Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Study Cohort
2.2. Crude VTE Incidence According to Chemotherapeutic Agent
2.3. Prediction of Cancer-Associated Thrombosis Beyond the CATS Score
2.4. Sensitivity Analysis
3. Discussion
4. Methods
Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Ay, C.; Pabinger, I.; Cohen, A.T. Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb. Haemost. 2017, 117, 219–230. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seng, S.; Liu, Z.; Chiu, S.K.; Proverbs-Singh, T.; Sonpavde, G.; Choueiri, T.K.; Tsao, C.-K.; Yu, M.; Hahn, N.M.; Oh, W.K.; et al. Risk of venous thromboembolism in patients with cancer treated with Cisplatin: A systematic review and meta-analysis. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2012, 30, 4416–4426. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moore, R.A.; Adel, N.; Riedel, E.; Bhutani, M.; Feldman, D.R.; Tabbara, N.E.; Soff, G.A.; Parameswaran, R.; Hassoun, H. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: A large retrospective analysis. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2011, 29, 3466–3473. [Google Scholar] [CrossRef] [PubMed]
- Qi, W.-X.; Lin, F.; Sun, Y.-J.; Tang, L.-N.; Shen, Z.; Yao, Y. Risk of venous and arterial thromboembolic events in cancer patients treated with gemcitabine: A systematic review and meta-analysis. Br. J. Clin. Pharmacol. 2013, 76, 338–347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verso, M.; Agnelli, G.; Barni, S.; Gasparini, G.; Labianca, R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: The Protecht score. Intern. Emerg. Med. 2012, 7, 291–292. [Google Scholar] [CrossRef] [PubMed]
- Di Nisio, M.; Van Es, N.; Rotunno, L.; Anzoletti, N.; Falcone, L.; De Tursi, M.; Natoli, C.; Tinari, N.; Cavallo, I.; Valeriani, E.; et al. Long-term performance of risk scores for venous thromboembolism in ambulatory cancer patients. J. Thromb. Thrombolysis 2019, 48, 125–133. [Google Scholar] [CrossRef] [PubMed]
- Van Es, N.; Di Nisio, M.; Cesarman, G.; Kleinjan, A.; Otten, H.-M.; Mahé, I.; Wilts, I.T.; Twint, D.C.; Porreca, E.; Arrieta, O.; et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: A prospective cohort study. Haematologica 2017, 102, 1494–1501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pabinger, I.; Van Es, N.; Heinze, G.; Posch, F.; Riedl, J.; Reitter, E.-M.; Di Nisio, M.; Cesarman-Maus, G.; Kraaijpoel, N.; Zielinski, C.C.; et al. A clinical prediction model for cancer-associated venous thromboembolism: A development and validation study in two independent prospective cohorts. Lancet Haematol. 2018, 5, e289–e298. [Google Scholar] [CrossRef]
- Ahlbrecht, J.; Dickmann, B.; Ay, C.; Dunkler, D.; Thaler, J.; Schmidinger, M.; Quehenberger, P.; Haitel, A.; Zielinski, C.; Pabinger, I. Tumor grade is associated with venous thromboembolism in patients with cancer: Results from the Vienna Cancer and Thrombosis Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2012, 30, 3870–3875. [Google Scholar] [CrossRef] [PubMed]
- Ay, C.; Vormittag, R.; Dunkler, D.; Simanek, R.; Chiriac, A.-L.; Drach, J.; Quehenberger, P.; Wagner, O.; Zielinski, C.; Pabinger, I. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: Results from the Vienna Cancer and Thrombosis Study. J. Clin. Oncol. 2009, 27, 4124–4129. [Google Scholar] [CrossRef] [PubMed]
