Supplemental Table 1. National Cancer Institute CTCAE version 2 and 3 for venous thromboembolism

Grade / Version 2 / Version 3
1 / - / -
2 / Deep vein thrombosis, not requiring anticoagulant / Deep vein thrombosis or cardiac thrombosis, intervention (e.g., anticoagulation, lysis, filter, invasive procedure) not indicated
3 / Deep vein thrombosis, requiring anticoagulant therapy / Deep vein thrombosis or cardiac thrombosis; intervention (e.g., anticoagulation, lysis, filter, invasive procedure) indicated
4 / Embolic event including pulmonary embolism / Embolic event including pulmonary embolism or life-threatening thrombus
5 / - / Death

Supplemental Table 2. National Cancer Institute CTCAE version 2 and 3 for arterial thromboembolism

Grade / Version 2 / Version 3
1 / Cardiac: Nonspecific T-wave flattening or changes, Cardiac troponin I (cTnI)≥0.03-<0.05 ng/mL.
CNS: -
Peripheral and visceral artery: - / Cardiac: Asymptomatic arterial narrowing without ischemia, cTnI 0.03-<0.05 ng/mL
CNS: -
Peripheral and visceral artery: -
2 / Cardiac: Asymptomatic, ST- and T-wave changes suggesting ischemia,
cTnI≥0.05-<0.1 ng/mL
CNS: -
Peripheral and visceral artery: Brief episode of ischemia managed nonsurgically and without permanent deficit. / Cardiac: Asymptomatic and testing suggesting ischemia; stable angina. cTnI ≥0.05-<0.1 ng/mL
CNS: Asymptomatic, radiographic findings only
Peripheral and visceral artery: Brief (<24 hrs) episode of ischemia managed nonsurgically/medically and without permanent deficit.
3 / Cardiac: Angina without evidence of infarction. cTnI ≥0.1-<0.2 ng/mL
CNS: Transient ischemic event or attack (TIA)
Peripheral and visceral artery: Requiring surgical intervention. / Cardiac: Symptomatic and testing consistent with ischemia; unstable angina; intervention indicated.
cTnI ≥0.1-<0.2 ng/mL
CNS: Transient ischemic event or attack (TIA) ≤24 hrs duration
Peripheral and visceral artery: Recurring or prolonged (≥24 hrs) and/or invasive intervention indicated.
4 / Cardiac: Acute myocardial infarction. cTnI ≥0.2 ng/mL
CNS: Permanent event (e.g., cerebral vascular accident)
Peripheral and visceral artery: Life-threatening or with permanent functional deficit. / Cardiac: Acute myocardial infarction. cTnI ≥0.2 ng/mL
CNS: Cerebral vascular accident (CVA, stroke), neurologic deficit >24 hrs
Peripheral and visceral artery: Life-threatening, disabling and /or associated with end organ damage
5 / - / Death

Supplemental Table 3. Baseline characteristics of 37 trials included in the meta-analysis (VTE).

