European Heart Journal Supplements (2020) 22 (Supplement C), C2–C14 The Heart of the Matter doi:10.1093/eurheartj/suaa004 Pharmacological cancer treatment and venous Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 thromboembolism risk Andre s J. Mun ~ oz Martín1*, Sara Pe  rez Ramírez1, Laura Ortega Mora n1, Magdalena Ruiz Zamorano2, María Carmen Vin ~ uela Bene  itez2, Inmaculada Aparicio Salcedo1, Ignacio García Escobar3, and  Manuel Soria Ferna Jose ndez4 1 Medical Oncology Department, Hospital General Universitario Gregorio Maran ~o n, Calle Doctor Esquerdo 46, 28007 Madrid, Spain; 2 Department of Medicine, Faculty of Medicine, Universidad Complutense, Av. Se neca 2, 28040 Madrid, Spain; 3 Medical Oncology Department, Hospital General Universitario de Ciudad Real, Calle Obispo Rafael Torija s/n, 13005 Ciudad Real, Spain; and 4  Sant Pau (IIB-SANT PAU), Joan Alcover, 7–2 2a, 08031 Genomic of Complex Disease Unit, Institut dinvestigacio Barcelona, Spain KEYWORDS Risk factors for cancer-associated thrombosis are commonly divided into three catego- Venous thromboembolism; ries: patient-, cancer-, and treatment-related factors. Currently, different types of Arterial thromboembolism; drugs are used in cancer treatment. Chemotherapy has been identified as an indepen- Cancer; dent risk factor for venous thromboembolism (VTE). However, it should be noted, that Chemotherapy; the risk of VTE is not consistent among all cytotoxic agents. In addition, different sup- Targeted therapy; portive care drugs, such as erythropoiesis stimulating agents or granulocyte colony Hormonotherapy; stimulating factors, and hormonotherapy have been associated to an increased risk of Immunotherapy; Supportive care VTE. Immunotherapy and molecular-targeted therapies have significantly changed the treatment of cancer over the past decade. The main subtypes include tyrosine-kinase inhibitors, monoclonal antibodies, small molecules, and immunomodulatory agents. The relationship between VTE and targeted therapies remains largely unknown. PALABRAS CLAVE Los factores de riesgo para la trombosis asociada al ca ncer se suelen dividir en tres tromboembolia venosa; categorías: factores relacionados con el paciente, con el ca ncer y con el trata- tromboembolia arterial; miento. En la actualidad, existen distintos tipos de farmacos que se emplean en el ncer; ca tratamiento del ca ncer. La quimioterapia se ha determinado como un factor de quimioterapia; riesgo independiente para el desarrollo de la tromboembolia venosa (TEV). No tratamiento dirigido; obstante, cabe destacar que el riesgo de padecer TEV no es coherente entre los hormonoterapia; agentes citotoxicos. Por otra parte, distintos fa rmacos de tratamiento paliativo, inmunoterapia; tratamiento paliativo; como los agentes estimulantes de la eritropoyesis o factores estimulantes de colonias de granulocitos, se han asociado a un aumento del riesgo de TEV. La inmunoterapia y los tratamientos dirigidos a dianas moleculares han supuesto un cambio significativo en el tratamiento del ca ncer en la ultima decada. En los principales subtipos se incluyen los inhibidores de las tirosina-cinasas, anticuerpos monoclonales, fa rmacos tradicionales y agentes inmunomoduladores. La relacio n entre la TEV y los trata- mientos dirigidos sigue siendo en gran medida desconocida.  Corresponding author. Tel: þ 34-914269394, Fax: þ 34-915737985, Email: andresmunmar@hotmail.com; ajmunoz.hgugm@salud.madrid.org Published on behalf of the European Society of Cardiology. # The Author(s) 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Cancer treatment and VTE risk C3 关键词 静脉血栓栓塞; 癌症相关性血栓形成的风险因素通常分为三类：患者相关、癌症相关和治疗相关因素。 动脉血栓栓塞; 当前, 用于治疗癌症的药物多种多样。化学疗法已确定为静脉血栓栓塞 (VTE) 的独立风 癌症; 险因素。但必须注意, 各种细胞毒性药物产生 VTE 的风险并不一致。另外, 不同的支持 化学疗法; 靶向治疗; 性护理药物（如促红细胞生成刺激剂或粒细胞集落刺激因子）以及激素疗法可增加 VTE 激素疗法; 风险。在过去的十年中, 免疫疗法和分子靶向疗法已大大改变了癌症的治疗方法。主要 免疫疗法; 亚型包括酪氨酸激酶抑制剂、单克隆抗体、小分子和免疫调节剂。VTE 和靶向疗法之间 支持性护理 的关系在很大程度上仍然未知 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 (symptomatic vs. incidental), prognosis, and possible rela- Introduction tionship with other supportive treatments. Mandala  et al.5 analysed a total of 28 randomized controlled clinical trials The close relationship between cancer and venous throm- on first-line chemotherapy in advanced colorectal cancer to boembolism (VTE) has been known for more than a cen- retrieve the reported VTEs. Overall, only 17.8% of clinical tury.1,2 Risk factors for cancer-associated thrombosis are trials reported this type of toxicity despite most studies had commonly divided into three categories: patient-, treat- been published in important medical journals after the in- ment-, and cancer-related factors. Chemotherapy has been clusion of VTE as a non-haematological adverse event in the identified as an independent risk factor for VTE. Data sug- US National Cancer Institute Common Toxicity Criteria gest that chemotherapy is associated with a six-fold in- Guidelines (CTCAE). In three out of the five clinical trials crease in the risk of VTE, reaching an estimated annual that reported the occurrence of VTE events, the incidence incidence of over 10% in tumours with high thrombogenic remained below 1%, which is clearly underestimated. potential.3 However, the risk of VTE is not consistent among Furthermore, connecting each drug with a specific venous all cytotoxic agents, as not only marked differences may be thromboembolic risk may result challenging as many studies found among different types of drugs but also for drugs evaluate simultaneously different combinations of antineo- within the same therapeutic group.4 Molecular-targeted plastic agents. Moreover, the individual risk of each anti- therapies and immunotherapy have significantly changed cancer drug often overlaps with other well-known thrombo- the landscape of cancer treatment over the past decade. embolic risk factors, such as central-venous catheters, etc. The main subtypes include tyrosine-kinase inhibitors (TKI), monoclonal antibodies (moAb), small molecules, and immu- nomodulatory agents. The relationship between VTE and Antiangiogenic monoclonal antibodies targeted therapies remains largely unknown and, there- fore, no clear recommendation has been made regarding Concerns have arisen regarding the risk of VTE and ATE thromboprophylaxis. In the last decade, due to there is a with antiangiogenic moAb. To date, three of these anti- significant variation in VTE risk between individual cancer cancer drugs are available for their use in daily clinical patient, partially driven by cancer treatment, the main practice: bevacizumab, aflibercept, and ramucirumab. guidelines have recommended VTE risk assessment at diag- Bevacizumab was the first moAb targeting the vascular nosis and periodically throughout cancer evolution specially endothelial growth factor (VEGF) approved in cancer when starting new systemic antitumour therapy. patients. Initially, this drug was associated with and in- At present two questions arise for VTE and cancer therapy: creased risk of both VTE and ATE. Nonetheless, since the do all drugs share the same venous thromboembolic risk? approval of bevacizumab, at least five meta-analyses6–10 Should we draw a line between chemotherapy and other can- and several other randomized controlled trials have cer therapies as immunotherapy or targeted therapy regard- yielded new data that disprove this initial perception. In ing VTE risk? In the other hand, pharmacological treatments three meta-analyses6–8 conducted in patients with a wide for cancer affect risk of VTE not only directly but also acting variety of advanced solid tumours, bevacizumab did not in- over the cancer itself and possibly reducing tumour-induced crease the occurrence of VTE (Table 1). Conversely, a more risk of VTE when tumour response is achieved. recent study investigating the association between bevaci- Venous thromboembolism risk associated to cancer zumab and VTE in patients with castration-resistant pros- treatments ranging from chemotherapy to supportive care tate cancer (CRPC) reported a potential protective effect is reviewed below. of this drug on venous thromboembolic risk [occurrence of grade 3 VTE in bevacizumab plus chemotherapy vs. pla- cebo plus chemotherapy 4.4% and 7.1%, respectively with a Venous thromboembolism and clinical trials hazard ratio (HR) of 0.6, 95% confidence interval (CI): 0.35– 1.02; P ¼ 0.059]11 based on the tumour control benefit Some essential information about VTE in cancer patients re- resulting from bevacizumab therapy. On the other hand, ceiving chemotherapy is seldom reported in randomized bevacizumab was associated with a modest but significant clinical trials: incidence of cancer-related venous and arte- two-fold increase of ATE.6,9,10 The occurrence of ATE rial thromboembolism (ATE), information with respect events was associated with age and previous medical his- thrombosis location, the clinical significance of the event tory; however, bevacizumab was not formally C4 ~oz Martín et al. A.J. Mun Table 1 Bevacizumab-associated venous and arterial thromboembolic risk: meta-analyses of randomized controlled trials Meta-analysis Year Patients/number Tumour subtypes VTE risk of studies VTE Scappaticci et al.6 2007 1745/5 mBC, mCRC, NSCLC RR: 0.89, 95% CI: 0.66–1.20; P ¼ 0.44 Nalluri et al.7 2008 7956/15 mBC, mCRC, NSCLC, RCC, PC, MS RR: 1.33, 95% CI: 1.13–1.56; P ¼ 0.001 a RR: 1.10, 95% CI: 0.89–1.36; P ¼ NS Hurwitz et al.8 2011 6055/10 mBC, mCRC, NSCLC, RCC, PC, RR: 0.89, 95% CI: 0.66–1.20; P ¼ 0.44 Meta-analysis Year Patients/number Tumour subtypes ATE risk Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 of studies ATE Scappaticci et al.6 2007 1745/5 mBC, mCRC, NSCLC RR: 2.0, 95% CI: 1.05–3.75; P ¼ 0.031 Ranpura et al.9 