When Don Stranathan’s left leg became swollen after a long day of shoveling granite for a buddy’s new bocce ball court, he didn’t think much of it. He even joked about it on Facebook.
“Typical me, I posted a pic and said, ‘I worked so hard, my leg’s all swollen,’” said the 66-year-old metastatic lung cancer patient from Santa Rosa, California. “Then somebody said, ‘Don, if you have lung cancer, there’s a good chance that could be DVT, deep vein thrombosis. You should get that checked; it could be serious.’”
As it turned out, it was serious — and not just for Stranathan. Blood clots, also known as thrombi, or, when they break loose and lodge in the lung, venous thromboembolisms, are the next leading cause of death in cancer patients after cancer itself. They are a side effect of both treatment and the biological nature of the disease. Cancer thickens the blood, releasing substances that make it “sticky” so clots form more easily, and treatment can exacerbate the risk. Surgeries immobilize patients, chemotherapy inflames the blood vessels and veins, and the blood becomes clogged with bits of dead cancer cells. In addition, anti-hormone therapies like Tamoxifen or targeted therapies like Avastin are known to encourage blood thickening or hypercoagulability.
Five to 25 percent of cancer patients (particularly those with metastatic disease) get blood clots. Not all of them go on to wreak havoc, but many do result in hospitalizations, pain and suffering, and even death, as well as, of course, high health care costs. A 2018 study found cancer patients who developed a venous thromboembolism, or VTE, while hospitalized had an average cost of $37,352, with an average length of stay of more than 12 days, compared to patients without VTEs who had average costs of $19,994 and spent about a week in the hospital.
They’re common, they’re scary, they’re potentially lethal and they’re pricey — yet they’re not always on the radar of patients or clinicians. Luckily, for the last three decades, they’ve been on the radar of Fred Hutchinson Cancer Research Center’s Dr. Gary Lyman.
An oncologist, health economist and longtime national thought leader on patient care, Lyman has plumbed the blood clot-cancer connection for years, even studying under the researcher who first discovered the link between the two. Now, he’s helping to set national policy on how blood clots can be prevented in order to stanch the flow of money and save patient lives.
“Patients may never get a blood clot,” Lyman said. “But if it happens, it can be serious, life-threatening and even fatal. Even if your cancer is going into remission or eradicated, a blood clot could do you in. There’s a real need for safe and effective clot-busting drugs.”
When Stranathan showed up at the clinic, the doctors there confirmed his DVT with a Doppler ultrasound, gave him an immediate injection of a blood thinner known as heparin to dissolve it, then told him to contact his oncologist right away for a scan.
Blood clots, as it turns out, can also be a sign of cancer development or progression.
“That was the first I’d heard of it,” said the national patient advocate who didn’t realize both his cancer type — and metastatic staging — put him at risk. “When they did the CT a week later, they found a new 1.2-centimeter tumor on my left lung.”
Clotting can also become a recurring problem. Stranathan was put on the blood thinner warfarin after the clot in his leg dissolved, but he quickly developed a second clot, which required additional treatment. Months later, two more clots ended up lodging in his lung as pulmonary emboli and nearly killed him, but his doctors were finally able to dissolve those and eventually he went back on heparin, which he now injects every morning and night.
“Once you’re prone to clots, you’re always going to be prone to them,” he said.
Clotting, of course, is beneficial when you’ve got an injury or a cut — it stops the bleeding so the body can heal. The potential for harm comes when a clot forms in the deep veins within the leg, groin or arm, then breaks loose and travels. If the clot, or embolus, travels to the lungs it can create a blockage known as a pulmonary embolism; if a clot travels all the way to the brain, it can cut off blood flow and cause an ischemic stroke.
Any of these scenarios can result in serious damage or death, one reason why there’s an urgent need to stratify patients — figure out who’s most at risk — and then find ways to reduce that risk. But there’s also a need to raise awareness of the issue — both in clinicians and in patients, Lyman said.
