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eRounds - Year-end 2013

Cancer Genomic Testing: Next Generation in a Real-World Setting

Nearly every major hospital or cancer treatment practice performs specific genomic testing on every cancer patient’s tumor sample — such as K-ras oncogene analysis for those with colorectal cancer or HER2 analysis in breast cancer. These standard-of-care tests detect a single genetic mutation associated with a patient’s tumor type. Since August, oncologists at Cleveland Clinic’s Taussig Cancer Institute have been enrolling patients in an expanded genomic testing clinical study in which 250 patients with 15 different tumor types will be analyzed over the next year for 236 cancer-related genes.

The genes tested have been implicated in cancer, with implications for cancer therapeutics. They are all included in the FoundationOne™ genomics assessment test. For this clinical investigation, Cleveland Clinic has partnered with FoundationOne’s developer, Foundation Medicine, a molecular information company specializing in comprehensive genomic analysis of tumors.

In the study, each patient’s tumor sample is tested with the FoundationOne genomics profile, which detects several types of DNA alterations — base substitutions, small insertions/ deletions, copy number alterations and gene rearrangements. The test includes those genes that show a high frequency of common alterations but also those on a tail on the curve, such as those mutations occurring at low frequency but across many different tumor types. This type of approach provides a strong rationale for looking broadly rather than just looking with disease-specific genes.

“We have chosen a variety of cancers that include the most common cancers,” says Davendra Sohal, MD, MPH, staff physician in the Department of Solid Tumor Oncology and principal investigator of the study. “The goal is to see if this type of expanded genomic testing can impact clinical outcomes in a meaningful way.”

“We understand the importance of genomic testing in a broad fashion and are investing heavily in this,” adds Brian J. Bolwell, MD, FACP, Chairman of the Taussig Cancer Institute. The target population for the study includes patients lacking good treatment options, such as those with metastatic disease or whose cancer has progressed despite one or two rounds of standard chemotherapy. “There is opportunity to make a difference for these people if we can apply the existing knowledge about cancer mutations to making useful treatment decisions.”

Feasibility And Utility

One of the trial’s goals is to study the feasibility of doing genomic analyses in a real-world setting. “We want to see how well tests like FoundationOne can be performed in a real-world setting in a variety of tumors,” comments Dr. Sohal. Questions to be answered include: How long does it take to process the test and for doctors at Cleveland Clinic to get the result? How long does it take for the patient to learn the result and recommendations for treatment?

The ultimate goal is to probe the clinical usefulness of expanded genomic testing. Every test result includes molecular details about a patient’s tumor along with supporting data suggesting a particular targeted therapy. This information is provided to a panel of oncologists within the Taussig Cancer Institute. This Genomics Tumor Board meets weekly to review each result independently and make recommendations for treatment — whether with approved drugs or as part of clinical trials in and around Cleveland. These recommendations are transmitted to the primary oncologist, who makes final personalized recommendations to the patient. “If many patients can get to useful treatments — whether FDA-approved or off-label, or under a clinical trial of a targeted therapy — then it can make a real difference,” says Dr. Sohal.

Because the science behind genomic testing is evolving rapidly, new genetic mutations are rapidly emerging. Cleveland Clinic has chosen to partner with Foundation Medicine as the company continually updates its testing panel to keep current with the latest research in cancer-related genetics.

For more information, call 216.444.7923 or 866.223.8100.

Statin Intolerance: Doesn’t Always Preclude Long-Term Treatment

Subsequent Statin Trials, Intermittent Dosing Can Be Effective Options

New guidelines issued by the American Heart Association and American College of Cardiology may potentially expand the number of patients using statins as a first-line therapy in hyperlipidemia management. Yet, some patients cannot tolerate the drugs due to muscle aches and weakness, gastrointestinal symptoms, liver enzyme abnormalities or other issues. This poses a challenge to reducing patients’ low-density lipoprotein cholesterol (LDL-C), considering statins’ demonstrated benefits in primary and secondary prevention of cardiovascular morbidity and mortality.

A major observational study by Cleveland Clinic offers some good news for these patients and their doctors: The majority of patients with previous intolerance can tolerate a subsequent statin trial. In addition, intermittent statin dosing can be effective in some patients and may result in the reduction of LDL-C levels and even the attainment of LDL-C goals.

