The past decade has witnessed a proliferation of oncology cost-control initiatives, primarily through the use of chemotherapy pathways programs.

 Pathways programs form part of a natural progression away from fee-for-service practice to bundled payments and accountable care organizations (ACOs; Figure), where oncologists are increasingly accountable for Triple Aim measures of patient experience, individual and population health outcomes, and costs. Pathways programs are limited because the focus is on controlling costs rather than outcomes and experience. Bundled payment models and ACOs have received significant attention.

 Yet despite the allure of ACOs to payers, most private oncology practices do not have the risk-based capital or the experience, at present, to successfully participate. This article describes the oncology medical home (OMH) model, which represents an intermediate space where community oncologists and payers can work collaboratively on Triple Aim goals.

The OMH model of care for patients with cancer is a natural evolution of provider-payer partnerships around the primary care patient-centered medical home (PCMH) model. PCMH is a model of care provided by physician practices aimed at strengthening the physicianpatient relationship by replacing episodic care, based on illnesses and patient complaints, with coordinated care in a long-term healing relationship (www.ncqa.org/Programs/Recognition/PatientCenteredMedicalHomePCMH.aspx). There are a number of attributes of the medical home, including access to care, patient engagement, care coordination, team-based care, decision support, and physician feedback, which are equally relevant and germane to oncology practices.

In collaboration with communitybased oncology practices, Priority Health, a regional Michigan-based insurance carrier, developed and implemented a 2-year oncology medical home program in February 2011. The core purpose of this program was to drive oncology patient care delivery redesign through the adoption of the oncology medical home and in doing so achieve Triple Aim objectives. Community oncologists were chosen as a partner because prevailing evidence shows these are the most cost-effective settings in which to provide cancer care.

The program, which now includes more than 60 physicians in 6 practices, embodies the 3 core elements of payment reform, care redesign, and measurement:

1. The practice agrees to develop and measure adoption of key elements of an oncology medical home model: a) adherence to preferred regimens for high-volume conditions, b) care enhancement including patient education and engagement and triage initiatives, c) advance care planning (ACP), and d) survivorship planning.

2. Priority Health agrees to pay a) a monthly care management fee for patients receiving active oral and/or infused chemotherapy, b) drug acquisition costs, c) an annual infrastructure payment, d) enhanced fees for ACP, treatment planning, genetic counseling, and other agreed-upon services, and e) a shared savings for reductions in emergency department (ED) encounters and hospitalizations.

3. The practice and Priority Health agree to adopt performance metrics to assess patient experience, health outcomes, and per capita utilization.

Since a core tenet of the program was to drive sustainability of community- based oncology practices, eligibility required practices to infuse chemotherapy in a private office setting, to be open to all products offered in the geographic area, and to have provided evaluation and management services to at least 10 Priority Health members in the preceding 12 months.

The first key element in the OMH initiative centers on payment reform. To facilitate care transformation from a purely fee-for-service method to an increasingly performance and outcomes-based system, the practices and the plan agreed to a 5-part payment reform strategy. This included drug reimbursement, care management, shared savings, infrastructure development, and enhanced services. These are outlined in the following section.

Through the OMH program, all eligible intravenous and oral drugs administered and billed by the practice will be paid at the practice’s acquisition cost, as mutually agreed upon by the practice and Priority Health. In essence, practices are no longer paid margins on drugs. Rather, they are paid a monthly case management fee (see below). This, in effect, separates the oncologist’s income from drug choice while enhancing the ability to comply with oncologist-developed preferred treatment regimens and other elements of an oncology medical home.

Typically the practice’s acquisition costs are a small percentage above ASP. This reflects the delay between price increases experienced by practices and the delay in reflecting those prices in the ASP. By mutual agreement, we did not factor rebates received by practices into the acquisition price because the net value of rebates has fallen dramatically and because incorporating them into net acquisition cost calculations would be difficult to operationalize. In most circumstances, acquisition cost estimates were independently verified by a neutral third party (www.iononline.com).

The practices and the plan agreed to a monthly care management (CM) fee for patients receiving active chemotherapy, including oral and IV therapy, in lieu of payment for margins on drugs.The fee is independent of cancer type or method of drug administration (oral or IV), although the actual CM fee varies by insurance product. For example, commercial fees are in the $200 to $250 per month range, while Medicare and Medicaid fees range between $50 and $100 per month.

