Heparin, a registered ontstollingsmiddel similar survival time of cancer patients with solid tumors and metastases without significantly affecting high, rising from 9.4 to 15.5 months

March 5, 2005: Source: Yahoo AMC and J Clin Oncol. 7 February 2005;

Dutch researchers including the AMC - Dr. Clara Clerk PhD on this study - accidentally discovered in an investigation into the effect of heparin on thrombosis opportunities that administration of low molecular weight heparin - called fraxiparine - in cancer patients without metastases but with a life expectancy of only 6 months a significant difference in survival time pass. In a subgroup of the study of a randomized study in 203 cancer patients - 148 were nadropine and 154 a placebo - showed the effect of low molecular weight heparin less than the survival time in cancer patients with a prognosis of survival of six months to renew 9, 4 to 15.5 months. And so with only low molecular weight heparin. Successively placed here the abstract of the study published this month in J. Clinical Oncology, after an extensive article in an internal journal of the AMC and below it two studies abroad have been made to this approach and demonstrated comparable results than in the AMC. Truly a very interesting discovery, thanks to that ad was attentive to us here.

The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced malignancy.

Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR.
Departments of Vascular Medicine, Medical Oncology, and Radiation Oncology, Academic Medical Center, University of Amsterdam, Department of Medical Oncology, Slotervaart Hospital, Amsterdam, Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital Maastricht, University of Maastricht, the Netherlands; Servizio malattie Tromboemboliche, IRCCS Policlinico San Matteo, Pavia, Department of Medical and Surgical Sciences, Clinica Medica II, University Hospital of Padua, Italy, Department of Oncology, Reinier de Graaf Group, Delft, the Netherlands.

PURPOSE: Studies in cancer patients with venous thromboembolism Suggested That low molecular weight heparin May ProLong survival. In a double-blind study, we Evaluated the effect of low molecular weight heparin on survival in patient with advanced malignancy without venous thromboembolism.

METHODS: Patients with metastasized or locally advanced solid tumors Were Randomly Assigned to receive a 6-week course or Subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding.

RESULTS: In total, 148 patients Were Allocated to nadroparin and 154 patiënten Were Allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) or nadroparin-treated patiënten and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of Patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 months and 9.4, respectively. For Patient With A Shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25).

CONCLUSION: A brief course or Subcutaneous low molecular weight heparin Influences favorably the survival in patient with advanced malignancy and deserves Additional clinical evaluation.

PMID: 15699479 [PubMed - as supp song by publisher]

This article copied from the website of the AMC

The unexpected effect of a plunger
For the first time is well researched what effect the anticoagulant heparin on cancer. Especially in an early stage of the disease appear to benefit patients with low molecular weight heparin. Clara Klerk saw that the survival in a subgroup of patients with increased half years. Oncologists are more curious.

Cancer increases the risk of blood clots that clog the vessels, tumor cells because the coagulation system that sharper adjustment. If you give cancer anticoagulant, can you perhaps reduce the risk of thrombosis. In the early nineties it was examined whether the use of low molecular weight heparin to reduce risk of blood clots just as safe and effective as standard therapy with unfractionated heparin. It proved impossible to determine which form of the drug was administered.
Remarkably, researchers saw a difference in survival. Cancer patients treated with fraxiparine, the low molecular weight heparin, lived slightlylonger than those who received unfractionated heparin. Where did that anti-tumor effect of fraxiparine come from? Or was it a fluke?
"No, it was no fluke," says medical researcher Clara Klerk, "because the effect is then in a similar meta-analysis of studies found. You looked at all the studies together, there would have fraxiparine treated cancer patients with a better survival. But the results were from thrombosis study, which was primarily designed to evaluate the effect on coagulation in the picture. "

Half year
Klerk PhD in January on a study where it was directly addressed the effect of anticoagulation on the survival of not cure cancer. Her research was part of a partnership between the departments of Vascular Medicine, Clinical Oncology and Cell Biology and Histology. Clerk: "We gave half the patients a placebo, an injection of saline, and the rest got fraxiparine. Neither the patient nor the doctor knew who the drug or placebo was administered. We have not restricted to one type of cancer. Besides people with breast cancer and we saw people with rarer forms such as pancreatic cancer. "
The results Klerk mapped, are remarkable. The average survival is fraxiparinegroep eight months, while the placebo group averaged about six and a half months after dies. "The mortality throughout fraxiparinegroep almost one quarter lower, that's pretty much", says De Klerk. Looking at those patients with an expected survival of six months or more - in short, to those at the beginning of the study are still relatively healthy - the difference is even greater. Clerk: "In the placebo group, the mean survival almost nine and a half Mon The group was almost fifteen half fraxiparine Mon It saves half years! "

Clerk examined whether mutations that promote clotting, such as the factor V Leiden and prothrombin mutation G202210A contribute to an increased risk of cancer. In both cases, she found no relationship. Cancer is a risk factor for thrombosis, but the reverse seems that relationship is less clear. Clerk was at least not by a genetically increased risk of thrombosis increases the risk of tumor formation.

