Online First/Online Only
Articles/items published ahead of print or only online.
Saturday, April 18, 2015
BY ROBERT H. CARLSON
A pharmacist-led medication assessment of geriatric cancer patients found a high prevalence of polypharmacy, excessive polypharmacy, and potentially inappropriate medication, according to the report online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.58.7550).
The researchers, from Thomas Jefferson University's Jefferson School of Pharmacy, reported that among 234 geriatric cancer patients:
· 41 percent were taking five to nine medications (including prescription, non-prescription, and complementary medications and supplements, but not cancer treatments);
· 43 percent were taking 10 or more medications, and
· 51 percent were taking potentially inappropriate medication.
The mean number of medications used by each patient in this study was 9.2; the mean age of patients was 80, and approximately two-thirds were female.
A comprehensive medication review is considered to be an integral part of the geriatric oncology assessment, but current guidelines do not state which health care professional should be performing the medication assessment, the researchers wrote.
“Physicians should be aware that a high percentage of patients are taking five or more concurrent medications, which increases the risk for adverse drug effects, drug-drug interactions, and non-adherence as a result of increased pill burden and regimen complexity,” the first author, Ginah Nightingale, PharmD, Assistant Professor in the Department of Pharmacy Practice at Jefferson, said in an e-mail exchange.
A comprehensive medication assessment should be done prior to anti-cancer therapy initiation and then periodically, she said. Because some senior adult oncology patients may have a poor prognosis or a diagnosis of terminal cancer, a comprehensive medication assessment is important to adjust or reduce the use of unnecessary medications.
“The focus of the assessment should be on prioritizing the patients’ goals of care, such as relieving symptoms and maintaining functionality.”
The most prevalent potentially inappropriate medications were benzodiazepines, gastrointestinal medications, NSAIDs, antiplatelet medications, and first-generation antihistamines.
Specific co-morbidities associated with those potentially inappropriate medications were cardiovascular, neurologic, and psychiatric conditions.
Nightingale said that including prescription, non-prescription, and complementary medications and supplements in the study did not overstate the problem of polypharmacy. Rather, “it provides a more transparent sneak peek of what’s in the 'medicine cabinet' of the cohort of senior adult oncology patients seen at our center, a sense of the landscape of their medication use.”
She noted that a patient can meet the criteria for excessive polypharmacy and not be on a potentially inappropriate medication, although the study did show that the more medications a patient takes the greater the potential for inappropriate medication use.
Potentially inappropriate medications were identified using the 2012 Beers Criteria, the Screening Tool of Older Person's Prescriptions (STOPP), and the Healthcare Effectiveness Data and Information Set (HEDIS). The researchers recommended the development of a medication assessment tool that integrates the 2012 Beers and STOPP criteria and said that clinicians should also consider cancer diagnosis, prognosis, and cancer-related therapy.
She noted that the 2012 Beers criteria are currently being updated by the American Geriatric Society, with the 2015 version scheduled to be released this summer.
She said her research team is awaiting this update, and is also evaluating the draft of the National Comprehensive Cancer Network update for the guidelines for treatment of older adults with cancer, which also address some of the limitations associated with the 2012 Beers criteria.
Nightingale and her coauthors acknowledged in the article that this single-institution study had a small sample size compared with previous studies and did not include any anticancer treatments or cancer-related therapies.
Also because medication use in this population changes continuously, especially for patients who will begin anticancer and/or supportive care-related therapies, follow-up data on the acceptance of pharmacist interventions would further strengthen the study findings, the paper stated.
“The literature shows that pharmacists are underused in the ambulatory oncology setting and have an opportunity to play a critical, long-term role in providing safe, effective, and affordable medication-related care,” Nightingale said.
‘We All Need to Be Geriatric Oncologists’
“All adult oncologists are now geriatric oncologists,” noted the author of an accompanying editorial (JCO: doi: 10.1200/JCO.2014.60.3548), Stuart M. Lichtman, MD, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College.
Geriatric oncology is no longer a niche field with only a few dedicated researchers. “Clinicians should not fear the words 'geriatric assessment.”
He elaborated in an e-mail exchange: “The fear of geriatric assessment is multiple: not enough time, not enough knowledge; and being uncertain how to use the information and not sure of its importance.”
Geriatric assessment should no longer be the purview of the geriatrician, but will need to be incorporated into daily practice in all oncology fields, he said.
