Barbara Sadick

LORI SMART, patient - PHOTO BY: LAWRENCE KNOX

WHEN LORI SMART WAS diagnosed with stage 4 follicular lymphoma 10 years ago at the age of 55, she wasn’t taking medications for any other chronic conditions. But as she moved through treatment for her cancer, she found herself awash in drugs.

Following a long “watch and wait” period and then a novel chemotherapy regimen that put her into a 21-month remission, Smart, who had been opposed to the option of stem cell transplant, resolved to try it. An oncology team at the University of Texas MD Anderson Cancer Center, in Houston, put her on lenalidomide to move the cancer into remission; she then underwent high-dose chemotherapy and, on Feb. 19, 2014, was infused with billions of stem cells from a donor who’d been found for her in Germany.

Hooked up to numerous bags of drugs, Smart recalls counting as many as 13 on her IV pole. “I was vigilant about my treatment, asked what each medication was supposed to do and always checked to make sure my name was on every new bag of medication before it was dispensed,” the Michigan resident says.

That was important, as patients often take many drugs — in some cases prescribed by numerous health care providers working independently of each other &mdash; that can cause problematic side effects, interactions or duplication. Some patients are already taking a host of medications for various health issues when they are diagnosed with cancer, and their new treatment plans only increase that risk, so close management is essential.

Smart ran into a problem with a drug reaction in the days following her transplant: Her heart rate and blood pressure increased, her oxygen level fell and she had difficulty breathing. Because a chest X-ray did not indicate pneumonia, Alison Gulbis, Pharm.D., BCOP, a clinical pharmacy specialist at MD Anderson with expertise in stem cell transplant, reviewed the drugs Smart was taking. Gulbis used a blood test to check Smart’s methemoglobin and found that her red blood cells were not properly releasing oxygen to the tissues in her body. As this was a known side effect of dapsone, an antibacterial drug Smart was taking, the medication was discontinued.

“I had never heard of a doctor of pharmacy, but I now understand how valuable high-level knowledge of medication is, because only someone with advanced training would have solved this,” says Smart. “Alison saved me from a life-threatening reaction.”

That was just the beginning when it came to the variety of drugs Smart took over the following years, which today include medications that fight off viruses and open the airways to her lungs. All told, there have been more than she cares to remember.

 At its simplest, the term “polypharmacy” refers to the taking of multiple medications concurrently to manage health problems. As people age, such problems appear more frequently. Today, about one-third of Americans over age 60 years take five or more medications daily to treat chronic conditions such as heart disease, diabetes and arthritis.

Yet, most people have never had a serious drug evaluation.

Drugs, both over-the-counter and prescribed, can be dangerous, making it imperative for patients and/or their caregivers to know exactly what the medications are, when they need to be taken and in what doses. There are many systems that can help with this: lists, computerized reminders, the linking of pill-taking with other daily activities, weekly pill organizers. Most important is that every treating physician has a complete list of all the medications a patient is taking.

Of course, it’s best for patients to take the smallest number of medications needed to maintain stability. More drugs means a higher risk for nonadherence, which can result in more visits to the emergency room, higher rates of hospitalization and greater potential for additional disease or even death. Supplements, over-the-counter drugs and herbal remedies can also interact badly with certain prescription drugs. Patients tend to forget to tell their doctors about over-the-counter medications, but it’s important to do so.

There are several types of drug interactions. One occurs when the combined effects of drugs accentuate each other — for example, with two drugs that cause drowsiness. Another type of interaction happens when one drug interferes with the metabolic activation or breakdown of another, making the drug level either higher or lower than expected.

Specifically, certain medications are known to exacerbate symptoms in patients receiving treatment for cancer. Gulbis says that, in older patients, diphenhydramine or other antihistamines can cause increased confusion and sedation. Aspirin and naproxen, both of which are purchased over the counter, may cause bleeding or ulceration of the stomach when taken together, and the combination may decrease the effectiveness of aspirin being taken to prevent heart attacks or strokes. Statins (cholesterol-lowering drugs) can cause muscle pain and weakness. Problems can also arise when medications such as blood pressure or cholesterol-lowering drugs are no longer needed, but haven’t been reassessed by doctors. Complex cancer treatments can involve multiple toxic medications at high dosages, increasing the chances for harmful interactions. Even normal levels of several drugs can cause serious consequences, such as slowdown of electrical conduction that governs the heartbeat, which can rarely result in sudden death.

While every member of a cancer treatment team should know about every medication, the oncologist is the team leader and should make all final decisions.

At major medical centers, patients and health care workers have access to electronic medical records that list medications and doses, but people outside those facilities may not be linked in, making it imperative for patients and caregivers to provide a drug list to every treating physician.

Ginah Nightingale, Pharm.D., BCOP, assistant professor of pharmacy at Thomas Jefferson University, in Philadelphia, says her research shows that about five in 10 patients are taking at least one inappropriate medication. “I ask my patients to bring in all medications and bottles, including herbal supplements, vitamins and over-thecounter drugs, so I can assess adherence to doses, determine whether any of the prescriptions have expired and check for duplication,” Nightingale says. “I want to make sure a patient can manage existing treatments before beginning to prescribe more.”

At most large hospitals and academic medical centers, pharmacists are important members of oncology teams. Their pharmacies maintain a database of patient medications and have preprogrammed systems that alert pharmacists to doses or frequencies that are out of the norm. Smaller treatment systems may not have in-house pharmacies, but many doctors and nurses consult online software, such as Lexicomp and Medi- Span, to help determine which drugs might result in dangerous interactions.

