Review Treatment of Metastatic Uveal Melanoma: Systematic Review
Cristina Rodriguez-Vidal, Daniel Fernandez, Beatriz Fernandez-Marta, Nerea Lago, María Pardo, Paula Silva, Laura Paniagua, María José Blanco- Teijeiro, Antonio Piñeiro and Manuel Bande
Supplementary Data
Table S1. Included studies of Conventional Chemotherapy.
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al outcomes al
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(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Excepcio Interval of ProgressionInterval of
Case Study CI 95% Series 0 Multiple* Pons [20] 2011 25 0 (0%) NP NP 10.8 (5.4 - NP ___ NP NP NP NP Comparative (0%) 16.3) (III)
Case Study
Temozolomide F. Bol [21] 2019 Series 32 32 (100%) NP NP TX 5.7 NP 1 year: 18.8% TX 2,5 NP NP ___ (III)
Case Study Multiple systemic TX T. Xu [22] 2019 Series 14 14 (100%) NP NP TX 10.3 NP NP ___ TX 4 NP NP not including CPIs** (III)
• AE 15 (100%): Fatigue 7(46.7%), Nausea 7(46.7%), Vomiting Phase II CI 5(33.3%), Platelet fall Temozolomideor Prospective CI 95% 95% 4(26.7%) Luke [23] 2019 15 9 (60%) NP NP TX 7.3 NP ___ TX 1.94 Dacarbazine Randomized (5.6 -NP) (1.8 - Trial 5.3) • Grade 3 or 4: 3 (20%): (Ib) Platelet Drop 2 (13.4%), Diarrhea 1 (6.7%), Nausea 1 (6.7%)
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10, 5 • AE: nausea, infections, Case Study CI 95% 1 year: 50% Tulokas 0 (range, declining performance Chemotherapy*** 2018 Series 8 8 (100%) NP TX (6.8 - 2 years: 0% ___ NP NP NP [24] (0%) 3 - status, liver and Comparative 13.3) 16.5) hematological toxicity. (III)
• Grades 1 and 2: 9(36%): Nausea and Vomiting 8(32%), Neurotoxicity Phase II 8(32%), Anemia 6(24%), Prospective 1 patient still alive Asthenia 6(24%) Cisplatin + Schinzari Non- 0 after first line Dacarbazine + 2017 25 25 (100%) NP TX 13 NP NP TX 5.5 NP [25] Randomised (0%) therapy at 72 • Grades 3 and 4: 5(20%): Vinblastine Trial months Neutropenia 4(16%), (IIa) Nausea and Vomiting 2(8%) Anemia 2(8%), Thrombocytopenia 1(4%)
Case Study 2.5 1 year: 25% Carling Series (range, CI 95% Dacarbazine 2015 14 NP NP TX 4,6 2 years: NP NP NP NP [26] Comparative 0.6- (1.4-13.7) ___ 0.05% (III) 4.7) Phase I 12,2 6.21 Prospective ___ Gemcitabine + 0 (range, CI 95% 1 year: 75% (range, Corrie [27] 2005 Non- 5 4 (80%) NP NP NP ND NP treosulfan (0%) 5 – (4.6-ND) 2 years: 0% 1.61 - Randomized 23.7) 8.74) Test (IIa)
• Pain 16 (73%), Fatigue 14 Phase II Non- (64%), Headache 14 Randomized ___ (64%), Myalgia 14 (64%) Docosahexaenoicacid- Homsi Open R- 3 (range, 2010 22 13 (59%) NP NP EP 9,8 NP NP NP paclitaxel [28] Prospective P 3-7) • Severe 3 or 4: Trial Neutropenia 5 (23%), (IIa) Musculoskeletal pain 2 (10%)
• Nausea and vomiting 37 (43.53%) Prospective CI Abdominal pain 33(38, multcenter CI 95% Leyvraz 0 1 patient still alive 95% 82%) Fotemustine 2014 randomized 85 85 (100%) NP EP 13,8 (10.2 - NP EP 3,7 [29] (0%) at 60 months (2.0– trial 17.2) 4.1) • Grade 3 or 4: (Ib) Thrombocytopenia (42.1 %) Neutropenia (62.6 %) • Neutropenia 3 (21%), CI Thrombocytopenia 9 Retrospective 14 1 year: 80% 6,56 Gemcitabine + Pföhler 0 CI 95% 95% (64.1%) 2003 case series 14 1 (7%) NP EP (range, (95% CI 54- EP (range, 8- treosulfan [30] (0%) (12 - 31) ____ (2.9- (III) 3-33.2) 100) 21.5) 14.2) • Grade 3 or 4: Neutropenia 2 (14%)
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Thrombocytopenia 9 (64.1%)
• Grade 1 or 2 nausea, Constipation, Abdominal pain
___ • Grade 3 or 4: 16 (45.71%): Neutropenia 7 Phase II Piperno- (20%), Rhombocytopenia Temozolomide + Prospective 0 Neumann 2016 35 35 (100%) NP TX 10 CI 95% NP NP 3 NP or Constipation or bevacizumab Trial (0%) [31] (8 - 15) itchiness 7 (20%), (IIb) Venous thromboembolism 1 (2.85%), Febrile neutropenia and pneumonitis grade 4 1 (2.85%)
Phase II • Grade 3 or 4: Prospective CI Leukopenia 9 (47.36%) Gemcitabine + Schmittel Non- CI 95% 95%, 2005 19 19 (100%) NP NP TX 7,7 1 year: 31%. EP 3 Thrombocytopenia 8 treosulfan + Cisplatin [32] Randomised (1.9 - ___ (1.8-3. (42.1%) Trial 13.8) 1) Anemia 3 (15.79%) (IIa)
CI • Grade 3 or 4: 95%, Gemcitabine + 95% CI Leukopenia 1 (14%) Phase II (0.6- treosulfan 2500 or 14 12 (86%) NP NP 6 (4 - 8) 1 year: 7.1 2 Thrombocytopenia 5 Prospective 3.4) 3000 mg/m2 ___ (36%), Anemia 0 (0%) Schmittel Non- 2005 TX EP [33] Randomised • Grade 3 or 4: Trial 95% Gemcitabine + 19 16 (84%) NP NP 9 CI 95% 1 year: 47.3% 3 Leukopenia 4 (21%), (IIa) CI treosulfan 3500 or (0 - 18) Thrombocytopenia 5 (1.7– 4000 mg/m2 (26%), Anemia 1 (5%) 4.3)
Phase II • Grade 3 or 4: Prospective 17 1 year: 65% 6.16 Leukopenia 1 (20%), Gemcitabine + Terheyden Non- 0 CI 95% 1 patient still alive TX 2004 20 8 (40%) NP TX (range, 2 years: 35% (range, 6- NP Thrombocytopenia 1 treosulfan [34] Randomised (0%) (8.8-25.2) at 57 months 1 - 57) 3 years: 20% 10.4) (20%), Anemia 1 (20%) Trial
(IIa) AE, adverse effect; CI, confidence interval; CPI, checkpoint inhibitors;EP, enrollment period; ND, not defined; NP, not provided; R-P, response-progression; OS, overall survival;TX, treatment， * Thirteen patients received dacarbazine, five received temozolomide with or without interferon, five received fotemustine, two received carboplatin/dacarbazine/interferon alpha/interleukin-2. Due to multiple different therapies, patients were included in the conventional chemotherapy
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group, but could not be arranged under a specific chemotherapy agent. **Carboplatin with paclitaxel, dacarbazine, temozolomide, sunitinib and interferon with stibogluconate， *** 7 patients received dacarbazine as 1st line and the other patient received docetaxel + cisplatin.
Table S2. Included studies of Chemoimmunotherapy.
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FI
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
rug / Intervention
Yearofpubl
Numberofpatients
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Excepcional Excepcional Outcomes Interval of ProgressionInterval of • AE 97 (100%): Nausea 60(62%), Rash 97 6.5 Selumetenib + 55(57%), Fatigue 43(44%), Diarrhea 97 (100%) 0 (0%) approx. 2.8 Dacarbazine Phase II 43 (44%).
