Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease
Abstract
:Simple Summary
Abstract
1. Introduction
2. VHL-Mechanism-Based Interventions for vPNEN
2.1. Tyrosine Kinase Inhibitors (TKIs) with Vascular Endothelial Growth Factor (VEGF) Receptor Inhibition Ability
2.1.1. Sunitinib
2.1.2. Vandetanib
2.1.3. Pazopanib
2.2. Hypoxia-Inducible Factors (HIF) Inhibitors
Belzutifan
3. Non-VHL-Mechanism-Related Treatments for vPNEN
3.1. Somatostatin Analogues (SSA)
3.2. SSA-Base-Based Peptide Receptor Radionuclide Therapy (PRRT)
3.3. Mechanistic Target of Rapamycin (mTOR) Inhibitors
Everolimus
3.4. Chemotherapy
Capecitabine and Temozolomide (CAPTEM)
4. Proposed Treatment Algorithm
5. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Treatment | Mechanism of Action | n (n vPNEN) | Efficacy n Response/Total Lesions | Toxicity % |
---|---|---|---|---|
Sunitinib [22] | VEGFR inhibitor | 15 (7) | RCC 10/18 SD, 6/18 PR, 2/18 PD PNEN 5/5 SD CNS HB 19/21 SD, 2/21 PD Retinal HB 7/7 SD | Stopped treatment—40% |
Vandetanib [23] ongoing, partial data | VEGFR inhibitor | 37 (2) | PNEN 2/2 DS CNS HB 2/2 SD | Stopped treatment—19% (11% due to side effects) |
Pazopanib [24] | VEGFR inhibitor | 32 (17 *) | RCC 28/59 SD, 29/59 PR, 2/59 CR Pancreatic lesions 8/17 SD, 9/17 PR, 0/17 CR CNS HB 47/49 SD, 2/49 PR, 0/49 CR | Dose reduction—58%, Stopped treatment—23% |
Belzutifan [25] | HIF 2 inhibitor | 61 (22) | RCC 30/61 SD, 30/61 PR PNEN 20/22 (91%) confirmed response, 3 CR CNS HB—15/50 confirmed response, 3 CR Retinal HB—12/12 confirmed response | Dose reduction—15%, Dose interruption—43%, Stopped treatment—11% |
Trial Name | Intervention | No. Patients (Intervention/Control, n) | No. Patients with PNEN (Intervention/Control, n) | Grade 1/2/3 (n) | PFS Intervention vs. Control (Months) HR, 95% CI, p Value | OS Intervention vs. Control (Months) HR, 95% CI, p value | Toxicity (%) | Notes |
---|---|---|---|---|---|---|---|---|
PROMID [38] | Octreotide LAR vs. Placebo | 42/43 | 0/0 | 81/3/1 | 14 vs. 6 € 0.33 (0.19–0.55, p < 0.001) | 0.81 (0.3–2.18, p = 0.77) | Most frequent (% not reported)—diarrhea, flatulence, cholelithiasis. | Advanced Midgut NEN |
CLARINET [39] | Lanreotide autogel vs. Placebo | 101/103 | 42/48 | 138/60/0 | NR vs 18 0.47 (0.3–0.73, p < 0.001) 0.58 (0.32–1.04) ¥ | NR | Serious AE: 3% Common AE: diarrhea 26%, abdominal pain 14%, cholelithiasis 10%. | Advanced GEP-NEN |
RADIANT-3 [40] | Everolimus vs. Placebo | 207/203 | 207/203 | 341/65/na * | 11.4 vs. 5.4 0.35 (0.27–0.45, p < 0.001) | 44 vs. 37 0.94 (0.73–1.2) | Common AE: stomatitis 64%, rash 49%, diarrhea 34%, fatigue 31%, infections 23%. Grade 3/4 AE: anemia 6%, thrombocytopenia 4%, hyperglycemia 5%, stomatitis 7%, diarrhea 3%. | Advanced PNEN |
NETTER-1 [41] | PRRT plus Octreotide LAR 30 mg vs. Octreotide LAR 60 mg | 116/113 | 0/0 | 157/72/0 | NR vs. 8.4 0.21 (0.13–0.33, p < 0.001) | NR 14 vs. 26 deaths, p < 0.01 # | Common AE: nausea 59%, vomiting 47%, fatigue 40%. Grade 3/4 AE: lymphopenia 9%, vomiting 7%, nausea 4%, thrombocytopenia 2%. | Advanced midgut NEN |
ECOG-ACRIN E221 [42] | CAPTEM vs. Temozolomide | 72/72 | 72/72 | 50/61/na | 23 vs. 14 0.58 (0.36–0.93, p = 0.022) # | 59 vs. 54 0.41 (0.21–0.82, p = 0.012) # | Common AE: CAPTEM—nausea 65%, fatigue 56%, constipation 48%, anemia 37%. Temozolomide—fatigue 63%, nausea 60%, constipation 31%, anemia 31%, thrombocytopenia 31%. | Advanced PNEN |
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Halperin, R.; Tirosh, A. Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease. Cancers 2023, 15, 1739. https://doi.org/10.3390/cancers15061739
Halperin R, Tirosh A. Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease. Cancers. 2023; 15(6):1739. https://doi.org/10.3390/cancers15061739
Chicago/Turabian StyleHalperin, Reut, and Amit Tirosh. 2023. "Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease" Cancers 15, no. 6: 1739. https://doi.org/10.3390/cancers15061739