Other guidelines that health professionals use to determine the appropriate prescription of medicine, specifically in older people, include the Beers Criteria, the Medication Appropriateness Index (MAI) and START/STOPP. The Beers Criteria identifies drugs or classes of drugs that pose a high risk when other, safer alternatives exist. It also identifies drugs that should not be taken with existing diseases or conditions because they increase the risk for polypharmacy or adverse drug reactions, hospitalization, emergency room visits, fractures and a poorer quality of life. MAI uses a10-item checklist to assess the degree of appropriateness of a medication. START/STOPP determines whether it makes sense to prescribe a specific new medication and evaluates existing medition regimens.

When a symptom that could be a bad reaction to medication occurs, patients or caregivers should immediately contact their oncology teams. At most major medical centers, someone from the oncology practice is on call 24 hours a day, but smaller cancer treatment centers may not have around-the-clock staffing. So, if a reaction is serious, such as difficulty breathing, Bryson recommends calling 911 immediately. For something like severe nausea and vomiting, confusion or dizziness in the middle of the night, she says, head for the emergency room.

 Stephanie Shuey, Pharm.D., BCOP, a clinical pharmacy specialist in medical oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in Baltimore, Maryland, says it’s not always clear whether a reaction is a medication side effect or a symptom of the cancer. “When, for example, a patient is experiencing a nonspecific issue like confusion, there are multiple things to rule out,” says Shuey, “and we have to assess all drug possibilities and often undergo a process of trial and error.” If every time a patient gets up he feels dizzy, that could be a symptom of dehydration or a problem with blood pressure.

While encouraging patients to be involved in all aspects of their own care, Nightingale warns about the amount of inaccurate information available online and elsewhere. Even if a patient thinks he knows the cause of a reaction, he should never self-diagnose or stop taking a medication without consulting a doctor or pharmacist, she says.

That was something Smart discovered when she experienced complications after her transplant.

“As the process of determining what was causing the symptoms unfolded,” she says, “I realized for the first time that my treatment was a team effort, and I was part of that team.”

Articles

The medications that help patients can be dangerous in combination if not closely monitored.

Too Much of a Good Thing: When Cancer Drugs Become Dangerous

For IDE MILLS, joining a patient registry was not just about helping researchers gather data, but about feeling like part of a community. - PHOTO BY DIANA LEE

When Ide Mills first learned about the Cancer Support Community Registry, she jumped at the chance to participate. Mills, who has stage 4 lung cancer, went online at 

 to answer demographic questions and in-depth queries about her experience with her illness, such as what worried her the most and what her everyday challenges were in living with her disease.

The registry collects information about the social and emotional experiences of cancer patients and their caregivers. Then, Cancer Support Community, a nonprofit patient advocacy group, uses the data to improve its own programs and to help enhance research and care programs offered by the health care community.

For Mills, of Maplewood, New Jersey, filling out the online form represented a chance to help someone else have a better cancer journey, but since then, the registry has come to mean even more to her. Mills not only participates actively in the registry, but is an advisor on one of its panels. She and other members of this community contribute to the study of trends, share their thoughts about research findings and help design programs that meet the needs of patients and caregivers.

“It’s important for patients to know they are not alone, and cathartic to share one’s story,” Mills says. “Most important, being a part of a larger community bonded by similar life experiences is invaluable.”

Registries are designed for the collection of data, but, unlike clinical trials, they are not designed to test drugs under controlled conditions; rather, registries look at established standards of care and choices made by patients and their doctors during the normal course of treatment. This means that registries answer different questions than clinical trials do. While a trial estimates the safety and/or effectiveness of a treatment, a registry determines whether a new treatment is being appropriately used in a population group and whether the benefits found in clinical trials are consistent with what is being observed in a more diverse population. In some cases, information is collected about a specific disease or clinical situation, rather than a specific therapy. Registries can also look for trends in cancer incidence that might be addressable through changes in health care practices.

There are two major kinds of cancer registries: hospital-based and population-based. A third type of registry collects information and data on a specific type of cancer — such as the Metastatic Breast Cancer Project (MBC Project), which asks patients with this condition, throughout the U.S. or Canada, to contribute tissue specimens and medical information for use in research.

Registries can be funded either publicly or privately. In most cases, patients participate anonymously, donating their time and information to help with research, and to be part of a community.

But those are just some of the returns that registries can bring.

Registries are the source for national cancer statistics on incidence, survival and prevalence of cancers. They are used to identify emerging trends within the population and to determine what those trends are telling us. For example, an increase in the incidence of a disease may reflect a change in risk factors within the population, such as a link between specific cancers and certain kinds of jobs.

Registry data is also used to assess the impact of cancer control efforts, such as those to reduce smoking, increase sun protection, make dietary changes or boost screening. This is also the information used to design programs that target specific behaviors.

And there’s more. Registry data may improve our understanding of the patterns of care within a population, and can help identify health disparities among population groups. On a more individual scale, it can be used to identify who might benefit from inclusion in a clinical trial.

A large and diverse number of studies have been performed using data that came from cancer registries. These studies are less expensive and simpler to run than randomized clinical trials, as they are less encumbered by regulatory red tape, although in some cases they still require subject consent and are bound by many of the same rules as trials. Still, some information can be extracted from registries and analyzed without consent of the patients, as long as all personal identifying information such as names, medical record numbers and addresses, is carefully guarded and not included in the report.

