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Friday, April 18, 2014

The American Society of Clinical Oncology has released three new evidence-based clinical practice guidelines on the prevention and management of symptoms that affect cancer survivors: neuropathy, fatigue and depression, and anxiety. The Society notes that these are the first three in a planned series of guidelines on survivorship care, and all are now available online ahead of print in the Journal of Clinical Oncology (specific citations below).

 

The topics came from a comprehensive list of many topics in cancer survivorship care, which was developed by the ASCO Survivorship Guideline Advisory Group, Gary Lyman, MD, MPH, FASCO, FRCP(Edin), Co-Chair of that committee, explained via email. The topics were then ranked in terms of importance and need in a survey, which included experts on the Guideline Advisory Committee and others.

 

“These three topics were at the top of the list and were considered a good starting point for developing what will become a large ASCO portfolio of survivorship guidelines,” he said, adding that he was not able to say when future guidelines would be released, but they are in the works. Lyman also serves as Co-Director of the Hutchinson Institute for Cancer Outcomes Research in the Public Health Sciences and Clinical Research Divisions at Fred Hutchinson Cancer Research Center, as well as Professor of Medicine and Medical Oncology at the University of Washington School of Medicine.

           

Chemotherapy-Induced Peripheral Neuropathy

The first guideline provides recommendations for prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) (doi: 10.1200/JCO.2013.54.0914). The guideline is based on evidence from 48 randomized controlled trials for the treatment of CIPN with primary outcomes being the incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life.

 

Key recommendations are:

  • Based on a lack of high-quality, consistent evidence, no established agents are recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with cancer undergoing treatment with neurotoxic agents—but the following agents may be offered for prevention: acetyl-L-carnitine, amifostine, amitriptyline, calcium and magnesium (CaMg), dietyldithio-carbamate, glutathione, nimodipine, Org 2766, all-trans retinoic acid, recombinant human leukemia inhibitory factor (rhuLIF), and vitamin E;
  • Venlafaxine is not recommended for routine use in clinical practice for prevention of CIPN (due to a lack of strong enough data to supports its utility); and no recommendations can be made on the use of N-acetylcysteine, carbamazepine, glutamate, glutathione (GSH) for patients receiving cisplatin or oxaliplatin-based chemotherapy, goshajinkigan, omega-3 fatty acids, or oxycarbazepine for the prevention of CIPN;
  • Clinicians may offer duloxetine to patients experiencing CIPN;
  • No recommendations can be made at this time regarding the use of acetyl-l-carnitine (ALC), tricyclic antidepressants, gabapentin, or the topical gel treatment containing baclofen, amitriptyline, and ketamine—although the guideline notes that some of those agents may be tried in some patients who meet the criteria specified in the guideline.

The guideline was developed by an ASCO Expert Panel that was co-chaired by Dawn L. Hershman, MD, Associate Professor of Medicine in the Division of Hematology/Oncology at Columbia University Medical Center, and Charles L. Loprinzi, MD, Professor of Oncology at Mayo Clinic.

           

Fatigue

The second guideline provides recommendations on screening, assessment, and treatment approaches for adult cancer survivors experiencing fatigue (doi: 10.1200/JCO.2013.52.4611). The document notes that the guideline is based on an adaptation of a Pan-Canadian guideline on fatigue and two National Comprehensive Cancer Network guidelines on cancer-related fatigue and survivorship.

 

The guideline was written using the method created by the ADAPTE Collaboration (an international group of researchers, guideline developers, and guideline implementers), and development of the guideline was led by an ASCO Expert Panel co-chaired by Julienne E. Bower, PhD, Assistant Professor of Psychiatry and Biobehavioral Sciences Health Psychology at David Geffen School of Medicine at UCLA, and Paul Jacobsen, PhD, Associate Center Director of the Division of Population Science at Moffitt Cancer Center.

 

The key recommendations are categorized in three areas:

  1. Screening:  All patients should be screened by health care providers for fatigue from the point of diagnosis onward, including following completion of primary treatment, then as clinically indicated and at least annually (and should be documented using a quantitative or semi-quantitative assessment);
  2. Assessment:  Health care providers should assess fatigue history, disease status, and treatable contributing factors in cancer patients; and
  3. Treatment and Care Options:  All patients should be offered education about fatigue following treatment (including the difference between normal and cancer-related fatigue, persistence of fatigue after treatment, and causes and contributing factors); patients should be offered advice on general strategies that help manage fatigue; and if treated for fatigue, patients should be followed and re-evaluated on a regular basis to determine whether treatment is effective or needs to be reassessed.

The fatigue guideline also recommends that clinicians encourage physical activity for cancer patients post-treatment as a way to help reduce cancer-related fatigue), and the guidelines make recommendations for psychosocial, mind-body, and pharmacological interventions that may be effective for reducing the condition.

