Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis
Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/− radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN.
Kaplan–Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 ≤ 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression.
28 patients (M = 17; age 16–78 years; Ki-67 ≤ 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG-avid disease prior to treatment. Most had 177Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 ≤ 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 ≤ 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen.
PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs.
KeywordsLutetium Neuroendocrine Octreotate Peptide receptors Radionuclide therapy G3
Professor Hicks’ research is supported by a National Health and Medical Research Council of Australia Program grant and practitioner fellowship. We thank our radiopharmacists and radiochemists for their excellent support of our theranostics program and our dedicated nuclear medicine technologists and nursing staff for the care of our patients. Finally, we are grateful for the trust invested in us by our patients, their families and their managing clinicians.
Compliance with ethical standards
Conflict of interest
All authors declare no conflicts of interest. No funding was received. All procedures performed were in accordance with the ethical standards of the institutional research committee and all patients provided informed consent for treatment.
- 1.Rindi G, Arnold R, Bosman FT, Bosman T, Carneiro F, Hruban R, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. WHO Classification of Tumours of the Digestive System 4th edn. Lyon: International Agency for Research on Cancer (IARC); 2010. 13–4.Google Scholar
- 3.Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24:152–60. https://doi.org/10.1093/annonc/mds276.CrossRefPubMedGoogle Scholar
- 7.Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, et al. The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):85–93.CrossRefPubMedGoogle Scholar
- 8.Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO grade 3 (G3) well-differentiated Neuroendocrine tumor (WD-NET) and poorly differentiated Neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–202. https://doi.org/10.1097/PAS.0000000000000662.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Tang LH, Untch BR, Reidy DL, O'Reilly E, Dhall D, Jih L, et al. Well-differentiated Neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated Neuroendocrine carcinomas. Clin Cancer Res. 2016;22(4):1011–7. https://doi.org/10.1158/1078-0432.CCR-15-0548.CrossRefPubMedGoogle Scholar
- 12.Garin E, Le Jeune F, Devillers A, Cuggia M, de Lajarte-Thirouard AS, Bouriel C, et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J Nucl Med. 2009;50(6):858–64. https://doi.org/10.2967/jnumed.108.057505.CrossRefPubMedGoogle Scholar
- 13.Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Neoplasia: peptide receptor radionuclide therapy with Radiolabeled Somatostatin analogues. Neuroendocrinology. 2017; https://doi.org/10.1159/000475526.
- 14.Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2015;42(2):176–85. https://doi.org/10.1007/s00259-014-2906-4.CrossRefPubMedGoogle Scholar
- 15.Armaghany T, Vahdati G, Thamake S, Hamidi M, Amerinia R, Delpassand E. Treatment of high grade metastatic neuroendocrine tumor (mNET) with peptide receptor radionuclide therapy (PRRT): Retrospective analysis in a single referral center. J Clin Oncol 33, 2015 (suppl; abstr e15175).Google Scholar
- 17.Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103:186–94. https://doi.org/10.1159/000443172.CrossRefPubMedGoogle Scholar
- 20.Kong G, Callahan J, Hofman MS, Pattison DA, Akhurst T, Michael M, et al. High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2017;44(3):476–89. https://doi.org/10.1007/s00259-016-3527-x.CrossRefPubMedGoogle Scholar
- 22.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(5):800–16. https://doi.org/10.1007/s00259-012-2330-6.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Kashyap R, Jackson P, Hofman MS, Eu P, Beauregard JM, Zannino D, et al. Rapid blood clearance and lack of long-term renal toxicity of 177Lu-DOTATATE enables shortening of renoprotective amino acid infusion. Eur J Nucl Med Mol Imaging. 2013;40(12):1853–60. https://doi.org/10.1007/s00259-013-2504-x.CrossRefPubMedGoogle Scholar
- 24.Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, et al. Assessment of predictors of response and longterm survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging. 2014;41(10):1831–44. https://doi.org/10.1007/s00259-014-2788-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity in-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm. 2009;24(5):527–33. https://doi.org/10.1089/cbr.2009.0644.CrossRefPubMedGoogle Scholar
- 26.Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-Octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging. 2010;37(10):1869–75. https://doi.org/10.1007/s00259-010-1483-4.CrossRefPubMedGoogle Scholar
- 28.Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71(3):663–70. https://doi.org/10.1007/s00280-012-2055-z.CrossRefPubMedGoogle Scholar
- 36.Strosberg JR, Coppola D, Klimstra DS, Phan AT, Kulke MH, Wiseman GA, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799–800. https://doi.org/10.1097/MPA.0b013e3181ebb56f.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 2011; 11: 4617–4622. doi: https://doi.org/10.1002/cncr.26124.