But unlike in a clinical trial that is a controlled experiment, observational data can be affected by biases, and these need to be identified, carefully considered and adjusted for analyses. For example, registry data may not indicate why a person did not receive a treatment, knowledge that would be important in linking treatments to outcomes.

Benjamin Smith, M.D., an associate professor in the Department of Radiation Oncology at MD Anderson Cancer Center, agrees that registry data may not always be accurate. He says that some registries are more reliable than others, making it important for researchers to be careful about drawing erroneous conclusions.

That’s why it’s important that certified tumor registrars — whose job is to enter data into a registry at the time of diagnosis &mdash; meet stringent standards of training, testing and continuing education so that they learn to properly compile and enter timely, accurate and complete cancer information that is in line with national standards. Tom Tucker, Ph.D., associate professor of epidemiology at the University of Kentucky and director of the Kentucky Cancer Registry, adds that software and electronic systems used by registries are valuable to the successful gathering, entering and sharing of data, and while progress has been made in this area, improvement is still needed.

One large registry that’s collecting data about a specific type of cancer is The MBC Project (mbcproject.org). Launched in October 2015, the registry is funded by the Broad Institute of MIT and Harvard and conducted in collaboration with Dana-Farber Cancer Institute and others. It offers an opportunity for patients with cancer, advocates, researchers, physicians and clinical specialists to collaborate to collect tumor samples for study.

One aim of the MBC Project is to bring more resources to an area of breast cancer that has traditionally been under-studied.

The program began with a series of conversations about what could be learned if researchers had access to specific tumor samples, says a founder and overseer of the program, Nikhil Wagle, M.D.

“If we were going to launch this project, we wanted to do it with patients and advocacy groups, and we wanted to be able to collect more data on metastatic breast cancer than the national registries collect. And, unlike most registries, we wanted to be able to look at that data longitudinally,” says Wagle, a medical oncologist at Dana- Farber Cancer Institute and a genomics researcher at the Broad Institute.

WENDY KOZEL, patient enrolled in the MBC Project registry - PHOTO BY ALYSSA CLOW

So far, more than 2,600 women are participating. Among them is Wendy Kozel, a 48-year-old Cleveland, Ohio resident who’s been living with metastatic breast cancer for the last six years. She first discovered the program online, where she signed up to contribute information about her cancer, give permission for the MBC Project to have copies of her medical records and samples of her stored tissue, and submit a saliva sample. Since then, she has become an active participant in the program’s projects, making herself available to provide information for studies.

“The MBC Project is invaluable, because it relates exclusively and directly to stage 4, or advanced, breast cancer patients, who make up about a third of all patients diagnosed with breast cancer,” she says. “Because metastatic breast cancer is so advanced, the bulk of the funding for research goes elsewhere, making this an extremely important resource for us.”

Over the next six months, Wagle says, the MBC Project plans to release its first set of data in several ways, including through the Genomic Data Commons at the National Cancer Institute (NCI), as well as through other data sharing sites.

“We are asking patients from all over the world to sign up to share their metastatic breast cancer information with us so that we can use innovative technologies and methods to study this disease that has been continually under-represented in the studies of breast cancer,” he says.

Other special cancer registries include the Breast Cancer Family Registry and the Colon Cancer Family Registry, established by NCI as resources to be used by investigators to conduct studies on the genetics and molecular epidemiology of breast and colon cancers. Known together as CFRs, the registries work to translate research into practice and to identify and characterize genes that trigger cancer, understand genetic and environmental interactions, and look for preventive and behavioral solutions in light of those findings.

The CFRs don’t fund studies, but researchers can apply for access to the data that include information on family histories, epidemiological risk factors, bio-specimens and molecular characterizations of participating families.

Government-funded cancer registries normally obtain information around the time of diagnosis, with patients being followed up for mortality outcomes to produce survival estimates, says Kathy Cronin, Ph.D., M.P.H., deputy associate director of the Surveillance Research Program in the Division of Cancer Control and Population Sciences at the NCI. That cancer registry information, she says, represents the consolidation of data from various sources that captures and reflects what is occurring in the population. These registries do not influence the course of treatment received or the implementation of study designs, but document what has already occurred.

For instance, every state has laws that mandate the reporting of all cancers, with the exception of some dermatologic cancers, to a central cancer registry that collects each patient's demographic information, including age, gender and race/ethnicity, and characteristics of a tumor at diagnosis, such as the cancer site, histology, stage of disease, some biomarkers and the first course of treatment.

The Kentucky Cancer Registry is an example of a successful, well-functioning, population-based central cancer registry. In the year 2000, it was selected to become part of NCI’s SEER program. SEER registries are considered to be among the most accurate and complete population-based cancer registries in the world. As with all population-based registries, the state’s cancer information is entered into a database without the consent or knowledge of a patient.

It is, however, by law, the responsibility of the registry not to disclose a person’s identity.

Tucker, director of Kentucky’s registry, says that researchers might look to the registry to find patients to participate in studies. When an investigator finds someone who is potentially eligible, he or she must contact that person’s doctor to determine if the patient is very ill or has dementia and should not be contacted. If the doctor says the patient might be well enough to participate, the registry then tries to contact him or her; however, without the patient's agreement, his or her identity will not be revealed to a researcher outside the registry.

In Kentucky, the registry was used to identify the tumor tissue of 500 women who had undergone breast cancer surgery between 2000 and 2007, and then a study was conducted. These patients were traced forward in time to find out how many had experienced recurrences and how many had not. Twelve percent were found to have had a recurrence. The tissue from patients who had experienced a recurrence and those who had not was used to determine whether there were different biologic markers in the tissue of patients in the two groups. “Without the registry, that kind of work could not be done,” says Tucker.

