lu-DOTATATE.

The standard CAPTEM regimen comprises of oral capecitabine (CAP), 750 mg/m2 twice daily for 14 days (D1-D14) and oral temozolomide (TEM) 200 mg/m2 once daily for 5 days (D10-D14) followed by two weeks rest period and another CAPTEM cycle given for total 28 days is followed by next cycle of PRRT at around 3 months (Figure 27). In a population of 38 patients with metastatic NENs with high uptake on both 68Ga-DOTATATE and 18F-FDG dual tracer PET/CT, who were treated with this Chemo-PRRT regimen, we found encouraging results with partial response in around 45%, stable

tion in a sizeable fraction of patients that could be made with neoadjuvant PRRT is substantial regression of liver disease, thereby facilitating surgical removal of primary and residual liver lesions. This has been also reported by investi-gators who have employed [90Y]Y-DOTATOC and [90Y]Y-DOTATATE in the neoadjuvant setting [51, 52].

Sandwich Chemo-PRRT in patients with avid [68Ga]Ga-DOTATATE and [18F]F-FDG uptake on dual tracer PET-CT: its comparison with PRCRT

From our initial years of experience with PRRT, we had observed that these group of tumors usually demonstrate aggressive biology, treat-ment refractoriness to PRRT alone and increased incidence of progressive disease and mortality in due course. Since 2013, we had adopted a combination approach (oral chemo-

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) pan-creatic 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.



Duo-PRRT with [90Y]Y-DOTATATE in combina-tion with [177Lu]Lu-DOTATATE in large volume lesions

The superior efficacy of [90Y]Y-DOTATATE for large sized lesions and heterogeneous lesions results from higher beta-particle energy of 2.28 MeV (mean energy of 0.94 MeV) of 90Y (maxi-mum soft tissue range ~11 mm) compared to that of 177Lu [Eβ(max) = 0.497 MeV, maximum soft tissue range ~2.5 mm].

With the availability of indigenous [90Y]Y-DOT- ATATE, 11 NET patients with large volume lesions have received [90Y]Y-DOTATATE PRRT (Figure 29). Post PRRT stable disease has been observed in all 11 patients in the limited period of time, on imaging response evaluation with no major acute adverse effects. We are in the process of optimizing the duo-PRRT regimen at our set-up (with different regimen for the meta-static and neoadjuvant settings), including opti-mization of post-therapy Bremsstrahlung and PET-CT imaging following [90Y]Y-DOTATATE treat-ment (Figures 29 and 30) [58, 59].

Radiation safety aspects in [177Lu]Lu-DOT-ATATE PRRT

In our institute PRRT is administered as in-patient therapy procedure. World-over, there is some variation in this regard, while some coun-tries consider PRRT as an outpatient procedure and some countries consider it as in-patient procedure. To minimise the radiation doses of

disease in 39% and progressive disease in 16% on RECIST 1.1 with an overall disease control rate of 84% in this aggressive group of tumors (unpublished work; personal communications) (Figure 28).

Amongst the various combination regimen, PRCRT using 177Lu-octreotate with concomitant 5-FU radiosensitizing infusional chemotherapy has been employed at other centres [53, 54] in patients with FDG-avid NET. The dosage of 5-FU in PRCRT in this regimen has been (200 mg/m2/24 h), starting approximately 4 days before the day of PRRT administration, and continued for 3 weeks in total and early discon-tinuation in the event of hand-foot syndrome or other acute toxicity. There was achievement of good partial response, with long progression-free survival of 48 months in a cohort of 52 patients [54]. The other investigators have used (i) First 14 days of capecitabine 1500 mg/m2 and last 5 days of temozolomide 200 mg/m2 commencing on the morning of PRRT [55], (ii) oral capecitabine (1250 mg/m2) for 15 consecutive days from the 1st day of PRRT [56], and (iii) oral capecitabine (500-1000 mg/m2) twice daily for 14 days (starting 1 day after the PRRT) and oral temozolomide (150-250 mg/m2) once per day for 5 days (days 10-14 after the PRRT) [57], with varying partial response (from 9% to 70%) being documented [55-57]. We believe that our aforementioned “sandwich chemo-PRRT” regimen could be more user friendly and easier to adopt in a busy clinical setting.