“We all need to become well-educated geriatric oncologists,” he said, but he added that it's going to take time for physician education to catch up.
Standard medical practice now incorporates drug use as part of routine evaluation, but it is well established that the traditional oncology evaluation is not adequate, and will fail to uncover many specific problems. “But with minor modifications this can be made to focus on older patients,” he said.
Discontinuing unnecessary medication is the most important thing, Lichtman said, particularly drugs like statins to lower cholesterol. “Does an older patient with advanced cancer really need statins?”
Lichtman said the study by Nightingale and colleagues highlights an important aspect of geriatric assessment in patients with cancer: “Evaluating polypharmacy by using the accepted guidelines is one way clinicians can begin to feel comfortable with geriatric evaluation and make a tangible impact on patient care.”
Friday, April 10, 2015
BY HEATHER LINDSEY
Ten quality indicators identified by the American Academy of Hospice and Palliative Medicine (AAHPM) and the Hospice and Palliative Nurses Association (HPNA) may help patients receive the best possible palliative and end-of-life care, according to the initial recommendations of the organizations’ consensus project, Measuring What Matters (MWM), published in the April issue of the Journal of Pain and Symptom Management (2015;49:773-781). The measures were developed so they can be applied to a variety of specialties, but may also have a direct application to oncology.
“We embarked on this project because we recognized a need among patients and their families,” said Joseph D. Rotella, MD, MBA, HMDC, FAAHPM, Co-chair of the MWM Clinical User Panel and AAHPM’s Chief Medical Officer. While there are more than a hundred published measures related to palliative and hospice care quality, there is no consistency among programs across the country regarding which measures are being used, he explained. Consequently, making sense of a patient’s experience is difficult.
The 10 measures range from an assessment of physical, psychological, social, spiritual, and functional needs, to having patients’ treatment preferences followed.
“If we could get programs around the country using some of the same measures, then we could develop benchmarks and best practices,” he said. Using the same quality indicators could also help physicians to more easily share information, which could then lead to the development of the next generation of measures.
‘Reasonable Starting Point’
Robert M. Taylor, MD, FAAN, FAAHPM, Associate Professor and a pain and palliative medicine physician at Ohio State University Comprehensive Cancer Center—Arthur G James Cancer Hospital and Richard J Solove Research Institute, called the 10 measures a reasonable starting point for assessing palliative and hospice care--. “It’s a challenge to come up with measurements that matter.”
And while these indicators are a good initial effort, they do have several limitations for measuring palliative care in the oncology setting, noted James T. D'Olimpio, MD, FACP, FAAHPM, Director of Supportive/Palliative Oncology and the Cancer Pain and Symptom Control Service at North Shore University Hospital in New York.
For this consensus project, paper authors evaluated 75 scientifically validated measures and determined which 10 would be the most meaningful to patients and their families for managing their palliative and hospice care needs.
Rotella explained that the team looked for indicators that are actionable, meaning that they can be directly assessed and used to improve quality of care. The indicators are also balanced to include pain and symptom management, health care decision-making, and spiritual and emotional needs, and to reflect the National Consensus Project (NCP) Palliative Care Guidelines domains.
The researchers narrowed the list of 75 measures through a modified Delphi rating process. A technical advisory panel judged the strength of the indicators, while a clinical user panel determined which were most clinically relevant.
Overall, the measures are intended to help palliative care and hospice providers systematically evaluate the effectiveness of their programs and to develop strategies to keep improving practice, ensuring that patients and families get the very best care possible across settings, Rotella said.
The authors evaluated "a huge body of work from the past 30 years and found the measures that make the most sense and have the most meaning in the context of clinical care," said Charles von Gunten, MD, Vice President of Hospice and Palliative Care at OhioHealth. “They synthesized what can be used in routine practice.”
Applications to Oncology
While the study is a good first step toward developing indicators for palliative and hospice care, the general measures may be challenging to apply to oncology, D’Olimpio said. Palliative and hospice care need to be integrated into each area of medicine—approaches for oncology patients may be much different from those for congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) patients.
Patients with cancer have a more rapid trajectory of decline toward the last few months of life than those with CHF or COPD, which tend to be associated with a series of losses of function, he added. Ultimately, each medical specialty will likely have its own comprehensive set of palliative and hospice care indicators.
