|
1
|
Liang Z, Huang X, Mao J, Xie J, Li X, Qin L. The impact of KRAS mutations on risk of venous thromboembolism recurrence in patients with metastatic colorectal cancer. BMC Gastroenterol 2025; 25:240. [PMID: 40211193 PMCID: PMC11987216 DOI: 10.1186/s12876-025-03843-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 04/02/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND The relationship between KRAS mutations and the risk of venous thromboembolism (VTE) recurrence in metastatic colorectal cancer (mCRC) patients with established cancer-associated thrombosis (CAT) remains uncertain. This study aims to (1) evaluate the predictive value of seven KRAS mutation subtypes for VTE recurrence and (2) assess the impact of incorporating these mutations into two existing VTE risk scores: the Khorana score and the Ottawa score. METHODS Between 2019 and 2023, we identified patients with histologically confirmed mCRC who had symptomatic or incidental index VTE and received anticoagulation therapy. Regression analyses were conducted to calculate hazard ratios (HRs) for recurrent VTE associated with the seven KRAS mutation subtypes. We used receiver operating characteristic (ROC) curves to assess the performance of both the original scores and the modified scores that included KRAS mutations. To quantify the improvements of the modified scores, we calculated the net reclassification improvement (NRI). RESULTS A total of 2,195 patients were enrolled. KRAS G12C, KRAS G12A, and KRAS G13D mutations were significantly associated with a higher risk of recurrent VTE compared to other subtypes, with HRs of 1.84 (95% CI: 1.09-2.97), 2.02 (95% CI: 1.07-3.79), and 1.55 (95% CI: 1.02-2.27), respectively. The original Khorana and Ottawa scores demonstrated moderate predictive ability for VTE recurrence, each with an area under the ROC curve (ROC-AUC) of 0.56 (95% CI: 0.52-0.60). Incorporating the KRAS G12C, KRAS G12A, and KRAS G13D mutations improved the AUCs to 0.70 (95% CI: 0.67-0.74) for the modified Khorana score and 0.71 (95% CI: 0.67-0.74) for the modified Ottawa score. After dichotomizing risk using thresholds from ROC analysis, the NRI values were 0.54 (95% CI: 0.43-0.65) for the modified Khorana score and 0.48 (95% CI: 0.37-0.60) for the modified Ottawa score. CONCLUSIONS The KRAS G12C, KRAS G12A, and KRAS G13D mutations are significantly associated with an increased risk of recurrent VTE. Incorporating these specific KRAS mutations into existing risk scores may enhance their predictive accuracy for recurrent VTE in patients with mCRC.
Collapse
Affiliation(s)
- Zhikun Liang
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Huang
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jieling Mao
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Jingwen Xie
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Li
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Department of Pharmacy, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 26 Erheng Road of Yuan Village, Tianhe District, Guangzhou, 510655, China.
| | - Li Qin
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Department of Pharmacy, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 26 Erheng Road of Yuan Village, Tianhe District, Guangzhou, 510655, China.
| |
Collapse
|
|
2
|
Takahashi Y, Fujiwara H, Yamamoto K, Yamaguchi S, Nagao S, Takano M, Miyamoto M, Hasegawa K, Miwa M, Yasuoka T, Yamashita S, Hirakawa T, Nagai T, Hamada Y, Uno M, Mori-Uchino M, Ohwada M, Mitsuhashi A, Satoh T, Fujiwara K, Suzuki M. Incidence and risk factors for venous thromboembolism in gynecological cancer: the GOTIC-VTE trial. J Thromb Thrombolysis 2025; 58:299-308. [PMID: 39602066 PMCID: PMC11885320 DOI: 10.1007/s11239-024-03055-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/29/2024]
Abstract
Real-world data on venous thromboembolism (VTE) in Japanese patients with gynecological cancer are lacking. The GOTIC-VTE trial aimed to evaluate the frequency of VTE-associated events and risk factors at the time of cancer diagnosis and during 1-year follow-up. From July 2017 to February 2019, patients with endometrial, cervical, ovarian, tubal, or peritoneal cancer who underwent VTE screening within 2 months before registration, were enrolled. Of the 1008 patients enrolled, 881 were included in the analysis set, 51 (5.8%) had VTE at the time of cancer diagnosis (baseline), 7 (0.8%) had symptomatic VTE, and the majority had asymptomatic VTE (n = 44; 5.0%). Patients with ovarian, tubal, or peritoneal cancer had a higher incidence of VTE (13.7%) than those with other cancer types. During the 1-year follow-up, 0.9% (n = 8) of the patients had symptomatic VTE, 3.5% (n = 31) had composite VTE (symptomatic VTE and incidental VTE requiring treatment), 0.2% (n = 2) had bleeding events, and 4.3% (n = 38) had all-cause death, all of which were significantly higher in the VTE group at baseline. In the multivariate analysis, chemotherapy was an independent risk factor for composite VTE during the 1-year follow-up (hazard ratio 3.85, 95% confidence interval 1.39-13.63, p = 0.018). Among gynecological cancers, VTE incidence is particularly high in ovarian, tubal, or peritoneal cancer, and patients undergoing chemotherapy should be cautioned against VTE occurrence during treatment.The GOTIC-VTE trial Unique identifier, jRCTs031180124; Registration date, April 06, 2017.
Collapse
Affiliation(s)
- Yoshifumi Takahashi
- Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
| | - Hiroyuki Fujiwara
- Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Kouji Yamamoto
- Department of Biostatistics, School of Medicine, Yokohama City University, Kanagawa, Japan
| | - Satoshi Yamaguchi
- Department of Gynecologic Oncology, Hyogo Cancer Center, Hyogo, Japan
| | - Shoji Nagao
- Department of Gynecologic Oncology, Hyogo Cancer Center, Hyogo, Japan
- Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masashi Takano
- Department of Obstetrics and Gynecology, National Defense Medical College, Saitama, Japan
| | - Morikazu Miyamoto
- Department of Obstetrics and Gynecology, National Defense Medical College, Saitama, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Maiko Miwa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Toshiaki Yasuoka
- Department of Obstetrics and Gynecology, Ehime University, Graduate School of Medicine, Ehime, Japan
| | - Soichi Yamashita
- Department of Gynecology, Gunma Prefectural Cancer Center, Gunma, Japan
| | - Takashi Hirakawa
- Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Tomonori Nagai
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Yoshinobu Hamada
- Department of Obstetrics and Gynecology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
| | - Masaya Uno
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
| | - Mayuyo Mori-Uchino
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Michitaka Ohwada
- Department of Obstetrics and Gynecology, International University of Health and Welfare, Tochigi, Japan
| | - Akira Mitsuhashi
- Department of Obstetrics and Gynecology, School of Medicine, Dokkyo Medical University, Tochigi, Japan
| | - Toyomi Satoh
- Department of Obstetrics and Gynecology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Mitsuaki Suzuki
- Department of Obstetrics and Gynecology, Shinyurigaoka General Hospital, Kanagawa, Japan
| |
Collapse
|
|
3
|
Schulman S, Makatsariya A, Khizroeva J, Bitsadze V, Kapanadze D. The Basic Principles of Pathophysiology of Venous Thrombosis. Int J Mol Sci 2024; 25:11447. [PMID: 39519000 PMCID: PMC11547114 DOI: 10.3390/ijms252111447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 10/19/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
The past few decades have brought tremendous insight into the molecular and pathophysiological mechanisms responsible for thrombus generation. For a clinician, it is usually sufficient to explain the incident of deep vein thrombosis (DVT) with provoking factors such as trauma with vascular injury, immobilization, hormonal factors, or inherited or acquired coagulation defects. About half of DVTs are, however, lacking such triggers and are called unprovoked. Venous stasis and hypoxia at the valve sinus level may start a chain of reactions. The concept of immunothrombosis has added a new dimension to the old etiological triad of venous stasis, vessel wall injury, and changes in blood components. This is particularly important in COVID-19, where hyperinflammation, cytokines, and neutrophil extracellular traps are associated with the formation of microthrombi in the lungs. To better understand the mechanisms behind DVT and reach beyond the above-mentioned simplifications, animal models and clinical epidemiological studies have brought insight into the complex interplay between leukocytes, platelets, endothelium, cytokines, complements, and coagulation factors and inhibitors. These pathways and the interplay will be reviewed here, as well as the roles of cancer, anticancer drugs, and congenital thrombophilic defects on the molecular level in hypercoagulability and venous thromboembolism.
Collapse
Affiliation(s)
- Sam Schulman
- Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Alexander Makatsariya
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Jamilya Khizroeva
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Victoria Bitsadze
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Daredzhan Kapanadze
- Center of Pathology of Pregnancy and Hemostasis «Medlabi», Tbilisi 340112, Georgia;
| |
Collapse
|
|
4
|
Walker CA, Edwards C, McIntire D, Makepeace L, Holloway SB, Kakadiaris E, Spirtos AN, Miller DS, Lea JS. Predicting VTE and utility of thromboprophylaxis in metastatic and recurrent cervical cancer. Gynecol Oncol 2024; 188:22-26. [PMID: 38875744 DOI: 10.1016/j.ygyno.2024.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 05/25/2024] [Indexed: 06/16/2024]
Abstract
OBJECTIVE Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting. METHODS We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum. RESULTS 232 patients were included for evaluation. Mean age was 49 years (range 20-83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE. CONCLUSION Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.
Collapse
Affiliation(s)
- Christopher A Walker
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Carson Edwards
- Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Don McIntire
- Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Lydia Makepeace
- Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Steven Blaine Holloway
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Ev Kakadiaris
- Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Alexandra N Spirtos
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - David S Miller
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Jayanthi S Lea
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
| |
Collapse
|
|
5
|
Liang H, Wang T, Liu D, Wang H, Ba Z, Xiao Y, Liu Y, Yuan J, Yang W. Cardiovascular comorbidities and their prognostic value in small cell lung cancer patients with chemoradiotherapy. Clin Transl Oncol 2024; 26:1348-1356. [PMID: 38103121 DOI: 10.1007/s12094-023-03359-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND Small cell lung cancer (SCLC) is an extremely malignant subtype of lung cancer because of its high potential for metastases. Cardiac invasion of SCLC is a serious concern that may lead to systemic embolism or tract obstruction. It has aroused much concern that cardiovascular comorbidities may significantly affect the survival of SCLC patients and their treatment decisions. METHODS We consecutively recruited 772 small cell lung cancer (SCLC) patients between January 2011 and December 2018 from 4 cancer specialty hospitals in China. Only newly diagnosed primary cancer inpatients were included. Univariable and multivariable adjusted Cox proportional hazard models were conducted to evaluate the risk factors associated with mortality. Hazard ratios (HRs) for mortality and corresponding 95% confidence intervals (95% CIs) were calculated. RESULTS The prevalence of cardiovascular diseases (CVDs) was 34.6% in all SCLC patients. Log-rank analysis presented statistically significant differences in median survival time (MST) between patients with CVD and without CVD in all SCLC patients (9.0 months vs. 15.0 months, P = 0.005) and patients with chemotherapy only (12.0 months vs. 18.0 months, P = 0.048). Pericardial effusion (HR 1.671, 95% CI 1.082-2.580, P = 0.021) and heart failure (HR 1.752, 95% CI 1.290-2.379, P < 0.001) were independent risk factors associated with mortality in all SCLC patients. VTE is related to poorer prognosis in patients with chemotherapy only (HR 5.558, 95% CI 1.335-23.135, P = 0.018) and chemoradiotherapy (HR 3.057, 95% CI 1.270-7.539, P = 0.013). CONCLUSIONS Comprehensive management of CVD comorbidities is of vital importance for the long-term prognosis of SCLC patients.