Prospective ___ Carvajal [39] 2018 NP EP NP NP EP NP Randomized • Grade 3 or 4: 60 (61%): Neutropenia
Placebo + Trial (Ib) 19 (19%), Thrombocytopenia 32 32 0 (0%) 5.9 1.8 Dacarbazine 12(12%), ETS 8(8%), LFT alteration (100%) approx. 6(6%).
• Photomustine IA: Leucopenia 2 (4.17%), Thrombocytopenia 4 (8.33%), ComplCIations derived from the intra-arterial catheter: -Erosive gastritis 1 (2.08%) Prospective -GastrCI Ulcer 1 (2.08%) Fotemustine non- 95% CI 12 ___ -Arterial wall dissection 1 (2.08%) IA/IV + IL2 + Becker [40] 2002 randomized 48 NP 0 (0%) NP TX 12 (11,4 - NP TX (range NP -Angiospasm 1 (2.08%) IFN-alpha2 comparative 12,8) 5.1-28.1)
trial (IIa) • Photomustine IV: Leucopenia 6 (12.5%), Thrombocytopenia 12 (25%)
• Immunotherapy Grade 3 or 4: Cold 8 (16.7%), Fatigue 6 (12.5%), Hypotension 5 (10.41%)
Phase II • Grades 1 and 2: Nausea 15 (63%), Non- CI Fever 18(75%), Flu-like syndrome 21 BOLD + IFN- Randomized 24 CI 95% ___ 95% (87%), Alopecia 4(46%), Liver Kivelä[41] 2003 24 0 (0%) NP TX 10,6 NP TX 1.9 alpha2b Prospective (100%) (6.9-16.4) (1.8- Toxicity 19 (80%) Multicenter 3.4) Trial (IIa) • Grade 3 or 4: Alopecia 12 (51%), Neurotoxicity 12 (51%)
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• Alopecia (90%), Leukopenia (95%), Liver Toxicity (50%) Phase II Prospective ___ 95% • Grade 3 or 4: Leukopenia (40%), BOLD + 18 CI 95% Pyrhönen[42] 2002 non- 22 0 (0%) NP TX 12 NP TX 4 CI Alopecia (25%), Thrombocytopenia leucocyte IFN (82%) (8-22) Randomised (2-10) (20%), Constipation (15%) Trial (IIa) • Deaths: Myocardial Infarction 1 (4.55%), Sepsis 1 (4.55%)
Prospective non- 3,7 1 year: 1.7 95% Thalidomide + randomised (range, CI 95% 16.6% Solti[43] 2007 6 0 (0%) NP NP TX ___ TX (range, CI Not specified for uveal melanoma IFN-alpha2b comparative 0.9- (0.9 -ND) 2 years: 0.8-14) (1.3-2) pilot study ND) 16.6% (IIa)
1 year: 100% Fotemustine 2 2 years: 8 Case Study 3 1 patient IV + IL2 + Terheyden[44] 1998 3 0 (0%) (range, TX ND ND 66.7% TX (range, ND NP Series (III) (100%) alive at 57 IFN-alpha2b 2-4) 3 years months 8-49) 66.7%:
• Grades 1 and 2: Diarrhoea 2 (50%), 10.8 Dacarbazine + Phase II 1 year: 25% 1.6 Hoarseness (50%), Fatigue 2 (50%) 4 (range CI 95% IFN-alpha2a + Vihinen[45] 2010 Prospective 4 0 (0%) NP TX 2 years: 25% ___ TX (range, ND (100%) ,6.5- (6.5–ND) bevacizumab Trial (IIb) 3 years 25%: 1.6-8.1) • Grade 3 or 4: Hypertension ND) intracerebralhaemorrhaged
AE, adverse effect; CI, confidence interval; CPI, checkpoint inhibitors; EP, enrollment period; IA, intra-arterial; IV, intravenous;ND, not defined; NP, not provided; OS, overall survival; TX, treatment.
Table S3. Included studies of Intra-arterial Liver Chemotherapy (ILC).
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FI
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Exceptional Interval of ProgressionInterval of Prospective multicenter 1 patient still CI95% Leyvraz 86 CI 95% Fotemustine 2014 randomized 86 0(0%) NP EP 14,6 NP alive at 60 EP 4.5 (4.1– (28 patients evaluated) [29] (100%) (10.2-15.4) trial months 6.0) (Ib)
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• Grade >3: Neutropenia 6 (21%), Thrombocytopenia 6(21%), Transient asymptomatic elevation of
glutamyltransferase(>x5 normal levels): 13 (48%)
2,9 1 year: Boone Case Study 10 (range, CI 95% (0.2 7.1% ___ Melphalan 2018 14 NP NP TX NP NP NP NP [49] Series (71,42%) 0.2- – 5.6) 2 years: (III) 15.8) 0%
Case Study ___ Itchins CI 95% (13.3 Fotemustine + IPC 2017 Series 12 NP NP NP DX 19 NP NP NP NP (No detailed information) [50] - NP) (III)
Phase II • Myelosuppression (most Prospective 1 year: frequent), Nausea and 15* Cantore Non- CI 95% (7.0- 62.5% vomiting, Mild epigastric Carboplatin 1994 8 5 (63%) NP NP TX (range, ___ NP NP NP [51] Randomised 20.0) * 2 years: pain 2 (25%), Gastric ulcer 1 8-29). Trial 25% (12.5%), Altered liver (IIa) function tests 3 (37.5%)
• Anemia 7(100%), Nausea 1 year: and Vomiting 7(100%) Non- 71.42% 2 CI 95% Thrombocytopenia 7(100%) Egerer Randomized 2 years: 16 (range, Fotemustine 2001 7 5 (71%) 0(0%) (range, TX 18** (14.4 – 25.6) ___ TX NP [52] Prospective 28.6% 0-43) 1-10) ** • Grade Pilot Study(IIa) 3 years: >3:Thrombocytopenia 14.3% 1(14.28%)
• 15 (65.2%) some form of CI Case Study adverse event:10 (43.5%) Farolfi CI 95% 95% Fotemustineorcarboplatin 2011 Series 18 NP NP NP TX 21 NP ___ TX 6.2 grade 1/2 Toxicity, 5 (21.7%) [53] (8 - 39) (3.7- (III) grade 3 hematological 10.5) toxicity (carboplatin). • Thrombocytopenia 30 Melphalan CI 95% (5.0- (49.2%), Leucopenia 21 38 NP 10.3 Case Study 3.3 15.6) (34.4%), Neutropenia 1 Heusner 2011 Series 43 (70%) (range, TX NP ___ NP NP NP (1.6%) [54] Melphalan and Comparative 0.5-2) 23 NP 8.7 additional agents*** (III) CI 95% (8.1- • Death from liver failure 9.3) after treatment 1 (1.6%)
Prospective 1 year: • Grade 1 and 2: Nausea and non- Leyvraz 31 60% Vomiting, Abdominal Pain Fotemustine 1997 randomized 31 NP NP DX 14 NP ___ 11 NP NP [55] (100%) 2 years: trial 22.6% • Grade 1 and 4: (IIa) Thrombocytopenia,
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Neutropenia, Elevation of y- glutamyltransferase
1 year: 1 patient alive Case Study 60% until 69 1.4 Cisplatin + Vinblastine + Melichar Series CI 95% (5.0- 2 years: months 2009 10 7 (70%) 0(0%) (range, TX 16 NP NP NP NP Dacarbazine [56] (III) 19.0) 20% 0.5-9.5) 3 years: 10 %
Prospective non- Fotemustine or Salmon randomized Dacarbazine + Cisplatin, 1998 16 16(100%) 0(0%) NP NP NP NP NP NP NP NP [57] comparative ___ NP post-biopsia† case series (III)
• Grade 1 and 2: Nausea and
Vomiting (17%), Abdominal
22 Pain (7%) Siegel Case Study Fotemustine 2007 18 NP 0(0%) (range, TX 22 NP NP NP NP NP [58] Series ___ 6-63) • Grade>3: (III) Thrombocytopenia (30%),
Neutropenia (7%)
• Organic damage: 2 (2%), Pancretaitis 1 (1%), Sclerosing cholangitis 1 (1%)
• Grade >3 1 year: (11%):,Hematotoxicity (4%) 67% (95% CI • Risks associated with early Case Study 57-75%). intraarterial catheter 9 (9%): 101 39 1.9 Series CI 95% Thrombosis 2 (2%), Stenosis Fotemustine†† Peters[59] 2006 101 (100%) (39%) (range, DX 15 ___ NP NP NP (III) (12.1-17.6) 2 years: / Obstruction 2 (2%), NC ‡ 0.1-45) 29%. Dislocation 2 (2%)
3 years: • Risks associated with intra- 12% arterial catheter after several months (catheter thrombosis) 21 (21%)
• Post-surgical jaundice 1 (1%)
Approx, approximate; AE, adverse effect; CI, confidence interval; CPI, checkpoint inhibitors; DX, diagnosis; NC, non-chemo, no prior systemic treatment; NP, not provided; LFT, liver function tests; EP, enrollment period; R-P, response-progression; OS, overall survival; TX, treatment. * The median survival is 12 months when calculated from Table 1; the median proportionate survival of 15 months appears to correspond to the median survival. The CI OS: CI 95% (7.0-20.0) is calculated
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from Table 1 too. ** The median 18 seems to be calculated arithmetically and not as a Kaplan-Meier estimate.The median survival is 20 months when calculated from Table 1; The CI OS :CI 95% (14.4-25.6) is calculated from Table 1 too. *** Dacarbazine, doxorubicin, fotemustine, gemcitabine, mitomycin C. † Patients received at least two months of fotemustine or dacarbazine and cisplatin after the biopsy. † † In addition, 38 patients underwent volume reduction surgery at the time of catheter placement. In the Kaplan-Meier diagram, 100 patients were represented. ‡ Previous treatment of 11 patients is unknown.
