Alok Khorana, MD, professor of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Sondra and Stephen Hardis chair in Oncology Research, vice-chair, Clinical Services of the Taussig Cancer Institute, director, the Gastrointestinal Malignancies Program at the Cleveland Clinic, discusses increasing rates of young-onset pancreatobiliary adenocarcinoma.

A retrospective analysis evaluated a cohort of patients to determine trends and characteristics of young-onset pancreatobiliary adenocarcinoma compared with average onset of the disease.

Investigators identified a 33% increase in the rate of young-onset pancreas and biliary cancer, Khorana says. A large increase in the incidence of pancreas and biliary cancers regardless of age has been seen, though the rising rates in younger patients is troubling, Khorana explains. Moreover, it was found that patients who are minorities, including African American and Hispanic patients, had a disproportionately higher rate of increase, Khorana adds.

Due to this overall rise, more research is needed to understand why rates of young-onset pancreatobiliary adenocarcinoma are increasing, Khorana concludes.

Videos

Alok Khorana, MD, discusses increasing rates of young-onset pancreatobiliary adenocarcinoma. 


Dr. Khorana on Rates of Young-Onset Pancreatobiliary Adenocarcinoma

Alok A. Khorana, MD, professor of Medicine, Department of Hematology and Oncology, Cleveland Clinic, discusses a study that examined practice patterns and patient persistence on anticoagulant treatments for cancer-associated thrombosis.

Patients with cancer are likely to develop blood clots, and there are select anticoagulant treatments available, Khorana explains, including heparin and rivaroxaban.

Khorana says that although heparin is the guideline-recommended agent to treat cancer-associated thrombosis, it is only used in approximately 25% of patients. Rivaroxaban, which is a newer agent with a broad indication, was found to also be used in only 25% of patients. Although warfarin has been used the longest and interacts with other agents, it remains to be the dominant choice of the three agents, Khorana says.

Alok A. Khorana, MD, professor of Medicine, Department of Hematology and Oncology, Cleveland Clinic, discusses a study that examined practice patterns and patient persistence on anticoagulant treatments for cancer-associated thrombosis.


Dr. Khorana on Current Practice Patterns on Anticoagulant Treatments for Thrombosis

Alok Khorana, MD, medical oncologist, Cleveland Clinic, discusses blood clot risk and treatment for patients with cancer.

On average, one-fifth of patients with cancer will experience a blood clot, says Khorana. For years, the standard of care for treating blood clots in cancer patients was low molecular weight heparins. More recently, direct oral anticoagulants have become common for the treatment of blood clots.

However, there have been no cancer patient-specific studies evaluating these new agents. Patients' absorption is different and they may have different interactions to these blood clots therapies than non-cancer therapies, says Khorana. In a collaboration with Janssen Pharmaceuticals, Cleveland Clinic is investigating these new agents in a cancer patient-specific trial.

Dr. Khorana on Blood Clots in Patients with Cancer

	With the adoption of electronic medical records (EMRs), healthcare systems in the United States are moving rapidly toward digitization. This movement is being driven by a variety of influences, including regulatory and governmental authorities, with the aim to increase accessibility to information, reduce errors, and improve compliance with quality and performance measures. The overarching objective is to allow physicians to gain control over the ever-increasing complexity of the current healthcare system. Indeed, the American Recovery and Reinvestment Act provides for both financial incentives and punitive measures that are designed to accelerate the adoption of EMRs.

	I personally welcome the introduction of EMRs into healthcare. My own research program has benefited from the advent of information technology. Our group has utilized large healthcare data sets to conduct analyses that would not be possible with clinical trials alone and has used electronic order entry alerts to improve patient outcomes.

 From a clinical oncology perspective, writing chemotherapy orders is perceived to be safer and easier in EMRs, and most of us appreciate not having to hunt down paper charts for writing orders or for finding patient heights and weights.

	Having transitioned to an EMR at my institution earlier this year, however, I find note-writing to be the EMR’s major shortcoming, as it tends to disrupt many of the intended uses of the traditional patient-progress note. The progress note has a long and storied tradition in healthcare, and it serves many purposes. The first is documentation, as it captures essentials of the visit and reminds physicians of their discussions with the patient. A second purpose is communication, with versions of progress notes (“letters”) sent to other providers for either information or to request input. A third—and more recent&mdash;purpose is compliance, with notes documenting mandatory preventive measures (for example, thromboprophylaxis in the inpatient setting or influenza vaccination in the outpatient setting) that can later be queried for quality-of-care audits.