           

Anxiety & Depression

The third new ASCO guideline provides recommendations on screening, assessment, and care of psychosocial distress—including depression and anxiety—in adults with cancer (doi: 10.1200/JCO.2013.53.4495). The guideline is based on an adaptation of the Pan-Canadian Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults with Cancer, also using the ADAPTE method.

 

The ASCO Expert Panel who developed the guideline was co-chaired by Barbara L. Andersen, PhD, Professor at Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and Julia Howe Rowland, PhD, Director of the Office of Cancer Survivorship at the National Cancer Institute.

 

Key recommendations are:

  • All patients with cancer and cancer survivors should be evaluated for symptoms of depression and anxiety at periodic times across the trajectory of care (and assessment should be performed using validated measures;
  • Supportive care services (e.g., education about normalcy of stress in the context of cancer, signs and symptoms of distress, stress reduction strategies, and fatigue management) should be offered to all survivors;
  • Depending on the levels of symptoms reported, more specific treatment pathways are recommended in the guideline—and the guideline notes that failure to identify and treat anxiety and depression in the context of cancer increases the risk for poor quality of life, and potentially increased disease-related morbidity and mortality;
  • Health care providers should assess follow-through on referrals and compliance with treatment recommendations (as the guideline notes, it is common for patients with symptoms of depression and/or anxiety to disregard such recommendations); and
  • Health care practitioners implementing the recommendations should first identify the available resources in their institutions and community for the treatment of depressive and anxiety symptoms (availability and accessibility of supportive care services being important in preventing or reducing the severity of these symptoms).

Thursday, April 17, 2014
 
The U.S. Food and Drug Administration has approved Arzerra (ofatumumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate.

 

Arzerra is a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops. The drug had been granted breakthrough therapy designation last year (OT 10/10/13 issue).

 

The drug’s approval is based on results from a Phase III study of 447 patients with previously untreated CLL (and for whom fludarabine-based therapy was considered inappropriate by study investigators).

 

The data showed a statistically significant improvement in median progression-free survival in patients who received Arzerra and chlorambucil compared with patients who received chlorambucil alone (22.4 months versus 13.1 months, respectively).

 

The most common adverse events for patients receiving Arzerra were neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Infusion reactions were seen in 67 percent of patients receiving Arzerra, 10 percent being grade three or higher.

Arzerra is being developed under a co-development and collaboration agreement between Genmab and GlaxoSmithKline.


Thursday, April 17, 2014

 

The U.S. Food and Drug Administration has granted orphan drug designation to volasertib for the treatment of acute myeloid leukemia (AML). The drug—an investigational inhibitor of polo-like kinase (Plk)—is currently being evaluated for safety and efficacy in a Phase III clinical trial for the treatment of patients who are 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

 

The Orphan Drug designation—to encourage development of drugs in the diagnosis, prevention, or treatment of a medical condition affecting fewer than 200,000 people in the U.S.—grants a product market exclusivity for a seven-year period if the sponsor complies with certain FDA specifications, as well as tax credits and prescription drug user fee waivers. The designation does not, though, shorten the duration of the regulatory review and approval process.

 

About 18,860 new cases of AML are expected to be diagnosed this year, according to estimates from the American Cancer Society. The average age at diagnosis is 66.

 

Volasertib (Boehringer Ingelheim Pharmaceuticals, Inc.) received the FDA’s Breakthrough Therapy Designation in 2013 based on Phase I and II trial data (OT 10/25/13 issue), which is expected to be published later this year, according to a news release from the drug company.


Tuesday, April 15, 2014

BY KURT SAMSON

 

Asking bone marrow recipients to rate their breathing difficulties on a scale of 0 to 3 appears to identify lung involvement due to graft-versus-host disease (GVHD) and predict overall survival, including non-relapse mortality, researchers have found.

 

Reporting in the journal Biology of Blood and Marrow Transplantation (2014;20:337-344), a team led by Stephanie J. Lee, MD, MPH, Professor of Oncology at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, conducted a prospective analysis of 1,591 visits by 496 patients at various treatment centers. The results showed a clear association between increased mortality among patients with worse breathing scores, but even those with less pronounced problems had shorter survival than those without any problems.

 

The study, part of the Chronic GVHD Consortium, included patients recently diagnosed with chronic GVHD as well as those who had had it for several years.

 

For marrow recipients, the likelihood of developing chronic GVHD is in the range of 30 to 50 percent, and of those who do develop it, about 15 to 20 percent have lung involvement, the team noted.

 

In 2005 the National Institutes of Health recommended testing lung function in patients with chronic GVHD, using both pulmonary function tests and symptom assessment, including a three-point questionnaire – 0 for no symptoms, 1 for shortness of breath walking up stairs, 2 for shortness of breath while walking on flat ground, and 3 for shortness of breath when resting or when oxygen therapy is necessary.

