Long-term hematologic toxicity of 177Lu-octreotate-capecitabine-temozolomide therapy of GEPNET

in Endocrine-Related Cancer
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  • 1 Department of Oncology, School of Medicine, The University of Western Australia, Perth, Australia
  • 2 Department of Oncology, Fiona Stanley Hospital, Perth, Australia

Correspondence should be addressed to M Kesavan: murali.kesavan@research.uwa.edu.au
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Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1–10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45–24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80–55.20), and the median OS was 86 months (95% CI: 56.90–115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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  • Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M & Vardiman JW 2016 The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood 127 23912405. (https://doi.org/10.1182/blood-2016-03-643544)

    • Search Google Scholar
    • Export Citation
  • Baum RP, Kulkarni HR, Singh A, Kaemmerer D, Mueller D, Prasad V, Hommann M, Robiller FC, Niepsch K, Franz H, et al. 2018 Results and adverse events of personalized peptide receptor radionuclide therapy with (90) Yttrium and (177)Lutetium in 1048 patients with neuroendocrine neoplasms. Oncotarget 9 1693216950. (https://doi.org/10.18632/oncotarget.24524)

    • Search Google Scholar
    • Export Citation
  • Bergsma H, Van Lom K, Raaijmakers MHGP, Konijnenberg M, Kam BLBLR, Teunissen JJM, De Herder WW, Krenning EP & Kwekkeboom DJ 2018 Persistent hematologic dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE: incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. Journal of Nuclear Medicine 59 452458. (https://doi.org/10.2967/jnumed.117.189712)

    • Search Google Scholar
    • Export Citation
  • Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O'dorisio MS, O'dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, et al. 2013 The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. European Journal of Nuclear Medicine and Molecular Imaging 40 800816. (https://doi.org/10.1007/s00259-012-2330-6)

    • Search Google Scholar
    • Export Citation
  • Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, Lepensky C, Kwekkeboom DJ, Baum RP, Krenning EP, et al. 2015 Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. European Journal of Nuclear Medicine and Molecular Imaging 42 519. (https://doi.org/10.1007/s00259-014-2893-5)

    • Search Google Scholar
    • Export Citation
  • Brabander T, Van Der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, De Herder WW, Van Eijck CHJ, Franssen GJH, Krenning EP & Kwekkeboom DJ 2017 Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research 23 46174624. (https://doi.org/10.1158/1078-0432.CCR-16-2743)

    • Search Google Scholar
    • Export Citation
  • Claringbold PG & Turner JH 2015 NeuroEndocrine tumor therapy with lutetium-177-octreotate and everolimus (NETTLE): a phase I study. Cancer Biotherapy and Radiopharmaceuticals 30 261269. (https://doi.org/10.1089/cbr.2015.1876)

    • Search Google Scholar
    • Export Citation
  • Claringbold PG & Turner JH 2016 Pancreatic neuroendocrine tumor control: durable objective response to combination 177Lu-octreotate-capecitabine-temozolomide radiopeptide chemotherapy. Neuroendocrinology 103 432439. (https://doi.org/10.1159/000434723)

    • Search Google Scholar
    • Export Citation
  • Claringbold PG, Price RA & Turner JH 2012 Phase I–II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biotherapy and Radiopharmaceuticals 27 561569. (https://doi.org/10.1089/cbr.2012.1276)

    • Search Google Scholar
    • Export Citation
  • Gatenby RA & Brown JS 2020 Integrating evolutionary dynamics into cancer therapy. Nature Reviews: Clinical Oncology 17 675686. (https://doi.org/10.1038/s41571-020-0411-1)

    • Search Google Scholar
    • Export Citation
  • Herrera-Martinez AD, Hofland J, Hofland LJ, Brabander T, Eskens FALM, Galvez Moreno MA, Luque RM, Castano JP, De Herder WW & Feelders RA 2019 Targeted systemic treatment of neuroendocrine tumors: current options and future perspectives. Drugs 79 2142. (https://doi.org/10.1007/s40265-018-1033-0)

    • Search Google Scholar
    • Export Citation
  • Hirmas N, Jadaan R & Al-Ibraheem A 2018 Peptide receptor radionuclide therapy and the treatment of gastroentero-pancreatic neuroendocrine tumors: current findings and future perspectives. Nuclear Medicine and Molecular Imaging 52 190199. (https://doi.org/10.1007/s13139-018-0517-x)

    • Search Google Scholar
    • Export Citation
  • Kennedy JA & Ebert BL 2017 Clinical implications of genetic mutations in myelodysplastic syndrome. Journal of Clinical Oncology 35 968974. (https://doi.org/10.1200/JCO.2016.71.0806)

    • Search Google Scholar
    • Export Citation
  • Kesavan M & Turner JH 2016 Myelotoxicity of peptide receptor radionuclide therapy of neuroendocrine tumors: a decade of experience. Cancer Biotherapy and Radiopharmaceuticals 31 189198. (https://doi.org/10.1089/cbr.2016.2035)