Largest Statin Intolerance Study

The study, published in September’s American Heart Journal, is the largest to date to review different treatment regimens and their effect on LDL-C in patients with statin intolerance. The retrospective analysis included medical records of 1,605 patients referred for statin intolerance to Cleveland Clinic between 1995 and 2010, with at least a six-month follow-up.

“We found that in patients who previously reported statin-related events, most were eventually able to tolerate long-term use of a statin and benefit from its cholesterol-lowering effects,” says Leslie Cho, MD, the study’s lead author and Section Head of Preventive Cardiology and Rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine.

Co-author Michael Rocco, MD, Medical Director of Cardiac Rehabilitation and Stress Testing, Section of Preventive Cardiology, explains: “Even though statins work by similar mechanisms, intolerance to one does not predict a poor response to another.”

Once Statin-Intolerant Doesn’t Mean Always

During a median follow-up of 31 months, 72.5 percent of patients previously identified as “statin-intolerant” remained on regular statin therapy — including 63.2 percent on a daily regimen and 9.3 percent on intermittent dosing (ranging from once weekly to six days a week). Statins were completely discontinued in only 27.5 percent of patients.

“Even if patients cannot tolerate a daily dose of a statin, it’s possible to see a significant reduction in cholesterol levels from taking the drug less often, even as infrequently as once a week,” Dr. Cho says.

Patients on intermittent statin dosing had significantly less LDL-C reduction compared with those on daily dosing (21.3% ± 4% vs. 27.7% ± 1.4%; P < .001); but compared with patients who discontinued statins, those on intermittent dosing had significantly greater LDL-C reduction (21.3% ± 4% vs. 8.3% ± 2.2%; P < .001). Also, a significantly higher portion of patients on intermittent dosing vs. those who discontinued statin therapy achieved Adult Treatment Panel III LDL-C goals (61% vs. 44%; P < .05).

Higher Doses Not Always Needed

Some studies with atorvastatin, fluvastatin and rosuvastatin have suggested that every-other-day dosing regimens need to be nearly twice the daily dose to result in comparable LDL-C lowering, but Cleveland Clinic’s analysis found that reasonable reduction can be achieved with the same or even low doses in both daily and intermittent dosing strategies.

Also, Dr. Rocco says: “Starting at a low dose of a potent statin with intermittent dosing and gradually increasing the dose and frequency over time can promote better tolerance.”

To refer a patient to any of our heart specialists at the Sydell and Arnold Miller Family Heart & Vascular Institute, call 855.REFER.123.

Dealing with Statin Intolerance

Fortunately, many patients are able to tolerate statins without side effects, but it is not uncommon for some patients to complain of symptoms they believe are caused by their lipid-lowering medication. These guidelines can help you respond:

Patient history. Headaches, gastrointestinal complaints, muscle toxicity (weakness and/or pain) and elevated hepatic enzymes have been shown to be related to statin usage. Since those symptoms also may result from factors unrelated to statin intake — increased physical activity, hypothyroidism, heavy alcohol use, acute viral disease or drug interactions, for example — it’s important to first conduct a thorough history of your patient to rule out other causes.

Rechallenge. Discontinuing the statin to determine if adverse muscle or hepatic events resolve, and rechallenging with the previous or lower dosage to determine if symptoms return, can help confirm whether intolerance is the root cause.

Dosage or drug changes. If symptoms resume on rechallenge, consider reducing the dosage amount or administration frequency of the existing statin, or prescribing a different one. Statins with alternative metabolic pathways may provide symptom relief. Those with longer-acting formulas may enable intermittent — i.e., every-other-day or weekly — dosing while still helping reduce low-density lipoprotein cholesterol (LDL-C). However, it remains unclear whether such intermittent statin dosing results in the same cardiac risk reduction as daily administration.

Other alternatives. If statin-related symptoms still persist, LDL-C-reducing options alone or in combination include non-statin drugs such as ezetimibe, bile acid sequestrants and niacin. It is important to emphasize the role of physical exercise and dietary additions such as soy, viscous fiber (found in whole grains, beans, nuts), plant sterols and stanols (from fruits, vegetables, nuts, seeds, cereals and legumes). Caution is advised, because clinical trials have not compared the long-term outcomes of various statin intolerance-management strategies.