The set of initial 75 measures included some that were specific to cancer patients--for example, those endorsed by ASCO in its Quality Oncology Practice Initiative, Rotella noted. However, when narrowing the 75 to 10, “we had to choose measures that could be used more broadly. I agree that oncologists might want to have certain measures focused just on cancer patients, and many of those measure exist and are used in quality programs.”
Another limitation, D’Olimpio said, was that early referrals and outpatient palliative care management were not thoroughly addressed in this paper.
The authors did not discuss at length the clinical limitations of the measures, “and we’re not at the point where we can take this information and apply it to outpatient practice,” he said. The lack of outpatient quality metrics is the next big challenge in palliative care.
Rotella said that that many of the 10 measures can be applied to oncology patients, whether they are receiving palliative care in the outpatient setting, concurrently with other treatments that have the potential of cure, or at the end of life. For example, measure #2, screening for pain, shortness of breath, nausea, and constipation can be done across all points of cancer care.
Von Gunten agreed: “The measures are applicable all the way through cancer care,” and distinctions between outpatient palliative and end-of-life hospice care don’t make sense clinically when using these measures for oncology patients, he said. “Everyone who walks into an oncologist’s office has needs in the physical--like pain--spiritual, practical and psychological domains, and that’s what these measures assess.”
And while the indicators will be refined over time, using them immediately could help move cancer care forward, he added: “They match what patients and families tell us they’re looking for in cancer care. Comprehensive cancer care is about the person and his or her family and not just the cancer. These measures help to capture this principle.”
Additionally, said Eduardo Bruera, MD, FAAHPM, Founder, Department Chair, and Professor of Palliative Care and Rehabilitation Medicine at the University of Texas MD Anderson Cancer Center, the indicators help in personalizing palliative care for oncology patients: “We have developed exquisite genomic tools for the personalized care of a tumor. These measures are an attempt at personalizing the care of the patient who brings that tumor to the cancer center."
Bruera said that while it makes sense to document palliative care because it ensures that you are caring for patients according to their wishes, there is still the question of how to operationalize this process: “Do you have a way to score some factors of care as more important than others, or to rate an institution based on the presence of having all or some of these indicators present?”
Some of the measures could be established as threshold items that institutions would need to implement to be considered compliant, he said. “Regrettably, we still do not have a lot of research on many of these items.” However, from a patient and family perspective, discussion, screening and treatment of physical symptoms and addressing psychological needs are the most relevant to managing suffering at the end of life.
Next Steps for Measuring What Matters
The next step of the MWM project is to have providers of palliative and hospice care, no matter what setting, to apply two or three of the existing measures to their quality improvement programs. “We want them to experience trying them out and sharing what’s working and what’s not,” Rotella said.
He recommends that the measures be used just as they were designed. For example, half of the MWM measures come from the PEACE (“Prepare, Embrace, Attend, Communicate, Empower”) hospice and palliative care quality measure set; helpful tools and resources for those measures are available online at www.med.unc.edu/pcare/resources.
Using even just a few indicators can help institutions compare “apples to apples, rather than apples to oranges,” Taylor noted.
Rotella said that another future goal for the MWM group is to develop a way to identify patients who would benefit from palliative or hospice care. Many patients are not referred to this form of care or are referred for only a short amount of time before they die.
Additionally, the researchers found no appropriate measures for the important cultural and social domains of care, indicating another gap that needs to be addressed, he said. “Ultimately, we want to be sure that patients get the care that matters the most and that provides the best quality of life.”
10 Palliative and Hospice Care Measures
1. Palliative care and hospice patients receive a comprehensive assessment (physical, psychological, social, spiritual, and functional) soon after admission;
2. Seriously ill palliative care and hospice patients are screened for pain, shortness of breath, nausea, and constipation during admission;
3. Seriously ill palliative care and hospice patients who screen positive for at least moderate pain receive treatment within 24 hours;
4. Patients with advanced or life-threatening illness are screened for shortness of breath and, if positive to at least a moderate degree, have a plan to manage it;
5. Seriously ill palliative care and hospice patients have a documented discussion regarding emotional needs;
6. Hospice patients have a documented discussion of spiritual concerns or preference not to discuss them;
7. Seriously ill palliative care and hospice patients have documentation of the surrogate decision-maker’s name (such as the person who has health care power of attorney) and contact information, or absence of a surrogate;
8. Seriously ill palliative care and hospice patients have documentation of their preferences for life-sustaining treatments;
9. Vulnerable elders with documented preferences to withhold or withdraw life-sustaining treatments have their preferences followed; and
10. Palliative care and hospice patients or their families are asked about their experience of care using a relevant survey.
