cancers Article Cancer Histology and Natural History of Patients with Lung Cancer and Venous Thromboembolism Pedro Ruiz-Artacho 1,2,3, * , Ramón Lecumberri 4,5 , Javier Trujillo-Santos 6 , Carme Font 7 , Juan J. López-Núñez 8,9,10 , María Luisa Peris 11,12 , Carmen Díaz Pedroche 13 , José Luis Lobo 14 , Luciano López Jiménez 15 , Raquel López Reyes 16 , Luis Jara Palomares 17 , José María Pedrajas 18 , Isabelle Mahé 19 , Manuel Monreal 3,20 and The RIETE Investigators † 1 Department of Internal Medicine, Clínica Universidad de Navarra, 28027 Madrid, Spain 2 Interdisciplinar Teragnosis and Radiosomics Research Group (INTRA-Madrid), Universidad de Navarra, 28027 Madrid, Spain 3 CIBER Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain 4 Hematology Service, Clínica Universidad de Navarra, 31008 Pamplona, Spain 5 CIBERCV, Instituto de Salud Carlos III, 28220 Madrid, Spain 6 Department of Internal Medicine, Hospital General Universitario Santa Lucía, Universidad Católica de Murcia, 30107 Murcia, Spain 7 Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain 8 Department of Internal Medicine, Hospital Germans Trias i Pujol, 08916 Badalona, Spain 9 Department of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain 10 Institut de Recerca Germans Trias i Pujol, 08916 Badalona, Spain 11 Department of Internal Medicine, Consorcio Hospitalario Provincial de Castellón, 12002 Castellon, Spain 12 Medicine Department, CEU Cardenal Herrera University, 46115 Valencia, Spain 13 Department of Internal Medicine, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain 14 Department of Pneumonology, Hospital Universitario Araba, 01009 Vitoria-Gasteiz, Spain 15 Department of Internal Medicine, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain Citation: Ruiz-Artacho, P.; 16 Department of Pneumonology, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain Lecumberri, R.; Trujillo-Santos, J.; 17 Department of Pneumonology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain Font, C.; López-Núñez, J.J.; Peris, 18 Department of Internal Medicine, Hospital Clínico San Carlos, 28040 Madrid, Spain M.L.; Díaz Pedroche, C.; Lobo, J.L.; 19 Department of Internal Medicine, Hôpital Louis Mourier, Colombes (APHP), University Paris 7, López Jiménez, L.; López Reyes, R.; 75013 Paris, France et al. Cancer Histology and Natural 20 Chair for the Study of Thromboembolic Disease, Faculty of Health Sciences, UCAM–Universidad Católica History of Patients with Lung Cancer San Antonio de Murcia, 30107 Murcia, Spain and Venous Thromboembolism. * Correspondence: ruizpedroc@gmail.com; Tel.: +34-9135-31920 Cancers 2022, 14, 4127. https:// † A full list of the RIETE investigators is included in the Appendix A. doi.org/10.3390/cancers14174127 Simple Summary: Cancer is a widely heterogeneous disease, and the natural history of patients Academic Editor: Ioannis Mitroulis with cancer-associated thrombosis may differ according to the cancer site. Lung cancer is the most Received: 1 July 2022 common malignancy, and a leading cause of death. A number of studies in the literature suggest Accepted: 23 August 2022 that patients with adenocarcinoma may have a worse outcome than those with squamous or other Published: 26 August 2022 types of lung cancer. The aim of the current study was to assess the potential impact of lung cancer Publisher’s Note: MDPI stays neutral histology on the incidence rates of VTE recurrences, major bleeding, or death appearing during the with regard to jurisdictional claims in course of anticoagulation, in patients with lung cancer and VTE. Our findings, obtained from a large published maps and institutional affil- series of consecutive patients with lung cancer and VTE (482 patients), reveal important differences iations. between patients with adenocarcinoma vs. other histologies in their outcomes during anticoagulation. This might likely help to design better therapeutic strategies for patients with lung cancer. Abstract: Background: In patients with lung cancer and venous thromboembolism (VTE), the in- Copyright: © 2022 by the authors. fluence of cancer histology on outcome has not been consistently evaluated. Methods: We used Licensee MDPI, Basel, Switzerland. the RIETE registry (Registro Informatizado Enfermedad