Table S4. Included studies of Transarterial Liver Chemoembolization (TACE).
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FI
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Exceptional Outcomes Interval of ProgressionInterval of
• 4 patients: total liver volume increasing between 62.5 and 31.1 1 % post treatment year: 4.1 Comparative 9.4 25%. • 1 patient died 10 days 11 1 (range, Irinotecan-elutingbeads Carling [26] 2015 retrospective 14 TX (range, NP 2 ___ NP NP NP after the fourth (79%) (7%) 1.2- case series 3-39) years: procedure, due to 12.7) (III) 20%. disseminated intravascular coagulation (DIC) and multiple cerebral infarctions.
• Grade 1 and 2: Liver pain, hiccups, nausea and/or vomiting 7 (23%)
• Grade 3 or 4: 8 (26.66%): ___ Hepatic vein thrombosis Phase II 5,2 24 0 6.7 2 (6.66%), portal vein BCNU + gelatinsponge Patel [60] 2005 Prospective 30 NP TX (range, NP NP TX NP (80%) (0%) (range, thrombosis 1 (3.33%), Trial (IIb) 0,1-27,6) 2.5-20.2) splenic infarction 1 (3.33%), thrombocytopenia 1 (3.33%), acute renal failure 1 (3.33%), liver failure 3 (10%)
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1 ___ year: 73%. Case Study 2 21 Mitomycin C Farshid [61] 2013 Series 20 NP NP NP TX 20 NP NP NP NP years: approx (III) 56%. 5 years: 28% Phase I/II
Prospective 13 0 ___ Cisplatinwith/withoutpolyvinylsponge Agarwala [62] 2004 19 NP NP 8,5 NP NP NP NP NP NP Randomized (68%) (0%)
Trial (Ib)
Case Study Cisplatin + Doxorubicin + MMC + 17 1 ___ Dayani [63] 2009 Series 21 NP TX 7.6‡ NP NP NP NP NP NP gelatinsponge (81%) (5%) (III)
CI Case Study • Fever 4 (19.05%), Pain Fotemustine + polyvinyl alcohol 2 0 CI 95% ___ 95%, Edelhauser[64] 2012 Series 21 NP DX 28.7 NP TX 7.3 3 (14%), Nausea 5 particles (10%) (0%) (4.2-53) (3.3- (III) (23.81%) 11.3)
• Grade 2 abdominal pain (NP%) Phase II 44 Prospective 0 • Grade 3 abdominal Irinotecan-elutingbeads Fiorentini [65] 2009 10 0 (0%) (range, TX NR‡‡ NP NP NP NP NP Trial (0%) ------pain (NP%), Transient 24-84) (IIb) paralytic ileus 1 (10%) Hepatitis without jaundice 4 (40%)
• Pain, weight loss or fatigue: 35 (70%)
___ • Asymptomatic Case Study 7,1 1 50 0 5 (range, transaminitis grade 4: BCNU + gelatinsponge Gonsalves [66] 2015 Series 50** NP TX (range, NP year: TX NP (100%) (0%) 1.1-32.3). 13 (26%) (III) 1,2-32,3) 22%
• No treatment related deaths or major complications.
• Anemia and/or thrombocytopenia 16 CI Case Study (12.8%), Ascites Cisplatin*** + gelatin sponge or 82 7(range, CI 95% 95% Gupta [67] 2010 Series 125 NP TX 6,7 NP TX 3.81 with/without polyvinyl alcohol particles (66%) 1-122) (4.9-8.5) (3.15- (III) ___ anasarca 10 (8%), 4.93) Bacteremia 7 (5.6%) Tumour lysis syndrome associated
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with renal failure 3 (2.4%)
• Deaths 5 (4%): Acute liver and kidney failure 2 (1.6%), Sepsis and airway failure 2 (1.6%), Myocardial infarction 1 (0.8%)
1 year: 1 • Abdominal pain, fever, Prospective 50% patient nausea and vomiting. 14 non- 4.5 11,5 CI 95% 1.5 8.5 Cisplatin or carboplatin + polyvinyl 8 1 still R- (100%), Huppert [68] 2010 randomised 14 (range, TX (range, (10,3- years: (range 5- NP alcohol particles (57%) (7%) alive at P comparative 1 - 38) 3-69) 13,8) 28 % 35) 69 • Acute kidney failure 1 pilot study (IIa) 2 months (7.14%) years: 14%.
• Severe abdominal pain 1 associated with transient patient hepatitis with altered Case Study 19 0 95% CI still LFT 30 (100%), Transient Cisplatin + polyvinylsponge Mavligit [69] 1988 Series 30 NP DX 11 NP NP NP NP (63%) (0%) (9-18) alive at Hyperbilirubinemia (III) 54 (25%), Transient Paralytic months Ileus 1, Significant losses of K and Mg (35%)
• Grade 1 and 2: 19 (76%): Liver pain 15 (60%), Nausea and/or vomiting 16 (64%), Fatigue 4 (16%), Fever 2 (8%)
Case Study 9 1 95% Photemistine or cisplatin + starch 6 (range, 95% CI 3 (range, Schuster [70] 2010 Series 25 0 (0%) NP (range, TX year: ___ TX CI • Grade 3 or 4: 6: Fever in microspheres 0-32) (5-7) 0-9) (III) 2-24) 15% (2-4) the absence of outbreak 3
(12%), Splenic infarction 1 (4%), Thrombocytopenia 1 (4%), Gastric ulcer 1 (4%)
1 year: • Most common AEs: LFT 72.4%. 29 alloy (100%), Nausea Case Study 23 2 21 (72.4%), Abdominal Shibayama 27 1 Cisplatin + geatinesponge 2017 Series 29 NP TX (range, NP years: TX 6 NP pain 18(65.5%) [71] (93%) (3%) (III) 2-47) 39.4% Vomiting 16 (55.2%), 5 ___ Post-embolization years: syndrome 10(34.5%), 0% Pyrexia 7 (24.1%).