Friday, April 10, 2015
BY KURT SAMSON
A group of leading lymphoma researchers have issued a list of priorities to improve the current research paradigm and identify future investigational needs.
In a Letter to the Editor in Blood (2015;125:2175-2177), David M. Weinstock, MD, Associate Professor at Harvard Medical School and an attending physician in the Medical Oncology Service at Dana-Farber Cancer Institute, and 11 other lymphoma experts, outline a plan to better address current shortcomings in research approaches and what can be done to improve investigations and collaborations.
The recommendations are the result of a collaborative initiative by the American Society of Hematology, which started the project during a forum on basic and translational science relevant to lymphoma that began at an August 2014 meeting on lymphoma biology. The authors of the letter, members of the meeting’s steering committee, were asked to create a research “roadmap” for future efforts in order to better guide funding, especially requests from the National Institutes of Health, as well as advocacy by ASH and other associated organizations.
“Our goal is to help inform future research directions and funding decisions by partners at government agencies and in the private sector,” said Weinstock, Co-chair of the ASH initiative.
Although almost half of all blood cancer cases are lymphomas, of which there are numerous unique disease subtypes, recent advances have led to better characterization on how lymphoma cells proliferate and interact with other cells and tissues, leading to powerful, targeted therapies with fewer side effects than approaches in the past.
Nonetheless, limitations in research infrastructure, funding, and collaborative approaches present potential challenges in the development of better treatments. The report outlines key priorities for research and infrastructure to improve the understanding of lymphoma biology across its diverse subtypes.
“The roadmap outlines our most pressing needs, that if not addressed will stand in the way of transformative changes in how we study and treat lymphomas,” Weinstock said. “We want to help facilitate and guide collaborative efforts toward the most high-impact areas that might lead to more rapid development of new treatments.”
According to the panel, investigation of individual lymphoma subtypes is largely limited by many of the same issues with other tumors, including inadequate numbers of representative cell lines and in vivo models, including patient-derived xenografts and genetically engineered mouse models; inadequate characterization of the genetic, epigenetic, transcriptional, proteomic, and metabolomic landscape of each subtype; limited interest from the pharmaceutical industry in rare subtypes with poorly understood pathobiology; and insufficient collaboration across centers.
These shortcomings are made more complicated by biologic heterogeneity within each lymphoma subtype, and preclinical studies addressing this heterogeneity will require large numbers of samples and/or models for stratifying patients and validating potential biomarkers, according to the letter.
“So far the response has been somewhat muted,” Weinstock said. “We are inviting clinicians, scientists, advocates, and patients to weigh in on this so that it reflects the input of everyone in the community.”
The panel will share its findings on priorities with funding agencies, advocacy groups, and others who can help address the challenges identified.
Weinstock said that because of the current lack of a coordinated research approach, many lymphoma patients have poor outcomes, including those with mantle cell lymphoma, subtypes of peripheral T-cell lymphoma, and lymphomas that harbor specific genetic markers.
Moreover, the consequences of most genetic mutations remain unclear, making it necessary to develop functional approaches to distinguish driver events and more clearly define critical dependencies that can be exploited therapeutically.
“The most important priority is to developing model cell lines in vivo and cell lines in lesser and more common subtypes,” he said.
Another high priority is developing new prognostic models that incorporate biologically informative predictive factors along with clinical factors to enable patient selection for clinical trials and highlight the biological pathways and mechanisms that can influence therapeutic response.
“Comprehensive investigations of larger collections of clinically annotated patient samples are needed to identify additional determinants of treatment response, and these predictive features will inevitably shift with new therapies,” he said.
“A lot of this research is now being done at academic centers, but because they rely on outside funding there are proprietary reasons to protect their findings--so many institutions are research silos. Once findings are published, much of the data is available to the oncology community, and most cell lines are already in circulation. This is a significant challenge and a major roadblock.”
‘Difficult to Get Everyone on the Same Page’
There is some skepticism that this will change any time soon, Weinstock admitted.
“It is difficult to get everyone on the same page. With some subtypes there are fewer than 1,000 patients, so this is not just hysteria. There have been efforts like this before, but this is the most comprehensive. Targeted immunotherapy has shown promise against some lymphomas and others are being tried. I can almost see the endgame.”