2010 12 611/20 Advanced solid tumours RR: 1.44, 95% CI: 1.08–1.91; P ¼ 0.013 Schutz et al.10 2011 13 026/20 mBC, mCRC, NSCLC, RCC, PC, MS RR: 1.46, 95% CI: 1.11–1.93; P ¼ 0.007 mBC, metastatic breast cancer; mCRC, metastatic colorectal carcinoma; MS, mesothelioma; NS, not significant; NSCLC, non-small-cell lung cancer; PC, pancreatic cancer; RCC, renal cell carcinoma; RR, risk ratio. a Exposure-adjusted VTE RR. contraindicated in this subset of patients as clinical benefit 4996 patients from six different Phase 3 placebo-controlled was found to be consistent in all the subgroups examined clinical trials including different neoplasms (gastric/gas- including elderly patients and patients with previous ATE. tro-oesophageal junction, non-small-cell lung, and meta- Furthermore, no dose-effect relationship between bevaci- static colorectal cancers). Ramucirumab was not zumab and ATE was reported with a relative risk (RR) of associated to an increased risk of VTE all grades (RR: 0.7, 1.52 vs. 1.5 for bevacizumab at 2.5 and 5.0 mg/kg/week, 95% CI: 0.5–1.1) and Grade 3–4 VTE (RR: 0.7, 95% CI: 0.4– respectively.9 1.2). Similar results were described for ATE events, ATE all- Aflibercept is a recombinant fusion protein that binds to grade (RR: 0.8, 95% CI: 0.5–1.3) and Grade 3–4 ATE (RR: 0.9, circulating VEGFs thereby inhibiting the activity of VEGF-A, 95% CI: 0.5–1.7). VEGF-B, and placental growth factor. It is been approved for use in combination with FOLFIRI for metastatic colorec- tal cancer that is resistant to or has progressed following Non-antiangiogenic monoclonal antibodies treatment with an oxaliplatin-containing regimen. As pre- viously reported with bevacizumab, the addition of afliber- To date, no randomized controlled clinical trials have ex- cept to concurrent chemotherapy did not increase the risk plored the incidence of VTE or ATE in cancer patients of VTE (occurrence of Grade 3–4 VTE aflibercept 6.1% vs. treated with non-antiangiogenic moAb. Nonetheless, an placebo 6.4%, RR: 0.95, 95% CI, 0.71–1.28).12 Even though important number of these targeted drugs have been re- aflibercept displays a stronger inhibition of the VEGF path- cently approved for the treatment of different neoplasms. way, the incidence of VTE remains similar to patients The anti-epidermal growth factor receptor (EGFR) treated with bevacizumab. Several studies13 have reported agents cetuximab and panitumumab are associated with a a trend towards an increased risk of ATE. Most events significant increase in the risk of VTE in patients with ad- peaked in early treatment cycles and decreased sharply vanced solid tumours specially in colorectal and head and following initial presentation.14 In a meta-analysis of anti- neck malignancies.20 In a meta-analysis including 13 stud- VEGF class adverse events, the ATE incidence was low and ies, the RR of VTE in patients assigned to anti-EGFR agents a non-significant difference of ATE was observed (afliberc- (cetuximab and panitumumab) vs. controls was 1.32 (95% pet 1.7% vs. placebo 1.0%; RR: 1.69, 95% CI, 0.85–3.34).12 CI: 1.07–1.63; P ¼ 0.01) suggesting a 32% higher risk of de- Ramucirumab is a fully humanized monoclonal antibody veloping VTE with anti-EGFR agents compared with con- of the IgG1 class that binds to the vascular endothelial trols. Most of the events were classified as high grade growth factor receptor-2 (VEGFR-2) thus preventing the according CTCAE with a RR of 1.36 in grade 3–4 events. binding of the VEGF ligand. Once more, this drug did not in- Additionally, five randomized Phase II and III clinical trials crease the risk of VTE.15–18 It is worth noting that in all four were available to calculate the risk of ATE resulting in a studies, the incidence of VTE was lower in the ramuciru- non-significant RR of 1.34 (95% CI: 0.94–1.9; P ¼ 0.11) in mab treatment arm (Table 2). The risk of ATE was uneven the anti-EGFR vs. the control arm. It should be highlighted among the main clinical trials with no significant increase that the risk of VTE increases when anti-EGFR agents are of grade 3 events reported (Table 2). A meta-analysis of combined with irinotecan- or cisplatin-based chemother- individual patient was presented in the European Society apy and in patients with clinically advanced malignancies of Medical Oncology (ESMO) Congress 2017.19 It analysed vs. those with complete tumour resection.21,22 Cancer treatment and VTE risk C5 Table 2 Randomized, controlled trials on venous and arterial thromboembolic risk associated with ramucirumab Randomized controlled trials Regimen (N) VTE (any grade) VTE (grade  3) VTE REGARD (2nd line GADC, EGJ-ADC), Fuchs et al.15 RM (236) 4% 1% Placebo (115) 7% 4% RAIBOW (2nd line GADC, EGJ-ADC), Wilke et al.18 RM þ paclitaxel (327) 4% 2.4% placebo þ paclitaxel (329) 5.5% 3.3% REVEL (2nd line NSCLC), Garon et al.16 RM þ Docetaxel (627) 3% 2% Placebo þ Docetaxel (618) 6% 3% Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 ROSE/TRIO-12 (1st line mBC), Mackey et al.17 RM þ Docetaxel (752) 2.4% 1.3% Placebo þ Docetaxel (382) 4.2% 2.1% Randomized controlled trials Regimen (N) ATE (any grade) ATE (grade  3) ATE REGARD (2nd line GADC, EGJ-ADC), Fuchs et al.15 RM (236) 2% 1% Placebo (115) 0% 0% RAIBOW (2nd line GADC, EGJ-ADC), Wilke et al.18 RM þ paclitaxel (327) 1.5% 0.9% placebo þ paclitaxel (329) 1.8% 0.9% REVEL (2nd line NSCLC), Garon et al.16 RM þ Docetaxel (627) 2% 1% Placebo þ Docetaxel (618) 2% 1% ROSE/TRIO-12 (1st line mBC), Mackey et al.17 RM þ Docetaxel (752) 1.1% 0.7% Placebo þ Docetaxel (382) 1.3% 0.3% ATE, arterial thromboembolism; EGJ-ADC, oesophago-gastric junction adenocarcinomas; GADC, gastric adenocarcinomas; mBC, metastatic breast cancer; N, number of patients; NSCLC, non-small-cell lung cancer; RM, ramucirumab; VTE, venous thromboembolism.  P < 0.05. Necitumumab is a recombinant human IgG1 monoclonal an- Furthermore, no differences were noted after stratified tibody that is designed to block the ligand-binding site of analysis for the underlying malignancy, age or trial design. EGFR. Necitumumab, in combination with gemcitabine and A second meta-analysis26 found that the use of VEGFR TKIs cisplatin, is approved for the firstline treatment of patients did not significantly increase this risk when compared to with metastatic squamous non small-cell lung cancer controls (RR: 0.912, 95% CI: 0.617–1.348; P ¼ 0.643) and (NSCLC) and it is the first biologic approved in this tumour reported a 3% global incidence of VTE. Once more, no dif- subtype. Necitumumab plus chemotherapy was associated ferences were observed in subgroup analyses based on the with increased VTE risk compared to chemotherapy alone VEGRF TKI agent administered or based on tumour type. To in the two randomized Phase III studies, SQUIRE trial (RR: sum up, according to both meta-analyses, TKIs did not in- 1.699, 95% CI 1.09–2.65) and INSPIRE trial (RR: 1.58, 95% CI crease significantly venous thromboembolic risk in can- 0.99–2.52).23,24 cer patients. The clinical use of anti-epidermal growth factor A meta-analysis including more than 10 255 patients se- receptor-2 (HER2) moAb (trastuzumab, pertuzumab, and lected from Phase II and III trials was conducted to deter- TDM-1) in breast and gastric cancer treatment does not in- mine the risk of ATE.27 The incidence of ATE associated crease the risk of VTE. Neither do the different classes of with the use of sunitinib and sorafenib was 1.4%, (95% CI: antibodies approved for the treatment of haematological 1.2–1.6%) with a RR of ATE compared with controls of 3.03 malignancies, such as rituximab, alentuzumab, and the (95% CI: 1.25–7.37%). No noticeable differences were found conjugate 90Y-ibritumomab tiuxetan. regarding tumour type. In another meta-analysis28 includ- ing 9711 patients from 19 randomized clinical trials, the reported incidence of ATE was 1.5% (95% CI: 1.0–2.3%). Vascular endothelial growth factor receptor Treatment with VEGFR TKIs significantly increased the risk tyrosine-kinase inhibitors of developing ATE when compared with controls [odds ratio (OR): 2.26, 95% CI: 1.38–3.68; P ¼ 0.001]. The most com- Several multitargeted VEGFR TKI agents have been ap- mon event reported for ATE was cardiac ischaemia (67.4%). proved for the treatment of solid tumours including suniti- In subgroup analyses, the OR was not significantly influ- nib, sorafenib, pazopanib, vandetanib, and axitinib. enced by the underlying malignancy, VEGFR TKI agent ad- A meta-analysis25 comprising 17 different Phase II and III ministered, treatment regimen, or trial phase. In summary, clinical trials and involving a total of 7441 patients both meta-analyses noted a significant increase of ATE reported no significant overall increase in the risk of VTE though the incidence rate remained below 2%. with VEGFR TKIs. The RR of all grade and high-grade VTE A most recent study analysing arterial thromboembolic for TKIs vs. no TKIs was 1.10 (95% CI: 0.73–1.66; P ¼ 0.64) risk and cardiovascular toxicity from the use of either suni- and 0.85 (95% CI: 0.58–1.25; P ¼ 0.41), respectively. tinib or sorafenib was published in October 2015.29 Using C6 ~oz Martín et al. A.J. Mun the Surveillance, Epidemiology and End Results (SEER) can- cancer, pancreatic neuroendocrine tumours, and RCC. An cer registries, the study analysed 670 patients who were at increased procoagulant state has been described in renal least 66 years old, diagnosed with renal cell carcinoma transplant recipients receiving immunosuppressive therapy (RCC) and treated with either sunitinib or sorafenib from with everolimus. The impairment of fibrinolysis, thrombin 2000 to 2009. Congestive heart failure, cardiomyopathy activation, and increased endothelial cell reactivity are (CHF/CM), acute myocardial