Tumor types / Author/year / Phase / Patients enrolled / Treatment arm / Median age (years) / Median treatment duration (months/cycles) / Median PFS/TTF (months) / Number of patients for analysis / Number of VTEs All-grade(High-grade) / Reported events / Jadad score
NSCLC / Heymach et al. (2007)1 / II / 127 / Vandetanib 300 mg +TXT / 61 / NR / 17 weeks / 44 / (1) / Pulmonary embolism / 3
Vandetanib 100 mg + TXT / 58 / NR / 18.7 weeks / 42 / (0) / -
Placebo + TXT / 60 / NR / 12 weeks / 41 / (0) / -
Heymach et al. (2008)2 / II / 181 / Vandetanib 300 mg + CP / 60 / NR / 24 weeks / 56 / 3(1) / Pulmonary embolism / 3
Vandetanib 300 mg / 63 / NR / 11.5 weeks / 73 / 2(1) / Pulmonary embolism
Placebo + CP / 59 / NR / 23.1 weeks / 52 / 4(0) / Pulmonary embolism
Goss et al. (2010)3 / II / 296 / Cediranib 30mg + CP / 60 / 20 weeks / 5.6 / 126 / 4(4) / Venous thromboembolism / 5
Placebo + CP / 58 / 19 weeks / 5 / 123 / 4(2) / Venous thromboembolism
Herbst et al. (2010)4 / II / 1391 / Vandetanib 100 mg + TXT / 59 / 12.1 weeks / 4 / 689 / 14 / Venous thromboembolism / 5
Placebo + TXT / 59 / 13 weeks / 3.2 / 690 / 27 / Venous thromboembolism
Scagliotti et al. (2010)5 / III / 926 / Sorafenib 400 mg + CP / 62 / 16.6 weeks / 4.6 / 464 / 8(7) / Thrombosis/embolism / 3
Placebo + CP / 63 / 17.9 weeks / 5.4 / 462 / 5(3) / Thrombosis/embolism
De Boer et al. (2011)6 / III / 534 / Vandetanib 100mg + pemetrexed / 60 / 102 days / 17.6 weeks / 260 / (1) / Fatal pulmonary embolism / 5
Placebo + pemetrexed / 60 / 85 days / 11.9 weeks / 273 / (1) / Fetal pulmonary embolism
Natale et al. (2011)7 / III / 1240 / Vandetanib 300 mg / 61 / 9.1 weeks / 2.6 / 623 / (2) / Pulmonary embolism / 3
Erlotinib / 61 / 8.6 weeks / 2.0 / 614 / (0) / Pulmonary embolism
Lee et al. (2012)8 / III / 924 / Vandetanib 300mg / 60 / 14.4 weeks / 1.9 / 619 / (3) / Pulmonary embolism / 5
Placebo / 60 / 10.7 weeks / 1.8 / 303 / (6) / Pulmonary embolism
Paz-Ares et al. (2012)9 / III / 904 / Sorafenib 400 mg + GC / 60 / 17 weeks / 6.0 / 385 / 14(13) / Thrombotic events / 5
Placebo + GC / 58 / 18 weeks / 5.5 / 384 / 13(11) / Thrombotic events
Scagliotti et al. (2012)10 / III / 1090 / Motesanib 125 mg + CP / 60 / 4.1 / 5.6 / 533 / (21) / Venous thrombosis / 5
Placebo + CP / 60 / 4.1 / 5.4 / 539 / (22) / Venous thrombosis
Scagliotti et al. (2012)11 / III / 960 / Sunitinib 37.5 mg + erlotinib / 61 / 12 weeks / 3.6 / 473 / (4) / Thrombosis/embolism / 5
Placebo + erlotinib / 61 / 12 weeks / 2.0 / 477 / (3) / Thrombosis/embolism
Groen et al. (2013)12 / II / 132 / Sunitinib 37.5 mg + erlotinib / 59 / 58.5 days / 2.8 / 64 / (0) / - / 5
erlotinib / 61 / 84.0 days / 2.0 / 64 / (2) / Pulmonary embolism, deep vein thrombosis
Reck et al. (2014)13 / III / 1307 / Nintedanib 200 mg + TXT / 60 / 3.4 / 3.4 / 652 / (0) / - / 5
Placebo + TXT / 60 / 2.8 / 2.7 / 655 / (3) / Pulmonary embolism
Gridelli et al. (2014)14 / II / 124 / Vandetanib 100 mg + Gemcitabine / 75.03 / 78.5 days / 183 days / 61 / (3) / Pulmonary embolism / 3
Placebo + Gemcitabine / 75.48 / 91 days / 169 days / 63 / (3) / Pulmonary embolism
Laurie et al. (2014)15 / III / 306 / Cediranib 20 mg / 63 / 19.7 weeks / 5.5 / 151 / 11(11) / Venous thrombosis / 4
Placebo / 62 / 19.1 weeks / 5.5 / 153 / 10(10) / Venous thrombosis
Heist et al. (2014)16 / II / 130 / Sunitinib 37.5 mg + Pemetrexed / 63 / NR / 3.7 / 41 / (2) / Pulmonary embolism / 4
Sunitinib 37.5 mg / 63 / NR / 3.3 / 47 / (0) / -
Pemetrexed / 63 / NR / 4.9 / 42 / (0) / -
Breast cancer / Barrios et al. (2010)17 / III / 482 / Sunitinib 37.5 mg / 53 / 61 days / 2.8 / 238 / (1) / Pulmonary embolism / 3
Capecitabine / 53 / 61 days / 4.2 / 240 / (0) / -
Rugo et al. (2011)18 / II / 168 / Axitinib + TXT / 55 / NR / 8.1 / 111 / 3(2) / Deep vein thrombosis, Pulmonary embolism / 5
Placebo + TXT / 56 / NR / 7.1 / 56 / 0(0) / -
