Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous Thromboemb
http://www.100md.com
《临床肿瘤学》
the McMaster University
The Henderson Research Centre, Hamilton, ON, Canada
The George Washington University and the Children's National Medical Center, Washington, DC
University of Western Australia, Perth, Australia
Pfizer Inc, New York, NY
Imperial College, London, United Kingdom
Academic Hospital of Maastricht, Maastricht, the Netherlands
ABSTRACT
PURPOSE: Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism.
PATIENTS AND METHODS: Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups.
RESULTS: During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02).
CONCLUSION: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.
INTRODUCTION
Clinical evidence in support of anticoagulants having an antitumor effect was first reported in a multicenter, randomized, controlled trial in 1981.1 In the Veterans Affairs Research Service Cooperative Study 75, warfarin was found to be associated with an improvement in median survival in patients with small-cell lung cancer who were receiving chemotherapy. Similarly, a randomized trial in the same patient population demonstrated a survival advantage for those patients treated with subcutaneous injections of unfractionated heparin.2 However, despite compelling experimental evidence for a pathogenic role of blood coagulation in tumor growth and metastasis,3-6 other studies in patients with solid tumors have failed to confirm a survival benefit for patients treated with anticoagulants.7-10
More recently, the question of whether anticoagulants can favorably influence the natural history of cancer has received renewed attention. Randomized controlled trials and meta-analyses of studies that compared low molecular weight heparins with unfractionated heparin for the initial treatment of venous thromboembolism have reported a reduction in the overall mortality of patients with cancer who were randomly assigned to receive a low molecular weight heparin.11-15 Although the reduction in mortality has been consistent across studies and could not be attributed to differences in fatal pulmonary embolism or bleeding, the observation that 5 to 7 days of low molecular weight heparin treatment reduced cancer mortality has been difficult to explain. A plausible biologic mechanism, however, is now emerging from experimental studies that show low molecular weight heparins can inhibit angiogenesis, a process that is critical for tumor growth and metastasis, in a dose-dependent fashion.3,4,16,17
To date, two randomized, placebo-controlled trials designed to evaluate whether low molecular weight heparins can improve survival in patients with advanced or incurable malignancies have been completed.18,19 To examine the influence of a low molecular weight heparin relative to coumarin derivatives on the survival of cancer patients with venous thromboembolism and to investigate the hypothesis that low molecular weight heparins have a greater impact on survival in cancer patients with limited disease than in those with disseminated cancer, we performed a posthoc analysis of the mortality data in patients with solid tumors who participated in the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial.20
METHODS
Study Population
The CLOT trial was an international, multicenter, open-label, randomized trial that evaluated the relative efficacy and safety of dalteparin (Fragmin; Pfizer, New York, NY), a low molecular weight heparin, with oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer.20 Briefly, patients with cancer and acute venous thromboembolism were randomly assigned to 6 months of treatment with dalteparin alone or dalteparin followed by a coumarin derivative (warfarin or acenocoumarol). In the dalteparin group, patients received dalteparin once daily by subcutaneous injections at 200 U/kg for the first month followed by approximately 150 U/kg for the subsequent 5 months. In the oral anticoagulant group, patients received dalteparin 200 U/kg once daily for the first week followed by an oral anticoagulant at doses that maintained the international normalized ratio between 2.0 and 3.0. The primary efficacy outcome was symptomatic, recurrent venous thromboembolism up to 6 months and patients were observed for death for up to 12 months. The study showed that dalteparin significantly reduced the risk of symptomatic, recurrent venous thromboembolism by 52% (P = .002) without increasing bleeding. At 6 months, 40% of the patients were dead and a difference in overall mortality between treatment groups was not observed (P = .53). Ninety percent of the deaths in both groups were attributed to progressive cancer.
Statistical Analysis
The analysis was performed according to the intention-to-treat principle and based on the time from random assignment to death. The extent of cancer in patients with solid tumors was classified at study enrollment by local investigators as metastatic disease, localized disease without evidence of metastases, and no clinical evidence of active malignancy. Staging according to TNM classification was not required at random assignment. An a priori decision was made by the Steering Committee to combine the two latter patient groups into a single group of patients without metastatic disease for the purpose of this analysis because of the small number of patients in each group.
The probability of death during the 12 months after random assignment was estimated according to the Kaplan-Meier method for each treatment group in patients with and without metastatic disease.21 The difference in treatment-related survival within the two subgroups of patients was compared using the two-sided log-rank test.22 Treatment-related survival was also analyzed with the exclusion of patients with specific tumor types if there were statistically significant imbalances in the number of patients with such tumor types between the treatment groups.