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• Grade 3 or 4 : ALT 15 Elevation (51.7%), AST 10 Elevation (34.5%), Creatinine 1 Elevation (3.4%)
• Nausea and/or vomiting 1 58 (100%), Abdominal Comparative year: ___ pain 43 (74.14%) CPT-11 charged retrospective 58 0 68% Valpione [72] 2015 58‡‡‡ NP TX 15,5 NP NP NP NP microbeads case series (100%) (0%) 2 • Grade 3 or 4: (III) years: Thrombocytopenia 5 34.6 (8.62%), Neutropenia 1 (1.72%)
• First week: Abdominal pain (38.9%) LFT alteration (17.3%),Haematological (15.3%)
1 -Grade 3 or 4: LFT Phase II patient CI CI 95% alteration (1.1%) Blandembolisation + Randomized still 95% Valsecchi [73] 2015 27 NP NP NP TX 17,2 (11.9- NP TX 7,1 gelatinsponge Prospective alive at (5- 22.4) • From the second week Study (Ib) 60 9,1) onwards: Abdominal months pain (26.9%), LFT alteration (9.6%), haematological (7.4%)
-Grade 3or 4: Less than 1%
• Mild nausea without 1 Prospective vomiting 1 (8.33%) year: non- CI 95% Transient headache MMC + iodisedoil + 4 21(range, 75% ___ Vogl [74] 2007 randomised 12 0 (0%) NP TX (13,3- NR NR NR 2(16.66%) Transient microspheres (33%) 5,5-30) 2 comparative 28,7) Fever 3 (25%) years: pilot study (IIa) 25% • Grade 3 or 4: 0 (0%)
Approx, approximate AE, adverse effect; BCNU,bis-chloroeilnitrosourea; CI, confidence interval; CPI, checkpoint inhibitors; MMC, Mitomycin C; NP, not provided; NR, not reached; LFT, liver function tests; EP, enrollment period; R-P, response-progression; OS, overall survival; TX, treatment. * Out of 19 patients, ten were treated with TACE. ** Fifty patients met the inclusion criteria, but 49 patients are included in the Kaplan-Meier analysis. *** Two patients received additional paclitaxel and one patient doxorubicin + MMC. ‡ Mean survival is calculated instead of median. ‡ ‡ Median overall survival was not reached, i.e. cumulative survival plot did not fall below 50%. ‡ ‡ ‡ Moreover, 49 patients received intravenous fotemustine three weeks after TACE.
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Table S5. Included Liver Perfusion Isolation Studies (IHP).
P
FI
P
FI
Intervention
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with surgical
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpublication
Numberofpatients
Drug /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Exceptional Otcomes Interval of ProgressionInterval of
• Leucopenia 15 (96%), Anemia 15 (96%), Thrombocytopenia 12 (75%), Nausea and Vomiting Retrospective CI 95% ___ CI 95% 10(61%) Melphalan Artzner 9 1 1 year: 2019 case series 16 NP TX 27,4 (4.1- TX 11,1 (4.9- (percutaneous) [76] (56.25%) (6.2%) 58% (III) 35.4) 23.6) • Grade 3 or 4: Anemia 4(14%), Leukopenia 4(14%), Thrombocytopenia 4(14%), Cardiovascular Event 1 (4%)
• Any AE 51 (100%): Anemia 51(100%), Thrombocytopenia 50(98%), Neutropenia 22(43%), ___ Fatigue 17(33%) Retrospective 4.56 Melphalan 9 1 year: Karydis[77] 2017 case series 51 NP (range 1 - TX 15,3 NP TX 8,1 NP (percutaneous) (17%) 64.6%. • Grades 3 or 4:19(37.5%): (III) 26.3) Neutropenia 16(31.3%), Thrombocytopenia 16(31.3%), Anemia 15 (29.4%), Cardiovascular events 9(17.6%)
Phase I/II • Grade 3 or 4: Transient liver 12,1 Alexander Prospective ___ Toxicity 19 (65%) Melphalan 2003 29 22 (76%) 0 (0%) NP EP (range, NP NP EP 8 NP [78] Trial 3-39) (IIb) • No treatment related deaths
• Grade 3 or 4: 6 (9.5%): Respiratory failure 2 (3.2%), Perforated duodenal ulcer Melphalan Retrospective ___ (diabetic patient) 1 (1.64%), Ben- with/without TNF- 2016 case series 61 Most NP NP TX 22,4 NP NP NP NP NP Transient liver failure 1 (1.64%), Shabat[79] alpha or cisplatin (III) Post-operative bleeding 1 (1.64%), Transient liver, respiratory and kidney failure 1 (1.64%)
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• Deaths from liver failure: 5 (8.20%)
• Veno-occlusive disease 2 (6.45%), 1 year: Non-infectious fever 1 (3.23%), 41.9% Liver enzyme elevation, Retrospective 10 1 patient de 2.3 (range, 2 years: 6 (range 1- Leucopenia Melphalan 2016 case series 31 27 (87%) 0 (0%) TX (range, NP alive at 50 TX NP Leede[80] 0.9-13.3) 19.4%. 16) (III) 0-50) months 3 years: • Deaths from liver failure due to 3.5% hepatic artery occlusion: 2 (6.45%)
1 year: 1 patient • Myelosuppression (most 60% CI 95% Retrospective 14.2 alive until common AE), Mild troponin CI 95% 2 years: 7,5(range0- 13.6 Melphalan Forster [81] 2014 case series 5 4 (80%) 0 (0%) NP TX (range, 46.4 TX elevations (10-ND) 40%. 14.9) (2.3- (III) 10-ND) months 3 years: 24.9) • No treatment related mortality 20%
1 year: Phase I 67% ___
van Prospective 18.7(7.8- 2 years: Oxaliplatin+melfalan 2014 3 2 (67%) 0 (0%) NP TX ND TX NP NP NP Iersel[82] Trial 30.7) 33%.
(IIb) 3 years: 0%
• Grade 3 or 4: during IHP: Hypotension (n = 2) (11.11%), Tachycardia (n = 1) (5.55%), Ventricular fibrillation (n = 1) ___ (5.55%), Coagulopathy (n = 1)(5.55%) Retrospective 5 9,6(range 1 year: 12.4 (range Melphalan Vogl[83] 2017 case series 18 7 (39%) NP TX NP TX NP (28%) 1.6–41.0) 44%. 0.9–41.0) • Grade 3 or 4: up to 30 days after (III) IHP and temporary: Leukopenia (n = 11) (61.11%), Thrombocytopenia (n = 8) (44.44%), Fever (n = 4) (22.22%), Edema (n = 2) (11.11%), Infection (n = 2) (11.11%)
AE, adverse effect; CI, confidence interval;EP, enrollmentperiod ; ND, not defined; NP, not provided; LFT, liver function tests; OS, overall survival; TX, treatment.
Table S6. Included studies of Immunotherapy.