	The EMR first causes disruption outside of the progress note itself. Patients do not feel as engaged with their physicians, who are looking at the computer screen rather than the live patient in front of them. While many of my patients are forgiving of my focus on the screen, I find it difficult to practice mindfulness when multiple items on the screen (eg, laboratory results, flagged messages, imaging results) are all vying for my attention and competing with the actual patient. One can accept disruptions if this leads to improvement over current capabilities. However, the primary uses of the progress note—documentation and communication&mdash;are disrupted as well, because EMR notes rely heavily on templates and pointand- click software applications. Although convenient for note-writing, such choices made by software designers (and not physicians) force us to reduce our patients to the “boxes” that have been provided by the software designer. For instance, if I wanted to document that the patient at a recent visit was anxious, but the choices offered by the program are “sleeping,” “active,” “cooperative,” or “distressed,” it might be easier to pick “distressed” even though it doesn’t accurately convey the situation. This is not the physician failing to write a good note; it is a software program deficiency that narrows available choices for physicians and leads to an inaccurate capture of reality.

	My concerns about this issue are affirmed by a recent critique of current software design by one of Silicon Valley’s own pioneers. In You Are Not a Gadget , computer scientist Jaron Lanier states that information underrepresents reality and that current software does not have the capability to capture the nuances of human interactions (let alone the complexities of physician-patient interactions).

 Even worse for future EMR development, Lanier describes the process known as software lockin, where software choices made early in program development become entrenched for all future iterations of the program.

 In other words, the choices made in currently existing programs, if accepted by end-users (physicians) as a sacrifice necessary for transitioning to EMR, will be kept for the next several generations of medical software. As Lanier points out, software lock-in “removes design options based on what is easiest to program, what is politically feasible, what is fashionable, or what is created by chance…[and] narrows the ideas that it immortalizes, by cutting away the unfathomable penumbra of meaning that distinguishes a word in natural language from a command in a computer program.”

	The genie, of course, cannot be put back in the bottle. EMRs are here to stay. What, then, can physicians do to optimize note-writing in the age of EMRs? The first step is to take ownership of the note: develop EMR “etiquette” based on consensus within your own group of physicians. When you open the record on the desktop, explain to the patient exactly what you are doing. For those who are new to EMRs, apologize in advance for having your back turned. Many of my patients find it useful if I tilt the screen toward them, so they can view what I’m viewing and I can run through vitals, medications, and test results with them. This empowers the patient to be part of the record-keeping process and reduces the mysteriousness of the screen that you keep looking at as an alternate source of information. Avoid the temptation of cutting and pasting the enormous amount of data that are freely available through the EMR and are merely repeated in the note. Keep only what is essential (with a nod to the gods of billing compliance) and capture the heart of that specific interaction with the patient, so that the primary purpose—communication&mdash; is preserved. Avoid point-and-click boxes if they do not sufficiently capture the interaction; use free text instead.

	All of this is, of course, harder to practice than preach. I am still learning, and my notes do not always achieve the ideal. But if we as physicians do not take ownership of the physician-patient interaction, who will?

1. D’Avolio LW. Electronic medical records at a crossroads: impetus for change or missed opportunity? 

2. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. 

3. Candelario GD, Francis CW, Panzer R, et al. A computerized prompt for thromboprophylaxis in hospitalized cancer patients. 

4. Lanier J. You Are Not a Gadget: A Manifesto. New York, NY: Alfred A. Knopf; 2010. 

Articles

The movement towards digitization is being driven by regulatory and governmental authorities, with the aim to increase accessibility to information, reduce errors, and improve compliance with quality and performance measures.

Physician Notes in the Age of Electronic Medical Records

It seems that every year, the list of Accreditation Council for Graduate Medical Education (ACGME) requirements grows longer and more bewildering. That’s no surprise in oncology. Our patients are increasingly complex, our therapies are more numerous and more sophisticated, and the ACGME’s reach extends beyond medicine into patient safety, quality improvements, and understanding medical systems. In addition, there is the burgeoning list of required conferences, institutional demands, and the dawning of the electronic age, complete with electronic medical records, electronic admission, electronic discharge, electronic sign-in and sign-out, and electronic communication, all of which conspire to keep us at our laptops far longer than at the bedsides of our patients.