"After the dramatic differences in survival among patients groups were found, we were naturally very curious about a biological mechanism that could explain this difference," says De Klerk. "The first animal experimental data yielded not so much. Fraxiparine in mice that we gave, we did not see smaller tumors, and the number of tumors was no less than the control mice. Maybe we should refine some animal model, perhaps there is something else going on. Anyway, we are very curious about the results of subsequent studies. And the responses of oncologists. "

Caution
Dick Richel is co-promoter of Clara Klerk. And oncologist. Especially after the details of its investigation, he considers that the heparin gradually start to become an important issue. In oncology, although oncologists still long boat to various reasons. And rightly so, says Richel, because until recently, the evidence is weak because it was based on indirect studies and meta-analysis. Now, with the so-called MALT study Klerk, the difference is actually for the first time directly demonstrated. It will be repeated in other studies, but still ... The differences are very clear. Ledge, "especially for those groups that are fairly well for it, the results are telling. An increase in survival by five to six months, you get even with the most cytostatics disagree. But let us be careful, until the investigation is confirmed by further clinical trials. " A remarkable point, that in the MALT study emerges is the broad scope of fraxiparine. While in recent years was mainly looking for very specific resources at a specific point in the tumorigenesis seize. 'That's right, "says Richel," we are the chemotherapy, aimed at damaging DNA and RNA, are increasingly shifted to the target therapy, with which you addressed a specific aspect of tumor formation approach. There we came back a little, because a treatment seems to work better if you take multiple targets simultaneously. In short: dirty drug that your tumor is widening tackles, gaining in importance. "
Low molecular weight heparin - and to a lesser extent the unfractionated heparin - is a broad-acting drug because in many tumor types effect. "If it really works, it is likely to seize on themetastasis, the spread of tumors, "says Ridge. "It impedes the spread, not primary tumor growth. Recent animal data indicate that heparins are able to block selected statins. These selected statins play a role in cell adhesion, the process of free-floating tumor cells adhere to platelets to counter the attacks of the immune protection. And the same shall then select statins also suggests that the tumor cells from adhering to endothelial cells in the blood vessel and then to form a new tumor. Why especially heparin in patients with relatively good survival is working? Probably because in them the process of metastasis at an earlier stage is blocked. " It is a hypothesis, Richel emphasized yet again. But an interesting and promising hypothesis. For something more remarkable: "In the various studies, heparin is often only one week or six, seven administered. However, we can see in the longer term the most obvious effects. Why? We do not know. But the heparin investigation, initially mainly by coagulation and vascular scientists were encouraged to move increasingly towards oncology. The threshold to begin with anticoagulant, is still lower. "

Pieter Lomans

J Clin Oncol. 2004 May 15, 1922 (10) :1944-8.

Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS).

Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC.
Department of Surgical Oncology and Technology, and Cancer Research UK Laboratories, Imperial College, London, United Kingdom. akkakkar@tri-london.ac.uk

PURPOSE: In experimental systems, interference with coagulation can-affect tumor biology. Further More, it Has Been Suggested That low molecular weight heparin therapy in patient survival ProLong May with cancer. The AIM of this study was primary to Assess survival at 1 year of Patients with advanced cancer.

PATIENT AND METHODS: Patients with advanced malignancy (N = 385) Were Randomly Assigned to Either receive a once-daily Subcutaneous injection of dalteparin (5000 IU), a low molecular weight heparin, or placebo for 1 year. RESULTS: The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for Patient receiving dalteparin Were 46%, 27% and 21%, respectively, compared with 41%, 18% and 12%, respectively, for Patients receiving placebo (P =. 19). In an analysis not specified a priori, it was survival in a subgroup of Patients Examined (dalteparin, n = 55, and placebo, n = 47) who had a better prognosis and who Were alive 17 months after randomization. Thesis in patiënten, Kaplan-Meier survival estimates at 2 and 3 years from randomization Were significantly improved for Patient receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =. 03). The Symptomatic venous thromboembolism Were rates of 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.

CONCLUSION: dalteparin administration did not significantly ImproveGhana 1-year survival rates in patient with advanced malignancy. However, the observed improved survival in a subgroup of Patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.

PMID: 15143088 [PubMed - indexed for MEDLINE]

J Clin Oncol. 7 February 2005

Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous thromboembolism.

Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. 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, and Academic Hospital of Maastricht, Maastricht, the Netherlands.

PURPOSE: Experimental studies and clinical evidence suggest indirectly That low molecular weight heparin 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. PATIENT AND METHODS: Survival data Were Examined in a posthoc analysis in patient 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 patient with and without meta static malignancy. The effect of dalteparin on survival was compared Between the two patientsubgroup. RESULTS: During the 12-month follow-up period, 356 or 602 Patients with solid tumors and acute venous thromboembolism died. Among Patients without meta static 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 meta-static 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 differentiate Between patiënten with and without meta-static disease (P = .02).

CONCLUSION: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patient with solid tumors who did not have meta-static disease at the time of an acute venous thromboembolic event. Additional studies are warranted to Investigate thesis findings.

PMID: 15699480 [PubMed - as supp song by publisher].