Figure 27. Protocol adopted for Sandwich Chemo-PRRT.



the limits set by the regulatory body are adhered. In our institute, all the liquid waste generated in isolation wards, including urine and faeces of NET patients are collected in dual delay tank. Once activity levels decrease to discharge limits set by our national regulato-ry body, discharges are let to municipal sewer-age system.

To establish the discharge criteria and ensure that public exposure is less than the limit set by national regulatory body radiation field from the patient’s body should be monitored. In litera-ture [60] it reported that the average exposure at one meter immediately after treatment is 19 ± 5 µSv/h (for mean administered activity 7.09 GBq) and at time of discharge (4-5 h) is 9.8 ± 3.1 µSv/h. In our experience we found that the average exposure at one meter immediately after treatment is 20.22 ± 3.21 µSv/h (for mean administered activity 7.4 GBq) and at time of discharge (18-20 h) is 7.05 ± 2.94 µSv/h (Table 11). The predictive effective dose

staff, carers and general public each institute have their own radiation safety protocols. Our institute also have evolved elaborate radiation safety protocols, the salient points among them are mentioned in this review. Prior to adminis-tration of the [177Lu]Lu-DOTATATE, patients and their relatives were provided with radiation safety and hygiene practices instructions. Patients were explained about their stay in spe-cial (isolation) ward, because this physical preparation of patients helps in minimizing the radiation exposure and contamination of physi-cians, nursing staff, other staff members and visitors. To avoid the spread of contamination, entry to the isolation ward is restricted. St- andard operating procedures are mandated to be followed by the physicians, radiation safety officers, radio-pharmacists and nursing staff, during synthesis of [177Lu]Lu-DOTATATE, prepa-ration of patient doses, administration of [177Lu]Lu-DOTATATE and discharge of patients from isolation wards. Regular radiation surveys and contamination checks are performed to ensure

Figure 28. Efficacy of ‘Sandwich Chemo-PRRT’. A diagnosed case of pancreatic NET (Ki-67 index = 8%) with he-patic 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 pa-tient 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.



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 excre-tion of 44% with in 5 hours, 58% within 24 hours and 65% within 48 hours. In our experi-ence 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 clear-ance 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). During our studies, we also found that the clear-ance of 177Lu is biphasic inside the NET patients with effective half-life of fast component is 2.23+/-0.95 hours and slow component is 36.20+/-16.47 hours (Table 11) [66].

ALARA principle for critical organs

Bone marrow and kidneys are the critical organs in PRRT. Proximal tubular reabsorption of the [177Lu]Lu-DOTATATE and subsequent retention results in high radiation exposure to the kidney. To reduce the high kidney retention of [177Lu]Lu-DOTATATE, positively charged amino acids are co-infused to completely inhibit reab-sorption of the [177Lu]Lu-DOTATATE in the kid-ney. The co-administration of these amino acids reduces the kidney dose significantly in the range of 9% to 53% [67]. Renal absorbed dose is further reduced by up to 39% by extend-

to the family members of NET patients is found to be less than 0.15 mSv (Occupancy factor 0.5) [61]. Before discharging the patients from the ward, once again all instruction of radiation safety and hygiene practices were provided in written as well as verbal, so as to minimise the dose to family members and general public.

In vivo kinetics of lutetium and labelled radio-pharmaceuticals

In vivo kinetics of lutetium

Till date there is no data available about the kinetics of lutetium in human body. However,

Figure 29. Treatment Protocol for “duo-PRRT” pro-tocol for large volume disease (lesion size >5 cm) in metastatic and advanced Neuroendocrine Neo-plasms (Reproduced with permission from Basu et al42).



Table 11. A comparison of Radiation Dosimetry and related parameters obtained with [177Lu]Lu-DOTATATE through direct neutron activation route with that of reported literatureParameters Types Our Study Literature Value ReferencesDose Ratea (µSv/h) Immediately after dosage administration

Per unit administered activity (µSv/h/GBq)3.92 ± 0.63 (2.69-5.61) 2.68-4.47 [60, 61, 72, 73]

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 44-460-24 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 0.03-0.07Total Body 0.071 ± 0.025 0.05-0.07Tumors 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.