The registry is also an essential tool in directing limited public health resources toward the most serious problems. Data from the Kentucky Cancer Registry showed that, in 2001, the incidence of colon cancer in Kentucky was the highest in the U.S., while the rate of screening for the disease among eligible state residents was found to be the second-lowest in the nation.

A statewide initiative to encourage age-eligible residents to undergo screening was implemented. A law was also passed requiring all insurers in the state to cover the cost of colon cancer screening for the eligible population. In 2002, one-third of age-eligible Kentuckians got screened; now, two-thirds regularly undergo screening. As a result of finding more precancerous polyps and discovering cancers at an earlier stage, the incidence rate has been reduced by 25 percent and the mortality rate from colon cancer was reduced by 30 percent.

“Without the registry, we would not have been able to identify the problem, and we would not have been able to measure the impact of our interventions,” Tucker says.

Joining cancer registries can help patients and the larger oncology community.

The Cancer Registry Rationale

Four years ago, James Smith was being treated for neuropathy when he began to experience difficulty breathing. He was rushed to his local emergency room, where a life-threatening embolism (a large blood clot), located just where the pulmonary artery splits, was discovered to be cutting off the blood supply to his pulmonary circulation. The now 62-year-old, who is president of a small gas exploration company in Corpus Christi, Texas, was treated with anticoagulation therapy and survived. But his health problems didn’t stop there.

Already aware that his neuropathy and certain proteins in his blood could indicate multiple myeloma, Smith discovered he had a tumor on his lower back. That led him to visit MD Anderson Cancer Center, in Houston, where he was diagnosed with the blood cancer and began treatment.

Like Smith, people with hematologic cancers — leukemia, lymphoma and multiple myeloma &mdash; are at increased risk for dangerous blood clots that can often be prevented by, and treated with, intravenous or oral anticoagulation therapies. In most blood cancers, the normal blood cell development process is impeded by the uncontrolled growth of abnormal types of blood cells. These abnormal, or cancerous, cells prevent blood from performing many of its normal functions, meaning that the patient will be prone to excess bleeding and may not be able to fight infections.

Jean Connors, M.D., assistant professor of medicine at Harvard Medical School, says there’s a balance in the body between pro-clotting and anti-clotting activity, and that cancer skews that balance in favor of clotting because it increases inflammation and compresses blood vessels. That’s why many cancer patients are routinely started on an ongoing preventive anticoagulation therapy routine.

Normal blood clotting, or coagulation, occurs when platelets (a type of red blood cell) combine with proteins in the blood to form clots that stop the bleeding at the site of an injury. Once an injury is healed, clots dissolve. Clotting takes place in the veins and arteries that are part of the circulatory system. Arteries carry oxygen and blood from the heart to other parts of the body, and veins do the opposite, carrying deoxygenated blood away from the body’s organs and back to the heart. Arterial clots usually occur as a result of plaque build-up or hardening of the arteries that can cause a rupture that precipitates a heart attack or stroke. Venous blockages can also damage the heart.

Deep vein thrombosis (DVT) is a blood clot that forms in a deep vein in the leg, arm or pelvic area. When a DVT detaches from a vein, breaks up, travels to the heart and is pumped into the lungs, a pulmonary embolism (PE) occurs. A thrombosis is a blood clot that develops locally and an embolism is a thrombosis that has broken off and traveled elsewhere. Together, DVTs and PEs are known as venous thromboembolism, or VTE.

Michael H. Kroll, M.D., professor of medicine and chief of the Section of Benign Hematology at MD Anderson Cancer Center, says that VTE is relatively common in all cancers, compared with the incidence in the general population, and can have a major impact on the survival of patients with cancer.

According to Connors, the overall incidence of clots in cancer patients is generally low, at 5 to 6 percent — and that, she adds, can be decreased by 50 percent through anticoagulation at low doses.

But some patients with cancer face a much higher risk of clots: those with acute leukemia, myeloma and cancers of the pancreas, stomach and brain, Kroll says. Patients with lymphoma, lung cancer and colorectal cancer are at intermediate risk, he says, and those who have undergone stem cell transplant or have breast cancer, prostate cancer or melanomas are at lower risk. Kroll adds that risk increases with the stage of cancer.

Blood clots can also be precipitated by cancer treatments. For instance, patients who have central venous catheters, or central lines that are inserted into the large vein in the chest or upper arm and are used to put medicines, blood products, nutrients or fluids into the blood, may be at higher risk for clots.

Chemotherapies increase the risk for developing VTE to different extents, but patients with acute lymphoblastic leukemia tend to be more likely to get clots when being treated with the chemotherapy drug asparaginase. Lymphoma patients are susceptible because lymph nodes compress the veins. Medications such as the thalidomide derivatives Revlimid (lenalidomide), an immunomodulator that is used to treat myeloma, increase the risk of clots. In addition, sometimes medications that alone don’t increase clot risk do so when combined with other drugs. For example, says Connors, a high dose of steroids and thalidomide for the treatment of myeloma can result in VTE rates as high as 20 to 30 percent.

In fact, thalidomide-based drugs are among two classes of medications that have the worst reputations for causing clots. Kroll says, however, that the VTE risk associated with the immunomodulatory drugs (Imids) and Avastin (bevacizumab), an angiogenesis inhibitor, is misunderstood. These drugs are thought to cause the vascular endothelium (cells lining blood vessels) to develop properties that promote thrombosis. Avastin therapy is only a small risk factor for developing VTE, while Imids, when they are combined with other therapies, are big risk factors for developing thrombosis. In neither case, however, are these drugs — when they are expected to be useful or known to be working &mdash; avoided or discontinued because of their effect on the risk of developing VTE. Treatment of VTE almost always accommodates the best cancer treatments available.