In order to pay the care management fee, a working definition of active chemotherapy was collaboratively developed. Active chemotherapy is defined as oral or IV administration of a cytotoxic, cytostatic, or biologic agent intended to treat cancer. A list of eligible drugs is maintained by the plan and periodically reviewed by the practices. It includes J9999 (antineoplastic drugs not otherwise classified), which is often used for new oncology agents. The parties agree to exclude some regimens considered maintenance chemotherapy, including oral anti-estrogen hormonal agents (eg, Aromasin, Arimidex), from the case management fee while including others such as maintenance chemotherapy for multiple myeloma.

A prevailing theme during discussions with physicians was a desire to be paid for their cognitive and ancillary services, not for margins on drugs. The care management fee supports services that are not typically compensated, including medication therapy management, patient education, psychologic assessment, team conferences, and financial and social work assistance (

To incent participation in the oncology medical home program, the plan incorporated a 33% increase in drug margins by using ASP+12% as the allowed amount rather than the current ASP+10% commercial fee schedule. If a practice’s true acquisition cost is ASP+4%, then margins for purposes of calculating CM fees increase to 8% from 6%, or a 33% increase.

A primary goal of the OMH project is to reduce avoidable ED visits and inpatient (IP) care and, in turn, reduce per capita cost. Priority Health and the practices will share any savings achieved if there is a statistically significant reduction in these 2 measures. The payout is on an annual basis. The plan provides baseline ED and hospitalization rates and interim utilization reports without financials to physician practices for tracking purposes.

Shared savings are not predicated on reducing drug costs or the total cost of care. However, shared savings do require compliance with the preferred cancer regimens. If practices are at least 90% average compliant with National Comprehensive Cancer Network (NCCN) or 80% average compliant with practice-developed preferred regimens for 4 selected tumor types, savings are shared 50:50. In contrast, if practices are only 70% compliant with NCCN or 60% compliant with practice-developed preferred regimens, then practices receive only 20% of the net savings.

A critical element of the medical home is the development of clinical information systems with decision support, which can include electronic health records, electronic medical records (EMRs), patient registries, embedded practice guidelines, electronic care alerts and opportunities, and other decision- support tools. The infrastructure for managing patients’ plans of care incorporates systems for registering, tracking, measuring, and improving essential coordinated services for highrisk patients. Although all practices are eligible for federal funding for EMRs through the Health Information Technologyfor Economic and Clinical Health Act, these dollars are only available retroactively. Restructuring the care delivery systems within a practice requires intellectual, time, and financial resources. In recognition of the efforts required to transform a practice, the plan agreed to pay a $1500 per year per physician infrastructure payment support for the first 2 years of the program.

Tele-visits and e-visits. Not all health services require face-to-face visits. Priority Health allows the use of synchronous visits (tele-visits) or asynchronous visits (e-visits) when physical examination is not required. This reimbursement provides an alternative to the payment rule that precludes an evaluation and management service and chemotherapy infusion service on the same day. Reimbursement for alternate visit types is consistent with primary care medical home initiatives.

 Two new treatment planning codes (S0353 and S0354) allow physicians to be compensated for treatment planning and care coordination both for initial treatment and with a change of regimen. These codes are similar to those used by radiation oncologists planning radiation treatment. The use of these codes is not well defined. For the purposes of the OMH program, the plan and practices have agreed to the following criteria:

1. Diagnosis including histology, stage, and relevant biomarkers

2. Current performance status (Eastern Cooperative Oncology Group [ECOG], Karnofsky, or other)

4. Chemotherapy regimen, dosing and frequency, and planned number of cycles

5. A patient treatment plan to include criteria 1 through 4 and written side effect and management information, cancer-related resources, and key practice contacts and their role in the patient’s care

Reimbursement for other services including E&M codes, drug administration codes, and laboratory and imaging services is unchanged and paid according to the health plan fee schedule. Dispensing of oral drugs is permissible within the program; these drugs are subject to the preferred regimens previously described. Copays, coinsurance, deductibles, and out-of-pocket maximums for patients remain in effect; these do not apply to the patient case management fee or to ACP.