Add to this the stress of our clinical work. We try to satisfy the needs of our patients and their families, many of whom are facing life’s biggest crisis. They deserve more attention than our crowded and fragmented schedules will allow; this only heightens our stress. For the fellow, this stress can be still greater. There are the additional burdens of being less experienced, being less appreciated by families, struggling with difficult decision-making and poor outcomes, and managing the competing demands of patients, faculty, the fellowship program, and the fellow’s own family life.

Given the stresses and demands of our field, it is not surprising that the prevalence of burnout is high. Burnout is defined as emotional exhaustion, depersonalization (ie, treating patients as objects), and a low sense of accomplishment. However, there are many ways to maintain the deep satisfaction that comes with working with patients with cancer and their families and with our colleagues. Incorporating medical humanities into one’s medical practice and the fellowship curriculum is one such way. Medical humanities is simply application of history, literature, art, music, and other fine arts to the practice of medicine and the care of the patient.

There is not much literature on this approach, particularly in oncology. Gilewski describes a forum for fellows at Memorial Sloan-Kettering Cancer Center that focuses on end-of-life care and the stresses of such care on fellows and other caregivers.

 Sands et al reported on a narrative training course, in which members of a pediatric oncology team wrote about their own personal experiences with their patients.

 The 19 participants in this course displayed improved perspective on their patients’ problems, higher empathy scores, and better teamwork.

In 2009, we introduced a seminar at the James P. Wilmot Cancer Center in Rochester, New York, titled “Narratives in Oncology,” which was designed for medical and pediatric oncology fellows and radiation oncology residents. Our goal was to introduce our trainees to literature, poetry, and essays in the lay press as well as in the medical literature that focus on the human side of patient care. We hoped that such literature would open the eyes of our fellows to a rich source of thought-provoking material on patient and physician perspectives on life, death, and medical care. We also hoped that discussion of these essays would stimulate dialogue among us about subjects we seldom discuss: what to tell (or not to tell) our patients, the challenges of communicating bad news, how to deal with difficult families, coping with loss, and our own personal stresses caring for so many medically and emotionally needy patients.

The seminar was designed so that we would meet in a 1-hour session once a month for 6 months. The faculty preceptors and the fellowship director chose articles to review, and 1 week prior to each session 1 or 2 essays/articles were distributed to the fellows. We chose articles that provided the patient’s perspective and that highlighted common clinical dilemmas. For example, for our first session we read an essay by Stephen Jay Gould called “The Median Isn’t the Message,” which discusses how a patient might look at odds of survival very differently than would a physician.

 In another session, we read a Glamour magazine excerpt, “I Want My Life Back,” by Andrea Coller, a young patient with multiply recurrent Hodgkin lymphoma, and learned what it feels like to be 27 years old and go through intensive chemotherapy and how we physicians look from the perspective of a young adult. (It wasn’t pretty!)

 We read a painful essay called “Facing Our Mistakes” by David Hilfiker

 and watched Casey’s Legacy, a video of a physician who tearfully describes a mistake he made in caring for a child.

 For the last session, fellows were asked to write an essay about a moving interaction with a patient, and selected essays were read at that session.

The seminar was quite successful. Attendance ranged from 11 to 18 fellows and it was clear they had read the assigned material. Discussion was lively and almost all the fellows actively participated. Faculty preceptors guided the discussion, but little stimulation was needed to provoke conversation. Fellows frequently cited their own patient scenarios that related to articles we reviewed. They frequently brought up the unique aspects of being a fellow and dealing with stressful patient encounters. They cited such examples as not feeling comfortable with the attending physician’s communication skills, their own lack of experience when patients ask difficult questions, their discomfort when delivering bad news, and their unhappiness about knowing that, as a trainee, they cannot always speak freely. As the word spread about the seminar, we were joined by other faculty members, nurses, and nurse practitioners.

For the final session, fellows and faculty were asked to write a brief essay. One fellow wrote a moving piece about running into a very grateful couple in the grocery store and how he just could not remember who they were. He explained how embarrassed he was to have no memory of them. Was one a former patient? Were they bereaved family members? But at the same time, it made him realize that through his actions he can have a real impact on his patients’ lives. Another fellow wrote about her interactions with a demanding daughter, a hospital executive who tested the limits of the fellow’s patience. The fellow described how, tough as the executive in her power suit seemed, deep down she was scared of losing her mom, who eventually died of cancer. The fellow said that she knows how this feels because she, too, lost her mother.

