The NCCN guideline committee has designated a direct oral anticoagulant as a preferred frontline treatment for most patients with cancer-associated venous thromboembolism.
Michael B. Streiff, MD
The standard of care for patients with cancer who suffer dangerous blood clots has been painful and expensive daily injections with unfractionated or low-molecular-weight heparin (LMWH). Now clinical trial findings published in the New England Journal of Medicine1 have helped convince a National Comprehensive Cancer Network (NCCN) panel to make a change. The guideline committee has designated a direct oral anticoagulant (DOAC) as a preferred frontline treatment for most patients with cancer-associated venous thromboembolism (VTE).2
“This is the biggest change we’ve made to the [VTE] treatment guidelines in years, and it may well be the most welcome change we’ve ever made,” said guideline committee chair Michael B. Streiff, MD, medical director of the Johns Hopkins Hospital Special Coagulation Laboratory at Johns Hopkins Medicine in Baltimore, Maryland.
“Nearly every patient I have treated over the years asked me about oral alternatives to low-molecular- weight-heparin, and a significant number of them chose to switch from low-molecular- weight-heparin to warfarin—even though they knew it wasn’t as effective—because they simply couldn’t stand the idea of performing 1 more injection into an abdomen that already looked like a very bruised pincushion,” Streiff said in an interview with OncologyLive®.
Overall, the new guidelines for the therapeutic management of VTE have been extensively revised. Edoxaban (Savaysa), an oral factor Xa inhibitor that is part of a new class of DOACs, has been added as a category 1 recommendation as part of a combination regimen with LMWH. Two other DOACs, rivaroxaban (Xarelto) and apixaban (Eliquis), may be considered as a monotherapy alternative for acute anticoagulation in patients who have reasons to avoid LMWH (Table).2The Hokusai VTE Cancer trial, which helped pave the way for the guideline change, was designed as a noninferiority study for patients with cancer who had acute symptomatic or incidental VTE, including deep-vein thrombosis (DVT), acute symptomatic pulmonary embolism (PE), or incidentally detected PE. Patients received a lead-in therapeutic dose of LWMH for at least 5 days and were then randomized to edoxaban or dalteparin (Fragmin), an LMWH. Edoxaban was administered orally at 60 mg daily with or without food, and dalteparin was given subcutaneously at 200 IU/kg daily for 1 month followed by 150 IU/kg daily.1
The primary outcome was a recurrence of VTE or major bleeding. VTE recurrence was defined as symptomatic new DVT or PE, incidental new DVT or PE involving segmental or more proximal pulmonary arteries detected by imaging tests conducted for other reasons, or fatal PE or unexplained death. Major bleeding was associated with a hemoglobin decrease of ≥2 g/dL, a transfusion of ≥2 units of blood, occurrence in a critical site, or contributing to death.
After 12 months of follow-up, 67 of the 522 patients (12.8%) treated with edoxaban had experienced VTE recurrence or major bleeding compared with 71 of the 524 patients (13.5%) who received dalteparin (HR, 0.97; 95% CI, 0.70- 1.36). The findings for edoxaban met the primary endpoint for noninferiority (P = .006) but were not statistically superior (P = .87).
There was a trend toward edoxaban superiority in preventing recurrent VTE, which occurred in 41 patients (7.9%) who received the drug versus 59 patients (11.3%) who had dalteparin, for a difference in risk of −3.4 percentage points (HR, 0.71; 95% CI, 0.48-1.06; P = .09). Nevertheless, edoxaban was associated with a significantly higher risk of major bleeding, which occurred in 36 patients (6.9%) versus 21 patients (4.0%) with dalteparin, for a difference in risk of 2.9 percentage points (HR, 1.77; 95% CI, 1.03- 3.04; P = .04).
The trial results were a major departure from those of earlier studies that pitted oral medications against heparin in clot-prone patients with cancer. Most of these older trials tested warfarin, an oral drug that inhibits the synthesis of vitamin K—dependent clotting factors, against LMWH, and their outcomes were greatly discouraging to patients who wanted a safe way to escape injections. A pooled analysis of such trials found recurrent VTE in 12.4% of patients who used warfarin compared with 7.3% for those who had used LMWH, according to a presentation at the 2018 NCCN Annual Conference.3
As for DOACs, there simply were not enough data before the Hokusai VTE Cancer trial to recommend usage. Findings from many large DOAC trials published in the past 10 years have included some patients with cancer, but the number of participants was very small, and the studies tested DOACs against warfarin rather than the standard-of-care LMWH. The edoxaban study was the first large trial to compare a DOAC with an LMWH but is no longer the only one to report results.
The new NCCN guidelines also take note of the findings of a smaller trial, Select-d, that randomized 406 patients between rivaroxaban and dalteparin. The results were much the same: Patients who received the DOAC were less likely to experience VTE recurrence than those who took dalteparin (4% vs 11%, respectively) but significantly more likely to experience major bleeds (17% vs 5%).4
Despite the greater risk of serious bleeding, there was a slight trend toward improved survival for patients who took rivaroxaban compared with those who took dalteparin. Among the 208 patients who completed 6 months of treatment, overall survival was 74% in the trial’s rivaroxaban arm (95% CI, 68%-80%) and 70% in the dalteparin arm (95% CI, 63%-76%).
The results of this second study were reported at the 2017 American Society of Hematology Annual meeting, but they have not yet appeared in a peer-reviewed journal, so the new NCCN guidelines give rivaroxaban a category 2A recommendation for the initial treatment of cancer-related VTE. That recommendation would likely move up to category 1 shortly after publication of the trial results, Streiff said. He also noted that researchers have begun enrolling patients with cancer for at least 1 more trial that will compare a DOAC against LMWH.
“The results from the first 2 trials are so similar that this may well be a class effect, but it’s way too early to say that with any level of confidence,” Streiff said. “A third set of very similar results from the trial that is recruiting now—which will test apixaban—would certainly provide major support for the class effect hypothesis, but the recommendations would still stick to those oral medications that have proven their efficacy in trials, rather than making any assumptions.”The new guidelines emphasize the importance of selecting patients with cancer-related VTE carefully for DOAC treatment. The Hokusai trial excluded patients with poor renal or hepatic function, so physicians are advised to be cautious about using edoxaban for these patient populations. Additionally, patients receiving nephrotoxic or hepatotoxic chemotherapy should be monitored with laboratory testing during therapy.
Patients with urinary or gastrointestinal tract lesions by pathology or instrumentation are probably best treated with LMWH, and those without such lesions are better candidates for DOACs, according to a presentation by Gerald A. Soff, MD, chief of the Hematology Service at Memorial Sloan Kettering Cancer Center in New York, New York, at the NCCN conference.3
Even patients who qualify for treatment with edoxaban will receive several injections. The Hokusai trial protocol was to start all patients on 5 to 10 days of dalteparin injections before switching to edoxaban, and the NCCN guidelines advise physicians to follow that protocol.
Nevertheless, most patients with cancer-related VTE will qualify for edoxaban after that initial period, which should save them both money and pain. “Heparin is reasonably complex to manufacture, and many insurers charge patients significantly more for heparin than they charge for oral anticoagulants,” Streiff said. “Cost doesn’t factor into the recommendations, of course, but at a time when cancer patients are constantly being asked to pay more for their care, it’s nice to be able to do something that will save them some money.”