The second key element of the OMH program is care delivery redesign. As part of the OMH program, Priority Health and the practices agreed to collaborate on care delivery redesign in 4 domains, including use of preferred regimens, care management, ACP, and survivorship. All parties agreed to focus on survivorship at a later date.

While many pathways programs implemented by third parties are based on state or regional consensus, they remain unnecessarily broad and lack input from individual oncologists and practices. In the OMH program, the plan and the practices mutually agreed to resolve both of these issues by having oncology practices establish single “preferred regimens” for at least 4 highvolume conditions in the adjuvant and first- and second-line metastatic settings, where appropriate. The regimens must be consistent with the most recent version of the NCCN guidelines (www.nccn.org).

Incorporation of performance status, such as the ECOG performance status or Karnofsky score, serves as a critical data point for decision making. It is relevant both for selecting the therapeutic options appropriate for an individual patient and for assessing whether or not chemotherapy should be given on a given day. In fact, the first ASCO Choosing Wisely quality improvement measure proposes avoiding unnecessary anticancer therapy, including chemotherapy, in patients with advanced solid-tumor cancers and a low performance status (3 or 4), and instead focusing on palliative and supportive care or clinical trials (http://connection.asco.org/Magazine/Article/ID/3190/Choosing-Wisely-Constructing-a-Top-Five-List-in-Oncology.aspx).

Early results demonstrate that practices can readily meet these requirements. Further, their selections of preferred regimens are very similar (

), which is remarkable because the practices developed these regimens independent of each other and without external input.

Articles

Evidence-Based Oncology

Lessons From an Oncology Medical Home Collaborative

Trying to Calculate the Economic Value of Dasatinib or Nilotinib for Imatinib-Resistant CML

Although it is now standard practice to utilize the second-generation tyrosine-kinase inhibitors dasatinib or nilotinib in patients whose chronic myeloid leukemia has recurred while taking imatinib treatment, published support for the economic value of this approach is lacking. Investigators from the University of Exeter, United Kingdom, conducted a review of the literature and produced an economic model to help fill this information gap.

They evaluated contributions to key databases (MEDLINE [including MEDLINE In-Process and Other Non-Indexed Citations], EMBASE [ISI Web of Science], Conference Proceedings Citation Index, as well as 4 other sites). Their research led to 15 relevant studies, the most recent from June 2009.

Two separate decision-analysis economic models for chronic myeloid leukemia (CML) were utilized, in which patients in chronic-phase CML either showed the potential to become or did become resistant to a normal dose of imatinib (imatinib resistant), or due to adverse events had to cease imatinib treatment (imatinib intolerant). Another was used to evaluate patients with CML that had progressed to blast crisis.

Although the number of studies regarding the effectiveness of dasatinib and nilotinib for treating chronic-phase CML patients (who were either imatinib resistant or imatinib intolerant) was limited, the investigators found ample evidence for the clinical effectiveness of these agents, based on positive cytogenetic and hematological responses.

However, it was very difficult, they stated, to come to any conclusions regarding cost-effectiveness with either dasatinib or nilotinib treatment of patients in those with imatinib-resistant CML. Serious data flaws were noted, in one way or another, for all the economic models produced.

All available data regarding accelerated and blast crisis came from observational observational single-arm trials. Unfortunately, meaningful comparisons between the treatments was greatly undercut because of various and possible baseline characteristic variations.

Accelerated phase and blast crisis de novo models could not be expanded because the available clinical data were deficient. In addition, there was sparse evidence regarding the effectiveness of second-generation tyrosine-kinase inhibitors (TKIs) compared with high-dose treatment with imatinib, which severely weakened the economic evaluations done by the manufacturers.

Interestingly, a separate review of the studies on the value of high-dose imatinib in patients with chronic-phase CML resistant to standard-dose imatinib revealed that up to one-third experienced a complete cytogenetic response (up to four-fifths experienced a complete hematologic response), with grade 3 or 4 adverse events occurring in 40% of patients (up to one-fifth discontinued because of these adverse effects). In an economic analysis, nilotinib appeared to have greater cost-effectiveness than high-dose imatinib, followed by dasatinib, in these resistant patients. However, they caution that the study was not based on direct comparisons with identical outcomes measures.

