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Chemotherapy in NEN: Still Has a Role?

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Chemotherapy in NEN: Still Has a Role? Reviews in Endocrine and Metabolic Disorders https://doi.org/10.1007/s11154-021-09638-0 Chemotherapy in NEN: still has a role? Paula Espinosa‑Olarte1 · Anna La Salvia1 · Maria C. Riesco‑Martinez1 · Beatriz Anton‑Pascual1 · Rocio Garcia‑Carbonero1 Accepted: 23 February 2021 © The Author(s) 2021 Abstract Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behav- ior. Primary tumor site, extent of disease, tumor diferentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well diferentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and 177Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms. Abbreviations EVO Evofosfamide 5-FU 5- Fluorouracil FFCD Fédération Francophonede Cancérologie AEs Adverse events Digestive BEVA Bevacizumab FOLFIRI 5-FU and Irinotecan BSC Best supportive care FOLFOX 5-FU and oxaliplatin CAP Capecitabine GEMOX Gemcitabine and oxaliplatin CAPOX Capecitabine and oxaliplatin GEP Gastroenteropancreatic CAPOXIRI Capecitabine, oxaliplatin and irinotecan GI Gastrointestinal CAPTEM Capecitabine and temozolomide HB Hepatobiliary CBDCA Carboplatin HN Head and neck CDDP Cisplatin IP Irinotecan and platinum CTX Cyclophosphamide IRI Irinotecan CTZ Chlorozotocin L Lung CYP450 Cytochrome P450 LAN Lanreotide DCR Disease control rate LDH Lactate dehydrogenase DOXO Doxorubicin m Months DTIC Dacarbazine MANEC Mixed adenoneuroendocrine carcinoma ECOG Eastern Cooperative Group MGMT O-6-methylguanine-DNA methyltransferase EP-NETs Extra-pancreatic neuroendocrine tumors MINEN Mixed neuroendocrine non-neuroendocrine EPI Epirubicin neoplasia EVE Everolimus MSI Microsatellite instability MTIC 3-Methyl-(triazen-1-yl) imidazole-4-carboxamide * Rocio Garcia-Carbonero NECs Neuroendocrine carcinomas [email protected] NENs Neuroendocrine neoplasias 1 Oncology Department, Hospital Universitario, 12 de NETs Neuroendocrine tumors Octubre, Imas12, UCM, Madrid, Spain Vol.:(0123456789)1 3 Reviews in Endocrine and Metabolic Disorders NR Not reported [1]. GEP-NENs are classifed based on morphology and pro- Ns Non signifcant liferation rate in well diferentiated neuroendocrine tumors NTR National tumor registry (NETs) (G1 to G3) or poorly diferentiated large or small NTRK Neurotrophic receptor tyrosine kinase 1 cell neuroendocrine carcinomas (NECs) (all G3) [2]. Lung- OCT Octreotide NENs are classifed based on morphology and mitotic count OR Odds ratio as well diferentiated typical or atypical carcinoids, or poorly ORR Objective response rate diferentiated large or small cell NECs [3]. Tumor diferen- OS Overall survival tiation in both GEP and lung NENs refect two major bio- P-NETs Pancreatic neuroendocrine tumors logically and genetically distinct entities with very diferent PARP Poly(ADP)-ribose polymerase clinical behavior, including response to available treatments. PAZO Pazopanib Primary tumor site, extent of disease, tumor expression of PDGFR Platelet derived growth factor receptor somatostatin receptors, proliferation and growth rates are PFS Progression-free survival also major prognostic factors that shall be taken into account PRRT​ Peptide receptor radionuclide therapy to defne treatment strategy. PS Performance status Treatment options for advanced disease have consider- Rb Retinoblastoma ably expanded in recent years, particularly for NETs [4]. RENATEN Groupe d’étude des Tumeurs Endocrines Most remarkable drugs recently incorporated to the treat- [GTE] ment armamentarium include somatostatin analogues (lan- RGETNE Registro del grupo español de tumores reotide, octreotide) for G1 or low G2 gastroenteropancreatic neuroendocrinos (GEP) NETs [5, 6], sunitinib for pancreatic NETs (P-NETs) RR Response rate [7], everolimus for non-functioning lung or gastrointesti- SCLC Small cell lung cáncer nal NETs (L-or GI-NETs) and P-NETs [8, 9], and 177Lu- STZ Streptozocin oxodotreotide for somatostatin-receptor-positive GEP-NETs SUN Sunitinib [10]. Despite these unquestionable steps forward, options are TEM Temozolomide still rather limited, and chemotherapy remains an essential TMB Tumor mutational burden component of the treatment strategy of patients with NENs, TTP Time to tumor progression particularly for those with bulky, symptomatic or rapidly U Unknown progressive tumors (generally G3 or high-G2 NENs). In