Intern Emerg Med DOI 10.1007/s11739-014-1087-2
IM - COMMENTARY
Impact of venous thromboembolism on survival in patients with advanced cancer: an unmet clinical need Gary H. Lyman
Received: 7 May 2014 / Accepted: 9 May 2014 Ó SIMI 2014
Introduction Retrospective studies have consistently demonstrated an increased risk of mortality in patients with cancer-associated venous thromboembolism (VTE) [1–3]. Reasons for increased mortality among cancer patients developing VTE are multiple, and include patient characteristics, cancer-, treatment-, and VTE-associated vascular events such as pulmonary embolism. Fatal pulmonary embolism is arguably the leading cause of sudden death among hospitalized patients, and may account for upwards of 10 % of inhospital deaths [4]. In fact, the true burden of VTE and its impact on mortality has likely been underestimated, as upwards of two-thirds of fatal pulmonary emboli are not detected prior to death [5, 6]. More recent studies also suggest that the survival of cancer patients with incidentally detected VTE is indistinguishable from that of patients with symptomatic VTE [7]. In an era of infrequent post mortem examinations and frequent attribution of mortality in cancer patients to the disease itself, it appears likely that the contribution of VTE to early mortality is much more common than currently recognized. Early mortality during the course of active treatment is most often presumed to be, at least in part, treatmentrelated, and has been reported to occur in 1 % to as high as 20 % of patients [8–11]. In a French study, more than half of deaths during the first month of therapy were attributed to treatment-associated or vascular complications [8]. A
G. H. Lyman (&) Public Health Sciences, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center and the University of Washington, 11000 Fairview Ave N, M3B232, Seattle, WA 98109-1024, USA e-mail: [email protected]
prospective cohort study of ambulatory cancer patients receiving systemic chemotherapy concludes that not only is VTE associated with greater early mortality during the period of chemotherapy, but that other than the cancer itself, infection and thromboembolism, including venous and arterial events, are the leading causes of mortality, each accounting for nearly 10 % of deaths [12, 13]. Patient-specific risk factors for developing VTE in cancer patients reported in various studies include older age, obesity, prior history of VTE, certain inherited prothrombotic mutations, and circumstances leading to greater immobilization including hospitalization. Cancer-related factors associated with VTE relate primarily to the primary site and perhaps the stage of disease. Finally, treatmentrelated factors for VTE include systemic therapies such as chemotherapy, hormonal therapy, antiangiogenic agents as well as the use of central lines for treatment administration. Even supportive care agents such as recombinant erythropoietin have been associated with an increased risk of VTE. Previous randomized controlled clinical trials and metaanalyses have suggested that prophylactic anticoagulation with a low molecular weight heparin (LMWH) in patients with cancer may be associated with a reduction in all-cause mortality [14]. While more recent randomized trials of primary prophylaxis with LMWHs have failed to confirm a significant reduction in early mortality, these studies were not powered for survival, often included a variety of primary cancer sites, and the duration of follow-up was generally limited [15–17]. It has been proposed that thromboprophylaxis targeted toward subgroups of cancer patients at high risk for VTE may reduce the risk of early mortality [17, 18]. In addition, recent population studies of unselected cancer patients receiving chemotherapy and followed over a longer period of time have demonstrated
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Intern Emerg Med
that the risk of VTE and its consequences may be considerably greater than that reflected in the randomized trials [19]. The Master Oncology Study, presented in this issue of the journal, was a prospective multicenter case-control study of adult patients with advanced solid tumors designed to evaluate risk factors of VTE, as well as survival over a period of at least 10 months [20]. Cases included patients with gastrointestinal, genitourinary, breast, or ovarian cancers accrued at 51 oncology centers within 2 months of a symptomatic or incidentally-detected VTE, who were at least 2 months from surgery, and had a life expectancy of at least 3 months. Controls were unscreened cancer patients without symptomatic VTE enrolled from the same oncology units. An initial plan called for 2:1 matching of controls to cases