 

A comparison of survival rates with clinician- and self-reported lung function based on this technique revealed that a score of 3 was strongly associated with short survival, but that even patients with a score of 1 or 2 had worse outcomes than those with a score of 0.

 

The results showed that the questionnaire outperformed other tests typically used to assess lung function, including spirometry, lung volume measurement, lung diffusion capacity, and measurement of oxygen levels.

 

Pulmonary function test (PFT) data, including the higher lung function score (LFS) and obstructive physiology, were not associated with overall survival or non-relapse mortality, nor was a diagnosis of bronchiolitis obliterans syndrome (BOS).

 

In the study, lung function scoring was based on forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). Obstructive disease was defined as a decreased FEV1 (tested at <50%, <75%, and <80%) and FEV1/FVC of less than 0.70.

 

Obstructive physiology (FEV1<80%) was found in 184 patient visits, and 54 visits (6%) had FEV1< 50%.  BOS was reported on 122 visits. Median follow-up time was 20 months, with a range of 2.9 to 47.7 months. Median survival had not been reached by the time of the paper’s publication.

 

The researchers cautioned that there were limitations regarding inconsistent practices in performing the tests, and that of the 1,591 patient visits used in the analysis, only half had recorded PFTs.

 

Could Hasten Treatment

Use of the questionnaire scoring system could help physicians identify early GVHD lung problems and hasten treatment to reduce or manage symptoms, said Lee, who provides hematopoietic cell transplants for patients with leukemia and myelodysplastic syndromes.

 

“The results put us on notice to be more careful and attentive to lung symptoms in people with chronic GVHD,” she said in an interview. “A poor score can also serve as a reminder to make sure the patient has had a pneumonia vaccination and is taking other precautions to minimize ongoing loss of lung function.

 

“It is important that we pay closer attention to patients with poor lung scores. If we can identify patients when they first develop lung problems, we can try to intervene and prevent severe loss of lung function. Currently, physicians tend to focus on other health issues, but we need to look at the entire spectrum of this disease, and lung function needs more attention.”

 

Patients need to be asked directly about any breathing problems, she emphasized, although this can be difficult because lung involvement typically evolves slowly and patients often get used to symptoms or attribute them to other causes like not exercising, she said.

 

“Not all breathing problems can be attributed to GVHD, but the combination of chronic GVHD and lung symptoms is concerning. Patients with chronic GVHD should be asked at every clinic visit whether they have noticed any shortness of breath.”

 

She said that because the research team now has a large number of patients and stored blood samples, they are looking to collaborate with other investigators to better understand lung involvement in chronic GVHD.

 

“Researchers are searching for other ways to identify patients at higher risk of lung involvement as well as possible biomarkers in the blood,” she noted. There is a lot of activity in this field, especially for biomarkers, and there are a lot of leads.”

 

Questions Remain

What leads up to worsening lung function is unknown, added the study’s first author, Jeanne Palmer, MD, of the Blood and Marrow Transplant Program at the Mayo Clinic in Phoenix, Ariz.

 

How best to identify those who will develop pulmonary complications remains a subject of investigation, she said, and investigators are evaluating CT imagining modalities in this direction. There are also ongoing studies to evaluate the effect of early therapy among patients who show a decline in lung function.

 

In addition to improved screening to identify patients when they have subclinical disease, improved understanding of the underlying biology is also needed, she said.

 

“The basic takeaway message is that if GVHD is bad enough that a patient has pulmonary symptoms, it correlates with worse outcomes, and we need to identify these patients before they develop pulmonary symptoms.”

 

Greater Awareness Needed

Asked for his opinion for this article, Gerhard Carl Hildebrandt, MD, Medical Director of the Huntsman Cancer Hospital Blood and Marrow Transplant Program and Associate Professor of Medicine, at the University of Utah,  said the paper should help raise awareness of the potential for lung involvement in GVHD.

 

“This is a very important paper because it highlights the fact that the lungs are a potential target organ and confirms clinical observations of this issue over the long-term,” he said. “The study illustrates not only that these patients might be at risk, but that both patients and physicians to be more aware of the potential for lung involvement.”

 

He said most primary care physicians presented with a patient experiencing breathing problems typically assume that there is an infection, but they need to be aware that the lungs are sensitive to GVHD in transplant recipients for years after treatment. Physicians need to ask the appropriate questions and test patients for lung function, which will in turn provide more data for researchers and transplant centers.

 

“This simple questionnaire can provide primary care doctors with an easy way to ask patients about pulmonary symptoms and document potential GVHD lung involvement,” he said.

 

Regarding the study limitations, he also noted that the follow-up period was too short to gauge the full scope of the scoring system, and the lack of LFT data in about one-third of the trial subjects was also problematic.