Although the second-generation TKIs appear to add clinical value to the armamentarium against CML, the clinicians acknowledge that a meaningful costeffectiveness conclusion is not possible. Until a randomized, 3-way, double-blind clinical study involving dasatinib, nilotinib, and high-dose imatinib is conducted, they added, the true economic value of the second-generation TKIs cannot be revealed.

Rogers G, Hoyle M, Thompson Coon J, et al. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(22):1-410.

Loveman E, Cooper K, Bryant J, et al. Dasatinib, high-dose imatinib, and nilotinib for the treatment of imatinibresistant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(23): iii-xiii, 1-137.

Chronic Myeloid Leukemia Treatment Practices in the United States

The multinational, prospective WORLD CML registry was established in order to measure how patients with CML are managed by evaluating global clinical practice patterns. This registry, with sites around the world, recently examined results for patients with CML at locations in the United States and assessed how practice patterns correspond with National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.

The care of 377 patients (median age, 53 years; range, 18-91 years) with a confirmed CML diagnosis enrolled in the United States from February 2008 to December 31, 2010, was analyzed by American researchers. Of these participants, 363 (96%) received a chronic phase diagnosis.

First-line therapy of imatinib was prescribed for 73% of patients with chronic phase CML, compared with hydroxyurea (6%), nilotinib (3%), and dasatinib (1%). (The clinicians noted that patients may have received more than 1 medication.) The median treatment period lasted 7.6 months (range, 0.1-33.5 months). The dose of imatinib treatment was increased in 29 of the 363 patients with chronic phase CML (8%) primarily as a result of physician request and lack of efficacy. In 32 patients (9%), the imatinib dose was reduced, primarily because of adverse events and physician request. Lack of efficacy and adverse events led to the treatment regimen being changed from imatinib to nilotinib in 21 patients (6%) and to dasatinib in 20 patients (6%).

Clinicians most commonly used hematology assessments to evaluate CML treatment progress (

). After 3 months of imatinib treatment, a molecular assessment was sought for only 16% of patients, although up to 64% of patients underwent molecular disease testing by 2 years of therapy. The least common assessment, cytogenetics, was performed in only 13% of patients after 3 months and up to 34% after 6 months of treatment.

The investigators concluded that many patients being treated with firstline imatinib for chronic phase CML did not routinely undergo cytogenetic or molecular assessments. According to NCCN guidelines, such testing should be conducted more frequently (

). They indicate that access to molecular testing may have been an issue during the study period, and that these findings therefore should be updated to reflect more current availability of cytogenetic and molecular testing.

Hermann R, Miller CB, Catchatorian R, et al. Understanding US treatment practices for the management of chronic myeloid leukemia (CML) in clinical practice: a US subgroup analysis of the WORLD CML Registry. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

Unfavorable Results of Imatinib Treatment in Patients With High BCR-ABL Levels

With several TKIs available today to treat patients whose CML has recurred despite standard imatinib therapy, it may be beneficial to predetermine in some way those patients who may be optimally treated with alternative agents. This points to the need for a better understanding of the relevant biomarkers to predict who will not respond sufficiently to imatinib treatment.

Recent reports have suggested that after 3 months of treatment with imatinib, patients with CML may experience inferior outcomes (in terms of both progression- free survival and overall survival [OS]) when they experience BCR-ABL/ ABLIS levels above 10%, or more than 1% after 6 months of imatinib therapy. Italian and German researchers have attempted to extend this finding by 1 step: to determine whether high levels of BCR-ABL transcripts found at the time of diagnosis would also be connected with an inadequate reaction to imatinib treatment.

The researchers analyzed BCR-ABL levels of 230 patients with newly diagnosed CML who were to receive imatinib /day. Either ABL or glucuronidasebeta (GUS) was used as reference genes for all molecular verifications.

