In a prior post we touched on some reasons why heparins, blood thinners that are given IV or under the skin (subcutaneously), may have direct anti-tumor effects that could improve cancer outcomes, and another post covered the mixed results with the oral anticoagulant (blood thinner) coumadin in cancer, most notably SCLC.   Heparins are divided into unfractionated heparin, which contains a broad range of proteins that can be quite variable in the degree of blood thinning achieved, is most typically administered as a continuous IV infusion (some settings use unfractionated heparin in a subcutaneous (under the skin) injection), and usually requires at least daily monitoring with lab tests, and low molecular weight heparin (LMWH), which is a more filtered product that produces a more reliable amount of blood thinning activity and, depending on the particular formulation, are given once or twice daily as a subcutaneous injection.  Although still requiring injections and quite expensive, the work on heparins over the last several years has indicated that LMWH is as or more effective than unfractionated heparin in treating established blood clots and preventing new ones, and LMWH allows for safe outpatient treatment in many settings (although some situations, such as pulmonari emboli, are still most commonly treated conservatively with inpatient management).  This typically resolves once heparin is discontinued. Over the past decade, more and more of the use of unfractionated heparin has switched over to LMWH of one brand or another.  Aside from bleeding complications, which are always a risk with blood thinners, 10-20% of patients receiving heparin develop heparin-induced thrombocytopenia (HIT), or low blood counts from heparin, which is an immune-mediated condition in which a person who has been on heparin (most commonly unfractionated heparin, but this can occur with LMWH as well) develops antibodies to heparin that cross-react with platelets, leading to a potentially serious decline in the platelet count in patients who remain on heparin.  So there can be negative consequences with these agents, so we’ll need to carefully explore the favorable and unfavorable findings with this class of drugs in cancer management.

 Similar to coumadin, some early research suggested that patients with SCLC can have an improvement in response rate as well as survival with administration of subcutaneous unfractionated heparin for five weeks along with chemo (abstract here):

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Among the 277 enrolled patients, the benefit was actually seen in the subset of 121 patients with limited stage SCLC, not in the 156 patients with extensive disease:

   Several more recent trials have also suggested a survival benefit for at least a subset of patients with cancer from heparin.  First, several trials that have been conducted to compare unfractionated heparin to LMWH in the treatment of patients with blood clots, and several have analyzed survival as well and found improved survival in cancer patients who received LMWH (summary article reference here).  These survival benefits were not clearly seen in trials that compared LMWH to coumadin on a long-term basis, with the exception of the trial by Lee and colleagues that I described in a prior post.   But there have also been a few trials specifically developed to test whether LMWH can improve survival in patients with cancer.

   The first of these is the Fragmin Advanced Malignancy Outcome Study (FAMOUS)(abstract here), which enrolled 385 patients with advanced cancer (several types, and the percent with lung cancer was not listed but was not in the top 4) to receive the LWMH dalteparin (Fragmin) once daily under the skin or a placebo injection for one year or until death, whichever occurred first.  The primary endpoint was one-year survival, so the trial was testing whether LMWH significantly improved survival one year after starting the trial.  There was only a non-significant trend favoring one-year survival after LMWH vs placebo (46% vs. 41%), and overall survival in general throughout the trial did favor recipients of LMWH, but the two groups were not significantly different.  However, when they did an unplanned analysis in which they restricted the results to those patients who lived longer than 17 months, they saw a significant benefit in those who received LMWH.  Here are the overall curves and the more limited, better survival subset:

That’s interesting, and really very similar to what Lee and colleagues saw in their trial of LMWH vs. coumadin (abstract here), in which they noted that while the overall trial didn’t show a survival difference for either arm, the LMWH arm did better for the subset of patients who didn’t have metastases (and therefore preumably had a more favorable prognosis).  But it’s not really fair to take your negative results the way you designed the trial, comb over the findings and then reanalyze them in a way that generates positive results, and call your trial positive.  That doesn’t mean there’s no benefit (absence of proof isn’t proof of absence), but these trials don’t definitively deliver the answer that LMWH improves survival, since we can’t say who will do better and get the benefit from these agents until they’ve already done well, and these trials didn’t specify these patients as the target group until after the fact

   We’ll continue with more on this subject in part 2 of this subject post.  For now, we’re left with some intriguing leads, but not enough for almost any expert to consider this to be a standard of care, especially considering that this treatment is not risk-free.