 

“Many centers do ongoing serial lung function testing of all transplant recipients,” he said. “At our center we test them at three, six, 12, 18, and 24 months after a transplant, and then annually afterwards, and we also exclude infection at each visit. Some centers do not do, and a general advisory for annual testing would be welcomed.”


Monday, April 14, 2014

 

BY ED SUSMAN

 

HOLLYWOOD, Fla. -- An oral antidote to life-threatening toxicity from the rare situation of fluorouracil (5-FU) overdose or hypersensitivity appears to be highly successful, researchers reported here at the National Comprehensive Cancer Network conference.

 

The investigational drug, uridine triacetate, was successful in 97 percent -- 128 of 132 -- cases of 5-FU overdose caused by errors in dosing, infusion pump malfunctioning, or excess ingestion of oral 5-FU sources such as capecitabine, said Michael Bamat, PhD, Vice President of Research and Development at Wellstat Therapeutics Corporation in Gaithersburg, Md.

 

In the time since his poster study was presented in March, there have been five additional cases that came to the team’s attention, Bamat said in a follow-up interview, and the treatment has been successful in 133 of these incidents.

 

He explained that usual treatment for 5-FU toxicity has been best supportive care, but unfortunately, historical data suggest that this strategy is often unsuccessful. In his poster presentation at the NCCN meeting, researchers determined that in a historical control group of 40 patients with 5-FU toxicity, just four patients achieved a complete recovery. The rest of these patients died. Information on dosages and outcomes for the historical 5-FU overdose cases were obtained from publicly available reports, he noted.

 

“These clinical data illustrate the serious, debilitating, and life-threatening nature of 5-FU overexposure and the need for safe, effective antidotal treatment,” he said in the interview.

 

Very Rare, but Accidents Do Occur

Asked for her opinion, Edith Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Fla., said, “The risk of 5-FU overdose is extremely low. All chemotherapy units should have carefully outlined procedures to prevent incorrect doses of chemotherapy being given to patients.”

 

Nevertheless, accidental overdoses of 5-FU occur. Bamat cited National Institutes of Health estimates that 275,000 cancer patients are treated with 5-FU every year, and that 8,250 of these patients develop serious toxic reactions and that more than 1,300 patients die each year from 5-FU overexposure.

 

He said that about 60 percent of the cases that have been treated with uridine triacetate were caused by miscalculation or mismanagement of the intravenous delivery. Because 5-FU is administered at or near its maximum tolerated dose over one to four days, life-threatening or lethal toxicity can be caused by these pump-related errors, he said.

 

In addition, there are other patients who have dihydropyridimine dehydrogenase (DPD) deficiency and other forms of 5-FU elimination or hypersensitivity that can also result in serious or lethal toxicity following standard doses of infusional 5-FU or oral capecitabine. For example, unusual susceptibility to 5-FU can result in severe and sudden onset cardiac and/or neurological toxicities, he said, noting that 10 of the patients treated in his case series have been found to have DPD deficiency. Six children were included in the study.

 

Over-ingestion of capecitabine has also been a cause of overdose, including some cases in which patients attempted to commit suicide by ingesting capecitabine in lethal amounts.

 

Uridine, Bamat explained, is a direct biochemical antidote for 5-FU poisoning, but the drug has poor oral bioavailability, and complications during its infusion preclude use of uridine itself as a viable antidote. Hence, the researchers developed uridine triacetate as an orally available prodrug of uridine. Uridine triacetate is rapidly converted to circulating uridine by deacetylation.

 

The agent is administered at a dose of 10 grams every six hours for 20 doses in adults and at an equivalent dose of 6.2 grams/m2 every six hours for 20 doses. Treatment with uridine triacetate was initiated seven to 96 hours following the end of treatment with fluorouracil.

 

Based upon data collected to date, uridine triacetate appears to provide clinical benefit to patients even in cases where a lethal outcome otherwise would have been expected,” he said.

 

The patients in the study were treated after their physicians contacted the company to use the drug in a Food and Drug Administration-approved expanded access protocol for emergency use. Uridine triacetate was administered seven to 96 hours after 5-FU treatment was halted.

 

About half the patients were able to resume their chemotherapy regimens within three weeks after overexposure, Bamat reported. In addition, treatment with uridine did not appear to cause serious adverse events. The adverse events that did occur were considered mild, and many of the patients treated with uridine triacetate had no adverse events at all.

 

Uridine triacetate had previously received Orphan Drug designation as an antidote to treat patients at risk of excess 5-FU toxicity from both the Food and Drug Administration and the European Medicines Agency. Bamat said the company expects to file a New Drug Application for uridine by the end of the year.

 

A Phase III study is not possible in a treatment that is based on emergency overdose, he added. “When we submit our application for approval of uridine triacetate it will include the number of patients treated and their outcomes. We are continuing to treat patients under the expanded access program.”