infarction (AMI), stroke, and deemed responsible for this increased thrombotic risk.41 In cardiovascular deaths were considered possible cardiovas- the Phase III trial BOLERO-2,42 in which women with cular adverse events. A total of 171 cardiovascular events hormone-receptor-positive, HER2 negative advanced were registered among patients who received either suniti- breast cancer received everolimus in combination with nib or sorafenib, which represents an overall incidence of exemestane vs. exemestane alone, no increase of TEs was 25.5%. The incidence rates for CHF/CM, AMI and stroke noted (no Grade 3–4 TEs reported). Similarly, no Grade 3–4 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 were 0.87, 0.14, and 0.14 per 1000 person-days, respec- TEs were described in the RADIANT-3 study,43 a Phase III tively. These results were compared to those obtained double-blind clinical trial, conducted to determine from 788 patients diagnosed with RCC between 2000 and whether everolimus, as compared with placebo, would 2009 who did not receive TKIs. After adjustments for base- prolong progression-free survival among patients with ad- line characteristics, the risk of any cardiovascular event vanced pancreatic neuroendocrine tumours. Finally, no in- among those who received sunitinib or sorafenib was higher crease in venous or arterial thromboembolic risk was noted than the risk for the comparison group with an HR of 1.38 in the RECORD-144 clinical trial of everolimus for meta- (95% CI: 1.02–1.87%). The study concluded that the clinical static RCC. Considering these findings, it can be concluded use of VEGFR-TKIs in the elderly increased the risk of car- that treatment with everolimus does not increase the risk diovascular events. of TEs in patients with different types of ad- vanced neoplasms. Palbociclib is an inhibitor of cyclin-dependent kinases Non-antiangiogenic tyrosine-kinase (CDK) 4 and 6 that blocks cell progression from the G1 into inhibitors and new molecules the S phase of the cell cycle. This drug is indicated for use in combination with letrozole for first-line treatment of Erlotinib and gefitinib are EGFR TKIs approved for the postmenopausal women with oestrogen receptor positive, treatment of lung and pancreatic cancer. At least one HER2 negative metastatic breast cancer. In Phase II meta-analysis has explored the risk of thrombotic events PALOMA-1/TRIO-18 trial,45 which granted accelerated ap- (TEs) with anti-EGFR drugs, showing that, overall, they do proval of palbociclib, a higher incidence of PE was observed not significantly increase the risk of VTE (RR: 1.16, 95% CI: in patients who received this drug compared with those 0.61–2.18%; P ¼ 0.65) or ATE (RR: 1.34, 95% CI: 0.94–1.9%; treated with placebo (5% vs. 0%). On the other hand, in the P ¼ 0.11) in contrast to the data presented previously with Phase III PALOMA-3 trial46 of palbociclib and fulvestrant vs. EGFR moAb.20 palbociclib alone after progression on endocrine therapy, Afatinib is another TKI that irreversible binds to ErbB the incidence of TEs in women allocated to combination family receptors and is indicated in patients with meta- therapy was 2% in contrast to 0% among patients receiving static NSCLC with EGFR mutations. No increase in the risk monotherapy. The PALOMA-2 randomized trial showed sim- of TEs have been noted in any of the studies conducted ilar results with a VTE incidence of 0.9% in the palbociclib- with this agent (estimated incidence rate < 1%).30,31 letrozole arm vs. 1.4% in the placebo-letrozole arm.47 Two Crizotinib is a selective TKI of ALK, MET, and its onco- other CDK inhibitors have been approved by Food and Drug genic variants (ALK fusion events and selective ALK mu- Administration (FDA), ribociclib, and abemaciclib. The tated). It has been approved in patients with ALK-positive MONARCH-2 trial48 described an increased VTE incidence metastatic NSCLC. Recent studies have reported a higher of VTE for the combination of abemaciclib plus fulvestrant risk of TEs in ALK-positive lung adenocarcinomas than in compared to placebo plus fulvestrant (5.0% vs. 0.9%). In other lung cancer subtypes (EGFR and KRAS mutated).32–34 the MONARCH-3 trial,49 similar findings were observed with In the two articles published in the New England Journal of an increased rate of VTE related to abemaciclib [abemaci- Medicine (NEJM) regarding the use of crizotinib in first35 clib-non-steroidal aromatase inhibitor (AI) 4.9% vs. pla- and second36 line treatments, no significant increase in the cebo-non-steroidal AI 0.6%]. In addition, two deaths were risk of venous or arterial TEs was highlighted. Nonetheless, related to VTE events in the abemaciclib arm and no deaths and according to the data compiled in the appendix of both were considered attributable to VTE in the placebo arm. studies, while the overall incidence of pulmonary embolism Finally, the MONALEESA study50 reported a similar inci- (PE) was higher among patients receiving second-line dence of VTE with ribociclib-letrozole compared to treatment with crizotinib compared to those with chemo- placebo-letrozole (0.6% vs. 0%). Considering all these therapy (5% vs. 2%),36 the opposite was observed in the results together, some authors have suggested VTE could first-line setting where PE was reported in 6% of the be considered a class effect of CDK inhibition. However, patients receiving crizotinib and in 7% of the patients man- the physiopathology of VTE observed in patients treated aged with chemotherapy.35 with CDK inhibitors and the differences in VTE rates de- No evident relationship has been established between scribed among different drugs cannot be explained with imatinib,37,38 lapatinib,39,40 and VTE/ATE. Everolimus is a the current data. Several Phase II and III clinical trials are selective inhibitor of the mammalian target of rapamycin evaluating the combination of abemaciclib or palbociclib with recognized antitumour activity in advanced breast plus tamoxifen in premenopausal women (NCT02747004 Cancer treatment and VTE risk C7 and NCT02668666), these combinations should be assessed PROTECHT score57 (PROphylaxis of ThromboEmbolism dur- carefully regarding the VTE risk. ing ChemoTherapy) is a modified Khorana risk assessment So far, no increase in TEs has been reported with BRAF score that adds platinum or gemcitabine-based chemother- and MEK inhibitors in monotherapy (dabrafenib,51 vemura- apy to the predictive values already included in the fenib,52 and trametinib53) in single clinical trials. However, Khorana score. Therefore, in the Protecht predictive score, a recent systematic review and meta-analysis published in treatment with cisplatin, carboplatin, or gemcitabine adds August 2019 described a significant increase in the risk of one point and the combination of the previous drugs two PE in melanoma patients treated with the combination of points to the Khorana score.58 This modified risk assess- BRAF and MEK inhibitors compared to BRAF inhibitors ment score may improve the ability to identify patients at monotherapy (RR: 4.36, 95% CI: 1.23–15.44; P ¼ 0.02). Five high risk for VTE however it has not been validated. randomized clinical trials including 2317 patients, that re- Carboplatin is an analogue of cisplatin with similar bio- Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 ceived vemurafenib, dabrafenib, encorafenib, trametinib, chemical properties. Even though several studies have binimetinib, and cobinimetinib, were analysed. The risk of reported a significant increase of venous thromboembolic PE was higher for patients with a mean follow-up time lon- risk in patients receiving carboplatin-based chemotherapy, ger than 15 months (RR: 7.70, 95% CI: 1.40–42.12; the rates of TEs seem to be higher with cisplatin.59 P ¼ 0.02). The mechanism of PE caused by this combination Oxaliplatin belongs to a new class of platinum com- is not completed understood. The authors suggest the inhi- pounds with a central atom of platinum surrounded by the bition of the nitric oxide pathway as the main hypothesis of group 1,2-diaminocyclohexane and a ligand represented by PE occurrence. bidentate oxalate. It is one of the main drugs used for the treatment of gastrointestinal tumours. The global inci- dence of oxaliplatin associated VTE is around 2%.60,61 In the Classic cytostatic agents PROTECHT study, oxaliplatin had the lowest incidence of VTE compared with cisplatin and carboplatin (incidence of Chemotherapy has been identified as an independent risk thrombosis: cisplatin 7%, carboplatin 5.5%, and oxaliplatin factor for TEs in cancer patients.54 Although the mecha- 1.1%, respectively).59 A clinical trial conducted in patients nisms underlying the procoagulant effect are not fully un- with advanced gastro-oesophageal cancer demonstrated a derstood, a prominent role can be attributed to different thrombotic risk according to the platinum com- endothelial damage. Data suggest that chemotherapy is as- pound used. Significantly fewer TEs were reported with sociated with a six-fold increase in TEs.3 However, it should oxaliplatin compared with cisplatin (7.6% vs. 15.1%; be noted that the risk of VTE is not consistent among all cy- P ¼ 0.0003). Similar results were observed in VTE (6.5% vs. tostatic agents, as not only marked differences may be 12.2%; P ¼ 0.002) and ATE (2.9% vs. 1.1; P ¼ 0.044). After found between different types of drugs but also among adjustments for potential risk factors, this difference drugs within the same category. Among chemotherapeutic remained highly significant in the multivariate analysis (HR agents, cisplatin has been associated with the highest risk 0.51; P ¼ 0.001).4 of TEs. Cisplatin is classified as an alkylating agent and was Several chemotherapeutic