‘A First Step’
Asked for his perspective, Jason Westin, MD, Assistant Professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, said: “I think this is an important first step in getting the lay of the land. Without a consensus it is very difficult to get down to the bare bones of what needs to be done to get big data for cooperative studies.”
Westin has been involved in research on diffuse large B-cell lymphoma; development of systems to identify novel, optimal therapeutic combinations for individual patients, as well as drug synergy, additivity, and antagonism, scale free networks and their role in cancer therapy; and development of highly sensitive disease monitoring methods.
In an article published in January in Future Oncology (2015;11:73-77), he posed the question of what complex networks, such cancer cells, airplane flight patterns, and the Internet share in common. The answer? All have both remarkable robustness and great vulnerability.
“Complex networks follow remarkably similar patterns across seemingly unconnected fields, and it is possible that cancer researchers could thus learn from the advances in complex network theory,” he wrote, noting that very limited but coordinated specific targeting of the most critical parts of such networks can have dramatically outsized effects.”
He said that developing a coordinated and systematic approach is very difficult--“but the more we cooperate, the more we understand how to do it. All of the authors of this plan are really leading researchers in lymphomas, but the proof is in the projects that may result.”
He said that creating central repositories of tissues and cells in patients who do well or not is especially important for future research because most studies undertaken have relatively small sample sizes.
“Sharing this data and samples in an open-format central repository would be huge,” especially because of the increasing robustness of data from tissue samples fixed in formalin.
Even so, Westin continued, it will take some effort to build this due to potential resistance from individual research groups at institutions with a stake in protecting their findings until publication.
“This is one main stumbling block as I see it, but it could be done if such data, especially genomic information about patients, were somehow protected.”
There are a number of good precedents for such an approach, especially the Cancer Genome Atlas at NIH, he noted: “I would really like to change this. I am not sure it will happen tomorrow, but the more we try, the more value will become apparent. This roadmap lays the groundwork and it may take years, but ultimately it is the patients who will benefit.”
The other coauthors of the Roadmap letter in Blood are: Riccardo Dalla-Favera, Randy D. Gascoyne, John P. Leonard, Ronald Levy, Izidore S. Lossos, Ari M. Melnick, Grzegorz S. Nowakowski, Oliver W. Press, Kerry J. Savage, Margaret A. Shipp, and Louis M. Staudt.
The plan identifies the following priorities in infrastructure and research:
· Develop an adequate number of disease models for each lymphoma subtype;
· Establish a central repository of biospecimens, cell lines, and in vivo models with open access; and
· Organize patient advocacy to support research.
· Catalogue how lymphoma cells differ across disease subtypes;
· Better define and identify mutations and other abnormalities associated with the disease;
· Develop strategies to identify high-risk patients who may benefit most from clinical trials;
· Enhance efforts to use immune therapies to cure lymphoma; and
· Better understand how lymphoma cells communicate with normal cells.
From Weinstock et al: Blood 2015;125 (13):2175-2177
Friday, April 10, 2015
BY KURT SAMSON
Although it occurs in only a small number of melanoma patients, immunotherapy-induced vitiligo-like depigmentation appears to be a sign of reduced risk of disease progression and increased survival, according to a review of the medical literature published in the Journal of Clinical Oncology (2015;33:773-781).
The researchers, from the Netherlands Institute for Pigment Disorders, note that although research specifically addressing vitiligo is very limited, such patients have two to four times less risk of disease progression and death, respectively, compared with patients who do not develop vitiligo from treatment.
The team reviewed data on 5,737 patients with stages III to IV melanoma treated with immunotherapy that had autoimmune toxicity and/or vitiligo between 1995 and 2013. Included were 11 papers on general immune stimulation, 84 on vaccine-associated vitiligo, 28 on antibody-based treatment studies, and 16 on adoptive transfer trials.
The researchers—first author was Hansje-Eva Teulings, MD—found that in 27 studies the cumulative incidence of vitiligo was 3.4 percent and was significantly associated with progression-free melanoma outcomes. In 85 of 139 treatment arms, patients developed vitiligo-like depigmentation on immunotherapy and 304 of 5,737 patients developed vitiligo. Adoptive transfer of cytotoxic T-lymphocyte therapy accounted for most cases (6.3%).
The senior author, Rosalie M. Luiten, PhD, Professor of Dermatology, noted that in a small number of patients, vitiligo-like depigmentation is caused by strong anti-melanoma immunity that also targets healthy melanocytes. One large prospective, hospital-based, observational study found a cumulative incidence of 2.8 percent in 2,954 patients with different stages of melanoma, regardless of treatment.