Judith Lin, M.D., assistant professor of hematology and oncology and a specialist in coagulation at the Icahn School of Medicine at Mount Sinai in New York, says that blood clots can be a serious complication to the care and survival of patients with hematologic malignancies. Arterial blood clots are generally difficult to ignore, as they often cause rapid tissue or organ damage, stroke or heart attack. Venous clots, however, occur more commonly in patients with cancer, and depending on their extent, size and location, can cause a range of symptoms from subtle and initially difficult to recognize to disabling with painful swelling or breathlessness to sudden death by pulmonary embolism. Treating clots with anticoagulants also adds to the medical burden for patients by increasing their risk of internal bleeding and may delay their cancer treatment plans.

Anticoagulation is the use of oral, intravenous or subcutaneous treatments to prevent, stop or slow down the formation of blood clots. These medications can offer the body time to at least partially digest the thrombus through the natural process known as thrombolysis and restore an intact vascular lining of endothelial cells.

Clotting, says Connors, starts with a cascade of factors that come together to create what she calls a “perfect storm.” One clot, she says, can set off another, or a clot can get bigger. The risk for additional clots is higher for a patient who has already had one. Specific medications, drug dosages and protocols for treatment of clots are determined by symptoms and the various manifestations of cancer.

A main side effect of anticoagulation is bleeding, and some with cancer are at higher risk for that than the average patient, especially if their platelet counts are low. Other side effects can include gangrene of the skin, rash, diarrhea, bloating, jaundice, hair loss and itchy or painful feet. The following are the various types of anticoagulants, as outlined by Kroll:

 An oral drug, warfarin (marketed under the brand names Coumadin and Jantoven) is used to treat VTE in patients with cancer. It works by inhibiting the metabolism of vitamin K in the liver that is required by the liver to produce blood-clotting proteins. The drug is sensitive to changes in diet and medications, so a doctor needs to determine the best option for each individual and monitor its use carefully through blood testing (prothrombin time). It takes about five days before full anticoagulation develops.

Injected under the skin, often by patients themselves at home, LMWHs inhibit the activity of a specific coagulation factor (activated factor X, or Xa). This class of drugs is used to prevent and treat VTE in patients with cancer. Fragmin (dalteparin) is the only LMWH that is FDAapproved for treatment of VTE in patients with cancer using a once-a-day dose. It doesn’t require routine monitoring, and is often used as the first line of therapy for cancer-associated VTE, because it may be more effective than warfarin in preventing recurrent blood clots. Although not approved specifically for use in patients who have cancer, Lovenox (enoxaparin) is also often used.

This new class of anticoagulants blocks the activity of clotting factor Xa. These drugs are being studied as treatments for VTE in patients with cancer, but the National Comprehensive Cancer Network and the American Society of Clinical Oncology guidelines discourage their use in patients with cancer at this time, due to a paucity of clinical data. Nevertheless, two classes of these pills have been FDA-approved for use for preventing and treating VTE:

Oral drugs such as Xarelto (rivaroxaban), Eliquis (apixaban) and Savaysa (edoxaban) directly inhibit activated factor X. They have proven to be safer than, and at least as effective as, warfarin in preventing recurrent VTE. No monitoring is required and an antidote for use in case of lifethreatening bleeding or emergency surgery is expected to soon be FDA-approved. A patient should not stop taking this medication without speaking with a doctor first, as it may cause paradoxical rebound clotting if it is abruptly stopped.

 Pradaxa (dabigatran) is taken orally and directly inhibits the enzyme thrombin in blood; thrombin causes the clotting of blood by converting the protein fibrinogen, produced by the liver, to insoluble fibrin, the main component of a venous thrombus or clot. Pradaxa is also as safe and effective as warfarin in preventing recurrent VTE. No monitoring is required, and an antidote is available for use in the case of life-threatening bleeding or emergency surgery. This medication should also not be stopped without speaking with a doctor first.

Treatment guidelines recommend that all hospitalized cancer patients receive thromboprophylaxis, or clot prevention, and that all patients who have cancer discuss the option of these preventive measures with their doctors. For most patients who have both cancer and VTE, the recommended length of treatment is at least six months, often continuing beyond that if the patient has active cancer and is undergoing chemotherapy treatment. Studies have shown that the dose of an anticoagulant can be safely reduced by about 30 percent after the first six weeks of treatment. While anticoagulation does sometimes take place in hospitals, most of these drugs can be selfadministered outside the hospital.

Although many may have heard aspirin referred to as a “blood thinner,” Lin clarifies that aspirin is not an anticoagulant and is not the standard of care for preventing VTE in patients with cancer. It is, however, standardly used for the prevention of arterial clots involved in heart attacks or thrombotic strokes in patients who don’t have cancer. Lin says that doctors recommend aspirin to prevent venous clots for patients with cancer in certain circumstances. For example, multiple myeloma patients receiving Revlimid may be given the option of aspirin instead of standard anticoagulant when they have no past history of clots or when standard anticoagulants may be contraindicated or not tolerated.