agents of different therapeu- the first of the so-called platinum salts approved for cancer tic groups have been associated with an increase in VTE. treatment in 1970. From a physiopathological point of view, cisplatin can induce endothelial damage and platelet • In a retrospective study performed in patients with activation. In addition, renal impairment has been pro- advanced solid malignancies, TEs occurred in 7.3% of posed as a surrogate marker of the endothelial injury the patients treated with fluorouracil. The risk was prompted by this drug. Numerous case series and many ret- higher when chemotherapy was administered as a con- rospective studies have provided evidence of the thrombo- tinuous infusion.62 genic potential of this cytostatic agent. In a recent • Another retrospective study conducted at Memorial retrospective study conducted by Moore et al.55 In 47 clini- Sloan Kettering Cancer Center including more than cal trials, which included 932 patients with solid malignan- 2000 patients with metastatic non-haematological ma- cies treated with cisplatin-based chemotherapy, 18% of lignancies treated with systemic therapy, identified patients experienced a TE event and most of these events irinotecan as an independent risk factor for VTE (HR: (88%) occurred within the first 3 months of starting cis- 1.89, 95% CI: 1.29–3.59%; P ¼ 0.05).63 In addition, platin. Hence, ambulatory thromboprophylaxis should be irinotecan-based chemotherapy used in colorectal considered for patients with low-bleeding risk who receive cancer treatment has been associated with fatal vas- cisplatin-based chemotherapy. Other meta-analyses have cular thromboembolic events.64 focused on evaluating the incidence and risks of TEs associ- • The relationship between gemcitabine and thrombosis ated with cisplatin-based chemotherapy. In this regard, risk has been pointed out in multiple case reports, the meta-analysis published in 2012 by Seng et al.56 case series, and small studies. To our knowledge, the revealed that patients receiving cisplatin-based chemo- study that best examines the specific contribution of therapy had a 1.67-fold increased likelihood of experienc- gemcitabine to the development of venous and arte- ing a TEs (95% CI: 1.25–2.33%, P ¼ 0.01) with the highest rial TEs is a meta-analysis published in 2013 including risk observed in patients receiving weekly doses of cisplatin a total of 4845 patients from 19 randomized clinical >30 mg/m2. Recently and for the first time, risk assess- trials (eight Phase II studies and 11 Phase III studies). ment scores for VTE in cancer patients are considering the The incidence of venous and arterial TEs in patients specific value of individual chemotherapeutic agents. The receiving gemcitabine was 2.1% and 2.2%, C8 ~oz Martín et al. A.J. Mun respectively. Moreover, the ORs of gemcitabine associ- Several meta-analyses82–86 have examined the benefits ated VTE and ATE were 1.56 (95% CI: 0.86–2.83; P ¼ and risks of ESAs. Overall, all studies reported an increase 0.15) and 1.82 (95% CI: 0.89–3.75; P ¼ 0.10), respec- in the risk of thrombosis close to 50%. They also communi- tively. This study was the first to demonstrate that the cated negative data regarding mortality. These cases use of gemcitabine tends to increase the risk of seemed to be restricted to patients not receiving chemo- thrombosis.65 The incidence of Grade 3–4 TEs in a therapy. For this reason, ESAs are not recommended in this study that examined the combination of carboplatin, clinical setting (Table 3). gemcitabine, and bevacizumab in the treatment of Although no direct comparative data exist regarding the advanced and irresectable or metastatic urothelial risk of thrombosis between different ESAs, a similar risk tumours was 20%.66 among all erythropoietin agents has been suggested.86 • Anthracyclines: a retrospective study that included The risk of experiencing TEs in patients receiving ESAs Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 >400 newly referred lymphoma patients considered increases according to baseline haemoglobin levels (for anthracycline-based chemotherapy as a significant in- haemoglobin < 10 g/dL, RR: 1.41, 95% CI: 1.06–1.99; for dependent risk factor for VTE (OR: 3.47, P ¼ 0.003).67 haemoglobin 10–12 g/d, RR: 1.64, 95% CI: 1.33–2.03; for In breast cancer patients, a 6% incidence rate of TEs haemoglobin > 12 g/dL, RR: 1.41, 95% CI: 1.15–1.80). has been reported with anthracycline-based regimens Current recommendations proposed by the National in the adjuvant setting,68 TEs have also been related Comprehensive Cancer Network (NCCN),87 European to the clinical use of liposomal anthraciclines69,70 and Organization for Research and Treatment of Cancer epirrubicin71 (oesophago-gastric cancer). (EORTC),88 ASCO/ASH,81 ESMO,89 and Sociedad Espan ~ola de • Other cytostatic drugs that increase VTE risk Oncología Me dica90 on how to use ESAs suggest a haemoglo- are cyclophosphamide,72 mitomycin-c,73–75 and bin target around 12 g/dL and avoid ESAs in patients not re- methotrexate.76 ceiving chemotherapy. Leaving aside the common risks arising from the use of Occasional venous TEs have been notified with docetaxel ESAs in cancer patients, it has been noted that treatment and paclitaxel.77 A wide range of chemotherapeutic agents with darbepoetin alfa in patients with chronic renal failure used in the treatment of different types of neoplasms have and anaemia increases the risk of cerebrovascular acci- not been associated with an increase in the risk of VTE. dents (HR: 1.92, 95% CI: 1.38–2.68). Among them pemetrexed, raltitrexed, bleomycin, temozo- Despite the clear relationship that has been established lomide, and vinca alkaloids must be pointed out. No clear between ESAs and thrombosis in cancer patients, no conclusion has been established with novel cytostatic randomized clinical trial has yet evaluated the possible agents such as nab-paclitaxel, but data suggest that the role of thromboprophylaxis in this context. To date, sys- use of this agent does not significantly increase the risk temic prophylaxis with low-molecular-weight heparins or of TEs.78 anti-platelet drugs (acetylsalicylic acid) is not generally recommended. However, it should be advised in those Palliative and supportive care cases with low bleeding risk in which a considerable num- ber of risk factors for thrombosis converge. Blood transfusions Anaemia is a frequent finding in cancer patients attributed to the underlying malignancy and exacerbated by myelo- Granulocyte colony stimulating factors (G-CSF) toxic chemotherapy. Though blood transfusions offer a The use of G-CSF has been associated with an increase in rapid increase in haemoglobin levels, they are, however, the risk of VTE in patients with solid tumours (HR: 1.69, not devoid of risks which include infection, transfusion- 95% CI: 1.09–2.64; P ¼ 0.02).63 related reactions, fluid overload, and alloimmunization among others.79 Besides the aforementioned, transfusions Corticosteroids are associated with increased risk of VTE (OR: 1.60, 95% CI: Corticosteroid treatment increases the risk of VTE.91 A pro- 1.53–1.67) and ATE (OR: 1.53, 95% CI: 1.46–1.61) in hospi- spective observational cohort study conducted in the UK talized cancer patients.80 found a significant and independent increased risk of VTE and PE among oral corticosteroids users similar to that de- Erythropoiesis stimulating agents (ESAs) scribed with other commonly known risk factors such as ESAs represent an alternative to blood transfusions when oral contraceptives, obesity, surgery, varicose veins, etc.91 there is no urgent need in rising haemoglobin levels. This risk increases with extended treatment duration and According to the American Society of Oncology (ASCO) and elevated doses. A case–control study remarked a 1.2 to 2- to the American Society of Hematology (ASH) guidelines, fold increase in venous thromboembolic risk in patients re- the higher the levels of haemoglobin, the higher the inci- ceiving systemic corticosteroid therapy for >3 months.92 dence of ESA-induced TEs.81 Therefore, in patients treated The magnitude of the association between corticosteroid with ESAs, the optimal target haemoglobin concentration use and VTE depended on the administration form. Hence, should be around 11 g/dL. Higher haemoglobin levels have the risk increased with cumulative doses so that it doubled been associated with a significant increase of VTE.81 Other with an equivalent dose of prednisolone of 1–2 g compared reasons different from haemoglobin levels that could ex- to doses below 10 mg. Also, patients who received cortico- plain the thrombotic potential of ESAs are endothelial acti- steroid treatment for the first time had a higher venous vation and increased platelet reactivity. thromboembolic risk (RR: 3.06, 95% CI: 2.77–3.38) than Cancer treatment and VTE risk C9 Table 3 Review of the main meta-analyses of safety of erythropoietin stimulating agents Author Year Studies included Global mortality Mortality in studies with Thrombotic risk chemotherapy Bohlius 2006 Cancer patients with/ HR: 1.08, 95% CI: 0.99–1.18; RR: 1.02, 95% CI: 0.90–1.15; RR: 1.67, 95% CI: 1.35–2.06; et al.82 without anaemia, with/ 42 studies, 8167 patients 30 studies, 6282 patients 35 studies, 6769 patients without chemotherapy receiving ESAs. Bennett 2008 Cancer patients receiving HR: 1.10, 95% CI: 1.01–1.2; RR: 1.57, 95% CI: 1.31–1.87; et al.83 chemotherapy and dar- 51 studies, 13 611 patients 31 studies, 8172 patients Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 bopoetin alfa Ludwig 2009 Cancer patients with che- HR: 0.97, 95% CI: 0.85–1.1; RR: 1.57, 95% CI: 1.10–2.26; et al.84 motherapy-induced 6 studies, 2211 patients 6 studies, 2122 