At the conclusion of the seminar series, we formally surveyed the fellows for feedback on the course. Ten of the 11 fellows who returned the survey felt that the course was a useful part of their curriculum. The fellows “repeatedly cited the openness to discussion of issues that typically are not part of the traditional oncology curriculum, as well as the relevance of the specific articles chosen.”

 As one of the fellows said, the course “provided a forum in which we could discuss our experiences and explore difficult issues with others who have shared similar experiences.”

 Ten of the 11 fellows said the course had a positive impact on their interaction with patients, enabling them to have a more “humanistic approach,” be “more aware of patients’ feelings,” and hang on to empathy when it might otherwise have been lost. The majority of fellows felt that the writing exercise was useful, albeit difficult. It should be noted that 1 respondent did not find the course helpful at all; hence, a reminder that this is not an approach that is useful for everyone, and that we need to be sensitive to the needs of individuals who may choose to deal with patient care dilemmas more privately.

Overall, there was consensus among the fellows and faculty that the “Narratives in Oncology” seminar is a valuable part of the fellowship curriculum, and that the principles and practices we discuss can be incorporated into patient care, help to improve patient-physician communication, and make care of the patient with cancer more gratifying. As we move into year 2 of the seminar, we hope to expand to include other forms of artistic expression, such as art, music, and video, and perhaps expand our audience to other healthcare providers and other subspecialists.

*This article is adapted by the authors from: Khorana AA, Shayne M, Korones DN. Can literature enhance oncology training? A pilot humanities curriculum.

David N. Korones, MD, is professor of pediatrics, oncology, and neurology at University of Rochester School of Medicine and Dentistry in Rochester, New York. He is also a pediatric hematologist/oncologist and palliative care specialist.

	Michelle Shayne, MD, is assistant professor of medicine and oncology at University of Rochester School of Medicine and Dentistry in Rochester, New York. She is a medical oncologist with expertise in breast cancer and is the Hematology/Oncology Fellowship Program director.

	Alok A. Khorana, MD, is associate professor of medicine and oncology at University of Rochester School of Medicine and Dentistry in Rochester, New York. He is a medical oncologist with expertise in GI oncology and thrombosis.

University of Rochester Medical Center. Medical Humanities Web site. http://www.urmc.rochester.edu/smd/medical-humanities. Accessed May 8, 2011.

Gilewski T. The art of medicine: teaching oncology fellows about the end of life. 

Sands SA, Stanley P, Charon R. Pediatric narrative oncology: interprofessional training to promote empathy, build teams, and prevent burnout. 

Full House: The spread of Excellence From Plato to Darwin

. New York, NY: Harmony Books; 1996:45-56.

Coller A. Non-fiction contest winner: I want my life back. Glamour magazine Web site. http://www.glamour.com/magazine/2008/05/essay-winner-surviving-cancer. Accessed May 11, 2011.

Khorana AA, Shayne M, Korones DN. Can literature enhance oncology training? A pilot humanities curriculum. 

It seems that every year, the list of Accreditation Council for Graduate Medical Education (ACGME) requirements grows longer and more bewildering.

Introducing Humanities Into the Oncology Curriculum

Cancer-associated thrombosis occurs commonly in patients with cancer, particularly during treatment with anticancer therapies. Recent reports suggest a steep increase in the incidence of cancer-related thrombotic events starting in the late 1990s.

 Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), has important consequences for patients with cancer: a requirement for long-term anticoagulation, a 12% annual risk of bleeding complications, a 21% annual risk of recurrent VTE,

 and the potential to affect chemotherapy delivery and quality of life. Most importantly, thrombotic events are the second leading cause of death in patients with cancer (after cancer itself) and are associated with decreased short-term and long-term survival.

 Thus, it is crucial to reduce the occurrence of VTE, especially considering that there are multiple available agents for thromboprophylaxis, including low-molecular-weight heparins (LMWHs) and warfarin.

VENOUS THROMBOEMBOLISM IN THE OUTPATIENT SETTING

The focus of thromboprophylaxis studies in the past has largely been in the hospital inpatient and postsurgical settings. Although these continue to be important settings, an increasing proportion of VTE events occur in the outpatient setting.