based on study center, age, gender, cancer type, histology, and stage. Difficulties with accrual led to more limited matching as described above. The projected sample size for cases and controls was recalculated in order to evaluate reasonable effect size and statistical assumptions. Of the 611 patients enrolled, 576 were deemed evaluable although analyses were performed on both enrolled and evaluable populations. All VTE cases were treated with anti-thrombotic therapy, with 90 % receiving a LMWH. While two-thirds of patients with deep venous thrombosis were symptomatic, only one-third with pulmonary emboli were considered symptomatic at diagnosis. Of note, no significant differences between cases and controls were observed for the original matching baseline variables. Significant risk factors for VTE in multivariate analysis included: a greater body mass index, poorer ECOG performance status, and more recent cancer diagnosis potentially contributing to more than half of the VTE risk, although considerable caution must be used in interpreting combinations of attributable population risk [21]. Analgesics and corticosteroids were significantly associated with VTE, while cancer treatments were not, including chemotherapy, radiation therapy, and other supportive care measures although the limited final sample size must be kept in mind. Patients with VTE experienced a significantly poorer survival than controls with the worst prognosis seen in those patients with symptomatic VTE. Survival differences remained statistically significant after adjustment for selected covariates. In addition to VTE, significant covariates for mortality included poor ECOG performance status, lung cancer, undifferentiated histology, metastatic disease, chemotherapy, and the use of analgesics or corticosteroids, but not age, gender, BMI, radiotherapy, antiangiogenic, hormonal, or other supportive therapies. Caution should be used in interpreting these intriguing results given the relatively modest sample size and the acknowledged heterogeneity of the patient population and
123
treatments. In addition, concern has been expressed about using Kaplan–Meier estimates of the cumulative risk of VTE in populations of patients with advanced cancer associated with considerable censoring as seen here [22]. For this reason, the International Society on Thrombosis and Haemostasis has recently recommended use of competing risk analysis for evaluating the cumulative risk of VTE in controlled clinical trials to adjust for the likely presence of competing risks in this setting. Clearly, the results reported by Agnelli and colleagues in this issue add considerably to our understanding of the contribution of patient, cancer, and treatment related factors to the risk of VTE, as well as the impact of VTE and several important covariates on the survival of patients with advanced cancer [20]. The relative impact of both symptomatic and incidental VTE adjusted for performance status, cancer type, histology, and stage as well as chemotherapy and certain supportive care interventions, is confirmatory of previous studies, but has also identified a number of new opportunities to further refine our understanding of the complex interplay among cancer, the coagulation system, and the patient at risk. The limitations discussed above aside, these data represent an important contribution to our understanding of cancer and thrombosis, and represent a source of new hypotheses to be addressed in future studies. Further research is needed on the contribution of individual risk factors as well as the potential role of multivariate risk models in identifying patients with cancer at greatest risk for VTE and its consequences who are potential candidates for effective and safe thromboprophylaxis. Conflict of interest
None.
References 1. Sorensen HT, Mellemkjaer L, Olsen JH et al (2000) Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846–1850 2. Khorana AA, Rosenblatt JD, Sahasrabudhe DM et al (2003) A phase I trial of immunotherapy with intratumoral adenovirusinterferon-gamma (TG1041) in patients with malignant melanoma. Cancer Gene Ther 10:251–259 3. Komrokji RS, Uppal NP, Khorana AA et al (2006) Venous thromboembolism in patients with diffuse large B-cell lymphoma. Leuk Lymphoma 47:1029–1033 4. Nicolaides AN, Kakkar VV, Field ES (1973) Origin of deep vein thrombosis of the leg. Bull Soc Int Chir 32:101–106 5. Sandler DA, Martin JF (1989) Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med 82:203–205 6. Stein PD, Henry JW (1995) Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108:978–981 7. den Exter PL, Hooijer J, Dekkers OM et al (2011) Risk of recurrent venous thromboembolism and mortality in patients with
Intern Emerg Med
8.