Cox proportional hazards regression models were used to adjust the treatment effect on survival for baseline factors for all patients with solid tumors, and for the subgroups with and without metastases. These variables, identified a priori as potentially important predictors, and recorded at the time of randomization, included age (either continuous or by decade), sex, Eastern Cooperative Oncology Group performance status, smoking status (ever v never), qualifying episode of venous thromboembolism (pulmonary embolism v deep vein thrombosis), type of cancer treatment (radiation v none, chemotherapy v none), and major primary tumor site (breast, colorectal, lung, gynecologic, genitourinary, brain, pancreas, and other). Treatment and tumor site were forced into all regression models. Using a manual backward elimination modeling strategy, a variable remained in the model if the associated P value was less than .10 using both the Wald and score tests. The residuals from the final models were inspected for possible outliers, influential observations, and unusual patterns. Hazard ratios and their corresponding 95% CIs were estimated in the modeling process. To determine whether there was a difference in the influence of dalteparin on mortality between patients with and without metastatic disease, the unadjusted hazard ratios were compared using a two-sided z test. A two-sided P value of less than .05 was considered to be statistically significant. The Clinical Trials Methodology Group at the Henderson Research Centre, Hamilton Health Sciences (Hamilton, ON, Canada) was responsible for data management and statistical analyses. The Steering Committee was responsible for supervising and providing final approval of these activities and preparation of this article.
RESULTS
A total of 602 patients with solid tumors were included in the CLOT study and data on their survival at 12 months after random assignment were available for inclusion in the analysis. The baseline characteristics of the 452 patients with metastatic disease and the 150 patients without metastases are provided in Table 1. An assessment of the potential imbalance in each of the prognostic baseline factors between treatment groups was undertaken for each subgroup of patients with and without metastases. No statistically significant differences were observed between treatment groups for baseline variables in patients with metastatic disease. In the subgroup of patients without metastases, statistically significantly fewer patients with lung cancer (P = .04) were treated with dalteparin than with oral anticoagulant.
During the 12-month follow-up period, 174 of 296 patients in the dalteparin group died, compared with 182 of 306 patients in the oral anticoagulant group. The difference was not statistically significant (P = .62; Fig 1). In patients without known metastases, 15 of 75 patients in the dalteparin group and 26 of 75 patients in the oral anticoagulant group died. The Kaplan-Meier estimate of the probability of death at 12 months was 20% in the dalteparin group, compared with 36% in the oral anticoagulant group (Fig 2). The difference is statistically significant, with a hazard ratio of 0.50 (95% CI, 0.27 to 0.95; P = .03), in favor of dalteparin. Adjusting for baseline prognostic factors did not change the findings dramatically (adjusted hazard ratio, 0.41; 95% CI, 0.19 to 0.86; P = .02). When patients with lung cancer were excluded from the analysis, the hazard ratio remained in favor of dalteparin (unadjusted hazard ratio, 0.63; 95% CI, 0.31 to 1.3; P = .19; adjusted hazard ratio, 0.37; 95% CI, 0.17 to 0.83; P = .02).
In contrast, in patients with known metastatic malignancy, 159 of 221 patients assigned to dalteparin and 156 of 231 patients allocated to oral anticoagulant died. The probability of mortality at 12 months was 72% and 69%, respectively (Fig 2). The hazard ratio in the dalteparin group as compared with the oral anticoagulant group in patients with metastatic disease was 1.1 (95% CI, 0.87 to 1.4; P = .46). A comparison of the two hazard ratios of dalteparin to oral anticoagulant between the subgroups of patients with and without metastatic disease was statistically significant (P = .02).
In the best-fitting regression model, the treatment effect for dalteparin versus oral anticoagulant adjusted for statistically significant baseline risk factors was 0.43 (95% CI, 0.21 to 0.89; P = .02) for patients without metastases, and 1.1 (95% CI, 0.91 to 1.4; P = .24) for patients with known metastases. In addition, performance status, smoking, and treatment with chemotherapy were also independent predictors for survival (Table 2).
DISCUSSION
In this subgroup analysis of the CLOT trial, we examined the effect of a low molecular weight heparin dalteparin on the survival of patients with cancer and venous thromboembolism. Although a difference in survival at 12 months was not observed for the entire study population and patients with known metastases, we demonstrated a statistically significant improvement in overall survival associated with dalteparin, relative to oral anticoagulant therapy, in patients with solid tumors who were not known to have metastatic disease at the time of their thromboembolic event. The 50% relative risk reduction in the 12-month mortality remained significant after adjusting for known prognostic factors. A higher Eastern Cooperative Oncology Group status and smoking predicted for higher mortality, whereas age, sex, and the type of thrombotic event did not. The lack of effect on survival in patients with metastatic disease suggests that the mechanisms of action of dalteparin may be dependent on or interact with the stage of cancer or extent of tumor burden.
Although our results do not confirm a causal relationship between low molecular weight heparin and inhibition of tumor growth or progression, they are consistent with previous observations from clinical studies, including two recently completed randomized, placebo-controlled trials designed to investigate the influence of low molecular weight heparin on cancer survival.18,19 In the study by Kakkar et al18 (Fragmin Advanced Malignancy Outcome Study [FAMOUS] trial), which randomly assigned 382 patients with metastatic or advanced solid malignancies to once-daily injections of dalteparin or placebo for 1 year, a survival difference between treatment groups was not observed. The 1-year survival was 45% and 42%, respectively (P = .29). However, in those patients who survived beyond 17 months, an improvement in survival was observed in patients who received dalteparin (P = .04). In the Malignancy and Low Molecular Weight Heparin Therapy (MALT) trial reported by Klerk et al,19 approximately 300 patients with incurable solid tumors were randomly assigned to the low molecular weight heparin nadroparin or placebo for 6 weeks. A statistically significant improvement in overall survival was observed for nadroparin relative to placebo. The reduction in mortality was also in favor of nadroparin in the subgroup of patients who were identified as having a life expectancy of greater than 6 months. In all three studies, the use of low molecular weight heparin was associated with improved survival in patients with relatively good prognosis.