 Recent studies of thromboprophylaxis conducted primarily in the outpatient setting have implications for clinical practice.

PROTECHT (Prophylaxis of Thromboembolism During Chemotherapy Trial) was a multicenter, randomized, placebo-controlled, double-blind study in which prophylaxis was studied in patients with high-risk sites of cancer, including locally advanced or metastatic lung, gastrointestinal, pancreatic, breast, ovarian, and head/neck cancers, who were actively receiving chemotherapy.

 Patients receiving adjuvant or neoadjuvant chemotherapy, patients actively receiving antithrombotic treatment, and those with contraindications to anticoagulation were excluded.

Patients received either injections of nadroparin (an LMWH approved in Europe) or placebo in a 2:1 randomization ratio for the duration of chemotherapy or for a maximum of 4 months. The primary outcome in the trial was a combined endpoint of symptomatic VTE of the extremities, peripheral arterial thromboembolism, PE, cerebral or visceral venous thrombosis, myocardial infarction, ischemic stroke, and death secondary to a thromboembolic event. The study did not screen for asymptomatic events.

Overall, 2% of patients in the treatment group and 3.9% (n = 15) in the placebo group developed a thromboembolic event (one-sided; 95% CI, 0.303%; 

 = .02). DVTs comprised the majority of events in both arms, followed by PE, visceral venous thrombosis, and stroke/peripheral thrombosis (

). No survival benefit was observed. Patients in the treatment arm were more likely than patients in the control arm to experience major bleeding (0.17% vs 0%, respectively; 

This is the largest study of thromboprophylaxis conducted in outpatients with cancer to date, and it represents a significant advance in the prevention of VTE in this population. Although the study met its primary endpoint, the overall low event rate has not led to recommendations for the use of prophylaxis in outpatients. It is quite possible that the event rate is higher in specific subgroups of patients with cancer and that the risk-benefit ratio would have been more optimal for prophylaxis if higher-risk patients had been selected using either biomarkers or risk-assessment tools, which will be discussed later in this article.

It has been well established that patients with pancreatic cancer are at particularly high risk for VTE.

 The PROSPECTCONKO 004 (Prospective Randomized Trial of Simultaneous Pancreatic Cancer Treatment With Enoxaparin and Chemotherapy) study was a prospective, open, randomized multicenter phase III trial that evaluated thromboprophylaxis in patients with pancreatic cancer receiving gemcitabine (Gemzar)-based chemotherapy. The study was designed after an initial pilot study determined that adding enoxaparin to a chemotherapy regimen of gemcitabine, 5-fluorouracil, folinic acid, and cisplatin (GFFC) was safe and efficacious in advanced pancreatic cancer.

Individuals with confirmed advanced pancreatic cancer and no prior chemotherapy or recent VTE events were eligible for enrollment. Patients were stratified according to Karnofsky performance status and renal function. Those with normal renal function and good performance status (>80%) received GFFC chemotherapy, whereas patients with elevated plasma levels of creatinine and worse performance status received gemcitabine alone. Patients were randomized to observation or prophylactic enoxaparin, receiving 1 mg/kg per day for 3 months, then 40 mg daily. The primary endpoint was reduction of symptomatic VTE. Time to progression (TTP) and overall survival (OS) were secondary outcomes.

VTE occurred in 5.0% (8 of 160) of patients in the enoxaparin arm compared with 14.5% (22 of 152) of patients in the observation arm (

 <.01). The incidence of major bleeding was paradoxically higher in the observation arm, although this was not statistically significant (6.3% vs 9.9%, respectively; 

 = .18). No differences were observed between the groups in median OS or TTP.

 The results of this study show that thromboprophylaxis can safely and clinically produce a significant reduction in the rate of VTE in patients with pancreatic cancer.

The dose of LMWH used in this setting was higher than the commonly accepted prophylaxis dose of 40 mg per day, although it was not as high as the therapeutic dose of 1 mg/kg twice daily. Given the unique hypercoagulability of patients with cancer, it is quite possible that higher doses of anticoagulants are needed to achieve significant reduction in VTE. One limitation of this study was the use of the GFFC combination, which is not considered standard of care; one of the regimen’s components—cisplatin&mdash;is known to increase the risk of VTE in patients with cancer.

 Full results in manuscript form are awaited.