Cancers 2020, 12, x 62 of 27
al al
P
ation
FI
ic
P
from from
rgic
FI
CIOS
(FIP)
CI CI
(range) (range)
Author
onal onal outcomes
AnnualOS
Median OS
Median
with su
Median tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Excepti Interval of ProgressionInterval of
24 1 year: (100%) 50% 1 pacient 24 9,9 3 Ipilimumab alive until Retrospective 43 1 year: 46 months Bol [21] 2019 case series 43 NP NP TX 10,3 NP TX 4,8 NP NP Pembrolizumab (100%) 38.7% approx (III)
19 18,9 4 Ipilimumab /Nivolumab 19 1 year: (100%) 57.6%
Retrospective Ipilimumab or 18 Xu[22] 2019 case series 18 NP NP TX 15,8 NP NP TX 3 NP NP Nivolumab or Pembrolizumab (100%) ___ (III)
95% CI • Pruritus 4 (66,7%), Ipilimumab or Retrospective CI ___ 95% Hypothyroidism 2 Pembrolizumab or Nivolumab Itchins [50] 2017 case series 6 NP NP NP DX 18,2 NP TX 7 (10.9- (2- (33,3%), Hypophysitis 2 + HIA (III) NR) NR) (33%)
1 year: Retrospective Ipilimumab or Klemen 50% 4 patients 2020 case series 30 NP NP NP TX 12,2 NP NP NP NP NP Nivolumab or Pembrolizumab [85] 5 years alive at 60 (III) or Atezolizumab 22% months
1 year: 66.7% 2 years:
0 33.3% 3 (100%) • AE 18 (94.7%): Diarrhea 7 (0%) 3 years: 3 NP EP NP NP EP NP NP (37%), Fatigue 6 (32%), 33.3% Nausea 6 (32%), Pruritus 6 ___ Ipilimumab 3mg/ kg + RFA (32%)
Phase Ib/II Grade 3 or 4: 6 (32%): 1 year: non- 19 Colitis 5(26%) Rozeman 0 42.1% Ipilimumab 3mg/ kg + RFA 2019 randomized 19 (100%) NP EP 9,7 NP EP 2,76 NP [86] (0%) 2 years: prospective 0% trial (IIa) • AE 18 (94.7%): Diarrhea
Ipilimumab 10 mg/kg + RFA 11 (58%), Rash 9 (47%),
Fatigue 4 (21%), Pruritus 4 1 year: 19 19 NP EP 14,2 NP EP 2,76 NP (21%) 0 57.9% (100%) Grade 3or 4: 10 (52%): (0%) 2 years: Colitis 9 (47%) 10.5% 3 years: 5.3%
Cancers 2020, 12, x 63 of 27
• AE: 37 (60.9%) CI CI Ipilimumab + Multi-centre 50 95% ___ 95% • Grade 3 or 4: 25(39.1%): NivolumbaborPembrolizumab Heppt[87] 2019 etrospective 64 NP NP TX 16,1 NP TX 3 (78.1%) (12.9- (2.4– Colitis 13(20.3%), * study (III) 19.3) 3.6) Hepatitis 13(20.3%), Thyroiditis 10(15.6%), Pituitary 5(7.8%) 1 year: CI Retrospective 62.5%*** ___ Karivedu 7 0 95% • Autoimmune Colitis 4 Ipilimumab + Nivolumab** 2019 case series 8 NP TX 14,2 2 years: NP NP NP [88] (87,5%) (0%) (1.9- (50%) (III) 12.5%*** 24) ***
• Grade 1: hypothyroidism CI Observational 2(11.7%) 17 0 95% Pembrolizumab Rossi [89] 2019 prospective 17 NP TX NR NP NP TX 3,8 • Grade 2: hypophysistis (100%) (0%) ___ (2.9- cohort (III) 1(5.8%) 9.7) • No grade 3 and 4
• AE: Fatigue 8(57%), Pruritus 7(50%), Nausea ___ 6(43%), Altered liver tests 13.8 1 year: CI Retrospective 6(43%) Namikawa 6 0 (range 66,6% 2.3 (range, 95% Nivolumab 2019 case series 14 NP TX NP TX [90] (42,86%) (0%) 1.15- 2 years: 1-24.2) (0- (III) • Grade 3 or 4: 24.16) 14,2% 9,18) Hyperglycemia 1(7%), Dyspnea 1(7%), Pneumonitis 1(7%)
Retrospective CI Ipilimumab Yasar [91] 2019 case series 20 NP NP NP NP 5 95% NP ___ NP NP NP NP (III) (1-17) 1 year: Retrospective Kirchberger 77,7% Ipilimumab+Pembrolizumab 2018 case series 9 1 (11%) NP NP TX 18,4 NP ___ NP NP NP NP [92] 2 years: (III) 22,2%
• AE: 14(25.9%) 35 Pembrolizumab • Grade 3 or 4: 4(7.4%): 54 (64,8%) 14 3,1 Arthritis 1(1.8%),
Autoimmune Hepatitis
1(1.8%), Cardiac Toxicity
Nivolumab Retrospective 1(1.8%), Serum Lipase 32 23 10 2,8 Heppt [93] 2017 case series NP NP TX NP NP TX NP Elevation 1(1.8%) (71,9%) (III) ___
• AE: 13(40.6%)
Ipilimumab+ • Grade 3 or 4: 4(71.4): 15 NR 2,8 (PembrolizumaborNivolumab) Colitis 1(4.3%), Heart 6 (40%) Toxicity 1(4.3%),
Arthralgia 1(4.3%), Fatigue 1(4.3%)
Cancers 2020, 12, x 64 of 27
• AE: 7(46.7%) • Grade 3 or 4: 2(13.3%): Thyroiditis, colitis, and pituitary disease
Retrospective 5 (range ___ 3 (range • Autoimmune Hepatitis 1 NivolumaborPembrolizumab Bender [94] 2017 case series 15 6 (40%) NP NP NP NP NP NP NP 1-16) 0.75-6.75) (6.6%) (III)
Prospective non- • AE: 29(96.6%) randomised, ___ Nivolumab + Ipilimumab + 1 year: Pelster[96] 2019 non- 30 NP NP NP TX 19,1 NP NP 6 NP (Nivolumab as maintenance) 62% • Grade 3 or 4: 14(46.6%) comparison (No detailed information) phase II trial (IIb)
• Fatigue (19.6%), Pruritus ___ (12.5%), Rash (10.7%), Nausea (10.7%), Hypothyroidism (7.1%), CI CI Pembrolizumabornivolumabor Retrospective Diarrhea (8.9%) 0 95% 95% atezolizumab Algazi [97] 2016 case series 56 8 (14%) NP TX 7,7 NP TX 2,6 (0%) (0.7- (2.4- (III) • Grade 3 or 4: 7 (12.5%) 14.6) 2.8) Nausea, Vomiting, Hyperbilirubinemia, Fatigue, Colitis, Arthralgia and Lymphopenia.
1 year: Prospective 8,3 CI 30.8% • Grade 3 or 4: 3 (23%): non- Danielli (range, 95% 2 Diarrhea 1 (7.70%), ALT Ipilimumab 2012 randomised 13 0 (0%) NP NP TX ___ NP NP NP [98] 0.5- (4.2- years:7.7% Elevation 1 (7.70%), AST Clinical Trial 39.6) 12.4) 3 Elevation 1 (7.70%) (IIa) years:7.7%
• Hyperthyroidism 2 CI ___ 95% (18.2%) Phase II 3 95% CI Tremelimumab Joshua [99] 2015 Prospective 11 NP NP EP 12,8 NP TX 2,9 (27%) (3.8- (2.8- • Grade 3 or 4: Rash 1 Trial (IIb) 19.7) 3) (9.1%), Nausea 2 (18.2%) Diarrhea 3 (27.3%)
• Grade 3 or 4: 5 (20%): 11.3 >7.4 Retrospective Transaminitis 1 (4%), Rash Karydis 3 (range (range, 1 year: > 3 (range, Pembrolizumab 2016 case series 25 0 (0%) TX NR ___ TX NR and itching 1 (4%), [100] (12%) 3.7- 0.2- 28% 0.3-10.6) (III) Pituitary 2 (8%), Fatigue 1 65.1) 16.4) (4%), Diarrhea 1 (4%)
Cancers 2020, 12, x 65 of 27
CI CI Retrospective • Grade 3 or 4: 5 (22.72%), Kelderman 95% 1 year: 95% Ipilimumab 2013 case series 22 0 (0%) NP NP TX 5,2 ___ TX 2,9 Colitis 2 (9.1%), Hepatitis [101] (4.9- 27% (2.3- (III) 1 (4.5%) Other 3 (13.6%) 9.6) 5.3)
• Rash 11 (28.21%), Thyroiditis 4 (10.26%) CI ___ Retrospective 95% • Grade 3 or 4: Diarrhea and Ipilimumab Luke [102] 2013 case series 39 0 (0%) NP NP TX 9,6 NP NP NP NP (6.3- colitis 2 (5.13%), Hepatitis (III) 13.4) and pancreatitis 1 (2.56%), Hypophystis 2 (5.13%), Uveitis 1 (2.56%)
Prospective • Any grade: Rash 8 (10%), CI CI non- ___ Pruritus 11 (13%) 95% 1 year: 95% Ipilimumab Maio [103] 2013 randomised 83 0 (0%) NP NP NP 6 NP 3,6 (4.3- 31% (2.8- clinical trial • Grade 3 or 4: Toxic 7.7) 4.4) (IIa) Hepatitis 2(2.5%), Diarrhea 2 (2.5%) CI CI Van Retrospective 90% ___ 95% • Toxicodermia grade 2: 1 NivolumaborPembrolizumab derKooij 2017 case series 17 8 (47%) NP NP TX 8,8 NP TX 2,3 (5.5- (1.7- (5.88%) [104] (III) 12.2) 3)
1 year: • Any grade: 35 (66%): 22% (CI Diarrhea 16 (30%), LFT 7 95% 12– ___ Alteration (13%), Colitis 9 CI 35) CI (17%), Pruritus 5(9%), Phase II Zimmer 95% 95% Rash 3 (6%) Ipilimumab 2015 Prospective 53 8 (15%) NP NP TX 6,8 TX 2,8 [105] (3.7- 2 years: (2.5- Trial (IIb) 8.1) 7% 2.9) • Grade 3 or 4: 19 (36%): (CI 95%1– Diarrhea 7 (13%), LFT 18) alteration 4 (8%), Colitis 6 (11%)
Prospective • AE: 46(92%) non- Piulats randomised, ___ • Grade 3 or 4: 27(54%), 50 Nivolumab+Ipilimumab Rodriguez 2018 non- 50 NP NP TX 12,7 NP NP TX 3,27 NP Increase in liver enzymes, (100%) [106] comparison Dermatological phase II trial pathology, Hepatitis, (IIb) Diarrhea.