Collapse
Affiliation(s)
- Hanyang Liang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Tianjie Wang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Dong Liu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Hao Wang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Zhengqing Ba
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Ying Xiao
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Yilu Liu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Jiansong Yuan
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China.
- Key Laboratory of Pulmonary Vascular Medicine, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China.
| | - Weixian Yang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China.
- Key Laboratory of Pulmonary Vascular Medicine, National Center for Cardiovascular Diseases, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, 100037, China.
| |
Collapse
|
|
6
|
Tang L, Ding C, Li H, Yin G, Zhang H, Liu WS, Ji Y, Li H. A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database. Expert Opin Drug Saf 2024; 23:213-220. [PMID: 37581403 DOI: 10.1080/14740338.2023.2248876] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Bevacizumab is used for the treatment of advanced malignant tumors; it acts by inhibiting angiogenesis. This study aimed to examine adverse events (AEs) of bevacizumab, especially hemorrhage, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESEARCH DESIGN AND METHODS The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were used to analyze the AEs of bevacizumab using FAERS registration data from January 2004 to September 2022. Clinical information regarding hemorrhagic signals was further analyzed. RESULTS The number of bevacizumab-associated AE reports was 96,477. Our study found that 892 significant preferred terms (PTs) were spread throughout 25 organ systems. The system organ classes (SOCs) focus on general disorders, administration site conditions, blood and lymphatic system disorders, injury, poisoning, and procedural complications. A total of 2,847 bevacizumab-related hemorrhage cases were reported, and 37 hemorrhagic signals were identified. Hemorrhagic signals were focused on SOC levels in vascular, gastrointestinal, and nervous system disorders. Colorectal, lung, and breast cancers are the three most common malignancies associated with BV-induced hemorrhage. CONCLUSION The AE report from the present study confirms the majority of label information for bevacizumab, while also identifying new AEs. In addition, this was a large descriptive study of bevacizumab-induced hemorrhage.
Collapse
Affiliation(s)
- Linlin Tang
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Chuanhua Ding
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Hongying Li
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Guoqiang Yin
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Haixia Zhang
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Wen Shan Liu
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Yinghui Ji
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Hui Li
- Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| |
Collapse
|
|
7
|
Chen Y, Huang C, Lien L, Chen J, Hsieh F. Cardiovascular Toxicity of Angiogenesis Inhibitors Among Patients With Cancer in Taiwan: A Nested Case-Control Study. J Am Heart Assoc 2024; 13:e030263. [PMID: 38156594 PMCID: PMC10863808 DOI: 10.1161/jaha.123.030263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 12/06/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND Research on the cardiovascular toxicity of angiogenesis inhibitors among patients with cancer in Taiwan is lacking. This observational study explored the risk of major adverse cardiovascular events (MACEs) associated with angiogenesis inhibitors in Taiwan. METHODS AND RESULTS We conducted a nested case-control study using the TCR (Taiwan Cancer Registry) linked with the Taiwan National Insurance Claim Database. We matched every case with 4 controls using risk-set sampling by index date, age, sex, cancer type, and cancer diagnosis date. Conditional logistic regression was used to evaluate the risks of MACEs and different cardiovascular events using propensity score adjustment or matching. Sensitivity analyses were used to evaluate the risks matched by cancer stages or exposure within 1 year. Among a cohort of 284 292 after the exclusion of prevalent cases, the incidences of MACEs among the overall cohort and those exposed to angiogenesis inhibitors were 22.5 and 32.5 events per 1000 person-years, respectively. We matched 17 817 cases with 70 740 controls, with a mean age of 74.9 years, and 56.8% of patients were men. After propensity score adjustment, angiogenesis inhibitors were associated with increased risks of MACEs (odds ratio, 4.56; 95% CI, 1.78-11.59). Significantly increased risks were noted for heart failure hospitalization, myocardial infarction, cerebrovascular accident, and venous thromboembolism, but not for new-onset atrial fibrillation. Similar results were observed after matching by cancer stage or restriction of 1-year exposure. CONCLUSIONS Angiogenesis inhibitors were associated with increased risks of MACEs among patients with various malignancies in Taiwan but were not associated with new-onset atrial fibrillation.
Collapse
Affiliation(s)
- Yen‐Chou Chen
- Division of Cardiology and Cardiovascular Research CentreTaipei Medical University HospitalTaipeiTaiwan
- Taipei Heart Institute, Taipei Medical UniversityTaipeiTaiwan
- School of Public Health, College of Public HealthTaipei Medical UniversityTaipeiTaiwan
| | - Chun‐Yao Huang
- Division of Cardiology and Cardiovascular Research CentreTaipei Medical University HospitalTaipeiTaiwan
- Taipei Heart Institute, Taipei Medical UniversityTaipeiTaiwan
- Department of Biomedical Sciences and EngineeringNational Central UniversityTao‐YuanTaiwan
| | - Li‐Ming Lien
- School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
- Department of NeurologyShin Kong Wu Ho‐Su Memorial HospitalTaipeiTaiwan
| | - Jin‐Hua Chen
- Graduate Institute of Data Science, College of ManagementTaipei Medical UniversityTaipeiTaiwan
- Health Data Analytics and Statistics Centre, Office of Data ScienceTaipei Medical UniversityTaipeiTaiwan
| | - Fang‐I Hsieh
- School of Public Health, College of Public HealthTaipei Medical UniversityTaipeiTaiwan
- Master Program in Clinical Genomics and Proteomics, College of PharmacyTaipei Medical UniversityTaipeiTaiwan
| |
Collapse
|
|
8
|
Shin JI, Chee CG, Yoon MA, Chung HW, Lee MH, Lee SH. Vertebral Venous Congestion That May Mimic Vertebral Metastasis on Contrast-Enhanced Chest Computed Tomography in Chemoport Inserted Patients. Korean J Radiol 2024; 25:62-73. [PMID: 38184770 PMCID: PMC10788611 DOI: 10.3348/kjr.2023.0224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 08/20/2023] [Accepted: 09/22/2023] [Indexed: 01/08/2024] Open
Abstract
OBJECTIVE This study aimed to determine the prevalence of vertebral venous congestion (VVC) in patients with chemoport insertion, evaluate the imaging characteristics of nodular VVC, and identify the factors associated with VVC. MATERIALS AND METHODS This retrospective single-center study was based on follow-up contrast-enhanced chest computed tomography (CT) of 1412 adult patients who underwent chemoport insertion between January 2016 and December 2016. The prevalence of venous stenosis, reflux, and VVC were evaluated. The imaging features of nodular VVC, including specific locations within the vertebral body, were analyzed. To identify the factors associated with VVC, patients with VVC were compared with a subset of patients without VVC who had been followed up for > 3 years without developing VVC after chemoport insertion. Toward this, a multivariable logistic regression analysis was performed. RESULTS After excluding 333 patients, 1079 were analyzed (mean age ± standard deviation, 62.3 ± 11.6 years; 540 females). The prevalence of VVC was 5.8% (63/1079), with all patients (63/63) demonstrating vertebral venous reflux and 67% (42/63) with innominate vein stenosis. The median interval between chemoport insertion and VVC was 515 days (interquartile range, 204-881 days). The prevalence of nodular VVC was 1.5% (16/1079), with a mean size of 5.9 ± 3.1 mm and attenuation of 784 ± 162 HU. Nodular VVC tended to be located subcortically. Forty-four patients with VVC underwent CT examinations with contrast injections in both arms; the VVC disappeared in 70% (31/44) when the contrast was injected in the arm contralateral to the chemoport site. Bevacizumab use was independently associated with VVC (odds ratio, 3.45; P < 0.001). CONCLUSION The prevalence of VVC and nodular VVC was low in patients who underwent chemoport insertion. Nodular VVC was always accompanied by vertebral venous reflux and tended to be located subcortically. To avoid VVC, contrast injection in the arm contralateral to the chemoport site is preferred.
Collapse
Affiliation(s)
- Jeong In Shin
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Choong Guen Chee
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Min A Yoon
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Won Chung
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min Hee Lee
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Lee
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
9
|
Yhim HY, Lee J, Kim KH, Kim SA, Lee JY, Hwang HG, Hong J, Lee JO, Bang SM. Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea. Thromb Res 2023; 231:50-57. [PMID: 37804738 DOI: 10.1016/j.thromres.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 09/30/2023] [Accepted: 10/02/2023] [Indexed: 10/09/2023]
Abstract
INTRODUCTION Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.
Collapse
Affiliation(s)
- Ho-Young Yhim
- Department of Internal Medicine, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Juhyun Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Kyoung Ha Kim
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Sang-A Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Ji Yun Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Hun-Gyu Hwang
- Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Soonchunhyang University College of Medicine, Gumi, Republic of Korea
| | - Junshik Hong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Ok Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Soo-Mee Bang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
| |
Collapse
|
|
10
|
Al-Jazairi AS, Bahammam N, Aljuaid D, Almutairi L, Alshahrani S, Albuhairan N, Cahusac PMB, Korayem GB. Cardiovascular adverse events of antineoplastic monoclonal antibodies among cancer patients: real-world evidence from a tertiary healthcare system. CARDIO-ONCOLOGY (LONDON, ENGLAND) 2023; 9:35. [PMID: 37749652 PMCID: PMC10519122 DOI: 10.1186/s40959-023-00184-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 08/04/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND Antineoplastic monoclonal antibodies (mAbs), such as trastuzumab, bevacizumab, and pertuzumab have been the mainstay of therapy in cancer patients. Despite proven efficacy of the monoclonal antibodies, cardiovascular-induced adverse events such as heart failure, hypertension, ischemic heart disease, arrhythmias, thromboembolic events, and hemorrhage remain a major complication. The European society of cardiology address that concern with antineoplastic monoclonal antibodies issuing a guideline to manage and monitor chemotherapy-induced cardiotoxicity. There is limited evidence of the real-world prevalence of cardiovascular (CV) events induced by monoclonal antibodies among patients with cancer in Saudi Arabia. OBJECTIVE To evaluate the prevalence of cardiovascular adverse events among patients with cancer treated with monoclonal antibodies in Saudi Arabia. METHODS This is a retrospective study conducted in a tertiary care hospital, Riyadh, Saudi Arabia. Data were obtained from an electronic medical record of patients with cancer treated with one of the selected monoclonal antibodies, who met the inclusion criteria between January 2005 until June 2015 and have been followed up for at least one year. Patients were stratified into groups according to monoclonal antibodies treatment: trastuzumab, bevacizumab, pertuzumab, and combined mAbs. RESULTS A total of 1067 patient were included in the study, within the pre-determined study period. The prevalence of cardiovascular disease among patients with cancer treated with monoclonal antibodies was 16.3%. The prevalence of heart failure was relatively higher in the trastuzumab group (46/626 patients, 7.3%). Among 418 patients treated with bevacizumab, hypertension was the most frequent adverse event, reported in 38 patients (9.1%), followed by thromboembolism reported in 27 patients (6.5%). Treatment discontinuation owing to cardiovascular adverse events was reported in 42/1,067 patients (3.9%). CONCLUSION AND RELEVANCE Prevalence of antineoplastic monoclonal antibody induced cardiovascular adverse events among patients with cancer is substantially high in Saudi Arabia. There is an urgent need to streamline the practice for identifying high risk patients and flexible referral system for cardio-oncology care.
