warfarin and Carcinoma--Small-Cell

Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and antithrombotic effect, yet increase the risk of bleeding.. To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017.. Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. Using a standardized form, we extracted data in duplicate on study design, participants, intervention outcomes of interest and risk of bias. Outcomes of interest included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook).. Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence).The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence).. The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding.Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).. Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).. Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect.. To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect.. To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed.. We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38).. Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

To evaluate the effectiveness and safety of oral anticoagulants in improving survival of cancer patients. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We extracted data on methodological quality, participants, interventions and outcomes using a standardized form. Five RCTs fulfilled the inclusion criteria and all compared warfarin to either placebo or no intervention. Their overall methodological quality was acceptable. The effect of warfarin on mortality was not statistically significant at 6 months (RR = 0.96; 95% CI 0.80-1.16), at 1 year (RR = 0.95; 95% CI 0.86-1.05), at 2 years (RR = 0.97; 95% CI 0.87-1.08) or at 5 years (RR 0.91; 95% CI 0.83-1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at 6 months (RR = 0.69; 95% CI 0.50-0.96) but not at 1 year (RR = 0.88; 95% CI 0.77-1.01). This 6 months mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45-0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36-1.28). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85-9.68) and minor bleeding (RR = 3.34; 95% CI 1.66-6.74). The evidence suggests a survival benefit from warfarin in patients with extensive SCLC, but not in other patient groups. This survival benefit should be weighed against the increased risk for hemorrhage.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

Activation of coagulation and of the fibrinolytic system has been identified in small cell and non-small cell cancers respectively. For the clinician this poses the diagnostic problem of a thrombosis, which is most often venous with or without pulmonary emboli, complicating the evolution of an already diagnosed cancer. The inverse is that these features may reveal an underlying neoplasm and amongst the most common of these would be bronchopulmonary cancer. Numerous laboratory studies have shown the existence of a state of hyper-coagulability, with disseminated intra-vascular coagulation, which is more or less compensated and is the more marked, the more advanced the cancer is. One should not fail to recognise that this state of hyper-coagulability may be aggravated by certain cytotoxic drugs. At the level of the tumour itself, there seems to be interactions between the cancer cells and the coagulation and fibrinolytic system: these interactions are very different according to the histological type as to whether they are small cell or non-small cell bronchopulmonary cancers.

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation; Blood Coagulation Disorders; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Lung Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Thromboembolism; Thrombosis; Warfarin

Studies of malignancy in experimental animal models have indicated that cause-effect relationships exist between coagulation activation and cancer progression. Evidence for coagulation activation in human malignancy together with favorable results from pilot clinical trials led to the establishment of a prospective, randomized therapeutic trial of warfarin in cancer. A statistically significant prolongation of survival was observed in patients with small cell carcinoma of the lung entered into this study. Demonstration of an initiator of coagulation activation together with coagulation factor intermediates and fibrin in situ associated with viable tumor cells in small cell carcinoma of the lung is consistent with the hypothesis that tumor-initiated thrombin formation might contribute to progression of this tumor type. These observations suggest novel experimental treatment strategies for small cell carcinoma of the lung. Warfarin anticoagulation may be of value in the treatment of certain other types of malignancy.

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Thrombin; Warfarin

Evidence indicates that progression of the Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans is retarded by warfarin administration. This suggests that vitamin K-dependent pathways are of importance in the pathogenesis of these tumors. Available data were reviewed for these tumor types in an attempt to explore mechanisms and to gain insights that might guide the selection of other coagulation-reactive drugs for testing in future controlled clinical trials in small cell carcinoma of the lung. While many differences exist between the Lewis lung tumor and small cell carcinoma of the lung, both are rapidly growing malignancies of pulmonary origin that metastasize early to kill the host after a short time. Both are favorably influenced by combination chemotherapy and radiation therapy as well as anticoagulant treatment. Peripheral blood changes indicative of disseminated intravascular coagulation occur in each of these tumor types, and tumor cells from both are capable of interacting with the coagulation mechanism. While many details concerning the host-tumor interaction remain to be elucidated, the considerable and diverse information available for these tumor types provides a secure base for future investigation. It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warfarin might be effective for tumor types that are not responsive to this agent.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Disease Models, Animal; Humans; Lung Neoplasms; Mice; Warfarin