tion absorbed dose per unit cumulative activity and τ is the residence time/disintegrations cor-responding to the total number of decays occur-ring in the organ divided by A0. For individual-ized patient dosimetry the values of S-factor rescaled according to the mass of the patient organ. Once the integral activities in the organs of interest are determined using mathematical models, absorbed doses are generally calcu-lated using dedicated software programs such as OLINDA/EXM 1.0 or its newer version OLINDA 2.2.0. For obtaining the integral activi-ties in the organs of interest input data include data from blood, urine, and whole-body scans at different time intervals sufficiently covering decay of fast and slow component of the radio-isotope after PRRT. The planar images are use-ful to derive biokinetics over time, while SPECT and SPECT/CT fused images, although requir-ing more time to acquire, provide insight into organ-specific three-dimensional activity distri-bution. In our experience the radiation absorbed dose (mGy/MBq) to the kidney, spleen, liver, bone marrow, whole body and tumour are 0.69 ± 0.23, 0.93 ± 0.58, 0.13 ± 0.06, 0.04 ± 0.02, 0.06 ± 0.02 and 4.91 ± 3.73 respectively (Table 11, results from ongoing 177Lu-DOTATATE do-

ing the infusion time of the amino acids solu-tion over 10 h, and up to 65% by extending the protection over 2 days after radiopeptide administration, thereby covering the renal excre-tion phase more efficiently [68, 69].

Internal dosimetry

The absorbed dose estimation of normal organs and tumour/metastatic lesions provides the means for optimizing the dose administra-tion of radio-peptide in PRRT, thereby full thera-peutic window can be achieved with limited radiation-induced side effects to normal organs, particularly the kidney and bone marrow, which are considered as dose limiting organs in PRRT. The MIRD (Medical Internal Radiation Dose) scheme provides reference techniques for internal dosimetry. PRRT dose estimates in organs are generally calculated using the MIRD scheme, with the basic formula [70]:

Ď = Ã×S = A0 × τ × S

Where Ď is the Mean absorbed dose to target organ from a uniformly distributed activity in source organ, Ã is the Cumulative activity in the source organ, S is the ‘S’ factor, it is the radia-

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.



[2] Das T and Pillai MR. Options to meet the future global demand of radionuclides for radionu-clide therapy. Nucl Med Biol 2013; 40: 23-32.

[3] Banerjee S, Pillai MR and Knapp FF. Lute-tium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practi-cal applications. Chem Rev 2015; 115: 2934-2974.

[4] Cutler CS, Hennkens HM, Sisay N, Huclier-Markai S and Jurisson SS. Radiometals for combined imaging and therapy. Chem Rev 2013; 113: 858-883.

[5] Chakraborty S, Vimalnath KV, Lohar SP, Shetty PS and Dash A. On the practical aspects of large-scale production of 177Lu for peptide re-ceptor radionuclide therapy using direct neu-tron activation of 176Lu in a medium flux re-search reactor: the Indian experience. J Radioanal Nucl Chem 2014; 302: 233-242.

[6] Mikolajczak R, Parus JL, Pawlak D, Zakrzewska E, Michalak W and Sasinowsk I. Reactor pro-duced 177Lu of specific activity and purity suit-able for medical applications. J Radioanal Nucl Chem 2003; 257: 53-57.

[7] Dvorakova Z, Henkelmann R, Lin X, Türler A and Gerstenberg H. Production of 177Lu at the new research reactor FRM-II: irradiation yield of 176Lu(n,gamma)177Lu. Appl Radiat Isotope 2008; 66: 147-151.

[8] Chakravarty R, Das T, Dash A and Venkatesh M. An electro-amalgamation approach to iso-late no-carrier-added 177Lu from neutron irradi-ated Yb for biomedical applications. Nucl Med Biol 2010; 37: 811-820.

[9] Mirzadeh S, Du M, Beets AL and Knapp FF Jr. Method for preparing high specific activity 177Lu. United States Patent 2004; 6716353.

[10] Lebedev NA, Novgorodov AF, Misiak R, Brock-mann J and Roesch F. Radiochemical separa-tion of no-carrier-added 177Lu as produced via the 176Yb(n, γ)177Yb→177Lu process. Appl Radiat Isotope 2000; 53: 421-425.

[11] Bilewicz A, Zuchowska K and Bartos B. Separa-tion of Yb as YbSO4 from 176Yb target for pro-duction of 177Lu via the 176Yb(n, γ)177Yb→177Lu process. J Radioanal Nucl Chem 2009; 280: 167-169.

[12] Atlas of neutron capture cross sections (1997). IAEA Nuclear Data Section, Vienna.