- Herrmann, J.; Yang, E.H.; Iliescu, C.A.; Cilingiroglu, M.; Charitakis, K.; Hakeem, A.; Toutouzas, K.; Leesar, M.A.; Grines, C.L.; Marmagkiolis, K. Vascular toxicities of cancer therapies. Circulation 2016, 133, 1272–1289. [Google Scholar] [CrossRef] [PubMed]
- Yu, M.; Han, J.; Cui, P.; Dai, M.; Li, H.; Zhang, J.; Xiu, R. Cisplatin up-regulates ICAM-1 expression in endothelial cell via a NF-κB dependent pathway. Cancer Sci. 2008, 99, 391–397. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y.; Inoue, S.; Shinozaki, R.; Fukue, K.; Kougo, T. Release of cytokines from human umbilical vein endothelial cells treated with platinum compounds in vitro. Jpn. J. Cancer Res. 1998, 89, 757–767. [Google Scholar] [CrossRef] [PubMed]
- Mikuła-Pietrasik, J.; Witucka, A.; Pakuła, M.; Uruski, P.; Begier-Krasińska, B.; Niklas, A.; Tykarski, A.; Książek, A. Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells. Cell. Mol. Life Sci. 2018, 76, 681–697. [Google Scholar] [CrossRef] [Green Version]
- Dasanu, C.A. Gemcitabine: Vascular toxicity and prothrombotic potential. Expert Opin. Drug Saf. 2008, 7, 703–716. [Google Scholar] [CrossRef]
- Bang, Y.-J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet (Lond. Engl.) 2010, 376, 687–697. [Google Scholar] [CrossRef]
- Von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ay, C.; Simanek, R.; Vormittag, R.; Dunkler, D.; Alguel, G.; Koder, S.; Kornek, G.; Marosi, C.; Wagner, O.; Zielinski, C.; et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: Results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008, 112, 2703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ay, C.; Posch, F.; Kaider, A.; Zielinski, C.; Pabinger, I. Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality. J. Thromb. Haemost. 2015, 13, 390–397. [Google Scholar] [CrossRef] [PubMed]
- Fine, J.P.; Gray, R.J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 1999, 94, 496–509. [Google Scholar] [CrossRef]
Variable | Overall (n = 1409) | No Gemcitabine (n = 1174) | Gemcitabine (n = 235) | p1 | No Platinum (n = 908) | Platinum (n = 501) | p1 |
---|---|---|---|---|---|---|---|
Clinical Variables | |||||||
Age at entry (years) | 62.9 (54.2–68·9) | 63.0 (53.6–68·9) | 62.6 (56.1–69.6) | 0.256 | 63.7 (53.9–70.4) | 61.2 (54·4–67.2) | 0.003 |
BMI (kg/m2) | 25.1 (22.1–28.3) | 25.3 (22.5–28.5) | 24.0 (20.9–26.5) | <0.0001 | 25.4 (22.5–28.7) | 24.5 (21.6–27.3) | <0.0001 |
Male sex | 760 (54%) | 640 (55%) | 120 (51%) | 0.333 | 472 (52%) | 288 (57%) | 0.047 |
Tumor site | |||||||
Low/intermediate risk of VTE | 378 (27%) | 366 (31%) | 12 (5%) | <0.0001 | 373 (41%) | 5 (1%) | <0.0001 |
Breast | 226 (16%) | 215 (18%) | 11 (5%) | <0.0001 | 224 (25%) | 2 (0%) | <0.0001 |
Prostate | 153 (11%) | 151 (13%) | 1 (<1%) | <0.0001 | 149 (16%) | 3 (1%) | <0.0001 |
High Risk of VTE | 854 (61%) | 733 (62%) | 121 (51%) | <0.0001 | 467 (51%) | 387 (77%) | <0.0001 |
Lung | 289 (21%) | 213 (18%) | 76 (32%) | <0.0001 | 88 (10%) | 201 (40%) | <0.0001 |
Colorectal | 171 (12%) | 170 (14%) | 1 (<1%) | <0.0001 | 68 (7%) | 103 (21%) | <0.0001 |
Kidney | 42 (3%) | 33 (3%) | 9 (4%) | 0.401 | 39 (4%) | 3 (1%) | <0.0001 |
Lymphoma | 247 (18%) | 241 (21%) | 6 (3%) | <0.0001 | 227 (25%) | 20 (4%) | <0.0001 |
Other sites | 105 (7%) | 76 (6%) | 29 (12%) | 0.002 | 45 (5%) | 60 (12%) | <0.0001 |
Very high risk of VTE | 177 (13%) | 75 (6%) | 102 (43%) | <0.0001 | 68 (7%) | 109 (22%) | <0.0001 |
