Table 1.
Papers About Everolimus And Stomatitis
| Study | Year | Title | Therapy | Patients, n | Stomatitis, n (%) | G1/2, n (%) | G3/4, n (%) |
|---|---|---|---|---|---|---|---|
| Amato et al27 | 2009 | A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer | Everolimus at a dose of 10 mg daily orally without interruption (28-day cycle), with dose modifications for toxicity (graded according to National Cancer Institute Common Toxicity Criteria version 3.0). Patients were evaluated every two cycles (8 weeks) using Response Evaluation Criteria in Solid Tumors (RECIST) | 39 | 12 (30.8) | G1 4 (10.3) G2 8 (20.5) |
|
| Andre et al28 | 2014 | Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial | In this randomised, double-blind, placebo-controlled, phase III trial, authors recruited women with HER2-positive, trastuzumab-resistant advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient-screening and -randomization system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m2) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use | 280 | 175 (62) | 138 (49) | G3 37 (13) |
| Angelousi et al29 | 2017 | Sequential everolimus and sunitinib treatment in pancreatic metastatic well-differentiated neuroendocrine tumours resistant to prior treatments | A: 20 1st-line everolimus B: 11 2nd-line everolimus |
A: 20 B: 11 |
A: 2 (10) B: 1 (9) |
A: 2 (10) B: 1 (9) |
|
| Armstrong et al30 | 2016 | Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN — a multicentre, open-label, randomised phase 2 trial) | Everolimus orally at 10 mg once daily | 52 | 27 (48) | 22 (39) | G3 5 (9) |
| Bajetta et al31 | 2014 | Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors | Treatment-naïve patients with advanced well-differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily in combination with octreotide LAR 30 mg every 28 days | 50 | 31 | 26 (52) | G3 4 (8) G4 1 (2) |
| Baselga et al32 | 2012 | Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer | Double-blind phase III study, patients randomly assigned to treatment with oral everolimus or matching placebo (10 mg daily) in conjunction with exemestane (25 mg daily) | 482 | 56 (11.61) | 48 (9.95) | G3 8 |
| Baselga et al33 | 2009 | Phase II randomized study of neoadjuvant everolimusplus letrozole compared with placebo plus letrozole inpatients with estrogen receptor–positive breast cancer | 270 postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo | 137 | 50 (36.5) | 47 (34.3) | 3 (2.2) |
| Bergmann et al34 | 2015 | Everolimus in metastatic renal cell carcinoma after failure of initial anti–VEGF therapy: final results of a noninterventional study |
Patients received everolimus 10 mg once daily until disease progression or unacceptable | 334 | 22 (7) | 18 (81) | 4 (18) |
| Besse et al35 | 2014 | Phase II study of everolimus–erlotinib in previously treated patients with advanced non-small-cell lung cancer | Everolimus 5 mg/day + erlotinib 150 mg/day | 66 | 48 (72.6) | G1 11 (16.7) G2 16 (24.2) | G3 21 (31.8) |
| Campone et al36 | 2009 | Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours | Everolimus was dose-escalated from 15 to 30 mg and administered with paclitaxel 80 mg/m2 on days 1, 8, and 15 every 28 days | 16 | 6 (37.5) | 5 (31.25) | G3 1 (6.25) |
| Castellano et al37 | 2013 | Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study | Everolimus plus octreotide | 19 | 11 (57.9) | ||
| Chan et al38 | 2013 | A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor | Patients treated with temozolomide 150 mg/m2 per day on days 1–7 and 15–21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolo mide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily | 43 | 27 | G1 22 (51) G2 4 (9) |
G3 1 (2) |
| Choueiri et al39 | 2015 | Cabozantinib versus everolimus in advanced renal cell carcinoma | Everolimus at a dose of 10 mg daily | 322 | 77 (24) | 70 (21.7) | 7 (2.2) |