Joining Forces for Efficient, Effective Care

A pilot program offers new opportunities for community-based primary care physicians and Cleveland Clinic orthopaedic specialists to collaborate to provide coordinated, high quality patient care.

“This partnership supports the creation of a complete care plan for each patient, and gives us the chance to work closely with the PCP to be certain we get the best possible patient outcomes,” says Mark Froimson, MD, MBA, President of Euclid Hospital and staff physician in the Department of Orthopaedic Surgery.

The pilot program was created by the Centers for Medicare & Medicaid Services under the Affordable Care Act. Using a system of bundled payments, it establishes both performance and financial accountability for episodes of patient care.

Cleveland Clinic’s participation includes hip and knee replacements at Euclid Hospital. The hospital receives one predetermined Medicare payment for all services related to these procedures, and it must meet quality-of-care targets.

Enhanced Patient Care

“Patients typically express concern about transitions of care and fragmented care,” explains Dr. Froimson. “Close collaboration with PCPs in this new program improves quality and enhances the patient experience. It means better care delivered more efficiently.”

The development of a complete care plan begins when a PCP refers a patient for joint replacement. The orthopaedic surgery team works with the PCP to optimize the patient prior to surgery, getting him or her in the best possible shape to avoid the risk of complications or readmission. Six areas are addressed:

  • Smoking
  • Diabetes
  • Obesity
  • Chronic anemia
  • Poor dental hygiene
  • Malnutrition

If any of these problems exists, Cleveland Clinic staff assists the PCP to get them under control. “This can really act as a motivator for patients and help PCPs gain compliance,” notes Dr. Froimson.

Under the pilot program, there is greater flexibility with postoperative care. This allows participating providers to bend some Medicare rules, which ultimately benefits the patient, Dr. Froimson says. “For example, we can discharge a patient to a post-acute care facility without first keeping them in the hospital for three days. And, we can waive the typical strict requirements for home care and provide services that allow more patients to recover where they’re most comfortable — at home.”

Much of this flexibility stems from the financial risk that Cleveland Clinic assumes with the bundled payment approach. “We are willing to take on that risk,” Dr. Froimson explains, “because we have such confidence in the care we deliver.”

Although the PCP’s relationship with Medicare remains the same for now, Dr. Froimson believes there will be opportunities for gain-sharing in the future. He also is confident that the program will expand to other medical conditions and Cleveland Clinic sites. “We think this is the future of healthcare, and we are excited to be leading the way and learning what is most successful for our patients,” he says.

For more information about the complete care program for joint replacement patients, contact Maryann Horrigan, RN, at or 216.692.9130.

A Hidden “GEM:” When Your Patients Might Benefit from a Geriatric Evaluation

When an older person’s care requires in-depth investigation beyond the limits of a typical office visit, a geriatric consult at Cleveland Clinic can lend a hand.

Patients age 65 or older are eligible, and the average age of referrals for geriatric evaluation and management (GEM) is 85. The consult seeks to address geriatric syndromes such as:

  • Memory problems or confusion
  • Balance and walking problems
  • Falls
  • Medication issues such as nonadherence, interactions or adverse effects
  • Unexplained weight loss
  • Behavioral changes such as sadness, apathy, depression, anxiety or withdrawal

“We work in collaboration with the primary care physician, allowing you to focus on managing the patient’s medical conditions, such as hypertension, diabetes or heart failure,” explains Barbara Messinger-Rapport, MD, PhD, Director of the Center for Geriatric Medicine. “A mood disorder, recurrent falls or urinary incontinence in an older adult is unlikely to resolve unless multiple aspects of aging are acknowledged and addressed.”

Assessments typically are done at Cleveland Clinic’s main campus, although house calls are possible through the Home Care Department. Dr. Messinger-Rapport strongly recommends that a family member accompany a patient to the one- to two-hour appointment.

The evaluation includes medication review, cognitive testing and depression screening. A geriatrician reviews the patient’s medical history, performs an examination, and interviews the family and patient about their goals and concerns.