9.
10.
11.
12.
13.
14.
cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 29:2405–2409 Ray-Coquard I, Ghesquiere H, Bachelot T et al (2001) Identification of patients at risk for early death after conventional chemotherapy in solid tumours and lymphomas. Br J Cancer 85:816–822 Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544 Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 Katopodis O, Ross P, Norman AR et al (2004) Sixty-day allcause mortality rates in patients treated for gastrointestinal cancers, in randomised trials, at the Royal Marsden Hospital. Eur J Cancer 40:2230–2236 Khorana AA, Francis CW, Culakova E et al (2007) Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 5:632–634 Kuderer NM, Khorana AA, Francis CW et al (2013) Risk score for venous thromboembolism (VTE) in ambulatory patients: impact of cancer type and risk score on VTE incidence, early mortality, and progression-free survival. Blood 122:3597 Kuderer NM, Khorana AA, Lyman GH et al (2007) A metaanalysis and systematic review of the efficacy and safety of
15.
16.
17.
18.
19.
20.
21. 22.
anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 110:1149–1161 Agnelli G, George DJ, Kakkar AK et al (2012) Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 366:601–609 Agnelli G, Gussoni G, Bianchini C et al (2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10:943–949 Maraveyas A, Waters J, Roy R et al (2012) Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283–1292 Lyman GH, Khorana AA, Kuderer NM et al (2013) Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 31:2189–2204 Lyman GH, Eckert L, Wang Y et al (2013) Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist 18:1321–1329 Agnelli G, Verso M, Mandala M et al (2013) A prospective study on survival in cancer patients with and without venous thromboembolism. Intern Emerg Med 1:9 (Published online) Rockhill B, Newman B, Weinberg C (1998) Use and misuse of population attributable fractions. Am J Public Health 88:15–19 Campigotto F, Neuberg D, Zwicker JI (2012) Biased estimation of thrombosis rates in cancer studies using the method of Kaplan and Meier. J Thromb Haemost 10:1449–1451
123
IM - COMMENTARY
Impact of venous thromboembolism on survival in patients with advanced cancer: an unmet clinical need Gary H. Lyman
Received: 7 May 2014 / Accepted: 9 May 2014 Ó SIMI 2014
Introduction Retrospective studies have consistently demonstrated an increased risk of mortality in patients with cancer-associated venous thromboembolism (VTE) [1–3]. Reasons for increased mortality among cancer patients developing VTE are multiple, and include patient characteristics, cancer-, treatment-, and VTE-associated vascular events such as pulmonary embolism. Fatal pulmonary embolism is arguably the leading cause of sudden death among hospitalized patients, and may account for upwards of 10 % of inhospital deaths [4]. In fact, the true burden of VTE and its impact on mortality has likely been underestimated, as upwards of two-thirds of fatal pulmonary emboli are not detected prior to death [5, 6]. More recent studies also suggest that the survival of cancer patients with incidentally detected VTE is indistinguishable from that of patients with symptomatic VTE [7]. In an era of infrequent post mortem examinations and frequent attribution of mortality in cancer patients to the disease itself, it appears likely that the contribution of VTE to early mortality is much more common than currently recognized. Early mortality during the course of active treatment is most often presumed to be, at least in part, treatmentrelated, and has been reported to occur in 1 % to as high as 20 % of patients [8–11]. In a French study, more than half of deaths during the first month of therapy were attributed to treatment-associated or vascular complications [8]. A
G. H. Lyman (&) Public Health Sciences, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center and the University of Washington, 11000 Fairview Ave N, M3B232, Seattle, WA 98109-1024, USA e-mail: [email protected]
prospective cohort study of ambulatory cancer patients receiving systemic chemotherapy concludes that not only is VTE associated with greater early mortality during the period of chemotherapy, but that other than the cancer itself, infection and thromboembolism, including venous and arterial events, are the leading causes of mortality, each accounting for nearly 10 % of deaths [12, 13]. Patient-specific risk factors for developing VTE in cancer patients reported in various studies include older age, obesity, prior history of VTE, certain inherited prothrombotic mutations, and circumstances leading to greater immobilization including hospitalization. Cancer-related factors associated with VTE relate primarily to the primary site and perhaps the stage of disease. Finally, treatmentrelated factors for VTE include systemic therapies such as chemotherapy, hormonal therapy, antiangiogenic agents as well as the use of central lines for treatment administration. Even supportive care agents such as recombinant erythropoietin have been associated with an increased risk of VTE. Previous randomized controlled clinical trials and metaanalyses have suggested that prophylactic anticoagulation with a low molecular weight heparin (LMWH) in patients with cancer may be associated with a reduction in all-cause mortality [14]. While more recent randomized trials of primary prophylaxis with LMWHs have failed to confirm a significant reduction in early mortality, these studies were not powered for survival, often included a variety of primary cancer sites, and the duration of follow-up was generally limited [15–17]. It has been proposed that thromboprophylaxis targeted toward subgroups of cancer patients at high risk for VTE may reduce the risk of early mortality [17, 18]. In addition, recent population studies of unselected cancer patients receiving chemotherapy and followed over a longer period of time have demonstrated