Approx, approximate; DX, diagnosis; AE, adverse effect; CI, confidence interval; CPI, checkpoint inhibitors; NC, no prior chemotherapy or systemic treatment; NP, not provided; NR, not reached; LFP, liver function tests; EP, enrollment period; R-P, response-progression; OS, overall survival; TX, treatment. *Ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks, followed by nivolumab 3 mg/kg every 2 weeks. Ipilimumab 1 mg/kg + pembrolizumab 2 mg/kg every 3 weeks, followed by pembrolizumab 2 mg/kg every 3 weeks. ** Combined with TACE. *** Calculated from the narrative of the manuscript. CI 95% of the median overall survival was
Cancers 2020, 12, x 66 of 27
not reached; i.e. cumulative survival plot did not fall below 50%. Three patients had undergone surgery, three palliative radiation therapy, one TACE, three systemic chemotherapy. One of the 83 patients was lost to follow-up, so the Kaplan-Meyer graph represents 82.
Table S7. Included Targeted Therapy Studies.
P
ree ree
FI
P
FI
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with surgical
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition F
Yearofpublication
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Exceptional Outcomes Interval of ProgressionInterval of
MAPK INHIBITORS
• AS 30 (100%): Increase AST 18 (58.1%) Increase ALT 18 (58.1%) Fatigue 14 CI (45.2%) HTA 14 (45.2%) Phase II Prospective 11 CI 95% 95% Cabozantinib Luke [23] 2019 Randomized Clinical 30 NP NP TX 6.3 NP ___ TX 2 (63.3%) (5.5-10.3) (1.8- • Grade 3 or 4: 16 (51.6%): Trial (Ib) 5.3) Fatigue 3(9.7%) ETS 3 (9.7%) Bilirubin 2 increase (6.5%) Thromboembolic event 4(12.9%)
• AE 97 (100%): Nausea 60(62%), Rash 55(57%), Fatigue 43(44%), Diarrhea 43 (44%). Phase III Prospective Selumetinib + Carvajal 97 0 10 2.8 2018 Randomized Clinical 97 NP EP NP NP ___ EP NP Dacarbazine [39] (100%) (0%) (approx.) (approx.) • Grade 3 or 4: 60 (61%): Trial (Ib) Neutropenia 19 (19%), Thrombocytopenia 12(12%), ETS 8(8%), LFT alteration 6(6).
• Any AE: Fatigue 18(90%), 1 year: Diarrhea 12(60%), Prospective non- Mahipal 3 44.4% CI Bleeding 11(55%), Sunitinib 2012 randomised pilot study 20 3 (15%) NP TX 8,2 NP ___ TX 4,2 NP [112] (15%) 95% (22.5- Anorexia 9(45%) (IIa) 64.4) • Grade 3: Fatigue 3(15%), Leucopenia 2(10%),
Cancers 2020, 12, x 67 of 27
Anorexia 2(10%), Vomiting 2(10%)
• Grade 3: 12(50%); Neutropenia 4(16.6%), Thrombocytopenia
3(12.5%), Diarrhea 2(8.3%), 1 year: 95% Pruritus 1(4.1%) Sorafenib + Bhatia Phase II Prospective 20 95% CI 42% CI 2012 24 NP NP EP 11 ___ EP 4 CI (1- Carboplatin + [113] Trial(IIb) (83%) (7-14) 95% (22- 6) • Grade 4: 7(29%); Paclitaxel 60) Neutropenia 6(25%),
Lymphopenia 2(8.3%), Febrile Neutropenia 1(4.1%)
• Any AE: Fatigue 19(59.4%), Diarrhea 18(56.2%), Nausea and Vomiting 17(53.1%), Hand 4,9 and Foot Syndrome Mouriaux Phase II Prospective 19 0 Sorafenib 2016 32 (range TX NP NP NP ___ NP NP NP 17(53.1%) [114] Trial(IIb) (59%) (0%) 0-8) • Grade 3 or 4: 10(34.3%); HTA 4(12.5%), Hand Foot Syndrome 2(6.2%), Rash 1(3.1%), Alopecia 1(3.1%)
• Hematological AE grades 1-3: 8(100%)
• Neutropenia and / 1 year: 15,9 CI 95% orthrombicytopenia: 3 Niederkorn Retrospective case 75% Sorafenib+Fotemustine 2014 8 2 (25%) NP NP TX (range, (11,7- ___ NP NP NP (37,5%) [115] series (III) 2 years: 5,6-29,6) 20,1) 12,5% • Hand-foot syndrome and / or maculopapular rash 4 (50%)
• Grade 3: Fatigue 4 (33%), Myalgia 2 (16,6%), Abdominal pain 3 (25%), Prospective non- Vomiting 7 Hofmann Imatinib 2009 randomised Clinical 12 8 (67%) NP NP TX 6,8** NP NP ___ NP NP NP (58,3%), Facial edema 2 [116] Trial (IIa) (16,6%)
• Grade 4: Vomiting 1 (8,3%), Anemia 1 (8,3%)
Cancers 2020, 12, x 68 of 27
• Any AE: 13(100%) ___ Phase II Prospective 0 • Grade 3 and 4: 5(38.5%); Imatinib mesilate Penel [117] 2008 13 6 (46%) NP TX 10,8 NP NP NP NP NP Trial(IIb) (0%) Hepatic cytolysis 3(23.1%), Vomiting 2(15.4%), Abdominal pain 2(15.4%), Myalgia 1(7.6%)
ProspectiveRandomized ___ Cabozantinib Daud [118] 2017 23 NP* NP NP TX 12,6 NP NP TX 4,8 NP NP* Trial (Ib)
HSP90 INHIBITOR
STA-9090 (Ganetespib) CI 90%
(4.0-13.0) CI 90% 17 NP NP NP 7 1,8 • AE: 17 (100%) Increase in (1,2-3,5) STA-9090 Phase II non- ___ transaminases, nausea, CI 90%. (Ganetespib) 200 randomised vomiting, diarrhea (3.7 - CI 90% mg / 1 time per Shah [111] 2018 controlled open- 7 NP NP NP TX 8.5 NP TX 1,6 28.7) (0.8-3.5) week label Clinical trial • Grade 3: 11(64.7%)
(IIa) CI 90%. CI 90% 10 NP NP NP 4.9 1,8 • Grade 4: 2 (11.7%) (3.2 - (0.9-7.1) STA-9090 13.0) (Ganetespib) 150mg / 2 times a week
Approx, approximate; AE, adverse effect; CI, confidence interval; EP, enrollment period; NP, not provided; OS, overall survival; TX, Treatment. * Provided the percentages of all patients, not uveal melanomas specifically. ** The median survival seems to correspond to the arithmetic mean.