“Blood clots are not at the top of the list of things doctors worry about or discuss with patients,” he said. “And they’re not on patients’ minds either. When they’re first diagnosed, they’re in a maze; they’re being told about their treatment and side effects like nausea, infection and hair loss.”
Martha Carlson, a 54-year-old metastatic breast cancer patient from Brookfield, Illinois, felt blindsided when she developed a cluster of clots around her port during chemo.
“I had no idea that this was a risk for people who have cancer until after I got out of the hospital,” she said. “Maybe I was alerted to the danger but I didn’t hear it because there was so much happening during those first stages.”
SIGNS AND SYMPTOMS OF BLOOD CLOTS
Deep vein thrombosis may cause the following to occur around the area of a blood clot:
Signs and symptoms of pulmonary embolism include:
Less common signs and symptoms of pulmonary embolism may include coughing, with or without blood; feelings of anxiety or dread; light-headedness or fainting; and sweating.
Contact your doctor right away if you suspect that you have signs or symptoms of VTE (venous thromboembolism). Deep vein thrombosis should be taken seriously, as it may lead to pulmonary embolism.
Courtesy of the National Heart, Lung and Blood Institute. More information.
Lyman said there’s “no question" ports or catheters in general foster the development of blood clots, usually in the arm, but these clots are rarely fatal. And not all cancers promote clotting. In fact, most patients don’t get blood clots, he said.
Cancers that are more prone to clots include gastrointestinal cancers like stomach and pancreatic, lung cancers, lymphomas, ovarian cancers, and genitourinary cancers like bladder and testicular. Obesity can also be a risk factor for blood clots; some people also carry a genetic mutation that can make them more susceptible.
In 2008, Lyman and his research partner (and spouse) Dr. Nicole Kuderer along with colleague Dr. Alok Khorana, now at the Cleveland Clinic, and others created a risk model — known as the Khorana score — that’s now commonly used to identify which patients are more at risk for clotting.
But determining who’s at risk is just half the battle, Lyman said.
Finding a preventive treatment that works well for patients is also essential. Daily heparin shots can reduce the risk of thrombosis by about half in those getting chemo, he said, but not all patients are happy about giving themselves an injection every day for a side effect that might develop, especially since the injection can also cause bleeding, which can also be life-threatening if not dealt with swiftly.
“Patients are reluctant to inject themselves for a hypothetical problem that may or may not happen,” Lyman said. “If they develop a clot, then they’ll do the injections. But for prevention, patients hate doing it daily for weeks and months on end.”
After a five-day hospital stay, Carlson was told she would need to be on blood thinners for the rest of her life. Her doctor recommended heparin injections, which kept her blood flowing smoothly.
But the shots rattled her emotionally.
“I have a terrible problem with needles,” she said. “It was destroying my quality of life, so after 8 months I begged my hem-onc for something else and he found an oral medication that works.”
Two recently published clinical trials, CASSINI and AVERT, sought to determine whether oral blood thinners might be a better option for high-risk cancer patients seeking a preventive. The drugs — rivaroxaban (Xarelto) tested in CASSINI and apixaban (Eliquis) tested in AVERT — have both been approved by the Food and Drug Administration for atrial fibrillation, but there was no data on how they performed in cancer patients. There was also no data on whether they would promote excessive bleeding.
Current guidelines recommend against their routine use as a preventive due to a lack of data.
“Until we have good safety and efficacy data in the cancer setting, the basic recommendation was to use heparin,” Lyman said.
The multi-institute CASSINI trial, which Lyman and Kuderer helped design, first screened participants for pre-existing blood clots then randomized them to either placebo or a daily rivaroxaban pill (5 percent of patients already had asymptomatic clots identified on baseline screening and couldn't enroll). In AVERT, high-risk cancer patients weren’t scanned but simply randomized to receive either a placebo or apixaban. (Lyman chaired the Data Safety Monitoring Committee on this trial.)