Collapse
Affiliation(s)
- Abdulrazaq S Al-Jazairi
- Division of Clinical Trials Transformation Initiative, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
- College of Pharmacy and Medicine, Alfaisal University, P.O. Box 50927, Riyadh, 11533, Kingdom of Saudi Arabia.
| | - Nahlah Bahammam
- College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 101283, 11655, Riyadh, Saudi Arabia
| | - Dhai Aljuaid
- College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 101283, 11655, Riyadh, Saudi Arabia
| | - Lama Almutairi
- College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 101283, 11655, Riyadh, Saudi Arabia
| | - Shroog Alshahrani
- College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 101283, 11655, Riyadh, Saudi Arabia
| | - Norah Albuhairan
- King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Peter M B Cahusac
- College of Pharmacy and Medicine, Alfaisal University, P.O. Box 50927, Riyadh, 11533, Kingdom of Saudi Arabia
| | - Ghazwa B Korayem
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia
| |
Collapse
|
|
11
|
Mayenga M, Falvo N, Mahé I, Jannot AS, Gazeau B, Meyer G, Gendron N, Sanchez O, Djennaoui S, Planquette B. Cancer-Associated Thrombosis on Bevacizumab: Risk of Recurrence and Bleeding When Bevacizumab Is Stopped or Continued. Cancers (Basel) 2023; 15:3893. [PMID: 37568708 PMCID: PMC10417508 DOI: 10.3390/cancers15153893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/08/2023] [Accepted: 07/09/2023] [Indexed: 08/13/2023] Open
Abstract
Cancer-associated thrombosis (CAT) is a common complication during cancer, with complex management due to an increased risk of both recurrence and bleeding. Bevacizumab is an effective anti-angiogenic treatment but increases the risk of bleeding and potentially the risk of venous thromboembolism (VTE). The aim of this study was to evaluate the efficacy and safety of anticoagulant therapy in patients with CAT receiving bevacizumab, according to the continuation or discontinuation of bevacizumab. In a retrospective multicenter study, patients receiving anticoagulant for CAT occurring under bevacizumab therapy were included. The primary endpoint combined recurrent VTE and/or major or clinically relevant non-major bleeding. Among the 162 patients included, bevacizumab was discontinued in 70 (43.2%) patients and continued in 92 (56.8%) patients. After a median follow-up of 318 days, 21 (30.0%) patients in the discontinuation group experienced VTE recurrence or major or clinically relevant non-major bleeding, compared to 27 (29.3%) in the continuation group. The analysis of survival following the first event showed no significant difference between the groups in uni- or multivariate analysis (p = 0.19). The primary endpoint was not influenced by the duration of bevacizumab exposure. These results suggest that the efficacy and safety of anticoagulant therapy in patients with CAT receiving bevacizumab is not modified regardless of whether bevacizumab is continued or discontinued.
Collapse
Affiliation(s)
- Marie Mayenga
- Department of Pulmonology and Intensive Care, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France (B.P.)
| | - Nicolas Falvo
- Department of Vascular Pathology, Centre Hospitalier Universitaire Dijon-Bourgogne, 21000 Dijon, France
| | - Isabelle Mahé
- Université Paris Cité, Service de Médecine Interne, Hôpital Louis Mourier, AP-HP, 92700 Colombes, France
- Innovative Therapies in Haemostasis, INSERM UMR_S1140, 75006 Paris, France
- INNOVTE-FCRIN, 42055 Saint-Etienne, France
| | - Anne-Sophie Jannot
- Department of Biostatistics, Medical Informatics and Public Health, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France
| | - Benoit Gazeau
- Department of Respiratory Medicine, Centre Hospitalier de Bourg-en-Bresse, 01012 Bourg-en-Bresse, France
| | - Guy Meyer
- Department of Pulmonology and Intensive Care, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France (B.P.)
- INNOVTE-FCRIN, 42055 Saint-Etienne, France
- Université Paris Cité, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France
| | - Nicolas Gendron
- Department of Biological Hematology, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France
- Université de Paris, Innovative Therapies in Haemostasis, Laboratoire de Recherches Biochirugicales (Fondation Carpentier), 75005 Paris, France
| | - Olivier Sanchez
- Department of Pulmonology and Intensive Care, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France (B.P.)
- INNOVTE-FCRIN, 42055 Saint-Etienne, France
- Université Paris Cité, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France
| | - Sadji Djennaoui
- Université Paris Cité, Service de Médecine Interne, Hôpital Louis Mourier, AP-HP, 92700 Colombes, France
- Innovative Therapies in Haemostasis, INSERM UMR_S1140, 75006 Paris, France
| | - Benjamin Planquette
- Department of Pulmonology and Intensive Care, Hôpital Européen Georges-Pompidou, AP-HP, 75015 Paris, France (B.P.)
- INNOVTE-FCRIN, 42055 Saint-Etienne, France
- Université Paris Cité, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France
| |
Collapse
|
|
12
|
Mitigating acute chemotherapy-associated adverse events in patients with cancer. Nat Rev Clin Oncol 2022; 19:681-697. [PMID: 36221000 DOI: 10.1038/s41571-022-00685-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2022] [Indexed: 11/08/2022]
Abstract
Despite the enthusiasm surrounding novel targeted agents and immunotherapies, chemotherapy remains the mainstay treatment for most human malignancies, either alone or in combination. Yet, the burden of chemotherapy-associated adverse events (CAAEs) remains high and, importantly, is associated with considerable morbidity, mortality and costs that affect patients across multiple dimensions, including physical, emotional and social functioning. CAAEs can directly affect patient outcomes and indirectly increase the risk of cancer recurrence by compromising treatment intensity and continuity. Systematic efforts to identify and critically summarize the evidence on management approaches for CAAEs remain limited. Herein, we review the most common acute CAAEs having a major effect on survival, quality of life, function and/or continuation of optimal therapy. We focus on selected acute toxicities that occur during treatment, summarizing their underlying pathophysiology, multifactorial aetiologies, evidenced-based treatments, prevention strategies and management recommendations. We also summarize the available evidence on risk factors, validated risk assessment tools and other efforts to optimize symptom control in patients most likely to benefit in order to personalize the prevention and treatment of acute CAAEs. Finally, we discuss innovative symptom monitoring and supportive care interventions that are under development to further improve the outcomes of patients with cancer.
Collapse
|
|
13
|
Kong Y, Xu XC, Hong L. Arteriovenous thrombotic events in a patient with advanced lung cancer following bevacizumab plus chemotherapy: A case report. World J Clin Cases 2022; 10:6507-6513. [PMID: 35979297 PMCID: PMC9294919 DOI: 10.12998/wjcc.v10.i19.6507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 11/15/2021] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In driver gene-negative non-small cell lung cancer patients who relapse following radical resection, combination chemotherapy using bevacizumab and platinum-based dual drugs is known to increase both progression-free and overall survival. Treatment initially includes bevacizumab, and if patients are able to tolerate it, bevacizumab can continue to be utilized until disease progression. Bevacizumab is a recombinant humanized monoclonal neutralizing antibody that acts against vascular endothelial growth factor (VEGF). Various anti-VEGF monoclonal antibodies, such as bevacizumab, can increase the risk of arterial thromboembolism. Current data indicate that VEGF-targeted treatment does not significantly increase the risk of venous thromboembolism events, except for bevacizumab.
CASE SUMMARY A 55-year-old man underwent radical resection for cancer of the right lung. Six months following surgery, multiple metastases were observed in his left lung. Subsequently, six cycles of bevacizumab combined with pemetrexed/carboplatin chemotherapy was given. Efficacy evaluation continued to be partial relief according to RECIST 1.1 standards, and no noticeable adverse reactions were noted. After three cycles of maintenance therapy using a combination of bevacizumab and pemetrexed, the patient developed dizziness and dyspnea. The patient was diagnosed with acute cerebral infarction and pulmonary embolism following head magnetic resonance imaging, computed tomography (CT) angiography, and chest enhanced CT. Although the patient received low-molecular-weight heparin anticoagulation and other treatment, the patient eventually died of respiratory failure 1 mo later. This case report may offer some insight into fatal arteriovenous embolism, which has not been previously reported.
CONCLUSION Bevacizumab combined with chemotherapy may also increase the risk of arteriovenous thromboembolism. Accordingly, patients who receive angiogenesis inhibitor therapy should be carefully selected. Furthermore, close monitoring and timely intervention are necessary in order to reduce the risk of such toxicities.
Collapse
Affiliation(s)
- Ying Kong
- Department of Oncology, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
| | - Xiao-Cheng Xu
- Department of Oncology, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
| | - Liang Hong
- Department of Oncology, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
| |
Collapse
|
|
14
|
Moik F, Ay C. Venous and arterial thromboembolism in patients with cancer treated with targeted anti-cancer therapies. Thromb Res 2022; 213 Suppl 1:S58-S65. [DOI: 10.1016/j.thromres.2022.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/21/2021] [Accepted: 01/03/2022] [Indexed: 10/18/2022]
|
|
15
|
Kirwan CC, Blower EL. Contemporary breast cancer treatment-associated thrombosis. Thromb Res 2022; 213 Suppl 1:S8-S15. [DOI: 10.1016/j.thromres.2021.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/07/2021] [Accepted: 12/24/2021] [Indexed: 10/18/2022]
|
|
16
|
Carmona-Bayonas A, Verso M, Sánchez Cánovas M, Rubio Pérez J, García de Herreros M, Martínez de Prado P, Fernández Pérez I, Quintanar Verdúguez T, Obispo B, Pachón V, Gómez D, Ortega L, Serrano Moyano M, Brozos EM, Biosca M, Antonio M, Teijeira Sánchez L, Hernández Pérez C, Cumplido Burón JD, Martínez Lago N, García Pérez E, Muñoz Langa J, Perez-Segura P, Martínez de Castro E, Jiménez-Fonseca P, Agnelli G, Muñoz A. Do antiangiogenics promote clot instability? Data from the TESEO prospective registry and Caravaggio clinical trial. Thromb Haemost 2022; 122:1653-1661. [PMID: 35381615 PMCID: PMC9512585 DOI: 10.1055/a-1816-8347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Background
Venous thromboembolism (VTE) is a common complication in cancer patients. Much of its morbidity stems from the development of fatal pulmonary embolisms (PE). Little is known about the factors involved in clot stability, with angiogenesis possibly being implicated.
Methods
The database is from the TESEO prospective registry that recruits cancer patients with VTE from 41 Spanish hospitals. Independent validation was conducted in a cohort from the Caravaggio trial. The objective is to evaluate the association between exposure to antiangiogenic therapies and the PE/VTE proportion in oncological patients.