TromboEmbólica) to compare the clinical This article is an open access article distributed under the terms and characteristics and outcomes during anticoagulation in patients with lung cancer and VTE, according conditions of the Creative Commons to the histology of lung cancer. Results: As of April 2022, there were 482 patients with lung cancer Attribution (CC BY) license (https:// and VTE: adenocarcinoma 293 (61%), squamous 98 (20%), small-cell 44 (9.1%), other 47 (9.8%). The creativecommons.org/licenses/by/ index VTE was diagnosed later in patients with squamous cancer than in those with adenocarcinoma 4.0/). (median, 5 vs. 2 months). In 50% of patients with adenocarcinoma, the VTE appeared within the first Cancers 2022, 14, 4127. https://doi.org/10.3390/cancers14174127 https://www.mdpi.com/journal/cancers Cancers 2022, 14, 4127 2 of 11 90 days since cancer diagnosis. During anticoagulation (median 106 days, IQR: 45–214), 14 patients developed VTE recurrences, 15 suffered major bleeding, and 218 died: fatal pulmonary embolism 10, fatal bleeding 2. The rate of VTE recurrences was higher than the rate of major bleeding in patients with adenocarcinoma (11 vs. 6 events), and lower in those with other cancer types (3 vs. 9 events). On multivariable analysis, patients with adenocarcinoma had a non-significantly higher risk for VTE recurrences (hazard ratio [HR]: 3.79; 95%CI: 0.76–18.8), a lower risk of major bleeding (HR: 0.29; 95%CI: 0.09–0.95), and a similar risk of mortality (HR: 1.02; 95%CI: 0.76–1.36) than patients with other types of lung cancer. Conclusions: In patients with lung adenocarcinoma, the rate of VTE recurrences outweighed the rate of major bleeding. In patients with other lung cancers, it was the opposite. Keywords: venous thrombolism; lung cancer; adenocarcinoma lung cancer; cancer associated thrombosis; histology 1. Introduction Patients with cancer are at increased risk of venous thromboembolism (VTE), and VTE appearing in patients with cancer implies an increased risk of VTE recurrences, bleed- ing, and mortality [1–4]. Current guidelines on antithrombotic therapy, based on the results of randomized clinical trials, provide recommendations that apply to patients with all types of cancers [5–7]. However, cancer is a widely heterogeneous disease, and the risk of recurrences, bleeding, or death may differ according to the cancer site or other variables [8–10]. Several patient-, disease-, or treatment-related factors may account for these differences, including the initial VTE presentation, different cancer therapies, the pres- ence of metastases, or the use of central venous catheters [1], but the association between the cancer histology and outcome after a VTE event has not been consistently evaluated thus far. Lung cancer is the most common malignancy, and a leading cause of death [11]. In a recent study on 1725 patients with lung cancer and VTE, we found that their rate of VTE recurrences during anticoagulation far exceeded the rate of major bleeding [12]. However, the histology of lung cancer was not considered. A number of studies in the literature suggest that patients with adenocarcinoma (with or without VTE) may have a worse outcome than those with squamous or other types of lung cancer [1,3,13–16]. Better knowledge of the potential impact of lung cancer histology on outcome might likely help to design better therapeutic strategies for patients with lung cancer. The RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry is an ongoing prospective, multicenter, multinational, observational registry of consecutive patients with objectively confirmed acute VTE (ClinicalTrials.gov identifier: NCT02832245). RIETE is currently the largest database of patients with VTE in the world [17–19]. The aim of the current study was to assess the potential impact of lung cancer histology on the incidence rates of VTE recurrences, major bleeding, or death during the course of anticoagulation in patients with lung cancer and acute VTE. 2. Methods 2.1. Patients Consecutive patients with acute deep vein thrombosis (DVT) or pulmonary embolism (PE) confirmed by objective tests (compression ultrasonography or contrast venography for suspected DVT; helical computed tomography (CT) scan, pulmonary angiography, or ventilation–perfusion lung scan for suspected PE) were included. Patients who were participating in a therapeutic clinical trial with a blinded treatment were excluded. 