| Chow et al40 | 2016 | A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer | Oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks | 24 | 14 (58.3) | 10 (41.6) | G3 4 |
| Chung et al41 | 2016 | Phase Ib trial of mFOLFOX6 and everolimus (NSC-733,504) in patients with metastatic gastroesophageal adenocarcinoma | Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6 | A: 6 | 4 (66) | G1 2 (33) | G3 2 (33) |
| Ciruelos et al42 | 2017 | Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain | Eligible patients started study treatment on day 1 with daily doses of everolimus (2/5/9 mg or 1/9/10 mg) and exemestane (25 mg) and continued until disease progression or unacceptable toxicity | 429 | 272 (63) | 232 (54) | G3 40 (9) |
| Ciunci et al43 | 2014 | Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer | Not reported | 29 | 4 (13.8) | G2 4 (13.8) | |
| Colon-Otero et al44 | 2017 | Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancer | Patients received oral everolimus 10 mg daily and letrozole 2.5 mg daily | 19 | 2 (10.5) | G3 2 (10.5) | |
| Courtney et al45 | 2015 | A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer | Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG- PET/computed tomography scan. Patient cohorts were subsequently treated at three dose levels of everolimus with docetaxel: 5–60 mg/m2, 10–60 mg/m2, and 10–70 mg/m2. The primary end point was the safety and tolerability of combination therapy. | 18 | 5 (27.7) | 5 (27.7) | |
| Deenen et al46 | 2012 | Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies | Fixed-dose everolimus 10 mg/day continuously plus capecitabine twice daily for 14 days in 3-weekly cycles | 18 | 9 (50) | 9 (50) | |
| Doi et al47 | 2010 | Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer | Everolimus 10 mg orally daily | A: 53 | 3 (5.7) | ||
| Elmadani et al48 | 2017 | EVESOR, a model-based, multiparameter, phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib | Everolimus + sorafenib | 26 | 6 (23.1) | 6 (23.1) | |
| Escudier at al.49 | 2016 | Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis | Oral everolimus 10 mg once daily until disease progression or unacceptable toxicity | 92 | 23 (25) | 23 (25) | |
| Fazio et al50 | 2013 | Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT-2 study |
Everolimus + octreotide | 33 | 3 (9.1) | ||
| Ferolla et al51 | 2017 | Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial | A: everolimus B: everolimus + pasireotide |
A: 42 B: 41 |
Total A: 30 (72) Total B: 15 (37) |
A: 26 (62) B: 13 (32) |
A: G3 4 (10) B: G3 2 (5) |
| Finn et al52 | 2013 | Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma | A: sorafenib + everolimus 2.5 mg once daily B: sorafenib + everolimus 5 mg once daily |
A: 16 B: 14 |
A: 6 (37.5) B: 6 (42.9) Ulcers total 6 (37.5) |
A: 6 (37.5) B: 5 (35.8) |
A: 0 B: 1 (7.1) |
| Fury et al53 | 2012 | A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors | Not reported | 30 | 11 (39) | 11 (39) | |
| Ghobrial et al54 | 2010 | Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenström macroglobulinemia | Everolimus 10 mg daily for two cycles | 50 | 4 (8) | 4 (8) | |
| Goldberg et al55 | 2015 | Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study | Not reported | 24 | 18 (75) | ||
| Gong et al56 | 2017 | Efficacy and safety of everolimus in Chinese metastatic HR positive, HER2 negative breast cancer patients: a real-world retrospective study | Everolimus was usually initiated at 10 mg or in some instances 5 mg daily, according to patients’ tolerance and request | 70 | 40 (57.1) | 34 (47.8) | G3 6 (9.3) |
| Grignani et al57 | 2015 | Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial | A: patients took 400 mg sorafenib twice a day together with 5 mg everolimus once a day | 38 | 20 | G1 11 (29) G2 7 (18) |
G3 2 (5) |
| Hainsworth et al58 | 2010 | Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma | All patients received bevacizumab 10 mg/kg intravenously every 2 weeks and everolimus 10 mg orally daily | 80 | 48 | 36 (45) | G3 12 (15) |