Results
In total, 1,536 subjects were evaluated; 58.4% (
n
= 894) had a PE and 7% (
n
= 108) received antiangiogenic therapy (bevacizumab in 75%). The PE/VTE proportion among antiangiogenic-treated individuals was 77/108 (71.3%) versus 817/1,428 (57.2%) among those receiving other alternative therapies (
p
= 0.004). The effect of the antiangiogenics on the PE/VTE proportion held up across all subgroups except for active smokers or those with chronic obstructive pulmonary disease. Exposure to antiangiogenics was associated with increased PEs, odds ratio (OR) 2.27 (95% CI, 1.42–3.63). In the Caravaggio trial, PE was present in 67% of the individuals treated with antiangiogenics, 50% of those who received chemotherapy without antiangiogenic treatment, and 60% without active therapy (
p
= 0.0016).
Conclusion
Antiangiogenics are associated with increased proportion of PE in oncological patients with VTE. If an effect on clot stability is confirmed, the concept of thrombotic risk in cancer patients should be reconsidered in qualitative terms.
Collapse
Affiliation(s)
| | - Melina Verso
- Dep. of Internal Medicine, Perugia Hospital Authority, Perugia, Italy
| | - Manuel Sánchez Cánovas
- Hematología y Oncología Médica, Hospital General Universitario Jose M Morales Meseguer, Murcia, Spain
| | | | | | | | | | | | - Berta Obispo
- Hospital Universitario Infanta Leonor Servicio de Medicina Interna, Madrid, Spain
| | - Vanessa Pachón
- Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain
| | - David Gómez
- Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Laura Ortega
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Elena María Brozos
- University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Mercè Biosca
- Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - Maite Antonio
- Catalan Institute of Oncology, L'Hospitalet de Llobregat, Spain
| | | | | | | | | | | | | | | | | | | | - Giancarlo Agnelli
- Internal and Cardiovascular Medicine,Department of Internal Medicine, Perugia Hospital Authority, Perugia, Italy
| | - Andres Muñoz
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
| |
Collapse
|
|
17
|
Risk of Thrombo-Embolic Events in Ovarian Cancer: Does Bevacizumab Tilt the Scale? A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:cancers13184603. [PMID: 34572830 PMCID: PMC8464807 DOI: 10.3390/cancers13184603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/08/2021] [Accepted: 09/12/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Thromboembolic events (TEs) are the second cause of death in cancer patients. Two forms of thromboembolic events may arise: arterial, such as ischemic stroke or myocardial infarction; and venous, such as deep vein thrombosis or pulmonary embolism. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and is widely used in advanced ovarian cancer. However, whether bevacizumab increases the risk of thromboembolic events in ovarian cancer is matter of debate since studies have shown conflicting results. In our systematic review and meta-analysis, we included 14 trials with bevacizumab in ovarian cancer. We found that the risk of arterial thromboembolic events more than doubled with a risk ratio of 2.45. Also the risk of venous thromboembolism increased 30% with bevacizumab treatment. Bevacizumab, therefore, can be considered an additional risk factor for selecting patients for primary prophylaxis with anticoagulants. Abstract Thromboembolic events are the second cause of death in cancer patients. In ovarian cancer, 3–10% of patients present with venous thromboembolism (VTE), but the incidence may rise to 36% along the disease course. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and in in vitro studies it showed a predisposition to hemostasis perturbation, including thrombosis. However, in vivo and clinical studies have shown conflicting results for its use as a treatment for ovarian cancer, so we conducted a systematic review and meta-analysis on the risk of arterial thromboembolism (ATE) and VTE in ovarian cancer patients treated with bevacizumab. The review comprised 14 trials with 6221 patients: ATE incidence was reported in 5 (4811 patients) where the absolute risk was 2.4% with bevacizumab vs. 1.1% without (RR 2.45; 95% CI 1.27–4.27, p = 0.008). VTE incidence was reported in 9 trials (5121 patients) where the absolute risk was 5.4% with bevacizumab vs. 3.7% without (RR 1.32; 95% CI 1.02–1.79, p = 0.04). Our analysis showed that the risk of arterial and venous thromboembolism increased in patients treated with bevacizumab. Thrombolic events (TEs) are probably underreported, and studies should discriminate between ATE and VTE. Bevacizumab can be considered as an additional risk factor when selecting patients for primary prophylaxis with anticoagulants.
Collapse
|
|
18
|
Di Liello R, Arenare L, Raspagliesi F, Scambia G, Pisano C, Colombo N, Frezzini S, Tognon G, Artioli G, Gadducci A, Lauria R, Ferrero A, Cinieri S, De Censi A, Breda E, Scollo P, De Giorgi U, Lissoni AA, Katsaros D, Lorusso D, Salutari V, Cecere SC, Lapresa M, Nardin M, Bogani G, Distefano M, Greggi S, Gargiulo P, Schettino C, Gallo C, Daniele G, Califano D, Perrone F, Pignata S, Piccirillo MC. Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial. Int J Gynecol Cancer 2021; 31:1348-1355. [PMID: 34462317 DOI: 10.1136/ijgc-2021-002786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/16/2021] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER NCT01706120.
Collapse
Affiliation(s)
- Raimondo Di Liello
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Laura Arenare
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Francesco Raspagliesi
- Dipartimento di Chirurgia, SC Chirurgia Ginecologica, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Giovanni Scambia
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Carmela Pisano
- Oncologia Clinica Sperimentale Uro-Ginecologica, Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | - Nicoletta Colombo
- Istituto Europeo di Oncologia IRCCS, and Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Milano, Italy
| | - Simona Frezzini
- Oncologia Medica II e Radiologia, Istituto Oncologico Veneto IRCCS, and Università di Padova, Padova, Italy
| | - Germana Tognon
- Divisione di Ostetricia e Ginecologia, ASST Spedali Civili di Brescia, Università di Brescia, Brescia, Italy
| | - Grazia Artioli
- Oncologia Medica, ULSS2 Marca Trevigiana, Treviso, Italy
| | - Angiolo Gadducci
- Dipartimento di Medicina Clinica e Sperimentale, UO Ginecologia e Ostetricia, Università di Pisa, Pisa, Italy
| | - Rossella Lauria
- Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Napoli, Italy
| | - Annamaria Ferrero
- Divisione Universitaria di Ginecologia e Ostetricia, AO Ordine Mauriziano, Torino, Italy
| | - Saverio Cinieri
- Oncologia Medica, Ospedale Senatore Antonio Perrino, Brindisi, Italy
| | | | - Enrico Breda
- Dipartimento di Oncologia, Ospedale S. Giovanni Calibita Fatebenefratelli, Roma, Italy
| | - Paolo Scollo
- UO Ostetricia e Ginecologia, Dipartimento Materno-Infantile, Ospedale Cannizzaro, Catania, Italy
| | - Ugo De Giorgi
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy
| | | | - Dionyssios Katsaros
- AOU Città della Salute, Dipartimento di Scienze Chirurgiche, Ginecologia Oncologica, Ospedale Ostetrico Ginecologico S Anna, Torino, Italy
| | - Domenica Lorusso
- Divisione di Ginecologia Medica, Istituto Europeo di Oncologia IRCCS, Milano, Italy
| | - Vanda Salutari
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Sabrina Chiara Cecere
- Oncologia Clinica Sperimentale Uro-Ginecologica, Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | - Mariateresa Lapresa
- Divisione di Ginecologia Medica, Istituto Europeo di Oncologia IRCCS, Milano, Italy
| | - Margherita Nardin
- Oncologia Medica II e Radiologia, Istituto Oncologico Veneto IRCCS, and Università di Padova, Padova, Italy
| | - Giorgio Bogani
- Dipartimento di Chirurgia, SC Chirurgia Ginecologica, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Mariagrazia Distefano
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Stefano Greggi
- SC Ginecologia Oncologica, Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Campania, Italy
| | - Piera Gargiulo
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Clorinda Schettino
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Ciro Gallo
- Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Gennaro Daniele
- Direzione Scientifica, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma, Italy
| | - Daniela Califano
- Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
| | - Francesco Perrone
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Sandro Pignata
- Oncologia Clinica Sperimentale Uro-Ginecologica, Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | - Maria Carmela Piccirillo
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| |
Collapse
|
|
19
|
Villanueva-Bueno C, Escudero-Vilaplana V, Collado-Borrell R, Giménez-Manzorro Á, Ribed A, Marzal-Alfaro B, Revuelta-Herrero JL, Gonzalez-Haba E, Herranz A, Sanjurjo M. Medication guide for the perioperative management of oral antineoplastic agents in cancer patients. Expert Opin Drug Saf 2021; 21:107-119. [PMID: 34357828 DOI: 10.1080/14740338.2021.1965990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Oral antineoplastic agents (OAAs) are high-risk drugs that may increase the risk of bleeding, difficulty in wound healing, or produce alterations in coagulation and/or platelet aggregation. These aspects had to be highly considered throughout the entire perioperative process. Our aim was to create a comprehensive management medication guide based on reconciliation and dose adjustment recommendations for OAAs in patients undergoing a surgical intervention. RESEARCH DESIGN AND METHODS We analyzed all OAAs approved by the EMA in November 2020. We assessed data related to dose adjustment, drug reconciliation, coagulation disturbances, or anticoagulant interactions from the FDA and EMA summary of product characteristics. RESULTS We analyzed 67 OAAs. We identified that 51 (76.2%) OAAs can produce alteration in the platelet count, 12 (17.9%) affect the wound healing and recovery process, and 32 (47.8%) require control and monitoring in case of combination with anticoagulants. Only 13 (19.4%) OAAs, most of them antiangiogenics, have specific recommendations for temporary suspension before surgery. CONCLUSIONS Most OAAs require perioperative monitoring. This review can serve as an easy (simple, effective) tool to help healthcare professionals involved in patient care to manage OAAs during the perioperative process.
Collapse
Affiliation(s)
- Cristina Villanueva-Bueno
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Vicente Escudero-Vilaplana
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Roberto Collado-Borrell
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Álvaro Giménez-Manzorro
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Almudena Ribed
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Belén Marzal-Alfaro
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - José Luis Revuelta-Herrero
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Eva Gonzalez-Haba
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Ana Herranz
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Maria Sanjurjo
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| |
Collapse
|
|
20
|
Cardiovascular toxicity of angiogenesis inhibitors and immune checkpoint inhibitors: synergistic anti-tumour effects at the cost of increased cardiovascular risk? Clin Sci (Lond) 2021; 135:1649-1668. [PMID: 34283204 DOI: 10.1042/cs20200300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/26/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022]
Abstract
In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.
Collapse
|
|
21
|
Lyman GH, Kuderer NM. Clinical practice guidelines for the treatment and prevention of cancer-associated thrombosis. Thromb Res 2021; 191 Suppl 1:S79-S84. [PMID: 32736784 DOI: 10.1016/s0049-3848(20)30402-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/13/2019] [Accepted: 12/23/2019] [Indexed: 12/20/2022]
Abstract
The risk of venous thromboembolism (VTE) is increased in patients with cancer and is greatest in those with cancers of the pancreas, stomach, brain, lung and ovary, late stage disease and in those undergoing treatment including chemotherapy, hormonal therapy, or surgery. VTE in patients with cancer is associated with a variety of adverse consequences including an increased risk of VTE recurrence, major bleeding, and early mortality. A VTE risk score for ambulatory patients receiving cancer chemotherapy has been extensively validated and has been used to select high risk patients for thromboprophylaxis trials. Several randomized controlled trials (RCTs) and meta-analyses of these trials have confirmed that LMWHs can significantly reduce the risk of VTE in patients with cancer. While the direct oral anticoagulants (DOACs) have been approved for the general population, previous guideline panels discouraged their use due to a lack of cancer-specific data. Recently RCTs for the treatment of established VTE in patients with cancer have demonstrated that the risk of recurrent VTE is lower while the risk of bleeding greater with DOACs compared to LMWH. Two thromboprophylaxis trials comparing low dose DOACs to placebo in high risk patients receiving cancer therapy have recently reported similar rates of VTE occurrence at 6 months in the control arms. A meta-analysis of the pooled results from these trials in higher risk ambulatory patients receiving cancer therapy confirmed a significant reduction in overall VTE incidence as well as pre-planned secondary outcomes on treatment. Several clinical practice guidelines addressing VTE in patients with malignant disease have been updated including those from the American Society of Clinical Oncology (ASCO). The addition of DOACs as an option for the management of VTE in patients with cancer is the latest major change to previous guidelines issued by these organizations. The updated recommendations from these guidelines are summarized in this review.