[13] Zhernosekov KP, Perego RC, Dvorakova Z, Hen-kelmann R and Türler A. Target burn-up cor-rected specific activity of 177Lu produced via 176Lu(n, gamma) 177Lu nuclear reactions. Appl Radiat Isotope 2008; 66: 1218-1220.

[14] Basu S, Parghane R, Ranade R, Thapa P, Ra-maswamy A, Ostwal V, Sirohi B, Panda D and Shrikhande SV. Peptide receptor radionuclide therapy in the management of neuroendocrine tumors (Neoplasms)*: fundamentals and sa-lient clinical practice points for medical oncolo-

simetry work), which are comparable with that reported in the literature [68].

Conclusion

Thus in this treatise, the multifaceted aspects of PRRT were discussed (encompassing the radiopharmaceutical aspects, clinical PRRT services, radiation safety and dosimetry involv-ing [177Lu]Lu-DOTATATE PRRT obtained from indigenous resources), with clinical practice points and lessons learnt over last 10 years from the experience of a large volume PRRT centre in India. The specific areas of clinical challenges such as combination regimen for FDG avid lesions and duo-PRRT for large sized tumors were emphasized. The role of alpha therapy with [225Ac]Ac-DOTATATE is evolving at this point and its place in the practice needs to be defined. The practical and unclear issues were discussed with examples and reference drawn from the published literature in each domain, to provide the readers an in-depth holistic overview of this subject.

Acknowledgements

The authors sincerely acknowledge the staff members of Reactor Group, Bhabha Atomic Research Centre for their valuable role in regu-lar operation and maintenance of Dhruva research reactor, which was utilized for produc-tion of 177Lutetium throughout last decade.

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.

Disclosure of conflict of interest

None.

Address correspondence to: Dr. Sandip Basu, Ra- diation Medicine Centre (BARC), Tata Memorial Hospital Annexe, Jerbai Wadia Road, Parel, Mumbai 400012, India. Tel: 91-22-24149428; Fax: 91-22-24157098; E-mail: [email protected]

References

[1] Pillai MR, Chakraborty S, Das T, Venkatesh M and Ramamoorthy N. Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot 2003; 59: 109-118.



[23] Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O’Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srira-jaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D and Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-dot-atate for midgut neuroendocrine tumors. N Engl J Med 2017; 376: 125-135.

[24] Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ and Zak-nun JJ. The joint IAEA, EANM, and SNMMI prac-tical guidance on peptide receptor radionu-clide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40: 800-16.

[25] Öberg K, Knigge U, Kwekkeboom D and Perren A; ESMO Guidelines Working Group. Neuroen-docrine gastro-entero-pancreatic tumors: ES- MO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7: vii124-30.

[26] Wang LF, Lin L, Wang MJ and Li Y. The thera-peutic efficacy of 177Lu-DOTATATE/DOTATOC in advanced neuroendocrine tumors: a meta-analysis. Medicine (Baltimore) 2020; 99: e19304.

[27] Zhang J, Song Q, Cai L, Xie Y and Chen Y. The efficacy of 177Lu-DOTATATE peptide receptor ra-dionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours: a system-atic review and meta-analysis. J Cancer Res Clin Oncol 2020; 146: 1533-1543.

[28] Ezziddin S, Khalaf F, Vanezi M, Haslerud T, Mayer K, Al Zreiqat A, Willinek W, Biersack HJ and Sabet A. Outcome of peptide receptor ra-dionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendo-crine tumours. Eur J Nucl Med Mol Imaging 2014; 41: 925-933.

[29] Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Ei-jck CHJ, Franssen GJH, Krenning EP and Kwek-keboom DJ. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in pa-tients with gastroenteropancreatic and bron-chial neuroendocrine tumors. Clin Cancer Res 2017; 23: 4617-4624.

[30] Parghane R, Talole S, Prabhash K and Basu S. Clinical response profile of metastatic/ad-vanced pulmonary neuroendocrine tumors to peptide receptor radionuclide therapy with 177Lu-DOTATATE. Clin Nucl Med 2017; 42: 428-435.

[31] Sabet A, Haug AR, Eiden C, Auernhammer CJ, Simon B, Bartenstein P, Biersack HJ and Ezzid-

gists. Indian J Med Paediatr Oncol 2019; 40: 165-71.