2.2. Inclusion Criteria In RIETE, we started to gather data on the histology of lung cancer on January 2021. Thus, the study included patients recruited from January 2021 to April 2022. For this study, Cancers 2022, 14, 4127 3 of 11 patients with biopsy-proven active lung cancer presenting with acute VTE were included. Characteristics of patients (sex, age, body weight, comorbidities, risk factors for VTE, concomitant medications), initial VTE presentation, and anticoagulant treatment (initial [first 1–3 weeks of treatment after VTE diagnosis, depending on the type of anticoagulant used] and long-term [after the initial acute phase] therapy), blood tests at baseline, and outcomes during anticoagulation, were recorded. Active lung cancer was defined as cancer diagnosed within 6 months before VTE, metastatic disease, or treatment for cancer during the previous 6 months (chemotherapy, radiotherapy, surgery, or hormonal or support therapy). 2.3. Follow-Up There was no standardization of treatment and patients were managed according to the clinical practice of each participating hospital. The anticoagulant therapy (type, dose, and duration) was recorded. All patients were followed-up during anticoagulant therapy, for at least 3 months, unless earlier death occurred. During follow-up, any signs or symptoms suggesting symptomatic VTE recurrences or bleeding events were noted. Clinically suspected symptomatic VTE recurrences were investigated by corresponding objective tests: compression ultrasonography, ventilation–perfusion lung scintigraphy, helical CT pulmonary, angiography, or pulmonary angiography. VTE recurrence was defined as a DVT in a new segment, a DVT of 4 mm larger in diameter when compared with prior venous ultrasound, a new intraluminal filling defect on a CT scan, or a new ventilation–perfusion mismatch in a repeat lung scan. Bleeding was considered as major if the event was overt and required ≥2 units of blood transfusions or more, involved a critical area (intracranial, retroperitoneal, spinal, or intrapericardial), or when it was fatal. In the absence of autopsy, fatal PE was defined as any death appearing within 10 days after PE diagnosis (either the index PE or recurrent PE), in the absence of any alternative cause of death. Fatal bleeding was defined as any death occurring within 10 days of a major bleeding episode, in the absence of an alternative cause of death. 2.4. Statistical Analysis Differences across subgroups were assessed using a chi-square test (two-sided) and Fisher’s exact test (two-sided) for categorical variables, and using Student’s t-test for variance analysis of continuous variables. Incidence rates were calculated as cumulative incidence (events/100 patient-years) and compared using the hazard ratios (HR) with corresponding 95% confidence intervals (CIs). The analyses used time-to-event methods. Risks of VTE recurrence or major bleeding were assessed with proportional hazard Cox models. Time zero was the date of the index VTE diagnosis. Patients were censored at the time of discontinuation of anticoagulation, at the time of death, or at the last date for which outcome data were available. A competing risk analysis for VTE recurrences and major bleeding with the Fine and Gray method was performed, with overall death as the competing event. Covariates entering in the adjusted model were selected by a significance level of p < 0.10 on univariable analysis, or by a well-known association reported in the literature. Then, a backward selection was used for the covariate selection in the multivariable model. SPSS software (version 20; SPSS, Chicago, IL, USA) and Stata 16.1 (StataCorp, College Station, TX, USA) were used for the statistical management of the data. A two-sided p < 0.05 was considered to be statistically significant. 