Peptide Receptor Radionuclide Therapy in the Management of Neuroendocrine Tumors (Neoplasms)^[*]: Fundamentals and Salient Clinical Practice Points for Medical Oncologists

Abstract

This editorial commentary is an expert summary of “Peptide Receptor Radionuclide Therapy (PRRT),” encompassing the essential fundamentals and salient clinical practice points, deliberated and designed in a point-wise manner with theme-based subheadings. Emphasis has been laid on the topics of practical relevance to the referring oncologists with relevant finer points where necessary. A part of the presented overview has been generated from the authors' own practical experience of more than 3500 successful therapies delivered over the last 9 years at a large tertiary care PRRT setting by the joint efforts of Radiation Medicine Centre (RMC), Bhabha Atomic Research Centre (BARC), and Gastrointestinal services of Tata Memorial Hospital (TMH) at the TMH-RMC premises. While the technical indigenization is beyond the scope of this treatise, we must mention here that India had been one of the frontrunners in this treatment modality, and the PRRT services in this country were developed purely as an indigenous effort right from the production of the radionuclide (177-Lutetium) at the reactor and radiolabeling and production of the radiopharmaceutical (177Lu-DOTATATE) by the radiopharmaceutical scientists at the BARC and RMC; such an endeavor allowed this very specialized therapy to be delivered at a very affordable cost in our setting which could be viewed as a major societal contribution of the atomic energy research in this country.

Keywords

Neuroendocrine tumor - neuroendocrine neoplasm - peptide receptor radionuclide therapy (PRRT) - Somatostatin receptor imaging - 68Ga-DOTATATE PET-CT - 99mTc-HYNIC-TOC SPECT - FDG-PET/CT - 177Lu-DOTATATE - 90Y-DOTATOC