[15] Garske-Román U, Sandström M, Fröss Baron K, Lundin L, Hellman P, Welin S, Johansson S, Khan T, Lundqvist H, Eriksson B, Sundin A and Granberg D. Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 pa-tients with advanced metastasized neuroen-docrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on out-come and toxicity. Eur J Nucl Med Mol Imaging 2018; 45: 970-988.

[16] Ilan E, Sandström M, Wassberg C, Sundin A, Garske-Román U, Eriksson B, Granberg D and Lubberink M. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE. J Nucl Med 2015; 56: 177-82.

[17] Wehrmann C, Senftleben S, Zachert C, Müller D and Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DO-TA-NOC. Cancer Biother Radiopharm 2007; 22: 406-416.

[18] Garkavij M, Nickel M, Sjögreen-Gleisner K, Ljungberg M, Ohlsson T, Wingårdh K, Strand SE and Tennvall J. 177Lu-[DOTA0,Tyr3] octreo-tate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer 2010; 116 Suppl: 1084-1092.

[19] Thapa P, Ranade R, Ostwal V, Shrikhande SV, Goel M and Basu S. Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric re-sponse evaluation correlating with primary tu-mor site, tumor proliferation index, and dual tracer imaging characteristics. Nucl Med Com-mun 2016; 37: 1030-7.

[20] Basu S, Ranade R and Thapa P. Metastatic neuroendocrine tumor with extensive bone marrow involvement at diagnosis: evaluation of response and hematological toxicity profile of PRRT with (177)Lu-DOTATATE. World J Nucl Med 2016; 15: 38-43.

[21] Basu S and Abhyankar A. The use of 99mTc-HYNIC-TOC and 18F-FDG PET/CT in the evalua-tion of duodenal neuroendocrine tumor with atypical and extensive metastasis responding dramatically to a single fraction of PRRT with 177Lu-DOTATATE. J Nucl Med Technol 2014; 42: 296-298.

[22] Bodei L, Kidd M, Paganelli G, Grana CM, Droz-dov I, Cremonesi M, Lepensky C, Kwekkeboom DJ, Baum RP, Krenning EP and Modlin IM. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging 2015; 42: 5-19.



ized model. Nucl Med Commun 2015; 36: 766-774.

[40] Basu S. Should grade of tracer uptake on so-matostatin receptor-targeted imaging be the major determinant and break the barrier of histopathologic criteria for determining the suitability of Peptide receptor radionuclide therapy? J Nucl Med 2013; 54: 2018-9.

[41] Jois B, Asopa R and Basu S. Somatostatin re-ceptor imaging in non-(131)I-avid metastatic differentiated thyroid carcinoma for determin-ing the feasibility of peptide receptor radionu-clide therapy with (177)Lu-DOTATATE: low frac-tion of patients suitable for peptide receptor radionuclide therapy and evidence of chromo-granin a level-positive neuroendocrine differ-entiation. Clin Nucl Med 2014; 39: 505-10.

[42] Basu S and Ranade R. Favorable response of metastatic merkel cell carcinoma to targeted 177Lu-DOTATATE therapy: will PRRT evolve to become an important approach in receptor-positive cases? J Nucl Med Technol 2016; 44: 85-7.

[43] Parghane RV, Talole S and Basu S. Prevalence of hitherto unknown brain meningioma detect-ed on 68Ga-DOTATATE positron-emission to-mography/computed tomography in patients with metastatic neuroendocrine tumor and ex-ploring potential of 177Lu-DOTATATE peptide receptor radionuclide therapy as single-shot treatment approach targeting both tumors. World J Nucl Med 2019; 18: 160-170.

[44] Basu S and Fargose P. 177Lu-DOTATATE PRRT in recurrent skull-base phosphaturic mesen-chymal tumor causing osteomalacia: a poten-tial application of PRRT beyond neuroendo-crine tumors. J Nucl Med Technol 2016; 44: 248-250.

[45] Adnan A and Basu S. Gratifying results with combined Chemo-PRRT (177Lu-DOTATATE and platinum-based chemotherapy) in recurrent metastatic sinonasal neuroendocrine carcino-ma with high uptake on both 68Ga-DOTATATE and 18F-FDG PET-CT: a Promising Therapeutic Option. J Nucl Med Technol 2020; [Epub ahead of print].