patients anaemia treated with darbopoetin alfa Glaspy 2010 Cancer patients with/ HR: 1.16, 95% CI: 0.97–1.15; OR: 1.03, 95% CI: 0.93–1.13; RR: 1.48, 95% CI: 1.28–1.72; et al.85 without anaemia, with/ 60 studies, 15 323 patients 47 studies, 12 108 patients 44 studies, 13 196 patients without chemotherapy receiving ESAs. Tonia 2012 Cancer patients with/ HR: 1.17, 95% CI: 1.06–1.29; RR: 1.52, 95% CI: 1.34–1.74; et al.86 without anaemia, with/ 70 studies, 15 935 patients 57 studies, 15 498 patients without chemotherapy receiving ESAs. CI, confidence interval; ESAs, erythropoietin stimulating agents; HR, hazard ratio; OR, odds ratio; RR, relative risk. those under chronic therapy. These findings were indepen- a retrospective study from the UK described that therapy dent of potential confounding risk factors, such as the se- with AIs was not associated with VTE (HR: 0.8, 95% CI: 0.5– verity of the underlying disease or the risk of thrombosis 1.4; absolute rate 28.3 per 1000 person-years).98 Several secondary to the tumour itself. There is currently insuffi- studies have compared tamoxifen with AIs for breast can- cient literature pertaining to the risk of VTE associated cer treatment with similar results regarding to venous with corticosteroid therapy in patients with solid tumours thromboembolic risk but a lower incidence of venous TEs in to support thromboprophylaxis. the AIs treatment arms (Table 4).99–101 All these data were subsequently confirmed in a meta-analysis published in 2011 including seven studies and 30 023 women that com- Non-steroidal anti-inflammatory drugs pared AIs and tamoxifen as primary adjuvant endocrine There are no specific studies of non-steroidal anti- therapy in postmenopausal women.102 Longer duration of inflammatory drugs (NSAIDs) and thrombosis in cancer AI treatment was associated with a 45% decrease in the RR patients. The only available information is based on popu- decrease of VTE in women who received an AI compared to lation studies. Systematic review and meta-analysis93 were those treated with tamoxifen (RR: 0.55, 95% CI: 0.46–0.64; conducted in 2014 including studies that reported ORs, P < 0.001). A second meta-analysis published in 2013 con- RRs, HRs, or standardized incidence ratios for VTE among firmed the significantly lower risk of TEs conferred by AIs NSAIDs users compared with non-users. Six studies with compared to tamoxifen (OR 0.61, P < 0.001).103 21 401 VTE were identified. The pooled risk ratio of VTE in Fulvestrant is a pure antioestrogen approved in breast NSAIDs users was 1.80 (95% CI: 1.28–2.52). Furthermore, cancer treatment. The prospectively combined analysis the intake of COX-2 inhibitors was also responsible for an from studies 0020 and 0021104 compared fulvestrant with increased risk of VTE (RR: 1.99, 95% CI: 1.44–2.75). anastrozole in the treatment of postmenopausal women with advanced breast cancer who had disease progression Hormone therapy after receipt of previous endocrine treatment. The con- joint analysis of both studies showed that fulvestrant was Since the approval of tamoxifen by the US FDA multiple not significantly different to anastrozole in terms of VTE in- studies have concluded that tamoxifen therapy in breast cidence rate (anastrozole 4.5% vs. fulvestrant 3.5%, cancer patients is an independent risk factor for the devel- P ¼ 0.46). Taken together, these data suggested that ful- opment of VTE.94–97 Women treated with tamoxifen have a vestrant appeared to have a slightly lower risk of VTE that 1.5 to 7.1-fold increased risk of VTE compared to those tamoxifen in women with hormone dependant advanced treated with placebo or observation only.94 In addition, AIs breast cancer. are also associated to VTE although its incidence falls be- Recently two new drugs with antiandrogenic activity low that of tamoxifen. However, not all the published stud- have been approved for the treatment of CRPC: enzaluta- ies have confirmed this finding. An observational cohort in mide and abiraterone. C10 ~oz Martín et al. A.J. Mun Table 4 Incidence of venous thromboembolism related to aromatase inhibitors compared with tamoxifen Study Number of patients Drug VTE results ATAC99 9366 Anastrozole Anastrozole 2.8% vs. tamoxifen 4.5% RR: 0.61, 95% CI: 0.47–0.80; P ¼ 0.004 BIG 1–98100 8010 Letrozole Letrozole 1.5% vs. tamoxifen 3.5% P < 0.001 TEAM101 9779 Exemestane Exemestane 1% vs. Tamoxifen-exemestane 2% P < 0.0001 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 VTE, venous thromboembolism. • Abiraterone inhibits androgen synthesis by blocking • It would be desirable that clinical trials analysed in the enzyme cytochrome P450 17 alpha-hydroxylase more detail the occurrence, clinical characteristics, and (CYP 17). This enzyme plays a critical role in the syn- possible relationship of TEs with cancer treatments. thesis of androgens in the adrenal glands, testes, • VTE risk assessment scores should include variables re- and prostate. lated to pharmacological therapy. • Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor sig- nalling pathway. It has been shown to competitively Funding inhibit androgen binding to androgen receptors and in- hibit androgen receptor nuclear translocation. This paper was published as part of a supplement sup- None of the Phase III studies105–108 that led to the ap- ported by an educational grant from Boehringer Ingelheim. proval of these drugs explicitly mention an increase in the Conflict of interest: A.J.M.M.: Consulting or advisory role: VTE risk. Celgene, Sanofi, Pfizer-BMS, LEO Pharma, Daiichi Sankyo, Bayer, and Halozyme. Speakers Bureau: Rovi. Research funding: Sanofi and Immunotherapy LEO Pharma. Travel, accommodations, and expenses: Celgene, Roche, and Merck Serono. S.P.R. received funding from Sanofi for In the last decade, immune checkpoint inhibitors have writing the article. L.O.: Personal fees: Sanofi. Non-financial sup- port: Leo Pharma and Rovi. I.G.E.: advisory role Leo Pharma. And been approved for different tumours. To date, no evidence all other authors have no conflict of interest to declare. The in- coming from randomized clinical trials exists to prove the formed consent statement, and the research involving human par- relationship between VTE with anti-cytotoxic T-lympho- ticipants statement are not applicable as this is a review article. cyte-antigen-4 (CTLA4) agents (ipilimumab), anti- programmed death-1 (PD-1) agents (nivolumab and pem- References brolizumab), and anti-programmed death-ligand 1 (PD-L1) agents (atezolizumab, avelumab, and durvalumab). 1. Bouillaud S. De lobliteration des veines et de son influence sur la Recently, several clinical cases published have suggested formation des hydropisies partielles: consideration sur la hydro- that checkpoint inhibitors may induce systemic inflamma-  ne pisies passive et ge ral. Arch Gen Med 1823;1:188–204. 2. Trousseau A. Phlegmasia alba dolens. Clinique Medical de l'Hotel- tion as main toxicity, possibly resulting in development of Dieu de Paris, 2nd edn. Paris, France: The Sydenham Society; venous thromboembolism.109 Other authors have reported 1865. p654–712. ATE associated to anti-PD1 moAb.110 The proposed physio- 3. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, pathology is accelerated atherosclerotic plaque develop- Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmo- ment and inflammation in predisposed cancer patients. An nary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–815. interesting finding is that these events were observed in 4. Starling N, Rao S, Cunningham D, Iveson T, Nicolson M, Coxon F, patients with cancer response to anti-PD1 therapy. The Middleton G, Daniel F, Oates J, Norman AR. Thromboembolism in same authors have suggested it is likely these events could patients with advanced gastroesophageal cancer treated with have been underestimated in clinical trials and not linked anthracycline, platinum, and fluoropyrimidine combination che- motherapy: a report from the UK National Cancer Research to checkpoint inhibitors. All this evidence suggests acute Institute Upper Gastrointestinal Clinical Studies Group. J Clin thrombosis could be considered a rare but potential fatal Oncol 2009;27:3786–3793. immune-related adverse event. 5. Mandala  M, Barni S, Floriani I, Isa L, Fornarini G, Marangolo M, Mosconi S, Corsi D, Rulli E, Frontini L, Cortesi E, Zaniboni A, Aglietta M, Labianca R. Incidence and clinical implications of venous throm- Conclusions boembolism in advanced colorectal cancer patients: the GISCAD-al- ternating schedule study findings. Eur J Cancer 2009;45:65–73. • In cancer patients, a thrombosis risk assessment 6. Scappaticci FA, Skillings JR, Holden SN, Gerber H-P, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz should be conducted before starting any type of phar- H. Arterial thromboembolic events in patients with metastatic macological systemic therapy (the risk of thrombosis carcinoma treated with chemotherapy and bevacizumab. J Natl varies significantly among the different agents). Cancer Inst 2007;99:1232–1239. Cancer treatment and VTE risk C11 7. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous 19. Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, thromboembolism with the angiogenesis inhibitor bevacizumab Mackey JR, Paz-Ares L, Baron AD, Okusaka T, Yoshino T, Yoon HH, in cancer patients. A meta-analysis. JAMA 2008;300:2277–2285. Das M, Ferry D, Zhang Y, Lin Y, Binder P, Sashegyi A, Chau I. Meta- 8. Hurwitz HI, Saltz LB, Van Cutsem E, Cassidy J, Wiedemann J, analysis of individual patient safety data from six randomized, n F, Lyman GH, Rohr U-P. Venous thromboembolic events Sirze placebo-controlled trials with the antiangiogenic VEGFR2-binding with chemotherapy plus bevacizumab: a pooled analysis of monoclonal antibody ramucirumab. Ann Oncol 2017; patients in randomized phase II and III studies. J Clin Oncol 2011; 28:2932–2942. 