“Our study shows that the development of vitiligo in melanoma patients receiving immunotherapy significantly correlates with prolonged survival,” she said. “Vitiligo is a clinically relevant parameter for the success of immunotherapy in melanoma. This is important because immunotherapy is currently one of the greatest breakthroughs in cancer therapy. Considering the low response rate of patients to immunotherapy, the priority of the field is finding biomarkers of therapy responsiveness.”
Luiten noted that many clinical studies fail to report the presence or absence of vitiligo development, so the study may underestimate its frequency in advanced melanoma patients. Also, little is known about the incidence of vitiligo in melanoma patients or the relationship with clinical outcome in general, because most evidence comes from individual studies or case reports.
“We recommend that physicians consider vitiligo when treating melanoma patients and register this information in national melanoma treatment registries. This will enable more precise measurement of the frequency of vitiligo in current and future clinical studies.”
Immune-related adverse effects after melanoma immunotherapy have been associated with increased clinical efficacy. Vitiligo-like depigmentation is a relatively harmless type of autoimmunity that can occur spontaneously in patients with melanoma or when they are on immunotherapy.
Current Prognostic Biomarkers
Current prognostic biomarkers in melanoma are based on the American Joint Committee on Cancer TNM staging system and include Breslow tumor thickness, ulceration, extent of nodal involvement, site(s) of distant metastases, and serum lactate dehydrogenase, all of which are associated with general disease progression and survival.
“Our review shows that the development of vitiligo in melanoma patients receiving immunotherapy significantly correlates with prolonged survival,” Luiten said. “This means that vitiligo is a clinically relevant parameter for the success of immunotherapy in melanoma patients. Response-predictive biomarkers to immunotherapy are scarce, and a prognostic factor to evaluate outcomes in melanoma treated with immunotherapy is needed.”
She added that the study’s limitations are similar to those with any large-scale review of the medical literature--The researchers had to combine survival and vitiligo development data across studies, with outcome definitions that vary across studies. More significant was that the vitiligo was observational and based on the each investigator’s level of awareness of vitiligo. Vitiligo was not an outcome parameter in any of the studies.
“No randomized studies and only a few Phase III studies were included because of a lack of grade 1 or 2 autoimmunetoxicity evaluations. The studies described only the absence or presence of any autoimmune toxicity defined as vitiligo negative,” she said.
Moreover, the researchers reported that dermatologists were not typically involved in the studies they reviewed, and it is not clear to what extent oncologists accurately diagnose vitiligo in patients with fair skin types.
Recommendation to Use Wood’s Lamp
The research team recommend that all future prospective immunotherapy studies in patients with melanoma should include complete skin examinations by a dermatologist using a Wood’s lamp--a hand-held fluorescent lamp that emits long-wave ultraviolet A light, which delineates areas of pigment loss--both at baseline and other time periods.
“Taken together, our results show a favorable effect of vitiligo induction as a relevant clinical parameter in patients with end-stage melanoma receiving immunotherapy,” she said.
Greater awareness of vitiligo induction in melanoma patients by oncologists may help better recognize patients with effective anti-melanoma immunity, and may influence their treatment options and prognosis, she added.
“To draw better conclusions in immunotherapy studies, we recommend the use of the immune-related adverse events criteria and reporting vitiligo systematically on an individual patient data level--in addition to monitoring of immune responses--in future melanoma immunotherapy studies.
Asked for his perspective, William Sharfman, MD, Associate Professor of Oncology and Clinical Co-director for Oncology at the Johns Hopkins Melanoma Program of Sidney Kimmel Comprehensive Cancer Center, said he was not surprised at the findings, which have been known for some time.
“What is surprising is that so few patients develop the condition,” he said. “Even with the most active therapy, only about two percent of patients develop the skin condition, and I believe that figure is more accurate. I did not find the paper terribly helpful. It was a review of earlier trials, not an actual analysis of new research.”
His areas of clinical expertise include cutaneous oncology, dermatology, gastrointestinal cancers, and immunotherapy, and he helped create the Johns Hopkins Melanoma Program in 1994.
He said the incidence of vitiligo is not becoming more common, and does not think that vitiligo helps prospectively predict who will get the disorder or what their risk actually might be.