There are also important differences between our study and these additional trials. First, patients in the above-mentioned two studies did not have acute venous thromboembolism at the time of random assignment. Given the strong association between coagulation and tumor biology, the presence of venous thromboembolism could have an influence on the effect, if any, of low molecular weight heparins on tumor progression. Second, our patients might have had a poorer prognosis than those in the other trials because cancer patients with venous thromboembolism have a shorter life expectancy than similar cancer patients without thrombosis.23,24 The short life expectancy of our patients with metastatic disease could have limited the detection of a survival benefit associated with any therapy. Another difference among the studies is the treatment regimens used in the experimental and control groups. In our study, full therapeutic doses of dalteparin were administered for the first month followed by 75% of the full dose for 5 months, whereas in the FAMOUS study prophylactic dose of dalteparin was used, and in the MALT study nadroparin was given at therapeutic doses for 2 weeks followed by half of this dose for 4 weeks. Lastly, the CLOT study differs from the FAMOUS and MALT trials in the duration of follow-up. In the latter trials, improvement in overall survival was not observed until at least 1 year after randomization. Therefore, it is possible that a survival benefit might become evident in patients with metastatic disease in the CLOT trial with longer follow-up.
The major limitation of our analysis is the potential imbalance of prognostic factors between treatment groups. Although our study was a randomized trial, stratification for tumor type and extent of disease was not performed because the primary outcome in the CLOT trial was not survival. In addition, we could not control for differences in previous or concurrent antineoplastic therapy. We did examine the possibility that the difference in the number of patients with lung cancer treated with dalteparin or oral anticoagulant in patients without metastases might have influenced the findings. Reanalyzing the results with exclusion of patients with lung cancer also produced a statistically significant hazard ratio in favor of dalteparin when adjusted for prognostic baseline factors. Lastly, we cannot exclude the possibility that our observations are due to chance and imbalance of unknown prognostic variables. Therefore, the results of this subgroup analysis should be interpreted with caution.25
The mechanisms for a potential antineoplastic effect of low molecular weight heparins remain unknown and will require further investigations in well-designed experimental studies. An antiangiogenic effect is an appealing possibility and is compatible with our observation that a survival benefit was evident in patients with limited disease and persisted beyond the administration of the agent.26 It can be hypothesized that in patients with disseminated cancer, tumor-related vasculature is sufficiently developed so that an antiangiogenic agent would have minimal impact, whereas impairing the establishment of such vasculature by an antiangiogenic agent could exert an inhibitory effect on tumor growth even beyond the time of drug exposure. Although it has been suggested that the improvement in cancer survival associated with low molecular weight heparins observed in previous trials may be due to a reduction in fatal pulmonary embolism as compared with unfractionated heparin, the survival benefit beyond the period of low molecular weight heparin administration observed in our study would argue against this hypothesis.
A strong association between cancer and thrombosis has been demonstrated consistently in experimental and clinical studies. Our results offer additional evidence that the coagulation system is intrinsically involved in tumorigenesis or tumor progression. Future studies designed to confirm the antitumor effects of low molecular weight heparins and explore the pathophysiological mechanisms are awaited.
Appendix