| Hatano et al59 | 2016 | Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: a single institution experience in Japan |
Everolimus set at 10 mg once a day for adults | 47 | 43 (91) | 42 (97.6) | 1 (2.3) |
| Hatano et al60 | 2017 | Intermittent everolimus administration for renal angiomyolipoma associated with tuberous sclerosis complex | Everolimus set at 10 mg once a day | 26 | 23 (88) | 22 | 1 |
| Hurvitz et al61 | 2013 | A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy | Everolimus 10 mg/day in combination with paclitaxel (80 mg/m2 days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles | 55 | 42 (76.3) | G1 13 (23.6)G2 18 (32.7) | G3 11 (20) |
| Jerusalem et al62 | 2016 | Safety of everolimus plus exemestane in patients with hormone-receptor–positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET) | Not reported | 2,131 | 1,126 (52.8) | 926 (43.4) | G3 198 (9.3) G4 2 (0.1) |
| Jovanovic et al63 | 2017 | A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus in patients with stage II/III triple-negative breast cancer (TNBC): responses and long-term outcome correlated with increased frequency of DNA damage response gene mutations, TNBC subtype, AR status and Ki67 | Not reported | 96 | 37 (39) | 37 (39) | |
| Jozwiak et al64 | 2016 | Safety of everolimus in patients younger than 3 years of age: results from EXIST-1, a randomized, controlled clinical trial | Everolimus initiated at 4.5 mg/m2/day and titrated to blood trough levels of 5–15 ng/mL | 18 | 12 (66.7) | ||
| Kato et al65 | 2014 | Efficacy of everolimus in patients with advanced renal cell carcinoma refractory or intolerant to VEGFR-TKIs and safety compared with prior VEGFR-TKI treatment | Not reported | 19 | 7 (37) | 6 (32) | 1 (5) |
| Kim et al66 | 2014 | A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma | Everolimus given at 10 mg daily until progression or occurrence of unacceptable toxicities | 34 | 27 (79.4) | 26 (96.2) | 1 (2.9) |
| Kim et al67 | 2018 | Clinical outcomes of the sequential use of pazopanib followed by everolimus for the treatment of metastatic renal cell carcinoma: a multicentre study in Korea |
Everolimus | 36 | 15 (41.7) | 14 (38.9) | 1 (2.8) |
| Koutsoukos et al68 | 2017 | Real-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib | Not reported | 31 | 8 (26) | G1 4 (13) G2 1 (3) |
G3 3 (10) |
| Kulke et al69 | 2017 | A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial | A: everolimus + pasireotide LAR B: everolimus |
A: 78 B: 81 |
A: 46 (59) B: 51 (63) |
A: 39 (50) B: 44 (54.4) |
A: 7 (9) B: 7 (8.6) |
| Kumano et al70 | 2013 | Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell carcinoma following failure of tyrosine kinase inhibitors |
Everolimus | 57 | 17 (29.8) | 14 (82.35) | 3 (5.3) |
| Moscetti et al71 | 2016 | Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: a multicenter Italian experience | Not reported | 181 | 115 (63.5) | G1 54 (29.8) G2 46 (25.4) | G3 15 (8.3) |
| Motzer et al72 | 2016 | Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)† | Not reported | 133 | 7 (5.26) | ||
| Motzer et al73 | 2014 | Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma | Everolimus | 238 | 53 (22.26) | 47 (19.74) | G3 6 (2.52) |
| Motzer et al17 | 2008 | Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial |
Everolimus 10 mg once daily | 269 | 107 (40) | 98 (36.43) | G3 9 (3.34) |
| Motzer et al74 | 2015 | Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial | Everolimus 10 mg day | 50 | 21 (42) | 20 (40) | G3 1 (2) |
| Oh et al75 | 2012 | Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas | Everolimus was administered daily at a dose of 10 mg for 4 weeks. | 34 | 6 (17.6) | 4 (11.7) | 2 (5.9) |
| Ohtsu et al76 | 2013 | Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study | Everolimus 10 mg/day + BSC | 437 | 174 (40) | 154 (35) | 20 (5) |