29:1757–1764. 20. Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and ar- 9. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia terial thromboembolic events associated with anti-EGFR agents: a and arterial thromboembolic events with the angiogenesis inhibi- metaanalysis of randomized clinical trials. Ann Oncol 2012; tor bevacizumab in cancer patients: a meta-analysis of random- 23:1672–1679. ized controlled trials. Acta Oncol 2010;49:287–297. 21. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, 10. Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK. Bevacizumab Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 increases the risk of arterial ischemia: a large study in cancer Amado RG. A randomized phase IIIB trial of chemotherapy, bevaci- patients with a focus on different subgroup outcomes. Ann Oncol zumab, and panitumumab compared with chemotherapy and bev- 2011;22:1404–1412. acizumab alone for metastatic colorectal cancer. J Clin Oncol 11. Patel JN, Jiang C, Hertz DL, Mulkey FA, Owzar K, Halabi S, Ratain 2009;27:672–680. MJ, Friedman PN, Small EJ, Carducci MA, Mahoney JF, Kelley MJ, 22. Li X, Shan B-E, Wang J, Xing L-P, Guo X-J, Zhang Y-H, Shi P-H, Morris MJ, Kelly WK, McLeod HL. Bevacizumab and the risk of arte- Wang Z-Y. Incidence and risk of treatment-related mortality with rial and venous thromboembolism in patients with metastatic, anti-epidermal growth factor receptor monoclonal antibody in castration-resistant prostate cancer treated on Cancer and cancer patients: a meta-analysis of 21 randomized controlled tri- Leukemia Group B (CALGB) 90401 (Alliance). Cancer 2015; als. PLoS One 2013;8:e81897. 121:1025–1031. 23. Young K, Paz-Ares LG, Thatcher N, Spigel DR, Shahidi J, 12. Tabernero J, Allegra CJ, Rougier PR, Scagliotti G, Philip PL, Soldatenkova V, Grau G, Kurek R, Shepherd FA. Pooled analysis of Ramlau R. Meta-analysis of anti-VEGF class adverse events from venous thromboembolism (VTE) from four trials of necitumumab three double-blind (DB), placebo (PBO)-controlled phase III trials and chemotherapy for stage IV non-small cell lung cancer with IV aflibercept (Afl). J Clin Oncol 2012;30(Suppl):3579. (NSCLC). J Clin Oncol 2016;34(Suppl):e20534. 13. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova  J, 24. Young K, Paz-Ares L, Thatcher N, Spigel DR, Shahidi J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, Soldatenkova V, Grau G, Kurek R, Shepherd FA. Venous thrombo- McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of embolism with EGFR monoclonal antibody necitumumab in stage aflibercept to fluorouracil, leucovorin, and irinotecan improves IV non-small cell lung cancer: a retrospective cohort analysis. survival in a phase III randomized trial in patients with metastatic Thromb Res 2018;167:50–56. colorectal cancer previously treated with an oxaliplatin-based 25. Sonpavde G, Je Y, Schutz F, Galsky MD, Paluri R, Rosenberg JE, regimen. J Clin Oncol 2012;30:3499–3506. Bellmunt J, Choueiri TK. Venous thromboembolic events with vas- 14. Ruff P, Ferry DR, Lakomy R, Prausova  J, Van Hazel GA, Hoff PM, cular endothelial growth factor receptor tyrosine kinase inhibi- Cunningham D, Arnold D, Schmoll HJ, Moiseyenko VM, McKendrick tors: a systematic review and meta-analysis of randomized clinical JJ, ten Tije AJ, Vishwanath RL, Bhargava P, Chevalier S, Macarulla trials. Crit Rev Oncol Hematol 2013;87:80–89. T, Van Cutsem E. Time course of safety and efficacy of aflibercept 26. Qi W-X, Min D-L, Shen Z, Sun Y-J, Lin F, Tang L-N, He A-N, Yao Y. in combination with FOLFIRI in patients with metastatic colorectal Risk of venous thromboembolic events associated with VEGFR- cancer who progressed on previous oxaliplatin-based therapy. Eur TKIs: a systematic review and meta-analysis. Int J Cancer 2013; J Cancer 2015;51:18–26. 132:2967–2974. 15. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami 27. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of ar- C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe terial thromboembolic events with sunitinib and sorafenib: a sys- M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, tematic review and meta-analysis of clinical trials. J Clin Oncol Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero 2010;28:2280–2285. J. Ramucirumab monotherapy for previously treated advanced 28. Qi WX, Shen Z, Tang LN, Yao Y. Risk of arterial thromboembolic gastric or gastro-oesophageal junction adenocarcinoma (REGARD): events with vascular endothelial growth factor receptor tyrosine an international, randomised, multicentre, placebo-controlled, kinase inhibitors: an up-to-date meta-analysis. Crit Rev Oncol phase 3 trial. Lancet 2014;383:31–39. Hematol 2014;92:71–82. 16. Garon EB, Ciuleanu T-E, Arrieta O, Prabhash K, Syrigos KN, Goksel 29. Jang S, Zheng C, Tsai H-T, Fu AZ, Barac A, Atkins MB, Freedman T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, AN, Minasian L, Potosky AL. Cardiovascular toxicity after antian- Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim J- giogenic therapy in persons older than 65 years with advanced re- H, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, nal cell carcinoma. Cancer 2016;122:124–130. Sashegyi A, Yurasov S, Pe rol M. Ramucirumab plus docetaxel ver- 30. Sequist LV, Yang JC-H, Yamamoto N, O'Byrne K, Hirsh V, Mok T, sus placebo plus docetaxel for second-line treatment of stage IV Geater SL, Orlov S, Tsai C-M, Boyer M, Su W-C, Bennouna J, Kato non-small-cell lung cancer after disease progression on platinum- T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, based therapy (REVEL): a multicentre, double-blind, randomised Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed phase 3 trial. Lancet 2014;384:665–673. in patients with metastatic lung adenocarcinoma with EGFR muta- 17. Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon tions. J Clin Oncol 2013;31:3327–3334. D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M, 31. Schuler M, Yang JC-H, Park K, Kim J-H, Bennouna J, Chen Y-M, Hegg R, Verma S, Gorbunova V, Abi Gerges D, Thireau F, Fung H, Chouaid C, De Marinis F, Feng J-F, Grossi F, Kim D-W, Liu X, Lu S, Simms L, Buyse M, Ibrahim A, Martin M. Primary results of ROSE/ Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, TRIO-12, a randomized placebo-controlled phase III trial evaluat- Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progres- ing the addition of ramucirumab to first-line docetaxel chemo- sion in patients with non-small-cell lung cancer following chemo- therapy in metastatic breast cancer. J Clin Oncol 2015; therapy, erlotinib/gefitinib and afatinib: phase III randomized 33:141–148. LUX-Lung 5 trial. Ann Oncol 2016;27:417–423. 18. Wilke H, Muro K, Van Cutsem E, Oh S-C, Bodoky G, Shimada Y, 32. Zugazagoitia J, Biosca M, Oliveira J, Olmedo ME, Do mine M, Nadal Hironaka S, Sugimoto N, Lipatov O, Kim T-Y, Cunningham D, E, Ruffinelli JC, Mun ~oz N, Luna AM, Herna ndez B, Martínez M, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Gallego I, Martínez de Castro E, Font C, Calvo V, Martínez-Marín V, Chandrawansa K, Schwartz JD, Ohtsu A. Ramucirumab plus pacli- Corral J, Noguero n E, Mondejar R, García Escobar I, Salvador- taxel versus placebo plus paclitaxel in patients with previously Coloma C, Juan O,  Sanchez Canovas M, Valdivia J, Ochoa MP, treated advanced gastric or gastro-oesophageal junction adeno- pez Castro R, Obispo B, Pangua C, Sereno M, Ferna Lo ndez Franco carcinoma (RAINBOW): a double-blind, randomised phase 3 trial. L, Mielgo X, Calzas J, Blasco A, Aparisi F, Chara L, Grau JF, Soares Lancet Oncol 2014;15:1224–1235. M, Go mez A, Zenzola V, García-Morillo M, Cacho D, Díaz-Serrano C12 ~oz Martín et al. A.J. Mun A, Aguado C, Ponce-Aix S, Gonza lez-Larriba JL, Mun~oz AJ, Lora D, dependent kinase 4/6 inhibitor palbociclib in combination with Paz-Ares L, Manzano A. Incidence, predictors and prognostic sig- letrozole versus letrozole alone as first-line treatment of oestro- nificance of thromboembolic disease in patients with advanced gen receptor-positive, HER2-negative, advanced breast cancer ALK-rearranged non-small cell lung cancer. Eur Respir J 2018;51: (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol pii:1702431. doi: 10.1183/13993003.02431-2017. 2015;16:25–35. 33. Zer A, Moskovitz M, Hwang DM, Hershko-Klement A, Fridel L, 46. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Korpanty GJ, Dudnik E, Peled N, Shochat T, Leighl NB, Liu G, Feld Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, R, Burkes R, Wollner M, Tsao M-S, Shepherd FA. ALK-Rearranged Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. non-small-cell lung cancer is associated with a high rate of venous Fulvestrant plus palbociclib versus fulvestrant plus placebo for thromboembolism. Clin Lung Cancer 2017;18:156–161. treatment of hormone-receptor-positive, HER2-negative meta- 34. Verso M, Chiari R, Mosca S, Franco L, Fischer M, Paglialunga L, static breast cancer that progressed on previous endocrine ther- Bennati C, Scialpi M, Agnelli G. Incidence of CT scan-detected pul- apy (PALOMA-3): final analysis of the multicentre, double-blind, monary embolism in patients with oncogene-addicted, advanced phase 3 randomised controlled trial. Lancet Oncol 2016; Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 lung adenocarcinoma. Thromb Res 2015;136:924–927. 17:425–439. 35. Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, Felip 47. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, Harbeck E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph Tursi J, Blackhall F. First-line crizotinib versus chemotherapy in S, Dieras V, Slamon DJ. Palbocicliband letrozole in advanced ALK-positive lung cancer. N Engl J Med 2014;371:2167–2177. breast cancer. N Engl J Med 2016;375:1925–1936. 