Collapse
Affiliation(s)
- Gary H Lyman
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA.
| | - Nicole M Kuderer
- University of Washington, Seattle, WA, USA; Advanced Cancer Research Group, Seattle, WA, USA
| |
Collapse
|
|
22
|
Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:329-359. [PMID: 33724754 DOI: 10.6004/jnccn.2021.0012] [Citation(s) in RCA: 890] [Impact Index Per Article: 222.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
Collapse
Affiliation(s)
- Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Alan P Venook
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Stacey Cohen
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Linda Farkas
- UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | | | - Steven Hunt
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Smitha Krishnamurthi
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | - Eric D Miller
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Mary F Mulcahy
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Katrina Pedersen
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Munn LL, Stylianopoulos T, Jain NK, Hardin CC, Khandekar MJ, Jain RK. Vascular Normalization to Improve Treatment of COVID-19: Lessons from Treatment of Cancer. Clin Cancer Res 2021; 27:2706-2711. [PMID: 33648989 DOI: 10.1158/1078-0432.ccr-20-4750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/17/2021] [Accepted: 02/25/2021] [Indexed: 12/21/2022]
Abstract
The dramatic impact of the COVID-19 pandemic has resulted in an "all hands on deck" approach to find new therapies to improve outcomes in this disease. In addition to causing significant respiratory pathology, infection with SARS-CoV-2 (like infection with other respiratory viruses) directly or indirectly results in abnormal vasculature, which may contribute to hypoxemia. These vascular effects cause significant morbidity and may contribute to mortality from the disease. Given that abnormal vasculature and poor oxygenation are also hallmarks of solid tumors, lessons from the treatment of cancer may help identify drugs that can be repurposed to treat COVID-19. Although the mechanisms that result in vascular abnormalities in COVID-19 are not fully understood, it is possible that there is dysregulation of many of the same angiogenic and thrombotic pathways as seen in patients with cancer. Many anticancer therapeutics, including androgen deprivation therapy (ADT) and immune checkpoint blockers (ICB), result in vascular normalization in addition to their direct effects on tumor cells. Therefore, these therapies, which have been extensively explored in clinical trials of patients with cancer, may have beneficial effects on the vasculature of patients with COVID-19. Furthermore, these drugs may have additional effects on the disease course, as some ADTs may impact viral entry, and ICBs may accelerate T-cell-mediated viral clearance. These insights from the treatment of cancer may be leveraged to abrogate the vascular pathologies found in COVID-19 and other forms of hypoxemic respiratory failure.
Collapse
Affiliation(s)
- Lance L Munn
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Natalie K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - C Corey Hardin
- Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Melin J Khandekar
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
24
|
Grover SP, Hisada YM, Kasthuri RS, Reeves BN, Mackman N. Cancer Therapy-Associated Thrombosis. Arterioscler Thromb Vasc Biol 2021; 41:1291-1305. [PMID: 33567864 DOI: 10.1161/atvbaha.120.314378] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
[Figure: see text].
Collapse
Affiliation(s)
- Steven P Grover
- UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill
| | - Yohei M Hisada
- UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill
| | - Raj S Kasthuri
- UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill
| | - Brandi N Reeves
- UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill
| | - Nigel Mackman
- UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill
| |
Collapse
|
|
25
|
Cerebral Venous Thrombosis in Patient with Metastatic Carcinoma Breast: Mimicking Brain Metastasis—a Case Report and Review of Literature. Indian J Surg Oncol 2020; 11:244-246. [DOI: 10.1007/s13193-020-01101-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/07/2020] [Indexed: 10/23/2022] Open
|
|
26
|
Ngo DTM, Williams T, Horder S, Kritharides L, Vardy J, Mandaliya H, Nordman IIC, Lynam J, Bonaventura T, Sverdlov AL. Factors Associated with Adverse Cardiovascular Events in Cancer Patients Treated with Bevacizumab. J Clin Med 2020; 9:E2664. [PMID: 32824667 PMCID: PMC7465018 DOI: 10.3390/jcm9082664] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/30/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody commonly used for the treatment of various cancers, is often associated with adverse cardiovascular effects such as hypertension, cardiac and cerebral ischemia, thrombosis, and bleeding events. Factors associated with increased risks of adverse cardiovascular effects with bevacizumab have not been intensively studied. In this study, we determined factors associated with hospital admissions due to cardiovascular complications in patients who received bevacizumab for cancer treatment. Methods and Results: We retrospectively collected data for all patients treated with bevacizumab between the 1st January 2016 and the 31st December 2017 at the Hunter New England Local Health District. Patients' characteristics and their medical history were obtained from hospital electronic medical records. Outcome data were sourced from the Institutional Cardiac and Stroke Outcomes Unit database. A total of n = 230 patients (mean age 65, males n = 124 (53.9%)) were treated with bevacizumab during the study period. N = 28 patients were admitted to hospital for a major cardiovascular-related event. Higher total treatment dose (p < 0.05), concomitant hypertension (p = 0.005), diabetes (p = 0.04), atrial fibrillation (p = 0.03), and lack of use of statin therapy (p = 0.03) were key contributors to hospital admission. Conclusions: Results of our study highlight the fact that patients with concomitant baseline cardiovascular disease/risk factors are at an increased risk of cardiovascular hospitalization related to bevacizumab treatment. Careful baseline cardiovascular assessment may be an essential step to minimize cardiovascular complications.
Collapse
Affiliation(s)
- Doan T. M. Ngo
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia;
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Hunter Cancer Research Alliance, Waratah, NSW 2298, Australia;
| | - Trent Williams
- Hunter New England Local Health District, Newcastle, NSW 2305, Australia; (T.W.); (J.L.)
| | - Sophie Horder
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia;
| | - Leonard Kritharides
- Department of Cardiology, Concord Repatriation General Hospital, Sydney Local Health District, Concord, NSW 2139, Australia;
- ANZAC Medical Research Institute, Faculty of Medicine, University of Sydney, Concord, NSW 2139, Australia
| | - Janette Vardy
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia;
- Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW 2139, Australia
| | - Hiren Mandaliya
- Hunter Cancer Research Alliance, Waratah, NSW 2298, Australia;
- Calvary Mater Newcastle, Waratah, NSW 2298, Australia; (I.I.C.N.); (T.B.)
| | - Ina I. C. Nordman
- Calvary Mater Newcastle, Waratah, NSW 2298, Australia; (I.I.C.N.); (T.B.)
| | - James Lynam
- Hunter New England Local Health District, Newcastle, NSW 2305, Australia; (T.W.); (J.L.)
- Calvary Mater Newcastle, Waratah, NSW 2298, Australia; (I.I.C.N.); (T.B.)
| | - Tony Bonaventura
- Calvary Mater Newcastle, Waratah, NSW 2298, Australia; (I.I.C.N.); (T.B.)
| | - Aaron L. Sverdlov
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Hunter Cancer Research Alliance, Waratah, NSW 2298, Australia;
- Hunter New England Local Health District, Newcastle, NSW 2305, Australia; (T.W.); (J.L.)
- Calvary Mater Newcastle, Waratah, NSW 2298, Australia; (I.I.C.N.); (T.B.)
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia
| |
Collapse
|
|
27
|
Leiva O, Connors JM, Al-Samkari H. Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients. Cancers (Basel) 2020; 12:cancers12071958. [PMID: 32707653 PMCID: PMC7409200 DOI: 10.3390/cancers12071958] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/13/2020] [Accepted: 07/16/2020] [Indexed: 12/19/2022] Open
Abstract
Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis.
Collapse
Affiliation(s)
- Orly Leiva
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA;
- Harvard Medical School, Boston, MA 02215, USA;
| | - Jean M. Connors
- Harvard Medical School, Boston, MA 02215, USA;
- Hematology Division, Brigham and Women’s Hospital, Boston, MA 02215, USA
| | - Hanny Al-Samkari
- Harvard Medical School, Boston, MA 02215, USA;
- Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
- Correspondence: ; Tel.: +1-617-643-6214
| |
Collapse
|
|
28
|
Moik F, Ay C, Pabinger I. Risk prediction for cancer-associated thrombosis in ambulatory patients with cancer: past, present and future. Thromb Res 2020; 191 Suppl 1:S3-S11. [DOI: 10.1016/s0049-3848(20)30389-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/14/2019] [Accepted: 12/23/2019] [Indexed: 01/29/2023]
|
|
29
|
Muñoz Martín AJ, Ramírez SP, Morán LO, Zamorano MR, Benéitez MCV, Salcedo IA, Escobar IG, Fernández JMS. Pharmacological cancer treatment and venous thromboembolism risk. Eur Heart J Suppl 2020; 22:C2-C14. [PMID: 32368194 PMCID: PMC7189737 DOI: 10.1093/eurheartj/suaa004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Risk factors for cancer-associated thrombosis are commonly divided into three categories: patient-, cancer-, and treatment-related factors. Currently, different types of drugs are used in cancer treatment. Chemotherapy has been identified as an independent risk factor for venous thromboembolism (VTE). However, it should be noted, that the risk of VTE is not consistent among all cytotoxic agents. In addition, different supportive care drugs, such as erythropoiesis stimulating agents or granulocyte colony stimulating factors, and hormonotherapy have been associated to an increased risk of 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.
Collapse
Affiliation(s)
- Andrés J Muñoz Martín
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 46, 28007 Madrid, Spain
| | - Sara Pérez Ramírez
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 46, 28007 Madrid, Spain
| | - Laura Ortega Morán
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 46, 28007 Madrid, Spain
| | - Magdalena Ruiz Zamorano
- Department of Medicine, Faculty of Medicine, Universidad Complutense, Av. Séneca 2, 28040 Madrid, Spain
| | | | - Inmaculada Aparicio Salcedo
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 46, 28007 Madrid, Spain
| | - Ignacio García Escobar
- Medical Oncology Department, Hospital General Universitario de Ciudad Real, Calle Obispo Rafael Torija s/n, 13005 Ciudad Real, Spain
| | - José Manuel Soria Fernández
- Genomic of Complex Disease Unit, Institut d’investigació Sant Pau (IIB-SANT PAU), Joan Alcover, 7–2° 2ª, 08031 Barcelona, Spain
| |
Collapse
|
|
30
|
Nowak AK, Brosseau S, Cook A, Zalcman G. Antiangiogeneic Strategies in Mesothelioma. Front Oncol 2020; 10:126. [PMID: 32133285 PMCID: PMC7040194 DOI: 10.3389/fonc.2020.00126] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/23/2020] [Indexed: 12/21/2022] Open
Abstract
There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.