| Ohyama et al77 | 2017 | Efficacy and safety of sequential use of everolimus in Japanese patients with advanced renal cell carcinoma after failure of first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor: a multicenter phase II clinical trial |
Not reported | A :53 | 26 (49.1) | 22 (41.6) | 4 (7.5) |
| Panzuto et al78 | 2014 | Real-world study of everolimus in advanced progressive neuroendocrine tumors | Everolimus | 169 | 37 (21.9) | 33 (19.6) | 4 (2.3) |
| Park et al79 | 2014 | Efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma following treatment failure with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor |
Everolimus | 100 | 42 (44) | 36 (38) | 6 (6) |
| Pavel et al80 | 2016 | Safety and QOL in patients with advanced NET in a phase 3b expanded access study of everolimus | Not reported | 123 | 29 (23.6) | 23 (18.7) | G3 6 (4.9) |
| Quek et al81 | 2011 | Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors |
Figitumumab (20 mg/kg IV every 21 days) with full-dose everolimus (10 mg orally once daily) | 21 | 21 (100) | G1 11 (52.4) G2 7 (33.3) |
G3 3 (14.3) |
| Safra et al82 | 2018 | Everolimus plus letrozole for treatment of patients with HR+, HER2–advanced breast cancer progressing on endocrine therapy: an open-label, phase II trial | Everolimus 10 mg daily and letrozole 2.5 mg daily | 72 | 39 (54.2) | 18 (45.9) | G3 21 (8.3) |
| Salazar et al83 | 2017 | Phase II study of BEZ235 versus everolimus in patients with mammalian target of rapamycin inhibitor-naïve advanced pancreatic neuroendocrine tumors |
Everolimus 10 mg once daily | 31 | 20 (64.5) | 18 (58) | 2 (6.5) |
| Sarkaria et al84 | 2011 | NCCTG phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in newly diagnosed glioblastoma multiforme patients | All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide | 18 | 11 (61.1) | G2 11 (61.1) | |
| Strickler et al85 | 2012 | Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors | 10 mg panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks | 12 | 4 (33) | 3 (25) | 1 (8) |
| Sun et al86 | 2013 | A phase 1b study of everolimus plus paclitaxel in patients with small-cell lung cancer |
A: everolimus 2.5 mg 6 B: everolimus 5 mg 11 C: everolimus 10 mg 3 |
20 | 8 (40) | A 2 10) B 5 (25) C 1 (5) |
|
| Takahashi et al87 | 2013 | Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results | Everolimus 1.5 mg/day starting dose (target trough 3–8 ng/mL) + reduced-dose cyclosporine | 61 | 14 (23) | ||
| Tobinai et al88 | 2010 | Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma everolimus 5 or 10 mg orally once daily |
Not reported | 13 | 7 (53.7) | G1 3 (23.7) G2 4 (30.7) |
|
| Vlahovic et al89 | 2012 | A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors | Everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks | 32 | 24 (76) | 20 (63) | 4 (13) |
| Wang et al90 | 2014 | Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single-arm, phase 2 study | Not reported | 58 | 12 (20.7) | 11 (19) | G3 1 (1.7) |
| Werner et al91 | 2013 | Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma | Oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. | 16 | 9 (56.25) | G1 8 (50) | G3 1 (6.25) |
| Wolpin et al92 | 2009 | Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer | Everolimus 10 mg daily | 33 | 10 (30) | G1 8 (24) G2 1 (3) |
G3 1 (3) |
| Yao et al93 | 2008 | Efficacy of everolimus and octreotide LAR in advanced low- to intermediate-grade neuroendocrinetumors: results of a phase II study
|
RAD001 5 mg/day or 10 mg/day and octreotide LAR 30 mg every 28 days | 64 | Aphtous ulcers 5 (8) Dysgeusia 1 (2) |
||
| Yao et al94 | 2011 | Everolimus for advanced pancreatic neuroendocrine tumors | 10 mg once daily | 204 | 131 (64) | 117 (57) | 14 (7) |
| Yee et al95 | 2006 | Phase I/II study of everolimus in patients with relapsed or refractory hematologic malignancies | Not reported | 27 | 10 (37) | 10 (37) | |
| Total over all | 8,201 | 3,490 (42.55) | |||||
| Total with grade | 7,796 | 3,347 (42.93) | 2,839 (36.41) | 508 (6.51) | |||