The following investigators and institutions participated in the CLOT Trial: Steering Committee: M. Levine (Chair), R. Baker, C. Bowden, M. Gent, A. Kakkar, A. Lee, M. Prins, F. Rickles. External Safety and Efficacy Monitoring Committee: J. Pater (Chair), H. Büller, S. Goldhaber. Central Adjudication Committee: J. Ginsberg, J. Hirsh, C. Kearon, G. Thomson, J. Weitz. Coordinating and Methods Centre: Clinical Trials Methodology Group, Henderson Research Centre, Hamilton, ON, Canada–J. Julian, S. Haley, A. Ling, Q. Guo, B. Rush, T. Finch, L. Bonilla-Escobedo, L. Matthews, J. Windsor, C. Tavormina, H. Nelson, G. Lewis, J. Sicurella. Clinical Centers (the number of patients contributed from each country follows the country): Canada (225)—Hamilton Health Sciences, Henderson Hospital, Hamilton, ON—A. Lee, N. Booker, S. Schmidt; London Health Sciences Centre, London, ON—M. Kovacs, B. Morrow; Queen Elizabeth II Health Sciences Centre, Halifax, NS—B. McCarron, S. Pleasance; Toronto General Hospital, Toronto, ON—W.F. Brien, S. Boross-Harmer; St. Joseph's Hospital, Hamilton, ON—J.D. Douketis, T. Schnurr; The Montreal General Hospital, Montreal, PQ—S. Solymoss, B. St. Jacques; Sunnybrook & Women's College Health Sciences Centre, Toronto, ON—W. Geerts, K. Code; British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC—S. Chia, S. Monkman; Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON—A.G.G. Turpie, J. Johnson; Kelowna General Hospital, Kelowna, BC—J. Sutherland, S. Shori; Australia (144) and New Zealand (16)—Australasian Society of Thrombosis and Hemostasis—Royal Perth Hospital, Perth, WA—R. Baker, J. Smith; Flinders Medical Centre, Bedford Park, SA—D.W. Coghlan, J.M. Osmond; Prince of Wales Hospital, Randwick, NSW—S. Dunkley, B. Chong; Box Hill Hospital, Monash University, Box Hill—H. Salem, L. Poulton; Westmead Hospital, Westmead, NSW—M. Hertzberg, P. Stavros; Auckland Hospital, Auckland—P. Ockelford, V. Rolfe-Vyson; St. George Hospital, Kogarah, NSW—T. A. Brighton, R. Ristuccia; Royal North Shore Hospital, University of Sydney, Sydney, NSW—C.M. Ward, K. Sheather; Royal Adelaide Hospital, Adelaide, SA—I.N. Olver, T. Marafioti; St. Vincent's Hospital, Sydney, NSW—D. Ma; Monash Medical Centre, Clayton, VIC—T. E. Gan, A. Cummins; Royal Melbourne Hospital, Parkville, VIC—A. Grigg, E. Cinc; United States (118) —University of Southern California, Keck School of Medicine, Los Angeles, CA—H. Liebman, I. Weitz; University of Texas, M.D. Anderson Cancer Center, Houston, TX—C.P. Escalante, P. Horace; Northwestern University, Chicago, IL—D. Green, M. Calimaran; University of North Carolina at Chapel Hill, Chapel Hill, NC—S. Moll, S.K. Jones; Arizona Cancer Centre, University of Arizona, Tucson, AZ—A. Stopeck, K. Glennie; Atlanta VA Medical Centre/Emory University—M. Ribeiro, L. Starke; The Cleveland Clinic Foundation, Cleveland, OH—S.R. Deitcher; Mt. Sinai Medical Center, New York, NY—L. Lipsey; St. Joseph Mercy Oakland, Pontiac, MI—A. Brady, R. Krishnan; University of Vermont & Fletcher Allen Health Care, Burlington, VT—M. Cushman, L. Chassereau; University of Virginia Health System, Charlottesville, VA—B.G. Macik, L. Newton; Lovelace Health System, Albequrque, NM—A. Tarnower, R.J. Weiler; Newark Beth Israel Medical Center, Newark, NJ—A.J. Cohen, E. White; University of Connecticut, Farmington, CT—R. Bona, K. Jennings; Italy (67)—Ospedali Riuniti, Bergamo—A. Falanga, R. Labianca; Clinica Medica II, University of Padua, Padua—P. Prandoni, A. Piccioli, E. Zanon; Angelo Bianchi Bonomi Hemophilia Thrombosis Center, University of Milan and National Cancer Institute of Milan—A.B. Federici, G. Pizzocaro; the Netherlands (41)—Academic Medical Center of the University of Amsterdam, Amsterdam—S.M. Smorenburg, C.P.W. Klerk; University Hospital Nymegen, Nymegen—F. v.d. Berkmortel, DJTh Wagener; Maasland Hospital, Sittard—F.L.G. Erdkamp; St. Elisabeth Hospital, Tilburg—C. van der Heul, C. Post; St. Antonius Hospital, Nieuwegein—D.H. Biesma; Van Weel Bethesda Hospital, Dirksland—C. Kroon, M. Kamphuis van der Poel; Spain(33)—Hospital Universitari Germans Trias i Pujol, Badalona—E. Davant, M. Monreal; United Kingdom (2)—Oldchurch Hospital, Romford, Essex—M. Quigley; Mount Vernon Cancer Centre, Northwood, Middlesex—G.J.S. Rustin, J. Boxall.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Chris Bowden, Bristol-Myers Squibb. Acted as a consultant within the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer; Ajay K. Kakkar, Aventis, Pfizer; Agnes Y.Y. Lee, Aventis, LEO Pharma, Pharmacia/Pfizer, Sanofi, Wyeth; Mark N. Levine, Pfizer. Performed contract work within the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer; Ajay K. Kakkar, AstraZeneca, Aventis, Pfizer; Agnes Y.Y. Lee, Pharmacia/Pfizer; Chris Bowden, Bristol-Myers Squibb; Mark N. Levine, Pharmacia/Pfizer.
Acknowledgment
We thank C.P.W. Klerk and H.R. Büller for their helpful review of the manuscript.
NOTES
Supported by a New Investigator Award from the Canadian Institutes of Health Research/Rx&D Research Program (A.Y.Y.L). M.N.L. is the Buffett Taylor Chair in Breast Cancer Research, McMaster University, Hamilton, Ontario, Canada.