Bergh et al. (2012)19 / III / 593 / Sunitinib 37.5 mg + TXT / 54 / 26 weeks / 8.6 / 296 / (1) / Severe pulmonary embolism / 5
TXT / 56 / 18 weeks / 8.3 / 297 / (0) / -
Johnston et al. (2013)20 / II / 150 / Pazopanib 400 mg + Lapatinib / 50 / NR / NR / 76 / (1) / Thromboembolism / 4
Lapatinib / 54 / NR / NR / 73 / (0) / -
HCC / Abou-Alfa et al. (2010)21 / II / 96 / Sorafenib 400mg + doxorubicin / 66 / 119.7 days / 6 / 47 / (0) / - / 5
Placebo + doxorubicin / 65 / 56.7 days / 2.7 / 49 / (1) / Thrombosis, thrombus, or embolism
Llovet et al. (2013)22 / III / 395 / Brivanib 800mg + BSC / 64 / 3.1 / 4.2 / 261 / 3 / Venous thromboembolism / 5
Placebo + BSC / 62 / 2.5 / 2.7 / 131 / 5 / Venous thromboembolism
RCC / Haas et al. (2016)23 / III / 1943 / Sunitinib 50mg / 56 / 48 weeks / NR / 625 / (5) / Thrombosis/thrombus/embolism / 5
Sorafenib 400mg / 55 / 48 weeks / NR / 628 / (8) / Thrombosis/thrombus/embolism
Placebo / 57 / 54 weeks / NR / 626 / (5) / Thrombosis/thrombus/embolism
Thyroid cancer / Elisei et al. (2013)24 / III / 330 / Cabozantinib 140mg / 55 / 204 days / 11.2 / 214 / (5) / Pulmonary embolism / 3
Placebo / 55 / 105 days / 4 / 109 / (0) / -
Pancreatic cancer / Spano et al. (2008)25 / II / 103 / Axitinib 5mg +gemcitabine / 65 / 113 days / 4.2 / 68 / 7(6) / DVT/pulmonary embolism / 3
Gemcitabine / 61 / 4 cycles / 3.7 / 31 / 2(2) / DVT/pulmonary embolism
Kindler et al. (2011)26 / III / 632 / Axitinib 5mg + gemcitabine / 61 / 2.8 / 4.4 / 305 / (8) / Pulmonary embolism, Deep-vein thrombosis / 5
Placebo + gemcitabine / 62 / 2.3 / 4.4 / 308 / (15) / Pulmonary embolism, Deep-vein thrombosis
GonÇalveset al. (2012)27 / III / 104 / Sorafenib 200mg + Gemcitabine / 61 / NR / 3.8 / 50 / 8(6) / Venous thrombosis, pulmonary embolism / 4
Placebo + Gemcitabine / 64 / NR / 5.7 / 52 / 6(6) / Pulmonary embolism
mCRC / Carrato et al. (2013)28 / III / 768 / Sunitinib 37.5 mg + FOLFIRI / 59 / NR / 7.8 / 384 / (16) / Deep vein thrombosis, subclavian vein thrombosis, thrombosis, venous thrombosis, pulmonary embolism / 3
Placebo + FOLFIRI / 58 / NR / 8.4 / 379 / (22) / Deep vein thrombosis, subclavian vein thrombosis, thrombosis, venous thrombosis, pulmonary embolism
Grothey et al. (2013)29 / III / 760 / Regorafenib 160 mg / 61 / 2.8 / 1.9 / 500 / (12) / thromboembolism / 5
Placebo / 61 / 1.8 / 1.7 / 253 / (4) / thromboembolism
Ovarian cancer / Pignata et al. (2015)30 / II / 74 / Pazopanib 800mg + paclitaxel / 56 / NR / 6.35 / 37 / 1(1) / Thromboembolic event / 4
Paclitaxel / 58 / NR / 3.49 / 36 / 2(1) / Thromboembolic event
R/M HNSCC / Gilbert et al. (2015)31 / II / 55 / Sorafenib 400mg + cetuximab / 28 / 65.1 days / 3.2 / 28 / (1) / Thromboembolic event / 3
Cetuximab / 27 / 86.1 days / 3 / 27 / (0) / -
Prostate cancer / Horti et al. (2009)32 / II / 86 / Vandetanib 100mg + DP / 67 / NR / NR / 43 / (2) / Pulmonary embolism / 5
Placebo + DP / 67 / NR / NR / 43 / (1) / Pulmonary embolism
Ward et al. (2011)33 / II / 37 / Pazopanib 800mg / NR / NR / NR / 18 / (1) / Pulmonary embolism / 3
observation / NR / NR / NR / 19 / (0) / -
Michaelson et al. (2014)34 / III / 873 / Sunitinib 37.5 mg + Prednisone / 69 / 98 days / 5.6 / 581 / (13) / Pulmonary embolism / 5
Placebo + Prednisone / 68 / 97 days / 4.1 / 285 / (3) / Pulmonary embolism
STS / Winette et al. (2012)35 / III / 369 / Pazopanib 800mg / 56.7 / 16.4 weeks / 4.6 / 239 / 13 / Venous thromboembolic events / 5
Placebo / 51.9 / 8.1 weeks / 1.6 / 123 / 3 / Venous thromboembolic events
SCLC / Arnold et al. (2007)36 / II / 107 / Vandetanib 300mg / 56.9 / 7 weeks / 2.7 / 52 / 1 / thromboembolism / 5
Placebo / 62.4 / 12 weeks / 2.8 / 53 / 3 / thromboembolism
PNET / Raymond et al. (2011)37 / III / 171 / Sunitinib 37.5mg / 56 / 4.6 / 11.4 / 83 / (0) / - / 5
Placebo / 57 / 3.7 / 5.5 / 82 / (2) / Pulmonary embolism