[46] Parghane RV, Ostwal V, Ramaswamy A, Bhan-dare M, Chaudhari V, Talole S, Shrikhande SV, Basu S. Long-term outcome of “Sandwich” chemo-PRRT: a novel treatment strategy for metastatic neuroendocrine tumors with both FDG- and SSTR-avid aggressive disease. Eur J Nucl Med Mol Imaging 2020; [Epub ahead of print].

[47] Basu S, Kand P, Mallia M, Korde A and Shimpi H. Gratifying clinical experience with an indig-enously formulated single-vial lyophilized HYN-IC-TOC kit at the radiopharmaceutical division of BARC: a pivotal boost for building up a pep-tide receptor radionuclide therapy programme

din S. Efficacy of peptide receptor radionuclide therapy with 177Lu-octreotate in metastatic pul-monary neuroendocrine tumors: a dual-centre analysis. Am J Nucl Med Mol Imaging 2017; 7: 74-83.

[32] Adnan A, Kudachi S, Ramesh S, Prabhash K and Basu S. Metastatic or locally advanced mediastinal neuroendocrine tumours: out-come with 177Lu-DOTATATE-based peptide re-ceptor radionuclide therapy and assessment of prognostic factors. Nucl Med Commun 2019; 40: 947-957.

[33] Parghane RV, Naik C, Talole S, Desmukh A, Chaukar D, Banerjee S and Basu S. Clinical utility of 177Lu-DOTATATE PRRT in somatostatin receptor-positive metastatic medullary carci-noma of thyroid patients with assessment of efficacy, survival analysis, prognostic vari-ables, and toxicity. Head Neck 2020; 42: 401-416.

[34] Beukhof CM, Brabander T, van Nederveen FH, van Velthuysen MF, de Rijke YB, Hofland LJ, Franssen GJH, Fröberg LAC, Kam BLR, Visser WE, de Herder WW and Peeters RP. Peptide re-ceptor radionuclide therapy in patients with medullary thyroid carcinoma: predictors and pitfalls. BMC Cancer 2019; 19: 325.

[35] Vaisman F, Rosado de Castro PH, Lopes FP, Kendler DB, Pessoa CH, Bulzico DA, de Carv-alho Leal D, Vilhena B, Vaisman M, Carneiro M and Corbo R. Is there a role for peptide recep-tor radionuclide therapy in medullary thyroid cancer? Clin Nucl Med 2015; 40: 123-127.

[36] Basu B and Basu S. Correlating and combining genomic and proteomic assessment with in vivo molecular functional imaging: will this be the future roadmap for personalized cancer management? Cancer Biother Radiopharm 2016; 31: 75-84.

[37] Adnan A, Sampathirao N and Basu S. Implica-tions of fluorodeoxyglucose uptake in low-inter-mediate grade metastatic neuroendocrine tu-mors from peptide receptor radionuclide therapy outcome viewpoint: a semi-quantita-tive standardized uptake value-based analysis. World J Nucl Med 2019; 18: 389-395.

[38] Basu S, Sirohi B and Shrikhande SV. Dual trac-er imaging approach in assessing tumor biolo-gy and heterogeneity in neuroendocrine tu-mors: its correlation with tumor proliferation index and possible multifaceted implications for personalized clinical management deci-sions, with focus on PRRT. Eur J Nucl Med Mol Imaging 2014; 41: 1492-1496.

[39] Basu S, Ranade R and Thapa P. Correlation and discordance of tumour proliferation index and molecular imaging characteristics and their implications for treatment decisions and outcome pertaining to peptide receptor radio-nuclide therapy in patients with advanced neu-roendocrine tumour: developing a personal-



vanced neuroendocrine tumors: a long-term-outcome, toxicity, survival, and quality-of-life study. Clin Nucl Med 2017; 42: e457-e466.

[57] Yordanova A, Ahrens H, Feldmann G, Brossart P, Gaertner FC, Fottner C, Weber MM, Ah-madzadehfar H, Schreckenberger M, Miederer M and Essler M. Peptide receptor radionuclide therapy combined with chemotherapy in pa-tients with neuroendocrine tumors. Clin Nucl Med 2019; 44: e329-e335.

[58] Basu S, Parghane RV and Banerjee S. Avail-ability of both [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTATATE as PRRT agents for neuroendocrine tumors: can we evolve a rational sequential duo-PRRT protocol for large volume resistant tumors? Eur J Nucl Med Mol Imaging 2020; 47: 756-758.