Collapse
Affiliation(s)
- Anna K Nowak
- National Centre for Asbestos Related Diseases, University of Western Australia, Crawley, WA, Australia.,Medical School, University of Western Australia, Crawley, WA, Australia.,Institute for Respiratory Health, University of Western Australia, Crawley, WA, Australia.,Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | - Solenn Brosseau
- Thoracic Oncology Department & CIC1425-CLIP2 Early Phase Cancer Clinical Trials Unit, University Hospital Bichat-Claude Bernard, Medical Faculty, University Paris-Diderot, Paris, France.,U830 INSERM "Cancer Heterogeneity, Plasticity", Institute Curie Research Centre, Paris, France
| | - Alistair Cook
- National Centre for Asbestos Related Diseases, University of Western Australia, Crawley, WA, Australia.,Medical School, University of Western Australia, Crawley, WA, Australia.,Institute for Respiratory Health, University of Western Australia, Crawley, WA, Australia
| | - Gérard Zalcman
- Thoracic Oncology Department & CIC1425-CLIP2 Early Phase Cancer Clinical Trials Unit, University Hospital Bichat-Claude Bernard, Medical Faculty, University Paris-Diderot, Paris, France.,U830 INSERM "Cancer Heterogeneity, Plasticity", Institute Curie Research Centre, Paris, France
| |
Collapse
|
|
31
|
Trone JC, Ollier E, Chapelle C, Bertoletti L, Cucherat M, Mismetti P, Magné N, Laporte S. Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis. Ann Oncol 2019; 29:803-811. [PMID: 29415169 DOI: 10.1093/annonc/mdy035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.
Collapse
Affiliation(s)
- J C Trone
- SAINBIOSE U1059, Equipe DVH, Université Jean Monnet - Saint-Etienne, Saint-Etienne, France.
| | - E Ollier
- SAINBIOSE U1059, Equipe DVH, Université Jean Monnet - Saint-Etienne, Saint-Etienne, France
| | - C Chapelle
- Clinical Research Unit, Innovation, Pharmacologie, France
| | - L Bertoletti
- SAINBIOSE U1059, Equipe DVH, Université Jean Monnet - Saint-Etienne, Saint-Etienne, France; Department of Vascular and Therapeutic Medicine, Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne, France; INSERM CIE1408, Saint-Etienne, France
| | - M Cucherat
- UMR CNRS 5558 Evaluation et Modélisation des Effets Thérapeutiques, Université Claude Bernard Lyon 1, Lyon, France
| | - P Mismetti
- SAINBIOSE U1059, Equipe DVH, Université Jean Monnet - Saint-Etienne, Saint-Etienne, France; Clinical Research Unit, Innovation, Pharmacologie, France; Department of Vascular and Therapeutic Medicine, Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne, France
| | - N Magné
- Department of Radiotherapy, Institut de Cancérologie Lucien Neuwirth, Saint-Etienne, France
| | - S Laporte
- SAINBIOSE U1059, Equipe DVH, Université Jean Monnet - Saint-Etienne, Saint-Etienne, France; Clinical Research Unit, Innovation, Pharmacologie, France; INSERM CIE1408, Saint-Etienne, France
| |
Collapse
|
|
32
|
Lee I, Adimadhyam S, Nutescu EA, Zhou J, Asfaw AA, Sweiss K, Patel PR, Calip GS. Bevacizumab Use and the Risk of Arterial and Venous Thromboembolism in Patients with High-Grade Gliomas: A Nested Case-Control Study. Pharmacotherapy 2019; 39:921-928. [PMID: 31332810 PMCID: PMC7395667 DOI: 10.1002/phar.2310] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
STUDY OBJECTIVE Bevacizumab is used in the treatment of recurrent glioblastoma, but evidence is limited on the incidence of thromboembolic complications regarding the use of this drug in real-world settings. We evaluated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) associated with the use of bevacizumab among adults diagnosed with high-grade gliomas in a commercially insured U.S. POPULATION DESIGN Nested case-control study. DATA SOURCE Truven Health MarketScan Commercial and Medicare Supplemental health claims databases (2009-2015). PATIENTS A total of 2157 patients with high-grade gliomas who underwent incident (first-time) craniotomy, radiation, and concurrent temozolomide treatment between 2009 and 2015 were identified. Overall, 25 cases of ATE and 99 cases of VTE were each identified in this cohort, and each case was matched to up to 10 controls (170 for ATE and 819 for VTE) based on sex, age, quarter year of index time, and follow-up duration by using incidence density sampling without replacement from the overall cohort. Controls were at risk for the outcome of interest (ATE or VTE) at the time of case occurrence and survived at least as long as their referent case. MEASUREMENTS AND MAIN RESULTS Exposure to bevacizumab was determined during inpatient or outpatient encounters between the index date (date of the incident craniotomy) and the ATE or VTE event or corresponding matched control date. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of ATE and VTE separately. A higher proportion of patients with ATE received bevacizumab compared with controls (28% vs 17%; adjusted OR 1.51, 95% CI 0.54-4.24), but this excess in odds was not statistically significant. Similarly, bevacizumab was not significantly associated with VTE (13% vs 9%; adjusted OR 1.40, 95% CI 0.71-2.75). CONCLUSION We found no significant association between the use of bevacizumab and the occurrence of thromboembolic events in patients with high-grade gliomas, although our study was limited by the small number of ATE events. Because the potential for complications from arterial thrombosis cannot be completely ruled out, further research is needed to confirm the thromboembolic safety of bevacizumab in a larger sample of patients with high-grade gliomas.
Collapse
Affiliation(s)
- Inyoung Lee
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Sruthi Adimadhyam
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Edith A. Nutescu
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
- Center for Pharmacoepidemiology & Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, IL
| | - Jifang Zhou
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Alemseged A. Asfaw
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Karen Sweiss
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Pritesh R. Patel
- Division of Hematology Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Gregory S. Calip
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
- Center for Pharmacoepidemiology & Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, IL
- Division of Public Health Sciences, Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA
| |
Collapse
|
|
33
|
Keramida K, Charalampopoulos G, Filippiadis D, Tsougos E, Farmakis D. Cardiovascular complications of metastatic colorectal cancer treatment. J Gastrointest Oncol 2019; 10:797-806. [PMID: 31392061 PMCID: PMC6657319 DOI: 10.21037/jgo.2019.03.04] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy in men and the second in women and the fourth cause of cancer death. Survival rates decrease greatly according to the stage of the disease at the time of diagnosis. Approximately 50% of CRC patients will develop metastatic disease (mCRC) with survival and prognosis depending on the timing of metastatic development, and the localization and number of metastatic sites. The overall survival of patients with mCRC has been significantly improved over the last years from approximately 12 to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. The optimal therapeutic strategy depends on the general condition and performance status of the patient, the resectability or not of metastases and the mutational status of the tumor in terms of BRAF and RAS. Cardiovascular (CV) complications of mCRC treatment may develop peri-operatively and mostly during chemotherapy. During first-line treatment, 90% of patients experience more than one adverse event (AE) and 39% of them are CV. Angina, hypertension, arrhythmias, arterial and venous thrombotic events (VTEs), heart failure (HF) and death are the main CV events resulting from the applied chemotherapy regimens. Cardio-oncology consultation for identification of high-risk patients, proper monitoring during and after therapy and timely intervention would allow the successful prevention and the efficient management of cardiotoxicity, rendering the patient able to receive the indicated cancer therapy and improving the overall outcome.
Collapse
Affiliation(s)
- Kalliopi Keramida
- Cardio-Oncology Clinic, Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
- University of Cyprus Medical School, Nicosia, Cyprus
| | - Georgios Charalampopoulos
- 2nd Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Dimitrios Filippiadis
- 2nd Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Elias Tsougos
- 2nd Department of Cardiology, Heart Failure and Preventive Cardiology Section, Henry Dunant Hospital, Athens, Greece
| | - Dimitrios Farmakis
- Cardio-Oncology Clinic, Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
- University of Cyprus Medical School, Nicosia, Cyprus
| |
Collapse
|
|
34
|
Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, Monte I, Novo G, Penna C, Pepe A, Spallarossa P, Varricchi G, Zito C, Pagliaro P, Mercuro G. From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview. Antioxid Redox Signal 2019; 30:2110-2153. [PMID: 28398124 PMCID: PMC6529857 DOI: 10.1089/ars.2016.6930] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.
Collapse
Affiliation(s)
| | - Christian Cadeddu
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Daniela Di Lisi
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Saveria Femminò
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Rosalinda Madonna
- 5 Center of Aging Sciences and Translational Medicine - CESI-MeT, "G. d'Annunzio" University, Chieti, Italy.,6 Department of Internal Medicine, The Texas Heart Institute and Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Donato Mele
- 7 Cardiology Unit, Emergency Department, University Hospital of Ferrara, Ferrara, Italy
| | - Ines Monte
- 8 Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy
| | - Giuseppina Novo
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Claudia Penna
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Alessia Pepe
- 9 U.O.C. Magnetic Resonance Imaging, Fondazione Toscana G. Monasterio C.N.R., Pisa, Italy
| | - Paolo Spallarossa
- 10 Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Gilda Varricchi
- 1 Department of Translational Medical Sciences, Federico II University, Naples, Italy.,11 Center for Basic and Clinical Immunology Research (CISI) - Federico II University, Naples, Italy
| | - Concetta Zito
- 12 Division of Cardiology, Clinical and Experimental Department of Medicine and Pharmacology, Policlinico "G. Martino" University of Messina, Messina, Italy
| | - Pasquale Pagliaro
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Giuseppe Mercuro
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| |
Collapse
|
|
35
|
Abstract
Colorectal carcinoma is the third most common cancer worldwide. Approximately 20% of patients with colorectal cancer will have metastatic disease at the time of initial diagnosis, and approximately 30% to 50% of patients with primary colon cancer will relapse and die of metastatic cancer. The 5-year survival rate of metastatic colorectal cancer remains disappointing at approximately 10%.Angiogenesis plays a significant role in tumor growth and metastasis in colorectal carcinoma. There are currently 4 US Food and Drug Administration-approved antiangiogenic agents for metastatic colorectal cancer. Bevacizumab is the only antiangiogenic agent approved by the US Food and Drug Administration for first-line treatment of metastatic colorectal cancer. Other antiangiogenic agents include ramucirumab, ziv-aflibercept, and regorafenib. We review the data supporting the use of antiangiogenics in this disease.