3. Results As of April 2022, a total of 482 patients with lung cancer and VTE had been recruited. Of these, 334 (69%) initially presented with PE (with or without concomitant DVT) and 148 (31%) presented with isolated DVT. Overall, 293 (61%) patients had adenocarcinoma, 98 (20%) patients had squamous cell carcinoma, 44 (9.1%) had small-cell carcinoma, and 47 (9.8%) were classified as other tumors, which included 9 neuroendocrine, 7 large cells (different to adenocarcinoma/squamous), 15 undifferentiated, and 16 other types. Com- Cancers 2022, 14, 4127 4 of 11 pared to patients with adenocarcinoma, those with squamous lung cancer were older and more likely to be men, to have chronic lung disease, anemia, or thrombocytope- nia, or to be using antiplatelet drugs at baseline, but were less likely to have metastases (p < 0.001) (Table 1). Moreover, the index VTE appeared earlier in patients with adenocarci- noma than in those with squamous cancer (median, 2 vs. 5 months after cancer diagnosis, p < 0.001). In 50% of patients with adenocarcinoma, the VTE appeared within the first 90 days, as compared to only 26% of patients with squamous carcinoma (p < 0.001). In 83 patients with adenocarcinoma (28%), the VTE was detected less than 30 days after cancer diagnosis. Patients with small-cell cancer were also less likely to have metastases than those with adenocarcinoma (p < 0.05), and the VTE was also detected later (median, 4 months, p < 0.05). Similar findings were observed in patients with other histologies. Interestingly, 89% of patients had stage III or IV tumors, with no differences between subgroups, and only 19% had an ECOG score > 2 points. Table 1. Clinical characteristics of the patients, according to the histology. Adenocarcinoma Squamous Small-Cell Other Patients, N 293 98 44 47 Clinical characteristics Male gender 200 (68%) 85 (87%) ‡ 32 (73%) 37 (79%) Age (mean years ± SD) 63 ± 11 67 ± 9.1 ‡ 66 ± 8.2 65 ± 8.6 Body weight (mean kg ± SD) 71 ± 13 71 ± 11 75 ± 13 72 ± 13 Smoking habit 52 (19%) 25 (27%) 11 (26%) 12 (27%) Chronic lung disease 67 (23%) 42 (43%) ‡ 9 (21%) 12 (26%) Chronic heart failure 13 (4.4%) 5 (5.1%) 1 (2.3%) 2 (4.3%) Additional risk factors for VTE Recent surgery 15 (5.1%) 6 (6.1%) 2 (4.5%) 4 (8.5%) Immobility ≥ 4 days 64 (22%) 13 (13%) 7 (16%) 8 (17%) Use of estrogens 5 (1.7%) 3 (3.1%) 1 (2.3%) 0 None of the above 215 (73%) 77 (79%) 35 (80%) 36 (77%) Prior VTE 17 (5.8%) 8 (8.2%) 5 (11%) 2 (4.3%) Initial VTE presentation Pulmonary embolism 211 (72%) 66 (67%) 32 (73%) 25 (53%) † In patients with PE SBP levels < 90 mm Hg 10 (5.1%) 1 (1.6%) 0 2 (8.3%) Heart rate > 100 bpm (N = 311) 74 (38%) 20 (32%) 8 (27%) 8 (35%) Sat O2 levels (mean % ± SD) 90 ± 8.1 92 ± 4.6 93 ± 3.8 94 ± 3.7 PESI ≥ 105 points 128 (61%) 54 (82%) † 22 (69%) * 17 (68%) Lower-limb DVT 53 (18%) 20 (20%) 8 (18%) 12 (26%) Upper-limb DVT 29 (9.9%) 14 (14%) 4 (9.1%) 10 (21%) * Cancer characteristics Metastases 240 (82%) 53 (54%) ‡ 30 (68%) * 31 (67%) * Time since cancer diagnosis Median months (IQR) 2 (0–11) 5 (2–15) ‡ 4 (1–11) * 3 (0–10) <90 days 139 (50%) 24 (26%) ‡ 13 (31%) * 21 (48%) Stage III–IV 266 (91%) 76 (78%) 42 (96%) 43 (92%) ECOG 3–4 61 (21%) 16 (17%) 6 (14%) 9 (19%) Concomitant therapies Antiplatelets 43 (15%) 25 (26%) * 7 (16%) 9 (19%) Corticosteroids 89 (30%) 24 (25%) 12 (27%) 11 (23%) Blood tests Anemia 159 (54%) 72 (74%) ‡ 26 (59%) 33 (70%) * Leukocyte count > 11,000/µL 106 (37%) 29 (31%) 9 (19%) 10 (22%) Platelet count < 100,000/µL 9 (3.1%) 10 (10%) † 1 (2.3%) 3 (6.4%) Platelet count > 450,000/µL 14 (4.8%) 8 (8.2%) 5 (11%) 9 (19%) ‡ CrCl levels < 60 mL/min 50 (17%) 22 (22%) 11 (25%) 8 (17%) Comparisons among groups (Adenocarcinoma as reference group): * p < 0.05; † p < 0.01; ‡ p < 0.001. Abbreviations: VTE, venous thromboembolism; SD, standard deviation; CrCl, creatinine clearance; CI, confidence intervals. Anemia is defined as hemoglobin levels <12.0 g/dL in women and <13.0 g/dL in men. Cancers 2022, 14, 4127 5 of 11 Most patients in all four subgroups (89%) received initial therapy with low-molecular- weight heparin (LMWH), with no significant differences in daily doses between subgroups (Table 2). Then, most (82%) patients maintained LMWH as long-term therapy. The me- dian duration of anticoagulant therapy ranged between 87 and 160 days, the difference between subgroups being not statistically significant. The proportion of patients receiving chemotherapy and/or radiotherapy also was similar in all four subgroups. Table 2. Treatment strategies according to the histology. Adenocarcinoma Squamous