Pancreas | 116 (8%) | 14 (1%) | 102 (43%) | <0.0001 | 49 (5%) | 67 (13%) | <0.0001 |
Stomach | 61 (4%) | 61 (5%) | 0 (0%) | <0.0001 | 19 (2%) | 42 (8%) | <0.0001 |
Tumor characteristics | |||||||
Newly diagnosed cancer | 997 (71%) | 819 (70%) | 178 (76%) | 0.066 | 606 (67%) | 391 (78%) | <0.0001 |
Tumor grade G3/G4 | 518 (38%) | 418 (36%) | 100 (43%) | 0.05 | 315 (36%) | 203 (41%) | 0.04 |
Tumor stage (UICC/AnnArbor) | / | / | / | <0.0001 | / | / | <0.0001 |
Stage I | 138 (10%) | 133 (12%) | 5 (2%) | / | 116 (14%) | 22 (4%) | / |
Stage II | 309 (23%) | 278 (25%) | 31 (13%) | / | 264 (31%) | 45 (9%) | / |
Stage III | 221 (16%) | 184 (17%) | 37 (16%) | / | 124 (15%) | 97 (19%) | / |
Stage IV | 672 (50%) | 511 (46%) | 161 (69%) | / | 336 (40%) | 336 (67%) | / |
Biomarker levels | |||||||
D-dimer (µg/mL) | 0.7 (0.4–1.5) | 0.7 (0.3–1.3) | 1.2 (0.6–2.6) | <0.0001 | 0.6 (0.3–1.2) | 1.0 (0.5–2.0) | <0.0001 |
VTE prediction model | |||||||
CATS score: predicted 6-month VTE risk (%) 2 | 5.0 (3.3–6.3] | 4.8 (2.8–5.70 | 7.4 (5.2–11.0) | <0.0001 | 4.6 (2.6–5.5) | 5.8 (5.0–8.6) | <0.0001 |
Outcomes | |||||||
Mortality | 532 (37.8%) | 377 (32.1%) | 155 (66.0%) | / | 253 (27.9%) | 279 (55.7%) | / |
VTE events | 111 (7.9%) | 87 (7.4%) | 24 (10.2%) | / | 53 (5.9%) | 58 (11.6%) | / |
Model | Variable | SHR | 95%CI | p |
---|---|---|---|---|
#1 | Gemcitabine | 0.83 | 0.53–1.31 | 0.432 |
Tumor type: Low/moderate VTE risk | Ref. | Ref. | Ref. | |
Tumor type: High VTE risk | 2.48 | 1.37–4.48 | 0.003 | |
Tumor type: Very high VTE risk | 5.48 | 2.82–10.68 | <0.0001 | |
#2 | Gemcitabine | 1.18 | 0.75–1.85 | 0.481 |
D-dimer (per doubling) | 1.44 | 1.25–1.66 | <0.0001 | |
#3 | Gemcitabine | 0.82 | 0.53–1.28 | 0.390 |
Tumor type: Low/moderate VTE risk | Ref. | Ref. | Ref. | |
Tumor type: High VTE risk | 2.26 | 1.24–4.10 | 0.008 | |
Tumor type: Very high VTE risk | 4.27 | 2.10–8.66 | <0.0001 | |
D-dimer (per doubling) | 1.31 | 1.11–1.53 | 0.001 | |
#4 | Platinum-based therapy | 1.46 | 0.97–2.21 | 0.073 |
Tumor type: Low/moderate VTE risk | Ref. | Ref. | Ref. | |
Tumor type: High VTE risk | 2.03 | 1.09–3.77 | 0.025 | |
Tumor type: Very high VTE risk | 3.89 | 1.87–8.11 | <0.001 | |
#5 | Platinum-based therapy | 1.84 | 1.26–2.69 | 0.002 |
D-dimer (per doubling) | 1.40 | 1.20–1.63 | <0.0001 | |
#6 | Platinum-based therapy | 1.44 | 0.96–2.17 | 0.080 |
Tumor type: Low/moderate VTE risk | Ref. | Ref. | Ref. | |
Tumor type: High VTE risk | 1.85 | 0.99–3.46 | 0.055 | |
Tumor type: Very high VTE risk | 3.08 | 1.45–6.57 | 0.004 | |
D-dimer (per doubling) | 1.31 | 1.1–1.53 | 0.001 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Moik, F.; van Es, N.; Posch, F.; Di Nisio, M.; Fuereder, T.; Preusser, M.; Pabinger, I.; Ay, C. Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study. Cancers 2020, 12, 2493. https://doi.org/10.3390/cancers12092493
Moik F, van Es N, Posch F, Di Nisio M, Fuereder T, Preusser M, Pabinger I, Ay C. Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study. Cancers. 2020; 12(9):2493. https://doi.org/10.3390/cancers12092493
Chicago/Turabian StyleMoik, Florian, Nick van Es, Florian Posch, Marcello Di Nisio, Thorsten Fuereder, Matthias Preusser, Ingrid Pabinger, and Cihan Ay. 2020. "Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study" Cancers 12, no. 9: 2493. https://doi.org/10.3390/cancers12092493