Collapse
|
|
36
|
Bong JW, Lee JL, Kim CW, Yoon YS, Park IJ, Lim SB, Yu CS, Kim TW, Kim JC. Risk Factors and Adequate Management for Complications of Bevacizumab Treatment Requiring Surgical Intervention in Patients With Metastatic Colorectal Cancer. Clin Colorectal Cancer 2018; 17:e639-e645. [PMID: 30031634 DOI: 10.1016/j.clcc.2018.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/23/2018] [Accepted: 06/25/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Bevacizumab (BV) has been approved for treating colorectal cancer since 2004. Although BV use may lead to adverse effects, few studies have reported incidences requiring surgical intervention. We aimed to identify the risk factors and adequate interventions for complications requiring surgical intervention after BV treatment. PATIENTS AND METHODS We retrospectively reviewed the records of patients with metastatic colorectal cancer treated with BV in our institute from January 2009 to December 2016. The baseline patient characteristics were used to evaluate the potential risk factors for complications requiring surgery. RESULTS Of the 1008 patients recruited for this study, 60 (5.9%) experienced complications necessitating surgery after BV therapy. Gastrointestinal perforation was the most frequently observed complication, occurring in 36 patients (3.5%), and diverting colostomy was the most commonly performed intervention (22 patients, 36.6%). Multivariate analysis helped identify poor differentiation, signet ring cell carcinoma, stent insertion status, rectal location of the primary tumor, and intact primary tumor status as the risk factors. Survival time remained unchanged regardless of a complication that required surgery. CONCLUSION Careful monitoring during BV treatment for metastatic colorectal cancer is essential for patients who have a predisposition to complications that may require surgery. After detection, adequate and timely surgical management is imperative for ensuring patient survival.
Collapse
Affiliation(s)
- Jun Woo Bong
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Lyul Lee
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan Wook Kim
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Sik Yoon
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In Ja Park
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seok-Byung Lim
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Sik Yu
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae Won Kim
- Department of Medical Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Cheon Kim
- Department of Surgery and Division of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| |
Collapse
|
|
37
|
Pachón V, Trujillo-Santos J, Domènech P, Gallardo E, Font C, González-Porras JR, Pérez-Segura P, Maestre A, Mateo J, Muñoz A, Peris ML, Lecumberri R. Cancer-Associated Thrombosis: Beyond Clinical Practice Guidelines-A Multidisciplinary (SEMI-SEOM-SETH) Expert Consensus. TH OPEN 2018; 2:e373-e386. [PMID: 31249964 PMCID: PMC6524906 DOI: 10.1055/s-0038-1675577] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 09/17/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the growing interest and improved knowledge about venous thromboembolism in cancer patients in the last years, there are still many unsolved issues. Due to the limitations of the available literature, evidence-based clinical practice guidelines are not able to give solid recommendations for challenging scenarios often present in the setting of cancer-associated thrombosis (CAT). A multidisciplinary expert panel from three scientific societies—Spanish Society of Internal Medicine (SEMI), Spanish Society of Medical Oncology (SEOM), and Spanish Society Thrombosis and Haemostasis (SETH)—agreed on 12 controversial questions regarding prevention and management of CAT, which were thoroughly reviewed to provide further guidance. The suggestions presented herein may facilitate clinical decisions in specific complex circumstances, until these can be made leaning on reliable scientific evidence.
Collapse
Affiliation(s)
- Vanessa Pachón
- Department of Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Pere Domènech
- Thrombosis and Haemostasis Unit, Hospital Universitario Bellvitge, L'Hospitalet de Llobregat, Catalonia, Spain
| | - Enrique Gallardo
- Department of Oncology, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Carmen Font
- Department of Medical Oncology, Hospital Clinic, Barcelona, Spain
| | | | | | - Ana Maestre
- Department of Internal Medicine, Hospital del Vinalopó, Elche, Spain
| | - José Mateo
- Hematology Service, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Andrés Muñoz
- Department of Oncology, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - María Luisa Peris
- Department of Internal Medicine, Hospital Provincial de Castellón, Castellón, Spain
| | - Ramón Lecumberri
- Hematology Service, Clínica Universidad de Navarra, IDISNA, CIBER-CV, Pamplona, Spain
| |
Collapse
|
|
38
|
Gouverneur A, Claraz P, Rousset M, Arnaud M, Fourrier-Réglat A, Pariente A, Aparicio T, Miremont-Salamé G, Noize P. Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and Younger Patients: a Study Using the International Pharmacovigilance Database. Target Oncol 2018; 12:805-814. [PMID: 29022151 DOI: 10.1007/s11523-017-0529-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly. OBJECTIVE This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life. PATIENTS AND METHODS An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups. RESULTS There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Median age was 64 years (Inter Quartile Range = 56-71) and 15% of patients were aged ≥75; 57% were male. Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only. CONCLUSIONS ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore, be treated with these targeted therapies.
Collapse
Affiliation(s)
- Amandine Gouverneur
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France. .,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France. .,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France.
| | - Pauline Claraz
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Marine Rousset
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Mickaël Arnaud
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France
| | - Annie Fourrier-Réglat
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Antoine Pariente
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Thomas Aparicio
- Gastroenterology and Digestive Oncology Department, Saint Louis Hospital, APHP, F-75010, Paris, France
| | - Ghada Miremont-Salamé
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Pernelle Noize
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| |
Collapse
|
|
39
|
Abstract
OBJECTIVE The hallmarks of cancer are mechanisms that cells develop to undergo malignant transformation. The targeting of these hallmarks by newer cancer therapies results in new mechanisms of response, toxicity, and resistance. The purpose of this article is to review these hallmarks, their associated targeted therapies, imaging features of responses, and toxicities. CONCLUSION Ten hallmarks, among them proliferative signaling, angiogenesis, immune response, and genome instability, are reviewed. Molecular targeted therapies, including antiangiogenic factors and immune checkpoint inhibitors, target these hallmarks.
Collapse
|
|
40
|
Mladěnka P, Applová L, Patočka J, Costa VM, Remiao F, Pourová J, Mladěnka A, Karlíčková J, Jahodář L, Vopršalová M, Varner KJ, Štěrba M. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev 2018; 38:1332-1403. [PMID: 29315692 PMCID: PMC6033155 DOI: 10.1002/med.21476] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/20/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.
Collapse
Affiliation(s)
- Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Lenka Applová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Jiří Patočka
- Department of Radiology and Toxicology, Faculty of Health and Social StudiesUniversity of South BohemiaČeské BudějoviceCzech Republic
- Biomedical Research CentreUniversity HospitalHradec KraloveCzech Republic
| | - Vera Marisa Costa
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
| | - Fernando Remiao
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
| | - Jana Pourová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Aleš Mladěnka
- Oncogynaecologic Center, Department of Gynecology and ObstetricsUniversity HospitalOstravaCzech Republic
| | - Jana Karlíčková
- Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Luděk Jahodář
- Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Marie Vopršalová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | - Kurt J. Varner
- Department of PharmacologyLouisiana State University Health Sciences CenterNew OrleansLAUSA
| | - Martin Štěrba
- Department of Pharmacology, Faculty of Medicine in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
| | | |
Collapse
|
|
41
|
Kuk A, Magnowska M, Suchy W, Swierczynska J, Zaborowski MP, Gaca M, Nowak-Markwitz E. Retrospective Evaluation of Thromboembolism Risk in Ovarian Cancer Patients Treated with Bevacizumab. Target Oncol 2018; 12:495-503. [PMID: 28580507 PMCID: PMC5524869 DOI: 10.1007/s11523-017-0496-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Bevacizumab is used in addition to standard, platinum-based chemotherapy to treat advanced-stage ovarian cancer patients. Thrombosis is a well-documented adverse effect of bevacizumab. Objective The aim of this study was to identify predictive parameters for thromboembolic events in ovarian cancer patients and to explain how bevacizumab increases the risk of these events. Patients and Methods Fifty-seven FIGO stage III ovarian cancer patients who underwent cytoreductive surgery and chemotherapy were identified and included in this retrospective study. Twenty-six patients were treated with carboplatin and paclitaxel (CP) only (control group), and 31 patients received CP with bevacizumab (study group). The two groups were compared with regard to thrombosis risk factors and laboratory parameters (total leukocytes, platelet count, hemoglobin, APTT, prothrombin time, INR, fibrinogen levels, D-dimer concentration) before treatment, after each course of chemotherapy, and during thromboembolic events. Results Only patients in the group receiving bevacizumab experienced venous thromboembolism (VTE) (p=0.03, χ² test). VTE occurred on average at the 13th cycle of chemotherapy. Patients who experienced VTE had increased BMI before chemotherapy as compared to patients with no thromboembolic event (27.2 vs. 23.3, p=0.005, Mann-Whitney test). D-dimer concentration before treatment was also elevated more in patients affected by VTE (3132.5) than in the non-VTE group (956.43) (p=0.0007, Mann-Whitney test). During the first four administrations of chemotherapy in patients with future VTE, there was a reduction in D-dimer concentration and an extension of APTT. A D-Dimer level higher than 485 ng/mL prior to first chemotherapy indicates for a risk of VTE with 94% sensitivity and 36% specificity. Conclusions An elevated D-dimer level and high BMI before chemotherapy are risk factors for VTE in ovarian cancer patients receiving bevacizumab. Bevacizumab possibly increases the risk for VTE.![]()
Collapse
Affiliation(s)
- Anna Kuk
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland.
| | - Magdalena Magnowska
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| | - Wiktor Suchy
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| | - Joanna Swierczynska
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| | - Mikolaj Piotr Zaborowski
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| | - Michal Gaca
- Department of Anesthesiology in Obstetrics and Gynecology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| | - Ewa Nowak-Markwitz
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, ul.Polna 33, 60-535, Poznan, Poland
| |
Collapse
|
|
42
|
Baillif S, Levy B, Girmens JF, Dumas S, Tadayoni R. [Systemic safety following intravitreal injections of anti-VEGF]. J Fr Ophtalmol 2018; 41:271-276. [PMID: 29567019 DOI: 10.1016/j.jfo.2017.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 10/22/2017] [Accepted: 11/09/2017] [Indexed: 01/16/2023]
Abstract
The goal of this manuscript is to assess data suggesting that intravitreal injection of anti-vascular endothelial growth factors (anti-VEGFs) could result in systemic adverse events (AEs). The class-specific systemic AEs should be similar to those encountered in cancer trials. The most frequent AE observed in oncology, hypertension and proteinuria, should thus be the most common expected in ophthalmology, but their severity should be lower because of the much lower doses of anti-VEGFs administered intravitreally. Such AEs have not been frequently reported in ophthalmology trials. In addition, pharmacokinetic and pharmacodynamic data describing systemic diffusion of anti-VEGFs should be interpreted with caution because of significant inconsistencies reported. Thus, safety data reported in ophthalmology trials and pharmacokinetic/pharmacodynamic data provide robust evidence that systemic events after intravitreal injection are very unlikely. Additional studies are needed to explore this issue further, as much remains to be understood about local and systemic side effects of anti-VEGFs.
Collapse
Affiliation(s)
- S Baillif
- Département d'ophtalmologie, hôpital Pasteur, 30, voie Romaine, 06000 Nice cedex 1, France.
| | - B Levy
- Institut des vaisseaux et du sang, département physiologie clinique, Inserm U970, hôpital Lariboisière, 75010 Paris, France
| | - J-F Girmens
- Département d'ophtalmologie du Professeur-Sahel-&-CIC, hôpital Quinze-Vingt, 75012 Paris, France
| | - S Dumas
- Clinique Nord-Vision, 59800 Lille, France
| | - R Tadayoni
- Département d'ophtalmologie, hôpitaux de Paris, hôpital Lariboisière, 75010 Paris, France
| |
Collapse
|
|
43
|
Chen YC, Chung CC, Lin YK, Chen YJ. Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors. Ann Med 2018; 50:46-56. [PMID: 28929822 DOI: 10.1080/07853890.2017.1383629] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs), are important as anticancer treatments through curbing tumour angiogenesis and growth. VEGF inhibitors have significant cardiovascular effects. By blocking VEGF receptors, ligands, or signal pathways, VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity, and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors. This review updates current understandings of VEGF inhibitors on cardiovascular toxicity, explores potential mechanisms, and clarifies whether genetic or ethnic factors contribute to their adverse effects. Key Messages VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors.