• References

• 1 Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E. et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; 31: 1770-86
• 2 Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS. et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40: 800-16
• 3 Öberg K, Knigge U, Kwekkeboom D, Perren A. ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (07) Suppl vii124-30
• 4 Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging. Semin Nucl Med 2002; 32: 84-91
• 5 Basu S. Should grade of tracer uptake on somatostatin 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
• 6 Parghane RV, Talole S, Prabhash K, Basu S. Clinical response profile of metastatic/advanced pulmonary neuroendocrine tumors to peptide receptor radionuclide therapy with 177Lu-DOTATATE. Clin Nucl Med 2017; 42: 428-35
• 7 Adnan A, Kudachi S, Ramesh S, Prabhash K, Basu S. Metastatic or locally advanced mediastinal neuroendocrine tumours: Outcome with 177Lu-DOTATATE-based peptide receptor radionuclide therapy and assessment of prognostic factors. Nucl Med Commun 2019; 40: 947-57
• 8 Jois B, Asopa R, Basu S. Somatostatin receptor imaging in non-(131) I-avid metastatic differentiated thyroid carcinoma for determining the feasibility of peptide receptor radionuclide therapy with (177) Lu-DOTATATE: Low fraction of patients suitable for peptide receptor radionuclide therapy and evidence of chromogranin A level-positive neuroendocrine differentiation. Clin Nucl Med 2014; 39: 505-10
• 9 Basu S, 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
• 10 Parghane RV, Talole S, Basu S. Prevalence of hitherto unknown brain meningioma detected on 68Ga-DOTATATE positron-emission tomography/computed tomography in patients with metastatic neuroendocrine tumor and exploring potential of 177Lu-DOTATATE peptide receptor radionuclide therapy as single-shot treatment approach targeting both tumors. World J Nucl Med 2019; 18: 160-70
• 11 Basu S, Fargose P. 177Lu-DOTATATE PRRT in recurrent skull-base phosphaturic mesenchymal tumor causing osteomalacia: A potential application of PRRT beyond neuroendocrine tumors. J Nucl Med Technol 2016; 44: 248-50
• 12 Sharma P, Singh H, Bal C, Kumar R. PET/CT imaging of neuroendocrine tumors with (68) Gallium-labeled somatostatin analogues: An overview and single institutional experience from India. Indian J Nucl Med 2014; 29: 2-12
• 13 Bozkurt MF, Virgolini I, Balogova S, Beheshti M, Rubello D, Decristoforo C. et al. Guideline for PET/CT imaging of neuroendocrine neoplasms with 68 Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18 F-DOPA. Eur J Nucl Med Mol Imaging 2017; 44: 1588-601
• 14 Basu S, Kand P, Mallia M, Korde A, Shimpi H. Gratifying clinical experience with an indigenously formulated single-vial lyophilized HYNIC-TOC kit at the radiopharmaceutical division of BARC: A pivotal boost for building up a peptide receptor radionuclide therapy programme in an Indian setting. Eur J Nucl Med Mol Imaging 2013; 40: 1622-4
• 15 Basu S, Sirohi B, Shrikhande SV. Dual tracer imaging approach in assessing tumor biology and heterogeneity in neuroendocrine tumors: Its correlation with tumor proliferation index and possible multifaceted implications for personalized clinical management decisions, with focus on PRRT. Eur J Nucl Med Mol Imaging 2014; 41: 1492-6
• 16 Sampathirao N, Basu S. MIB-1 index-stratified assessment of dual-tracer PET/CT with 68 Ga-DOTATATE and 18 F-FDG and multimodality anatomic imaging in metastatic neuroendocrine tumors of unknown primary in a PRRT workup setting. J Nucl Med Technol 2017; 45: 34-41
• 17 Basu S, Ranade R, 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 radionuclide therapy in patients with advanced neuroendocrine tumour: Developing a personalized model. Nucl Med Commun 2015; 36: 766-74
• 18 Basu B, 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
• 19 Ranade R, Basu S. 177Lu-DOTATATE PRRT in patients with metastatic neuroendocrine tumor and a single functioning kidney: Tolerability and effect on renal function. J Nucl Med Technol 2016; 44: 65-9
• 20 Naik C, Basu S. 177Lu-DOTATATE peptide receptor radionuclide therapy in patients with borderline low and discordant renal parameters: Treatment feasibility assessment by sequential estimation of triple parameters and filtration fraction. World J Nucl Med 2018; 17: 12-20
• 21 Pavel M, O'Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R. et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016; 103: 172-85
• 22 Zandee WT, de Herder WW. The evolution of neuroendocrine tumor treatment reflected by ENETS guidelines. Neuroendocrinology 2018; 106: 357-65
• 23 Thapa P, Ranade R, Ostwal V, Shrikhande SV, Goel M, Basu S. Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: A multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Nucl Med Commun 2016; 37: 1030-7
• 24 Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M. et al. 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
• 25 Basu S, Ranade R, 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
• 26 Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B. et al. Phase 3 Trial of 177 Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376: 125-35
• 27 Basu S, Ostwal V. The case for combined chemotherapy-peptide receptor radionuclide therapy (chemo-PRRT) strategy in metastatic neuroendocrine tumor: Predicting and looking at the possible case scenarios. Eur J Nucl Med Mol Imaging 2016; 43: 2453-5
• 28 Hofman MS, Michael M, Kashyap R, Hicks RJ. Modifying the poor prognosis associated with 18F-FDG-avid net with peptide receptor chemo-radionuclide therapy (PRCRT). J Nucl Med 2015; 56: 968-9
• 29 Kalshetty A, Ramaswamy A, Ostwal V, Basu S. Resistant functioning and/or progressive symptomatic metastatic gastroenteropancreatic neuroendocrine tumors: Efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy in this setting. Nucl Med Commun 2018; 39: 1143-9
• 30 Basu S, Ostwal V, Ranade R, Panda D. Supportive measures and finer practice points in 177Lu-DOTATATE PRRT for NET: Aiming for optimal disease management. J Nucl Med 2014; 55: 1916-7
• 31 Imhof Al, Brunner P, Marincek N, Briel M, Schindler C, Rasch H. et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29: 2416-23