Small-Cell Others Patients, N 293 98 44 47 Duration of therapy Mean days (±SD) 184 ± 212 195 ± 261 214 ± 203 175 ± 236 Median days (IQR) 114 (47–210) 105 (38–218) 160 (91–232) 87 (44–203) * Duration > 6 months 100 (35%) 30 (32%) 18 (41%) 12 (26%) Initial therapy Low-molecular-weight heparin 260 (89%) 89 (91%) 40 (91%) 39 (83%) Mean LMWH dose (IU/kg/day) 169 ± 41 170 ± 44 164 ± 42 164 ± 43 Unfractionated heparin 3 (1.0%) 0 0 2 (4.3%) Thrombolytics 6 (2.0%) 0 1 (2.3%) 0 Direct oral anticoagulants 1 (0.3%) 0 0 0 Inferior vena cava filter 2 (0.7%) 1 (1.0%) 0 0 Long-term therapy Low-molecular-weight heparin 240 (82%) 74 (76%) 39 (89%) 40 (85%) Mean LMWH dose (IU/kg/day) 159 ± 38 153 ± 37 155 ± 35 149 ± 47 Vitamin K antagonists 14 (4.8%) 6 (6.1%) 1 (2.3%) 1 (2.1%) Direct oral anticoagulants 2 (0.7%) 1 (1.0%) 0 1 (2.1%) Oncological therapy Chemotherapy 150 (52%) 55 (59%) 29 (66%) 23 (55%) Radiotherapy 60 (21%) 22 (24%) 11 (25%) 10 (24%) Other 12 (4.1%) 7 (7.1%) 5 (11%) * 1 (2.1%) Comparisons among groups (Adenocarcinoma as reference group): * p < 0.05. Abbreviations: SD, standard deviation; LMWH, low-molecular-weight heparin; IU, international units; CI, confidence intervals. During anticoagulation (median duration 104 days, IQR: 39–209 days), 9 patients developed PE recurrences, 5 had DVT recurrences, 15 suffered major bleeding (gastroin- testinal 4, intracranial 4, retroperitoneal 2, other sites 5), and 218 died (fatal PE 10, fatal bleeding 2) (Table 3). All patients dying because of PE had adenocarcinoma, and all of them died within the first 10 days after the index PE. Compared to patients with adeno- carcinoma, those with small-cell carcinoma had a non-statistically significant higher rate of intracranial bleeding (hazard ratio (HR): 4.11; 95%CI: 0.56–30.3). When considering patients with squamous, small-cell, or other types as a unique subgroup, patients with adenocarcinoma had a non-significantly higher rate of VTE recurrences (HR: 2.35; 95%CI: 0.66–8.42), a non-significantly lower rate of major bleeding (HR: 0.46; 95%CI: 0.16–1.30), and a similar mortality rate (HR: 1.15; 95%CI: 0.87–1.52) relative to these (Table 4). On multivariable analysis, patients with adenocarcinoma had a lower risk of major bleeding (HR: 0.29; 95%CI: 0.09–0.95), a non-significantly higher risk of VTE recurrences (HR: 3.79; 95%CI: 0.76–18.8), and a similar mortality risk (HR: 1.02; 95%CI: 0.76–1.36) compared to those with other tumor types (Table 4). Interestingly, the cumulative rate of VTE recurrences during anticoagulation outweighed the rate of major bleeding in patients with adenocarcinoma, while the opposite was observed in the other types of lung cancer (Figures 1 and 2). Cancers 2022, 14, 4127 6 of 11 Table 3. Clinical outcomes during the course of anticoagulant therapy, according to the histology. Adenocarcinoma Squamous Small-Cell Other Events per 100 Events per 100 Events per 100 Events per 100 N N N N Patient-Years Patient-Years Patient-Years Patient-Years Patients, N 293 98 44 47 Patient-years 106 101 153 85 of therapy PE recurrences 7 4.93 (1.98–10.1) 0 - 1 4.01 (0.05–22.3) 1 47.7 (0.06–26.5) DVT recurrences 4 2.82 (0.76–7.21) 1 2.08 (0.03–11.5) 0 - 0 - VTE recurrences 11 7.74 (3.86–13.9) 1 2.08 (0.03–11.5) 1 4.01 (0.05–22.3) 1 4.76 (0.06–26.5) Major bleeding 6 4.22 (1.54–9.19) 4 8.30 (2.23–21.3) 3 12.0 (2.42–35.2) 2 9.53 (1.07–34.4) Gastrointestinal 2 1.41 (0.16–5.08) 2 4.15 (0.47–15.0) 0 - 0 - Intracranial 2 1.41 (0.16–5.08) 0 - 2 8.03 (0.90–29.0) * 0 - Menorrhagia 1 0.70 (0.01–3.92) 0 - 0 - 0 - Retroperitoneal 1 0.70 (0.01–3.92) 0 - 1 4.01 (0.05–22.3) 0 - Hemopericardium 0 - 1 2.08 (0.03–11.5) 0 - 1 4.76 (0.06–26.5) Hemoptysis 0 - 1 2.08 (0.03–11.5) 0 - 1 4.76 (0.06–26.5) All-cause death 141 99.3 (83.6–117) 39 81.0 (57.6–110) 16 64.2 (36.7–104) 22 105 (65.7–159) Fatal PE 10 7.04 (3.37–12.9) 0 - 0 - 0 - Fatal bleeding 1 0.70 (0.01–3.92) 0 - 1 4.01 (0.05–22.3) 0 - Comparisons among groups (Adenocarcinoma as reference group): * p < 0.05. Abbreviations: VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; IQR, interquartile range. Table 4. Univariable and multivariable analyses for adverse events during the course of anticoagula- tion, according to cancer histology (adenocarcinoma vs. other). Hazard Ratio (95%CI) p