123
Intern Emerg Med
that the risk of VTE and its consequences may be considerably greater than that reflected in the randomized trials [19]. The Master Oncology Study, presented in this issue of the journal, was a prospective multicenter case-control study of adult patients with advanced solid tumors designed to evaluate risk factors of VTE, as well as survival over a period of at least 10 months [20]. Cases included patients with gastrointestinal, genitourinary, breast, or ovarian cancers accrued at 51 oncology centers within 2 months of a symptomatic or incidentally-detected VTE, who were at least 2 months from surgery, and had a life expectancy of at least 3 months. Controls were unscreened cancer patients without symptomatic VTE enrolled from the same oncology units. An initial plan called for 2:1 matching of controls to cases based on study center, age, gender, cancer type, histology, and stage. Difficulties with accrual led to more limited matching as described above. The projected sample size for cases and controls was recalculated in order to evaluate reasonable effect size and statistical assumptions. Of the 611 patients enrolled, 576 were deemed evaluable although analyses were performed on both enrolled and evaluable populations. All VTE cases were treated with anti-thrombotic therapy, with 90 % receiving a LMWH. While two-thirds of patients with deep venous thrombosis were symptomatic, only one-third with pulmonary emboli were considered symptomatic at diagnosis. Of note, no significant differences between cases and controls were observed for the original matching baseline variables. Significant risk factors for VTE in multivariate analysis included: a greater body mass index, poorer ECOG performance status, and more recent cancer diagnosis potentially contributing to more than half of the VTE risk, although considerable caution must be used in interpreting combinations of attributable population risk [21]. Analgesics and corticosteroids were significantly associated with VTE, while cancer treatments were not, including chemotherapy, radiation therapy, and other supportive care measures although the limited final sample size must be kept in mind. Patients with VTE experienced a significantly poorer survival than controls with the worst prognosis seen in those patients with symptomatic VTE. Survival differences remained statistically significant after adjustment for selected covariates. In addition to VTE, significant covariates for mortality included poor ECOG performance status, lung cancer, undifferentiated histology, metastatic disease, chemotherapy, and the use of analgesics or corticosteroids, but not age, gender, BMI, radiotherapy, antiangiogenic, hormonal, or other supportive therapies. Caution should be used in interpreting these intriguing results given the relatively modest sample size and the acknowledged heterogeneity of the patient population and
123
treatments. In addition, concern has been expressed about using Kaplan–Meier estimates of the cumulative risk of VTE in populations of patients with advanced cancer associated with considerable censoring as seen here [22]. For this reason, the International Society on Thrombosis and Haemostasis has recently recommended use of competing risk analysis for evaluating the cumulative risk of VTE in controlled clinical trials to adjust for the likely presence of competing risks in this setting. Clearly, the results reported by Agnelli and colleagues in this issue add considerably to our understanding of the contribution of patient, cancer, and treatment related factors to the risk of VTE, as well as the impact of VTE and several important covariates on the survival of patients with advanced cancer [20]. The relative impact of both symptomatic and incidental VTE adjusted for performance status, cancer type, histology, and stage as well as chemotherapy and certain supportive care interventions, is confirmatory of previous studies, but has also identified a number of new opportunities to further refine our understanding of the complex interplay among cancer, the coagulation system, and the patient at risk. The limitations discussed above aside, these data represent an important contribution to our understanding of cancer and thrombosis, and represent a source of new hypotheses to be addressed in future studies. Further research is needed on the contribution of individual risk factors as well as the potential role of multivariate risk models in identifying patients with cancer at greatest risk for VTE and its consequences who are potential candidates for effective and safe thromboprophylaxis. Conflict of interest
None.
