Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data

doi:10.1007/s10147-022-02257-y

Observational Study

. 2023 Jan;28(1):69-78.

doi: 10.1007/s10147-022-02257-y. Epub 2022 Nov 10.

Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data

Yukari Tsubata¹, Keita Kawakado², Kosuke Hamai³, Naoki Furuya⁴, Toshihide Yokoyama⁵, Ryota Saito⁶, Atsushi Nakamura⁷, Takeshi Masuda⁸, Megumi Hamaguchi², Shoichi Kuyama⁹, Ryoichi Honda¹⁰, Tadashi Senoo¹¹, Masamoto Nakanishi¹², Takamasa Hotta², Masahiro Yamasaki¹³, Nobuhisa Ishikawa³, Kazunori Fujitaka⁸, Tetsuya Kubota¹⁴, Kunihiko Kobayashi¹⁵, Takeshi Isobe²

Affiliations

¹ Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1 Enya-Cho, Izumo, Shimane, 693-8501, Japan. ytsubata@med.shimane-u.ac.jp.
² Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1 Enya-Cho, Izumo, Shimane, 693-8501, Japan.
³ Department of Respiratory Medicine, Hiroshima Prefectural Hospital, 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan.
⁴ Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
⁵ Department of Respiratory Medicine, Kurashiki Central Hospital, 1-1-1, Miwa, Kurashiki, Okayama, 710-8602, Japan.
⁶ Department of Respiratory Medicine, Tohoku University, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
⁷ Department of Pulmonary Medicine, Sendai Kousei Hospital, 4-15 Hirose-Machi, Aoba-ku, Sendai, Miyagi, 980-0873, Japan.
⁸ Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
⁹ Department of Respiratory Medicine, Iwakuni Clinical Center, 1-1-1 Atago-Machi, Iwakuni, Yamaguchi, 740-8510, Japan.
¹⁰ Department of Respiratory Medicine, Asahi General Hospital, I-1326 Asahi, Chiba, 289-2511, Japan.
¹¹ Department of Respiratory Medicine, National Hospital Organization, Kure Medical Center, 3-1 Aoyamacho, Kure, Hiroshima, 737-0023, Japan.
¹² Department of Medical Oncology, Yamaguchi-Ube Medical Center, 685 Higashikawa, Ube, Yamaguchi, 755-0241, Japan.
¹³ Department of Respiratory Disease, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, 1-9-6, Senda-Machi, Naka-ku, Hiroshima, 730-8619, Japan.
¹⁴ Department of Respiratory Medicine and Allergology, Kochi University Hospital, 185-1 Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan.
¹⁵ Department of Pulmonary Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.

PMID: 36357710
PMCID: PMC9823025
DOI: 10.1007/s10147-022-02257-y

Observational Study

Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data

Yukari Tsubata et al. Int J Clin Oncol. 2023 Jan.

. 2023 Jan;28(1):69-78.

doi: 10.1007/s10147-022-02257-y. Epub 2022 Nov 10.

Authors

Affiliations

¹ Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1 Enya-Cho, Izumo, Shimane, 693-8501, Japan. ytsubata@med.shimane-u.ac.jp.
² Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1 Enya-Cho, Izumo, Shimane, 693-8501, Japan.
³ Department of Respiratory Medicine, Hiroshima Prefectural Hospital, 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan.
⁴ Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
⁵ Department of Respiratory Medicine, Kurashiki Central Hospital, 1-1-1, Miwa, Kurashiki, Okayama, 710-8602, Japan.
⁶ Department of Respiratory Medicine, Tohoku University, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
⁷ Department of Pulmonary Medicine, Sendai Kousei Hospital, 4-15 Hirose-Machi, Aoba-ku, Sendai, Miyagi, 980-0873, Japan.
⁸ Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
⁹ Department of Respiratory Medicine, Iwakuni Clinical Center, 1-1-1 Atago-Machi, Iwakuni, Yamaguchi, 740-8510, Japan.
¹⁰ Department of Respiratory Medicine, Asahi General Hospital, I-1326 Asahi, Chiba, 289-2511, Japan.
¹¹ Department of Respiratory Medicine, National Hospital Organization, Kure Medical Center, 3-1 Aoyamacho, Kure, Hiroshima, 737-0023, Japan.
¹² Department of Medical Oncology, Yamaguchi-Ube Medical Center, 685 Higashikawa, Ube, Yamaguchi, 755-0241, Japan.
¹³ Department of Respiratory Disease, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, 1-9-6, Senda-Machi, Naka-ku, Hiroshima, 730-8619, Japan.
¹⁴ Department of Respiratory Medicine and Allergology, Kochi University Hospital, 185-1 Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan.
¹⁵ Department of Pulmonary Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.

PMID: 36357710
PMCID: PMC9823025
DOI: 10.1007/s10147-022-02257-y

Abstract

Background: Management of cancer-associated venous thromboembolism (VTE) is essential in cancer treatment selection and prognosis. However, currently, no method exists for assessing VTE risk associated with advanced lung cancer. Therefore, we assessed VTE risk, including driver gene mutation, in advanced lung cancer and performed a Khorana score validation.

Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study that included patients with advanced lung cancer. In the Rising-VTE/NEJ037 study, the Khorana score was calculated for enrolled patients with available data on all Khorana score components. The modified Khorana score was based on the body mass index of ≥ 25 kg/m², according to the Japanese obesity standard. A multivariate logistic regression analysis, including patient background characteristics, was performed to evaluate the presence of VTE 2 years after the lung cancer diagnosis.