Presented in part as a poster at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Smorenburg SM, Vink R, Otten HM, et al: The effects of vitamin K-antagonists on survival of patients with malignancy: A systematic analysis. Thromb Haemost 86:1586-1587, 2001
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Klerk CPW, Smorenburg SM, Otten JMMB, et al: Malignancy and low-molecular-weight heparin therapy: The MALT trial. Presented at Intl Soc Thromb Haemost XIX International Congress, Birmingham, UK, July 12-18, 2003
Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146-153, 2003
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Sorensen HT, Mellemkjaer L, Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846-1850, 2000
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The Henderson Research Centre, Hamilton, ON, Canada
The George Washington University and the Children's National Medical Center, Washington, DC
University of Western Australia, Perth, Australia
Pfizer Inc, New York, NY
Imperial College, London, United Kingdom
Academic Hospital of Maastricht, Maastricht, the Netherlands
ABSTRACT
PURPOSE: Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism.
PATIENTS AND METHODS: Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups.
RESULTS: During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02).
CONCLUSION: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.
INTRODUCTION
Clinical evidence in support of anticoagulants having an antitumor effect was first reported in a multicenter, randomized, controlled trial in 1981.1 In the Veterans Affairs Research Service Cooperative Study 75, warfarin was found to be associated with an improvement in median survival in patients with small-cell lung cancer who were receiving chemotherapy. Similarly, a randomized trial in the same patient population demonstrated a survival advantage for those patients treated with subcutaneous injections of unfractionated heparin.2 However, despite compelling experimental evidence for a pathogenic role of blood coagulation in tumor growth and metastasis,3-6 other studies in patients with solid tumors have failed to confirm a survival benefit for patients treated with anticoagulants.7-10
More recently, the question of whether anticoagulants can favorably influence the natural history of cancer has received renewed attention. Randomized controlled trials and meta-analyses of studies that compared low molecular weight heparins with unfractionated heparin for the initial treatment of venous thromboembolism have reported a reduction in the overall mortality of patients with cancer who were randomly assigned to receive a low molecular weight heparin.11-15 Although the reduction in mortality has been consistent across studies and could not be attributed to differences in fatal pulmonary embolism or bleeding, the observation that 5 to 7 days of low molecular weight heparin treatment reduced cancer mortality has been difficult to explain. A plausible biologic mechanism, however, is now emerging from experimental studies that show low molecular weight heparins can inhibit angiogenesis, a process that is critical for tumor growth and metastasis, in a dose-dependent fashion.3,4,16,17
To date, two randomized, placebo-controlled trials designed to evaluate whether low molecular weight heparins can improve survival in patients with advanced or incurable malignancies have been completed.18,19 To examine the influence of a low molecular weight heparin relative to coumarin derivatives on the survival of cancer patients with venous thromboembolism and to investigate the hypothesis that low molecular weight heparins have a greater impact on survival in cancer patients with limited disease than in those with disseminated cancer, we performed a posthoc analysis of the mortality data in patients with solid tumors who participated in the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial.20
METHODS
Study Population
The CLOT trial was an international, multicenter, open-label, randomized trial that evaluated the relative efficacy and safety of dalteparin (Fragmin; Pfizer, New York, NY), a low molecular weight heparin, with oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer.20 Briefly, patients with cancer and acute venous thromboembolism were randomly assigned to 6 months of treatment with dalteparin alone or dalteparin followed by a coumarin derivative (warfarin or acenocoumarol). In the dalteparin group, patients received dalteparin once daily by subcutaneous injections at 200 U/kg for the first month followed by approximately 150 U/kg for the subsequent 5 months. In the oral anticoagulant group, patients received dalteparin 200 U/kg once daily for the first week followed by an oral anticoagulant at doses that maintained the international normalized ratio between 2.0 and 3.0. The primary efficacy outcome was symptomatic, recurrent venous thromboembolism up to 6 months and patients were observed for death for up to 12 months. The study showed that dalteparin significantly reduced the risk of symptomatic, recurrent venous thromboembolism by 52% (P = .002) without increasing bleeding. At 6 months, 40% of the patients were dead and a difference in overall mortality between treatment groups was not observed (P = .53). Ninety percent of the deaths in both groups were attributed to progressive cancer.
Statistical Analysis
The analysis was performed according to the intention-to-treat principle and based on the time from random assignment to death. The extent of cancer in patients with solid tumors was classified at study enrollment by local investigators as metastatic disease, localized disease without evidence of metastases, and no clinical evidence of active malignancy. Staging according to TNM classification was not required at random assignment. An a priori decision was made by the Steering Committee to combine the two latter patient groups into a single group of patients without metastatic disease for the purpose of this analysis because of the small number of patients in each group.
The probability of death during the 12 months after random assignment was estimated according to the Kaplan-Meier method for each treatment group in patients with and without metastatic disease.21 The difference in treatment-related survival within the two subgroups of patients was compared using the two-sided log-rank test.22 Treatment-related survival was also analyzed with the exclusion of patients with specific tumor types if there were statistically significant imbalances in the number of patients with such tumor types between the treatment groups.