Table S8. Included Selective Internal Radiation Therapy (SIRT).
al al
P
ation
FI
ic
P
rgic
FI
CIOS
(FIP)
CI CI
(range) (range)
Author
ional Outcomes
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Except Interval of ProgressionInterval of
Cancers 2020, 12, x 69 of 27
95% 13.5 CI (range, 5.6 • Elevation of 1 year: 55.5% (3.6- 14 3.6-44.8) 95% CI (range, transaminases: 2 years: 27.7% 5.6) 18 (77,7%) 0 (0%) (4.4- ___ 1.3-40.8) grades 1-2: 3 years:11.1% 21) 11(61.1%) Case Study 95% 18.7 5.6 grades 3 and 4: Radioembolization, Series 1 year: 64.3% CI Tulokas [24] 2018 14 14 0 (0%) NP TX (range, TX (range, 2(11.1%) (Y-90) beads comparative 2 years: 35.7% (0.4- (100%) 8.2-44.8) 95% CI 1.3-40.8) (III) 3 years:14.3% 11.4) (0-33) • Clinical grade 1-2:
4 0 (0%) 3.7 15(83.33%) 1 year: 25% 95% 0 (0%) 7.8 (range, Nausea, abdominal pain, 2 years: 0% CI (range, ND 4.4-5.6) fatigue, fever. 3 years: 0% (2.8- 3.6-20.7) 4.6)
CI 1 year: >50% 1 patient alive 95% CI 95% approx until 95 (6.1- Radioembolization, 26 (18.9- 2 years: >40 12 TX months** TX 10.3 26.3) resin beads (Y-90) + 67.9) approx** 1 patient alive Immunotherapy* Retrospective until 120 Levey [125] 2019 NP NP NP NP case series (III) months**
CI Radioembolization, 9,5 CI 95% 1 year: 40% 12 TX ___ TX 2.7 95% resinbeads (Y-90) (5.5- approx (1.8- 19.7) 2 years: 20 5.2) approx**
• Grade 1 and 2: 9(41%) Abdominal pain and fatigue CI Radioembolization, 3 Retrospective 22 95% CI 95% resin or glass beads Ponti [126] 2019 22 0 (0%) (range TX 18 NP ___ TX 5 • Grade 3: 7(32%) case series (III) (100%) (8-28) (1.84- (Y-90) 1-5) Cholecystitis 3(13.6%), 17) Abdominal pain 2(9.1%) ,Liver failure 2(9.1%)
• Grade 4: Non-referral • Fatigue 22 (91.7%) ___ Increase in liver enzymes 8,1 CI 19 (79.2%) Abdominal Radioembolization, 18,5 1 year: 60.9% (range CI 95% 95% pain 14 (58.3%) Nausea resin beads (Y-90) 24 (range 2 yeras: 20.1% 3.3 – Phase II 24 (11.3- (6.4- and vomiting 14 (58.3%) (100%) 6.5-73.7) 3 years: 13% 33.7) Prospective 23.5) 11.8) Radioembolization, Gonsalves [127] 2019 Non- NP NP TX ___ TX • Grade 3: 3(12.5%): resin beads (Y-90) 1 year: 69.6%. Randomised 24 CI 95% CI Abdominal pain 2 (8.3%) post Immuno- 0 (0%) 19,2 2 yeras: 30.4% 5,17 Trial (IIa) (11.5- 95% and Nausea and vomiting embolization and (range 3 years: 8.7% (range 24) (3.7- 1 (4.1%), Fatigue 17(70.8%) progression 4.8–76.6) 2.9– 9.8) Liver enzyme increase 22.0) 21(87.5%) Nausea and vomiting 14(58.3%)
Cancers 2020, 12, x 70 of 27
CI 95% • Grade 1 or 2: 10 (90.9%): Radioembolization, TX 17 (1.8- Fatigue, nausea, anorexia, resin beads (Y-90) + CI 9 32.2) abdominal pain, altered Immunotherapy Retrospective 2 95% Zheng [128] 2018 11 NP (range, ___ TX 15 liver tests (Nivolumab or case series (III) (18,18%) (5.9- 2-37,5) Pembrolizumab or 24.1) DX 35,5 CI • Grade 3: 1 (9%) Ipilimumab) 1 year: 50% 95% pepticulcer
(10-55)
Case Study Radioembolization, CI 95% Series ___ resinbeads (Y-90) Xing [129] 2017 15 0 (0%) NP NP TX 10,9 (8.5- NP NP NP NP NP**** comparative 13.4) (III)
Radioembolization, 12,3 ___ 5,9 • Grades 1 and 2: Fatigue Eldredge-Hindy Retrospective 13 resinbeads (Y-90) 2016 50 NP 9,8 TX (range, NP NP TX (range, NP 31(44%), Abdominal pain [130] case series (III) (18%)*** 1,9-49,3) 1,3-19,1) 18(25%), Nausea 11(15%)
• Grades 1 and 2: Abdominal pain 5(38%), ___ Nausea 3(23%), Gastric Radioembolization, 5 Retrospective 7 (range, 1 year: 46,1% ulcer 1(7.6%) resinbeads (Y-90) Klingenstein[131] 2013 13 2 (15%) 1 (8%) (range TX ND NP NP NP case series (III) 2-25) 2 years: 7,6% 1-49) • Grade 4: Hepatomegaly and death from liver failure 1 (7.6%)
17.1 Radioembolization, 0.98 Retrospective (range 2,8(range, • Grade 2: Nausea 1 (12.5%) resinbeads (Y-90) Schelhorn[132] 2015 8 0 (0%) 0 (0%) TX NP NP ___ TX (range NP case series (III) 6.4- 0,85-14,4) • Grades 3 and 4: 0 (0%) 0.78-6.6) 23.2)
CI, confidenceinterval; NP, not provided; ND, not defined; EP, enrollment period; OS, overall survival; TX, treatment. * Immunotherapy 3 months before or after the Radioembolization Drugs: Ipilimumab, Nivolumab, Pembrolizumab or Il-2. **Kaplan-Meier diagram estimated data. *** Pre-treatment was reported for all 58 patients, not specifically for the 50 patients who had a pre-treatment PET/CT scan and were included in the Kaplan-Meier diagram. **** Provided the percentages of all patients, not uveal melanomas specifically.
Table S9. Included Immunoembolisation Studies (IE).
es
al al
P
ation
FI
ic
P
rgica
FI
CIOS
CI CI
Author
AnnualOS
Median
Median from Median from
treatment (%)
Studio design
with su
treatments (%)
DefinitionofOS
in months in(range) months in(range) months
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
of (FIP)of Progression
Adverse Adverse effects
Median OS publishedMedian OS
metastases treatmenttometastases
Exceptional Outcom Definition Free Interval Definition Free Interval
Cancers 2020, 12, x 71 of 27
• First week: Abdominal pain (51.6%), LFT alteration (19.9%), Haematological (2.1%)
• Grade 3 or 4: LFT alteration Phase II Immunoembolisationwith CI 95% 1 patient CI 95% (2.7%), Hematological (0.8%) Valsecchi Prospective GM-CSF 2015 25 NP NP NP TX 21,5 (18.5- NP still alive at TX 10,4 (7,5- [73] Randomized Trial 24.8) 50 months 13,2) • From the second week onwards: (Ib) Abdominal pain (20.1%), LFT alteration (12.2%), Haematological (11.2%)
• Grade 3 or 4: Lessthan 1%
1 year: 61% 1 patient
CI 95% (45- was alive at CI 95%
78.1) 40.8 (3.6- • Grade 3: Liver enzyme elevation Phase I Prospective CI 95% Hepatic: 4.8 Sato 3 months of 11.5) 3(8.8%), abdominal pain 1(2.9%). Immunoembolisationwith 2008 Trial 34 28 (82%) NP TX 14.4* (11.2- TX [133] (9%) follow-up GM-CSF (IIb) 22.3) Extrahepatic: 2 years: 26% CI 95% • Grade 4: Respiratoryfailure 10.4 CI 95% (6.8- 1(2.9%)
(11.2-41) 12.4)
CI, confidence interval; NP, not provided; LFT, liver function tests; OS, overall survival; TX, Treatment. * Median overall survival is reported for 34 patients by intention-to-treat analysis, while the Kaplan-Meier diagram includes 31 radiographically evaluable patients.
Table S10. Included studies of Immunosuppressant (IS).