Results: This study included 1008 patients with lung cancer, of whom 100 (9.9%) developed VTE. From the receiver operating characteristic curve analysis, VTE risk could not be determined because both the Khorana score (0.518) and modified Khorana score (0.516) showed very low areas under the curve. The risk factors for VTE in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2 and diastolic blood pressure.

Conclusion: The Khorana score, which is widely used in cancer-VTE risk assessment, was less useful for Japanese patients with advanced lung cancer. Prothrombin fragment 1 + 2, a serum marker involved in coagulation, was more suitable for risk identification.

Clinical trial information: jRCTs061180025.

Keywords: Deep vein thrombosis; Khorana score; Lung cancer; Prothrombin fragment 1 + 2; Pulmonary thromboembolism.

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Conflict of interest statement

Yukari Tsubata received grant and personal fees from Daiichi Sankyo Co., Ltd. and AstraZeneca K.K. and personal fees from Chugai Pharmaceuticals Inc. outside the submitted work. Naoki Furuya received personal fees from AstraZeneca K.K., Chugai Pharmaceutical, Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., MSD K.K., Pfizer Japan Inc. Taiho Pharmaceutical, and Novartis Pharma K.K. outside the submitted work. Toshihide Yokoyama received personal fees from Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., Takeda Pharmaceutical outside the submitted work. Atsushi Nakamura received grant and personal fees from AstraZeneca K.K., Thermo Fisher Scientific, Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., and personal fees from Taiho Pharmaceutical Co., Ltd., outside the submitted work. Takeshi Masuda received personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan, Nippon Boehringer Ingelheim Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., outside the submitted work. Kazunori Fujitaka received personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Eli Lilly Japan, and Nippon Boehringer Ingelheim Co., Ltd. outside the submitted work. Kunihiko Kobayashi received personal fees from AstraZeneca K.K., Takeda Pharmaceutical outside the submitted work. Takeshi Isobe received grant and personal fees from Daiichi Sankyo Co., Ltd., personal fees from AstraZeneca K.K., Pfizer Japan Inc., and Nippon Boehringer Ingelheim Co., Ltd., and grants from Pearl Therapeutics Inc. and Janssen Pharmaceutical K.K. outside the submitted work.

Figures

**Fig. 1**
Evaluation of the discriminating ability of Khorana score for venous thromboembolism (receiver operating characteristic curve). *AUC* area under the curve, CI confidence interval

**Fig. 2**
Evaluation of the discriminating ability of modified Khorana score for venous thromboembolism (receiver operating characteristic curve). *AUC* area under the curve, CI confidence interval

See this image and copyright information in PMC

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References

1. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–634. doi: 10.1111/j.1538-7836.2007.02374.x. - DOI - PubMed
1. Moore RA, Adel N, Riedel E, et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol. 2011;29:3466–3473. doi: 10.1200/JCO.2011.35.5669. - DOI - PMC - PubMed
1. Fernandes CJ, Morinaga LTK, Alves JL, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28:180119. doi: 10.1183/16000617.0119-2018. - DOI - PMC - PubMed
1. Takano N, Ariyasu R, Koyama J, et al. Improvement in the survival of patients with stage IV non-small-cell lung cancer: experience in a single institutional 1995–2017. Lung Cancer. 2019;131:69–77. doi: 10.1016/j.lungcan.2019.03.008. - DOI - PubMed
1. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38:496–520. doi: 10.1200/JCO.19.01461. - DOI - PubMed

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[1] Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–634. doi: 10.1111/j.1538-7836.2007.02374.x. - DOI - PubMed

[2] Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–634. doi: 10.1111/j.1538-7836.2007.02374.x. - DOI - PubMed

[3] Moore RA, Adel N, Riedel E, et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol. 2011;29:3466–3473. doi: 10.1200/JCO.2011.35.5669. - DOI - PMC - PubMed

[4] Moore RA, Adel N, Riedel E, et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol. 2011;29:3466–3473. doi: 10.1200/JCO.2011.35.5669. - DOI - PMC - PubMed

[5] Fernandes CJ, Morinaga LTK, Alves JL, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28:180119. doi: 10.1183/16000617.0119-2018. - DOI - PMC - PubMed

[6] Fernandes CJ, Morinaga LTK, Alves JL, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28:180119. doi: 10.1183/16000617.0119-2018. - DOI - PMC - PubMed

[7] Takano N, Ariyasu R, Koyama J, et al. Improvement in the survival of patients with stage IV non-small-cell lung cancer: experience in a single institutional 1995–2017. Lung Cancer. 2019;131:69–77. doi: 10.1016/j.lungcan.2019.03.008. - DOI - PubMed

[8] Takano N, Ariyasu R, Koyama J, et al. Improvement in the survival of patients with stage IV non-small-cell lung cancer: experience in a single institutional 1995–2017. Lung Cancer. 2019;131:69–77. doi: 10.1016/j.lungcan.2019.03.008. - DOI - PubMed

[9] Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38:496–520. doi: 10.1200/JCO.19.01461. - DOI - PubMed

[10] Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38:496–520. doi: 10.1200/JCO.19.01461. - DOI - PubMed

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Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data

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Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data

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