“At the end, we discuss what our assessment shows and what our recommendations are,” says geriatrician Ronan Factora, MD. Recommendations may include further testing, therapy evaluations, subspecialty referrals or resources to help the family deal with associated issues, such as a dementia diagnosis. The patient and family often leave the initial visit with a summary of the recommendations, which also are sent to the primary care physician. Sometimes additional information needs to be obtained, and the diagnosis and recommendations will come later.

Information from a geriatric consult can help individualize medical decisions, says Dr. Factora. Goals of the recommended interventions are to:

  • Support the patient’s efforts to remain independent and age well at home
  • Avoid complications related to medications
  • Reduce unnecessary hospitalizations
  • Ensure that medical, cognitive and psychological conditions are managed appropriately
  • Develop a care plan in line with each patient’s quality-of-life goals and life expectation

In a follow-up visit four to six weeks later, a nurse practitioner helps the patient and family understand the diagnosis and reviews new information, including laboratory or imaging results and counseling from resources such as the Alzheimer’s Association. “We determine if they are following our recommendations, address concerns and evaluate for changes,” says Dr. Factora. Further visits may occur as needed.

Medicare Part B and most private insurers cover GEM physician and nurse practitioner visits, plus diagnostic testing and brain imaging when medically indicated. Referrals — such as for physical therapy or occupational therapy — also are covered. Costs of specialist visits or additional services are discussed before scheduling.

To refer a patient for a GEM assessment, call 855.REFER.123.

Addressing The Attack: When (and Why) to Refer Kidney Stone Patients to a Specialist

Most patients suffering from a kidney stone attack visit their primary care physician (PCP) or the emergency department for immediate treatment of the pain. While preventive efforts to decrease the risk for future attacks is a good first step, many patients may benefit from seeing a specialist to determine both the cause of their stones and proper therapies.

“Since kidney stones are very common and widespread in the general population, most of those patients are seen by their PCPs,” says Cleveland Clinic nephrologist Juan C. Calle, MD.

“General instructions about diet and fluid intake for prevention of kidney stones are often sufficient if a patient has had only one stone formed (depending on the size and any associated comorbidities) with no complications.”

When Extra Help Is Needed

However, more than 40 to 50 percent of patients will have a recurrence of the disease within five years. For that reason, Dr. Calle says, this patient population would potentially benefit from seeing a specialist (either nephrology or urology) at least once.

A urologist and/or nephrologist will determine the exact cause of the kidney stones. Because there are several types of kidney stones and the causes for each vary, knowing this information is critical in determining the best course of treatment and prevention, including medical management of the condition on an ongoing basis.

“Our work as nephrologists is mainly to focus on prevention of the stone and to make sure no other associated diseases are the cause for them or a worsening factor,” Dr. Calle explains. “I believe almost all patients with multiple kidney stones or large kidney stones and associated diseases should have a referral to nephrology for prevention and management of those associated conditions.”

Our Imaging Toolkit

Typically, a urologist or nephrologist will conduct some sort of imaging during the appointment, whether that be a CT scan, X-ray or ultrasound.

Typically, Dr. Calle says, there should be a urine analysis and basic blood work. In cases involving more than one kidney stone or when other associated diseases are possible causes, a 24-hour urine collection may provide useful information.

“While the main focus is on diet and fluids, there are some conditions that require special treatments to handle the risk factors that promote the formation of kidney stones,” Dr. Calle adds. “Most definitely, patients who may have genetic abnormalities causing the stones should be treated by a specialist in the area.”

A Comprehensive Treatment System

Once the cause and type have been determined, there are now highly successful minimally invasive treatments, Dr. Calle says.

At Cleveland Clinic, most patients with stones have the potential to be seen by either specialist (preferably urology in the acute setting or nephrology to begin the workup). Treatment options include ureteroscopy, shock wave lithotripsy (SWL), SWL under conscious sedation and percutaneous nephrolithotomy.

These and other solutions are available to relieve your patients’ kidney stones and return them — pain-free — to your care.

To refer a patient to the Glickman Urological & Kidney Institute, please call 855.REFER.123.