Table 2.
Systemic management of refractory carcinoid syndrome
| Treatment | Mechanism of action | Trial | Symptoms and QOL assessment |
|---|---|---|---|
| SSA: octreotide and lanreotide | Agonist of somatostatin receptors, principally SSTR2. Antisecretory and antiproliferative effects | PROMID. Octreotide Phase 3 (Rinke A, 2009)37 | 38.8% patients with carcinoid syndrome. Symptomatic improvement, especially in flushing. QOL assessment (secondary end point). EORTC QLQ-C30 questionnaire. Similar scores in both arms. |
| CLARINET. Lanreotide Phase 3 (Caplin ME, 2014)38 | Number of functioning tumors included unknown. QOL assessment (secondary end point). EORTC QLQ-C30 and QLQ-GINET21 questionnaires. No differences in global health status in both arms. |
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| ELECT. Lanreotide Phase 3 (Vinik AI, 2016. Fisher GA, 2018)27,28 | All patients with carcinoid syndrome not refractory to SSA. Symptomatic relief (reducing use of short-acting SSA) primary end point: achieved. QOL assessment (secondary end point). EORTC QLQ-C30 and QLQ-GINET21 questionnaires. Improvement in global health status, gastrointestinal and endocrine symptoms scales in lanreotide arm compared with placebo arm. |
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| New generation SSA: pasireotide | SSA with high binding affinity to four somatostatin receptor subtypes (1, 2, 3 and 5), instead of only SSTR2. Antisecretory and antiproliferative effects |
Phase 2 (Kvols LK, 2012)40 | Number of functioning tumors included unknown. 21% patients experience partial symptom control (did not achieve primary aim: ≥30%) QOL assessment (secondary end point). FACIT-G and FACIT-D questionnaires. No significant changes during the treatment. |
| Phase 3 (Wolin EM, 2015)41 | Most of the patients have functioning tumors (based on u5-HIAA levels) 20% patients experience symptom control, the same as in control arm (octreotide LAR). No QOL assessment. |
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| Everolimus | mTOR inhibitor | RADIANT-2. Phase 3 (Pavel ME, 2011)52 | Included functioning tumors. Non assessment of symptom control. No QOL assessment. |
| RADIANT-3. Phase 3 (Yao JC, 2011)53 | Functioning tumors excluded. No assessment of symptom control. No QOL assessment. |
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| RADIANT-4. Phase 3 (Yao JC, 2016)54 | Functioning tumors excluded. QOL assessment (secondary end point). FACT-G questionnaire. No differences between both arms. |
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| Phase 3b (Pavel ME, 2016)55 | 42% functioning tumors. QOL assessment. EuroQOL-5 dimensions, EORTC QLQ-C30 and QLQ-GINET21 questionnaires. QOL stable in pancreatic NET and slightly impaired in nonpancreatic NET. |
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| COOPERATE-2. Phase 2 (Kulke MH, 2017)43 | Functioning tumors excluded. No QOL assessment. |
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| LUNA. Phase 2 (Ferolla P, 2017)42 | Patient with severe symptoms from carcinoid syndrome excluded. No assessment of symptom control. No QOL assessment. |
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| Sunitinib | Tyrosine kinase inhibitor of VEGFR-1 and 2, FLT3, KIT, PDGFR-A and B | Phase 3 (Raymond E, 2011. Vinik A, 2016)57,112 | Number of patients with carcinoid syndrome unknown (pancreatic NET, other hormone syndromes). QOL assessment (secondary end point). EORTC QLQ-C30 questionnaire. No differences between both arms. Worsening in diarrhea and fatigue scores with sunitinib. Longer time to deterioration in health global and functional status with sunitinib. |
| PRRT (177Lu-Dotatate) | Radiolabeled peptides specific for the SSTR2 | NETTER-1. Phase 3 (Strosberg J, 2017. Strosberg J, 2018)64,65 | Number of functioning tumors included unknown. QOL assessment (secondary end point). EORTC QLQ-C30 and QLQ-GINET21 questionnaires. Longer time to deterioration of QOL with PRRT in global health, physical functioning and role functioning. Improvement in diarrhea, fatigue and pain scores. |
| Interferon-alpha 2b | Immunomodulatory effect | Smith DB, 198745 | All patients presented with elevated u5HIAA, but only 9/14 (65%) had carcinoid symptoms. Important symptomatic relief (in 55% patients). Improvement in Karnofsky performance status. No QOL assessment. |
| Moertel CG, 198946 | Most of patients (85%) had functioning tumors (carcinoid syndrome). Important symptomatic relief (65% flushing and 33% diarrhea). No QOL assessment. |
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| Veenhof CHN, 199248 | Most of patients had functioning tumors (carcinoid syndrome). 58% experienced symptomatic relief. No QOL assessment. |
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| Chemotherapy | Cytotoxicity | STPZ-DX vs STPZ-5FU vs CLZ (Moertel GC, 1992)58 | Only pancreatic-NET. Functioning status unknown. No QOL assessment. |
| 5FUᵟ, DX and STPZ (Kouvaraki MA, 2004)59 | Only pancreatic-NET. 20% functioning, no carcinoid syndrome. No QOL assessment. |
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| STPZ and liposomal DX (Fjallskog MCH, 2008)113 | Only pancreatic-NET. 23% functioning, no carcinoid syndrome. No QOL assessment. |
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| TEM-CAP (Strosberg JR, 2011)60 | Only pancreatic-NET. 26% functioning, no carcinoid syndrome. No QOL assessment. |
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| CAP, STPZ ± Cisplatine (Meyer T, 2014)61 | Pancreatic and gut NET. 36% Functioning, % carcinoid syndrome unknown. QOL assessment. EORTC QLQ-C30 questionnaire. Worsening in QOL with triple therapy; no changes with double therapy compared to baseline. |
Abbreviations: SSA, somatostatin analog; QOL, quality of life; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; QLQ-GINET21, Quality of Life Questionnaire – Gastrointestinal Neuroendocrine Tumors 21; FACIT-G, Functional Assessment of Cancer Therapy – General; FACIT-D, Functional Assessment of Cancer Therapy – Diarrhea; u5-HIAA, urinary 5-hydroxyindoleacetic acid levels; NET, neuroendocrine tumors; PRRT, peptide receptor radionuclide therapy; STPZ, streptozocin; DX, doxorubicin; 5FU, 5-fluorouracil; CLZ, chlorozotocin; TEM, temozolomide; CAP, capecitabine.