    • Search Google Scholar
    • Export Citation
  • Kesavan M, Claringbold PG & Turner JH 2014 Hematological toxicity of combined 177Lu-octreotate radiopeptide chemotherapy of gastroenteropancreatic neuroendocrine tumors in long-term follow-up. Neuroendocrinology 99 108117. (https://doi.org/10.1159/000362558)

    • Search Google Scholar
    • Export Citation
  • Kuendgen A, Nomdedeu M, Tuechler H, Garcia-Manero G, Komrokji RS, Sekeres MA, Della Porta MG, Cazzola M, DeZern AE, Roboz GJ, et al. 2021 Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS. Leukemia 35 835849. (https://doi.org/10.1038/s41375-020-0917-7)

    • Search Google Scholar
    • Export Citation
  • Morton LM, Dores GM, Schonfeld SJ, Linet MS, Sigel BS, Lam CJK, Tucker MA & Curtis RE 2019 Association of chemotherapy for solid tumors With development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era. JAMA Oncology 5 318325. (https://doi.org/10.1001/jamaoncol.2018.5625)

    • Search Google Scholar
    • Export Citation
  • Paganelli G, Sansovini M, Nicolini S, Grassi I, Ibrahim T, Amadori E, Di Iorio V, Monti M, Scarpi E, Bongiovanni A, et al. 2021. 177 Lu-PRRT in advanced gastrointestinal neuroendocrine tumors: 10-year follow-up of the IRST phase II prospective study. European Journal of Nuclear Medicine and Molecular Imaging 48 152160. (https://doi.org/10.1007/s00259-020-04873-0)

    • Search Google Scholar
    • Export Citation
  • Palomo L, Ibáñez M, Abáigar M, Vázquez I, Álvarez S, Cabezón M, Tazón-Vega B, Rapado I, Fuster-Tormo F, Cervera J, et al. 2020 Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia. British Journal of Haematology 188 605622. (https://doi.org/10.1111/bjh.16175)

    • Search Google Scholar
    • Export Citation
  • Pavlakis N, Ransom DT, Wyld D, Sjoquist KM, Asher R, Gebski V, Wilson K, Kiberu AD, Burge ME, Macdonald W, et al. 2020 First results for australasian gastrointestinal trials group (AGITG) control net study: phase II study of 177Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) +/- capecitabine, temozolomide (CAPTEM) for midgut neuroendocrine tumors (mNETs). Journal of Clinical Oncology 38 604604. (https://doi.org/10.1200/JCO.2020.38.4_suppl.604)

    • Search Google Scholar
    • Export Citation
  • Rack KA, van den Berg E, Haferlach C, Beverloo HB, Costa D, Espinet B, Foot N, Jeffries S, Martin K, O'connor S, et al. 2019 European recommendations and quality assurance for cytogenomic analysis of haematological neoplasms. Leukemia 33 18511867. (https://doi.org/10.1038/s41375-019-0378-z)

    • Search Google Scholar
    • Export Citation
  • Ramage J, Naraev BG & Halfdanarson TR 2018 Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors. Seminars in Oncology 45 236248. (https://doi.org/10.1053/j.seminoncol.2018.08.004)

    • Search Google Scholar
    • Export Citation
  • Sabet A, Ezziddin K, Pape UF, Ahmadzadehfar H, Mayer K, Poppel T, Guhlke S, Biersack HJ & Ezziddin S 2013 Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. Journal of Nuclear Medicine 54 18571861. (https://doi.org/10.2967/jnumed.112.119347)

    • Search Google Scholar
    • Export Citation
  • Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, et al. 2016 RECIST 1.1-Update and clarification: from the RECIST committee. European Journal of Cancer 62 132137. (https://doi.org/10.1016/j.ejca.2016.03.081)

    • Search Google Scholar
    • Export Citation
  • Sperling AS, Gibson CJ & Ebert BL 2017 The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nature Reviews: Cancer 17 519. (https://doi.org/10.1038/nrc.2016.112)

    • Search Google Scholar
    • Export Citation
  • Strosberg JR, Wolin EM, Chasen BA, Kulke MH, Bushnell DL, Caplin ME, Baum RP, Hobday TJ, Hendifar AE, Lopera Sierra M, et al. 2018 First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. Journal of Clinical Oncology 36 40994099. (https://doi.org/10.1200/JCO.2018.36.15_suppl.4099)

    • Search Google Scholar
    • Export Citation
  • Turner JH 2018 An introduction to the clinical practice of theranostics in oncology. British Journal of Radiology 91 20180440. (https://doi.org/10.1259/bjr.20180440)

    • Search Google Scholar
    • Export Citation
  • Uri I & Grozinsky-Glasberg S 2018 Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Clinical Diabetes and Endocrinology 4 16. (https://doi.org/10.1186/s40842-018-0066-3)

    • Search Google Scholar
    • Export Citation
  • Villard L, Romer A, Marincek N, Brunner P, Koller MT, Schindler C, Ng QK, Macke HR, Muller-Brand J, Rochlitz C, et al. 2012 Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. Journal of Clinical Oncology 30 11001106. (https://doi.org/10.1200/JCO.2011.37.2151)

    • Search Google Scholar
    • Export Citation