FIP)
P
FI
P
first line line first
FI
(%)
CIOS
CI CI
Author
AnnualOS
Median
Median from Median from
Studio design
treatments (%)
DefinitionofOS
in months in(range) months in(range) months
Yearofpublication
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of
of ( of Progression
Adverse Adverse effects
Median OS publishedMedian OS
with surgical treatment with treatment surgical
metastases treatmenttometastases
Exceptional Outcomes Definition Free Interval Definition Free Interval
• Any AE: 14 (100%); Hyperglycemia 12(85.5%), Hypertriglycemia Phase II Shoushtari 11 (range, ___ 3.7 (range 10(71.4), Diarrhea Everolimus+Pasireotide 2016 Prospective 14 0 (0%) NP NP TX NP NP TX NP [139] 4.5-28.5) 1.6-7.6) 9(64.2%), Leukopenia Trial(IIb) 9(64.2%)
• Grade 3: Hyperglycemia 7(50%), Oral Mucositis
Cancers 2020, 12, x 72 of 27
2(14.2%), Diarrhea 1(7.1%), Hypokalemia 1(7.1%)
AE, adverse effects;CI, confidence interval; NP, not provided; OS, overall survival; TX, Treatment.
Table S11. Included studies of Liver-directed thermotherapy (LDT).
al al
P
ation
FI
ic
P
rgic
n n
FI
CIOS
CI CI
(range)
Author
AnnualOS
Media
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
in months in(range) months
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
of (FIP)of Progression
Adverse Adverse effects
Median OS publishedMedian OS
Exceptional Outcomes Definition Free Interval Definition Free Interval
For all patients (6 uveal, 14 ___ cutaneous) • No procedure-related Retrospective Radiofrequencystereotacticablation Bale [140] 2016 6 0 (0%) 0 (0%) NP TX 38 NP NP NP NP NP deaths case series (III) • In 34 SRFA sessions,a total of 3 complications (3 pleural effusions)
1 year:
88% ___ • Pain instead of CI 95% 3 years: Laser-inducedThermotherapy Retrospective injection18(100%), Eichler[141] 2014 18 NP** 4 (22%) NP TX 33.6 (12-60) 47%. NP NP NP (LITT) case series (III) Asymptomatic pleural 5 years: effusion 2(11.1%) 18%
CI, confidence interval;NP, not provided; OS, overall survival; TX, treatment. *The authors state: "The limitations of our study are the small number of patients and the non-homogeneous population with respect to various pre-LITT treatments such as immunochemotherapy and TACE".
Table S12. Included Dendritic Cell Vaccine Studies.
Cancers 2020, 12, x 73 of 27
al al
P
ation
FI
ic
P
first line line first
rgic
FI
FIP)
CIOS
(
CI CI
(range) (range)
Author
ional Outcomes
AnnualOS
Median OS
Median
with su
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpubl
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Except Interval of ProgressionInterval of
• Grade 1 and 2: Flu-like 1 year: 64% symptoms 8(57.1%), Prospective non- 2 years: 1 patient 95% CI Erythema 6(42.8%), randomised 8 3 50% alive at 84 Dendriticcellvaccine Bol[143] 2014 14 NP TX 19,2 (3.1-34.9) NP NP NP Fatigue 5(35.7%). comparative case series (57%) (21%) 3 years: months
(IIa) 29% • Grade 3 and 4: 0(0%)
CI, confidence interval; NP, not provided; OS, overall survival; TX, Treatment.
Table S13. Included studies of CIOVIR-5 Oncolytic Adenovirus.
P
FI
P
FI
CIOS
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with surgical
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpublication
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Exceptional Outcomes Interval of ProgressionInterval of
• Grade 3 Toxicity: 2(33.3%) Neutropenia 1
CIOVIR-5, (16.6), Increased Garcia Phase I Clinical trial 6 NP NP NP NP 8,9 NP NP ___ NP NP NP intravenousoncolytic 2018 Transaminase 1 (16.6), [146] IIb adenovirus Thrombocytopenia 1 (16.6)
CI, confidence interval; NP, not provided; OS, overall survival.
Table S14. Included studies of Surgical Resection.
P
FI
P
FI
CI OSCI
(FIP)
CI CI
(range) (range)
Author
AnnualOS
Median OS
Median
with surgical
Median from Median from tometastases
treatment (%)
Studio design
treatments (%)
DefinitionofOS
Definition Free
Yearofpublication
Numberofpatients
Drug Intervention /
Number of patientsNumber of
Number of first line Number of line first
treatment in months treatment in months
published in in publishedmonths
Adverse Adverse effects
Excepcional Excepcional Outcomes Interval of ProgressionInterval of
Cancers 2020, 12, x 74 of 27
Resection+
fotemustine or
dacarbazine IA+ 0 cisplatin IA Prospective non- 19 19 (100%) (0%) 22 ___ Salmon randomized NP NP NP NP NP NP NP NP CurativeResection 1998 [57] comparative case series
(III) 34 34 (100%) 0 NP
(0%) Tumourreduction
Comparative 8 patients still Hsueh Resection 2004 retrospective case 24 NP* NP NP DX 38** NP 5 years: 39% alive at 60 NP NP NP NP [148] series (III) months
65.6
Resection (range 0 11.5 to Comparative 14 (0%) TX R0 Frenkel NP) 2009 retrospective case NP NP NP NP ___ NP NP NP NP [149] series (III) 16.6 23 0 TX R1/R2 (range. (0%) 7.6-25.5)
CI 95% 2 patients still 19 Aoyama Retrospective case 0 5 years: Resection 2000 12 8 (57%) NP TX 27 (25.7- alive at 60 TX (range NP NP [150] series (III) (0%) 53.3%. 28.3) months 6-78)
Resection +
fotemustine IA or 0 2 years: cisplatin IA Kodjikian 14 14 (100%) (0%) TX 25** 59.9% ---- [151]/ Comparative R0 2005 NP NP NP NP NP NP Rivoire retrospective case
[152] series (III)
14 14 (100%) 0 TX 16 2 years: R2 (0%) 14.3%.
Phase II Prospective 5 years: 70% 10 patients still Servois 0 Resection + FEP 2019 Non-Randomised Trial 14 14 (100%) NP DX NP NP 10 years: alive at 60 NP NP NP NP [153] (0%) (IIa) 35% months
1 year: 100% • Any AE: 4(23.5%) Comparative 3 years: Gomez 27(range, 2 patients still • Grade 2: 3(16.6%) Resection*** 2014 retrospective case 18 NP NP NP TX NP 41.4%. NP NP NP [154] 14-90)** alive at 60 • Grade 3: 1(5.5%) series (III) 5 years: months • Grade 4: 0(0%) 41.4%.
Cancers 2020, 12, x 75 of 27
0 Resection 57 57 (100%) (0%) TX 27 TX 10 Comparative Mariani 2016 retrospective case NP NP NP ___ NP NP [155] series (III) Resection + FEP 13 13 (100%) 0 TX 28 TX 7 (0%)
1 year: 40% 5.5 Retrospective case CI 95% • Pleural effusion 1 PartialResection Yang [156] 2013 5 NP NP NP TX 11,5 2 years: 25% ___ TX (range, NP series (III) (7.5-15.8) (20%) 3 years: 0% 4.5-14)
2 years: 54.4%
0 3 years: 30% Resection± (0%) 76 TX 27 76 (100%) 2 years: R0 Comparative 68 Mariani 0 30.7% 2009 retrospective case 22 (range, TX 17 Global survival NP NP NP NP [157] 22 (100%) (0%) NP 3 years: R1 series (III) 19-81) at 60 months: 7% 13.6% 157 TX 11 157 (100%) 0 R2 (0%) 2 years:
14.4%. 3 years: 5.7%
AE, adverse effect; CI, confidence interval; DX, diagnosis; EP, enrollment period; IA, intra-arterial; NP, not provided; OS, overall survival; RFA, radiofrequency ablation; TX, treatment. * The authors state: "Postoperative chemotherapy was mandatory in all patients during the first years of our experience, but since 2005 it has been reserved for patients randomised in the intra-arterial arm of the European trial"; in addition, eight patients underwent RFA during laparotomy to achieve R0 resection. ** The reported median survival seems to be calculated arithmetically and not by a Kaplan-Meier estimate. *** A patient received RFA. ±The authors state: "Some patients received chemotherapy intravenously or through an intra-arterial liver port, and some received adjuvant immunotherapy. Of the five patients, two received adjuvant TACE therapy with or without immunotherapy.