Continuing on the issue of heparins potentially improving survival of cancer patients, other studies have suggested a survival benefit for low molecular weight heparin (LMWH) in cancer patients.  The Malignancy and Low-Molecular-Weight Hepatin Therapy study (MALT, a bit of a stretch) by Klerk and colleagues (abstract here) enrolled 302 patients with an advanced solid tumor (defined as a cancer that could not be treated curatively) to six weeks of a LMWH called nadroparin/Fraxiparine injected under the skin (subcutaneously, or SC) twice daily, or a placebo injection for six weeks.   There was a significant survival difference favoring the recipients of the active drug (median survival 8 vs. 6.6 months, hazard ratio (HR) of 0.75 (25% improvement in survival)) that was more impressive in the patients who had a better prognosis (predicted to have a survival of more than 6 months when they were entered onto the trial) (15.4 vs. 9.4 months, HR 0.64, or 36% improvement in survival):

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Not surprisingly, however, there was also a trend toward an increased number of major bleeds in patients who received blood thinner treatment compared with those on placebo (3% vs. 1%).

   Another trial, by Sideras an colleagues (abstract here) randomized a total of 138 people with advanced breast, prostate, lung, and colorectal cancer to receive daleparin (Fragmin or a placebo subcutaneously one time daily or standard care alone (initially placebo-controlled, the investigators dropped the control injection due to poor accrual on the trial).  The trial had been planned to accrual 540 patients, but given the difficulty in enrolling patients, the trial closed early, with the knowledge also by the Data Safety Monitoring Committee (DSMC) that one arm of the study was doing worse than the other at the time of an interim analysis in which the DSMC was charged with evaluating whether it would be appropriate to keep the trial going (the committee was blinded as to which arm was doing worse).    In this study, the median survival was not significantly different between the two arms but was overall worse in the LMWH arm (7.3 vs. 10.5 months).  Most strikingly, unlike several other trials with LMWH there was not a significant benefit for the LMWH arm even in the patients with a better prognosis at study entry (although they did far better than the poorer prognosis patients, with a median survival in good prognosis patients of 16.6 months for the LMWH group vs. 12 months in controls, not significant).  On the upside, however, there was no increased risk of major bleeding in the group receiving LMWH, and it was actually numerically lower in that arm (3% vs 7%, not significant).  It’s fair to say that this trial didn’t provide much support for LMWH improving survival in cancer patients, but it’s also important to note that this was a small trial that closed early due to poor accrual, which left it underpowered to show differences between the two arms.

   A final trial, by Altinbas and colleagues out of Turkey (abstract here) actually looked specifically at SCLC, as some trials have done with coumadin (see prior post on coumadin and cancer survival).   This was a small study, with just 84 patients enrolled and randomized to receive a standard but “old school” chemo regimen (cyclophosphamide, epirubicin, and vincristine) with or without 18 weeks of fragmin injected SC daily.  This trial included patients with LD-SCLC and ED-SCLC, and those with LD-SCLC who responded to chemo also received radiation to the chest.  The investigators reported a strong trend toward improvement in response rate in the patients who received LMWH along with chemo (69.2% vs. 42.5%, p = 0.07, not quite significant), which was actually significant in the subset with LD-SCLC (91.4% vs. 60.0%, p = 0.02), but not in those with ED-SCLC, although they also had an impressive difference in response rate that favored the recipients of LMWH (37.4% vs. 13.3%, p = 0.59).  Looking at survival, the LMWH arm demonstrated a significantly superior survival that was particularly notable in the better prognosis patients with LD-SCLC:

  Taking all of these results together, the data are not completely consistent, but they largely converge to suggest a potential improvement in response rates and a modest survival benefit for a very broad population with advanced cancers that is more consistently seen in the subset of folks with a better prognosis.  Unlike most aspects of the field of lung cancer, the population with SCLC has been studied more extensively in this setting, and the benefits, although not entirely consistent and overwhelming, have been more typically seen in SCLC patients and especially those with limited disease.  These findings, although really a promising lead for an emerging story, haven’t been consistent or clear enough to make the addition of LMWH a standard practice.  Part of this is due to small numbers in the trials, the wide range of patients involved (with all sorts of cancers), the risk of bleeding seen with LMWH in some of the trials, the need for daily injections, the lack of an optimal drug, dose, or schedule, and potentially also the cost, which is in the range of thousands per month.  Currently, I would consider anticoagulation, particularly with LMWH, to be an approach that may very well prove to increase survival, in cancer in general or perhaps just in patients with SCLC, and maybe just those patients with a better prognosis.  But it isn’t considered the standard of care by the groups that generate the guidelines, and I would have to say that I agree that the evidence is too broad to declare this approach a standard of care just yet.