36. Shaw AT, Kim D-W, Nakagawa K, Seto T, Crino  L, Ahn M-J, De Pas T, 48. Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Besse B, Solomon BJ, Blackhall F, Wu Y-L, Thomas M, O'Byrne KJ, Okera M, Masuda N, Kaufman PA, Koh H, Grischke E-M, Frenzel M, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. Tassell V, Polli A, Wilner KD, Ja €nne PA. Crizotinib versus chemo- MONARCH2: abemaciclib in combination with fulvestrant in therapy in advanced ALK-positive lung cancer. N Engl J Med 2013; women with HRþ/HER2- advanced breast cancer who had pro- 368:2385–2394. gressed while receiving endocrine therapy. J Clin Oncol 2017; 37. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, 35:2875–2884. Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, 49. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Park IH, Tre dan O, Chen S-C, Manso L, Freedman OC, Garnica Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, CDM, Joensuu H. Efficacy and safety of imatinib mesylate in ad- Di Leo A. MONARCH3: abemaciclib as initial therapy for advanced vanced gastrointestinal stromal tumors. N Engl J Med 2002; breast cancer. J Clin Oncol 2017;35:3638–3646. 347:472–480. 50. Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch- 38. De Matteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Shimon S, Campone M, Blackwell KL, Andre  F, Winer EP, Janni W, Demetri GD. Adjuvant imatinib mesylate after resection of Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, localised, primary gastrointestinal stromal tumour: a rando- Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke mised, double-blind, placebo-controlled trial. Lancet 2009; E-M, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot 373:1097–1104. T, Tseng L-M, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat 39. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, S, OShaughnessy J. Ribociclib as first-line therapy for HR-positive, Aura C, Go mez H, Dinh P, Fauria K, Van Dooren V, Aktan G, advanced breast cancer. N Engl J Med 2016;375:1738–1748. Goldhirsch A, Chang T-W, Horva th Z, Coccia-Portugal M, Domont J, 51. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward Tseng L-M, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, M, Rutkowski P, Blank CU, Miller WH, Kaempgen E, Martín-Algarra Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M. S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin A-M, Swann Lapatinib with trastuzumab for HER2-positive early breast cancer S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, Lancet 2012;379:633–640. open-label, phase 3 randomised controlled trial. Lancet 2012; 40. Piccart-Gebhart M, Holmes A, Baselga J, De Azambuja E, Dueck 380:358–365. AC, Viale G, et al. First results from the phase III ALTTO trial (BIG 52. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, therapy with lapatinib alone (L), trastuzumab alone (T), their se- Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, quence (T!L), or their combination (TþL) in the adjuvant treat- Kirkwood JM, Eggermont AMM, Dreno B, Nolop K, Li J, Nelson B, ment of HER2-positive early breast cancer (EBC). J Clin Oncol Hou J, Lee RJ, Flaherty KT, McArthur GA. Improved survival with 2014;32:5s (Suppl; abstr LBA4). vemurafenib in melanoma with BRAF V600E mutation. N Engl J 41. Baas MC, Gerdes VEA, ten Berge IJM, Heutinck KM, Florquin S, Med 2011;364:2507–2516. Meijers JCM, Bemelman FJ. Treatment with everolimus is associ- 53. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, ated with a procoagulant state. Thromb Res 2013;132:307–311. Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, 42. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Larkin JMG, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin A-M, Patel K, D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Schadendorf D. Improved survival with MEK inhibition in BRAF- Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal mutated melanoma. N Engl J Med 2012;367:107–114. hormone-receptor-positive advanced breast cancer. N Engl J Med 54. Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for 2012;366:520–529. chemotherapy-associated venous thromboembolism in a prospec- 43. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday tive observational study. Cancer 2005;104:2822–2829. TJ, Okusaka T, Capdevila J, de Vries EGE, Tomassetti P, Pavel ME, 55. Moore RA, Adel N, Riedel E, Bhutani M, Feldman DR, Tabbara NE, € Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K. Everolimus for ad- Soff G, Parameswaran R, Hassoun H. High incidence of thrombo- vanced pancreatic neuroendocrine tumors. N Engl J Med 2011; embolic events in patients treated with cisplatin-based chemo- 364:514–523. therapy. A large retrospective analysis. J Clin Oncol 2011; 44. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, 29:3466–3473. Gru€nwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud 56. Seng S, Liu Z, Chiu SK, Proverbs-Singh T, Sonpavde G, Choueiri TK, A. Phase 3 trial of everolimus for metastatic renal cell carcinoma: Tsao C-K, Yu M, Hahn NM, Oh WK, Galsky MD. Risk of venous final results and analysis of prognostic factors. Cancer 2010; thromboembolism in patients with cancer treated with cisplatin: a 116:4256–4265. systematic review and meta- analysis. J Clin Oncol 2012; 45. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, 30:4416–4426. Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, 57. Verso M, Agnelli G, Barni S, Gasparini G, La Bianca R. A modified Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin- Khorana risk assessment score for venous thromboembolism in Cancer treatment and VTE risk C13 cancer patients receiving chemotherapy: the PROTECHT score. 75. Torra R, Poch E, Torras A, Bombí LA, Revert L. Pulmonary hemor- Intern Emerg Med 2012;7:291–292. rhage as a clinical manifestation of hemolytic-uremic syndrome 58. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. associated with mitomycin C therapy. Chemotherapy 1993; Development and validation of a predictive model for 39:453–456. chemotherapy-associated thrombosis. Blood 2008;111:4902–4907. 76. Goodnough LT, Saito H, Manni A, Jones PK, Pearson OH. Increased 59. Barni S, Labianca R, Agnelli G, Bonizzoni E, Verso M, Mandala  M, incidence of thromboembolism in stage IV breast cancer patients Brighenti M, Petrelli F, Bianchini C, Perrone T, Gasparini G. treated with a five drug chemotherapy regimen: a study of 159 Chemotherapy-associated thromboembolic risk in cancer outpa- patients. Cancer 1984;54:1264–1268. tients and effect of nadroparin thromboprophylaxis: results of a 77. Docetaxel Product Information. http:// www. ema. europa. eu/ retrospective analysis of the PROTECHT study. J Transl Med 2011; docs/ es_ ES/ document_ library/ EPAR_ - _ Product_ Information/ 9:179. human/ 000073/ WC500035264. pdf (2 March 2020). 60. Schmoll HJ, Twelves C, Sun W, OConnell MJ, Cartwright T, 78. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, McKenna E. Effect of adjuvant capecitabine or fluorouracil, with Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 or without oxaliplatin, on survival outcomes in stage III colon can- S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, cer and the effect of oxaliplatin on post-relapse survival: a pooled Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. analysis of individual patient data from four randomised con- Increased survival in pancreatic cancer with nab-paclitaxel plus trolled trials. Lancet Oncol 2014;15:1481–1492. gemcitabine. N Engl J Med 2013;369:1691–1703. 61. Bekaii-Saab T, Wu C. Seeing the forest through the trees: a sys- 79. Chang J, Couture F, Young S, McWatters KL, Lau CY. Weekly epoe- tematic review of the safety and efficacy of combination chemo- tin alfa maintains hemoglobin, improves quality of life, and therapies used in the treatment of metastatic colorectal cancer. reduces transfusion in breast cancer patients receiving chemo- Crit Rev Oncol Hematol 2014;91:9–34. therapy. J Clin Oncol 2005;23:2597–2605. 62. Otten H-MMB, Mathijssen J, ten Cate H, Soesan M, Inghels M, 80. Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman Richel DJ, Prins MH. Symptomatic venous thromboembolism in GH. Blood transfusions, thrombosis, and mortality in hospitalized cancer patients treated with chemotherapy: an underestimated patients with cancer. Arch Intern Med 2008;168:2377–2381. phenomenon. Arch Intern Med 2004;164:190–194. 81. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak 63. Shah MA, Capanu M, Soff G, Asmis T, Kelsen DP. Risk factors for de- JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, veloping a new venous thromboembolism in ambulatory patients Regan DH, Somerfield MR. American Society of Clinical Oncology/ with non-hematologic malignancies and impact on survival for American Society of Hematology clinical practice guideline update gastroesophageal malignancies. J Thromb Haemost 2010; on the use of epoetin and darbepoetin in adult patients with can- 8:1702–1709. cer. J Clin Oncol 2010;28:4996–5010. 64. Shah MA, Ilson D, Kelsen DP. Thromboembolic events in gastric 82. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, cancer: high incidence in patients receiving irinotecan- and Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, bevacizumab-based therapy. J Clin Oncol 2005;23:2574–2576. Bennett CL, Langensiepen S, Hyde C, Engert A. Recombinant hu- 65. Qi WX, Lin F, Sun YJ, Tang LN, Shen Z, Yao Y. Risk of venous and ar- man erythropoietins and cancer patients: updated meta-analysis terial thromboembolic events in cancer patients treated with of 57 studies including 9353 patients. J Natl Cancer Inst 2006; gemcitabine: a systematic review and meta-analysis. Br J Clin 98:708–714. Pharmacol 2013;76:338–347. 83. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, 66. Balar AV, Apolo AB, Ostrovnaya I, Mironov S, Iasonos A, Trout A, Gleason KJ. Venous thromboembolism and mortality associated Regazzi AM, Garcia-Grossman IR, Gallagher DJ, Milowsky MI, with recombinant erythropoietin and darbepoetin administration Bajorin DF. Phase II study of gemcitabine, carboplatin, and bevaci- for the treatment of cancer-associated anemia. JAMA 2008; zumab in patients with advanced unresectable or metastatic uro- 299:914–924. thelial cancer. J Clin Oncol 2013;31:724–730. € 84. Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, 67. Zhou X, Teegala S, Huen A, Ji Y, Fayad L, Hagemeister FB, Gladish Fleishman A, Bridges K, Glaspy JA. Pooled analysis of individual G, Vadhan-Raj S. Incidence and risk factors of venous thromboem- patient-level data from all randomized, double-blind, placebo- bolic events in lymphoma. Am J Med 2010;123:935–941. controlled trials of darbepoetin alfa in the treatment of patients 68. Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, with chemotherapy-induced anemia. J Clin Oncol 2009; De Pauw S. The thrombogenic effect of anticancer drug therapy in 27:2838–2847. women with stage II breast cancer. N Engl J Med 1988; 85. Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, 318:404–407. Berlin JA, Tomita D, Bridges K, Ludwig H. Erythropoiesis-stimulat- 69. Briasoulis E, Pentheroudakis G, Karavasilis V, Tzamakou E, ing agents in oncology: a study- level meta-analysis of survival and Rammou D, Pavlidis N. Weekly paclitaxel combined with pegylated other safety outcomes. Br J Cancer 2010;102:301–315. liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose- 86. Tonia T, Mettler A, Robert N, Schwarzer G, Seidenfeld J, Weingart O, finding and pharmacokinetic study in patients with advanced solid Hyde C, Engert A, Bohlius J. Erythropoietin or darbepoetin for patients tumors. Ann Oncol 2004;15:1566–1573. with cancer. Cochrane Database Syst Rev 2012;12:CD003407. 70. Basso U, Roma A, Brunello A, Falci C, Fiduccia P, Banzato A, 87. National Comprehensive Cancer Network (NCCN) Guidelines. Bononi A, Gusella M, Vamvakas L, Zagonel V, Monfardini S. Cancer- and Chemotherapy-Induced Anemia. Version 3. 2018. Bi-weekly liposomal doxorubicin for advanced breast cancer https:// www. nccn. org/ professionals/ physician_ gls/ pdf/ ane in elderly women (70 years). J Geriatr Oncol 2013; mia. pdf (26 January 2019). 4:340–345. € 88. Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, 71. Khanna A, Reece-Smith AM, Cunnell M, Madhusudan S, Thomas A, Repetto L, Soubeyran P. EORTC guidelines for the use of erythro- Bowrey DJ, Parsons SL. Venous thromboembolism in patients re- poietic proteins in anaemic patients with cancer: 2006 update. ceiving perioperative chemotherapy for esophagogastric cancer. Eur J Cancer 2007;43:258–270. Dis Esophagus 2014;27:242–247. 89. Schrijvers D, De Samblanx H, Roila F; ESMO Guidelines Working 72. Swystun LL, Mukherjee S, Levine M, Liaw PC. The chemotherapy Group. Erythropoiesis-stimulating agents in the treatment of metabolite acrolein upregulates thrombin generation and impairs anaemia in cancer patients: ESMO Clinical Practice Guidelines for the protein C anticoagulant pathway in animal-based and cell- use. Ann Oncol 2010;21(Suppl 5):v244–v247. based models. J Thromb Haemost 2011;9:767–775. 90. Alberola Candel V, Carrato Mena A, Díaz-Rubio García E, Gasco n 73. Sheldon R, Slaughter D. A syndrome of microangiopathic hemolytic Vilaplana P, Gonza lez Baro n M, Martín Jime nez M, Alba Conejo E, anemia, renal impairment, and pulmonary edema in Cassinello Espinosa J, Colomer R, Cruz Herna ndez JJ, Barnadas I chemotherapy-treated patients with adenocarcinoma. Cancer Molins A, Camps Herrero C, Casas Ferna ndez de Tejerina AM, 1986;58:1428–1436. Carulla Torrent J, Constenla Figueiras M, Gavila  Gregori J, Isla 74. Abramson N. Drug-associated thrombocytopenia and anemia. Casado MD, Massuti Sureda B, Provencio Pulla M, Rodríguez Blood 2007;110:2229. nchez CA, Sanz Ortiz J; Spanish Society of Medical Oncology Sa C14 ~oz Martín et al. A.J. Mun (SEOM). Spanish Society of Medical Oncology consensus on the use Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, of erythropoietic stimulating agents in anaemic cancer patients. Jones SE. Adjuvant tamoxifen and exemestane in early breast can- Clin Transl Oncol 2009;11:727–736. cer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321–331. 91. Huerta C, Johansson S, Wallander MA, García Rodríguez LA, Risk 102. Amir E, Seruga B, Niraula S, Carlsson L, Ocan ~a A. Toxicity of adju- factors and short-term mortality of venous thromboembolism di- vant endocrine therapy in postmenopausal breast cancer patients: agnosed in the primary care setting in the United Kingdom. Arch a systematic review and meta-analysis. J Natl Cancer Inst 2011; Intern Med 2007;167:935–943. 103:1299–1309. 92. Johannesdottir SA, Horva th-Puho  E, Dekkers OM, Cannegieter SC, 103. Aydiner A. Meta-analysis of breast cancer outcome and toxicity in Jrgensen JOL, Ehrenstein V, Vandenbroucke JP, Pedersen L, adjuvant trials of aromatase inhibitors in postmenopausal women. Srensen HT. Use of glucocorticoids and risk of venous thromboem- Breast 2013;22:121–129. Cancer 2005;104:236–239. bolism: a nationwide population- based case-control study. JAMA 104. Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Intern Med 2013;173:743–752. Come SE, Osborne CK, Robertson JFR. Fulvestrant versus anastro- 93. Ungprasert P, Srivali N, Wijarnpreecha K, Charoenpong P, Knight zole for the treatment of advanced breast carcinoma: a prospec- Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_C/C2/5826770 by guest on 26 October 2023 EL. Non-steroidal anti-in ammatory drugs and risk of venous tively planned combined survival analysis of two multicenter trials. thromboembolism: a systematic review and meta- analysis. Cancer 2005;104:236–239. Rheumatology (Oxford) 2015;54:736–742. 105. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi 94. Deitcher SR, Gomes MP. The risk of venous thromboembolic dis- KN, Jones RJ, Goodman OB, Saad F, Staffurth JN, Mainwaring P, ease associated with adjuvant hormone therapy for breast carci- Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth noma. A systematic review. Cancer 2004;101:439–449. JD, Ryan CJ, Sternberg CN, Ellard SL, Fle chon A, Saleh M, Scholz M, 95. Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq Hamed A, Howell A, Powles T; IBIS Investigators. First results from CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased the International Breast Cancer Intervention Study (IBIS-I): a ran- survival in metastatic prostate cancer. N Engl J Med 2011; domized prevention trial. Lancet 2002;360:817–824. 364:1995–2005. 96. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous throm- 106. Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, de boembolism. Br J Clin Pharmacol 1998;45:608–612. Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, 97. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture chon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Fle J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, Margolese Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased sur- R, Robidoux A, Shibata H, Terz J, Paterson AHG, Feldman MI, vival with enzalutamide in prostate cancer after chemotherapy. Farrar W, Evans J, Lickley HL, Ketner M. A randomized clinical N Engl J Med 2012;367:1187–1197. trial evaluating tamoxifen in the treatment of patients with node- 107. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, negative breast cancer who have estrogen-receptor positive Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis tumors. N Engl J Med 1989;320:479–484. ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim C-S, Kimura G, 98. Walker AJ, West J, Card TR, Crooks C, Kirwan CC, Grainge MJ. Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung When are breast cancer patients at highest risk of venous throm- D, Saad F, Scher HI, Taplin M-E, Venner PM, Tombal B; PREVAIL boembolism? A cohort study using English health care data. Blood Investigators. Enzalutamide in metastasic prostate cancer before 2016;127:849–857. chemotherapy. N Engl J Med 2014;371:424–433. 99. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, 108. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PFA, Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee Combination) trial after completion of 5 years adjuvant treatment SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, for breast cancer. ATAC Trialists Group. Lancet 2005;365:60–62. Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin M-E, Park Y, 100. Breast International Group (BIG) 1-98 Collaborative Group, Kheoh T, Griffin T, Scher HI, Rathkopf DE. Abiraterone in metastatic Thu€rlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, prostate cancer without previous chemotherapy. N Engl J Med Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio 2013;368:138–148. M, Smith I, Wardley A, Wardly A, Price KN, Goldhirsch A. A compari- 109. Kunimasa K, Nishino K, Kimura M, Inoue T, Tamiya M, Kumagai T, son of letrozole and tamoxifen in postmenopausal women with Imamura F. Pembrolizumab-induced acute thrombosis: a case re- early breast cancer. N Engl J Med 2005;353:2747–2757. port. Medicine (Baltimore) 2018;97:e10772. 101. van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, 110. Boutros C, Scoazec JY, Mateus C, Routier E, Roy S, Robert C. Arterial Vannetzel J-M, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, thrombosis and anti-PD-1 blockade. Eur J Cancer 2018;91:164–166.