[59] Parghane RV, Mitra A, Upadhye T, Rakshit S, Banerjee S and Basu S. Sequential duo-PRRT with indigenous 90Y-DOTATATE and 177Lu-DOT-ATATE in large volume neuroendocrine tumors: post-therapy bremsstrahlung and PET-CT im-aging following 90Y-DOTATATE treatment. Clin Nucl Med 2020; 45: 714-715.

[60] Basu S, Parghane RV, Kamaldeep, Chakrabar-ty S. Peptide receptor radionuclide therapy of neuroendocrine tumors. Semin Nucl Med 2020; 50: 447-464.

[61] Nelson KL and Sheetz MA. Radiation safety ob-servation associated with 177Lu-Dotatate pa-tients. Health Phys 2019; 117: 680-687.

[62] Kamaldeep, Bhaktivinayagam A, Tervankar S, Kumar P, Kaisar S, et.al. Estimate of effective dose to comfortors/family members of pa-tients in peptide receptor radionuclide therapy with [lu-177]-DOTATATE. Proceedings of 31st National Conference on “Advances in Radia-tion Measurement Systems and Techniques. IARPNC- 2014, March 19 -21, 2014, Mumbai, pp-120.

[63] ICRP Publication 30 (Part 3). Limits for intakes of radionuclides by workers. Ann ICRP. 1981; 6.

[64] Advanced Accelerator Applications. Lutathera Package Insert. 2018. pp. 1-14.

[65] Sandström M, Garske-Román U, Granberg D, Johansson S, Widström C, Eriksson B, Sundin A, Lundqvist H and Lubberink M. Individualized dosimetry of kidney and bone marrow in pa-tients undergoing 177Lu-DOTA-octreotate treat-ment. J Nucl Med 2013; 54: 33-41.

[66] Kamaldeep, Wanage G, Sahoo S, Maletha P, Adnan A, Basu S, Das T and Banerjee S. Bioki-netic studies of 177Lu-DOTATATE in patients with advanced/metastatic neuroendocrine tumor receiving peptide receptor radionuclide thera-py. Indian Journal of Nuclear Medicine (Ab-stract Supplement Issue) 2017; 32: S28.

[67] De Jong M and Krenning EP. New advances in peptide receptor radionuclide therapy. J Nucl Med 2002; 43: 617-20.

in an Indian setting. Eur J Nucl Med Mol Imag-ing 2013; 40: 1622-4.

[48] Ramesh S, Kudachi S and Basu S. Peptide re-ceptor radionuclide therapy with 177Lu-DOT-ATATE in carcinoid heart disease: a contraindi-cation or a promising treatment approach bettering chances for corrective surgery? J Nucl Med Technol 2018; 46: 292-294.

[49] van Vliet EI, van Eijck CH, de Krijger RR, Nieveen van Dijkum EJ, Teunissen JJ, Kam BL, de Herder WW, Feelders RA, Bonsing BA, Bra-bander T, Krenning EP and Kwekkeboom DJ. Neoadjuvant treatment of nonfunctioning pan-creatic neuroendocrine tumors with [177Lu-DOTA0,Tyr3]Octreotate. J Nucl Med 2015; 56: 1647-1653.

[50] Barber TW, Hofman MS, Thomson BN and Hicks RJ. The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroen-docrine tumours resectable. Eur J Surg Oncol 2012; 38: 64-71.

[51] Stoeltzing O, Loss M, Huber E, Gross V, Eilles C, Mueller-Brand J and Schlitt HJ. Staged surgery with neoadjuvant 90Y-DOTATOC therapy for down-sizing synchronous bilobular hepatic me-tastases from a neuroendocrine pancreatic tumor. Langenbecks Arch Surg 2010; 395: 185-192.

[52] Sowa-Staszczak A, Pach D, Chrzan R, Trofimiuk M, Stefańska A, Tomaszuk M, Kołodziej M, Mikołajczak R, Pawlak D and Hubalewska-Dydejczyk A. Peptide receptor radionuclide therapy as a potential tool for neoadjuvant therapy in patients with inoperable neuroendo-crine tumors (NETs). Eur J Nucl Med Mol Imag-ing 2011; 38: 1669-1674.

[53] Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, Eu P, Michael M and Hicks RJ. Assessment of predictors of re-sponse and long-termsurvival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging 2014; 41: 1831-1844.