There are times, though they’re not frequent, when an anticoagulant can’t be used because a patient is already experiencing excess bleeding or facing heightened bleeding risk; patients whose platelet counts are low, who have ulcer/gastrointestinal bleeding or who have recently undergone stem cell transplants might fit into this category. In such rare circumstances, and when no other option exists, a filter can be inserted into the interior vena cava, a large vein that delivers blood from the legs to the heart, to capture clot fragments before they can travel to the heart and lungs.

When no longer needed, the filter is removed. Another option for those who can’t be given anticoagulants due to bleeding risk is thrombolytic therapy — treatment with a medication such as tissue plasminogen activator (TPA) that is administered through a catheter to break up clot fragments from a massive PE. A third but rare alternative, used when DVT is unusually severe and causing tissue injury, or when a patient is a poor candidate for other methods or has not responded to anticoagulation, is a thrombectomy, the surgical removal of a massive PE that’s become life-threatening. Connors says it’s important to know in advance if a patient who has been getting anticoagulation therapy needs to have surgery. This allows doctors to stop giving anticoagulants to these patients so they will not face an extra bleeding risk during surgery. If surgery is an emergency, patients must take an anticoagulant reversal medication beforehand, to protect against bleeding. According to Connors, current guidelines recommend that all patients with cancer receive intravenous thromboprophylaxis for one to four weeks after certain surgical procedures.

Other more common approaches to preventing clotting and keeping blood flowing include getting out of a hospital or other bed and moving around as often as possible, limiting the time spent sitting, staying well hydrated and knowing if there is a family history of clots. If there is, changes in diet and exercise can lessen the risk.

Kroll says he expects that ongoing research will keep improving the care of patients with cancer who suffer VTE, and he is optimistic that lives will be saved as we continue to improve the way cancer-associated VTE is prevented and treated.

Anticoagulants can reduce a heightened risk of blood clots in cancer patients.

Going with the Flow: Anticoagulants Can Reduce Blood Clot Risks for Patients With Cancer

Cancer patients have traditionally been treated based on where their tumors originate — lung tumors with treatments for lung cancer, breast tumors with therapies developed specifically for breast cancer. But what if doctors started caring less about where a tumor first emerged and more about the genetic mutations that caused it to appear in the first place? That principle is at the essence of precision medicine, a science focused on understanding each particular tumor and the molecular messages it sends, and treating it accordingly.

Ultimately, this branch of investigation could mean that a breast and a prostate cancer are treated with the same medicine, or that two people with melanoma of the same stage and location are given entirely different therapies. It's something that's already happening more and more in the world of cancer treatment, and it's given rise to a host of clinical trials with a new type of design.

Known as "basket trials" or "umbrella trials," these studies enroll patients with a variety of cancer types, find the specific mutations or abnormalities that drive their tumors, and then match the patients with medications that target those glitches. It doesn't matter where a cancer first emerged; tumor genetics are what determine trial eligibility. In basket trials, patients are eligible if their tumor harbors a specific genetic mutation that is a target for the therapy in question. A basket trial could enroll patients with several different types of tumors (skin, lung or colon cancer), but all of the tumors would share the same genetic abnormality. Alternatively, an umbrella trial might enroll patients with the same underlying origin of cancer (such as breast or pancreatic), but allocate patients to treatment with one of several different targeted therapies.

An example of a large umbrella trial is ALCHEMIST, or the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial, a government-sponsored study that is enrolling patients with early-stage, nonsquamous non-small cell lung cancer (NSCLC) after surgery. The trial will screen patients for EGFR mutations and ALK rearrangements, and then place them in two separate trials based on those biomarkers, evaluating treatment with either EGFR-targetingTarceva (erlotinib) or ALK-targeting Xalkori (crizotinib) versus placebo. Other large trials, such as NCI-MATCH and TAPUR, are enrolling patients with numerous cancer types and looking for a variety of genetic abnormalities to treat with targeted drugs, and so combine both approaches.

Many clinical trials of cancer drugs include some degree of personalization these days, but basket and umbrella trials remain a minority among studies because the level of collaboration they involve can make them difficult to organize. The costs of biopsies and genomic sequencing are also challenges. Still, experts say, we can expect to see more and more of these trials emerging over time.

In February of 2001, The Human Genome Project announced that a sequencing of the human genome had been completed. That project identified the locations of, and provided information about, the structure and organization of specific genes. It was the breakthrough that ushered in a new era of oncology research that has allowed investigators to study the genetic makeup of cancer tumors and reclassify them according to their composition.

A decade-and-a-half later, in his January 2015 State of the Union address, President Barack Obama recognized the significance of this line of study, and its evolution into an actionable body of work, by announcing the launch of the Precision Medicine Initiative, calling for $215 million dollars in government spending for fiscal year 2016. Seventy million dollars of that initial allocation went to the National Cancer Institute (NCI) for research in targeted, precision oncology.

Indeed, within the last decade, a significant focus within cancer research has been the push to understand how tumor genetics drive different cancers, and how to develop more focused drugs to target these molecular abnormalities. "The last decade has seen the development of several targeted therapies that can be very effective for a subset of patients with certain types of cancers, including lung cancer or melanoma. The challenges now are to try and extend these developments to other patients and to develop strategies to treat resistant tumors," says Amanda Redig, a medical oncologist at Dana-Farber Cancer Institute.

The gene mutations that occur in cancer are numerous. Primo Lara, a clinician-scientist at UC Davis Comprehensive Cancer Center, uses the commonly mutated gene KRAS as an example. It appears in 25 percent of lung cancers, 90 percent of pancreatic cancers and about half of all colon cancers. Further, approximately one-half of all cancers have a mutation in the tumor suppressor gene p53; this mutation releases the brakes on tumor growth, allowing unfettered cancer cell proliferation. Efforts are underway to identify and develop drugs that specifically target KRAS and p53, and to identify and clinically validate many more cancer-related mutations that could be clinically actionable.