TXT, docetaxel; NR, not reported; CP, paclitaxel plus carboplatin; GC, gemcitabine plus cisplatin; BSC, best supportive care; FOLFIRI, fluorouracil in combination with leucovorin and irinotecan; DP, docetaxel plus prednisolone; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; RCC, renal-cell carcinoma; mCRC, metastatic colorectal cancer; R/M HNSCC, recurrent and/or metastatic head and neck squamous cell carcinoma; STS, soft-tissue sarcoma; SCLC, small-cell lung cancer; PNET; pancreatic neuroendocrine tumors.

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Supplemental Table 4. Baseline characteristics of 22 trials included in the meta-analysis (ATE).

Underlying malignancies / Author/year / Phase / Patients enrolled / Treatment arm / Median age (years) / Median treatment duration (months/cycles) / Median PFS/TTF (months) / Number of patients for analysis / Number of ATEs All-grade(High-grade) / Reported events / Jadad score
NSCLC / Scagliotti et al. (2010)1 / III / 926 / Sorafenib 400 mg + CP / 62 / 16.6 weeks / 4.6 / 464 / (1) / Cardiac ischemia / 3
Placebo + CP / 63 / 17.9 weeks / 5.4 / 462 / (1) / Cardiac ischemia
Natale et al. (2011)2 / III / 1240 / Vandetanib 300 mg / 61 / 9.1 weeks / 2.6 / 623 / (0) / - / 3
Erlotinib / 61 / 8.6 weeks / 2.0 / 614 / (2) / Cerebrovascular accident
Scagliotti et al. (2012)3 / III / 1090 / Motesanib 125 mg + CP / 60 / 4.1 / 5.6 / 533 / (11) / arterial thrombosis/thromboembolism / 5
Placebo + CP / 60 / 4.1 / 5.4 / 539 / (5) / arterial thrombosis/thromboembolism
Groen et al. (2013)4 / II / 132 / Sunitinib 37.5mg + erlotinib / 59 / 58.5 days / 2.8 / 65 / (1) / Ischemia / 5
Placebo + erlotinib / 61 / 84.5 days / 2.0 / 67 / (0) / -
Paz-Ares et al. (2015)5 / III / 703 / Sorafenib 400 mg + BSC / 59 / 12 weeks / 2.8 / 346 / (3) / CNS ischemia, cardiac ischemia/infarction / 5
Placebo + BSC / 62 / 6.3 weeks / 1.4 / 351 / (0) / -
HCC / Llovet et al. (2008)6 / III / 602 / Sorafenib 400mg / 64.9 ± 11.2 / 5.3 / 5.5 / 297 / (9) / cardiac ischemia/infarction / 4
Placebo / 66.3 ± 10.2 / 4.3 / 2.8 / 302 / (3) / cardiac ischemia/infarction
Abou-Alfa et al. (2010)7 / II / 96 / Sorafenib 400 mg + doxorubicin / 66 / 119.7 days / 6 / 47 / (2) / cardiac ischemia or myocardial infarction / 5
Placebo + doxorubicin / 65 / 56.7 days / 2.7 / 49 / (0) / -
Llovet et al. (2013)8 / III / 395 / Brivanib 800mg + BSC / 64 / 3.1 / 4.2 / 261 / 5 / Arterial thromboembolism / 5
Placebo + BSC / 62 / 2.5 / 2.7 / 131 / 1 / Arterial thromboembolism
Bruix et al. (2015)9 / III / 1114 / Sorafenib 400mg / 58 / 12.5 / NR / 559 / (0) / - / 5
Placebo / 60 / 22.2 / NR / 548 / (1) / myocardial ischaemia
RCC / Escudier et al. (2007)10 / III / 903 / Sorafenib 400mg / 58 / 23 weeks / 5.5 / 451 / 12 / Cardiac ischemia or infarction / 5
Placebo / 59 / 12 weeks / 2.8 / 451 / 2