References 1. Sorensen HT, Mellemkjaer L, Olsen JH et al (2000) Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846–1850 2. Khorana AA, Rosenblatt JD, Sahasrabudhe DM et al (2003) A phase I trial of immunotherapy with intratumoral adenovirusinterferon-gamma (TG1041) in patients with malignant melanoma. Cancer Gene Ther 10:251–259 3. Komrokji RS, Uppal NP, Khorana AA et al (2006) Venous thromboembolism in patients with diffuse large B-cell lymphoma. Leuk Lymphoma 47:1029–1033 4. Nicolaides AN, Kakkar VV, Field ES (1973) Origin of deep vein thrombosis of the leg. Bull Soc Int Chir 32:101–106 5. Sandler DA, Martin JF (1989) Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med 82:203–205 6. Stein PD, Henry JW (1995) Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108:978–981 7. den Exter PL, Hooijer J, Dekkers OM et al (2011) Risk of recurrent venous thromboembolism and mortality in patients with
Intern Emerg Med
8.
9.
10.
11.
12.
13.
14.
cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 29:2405–2409 Ray-Coquard I, Ghesquiere H, Bachelot T et al (2001) Identification of patients at risk for early death after conventional chemotherapy in solid tumours and lymphomas. Br J Cancer 85:816–822 Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544 Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 Katopodis O, Ross P, Norman AR et al (2004) Sixty-day allcause mortality rates in patients treated for gastrointestinal cancers, in randomised trials, at the Royal Marsden Hospital. Eur J Cancer 40:2230–2236 Khorana AA, Francis CW, Culakova E et al (2007) Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 5:632–634 Kuderer NM, Khorana AA, Francis CW et al (2013) Risk score for venous thromboembolism (VTE) in ambulatory patients: impact of cancer type and risk score on VTE incidence, early mortality, and progression-free survival. Blood 122:3597 Kuderer NM, Khorana AA, Lyman GH et al (2007) A metaanalysis and systematic review of the efficacy and safety of
15.
16.
17.
18.
19.
20.
21. 22.
anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 110:1149–1161 Agnelli G, George DJ, Kakkar AK et al (2012) Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 366:601–609 Agnelli G, Gussoni G, Bianchini C et al (2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10:943–949 Maraveyas A, Waters J, Roy R et al (2012) Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283–1292 Lyman GH, Khorana AA, Kuderer NM et al (2013) Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 31:2189–2204 Lyman GH, Eckert L, Wang Y et al (2013) Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist 18:1321–1329 Agnelli G, Verso M, Mandala M et al (2013) A prospective study on survival in cancer patients with and without venous thromboembolism. Intern Emerg Med 1:9 (Published online) Rockhill B, Newman B, Weinberg C (1998) Use and misuse of population attributable fractions. Am J Public Health 88:15–19 Campigotto F, Neuberg D, Zwicker JI (2012) Biased estimation of thrombosis rates in cancer studies using the method of Kaplan and Meier. J Thromb Haemost 10:1449–1451
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