the VEGF Vascular endothelial growth factor setting of well diferentiated NENs, chemotherapy is pri- VINC Vincristine marily indicated in tumors of pancreatic origin (P-NETs), VP-16 Etoposide whereas its use in L- or GI-NETs shall be reserved for XELOX Capecitabine and oxaliplatin selected patients who have failed other more efective thera- y Year peutic options. In this manuscript we will critically review available evi- dence for the use of chemotherapy in lung and GEP NENs 1 Introduction and will discuss its current role in the treatment algorithm of this family of neoplasms (Fig. 1). Neuroendocrine neoplasias (NENs) are a heterogeneous family of malignancies of wide anatomic distribution, as they 1.1 Role of chemotherapy in neuroendocrine arise from neuroendocrine cells distributed throughout the tumors body forming glands or as part of the difuse neuroendocrine system. The majority of NENs are from gastroenteropan- Chemotherapy in NENs initially focused on the treatment of creatic (GEP) (66%) and bronchopulmonary origin (31%), islet cell carcinomas, that is P-NETs per current terminol- although they may develop in any organ. Their incidence has ogy, following the discovery of the alkylating agent strep- signifcantly increased over the past 4 decades, from 1,09 tozotocin (STZ), a glucose analogue isolated from Strepto- (1973) to 6,98 (2012) new cases per 100.000 inhabitants myces achromogenes that was found to be particularly toxic per year, as well as their prevalence (from 0.006% (1993) to the β-cell of the pancreas via GLUT2 transporter uptake. to 0.048% (2012) 20-year limited-duration prevalence) [1]. The frst randomized trials date from the 80 s’ and provided The raise in incidence has been observed across all tumor the frst evidence of drug antitumor activity in NETs, lead- sites, stages and grades, likely due to improved diagnostic ing to FDA-approval of STZ for the treatment of advanced techniques and greater clinical awareness. Survival has also islet cell carcinoma. This is the frst drug and solely cyto- improved over time as a consequence of earlier detection toxic agent ever approved in the feld of NENs. Subsequent and the therapeutic advances achieved over the past decades trials tested diferent classical cytotoxic regimens, mainly 1 3 Reviews in Endocrine and Metabolic Disorders Advanced NENs NET NEC Pancreatic Small intestine Lung G2-G3 G2-G3 CDDP or G1-G2 G1-G2 AC e or rapidly (Ki-67 10- (Ki-67 10- TC CBCDA and (Ki-67< 10%) (Ki-67 < 10%) progressive f, g 55%) 55%) VP-16 STZ-FU or FOLFOX or TEM based Ch Observation or SSA S S Ac EVE EVE FOLFIRI or or SUN or SSA CAPTEM f, h EVEb STZ-5FU or PRRT a or CAPTEM or PRRT a PRRT a PRRTa CAPTEM b EVE SUN or EVE EVE CAPTEM or PRRT a or INF CT not PRRT a STZ-5FU or or Platinum- indicated d FOLFOX based CT CT not routinely indicated d Fig. 1 Treatment algorithm of advanced NENs. AC, atypical car- be considered in G1 very indolent tumors, particularly in older or frail cinoid; CAPTEM, capecitabine-temozolomide; CDDP, cisplatin; patients. dCAPTEM may be considered after progression to all avail- CBCDA, carboplatin; CT, chemotherapy; EVE, everolimus; FOLFIRI, able treatments in selected patients with good PS and rapidly progress- 5-fuorouracil and irinotecan; FOLFOX, 5-fuorouracil and oxalipl- ing tumors. eChemotherapy may be considered upfront in selected atin; INF, interferon-alfa; NENs, neuroendocrine neoplasias; NET, patients (rapidly progressing tumors, Ki-67>20%).fEnrollement in neuroendocrine tumor; NEC, neuroendocrine carcinoma; PRRT, pep- clinical trials is recommended if available.gCarboplatin is preferred tide receptor radionucleotide therapy; SSA, somatostatine analogues; over cisplatin due to its more favorable toxicity profle.hThe treatment STZ-5FU, streptozocin-5 Fluorouracile; SUN, sunitinib;TC, typical choice should be based on response to prior therapy, toxicity profle, carcinoid; VP-16, etoposide. aIn somatostatin-receptor imaging posi- residual toxicity from prior chemotherapy (i.e. neurotoxicity) and tive tumors and/or refractory hormonal síndrome. bChemotherapy pre- patient’s comorbidities and preferences (i.e. oral vs iv) ferred upfront over targeted agents in G3 NETs. cWatch and wait may based in alkylating agents, antimetabolites and anthracy- subgroups, P-NETs and extrapancreatic-NETs, as the design clines. These trials globally demonstrated
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