The median follow-up time in the study population was 42 months. Cumulative incidences estimated at 5 years for complete hematologic responses, complete cytogenetic response (CCyR), and major molecular response were 98%, 89%, and 65%, respectively. Overall survival rate using 5-year probabilities was 93.8%, while a transformation-free survival rate, defined as survival without disease transformation to the accelerated phase or blast crisis, and failurefree survival (survival without imatinib failure as indicated in the 2009 European Leukemia Net recommendations) were 98% and 76%, respectively.

When GUS was used instead of ABL as a reference gene at diagnosis, connections between high BCR-ABL transcripts and the differential in inadequate IM responses were much greater. Both elevated BCR-ABL/GUSIS (

<.0001) levels were associated with a lower probability of optimal response. The investigators also indicated that after 12 months of imatinib therapy, a link existed between lower rates of cytogenetic response and higher BCR-ABL/ GUSIS measurements (

 <.0001) but not higher BCR-ABL/ABLIS values (

They noted that overall survival could not be predicted by levels of BCR-ABL/GUSIS or BCR-ABL/ABLIS at diagnosis. However, a more accurate connection between high levels of BCR-ABL/GUSIS and lower probabilities of failure-free survival (

 <.0001) and transformationfree survival (

 = .01) was found when compared with high levels of BCR-ABL/ABLIS (

After subdividing the patient cohort into optimal responders, suboptimal responders, and subjects failing first-line therapy, based on the 2009 European 16% of patients, although up to 64% of patients underwent molecular disease testing by 2 years of therapy. The least common assessment, cytogenetics, was performed in only 13% of patients after 3 months and up to 34% after 6 months of treatment.

The investigators concluded that many patients being treated with firstline imatinib for chronic phase CML did not routinely undergo cytogenetic or molecular assessments. According to NCCN guidelines, such testing should be conducted more frequently (Table 2). They indicate that access to molecular testing may have been an issue during the study period, and that these findings therefore should be updated to reflect more current availability of cytogenetic and molecular testing.

 Hermann R, Miller CB, Catchatorian R, et al. Understanding US treatment practices for the management of chronic myeloid leukemia (CML) in clinical practice: a US subgroup analysis of the WORLD CML Registry. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

Literature Review: Chronic Myeloid Leukemia

The Economic Value of Ipilimumab as a Second-Line Treatment in Patients With Advanced Melanoma

In early 2011, ipilimumab, an anti-CTLA- 4 monoclonal antibody with antitumor activity, was approved by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. Ipilimumab was compared with the gp100 vaccine in a clinical trial and patients survived a median of 3.7 months longer than those receiving the vaccine. In another trial, ipilimumab with dacarbazine was compared with dacarbazine in previously untreated patients with advanced melanoma. The investigators found that combination therapy yielded higher survivals at 1, 2, and 3 years.

Ipilimumab is an expensive treatment that is associated with positive clinical outcomes. Researchers from the United States and United Kingdom (and from Bristol-Myers Squibb, the manufacturer of ipilimumab) sought to evaluate the cost-effectiveness of ipilimumab compared with best supportive care in previously treated patients with advanced (unresectable or metastatic) melanoma.

Progression-free and overall survival data were used from a phase III trial of ipilimumab to model stable disease, progression, and death. Clinical outcomes, quality of life, and healthcare utilization were included in the analyses. The Markov model considered only the direct costs in patients with an average age of 55 years having advanced melanoma. A discount rate of 3% was utilized for both costs and outcomes.

Because no previous clinical trial with another therapy demonstrated a prolongation of survival, best supportive care was defined as disease management without active chemotherapy. The researchers acknowledged that this may provide a conservative cost benefit for ipilimumab, as most patients usually receive some type of chemotherapy that increases treatment costs of advanced melanoma. Both the incremental costeffectiveness ratio (ICER) and incremental cost utility ratio (ICUR) were estimated in the model. They included direct costs associated with pharmaceuticals, clinical management, and costs associated with toxicity-related events (

The model used ipilimumab clinical data from a trial comparing the agent with gp100, dacarbazine, interleukin-2, and temozolomide. Ipilimumab demonstrated benefits in both progressionfree survival and overall survival.

Those in the ipilimumab group demonstrated a mean gain of 1.88 life-years and 1.14 quality-adjusted life-years (QALYs) compared with patients receiving basic supportive care. The drug costs were higher in the ipilimumab group. They estimated the incremental cost-effectiveness ratios to be $78,000 per life-year gained and $129,000 for the incremental cost per QALY gained.