In the FRAGEM trial, patients in the United Kingdom with unresectable pancreatic cancer were randomized to gemcitabine alone or combined with daily dalteparin (Fragmin) for 12 weeks.

 The primary outcome was reduction in VTE; secondary outcomes were fatal VTE events, sudden death, and early death burden. An interim analysis was presented in 2009, encompassing data for 59 evaluable patients in the dalteparin arm and 64 evaluable patients in the chemotherapy-only arm. Within the first 100 days after randomization, 25% of patients in the control arm and 3.5% of patients in the dalteparin group experienced a VTE (relative risk [RR], 0.14; 95% CI, 0.03 to 0.58; 

 = .002). Overall incidence of VTE was 31% in the chemotherapy-only group versus 12% in the dalteparin arm (RR, 0.38; 95% CI, 0.17 to 0.84; 

 = .019). Further, 9% of patients in the chemotherapy-alone arm experienced a fatal VTE or sudden death compared with none of the patients in the thromboprophylaxis arm (RR, 0.08; 95% CI, 0.005-1.45; 

 Final results and a full manuscript from this study are pending, but the reported data are consistent with the known high rate of VTE in patients with pancreatic cancer and with the results of the CONKO 004 study.

 Trial of Prophylaxis in Patients With Myeloma

Patients with myeloma are at high risk for experiencing a VTE. This is particularly true of patients receiving thalidomideor lenalidomide (Revlimid)-based combination regimens. VTE rates of up to 34% have been observed in patients on these therapies.

A recent prospective study addressed the efficacy of thromboprophylaxis in 991 newly diagnosed myeloma patients.

 Since there is still controversy regarding the most appropriate thromboprophylaxis regimen, the authors conducted a prospective, multicenter phase III trial evaluating the safety and efficacy of LMWH, low-dose aspirin (ASA), or low-intensity, fixed-dose warfarin as anticoagulant prophylaxis. The endpoints were incidences of VTE, acute cardiovascular events, sudden death, and major and minor bleeding. The study population comprised 991 patients with newly diagnosed myeloma who were randomized to one of 4 regimens (

): Velcade, thalidomide, and dexamethasone (VTD); thalidomide and dexamethasone (TD); Velcade, melphalan, prednisone, and thalidomide (VMPT); or Velcade, melphalan, and prednisone (VMP). In a substudy, patients treated with VTD, TD, or VMPT were randomly assigned to receive 40 mg per day of LMWH (enoxaparin, n = 223), 100 mg per day of ASA (n = 227), or 1.25 mg per day of warfarin (n = 223) for the duration of induction therapy. Patients treated with VMP (n = 257) did not receive any prophylaxis and were used as controls; this was the only nonprophylaxis arm.

The incidence of VTE was 5% in the LMWH group, 6% in the ASA group, and 8% in the warfarin group (

 value not significant). VTE occurred in only 2% of patients in the VMP nonprophylaxis control arm. The rate of cardiovascular events was 2% in the LMWH group, 1% in the ASA group, and 0.5% in the warfarin group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group, and 1% in the warfarin group (

 value not significant). The combined incidence of thrombosis, bleeding, and cardiovascular events was 9% in the LMWH group, 10% in the ASA group, and 9% in the warfarin group (

 value not significant). Thus, patients receiving LMWH had a lower risk of VTE, although no statistical difference was observed. The authors concluded that LMWH, warfarin, and ASA are all likely to be effective thromboprophylactic regimens. Current American Society of Clinical Oncology (ASCO) guidelines on VTE prophylaxis in patients with cancer, however, recommend against the use of aspirin in this setting.

 Meta-Analysis of Prophylaxis Studies in Outpatients

Kuderer et al recently presented a meta-analysis investigating LMWH thromboprophylaxis in outpatients with cancer.

 This meta-analysis included all the recent studies discussed herein, with the exception of the myeloma prophylaxis study; older studies utilizing LMWH prophylaxis were also included. The authors identified a total of 7 randomized controlled trials (RCTs) of LMWH use in ambulatory patients with cancer (N = 2960), which consisted of 1685 patients who received LMWH and 1275 controls. The RCTs included 3 that enrolled patients with various solid tumors and 1 each for patients with breast cancer, lung cancer, pancreatic cancer, and glioblastoma.