The recognition that the vast majority of patients with small cell lung cancer have distant metastatic disease at the time of diagnosis led to the use of systemic chemotherapy and consequent major improvements in survival in the early to mid-1970's. In the past five years, however, the pace of therapeutic advances has slowed. Recently evaluated treatment strategies, including more intensive induction chemotherapy, "late intensive" therapy of responding patients, alternation of chemotherapeutic regimens, integration of chest irradiation with drug therapy, large field irradiation, and reappraisal of the value of surgical resection, are discussed in this review. Advances in understanding of the cell biology of small cell lung cancer which may eventually lead to new forms of treatment are summarized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Small Cell; Combined Modality Therapy; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Staging; Prognosis; Retrospective Studies; Time Factors; Warfarin

The current study assessed the psychologic and neuropsychologic functioning of patients with small-cell lung cancer who were randomized in a large clinical trial to receive intensive doxorubicin, cyclophosphamide, etoposide (ACE)/cisplatin, cyclophosphamide, etoposide (PCE) chemotherapy and radiation therapy (RT) to the primary tumor and prophylactic whole-brain irradiation with (regimen I) or without (regimen II) warfarin.. Patients' emotional states and cognitive functioning were assessed using the Profile of Mood States (POMS) and Trail Making B Test (Trails B), respectively. Two hundred ninety-five patients completed the POMS and Trails B at pretreatment, 224 patients after the completion of the ACE course of chemotherapy (week 9), and 177 patients after the completion of the PCE chemotherapy and RT (week 17).. No differences on the POMS or Trails B measures were found between the two treatment arms as predicted, given that the only difference between the two treatment arms was the presence or absence of warfarin. Analysis of the POMS revealed that, overall, mean scores remained stable over the course of treatment; however, women showed a trend toward higher mean scores, which indicated a higher level of distress, compared with men at the pretreatment assessment. Examination of cognitive functioning, measured by the Trails B, revealed improved performance from baseline to post-ACE chemotherapy, which is consistent with a practice effect, but a significant worsening of Trails B scores post-RT compared with the pre-RT assessments, which is consistent with impaired cognitive functioning because of treatment (P < .0001).. Emotional state, measured by the POMS, did not differ between the groups or change significantly over time in this study of small-cell lung cancer patients treated with a combination of chemotherapy and RT plus or minus warfarin. However, the pattern of relatively stable POMS scores and poorer Trails B performance post-RT suggested that this combination of chemotherapy and RT had a negative impact on cognitive functioning.

Topics: Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Cognition; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Doxorubicin; Emotions; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neuropsychological Tests; Trail Making Test; Warfarin

Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC.. Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity.. There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103).. Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.

Topics: Adult; Aged; Amsacrine; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Hemorrhage; Humans; Lung Neoplasms; Male; Middle Aged; Recurrence; Survival Analysis; Warfarin

Topics: Breast Neoplasms; Carcinoma, Small Cell; Double-Blind Method; Female; Humans; Lung Neoplasms; Prospective Studies; Thromboembolism; Warfarin

Topics: Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Lung Neoplasms; Reproducibility of Results; Warfarin

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Lomustine; Lung Neoplasms; Male; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Prognosis; Random Allocation; Remission Induction; Warfarin

Evidence indicates that progression of the Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans is retarded by warfarin administration. This suggests that vitamin K-dependent pathways are of importance in the pathogenesis of these tumors. Available data were reviewed for these tumor types in an attempt to explore mechanisms and to gain insights that might guide the selection of other coagulation-reactive drugs for testing in future controlled clinical trials in small cell carcinoma of the lung. While many differences exist between the Lewis lung tumor and small cell carcinoma of the lung, both are rapidly growing malignancies of pulmonary origin that metastasize early to kill the host after a short time. Both are favorably influenced by combination chemotherapy and radiation therapy as well as anticoagulant treatment. Peripheral blood changes indicative of disseminated intravascular coagulation occur in each of these tumor types, and tumor cells from both are capable of interacting with the coagulation mechanism. While many details concerning the host-tumor interaction remain to be elucidated, the considerable and diverse information available for these tumor types provides a secure base for future investigation. It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warfarin might be effective for tumor types that are not responsive to this agent.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Disease Models, Animal; Humans; Lung Neoplasms; Mice; Warfarin

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Topics: Adenocarcinoma; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Colonic Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation; Warfarin

In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.