[54] Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, Zannino D and Hicks RJ. Fa-vourable outcomes of 177Lu-octreotate pep-tide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tu-mours. Eur J Nucl Med Mol Imaging 2015; 42: 176-185.

[55] Claringbold PG and Turner JH. Pancreatic neu-roendocrine tumor control: durable objective response to combination 177Lu-octreotate capecitabine-temozolomide radiopeptide che-motherapy. Neuroendocrinology 2016; 103: 432-439.

[56] Ballal S, Yadav MP, Damle NA, Sahoo RK and Bal C. Concomitant 177Lu-DOTATATE and capecitabine therapy in patients with ad-



[76] Kwekkeboom DJ, Bakker WH, Kooij PP, Koni-jnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JL, de Jong M and Krenning EP. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med 2001; 28: 1319-25.

[77] Del Prete M, Buteau FA and Beauregard JM. Personalized (177)Lu-octreotate peptide re-ceptor radionuclide therapy of neuroendocrine tumours: a simulation study. Eur J Nucl Med Mol Imaging 2017; 44: 1490-500.

[78] Wehrmann C, Senftleben S, Zachert C, Muller D and Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DO-TA-NOC. Cancer Biother Radiopharm 2007; 22: 406-16.

[79] Gupta SK, Singla S, Thakral P and Bal CS. Do-simetric analyses of kidneys, liver, spleen, pitu-itary gland, and neuroendocrine tumors of pa-tients treated with 177Lu-DOTATATE. Clin Nucl Med 2013; 38: 188-94.

[80] Garkavij M, Nickel M, Sjögreen-Gleisner K, Ljungberg M, Ohlsson T, Wingårdh K, Strand SE and Tennvall J. 177Lu-[DOTA0,Tyr3] octreo-tate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer 2010; 116 Suppl 4: 1084-92.

[81] Svensson J, Berg G, Wangberg B, Larsson M, Forssell-Aronsson E and Bernhardt P. Renal function affects absorbed dose to the kidneys and haematological toxicity during (1)(7)(7)Lu-DOTATATE treatment. Eur J Nucl Med Mol Imag-ing 2015; 42: 947-55.

[68] Jamar F, Barone R, Mathieu I, Walrand S, Labar D, Carlier P, de Camps J, Schran H, Chen T, Smith MC, Bouterfa H, Valkema R, Krenning EP, Kvols LK and Pauwels S. (86YDOTA0)-DPhe1-Tyr3-octreotide (SMT487) - a phase 1 clinical study: pharmacokinetics, biodistribu-tion and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imaging 2003; 30: 510-8.

[69] Bodei L, Cremonesi M, Grana C, Rocca P, Bar-tolomei M, Chinol M and Paganelli G. Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3- octreotide (90Y-DOTATOC) in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2004; 31: 1038-46.

[70] Loevinger R, Budinger TF and Watson EE. MIRD primer for absorbed dose calculations. New York: The Society of Nuclear Medicine; 1991.

[71] Cremonesi M, Ferrari ME, Bodei L, Chiesa C, Sarnelli A, Garibaldi C, Pacilio M, Strigari L, Summers PE, Orecchia R, Grana CM and Botta F. Correlation of dose with toxicity and tumour response to 90Y- and 177Lu-PRRT provides the basis for optimization through individual-ized treatment planning. Eur J Nucl Med Mol Imaging 2018; 45: 2426-2441.

[72] Levart D, Kalogianni E, Carcoran B, Mulholl N and Vivian G. Radiation precautions for inpa-tient and outpatient 177Lu-DOTATATE peptide receptor radionuclide therapy of neuroendo-crine tumours. EJNMMI Phys 2019; 6: 7.

[73] Calais PJ and Turner JH. Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors. Ann Nucl Med 2014; 28: 531-539.

[74] Sandstrom M, Garske U, Granberg D, Sundin A and Lundqvist H. Individualized dosimetry in patients undergoing therapy with (177)Lu-DO-TA-D-Phe (1)-Tyr (3)-octreotate. Eur J Nucl Med Mol Imaging 2010; 37: 212-25.

[75] Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, Baio SM, Sansovini M and Paganelli G. Long-term evaluation of re-nal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOT-ATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging 2008; 35: 1847-56.

review article one decade of ‘bench-to-bedside’ peptide ... · volume tertiary cancer care...

Documents