Sternberg et al. (2010)11 / III / 435 / Pazopanib 800mg / 59 / 7.4 / 9.2 / 290 / 9(1) / Myocardial infarction/ischemia, cerebrovascular accident, and transient ischemic attack / 5
Placebo / 60 / 3.8 / 4.2 / 145 / 0(0) / -
Haas et al. (2016)12 / III / 1943 / Sunitinib 50mg / 56 / 48 weeks / NR / 625 / (8) / Cardiac-ischemia, cerebrovascular ischemia / 5
Sorafenib 400mg / 55 / 48 weeks / NR / 628 / (7) / Cardiac-ischemia, cerebrovascular ischemia, peripheral arterial ischemia
Placebo / 57 / 54 weeks / NR / 626 / (9) / Cardiac-ischemia, cerebrovascular ischemia, peripheral arterial ischemia
Thyroid cancer / Brose et al. (2014)13 / III / 419 / Sorafenib 400mg / 63 / 10.6 / 10.8 / 207 / (1) / Myocardial infarction / 5
Placebo / 63 / 6.5 / 5.8 / 209 / (0) / -
Pancreatic cancer / Spano et al. (2008)14 / II / 103 / Axitinib 5mg +gemcitabine / 65 / 113 days / 4.2 / 68 / 5(5) / Arterial thromboembolism, intestinal ischaemia / 3
Gemcitabine / 61 / 4 cycles / 3.7 / 31 / 2(2) / Arterial thromboembolism, intestinal ischaemia
Kindler et al. (2011)15 / III / 632 / Axitinib 5mg + gemcitabine / 61 / 2.8 / 4.4 / 305 / (1) / Cerebrovascular accident / 5
Placebo + gemcitabine / 62 / 2.3 / 4.4 / 308 / (1) / Cerebrovascular accident
GonÇalves et al. (2012)16 / III / 104 / Sorafenib 200mg + Gemcitabine / 61 / NR / 3.8 / 50 / 2(2) / Cerebrovascular accident / 4
Placebo + Gemcitabine / 64 / NR / 5.7 / 52 / 2(0) / Cerebrovascular accident
Breast cancer / Gradishar et al. (2013)17 / II / 237 / Sorafenib 400mg + Paclitaxel / 50.6 / 6.44 / 6.9 / 115 / (1) / Myocardial infarction / 5
Placebo + Paclitaxel / 53.1 / 6.8 / 5.6 / 118 / (0) / -
Hyams et al. (2013)18 / II / 62 / Cediranib 45mg + fulvestrant / NR / NR / 7.4 / 31 / (1) / Intracardiac thrombus / 3
Placebo + fulvestrant / NR / NR / 3.7 / 31 / (0) / -
mCRC / Carrato et al. (2013)19 / III / 768 / Sunitinib 37.5 mg + FOLFIRI / 59 / NR / 7.8 / 384 / (1) / Myocardial ischemia / 3
Placebo + FOLFIRI / 58 / NR / 8.4 / 379 / (0) / -
Ovarian cancer / du Bios et al. (2014)20 / III / 940 / Pazopanib 800mg / 56 / 8.9 / 17.9 / 477 / (1) / Myocardial infarction / 5
Placebo / 57 / 11.7 / 12.3 / 461 / (0) / -
GIST / Demetri et al. (2012)21 / III / 361 / Sunitinib 50mg / 57 / 12 weeks / 22.9 weeks / 228 / (1) / Cerebral ischemia / 5
Placebo / 55 / 6 weeks / 6.0 weeks / 114 / (0) / -
AML / Serve et al. (2013)22 / III / 211 / Sorafenib 400mg / 67.5 / NR / 5 / 102 / (0) / - / 4
Placebo / 69 / NR / 7 / 95 / (1) / Myocardial infarction

NR, not reported; CP, paclitaxel plus carboplatin; BSC, best supportive care; FOLFIRI, fluorouracil in combination with leucovorin and irinotecan; DP, docetaxel plus prednisolone; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; RCC, renal-cell carcinoma; mCRC, metastatic colorectal cancer; GIST, gastrointestinal stromal tumor; AML, acute myeloid leukemia.

References

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