“It is an interesting phenomenon, though. If treatment is killing melanocytes, the incidence of vitiligo in general is lower than expected, but I do not that this new data helps quantify the effect or choice of treatment.”
He added that is to be expected that rates would be lower in African-Americans because they have naturally higher melanin content in their skin.
“In my experience I do not remember any African-American patients developing vitiligo. Most are Caucasian patients, and what they experience is quite striking. So this new information does not change much from my clinical perspective.”
Thursday, April 09, 2015
BY HEATHER LINDSEY
The incidence of fractures is higher in patients with cancer who have undergone a hematopoietic stem cell transplant (HSCT) compared with individuals in the general population, according to new research now available online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.57.8195).
“Our results highlight that the risk of bone loss and fractures is a significant problem during the survivorship period following HSCT,” said the study’s corresponding author, Huifang Lu, MD, PhD, Associate Professor and Director of the Bone Health Clinic at the University of Texas MD Anderson Cancer Center. Published literature has shown that bone loss occurs early and rapidly after HSCT, although those earlier studies were small and of short duration, she added.
Fractures can lead to morbidity and mortality, but identifying patients at high risk and instituting treatment early on can potentially prevent this, Lu explained.
Asked for her perspective, Theresa Hahn, PhD, Professor of Oncology at Roswell Park Cancer Institute, said she considered the study to be well done, conducted with a large cohort of patients over a long period of time, and to have a strong statistical analysis. The paper may also help oncologists identify HSCT recipients who need to be monitored for fractures, she said.
To determine the rate of fractures because of bone loss, Lu and her colleagues conducted a retrospective study of 7,620 patients older than 18 who had received an HSCT at MD Anderson between January 1, 1997, to December 31, 2011; patients were observed until December 31, 2013.
The investigators compared the age- and sex-specific incidence rates per person-year of fracture with those reported for the U.S. general population, using the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey.
Overall, eight percent (602) of patients developed a fracture, including 11 percent (419) of patients who received an autologous transplant and five percent (183) of individuals who underwent an allogeneic procedure. Vertebral fractures (53%) were slightly more common than nonvertebral fractures (47%).
The estimated relative risk of having a fracture for women who had had a stem cell transplant was about eight times higher than in the general U.S. female population age 45 to 64, when compared with the two population databases. Men who underwent stem cell transplant who were 45 to 64 years old had an estimated relative risk of fracture seven to nine times higher than in the general U.S. male population.
The age of the patients who experienced fractures was surprising, Hahn said: “You wouldn’t be expecting a higher number of fractures in people in their 40s, 50s, and early 60s.”
After univariate cause-specific hazard models, being older than 50 at the time of transplant, having multiple myeloma, solid organ tumors, and autologous transplant were associated with a higher hazard of developing a fracture.
Multivariable models showed that compared with patients with other hematologic cancers, the risk of fracture among individuals with myeloma was five times higher. The risk was 1.6 times higher among those with solid organ and other tumors.
Additionally, patients who underwent autologous transplantation were 45 percent more likely to develop a fracture than those who underwent an allogeneic transplant. Lu said that she and her colleagues are currently exploring why the risk of fracture was higher in patients who received autologous transplant.
Oncologists need to ask whether the cancer is predisposing patients to fractures, or whether some other disease process is occurring, said Philip McCarthy, MD, Professor of Oncology and Internal Medicine and Director of the Blood and Marrow Transplant Center at Roswell Park Cancer Institute: “Is it the transplant itself, or the therapy that predisposes patients to bone loss?”
The immunosuppressive drug cyclosporine, radiation, intestinal injury from transplantation that causes poor calcium intake, not enough sun exposure, and not exercising enough are all reasonable explanations for why fractures may be occurring in transplant patients, said Joseph Antin, MD, Chief of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute.
Hahn noted that another possibility is the use of corticosteroids, more commonly used in the allogeneic transplant setting.
Also asked his opinion, Frederick Singer, MD, Director of the Endocrinology and Bone Disease Program at the John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California, said: “Steroids have a large influence on bone. You can get fractures without major apparent bone loss since the quality of bone is also affected.”
Another consideration is that most of the fractures in the study occurred in patients with multiple myeloma, who experience breaks as part of their condition, Antin noted. “Oncologists who are treating multiple myeloma expect to see skeletal complications.”
Myeloma patients are also more commonly treated with autologous transplant, Hahn pointed out. This may be one reason why there was a higher rate of fractures in the autologous transplant group in the study.