While the CASSINI study found no significant reduction in blood clots in the 180-day trial period, it did find a significantly lower incidence of clots while patients were actively taking the drug. Adherence again was an issue, but the drug did seem to work when taken. The AVERT trial reported that the oral medication apixaban “significantly” reduced the number of blood clots (by 6 percentage points) in high-risk patients going through chemo.
Overall, Lyman said there was around a 4 to 5 percent reduction in thrombosis using oral agents, so high-risk patients may soon have two new drugs they can take for prevention. But, Lyman said, it’s still essential that patients and doctors balance the risks and benefits of these potential preventive measures.
Findings from the two studies also showed about a 1 percent increase in major bleeding, he said, mainly in “mucosal tumors,” i.e., cancers of the upper intestine, colon, bladder, ureter, urethra or the lining of the bladder. Monitoring patients for bleeding will be critical with the new agents, Lyman said. Ditto for making sure there are no drug-drug interactions, which can sometimes happen with oral agents.
“And that’s where we are,” he said. “You need to stratify the risk, identify the high-risk patients and then have a discussion with them, particularly because there’s now the option to give them a pill.”
ADVICE ABOUT BLOOD CLOTS FROM PATIENTS
“The critical thing is not to massage your leg and try to work it out. It could break the clot loose and if it breaks from your leg, it will lodge in your lungs or your brain. Get it checked immediately — they have the Doppler test and a blood test that can test for DVT. There are medications that can dissolve the clot but it takes time. Don’t expect immediate results.”
— Lung cancer patient
“My whole left arm was swollen, but I’m not a physician. I thought I’d hurt it exercising or weeding or something. I ignored it, put it to the side. I thought the swelling would probably go down on its own. But it is a life-threatening situation. The one thing this experience did teach me was to be persistent. If I think there’s a problem or I think it’s important, I need to continue to contact my doctors and tell them I need be to be looked at.”
— Breast cancer patient
It is likely that little of this will trickle down into the clinic until the guidelines change, though.
Data from the latest two trials has now been sent on to the three organizations that create national guidelines for the treatment of cancer patients: the American Society of Clinical Oncology, the National Comprehensive Cancer Network and the American Society of Hematology. Recommendations from organizations like these set standards of care; guideline recommendations also often determine whether commercial insurers are likely to reimburse for such treatment.
Lyman, who’s chaired the ASCO guidelines on cancer and thrombosis for over a decade and also chairs the guidelines panel for ASH, said ASCO is poised to issue new recommendations on the prevention and management of blood clots this spring; the other organizations will follow.
A senior lead for health care quality and policy at the Hutchinson Institute for Cancer Outcomes Research, or HICOR, Lyman is hopeful the new guidelines will help ease the burden this major cancer complication puts on patients and society.
“As you can imagine, these aren’t easy decisions,” he said. “You can’t prophylactically treat everyone getting chemo, but you can assess the risk. The panels will have to decide if anticoagulation should be done with heparin or one of the oral agents. There may be a forthcoming recommendation for ultrasound screening for high-risk patients, too.”
One other twist: none of the aforementioned studies have factored in cost. And the oral agents “do have a price tag.”
Lyman and his HICOR colleagues are currently conducting a cost-effectiveness analysis on the issue, but he emphasized it’s not just a matter of comparing drug prices.
“When you think about the cost, you have to balance that with what you’re trying to prevent,” he said. “There’s the cost of the drug, but there’s also a real cost if a patient ends up with a pulmonary embolism. There’s the emergency room, the cost of hospitalization, the mortality, the suffering, the morbidity. And hospital costs, along with drug prices, have gone up astronomically.
“We need to balance the whole picture and then you can make a rational decision,” he said. “From a patient perspective, the cost is big and will remain so until we find effective ways to reduce prices and the enormous financial burden that cancer and cancer treatment represent.”
Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at firstname.lastname@example.org.