Cox proportional hazards regression models were used to adjust the treatment effect on survival for baseline factors for all patients with solid tumors, and for the subgroups with and without metastases. These variables, identified a priori as potentially important predictors, and recorded at the time of randomization, included age (either continuous or by decade), sex, Eastern Cooperative Oncology Group performance status, smoking status (ever v never), qualifying episode of venous thromboembolism (pulmonary embolism v deep vein thrombosis), type of cancer treatment (radiation v none, chemotherapy v none), and major primary tumor site (breast, colorectal, lung, gynecologic, genitourinary, brain, pancreas, and other). Treatment and tumor site were forced into all regression models. Using a manual backward elimination modeling strategy, a variable remained in the model if the associated P value was less than .10 using both the Wald and score tests. The residuals from the final models were inspected for possible outliers, influential observations, and unusual patterns. Hazard ratios and their corresponding 95% CIs were estimated in the modeling process. To determine whether there was a difference in the influence of dalteparin on mortality between patients with and without metastatic disease, the unadjusted hazard ratios were compared using a two-sided z test. A two-sided P value of less than .05 was considered to be statistically significant. The Clinical Trials Methodology Group at the Henderson Research Centre, Hamilton Health Sciences (Hamilton, ON, Canada) was responsible for data management and statistical analyses. The Steering Committee was responsible for supervising and providing final approval of these activities and preparation of this article.
RESULTS
A total of 602 patients with solid tumors were included in the CLOT study and data on their survival at 12 months after random assignment were available for inclusion in the analysis. The baseline characteristics of the 452 patients with metastatic disease and the 150 patients without metastases are provided in Table 1. An assessment of the potential imbalance in each of the prognostic baseline factors between treatment groups was undertaken for each subgroup of patients with and without metastases. No statistically significant differences were observed between treatment groups for baseline variables in patients with metastatic disease. In the subgroup of patients without metastases, statistically significantly fewer patients with lung cancer (P = .04) were treated with dalteparin than with oral anticoagulant.
During the 12-month follow-up period, 174 of 296 patients in the dalteparin group died, compared with 182 of 306 patients in the oral anticoagulant group. The difference was not statistically significant (P = .62; Fig 1). In patients without known metastases, 15 of 75 patients in the dalteparin group and 26 of 75 patients in the oral anticoagulant group died. The Kaplan-Meier estimate of the probability of death at 12 months was 20% in the dalteparin group, compared with 36% in the oral anticoagulant group (Fig 2). The difference is statistically significant, with a hazard ratio of 0.50 (95% CI, 0.27 to 0.95; P = .03), in favor of dalteparin. Adjusting for baseline prognostic factors did not change the findings dramatically (adjusted hazard ratio, 0.41; 95% CI, 0.19 to 0.86; P = .02). When patients with lung cancer were excluded from the analysis, the hazard ratio remained in favor of dalteparin (unadjusted hazard ratio, 0.63; 95% CI, 0.31 to 1.3; P = .19; adjusted hazard ratio, 0.37; 95% CI, 0.17 to 0.83; P = .02).
In contrast, in patients with known metastatic malignancy, 159 of 221 patients assigned to dalteparin and 156 of 231 patients allocated to oral anticoagulant died. The probability of mortality at 12 months was 72% and 69%, respectively (Fig 2). The hazard ratio in the dalteparin group as compared with the oral anticoagulant group in patients with metastatic disease was 1.1 (95% CI, 0.87 to 1.4; P = .46). A comparison of the two hazard ratios of dalteparin to oral anticoagulant between the subgroups of patients with and without metastatic disease was statistically significant (P = .02).
In the best-fitting regression model, the treatment effect for dalteparin versus oral anticoagulant adjusted for statistically significant baseline risk factors was 0.43 (95% CI, 0.21 to 0.89; P = .02) for patients without metastases, and 1.1 (95% CI, 0.91 to 1.4; P = .24) for patients with known metastases. In addition, performance status, smoking, and treatment with chemotherapy were also independent predictors for survival (Table 2).
DISCUSSION
In this subgroup analysis of the CLOT trial, we examined the effect of a low molecular weight heparin dalteparin on the survival of patients with cancer and venous thromboembolism. Although a difference in survival at 12 months was not observed for the entire study population and patients with known metastases, we demonstrated a statistically significant improvement in overall survival associated with dalteparin, relative to oral anticoagulant therapy, in patients with solid tumors who were not known to have metastatic disease at the time of their thromboembolic event. The 50% relative risk reduction in the 12-month mortality remained significant after adjusting for known prognostic factors. A higher Eastern Cooperative Oncology Group status and smoking predicted for higher mortality, whereas age, sex, and the type of thrombotic event did not. The lack of effect on survival in patients with metastatic disease suggests that the mechanisms of action of dalteparin may be dependent on or interact with the stage of cancer or extent of tumor burden.