Collapse
Affiliation(s)
- Yen-Chou Chen
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
| | - Cheng-Chih Chung
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan.,b Graduate Institute of Clinical Medicine, College of Medicine , Taipei Medical University , Taipei , Taiwan
| | - Yung-Kuo Lin
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
| | - Yi-Jen Chen
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan.,b Graduate Institute of Clinical Medicine, College of Medicine , Taipei Medical University , Taipei , Taiwan
| |
Collapse
|
|
44
|
Kim JH, Kim JE, Hong YS, Kim SY, Kim KP, Choi KE, Shin JH, Kim TW. Increased incidence of chemoport-related thrombosis in patients with colorectal cancer receiving bevacizumab: A single-institutional experience. Chin J Cancer Res 2018; 30:460-467. [PMID: 30210226 PMCID: PMC6129570 DOI: 10.21147/j.issn.1000-9604.2018.04.09] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective Chemoport-related thrombosis (CRT) is a serious complication that causes morbidities and interrupts administration of intravenous cancer therapy. We investigated the incidence and risk of CRT in colorectal cancer (CRC) patients treated with bevacizumab (BEV). Methods We retrospectively reviewed 1,534 CRC patients who received chemotherapy with or without BEV using a chemoport between 2014 and 2016. Results The participants had a median age of 58 (18−85) years, and 60.3% were male. All participants were stratified into three groups: adjuvant chemotherapy (AC) (n=670), palliative chemotherapy (PC) without BEV (n=356), and PC with BEV (n=508). The median follow-up was 20.19 (interquartile range, 14.07−27.19) months. CRT occurred in 3.8% of all patients; incidence of symptomatic and asymptomatic CRT was 2.9% and 0.9%, respectively. CRT occurred more in patients with BEV (5.7%) than in patients without BEV (2.9%, P=0.008). The cumulative incidence of CRT in patients administered PC with BEV was significantly higher than that in those administered AC (P=0.011) and there was a trend toward increased CRT in patients administered PC with BEV compared with those administered PC without BEV (P=0.044). Multivariate analysis found that BEV treatment was the only variable that was significantly associated with CRT (hazard ratio, 2.06; 95% confidence interval, 1.24−3.43; P=0.006). Conclusions BEV treatment was significantly associated with increased incidence of CRT in CRC patients.
Collapse
Affiliation(s)
- Jwa Hoon Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Jeong Eun Kim
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Yong Sang Hong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Sun Young Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Ki Eun Choi
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Ji Hoon Shin
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Tae Won Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| |
Collapse
|
|
45
|
|
|
46
|
Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, Mackey JR, Paz-Ares L, Baron AD, Okusaka T, Yoshino T, Yoon HH, Das M, Ferry D, Zhang Y, Lin Y, Binder P, Sashegyi A, Chau I. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol 2017; 28:2932-2942. [PMID: 28950290 PMCID: PMC5834052 DOI: 10.1093/annonc/mdx514] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).
Collapse
MESH Headings
- Angiogenesis Inhibitors/adverse effects
- Angiogenesis Inhibitors/immunology
- Angiogenesis Inhibitors/therapeutic use
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/immunology
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/immunology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Clinical Trials, Phase III as Topic
- Humans
- Randomized Controlled Trials as Topic
- Risk Assessment
- Vascular Endothelial Growth Factor Receptor-2/immunology
- Ramucirumab
Collapse
Affiliation(s)
- D Arnold
- Oncology, Instituto CUF de Oncologia (I.C.O.), Lisbon, Portugal
| | - C S Fuchs
- Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - J Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Ohtsu
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - A X Zhu
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA
| | - E B Garon
- Hematology Oncology, David Geffen School of Medicine at UCLA Translational Research in Oncology-US Network, Santa Monica, USA
| | - J R Mackey
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
| | - L Paz-Ares
- Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain
| | - A D Baron
- Division of Hematology Oncology, California Pacific Medical Center, San Francisco, USA
| | - T Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - T Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - H H Yoon
- Division of Medical Oncology, Mayo Clinic, Rochester, USA
| | - M Das
- Oncology, Eli Lilly and Company, Indianapolis, USA
| | - D Ferry
- Oncology, Eli Lilly and Company, Bridgewater, USA
| | - Y Zhang
- Oncology, Eli Lilly and Company, Bridgewater, USA
| | - Y Lin
- Oncology, Eli Lilly and Company, Indianapolis, USA
| | - P Binder
- Oncology, Eli Lilly and Company, Bridgewater, USA
| | - A Sashegyi
- Oncology, Eli Lilly and Company, Indianapolis, USA
| | - I Chau
- Department of Medicine, Royal Marsden Hospital, Sutton, UK
| |
Collapse
|
|
47
|
Chang HM, Okwuosa TM, Scarabelli T, Moudgil R, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2. J Am Coll Cardiol 2017; 70:2552-2565. [PMID: 29145955 PMCID: PMC5825188 DOI: 10.1016/j.jacc.2017.09.1095] [Citation(s) in RCA: 200] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/24/2017] [Accepted: 09/26/2017] [Indexed: 02/08/2023]
Abstract
In this second part of a 2-part review, we will review cancer or cancer therapy-associated systemic and pulmonary hypertension, QT prolongation, arrhythmias, pericardial disease, and radiation-induced cardiotoxicity. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. Newly developed targeted therapy can exert off-target effects causing hypertension, thromboembolism, QT prolongation, and atrial fibrillation. Radiation therapy often accelerates atherosclerosis. Furthermore, radiation can damage the heart valves, the conduction system, and pericardium, which may take years to manifest clinically. Management of pericardial disease in cancer patients also posed clinical challenges. This review highlights the unique opportunity of caring for cancer patients with heart problems caused by cancer or cancer therapy. It is an invitation to action for cardiologists to become familiar with this emerging subspecialty.
Collapse
Affiliation(s)
- Hui-Ming Chang
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Tochukwu M Okwuosa
- Division of Cardiology, Rush University Medical Center, Chicago, Illinois
| | - Tiziano Scarabelli
- Division of Cardiology, Virginia Common Wealth University, Richmond, Virginia
| | - Rohit Moudgil
- Department of Cardiology, University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Edward T H Yeh
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri.
| |
Collapse
|
|
48
|
Gampenrieder SP, Westphal T, Greil R. Antiangiogenic therapy in breast cancer. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2017; 10:194-201. [PMID: 29250196 PMCID: PMC5725520 DOI: 10.1007/s12254-017-0362-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 10/23/2017] [Indexed: 12/21/2022]
Abstract
Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2)-negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer.
Collapse
Affiliation(s)
- Simon Peter Gampenrieder
- IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.,Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg Cancer Research Institute, Salzburg, Austria.,Cancer Cluster Salzburg, Salzburg, Austria
| | - Theresa Westphal
- IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.,Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg Cancer Research Institute, Salzburg, Austria.,Cancer Cluster Salzburg, Salzburg, Austria
| | - Richard Greil
- IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.,Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg Cancer Research Institute, Salzburg, Austria.,Cancer Cluster Salzburg, Salzburg, Austria
| |
Collapse
|
|
49
|
GHERMAN ALEXANDRA, CĂINAP CĂLIN, CONSTANTIN ANNEMARIE, CETEAN SÎNZIANA, CĂINAP SIMONASORANA. Molecular targeted treatment of metastatic colorectal cancer: the cardiovascular adverse effects of Bevacizumab and Cetuximab. CLUJUL MEDICAL (1957) 2017; 90:377-384. [PMID: 29151784 PMCID: PMC5683825 DOI: 10.15386/cjmed-745] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 12/06/2016] [Indexed: 12/21/2022]
Abstract
Novel emerging therapies have changed paradigms in metastatic colorectal cancer. The advantages of molecular targeted treatments, either the anti-angiogenic or the anti-epidermal growth factor receptor drugs, reside in the fact that while their specificity for the cancer cell is higher, their toxicity on normal tissues is significantly lower when compared to chemotherapy. But when it comes to their safety, especially from a cardiovascular point of view, they still need to pass the test of time and further prospective studies are needed. Clinical trial patients are very well selected with regards to comorbidities and therefore, they often differ from real-life patients. In order to maximize the benefits from these drugs, we need to better identify the population at risk, understand and early diagnose their on- and off-target adverse effects and to adequately choose the diagnostic tools; with a better prevention and early treatment, the quality and quantity of our patients' lives can be significantly improved.
Collapse
Affiliation(s)
- ALEXANDRA GHERMAN
- 11th Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - CĂLIN CĂINAP
- 11th Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Prof. Dr. Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
| | - ANNE-MARIE CONSTANTIN
- 1st Department of Morphological Sciences, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - SÎNZIANA CETEAN
- 2nd Department of General and Inorganic Chemistry, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - SIMONA SORANA CĂINAP
- 2nd Pediatric Clinic, Cluj-Napoca, Romania
- 9th Department of Infant Care, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| |
Collapse
|
|
50
|
Brosseau S, Assoun S, Naltet C, Steinmetz C, Gounant V, Zalcman G. A review of bevacizumab in the treatment of malignant pleural mesothelioma. Future Oncol 2017; 13:2537-2546. [PMID: 29086616 DOI: 10.2217/fon-2017-0307] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. Systemic chemotherapy is the primary treatment modality for the majority of patients. VEGF plays a key mitogen for MPM cells physiopathology. Bevacizumab, a monoclonal anti-VEGF antibody, was a rational approach to be tested in MPM. Based on the results of the Phase III IFCT-0701 mesothelioma avastin cisplatin pemetrexed study, cisplatin-pemetrexed-bevacizumab is now the accepted standard in France. The National Comprehensive Cancer Network guidelines have also included this combination as an option for standard front-line therapy. This review summarized the efficacy and safety data of bevacizumab in the treatment of patients with MPM.
Collapse
Affiliation(s)
- Solenn Brosseau
- Department of Thoracic Oncology & CIC 1425/CLIP2 Paris-Nord, Bichat-Claude Bernard Hospital, APHP, Paris, France.,University Paris-Diderot, Paris, France
| | - Sandra Assoun
- Department of Thoracic Oncology & CIC 1425/CLIP2 Paris-Nord, Bichat-Claude Bernard Hospital, APHP, Paris, France
| | - Charles Naltet
- Department of Thoracic Oncology & CIC 1425/CLIP2 Paris-Nord, Bichat-Claude Bernard Hospital, APHP, Paris, France
| | - Christelle Steinmetz
- Pharmacy Department, Bichat-Claude Bernard Hospital, APHP, Paris, 46, rue Henri Huchard, 75877 Paris Cedex 18, France
| | - Valérie Gounant
- Department of Thoracic Oncology & CIC 1425/CLIP2 Paris-Nord, Bichat-Claude Bernard Hospital, APHP, Paris, France
| | - Gérard Zalcman
- Department of Thoracic Oncology & CIC 1425/CLIP2 Paris-Nord, Bichat-Claude Bernard Hospital, APHP, Paris, France.,University Paris-Diderot, Paris, France
| |
Collapse
|