Value Univariable analysis VTE recurrences 2.35 (0.66–8.42) 0.190 Major bleeding 0.46 (0.16–1.30) 0.145 Overall death 1.15 (0.87–1.52) 0.322 Fatal PE 6.5 (0.83–50.6) 0.075 Fatal bleeding 0.64 (0.04–10.2) 0.752 Multivariable analysis VTE recurrences 3.79 (0.76–18.8) 0.103 Major bleeding 0.29 (0.09–0.95) 0.042 Overall death 1.02 (0.76–1.36) 0.902 Fatal PE 5.74 (0.73–45.0) 0.096 Fatal bleeding 0.62 (0.04–9.94) 0.736 Abbreviations: VTE, venous thromboembolism; PE, pulmonary embolism; CI, confidence intervals. Multivariate analysis is a competing risk analysis for VTE recurrences and major bleeding, with overall death as the competing event. For overall death, a multivariate Cox analysis was conducted. Variables included in the multivariate analysis: anemia, initial VTE presentation (PE vs. isolated DVT), and time since cancer diagnosis <30 days, for VTE recurrences; stage IV (vs. I–III), for major bleedings; age ≥65 years, stage IV (vs. I–III), recent immobility ≥4 days, leukocyte count >11,000/µL, and ECOG 3–4 (vs. ≤2), for overall death; recent immobility ≥4 days, for fatal PE; and chronic heart failure for fatal bleeding. On multivariable analysis, patients with adenocarcinoma had a lower risk of major bleeding (HR: 0.29; 95%CI: 0.09–0.95), a non-significantly higher risk of VTE recurrences (HR: 3.79; 95%CI: 0.76–18.8), and a similar mortality risk (HR: 1.02; 95%CI: 0.76–1.36) compared to those with other tumor types (Table 4). Interestingly, the cumulative rate of VTE recurrences during anticoagulation outweighed the rate of major bleeding in patients Cancers 2022, 14, 4127 with adenocarcinoma, while the opposite was observed in the other types of lung cancer 7 of 11 (Figures 1 and 2). 0.125 0,125 VTE recurrences in Adenocarcinoma Major bleeding in Adenocarcinoma 0.100 0,100 Cumulative incidence rate 0.075 0,075 0.050 0,050 0.025 0,025 0 0,000 0 30 90 180 365 Days of anticoagulant treatment Adenocarcinoma: Patients at risk 293 229 169 97 42 VTE recurrences 3 7 7 11 Major bleeding 3 4 5 5 Cancers 2022, 14, x FOR PEER REVIEWFigure 1. 1. VTE VTE recurrences recurrences and 8 of 12 Figure andmajor majorbleeding bleedingwhile whileonon anticoagulant treatment anticoagulant for for treatment patients with patients with adenocarcinoma lung cancer. adenocarcinoma lung cancer. 0.125 0,125 VTE recurrences in other types of cancer Major bleeding in other types of cancer 0.100 0,100 Cumulative incidence rate 0.075 0,075 0.050 0,050 0.025 0,025 0 0,000 0 30 90 180 365 Days of anticoagulant treatment Other types of cancer: 189 154 109 60 25 Patients at risk 0 1 2 3 VTE recurrences 1 4 6 8 Major bleeding Figure 2. Figure 2. VTE VTE recurrences recurrences and and major major bleeding bleeding while while on on anticoagulant anticoagulant treatment treatment for for patients patients with with other types of lung cancer. other types of lung cancer. 4. Discussion consecutive patients with lung cancer Our findings, obtained from a large series of consecutive and VTE, reveal important differences between subgroups in and VTE, reveal important differences between subgroups in their their clinical clinical characteristics, characteristics, time elapsed from cancer diagnosis to VTE, and outcomes during anticoagulation. time elapsed from cancer diagnosis to VTE, and outcomes during anticoagulation. Patients Patients with adenocarcinoma (61% of the whole series) were slightly younger, less likely with adenocarcinoma (61% of the whole series) were slightly younger, less likely to be to be men, and the index VTE appeared earlier after the diagnosis of cancer than in patients with other histologies. During the course of anticoagulation, the rate of VTE recurrences was up to two-fold higher than the rate of major bleeding in patients with adenocarcinoma (11 vs. 6 events, respectively), while the rate of recurrences was one-third Cancers 2022, 14, 4127 8 of 11 men, and the index VTE appeared earlier after the diagnosis of cancer than in patients with other histologies. During the course of anticoagulation, the rate of VTE recurrences was up to two-fold higher than the rate of major bleeding in patients with adenocarcinoma (11 vs. 6 events, respectively), while the rate of recurrences was one-third the rate of major bleeding in those with