Among approved drugs are those that target EGFR, the epidermal growth factor receptor. Mutations to EGFR are found in 10 to 15 percent of lung cancers in the U.S. and in more than 50 percent of lung cancers in Asian populations, more prevalently in females than in males, according to Shakun Malik, head of thoracic and head and neck cancer therapeutics at NCI’s Cancer Therapy Evaluation Program.

Mutations to a different gene, BRAF, were at the heart of the first published results of a basket study — the Zelboraf (vemurafenib) trial &mdash; reported just last year by researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. BRAF inhibitor Zelboraf was approved by the U.S. Food and Drug Administration (FDA) in August 2011 for the treatment of metastatic melanoma, but since BRAF mutations occur across a variety of cancers, investigators wanted to test the drug's effect on other cancer types, including lung, colorectal and ovarian. They enrolled 122 patients from centers around the world, all of whose cancers carried the BRAF mutation.

In general, results showed that Zelboraf was able to target this mutation across a wide variety of cancers, proving that cancer type does not always matter.

Medical oncologist David Hyman, acting director of developmental therapeutics at MSKCC and the study’s first author, says an advantage of basket studies is that they can democratize access to targeted therapy for those who have rare cancers, who are often underrepresented in clinical trials. "The discovery has been that some patients with very rare cancers have similar mutations (as more common cancers) at even higher rates, and some have no ongoing trials or therapies available (specifically for their disease types)," he says.

A number of large precision medicine trials are underway now, with the eyes of the scientific and patient communities watching closely to see where this kind of study will take us.

Throughout the country, lung cancer is the No. 1 cancer killer, causing over 27 percent of cancer deaths, or 150,000, each year. But because squamous cell lung cancers that are often caused by smoking include a wide variety of cell types and can be deadly, progress in finding treatments has been slow.

Mary Redman, the architect of the statistical design of the Lung-MAP trial and a biostatistician at Fred Hutchinson Cancer Center in Seattle, says the hope is that by using targeted therapy — both single-agent and combination regimens &mdash; treatments will be found that are effective and can prolong lives. Lung-MAP is a public-private collaboration composed of the NCI, SWOG Cancer Research (a worldwide network of researchers that designs and conducts clinical trials), Friends of Cancer Research, the Foundation for the National Institutes of Health, five pharmaceutical companies, Foundation Medicine and several lung cancer advocacy organizations. It's a large trial for individuals with advanced squamous NSCLCs who have undergone no more than one round of chemotherapy treatment and are not responding to that treatment.

Lung-MAP's co-principal investigator and co-chair of its trial oversight and drug selection committees, Roy S. Herbst, says patients can join the trial at any of more than 700 medical centers, where their cancer cells will be tested for over 200 possible gene alterations. Based on the results of this screening, eligible patients are assigned to one of four sub-studies testing investigational or FDA-approved treatments, based on which best suits their cancer's genomic profile. Three arms are testing targeted drugs, and the fourth is testing immunotherapeutic treatments that do not target a specific mutation, possibly benefiting patients whose cancers lack genetic alterations that match any of the targeted investigational therapies. Specifically, the immunotherapy arm is testing the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) compared with Opdivo alone.

Unlike most trials that require the development of a protocol for each drug to be tested, Lung-MAP uses a "master protocol" that can be changed and adapted quickly as new drugs become available or drugs that are proven not to be useful are removed from the study, says Herbst, professor of medical oncology at Yale Cancer Center-Smilow Cancer Hospital. Furthermore, the study design is unusual in that, if it demonstrates that a drug is safe and effective, that agent will automatically be eligible for approval by the FDA.

Jerry Valentino was diagnosed two years ago with squamous NSCLC at the Veterans Administration in West Haven, Connecticut, a teaching affiliate of Yale Medical School. The 69-year-old underwent 35 radiation treatments in addition to chemotherapy, resulting in the disappearance of the tumor in his lung. But in September 2015, he thought he was having a stroke. An MRI showed that his lung cancer had traveled to his brain.

After receiving brain radiation, with few standard treatment options available, Valentino instead entered the Lung-MAP trial at the VA and submitted his tissue for genome profiling. Based on the results, he was assigned to a sub-study and received an oral CDK4/CDK6 inhibitor called Ibrance (palbociblib), which was approved by the FDA in 2015 for the treatment of breast cancer. During each of three cycles, he took one pill a day for 21 days, followed by a one-week break. Valentino has undergone restaging scans as part of Lung-MAP's surveillance regimen, which confirmed stability in two lung lesions and partial response in another.

"I have experienced no side effects except fatigue, my brain tumor has shrunk and there is no lung nodule visible now," he says, adding that he is glad to be getting treatment that doesn't make him feel sick all the time.

The NCI’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, which opened for enrollment in August 2015, explores more genetic abnormalities and drugs than any other cancer trial — and in the largest number of cancer types ever, according to lead investigator Keith Flaherty.

Funded entirely by the NCI and with investigational drugs provided by pharmaceutical corporations, the trial was co-developed by the NCI and the ECOG-ACRIN Cancer Research Group. Its aim is to match tumor signals with targeted drugs and drug combinations, leading to further study of the strategies that prove effective.