Although our results do not confirm a causal relationship between low molecular weight heparin and inhibition of tumor growth or progression, they are consistent with previous observations from clinical studies, including two recently completed randomized, placebo-controlled trials designed to investigate the influence of low molecular weight heparin on cancer survival.18,19 In the study by Kakkar et al18 (Fragmin Advanced Malignancy Outcome Study [FAMOUS] trial), which randomly assigned 382 patients with metastatic or advanced solid malignancies to once-daily injections of dalteparin or placebo for 1 year, a survival difference between treatment groups was not observed. The 1-year survival was 45% and 42%, respectively (P = .29). However, in those patients who survived beyond 17 months, an improvement in survival was observed in patients who received dalteparin (P = .04). In the Malignancy and Low Molecular Weight Heparin Therapy (MALT) trial reported by Klerk et al,19 approximately 300 patients with incurable solid tumors were randomly assigned to the low molecular weight heparin nadroparin or placebo for 6 weeks. A statistically significant improvement in overall survival was observed for nadroparin relative to placebo. The reduction in mortality was also in favor of nadroparin in the subgroup of patients who were identified as having a life expectancy of greater than 6 months. In all three studies, the use of low molecular weight heparin was associated with improved survival in patients with relatively good prognosis.
There are also important differences between our study and these additional trials. First, patients in the above-mentioned two studies did not have acute venous thromboembolism at the time of random assignment. Given the strong association between coagulation and tumor biology, the presence of venous thromboembolism could have an influence on the effect, if any, of low molecular weight heparins on tumor progression. Second, our patients might have had a poorer prognosis than those in the other trials because cancer patients with venous thromboembolism have a shorter life expectancy than similar cancer patients without thrombosis.23,24 The short life expectancy of our patients with metastatic disease could have limited the detection of a survival benefit associated with any therapy. Another difference among the studies is the treatment regimens used in the experimental and control groups. In our study, full therapeutic doses of dalteparin were administered for the first month followed by 75% of the full dose for 5 months, whereas in the FAMOUS study prophylactic dose of dalteparin was used, and in the MALT study nadroparin was given at therapeutic doses for 2 weeks followed by half of this dose for 4 weeks. Lastly, the CLOT study differs from the FAMOUS and MALT trials in the duration of follow-up. In the latter trials, improvement in overall survival was not observed until at least 1 year after randomization. Therefore, it is possible that a survival benefit might become evident in patients with metastatic disease in the CLOT trial with longer follow-up.
The major limitation of our analysis is the potential imbalance of prognostic factors between treatment groups. Although our study was a randomized trial, stratification for tumor type and extent of disease was not performed because the primary outcome in the CLOT trial was not survival. In addition, we could not control for differences in previous or concurrent antineoplastic therapy. We did examine the possibility that the difference in the number of patients with lung cancer treated with dalteparin or oral anticoagulant in patients without metastases might have influenced the findings. Reanalyzing the results with exclusion of patients with lung cancer also produced a statistically significant hazard ratio in favor of dalteparin when adjusted for prognostic baseline factors. Lastly, we cannot exclude the possibility that our observations are due to chance and imbalance of unknown prognostic variables. Therefore, the results of this subgroup analysis should be interpreted with caution.25
The mechanisms for a potential antineoplastic effect of low molecular weight heparins remain unknown and will require further investigations in well-designed experimental studies. An antiangiogenic effect is an appealing possibility and is compatible with our observation that a survival benefit was evident in patients with limited disease and persisted beyond the administration of the agent.26 It can be hypothesized that in patients with disseminated cancer, tumor-related vasculature is sufficiently developed so that an antiangiogenic agent would have minimal impact, whereas impairing the establishment of such vasculature by an antiangiogenic agent could exert an inhibitory effect on tumor growth even beyond the time of drug exposure. Although it has been suggested that the improvement in cancer survival associated with low molecular weight heparins observed in previous trials may be due to a reduction in fatal pulmonary embolism as compared with unfractionated heparin, the survival benefit beyond the period of low molecular weight heparin administration observed in our study would argue against this hypothesis.
A strong association between cancer and thrombosis has been demonstrated consistently in experimental and clinical studies. Our results offer additional evidence that the coagulation system is intrinsically involved in tumorigenesis or tumor progression. Future studies designed to confirm the antitumor effects of low molecular weight heparins and explore the pathophysiological mechanisms are awaited.