other cancer types (3 vs. 9 events, respectively). Moreover, all 10 patients dying of PE had adenocarcinoma. Thus, our findings suggest that, during anticoagulant therapy for VTE in patients with lung adenocarcinoma, physicians should be more concerned about the effectiveness than about safety of anticoagulation. On the contrary, among patients with other types of lung cancer, the most important issue is safety. Of note, patients with squamous lung cancer presented with a higher prevalence of anemia, and thrombocytopenia, and they were on antiplatelet treatment more frequently than patients with adenocarcinoma. These variables might imply an increased risk of major bleeding events [20]. Eighty-three patients with adenocarcinoma (28%) had developed the index VTE within the first 30 days after cancer diagnosis, when some patients had not started yet oncological therapy, and we hypothesize that this may have influenced the higher mortality rate in this subgroup. Anticancer therapy may harbor some prothrombotic effects, but the control of the malignancy implies a reduction in cancer-related hypercoagulability. This might likely explain the higher rate of VTE recurrences and fatal PE in patients with adenocarcinoma, since anticoagulant therapy may also need good cancer control to be effective [21–23]. In a retrospective study that included 727 patients with lung cancer, those with an early VTE event had worse overall survival when compared to all other patients (median 4 vs. 17 months, p < 0.0001), irrespective of the disease stage (HR 2.4; 95%CI 1.6–3.3) [23]. In a prior RIETE study on 1725 patients with lung cancer-associated thrombosis, we found that 50% had been diagnosed with cancer less than 3 months before the VTE, and 32% less than 30 days. Up to 32% had not received radio- or chemotherapy yet. Almost one in every six patients (16%) with fatal PE died within the first 24 h, with little time for anticoagulant treatment to become effective. Therefore, the precise identification of patients at risk would probably help the implementation of adequate preventive measures and favor early detection of VTE [12]. In the present study, we noticed that the histology could be a key characteristic to take into account. Of note, patients with adenocarcinoma were more likely to have metastases than squamous or small-cell cancer, which could explain an increased risk of developing VTE earlier. This study has some limitations. First, because of the sample size, the events during follow-up were scarce. Thus, the capacity to find significant differences between subgroups was limited. Second, because of the observational design of RIETE registry, anticoagulant treatment may vary according to local practices, but the majority of patients were treated similarly with LMWH for initial and long-term therapy, with a small proportion of patients receiving oral anticoagulants, and no significant differences between subgroups. Third, the study was limited to the anticoagulant treatment period and cannot provide information regarding the duration of anticoagulation. Fourth, not having a central adjudication committee could entail a risk of under- or overestimation of some outcomes, such as the cause of death, but without expected differences between subgroups of the study. Fifth, we did not have information on tumor genetics which may influence the risk of thrombosis, as some oncogenic rearrangements (for example, ALK or ROS1) are more frequent in patients with adenocarcinoma [24,25]. Overall, the design of the study only allows for generating hypotheses. 5. Conclusions In conclusion, the rates of VTE recurrences and major bleeding during anticoagulation in lung cancer patients with VTE appear to vary according to the histology. In patients with adenocarcinoma, the rate of VTE recurrences outweighed the rate of major bleeding. In those with other lung cancers, the opposite occurred. If these findings are externally Cancers 2022, 14, 4127 9 of 11 validated, they could be the basis to start individualizing anticoagulant therapy for VTE in patients with lung cancer. Author Contributions: Conceptualization, P.R.-A. and M.M.; data curation, P.R.-A., R.L., J.T.-S., C.F., J.J.L.-N., M.L.P., C.D.P., J.L.L., L.L.J., R.L.R., L.J.P., J.M.P., I.M. and M.M.; formal analysis, J.T.