Patients receiving LMWH experienced 47 VTE events compared with 74 VTE events for control subjects, for crude rates of 2.79% and 5.80%, respectively. The RR for VTE across all trials was estimated at 0.54 (95% CI, 0.38-0.78; 

 = .001), while the absolute risk decrease was 2.55% (95% CI, 1.06%-4.05%; 

 <.001). A total of 30 patients receiving LMWH experienced major bleeding events compared with 15 control subjects, for crude rates of 1.78% and 1.18%, respectively. The RR for major bleeding across all trials was estimated at 1.74 (95% CI, 0.95-3.18; 

 = .071), while the absolute risk increase was 0.75% (95% CI, 0.17%-1.33%; 

 = .011). The RR for major bleeding across the 5 primary prophylaxis trials was 2.27 (95% CI, 1.12-4.59; 

 = .022) with the absolute risk increase estimated at 1.27% (95% CI, 0.27%-2.27%; 

The authors concluded that LMWH thromboprophylaxis in ambulatory patients with cancer is effective and results in a significant 46% reduction in the RR of VTE. The overall risk of VTE is low in this setting, however, and the absolute RR with prophylactic anticoagulation is only 2.6%; the increase in major bleeding events invites concern. This meta-analysis points to the need for risk stratification when selecting patients for thromboprophylaxis.

The results of recent studies strongly suggest a benefit from using thromboprophylaxis in select patient populations. The results from PROTECHT, which had a low rate of VTE events, are more applicable to a general population of patients with cancer. The studies in patients with pancreatic cancer and myeloma demonstrate high event rates, but these data apply to small subsets of patients with cancer. For ambulatory patients with myeloma, current ASCO guidelines recommend prophylaxis only for those receiving thalidomide- or lenalidomide-based regimens and not for other ambulatory populations.

 A consensus statement from major guidelines panels emphasizes a similar selection of outpatients for prophylaxis.

To reduce the public health burden of cancer-associated VTE, it is crucial to develop ways to stratify cancer patients according to their risk for VTE and identify appropriate prophylactic regimens. A risk assessment model that applies to a broad population of patients with cancer was created (

 after studying risk factors for VTE in a development cohort of 2701 ambulatory patients from a prospective registry. A risk score for VTE was devised using regression coefficients estimated in the multivariate model. The score was then validated in an independent cohort of 1365 patients from the same study.

The stage-adjusted multivariate model identified 5 predictive variables as significant risk factors for chemotherapy-associated VTE and categorized risk as low (score of 0), intermediate (score of 1 or 2), or high (score ≥3).  Observed rates of VTE in the development and validation cohorts were 0.8% and 0.3%, respectively, in the low-risk category; 1.8% and 2%, respectively, in the intermediate-risk category; and 7.1% and 6.7%, respectively, in the high-risk category.

A recent report from Vienna CATS (Cancer and Thrombosis Study), a trial that enrolled 834 patients with cancer, has now externally validated this model.

 The study determined that the 6-month cumulative probability of developing VTE was 1.5% for patients with a score of 0, compared with 3.8% for patients with a score of 1, 9.4% for patients with a score of 2, and 17.7% for patients with a score ≥3.

Three large RCTs are underway that will add to the available data on thromboprophylaxis for patients with cancer (

). The largest is SAVE-ONCO (Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy), which is investigating the efficacy of the novel agent semuloparin (AVE5026) at preventing VTE. Patients undergoing chemotherapy for locally advanced or metastatic solid tumors of the lung, gastrointestinal tract, bladder, or ovary are eligible for the study.

The National Institutes of Health is sponsoring PHACS (a Prospective Randomized Multicenter Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients) at the University of Rochester in New York and Duke University in Durham, North Carolina. The study uses the risk model discussed above to identify outpatients with cancer who have a high risk of experiencing a VTE during chemotherapy. Patients with a risk score ≥3 are being randomized to 12 weeks of dalteparin or observation.

The third trial, referred to as MicroTEC (Microparticles and Thromboprophylaxis With Enoxaparin in Cancer), is investigating enoxaparin in patients with pancreatic, lung, and colorectal cancer who have elevated plasma levels of tissue factor—bearing microparticles. The results of these novel approaches to risk stratification and prophylaxis will add to the growing information in this area and allow clinicians to individualize decisions regarding thromboprophylaxis for ambulatory patients with cancer.

Cancer-associated thrombosis occurs commonly in patients with cancer, particularly during treatment with anticancer therapies.

Alok A. Khorana, MD