Topics: Antineoplastic Agents; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Lung Neoplasms; Random Allocation; United States; United States Department of Veterans Affairs; Warfarin

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Neoplasms; Survival Rate; Vitamin K; Warfarin

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Thromboembolism; Warfarin

Common indices for the quantal assessment of treatment efficacy are reviewed. The absolute risk reduction is a practical index for public health considerations. Its reciprocal has been termed the 'Number Needed to Treat' (NNT), representing the health effort that must on average be expended to accomplish one tangible treatment target. We extend the NNT to evaluate outcome combinations of treatment benefits versus treatment harms.. We describe the mathematical context of the NNT, and extend it to evaluate outcome combinations (treatment success/failure with/without treatment-induced adverse effects) in a treated population. These extensions are carried out assuming either independence or positive association between treatment benefit and treatment harm. A method is provided for calculating the standard errors of these extended NNT values. Applications to cost-effectiveness analysis are discussed.. We calculate NNT in three recent therapeutic studies. The results of a trial of the prevention of strokes with warfarin in patients with non-valvular atrial fibrillation are analysed to evaluate treatment success (stroke prevention) against treatment-induced bleeds. An NNT-related cost-benefit analysis is also carried out. We also analyse the results of a study of two modalities of chemotherapeutic treatment in small-cell lung cancer, and of two modalities of surgical intervention in the treatment of cholelithiasis.. The NNT are useful in direct evaluation of outcome-specific treatment benefits versus treatment-induced harms. They may also be used in cost-effectiveness analyses and are helpful in guiding public health programmes towards the identification of optimal treatment strategies.

Topics: Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Carcinoma, Small Cell; Cerebral Hemorrhage; Cerebrovascular Disorders; Cholecystectomy; Clinical Protocols; Cost-Benefit Analysis; Decision Support Techniques; Evaluation Studies as Topic; Health Care Costs; Humans; Models, Theoretical; Postoperative Complications; Quality-Adjusted Life Years; Sweden; Therapeutics; Treatment Failure; Treatment Outcome; Warfarin

CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C9*2) has been described that results in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C9*2 variant allele and risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C9*2 variant allele was lower (p = 0.00002) among African-Americans (0.036) than among Caucasians (0.100). The presence of the CYP2C9*2 variant allele was not associated with a decreased risk of lung cancer; slight but nonstatistically significant elevations in risk were observed for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48). The ORs were slightly and nonsignificantly elevated for all histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C9*2 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps. Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C9*2 variant allele in our data is consistent with chance and should not be overinterpreted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Alleles; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Black People; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cohort Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Genetic Variation; Genotype; Humans; Los Angeles; Lung Neoplasms; Middle Aged; Polymorphism, Genetic; Reference Values; Risk Factors; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Warfarin; White People

Urokinase-type plasminogen activator has been administered by other investigators to patients with small cell carcinoma of the lung (SCCL) in an attempt to induce lysis of fibrin that is known to exist in the connective tissue stroma of this tumour type and that may support tumour growth. To study the fate of infused urokinase in this disease, a biopsy of a scalp metastasis was obtained from a patient with SCCL (entered on a phase I clinical trial of urokinase plus combination chemotherapy) immediately following urokinase infusion during the fourth course of therapy a time when this tumour mass had decreased to approximately 25% of its original size. Immunohistochemical procedures revealed abundant stromal fibrin in accord with previous observations from this laboratory. By contrast, urokinase, that is not a feature of small cell tumour cells, was present on the tumour cells in this specimen. Urokinase infusion was associated with a rapid increase in the amount of this enzyme associated with isolated peripheral blood monocytes. These results are consistent with uptake of infused urokinase onto monocytes and possibly tumour cells. It is postulated that substantial tumour fibrinolysis may not accompany such therapy and that urokinase, or its amino terminal fragment that bears the growth factor domain of this molecule, may bind to and alter the growth of the tumour cells.

Topics: Aged; Carcinoma, Small Cell; Drug Therapy, Combination; Humans; Immunohistochemistry; Infusions, Intravenous; Lung Neoplasms; Male; Monocytes; Urokinase-Type Plasminogen Activator; Warfarin

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms; Warfarin

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC.. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible.. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation.. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Survival Analysis; Treatment Outcome; Warfarin

Topics: Carcinoma, Small Cell; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Tumor Cells, Cultured; Warfarin