-S.; methodology, P.R.-A., J.T.-S., and M.M.; writing—original draft, P.R.-A. and M.M.; writing—review and editing, P.R.-A., R.L., J.T.-S., C.F., J.J.L.-N., M.L.P., C.D.P., J.L.L., L.L.J., R.L.R., L.J.P., J.M.P., I.M. and M.M. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University Hospital Germans Trias i Pujol, Barcelona, Spain (Protocol code v3-17_03_2017–PI-17-053- dated 4 July 2017). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Acknowledgments: We express our gratitude to Sanofi Spain, LEO PHARMA, and ROVI for sup- porting this Registry with an unrestricted educational grant. We also thank the RIETE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, and logistic and administrative support. Conflicts of Interest: The authors declare no conflict of interest. Appendix A Coordinator of the RIETE Registry: Manuel Monreal. RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner, and Do- minique Farge-Bancel. RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), Hanh My Bui (Vietnam). RIETE Registry Coordinating Center: S & H Medical Science Service. Members of the RIETE Group: SPAIN: Adarraga, M.D.; Agudo, P.; Alonso-Carrillo, J.; Amado, C.; Arcelus, J.I.; Ballaz, A.; Barba, R.; Barrón, M.; Barrón-Andrés, B.; Beddar-Chaib, F.; Blanco-Molina, A.; Cañas, I.; Carriel, J.; Casado, I.; Cerdá, P.; Chasco, L.; Criado, J.; de Ancos, C.; de Miguel, J.; del Toro, J.; Demelo-Rodríguez, P.; Díaz-Brasero, A.M.; Díaz-Pedroche, M.C.; Díaz-Peromingo, J.A.; Domínguez, I.M.; Escribano, J.C.; Espósito, F.; Farfán-Sedano, A.I.; Falgá, C.; Fernández- Capitán, C.; Fernández-Jiménez, B.; Fernández-Muixi, J.; Fernández-Reyes, J.L.; Fidalgo, M.A.; Font, C.; Francisco, I.; Galeano-Valle, F.; García, M.A.; García-Bragado, F.; García de Herreros, M.; García-León, N.; Gavín-Blanco, O.; Gil-Díaz, A.; Gómez-Cuervo, C.; Gómez- Mosquera, A.M.; González-Moreno, M.; Grau, E.; Guirado, L.; Gutiérrez, J.; Hernández- Blasco, L.; Jara-Palomares, L.; Jaras, M.J.; Jiménez, D.; Jiménez, R.; Jou, I.; Joya, M.D.; Lacruz, B.; Lainez-Justo, S.; Latorre, A.; Lecumberri, R.; Lima, J.; Lobo, J.L.; López-Brull, H.; López- De la Fuente, M.; López-Jiménez, L.; López-Meseguer, M.; López-Miguel, P.; López-Núñez, J.J.; López-Reyes, R.; López-Sáez, J.B.; Lorente, M.A.; Lorenzo, A.; Madridano, O.; Maestre, A.; Manrique-Abos, I.; Marchena, P.J.; Marcos, M.; Martín-Guerra, J.M.; Martín-Martos, F.; Martínez-Redondo, I.; Mellado, M.; Mena, E.; Moisés, J.; Mercado, M.I.; Monreal, M.; Muñoz-Blanco, A.; Muñoz-Gamito, G.; Morales, M.V.; Nieto, J.A.; Noguera-Gras, E.; Núñez- Fernández, M.J.; Olid-Velilla, M.; Osorio, J.; Otalora, S.; Otero, R.; Paredes-Ruiz, D.; Parra, P.; Parra, V.; Pedrajas, J.M.; Peris, M.L.; Pesce, M.L.; Porras, J.A.; Poyo-Molina, J.; Puchades, R.; Riera-Mestre, A.; Rivera-Civico, F.; Rivera-Gallego, A.; Roca, M.; Rosa, V.; Rodríguez-Cobo, A.; Rodríguez-Matute, C.; Ruiz-Artacho, P.; Ruiz-Giménez, N.; Ruiz-Ruiz, J.; Salgueiro, G.; Cancers 2022, 14, 4127 10 of 11 Sancho, T.; Sendín, V.; Sigüenza, P.; Soler, S.; Suárez-Rodríguez, B.; Suriñach, J.M.; Tiberio, G.; Torres, M.I.; Trujillo-Santos, J.; Uresandi, F.; Usandizaga, E.; Valle, R.; Varona, J.F.; Vela, L.; Vela, J.R.; Villalobos, A.; Villares, P. AUSTRIA: Ay, C.; Nopp, S.; Pabinger, I. BELGIUM: Engelen, M.M.; Martens, C.; Verhamme, P. BRAZIL: Yoo, H.H.B. COLOMBIA: Arguello, J.D.; Montenegro, A.C.; Roa, J. CZECH REPUBLIC: Hirmerova, J.; Malý, R. FRANCE: Accassat, S.; Bertoletti, L.; Bura-Riviere, A.; Catella, J.; Chopard, R.; Couturaud, F.; Espitia, O.; Falvo, N.; Hammoudi, L.; Le Mao, R.; Mahé, I.; Moustafa, F.; Plaisance, L.; Sarlon- Bartoli, G.; Suchon, P.; Versini, E. GERMANY: Schellong, S. ISRAEL: Braester, A.; Brenner, B.; Kenet, G.; Tzoran, I. IRAN: Sadeghipour, P. ITALY: Basaglia, M.; Bilora, F.; Bortoluzzi, C.; Brandolin, B.; Ciammaichella, M.; Colaizzo, D.; De Angelis, A.; Dentali, F.; Di Micco, P.; Grandone, E.; Imbalzano, E.; Merla, S.; Pesavento, R.; Prandoni, P.; Siniscalchi, C.; Tufano, A.; Visonà, A.; Vo Hong, N.; Zalunardo, B. LATVIA: Kigitovica, D.; Skride, A. PORTUGAL: Fonseca, S.; Manuel, M.; Meireles, J. REPUBLIC OF NORTH MACEDONIA: Bosevski, M.; Trajkova, M.; Zdraveska, M. 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