The transplant data in the study also includes women with breast cancer, who used to undergo autologous procedures for their malignancies, McCarthy said, adding that this treatment approach is no longer used. Specifically, of the 801 patients who underwent an HSCT for a primary solid tumor, 46 percent had breast cancer.
Advanced breast cancer often attacks the bone and could help to explain why the risk of fracture was higher in the autologous group. “In someone five years out from an autologous transplant for breast cancer with bone metastases, there is no surprise at the risk for fracture,” he said.
Research conducted at Roswell Park by McCarthy, Hahn, and their colleagues [Biol Blood Marrow Transplant 2010;16:1130-1137) demonstrated that risk factors for bone mineral density loss were different between autologous and allogeneic stem cell transplant patients. Specifically, lymphoma was associated with more bone loss after autologous transplant than myeloma, while increased steroid dose was a significant risk factor after allogeneic transplant, McCarthy explained.
Hahn said that because transplant patients are at risk of fractures more than a decade after the procedure, oncologists need to make sure to do a good job of screening them for osteoporosis and fracture risk.
Bone density loss and fracture risk are independent of one another—“you can have normal bone density and still have a high risk of bone fractures,” she explained. This study helps with identifying and quantifying who needs to be screened and watched for fractures after HSCT. Older patients with myeloma are particularly at risk, and both autologous and allogeneic transplant recipients need to be monitored.
Identifying patients at high risk for fractures following HSCT can have a tremendous clinical impact with early intervention and prevention of bone loss, Lu said. “We would like to focus on the fact that prevention of bone loss is better than reversal of bone loss, since bone loss is a multifactorial, dynamic, and complicated process.”
She said that she and her colleagues recommend:
· Screening all patients shortly before or after HSCT and possibly six months later;
· Instituting general supportive measures such as calcium and vitamin D supplementation;
· Counseling on healthy living habits; and
· Use of pharmacological interventions when indicated, instituted sooner rather than later.
“We believe that instituting preventive measures early on will be instrumental in reducing the morbidity and mortality related to bone loss during the survivorship period,” Lu said.
Singer pointed out that while Lu et al emphasize preventive measures for bone loss and fractures, there was very little discussion about medical treatment. ”Fractures may occur in cancer patients years after treatment, and the incomplete attention to preventing them astonishes me,” he said.
He noted that in 1991, the FDA approved the bisphosphonate Fosamax (alendronate) for treating osteoporosis, and data for the present study goes back to 1997, six years after the drug’s availability. In the time since then, many other drugs to prevent osteoporosis have been approved.
McCarthy said that physicians at Roswell Park aggressively use bisphosphonates to prevent bone less, especially after it was noticed that patients would lose as much density in three months on a DEXA scan as the general population would over the span of five to 15 years. Roswell Park physicians perform a DEXA scan before transplant to see if patients are already osteoporotic or osteopenic and could benefit from the agents, he explained.
Bisphosphonates are not without their drawbacks, however, McCarthy cautioned, pointing to the well-known possible side effect of osteonecrosis of the jaw (ONJ), for example.
Other options from other classes of drugs are the rank ligand inhibitor denosumab, which also may cause ONJ in patients with poor dentition, and teriparatide, which can increase the risk of bone cancer. He said that patients need to be monitored closely for side effects, but the risk is often worth the benefit of preventing fracture.
One recent paper found that intravenous zoledronic is effective for preventing bone loss in adult allogeneic stem cell transplant patients at risk for developing osteoporosis, McCarthy noted, citing Biol Blood Marrow Transplant. 2013;19:1361-1367.
Singer said that studies are available that demonstrate that bisphosphonates prevent fractures in patients with osteoporosis but not in stem cell transplant patients. And while conducting a large, randomized, double-blind trial would be ideal for demonstrating that osteoporosis drugs can help prevent fractures in patients who undergo stem cell transplantation, such a trial probably will not be able to be done because of the recruitment challenges.
Moreover, he said, clinicians don’t necessarily need this type of data to support the benefits of prescribing bisphosphonates--“If you prevent bone loss, you should reduce the number of fractures.”
Regarding avenues of research, Antin said that research needs to answer some overarching questions about the best way to prevent bone loss or regenerate bone in high-risk groups.
McCarthy agreed, noting that investigators need to come up with strategies to prevent bone loss and look at risk factors, both clinical and genetic.