Appendix
The following investigators and institutions participated in the CLOT Trial: Steering Committee: M. Levine (Chair), R. Baker, C. Bowden, M. Gent, A. Kakkar, A. Lee, M. Prins, F. Rickles. External Safety and Efficacy Monitoring Committee: J. Pater (Chair), H. Büller, S. Goldhaber. Central Adjudication Committee: J. Ginsberg, J. Hirsh, C. Kearon, G. Thomson, J. Weitz. Coordinating and Methods Centre: Clinical Trials Methodology Group, Henderson Research Centre, Hamilton, ON, Canada–J. Julian, S. Haley, A. Ling, Q. Guo, B. Rush, T. Finch, L. Bonilla-Escobedo, L. Matthews, J. Windsor, C. Tavormina, H. Nelson, G. Lewis, J. Sicurella. Clinical Centers (the number of patients contributed from each country follows the country): Canada (225)—Hamilton Health Sciences, Henderson Hospital, Hamilton, ON—A. Lee, N. Booker, S. Schmidt; London Health Sciences Centre, London, ON—M. Kovacs, B. Morrow; Queen Elizabeth II Health Sciences Centre, Halifax, NS—B. McCarron, S. Pleasance; Toronto General Hospital, Toronto, ON—W.F. Brien, S. Boross-Harmer; St. Joseph's Hospital, Hamilton, ON—J.D. Douketis, T. Schnurr; The Montreal General Hospital, Montreal, PQ—S. Solymoss, B. St. Jacques; Sunnybrook & Women's College Health Sciences Centre, Toronto, ON—W. Geerts, K. Code; British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC—S. Chia, S. Monkman; Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON—A.G.G. Turpie, J. Johnson; Kelowna General Hospital, Kelowna, BC—J. Sutherland, S. Shori; Australia (144) and New Zealand (16)—Australasian Society of Thrombosis and Hemostasis—Royal Perth Hospital, Perth, WA—R. Baker, J. Smith; Flinders Medical Centre, Bedford Park, SA—D.W. Coghlan, J.M. Osmond; Prince of Wales Hospital, Randwick, NSW—S. Dunkley, B. Chong; Box Hill Hospital, Monash University, Box Hill—H. Salem, L. Poulton; Westmead Hospital, Westmead, NSW—M. Hertzberg, P. Stavros; Auckland Hospital, Auckland—P. Ockelford, V. Rolfe-Vyson; St. George Hospital, Kogarah, NSW—T. A. Brighton, R. Ristuccia; Royal North Shore Hospital, University of Sydney, Sydney, NSW—C.M. Ward, K. Sheather; Royal Adelaide Hospital, Adelaide, SA—I.N. Olver, T. Marafioti; St. Vincent's Hospital, Sydney, NSW—D. Ma; Monash Medical Centre, Clayton, VIC—T. E. Gan, A. Cummins; Royal Melbourne Hospital, Parkville, VIC—A. Grigg, E. Cinc; United States (118) —University of Southern California, Keck School of Medicine, Los Angeles, CA—H. Liebman, I. Weitz; University of Texas, M.D. Anderson Cancer Center, Houston, TX—C.P. Escalante, P. Horace; Northwestern University, Chicago, IL—D. Green, M. Calimaran; University of North Carolina at Chapel Hill, Chapel Hill, NC—S. Moll, S.K. Jones; Arizona Cancer Centre, University of Arizona, Tucson, AZ—A. Stopeck, K. Glennie; Atlanta VA Medical Centre/Emory University—M. Ribeiro, L. Starke; The Cleveland Clinic Foundation, Cleveland, OH—S.R. Deitcher; Mt. Sinai Medical Center, New York, NY—L. Lipsey; St. Joseph Mercy Oakland, Pontiac, MI—A. Brady, R. Krishnan; University of Vermont & Fletcher Allen Health Care, Burlington, VT—M. Cushman, L. Chassereau; University of Virginia Health System, Charlottesville, VA—B.G. Macik, L. Newton; Lovelace Health System, Albequrque, NM—A. Tarnower, R.J. Weiler; Newark Beth Israel Medical Center, Newark, NJ—A.J. Cohen, E. White; University of Connecticut, Farmington, CT—R. Bona, K. Jennings; Italy (67)—Ospedali Riuniti, Bergamo—A. Falanga, R. Labianca; Clinica Medica II, University of Padua, Padua—P. Prandoni, A. Piccioli, E. Zanon; Angelo Bianchi Bonomi Hemophilia Thrombosis Center, University of Milan and National Cancer Institute of Milan—A.B. Federici, G. Pizzocaro; the Netherlands (41)—Academic Medical Center of the University of Amsterdam, Amsterdam—S.M. Smorenburg, C.P.W. Klerk; University Hospital Nymegen, Nymegen—F. v.d. Berkmortel, DJTh Wagener; Maasland Hospital, Sittard—F.L.G. Erdkamp; St. Elisabeth Hospital, Tilburg—C. van der Heul, C. Post; St. Antonius Hospital, Nieuwegein—D.H. Biesma; Van Weel Bethesda Hospital, Dirksland—C. Kroon, M. Kamphuis van der Poel; Spain(33)—Hospital Universitari Germans Trias i Pujol, Badalona—E. Davant, M. Monreal; United Kingdom (2)—Oldchurch Hospital, Romford, Essex—M. Quigley; Mount Vernon Cancer Centre, Northwood, Middlesex—G.J.S. Rustin, J. Boxall.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Chris Bowden, Bristol-Myers Squibb. Acted as a consultant within the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer; Ajay K. Kakkar, Aventis, Pfizer; Agnes Y.Y. Lee, Aventis, LEO Pharma, Pharmacia/Pfizer, Sanofi, Wyeth; Mark N. Levine, Pfizer. Performed contract work within the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: Frederick R. Rickles, Pharmacia/Pfizer; Ajay K. Kakkar, AstraZeneca, Aventis, Pfizer; Agnes Y.Y. Lee, Pharmacia/Pfizer; Chris Bowden, Bristol-Myers Squibb; Mark N. Levine, Pharmacia/Pfizer.
Acknowledgment
We thank C.P.W. Klerk and H.R. Büller for their helpful review of the manuscript.
NOTES
Supported by a New Investigator Award from the Canadian Institutes of Health Research/Rx&D Research Program (A.Y.Y.L). M.N.L. is the Buffett Taylor Chair in Breast Cancer Research, McMaster University, Hamilton, Ontario, Canada.
Presented in part as a poster at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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