Flaherty explains that the study arms, which will grow from 10 to 20 as the trial progresses, are for adults with advanced solid tumors and lymphomas that no longer respond to, or have never responded to, standard therapy, and for those with rare cancers for which there is no standard treatment. While patients with all kinds of cancers can enroll for screening, the goal is that at least 25 percent of enrollees will have cancers that are considered rare.

The trial is looking at 143 genes associated with cancer using cutting-edge molecular analysis. Tumor biopsies will be taken from about 3,000 patients. Those biopsies are sent to any of four labs, where the DNA is sequenced and analyzed in other ways to identify genetic abnormalities believed to be driving the growth of cancer. Drugs and drug combinations being tested have been approved by the FDA for specific cancers or have been used in other trials and have shown some effectiveness against certain genetic alterations.

When and if genetic abnormalities are found in participants, such as mutations in BRAF or EGFR, or HER2 amplification, these patients will be further evaluated for eligibility to enroll in the corresponding treatment arm; if they qualify, they will be treated for as long as their tumors shrink or remain stable.

So far, of 645 biopsies successfully evaluated, 9 percent (56 patients) had a gene mutation that matched a drug or drug combination being studied, 5.1 percent (33 patients) were assigned to a treatment arm and 16 patients actually entered into seven of the 10 available arms. Ultimately, investigators want to treat 1,000 patients across all arms of the trial. For an approach to be considered promising within any arm of the study, at least 16 percent of patients have to show tumor shrinkage. If a first drug treatment is unsuccessful, a patient may be eligible to receive therapy in another arm of the trial if there is a remaining drug that matches one of the mutations found in his or her tumor. For each arm of the trial, the major endpoint will be the overall response to treatment, with a second endpoint being six months of progression-free survival, time to disease progression, toxicity and biomarker status.

The trial was designed, says Flaherty, so that when 500 patients were accepted as eligible to submit tissue for mutation screening, the study would be paused for analysis to determine how it should proceed, with patients already being treated continuing to receive their medications. During the current pause that began in November 2015, the diversity of cancer types is being studied, data for those with mutations that correlate with treatments in the trial are being analyzed, and an assessment of changes needed to move forward is being worked out. Facilitating a steady flow of tissue screening through the participating labs is one task being addressed during the pause, but a more vital one has involved adding more study arms, which will lead to the treatment of more patients, leaders say.

The interim analysis will be completed soon, and enrollment in the trial is expected to resume in late May. "It was assumed years ago that cancers that harbored the same genetic mutation, for which we have targeted therapies in development, would be equally likely to respond," says Flaherty. "We have learned recently that there is a lot of variability based on the presence of co-occurring mutations or biology that stems from the tissue of origin for a given cancer. The MATCH trial is the largest endeavor undertaken to explore the consistency or variability of response to targeted therapy across the entire cancer population."

The first trial ever to be run by the American Society of Clinical Oncology (ASCO), the Targeted Agent and Profiling Utilization Registry (TAPUR) is being launched at the sites of the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan and the Levine Cancer Institute at Carolinas HealthCare System. Its aim is to simplify access to cancer treatments for patients with various tumor types that carry genetic variations known to be the targets of any existing approved drugs — including lung and other kinds of advanced solid tumors, multiple myeloma or non-Hodgkin lymphoma. Patients who have at least one genomic variant that can potentially be targeted by one or more available drugs and are not responding to standard therapies, or for whom no treatment is available, are eligible for enrollment in TAPUR.

In addition to providing drugs to which patients might not otherwise have had access, the objectives of TAPUR are to assess safety and efficacy and to target multiple tumor types. To begin with, the study will enroll patients at three sites nationally to evaluate 10 to 15 drugs, with up to 28 patients per drug treatment.

Unlike Lung-MAP, which is studying both investigational and approved drugs, TAPUR will look strictly at drugs that have been OK'd by the FDA. The study will include more genomic aberrations and more drugs than Lung-MAP, which exclusively targets squamous NSCLC. The trial has more in common with NCI-MATCH, because, like MATCH, it targets rare genetic aberrations with drugs designed to quiet them. However, it is simpler than MATCH, as there is not a different protocol for each drug being tested.

As those trials across a spectrum of cancers and mutations continue, others are popping up that consider more specific questions.

 study) is a phase 2 basket clinical trial that is open to enrollment in the U.S. for patients with solid tumors. Eligible patients will be treated with 

, an investigational drug that specifically targets certain cellular pathways that are involved in the development and progression of cancer. Recently launched by the drug’s developer, Ignyta, Inc., the clinical trial will seek to enroll patients with locally advanced or metastatic solid tumors that have a specific mutation (called a “gene rearrangement” or “fusion”) that is found in the 

 or ALK genes. It is believed that these types of mutations have the potential to be oncogenic drivers. Ignyta and other labs offer a test to help determine if one of these mutations is detected within a sample of tumor tissue. The trial will include a variety of cancer types (i.e., different baskets), among them non-small cell lung cancer, colorectal cancer, 

, papillary thyroid cancer, melanoma and 

. Depending on cancer type and gene rearrangement/fusion, eligible patients will be assigned to a specific basket for treatment with entrectinib.

"What we are seeing is that, regardless of the originating tumor type, these oncogene-driven tumors behave similarly in their response to targeted drugs," says Robert C. Doebele, an investigator for the entrectinib trial at the University of Colorado School of Medicine, where he is an associate professor in the Division of Medical Oncology. "This seems to be a new paradigm in study design."

When determining treatment plans, some doctors are turning to genetic mutations that caused the cancer instead of the cancer type. 

Barbara Sadick

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