Based on their sensitivity analysis, and assuming a willingness-to-pay threshold of $113,000 per QALY, the researchers estimated a 6% chance that ipilimumab would be considered costeffective. However, if the threshold were raised to $146,000/QALY, ipilimumab would be considered cost-effective in better than 95% of the scenarios.

The investigators explained that the differences between the ICER and ICUR were expected, owing to the definitions utilized for disease progression from stable disease to progressive disease in the model. Using the costs of alternative therapies that have no shown benefit in survival would increase the cost-effectiveness of ipilimumab, as this therapy has been proved to improve survival.

 Barzey V, Atkins MB, Garrison LP, et al. Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J Med Econ. 2013;16(2):202-212.

Combined BRAF and MEK Inhibition in Melanoma Improves Cytogenic Response

Vemurafenib is a valuable treatment in patients with advanced melanoma who have the BRAF V600E mutation. However, roughly half of patients treated with vemurafenib have progression-free survivals of about 7 months before melanoma activity recurs. An international group of researchers from multiple centers sought to determine if a combination of investigational BRAF and MEK inhibitors might produce a more durable response.

This investigation was part of a larger study that determined the pharmacokinetic activity, clinical activity, and safety of oral dabrafenib (a BRAF inhibitor) and trametinib (an MEK or MAPKkinase inhibitor). The trial of interest was an open-label, randomized, phase II trial that included 162 patients with advanced melanoma who were therapy- naïve or received no more than 1 chemotherapy regimen (excluding any prior treatment with BRAF or MEK inhibitors).

The patients were randomly assigned treatment with either 150 mg dabrafenib bid monotherapy (54 patients; median age, 50 years) or 150 mg dabrafenib bid plus 1 daily dose of trametinib 1 mg (combination 150/1 therapy) (54 patients; median age, 49 years) or 2 mg (combination 150/2 therapy) (54 patients; median age, 58 years). Each of the 3 study groups in this phase had similar poor prognostic attributes including brain metastases, M1c disease, and high lactate dehydrogenase levels. The frequency of cutaneous squamous-cell carcinoma (including keratoacanthoma) was 19% for the dabrafenib monotherapy group, 2% for the combination 150/1, and 7% for the combination 150/2 group (

The median follow-up time was 14.1 months (range, 10.8-17.6 mo) at the time of the planned efficacy analysis. The researchers calculated progression- free survivals (PFSs) of 9.4 months for the combination 150/2 patients, 9.2 months for the combination 150/1 patients, and 5.8 months for monotherapy patients. An independent review committee assigned a hazard ratio for progression or death of 0.55 (95% confidence interval, 0.33 to 0.93; 

= .02) for those receiving the 150/2 combination (

After 12 months, 41% of patients in the 150/2 group were still experiencing PFS compared with only 9% of monotherapy patients (

<.001). When investigators stratified patients according to BRAF V600E mutation or V600K mutation, they did not find any difference in outcome.

Seventy-six percent of the patients in the combination 150/2 group experienced a complete or partial response compared with 54% in the monotherapy group (54%; P = .03). The median overall survival rate, acknowledged the authors, could not be analyzed, because it had not yet been reached.

At 1 year, 79% of the patients in the 150/2 group and 70% in the monotherapy group were alive. When the disease progressed in patients currently receiving monotherapy with the BRAF inhibitor, 80% crossed over to the 150/2 combination therapy group.

The side effect of rash was higher in the monotherapy group (36%) versus the combination 150/1 and 150/2 populations (20% and 27%, respectively). However, the combination groups had a more widespread MEK-inhibitorassociated acneiform dermatitis than the monotherapy subjects (11% for 150/1, 16% for 150/2, 4% for monotherapy treatments).

Adverse events that were seen more frequently in the combination 150/2 group were pyrexia (all grades, 71%) and chills (all grades, 58%). In addition, other adverse events that occurred more frequently in the combination 150/2 group than in the monotherapy patients were fatigue (53% of patients), nausea (44%), vomiting (40%), and diarrhea (36%).

The investigators conclude that this combination of BRAF-MEK inhibitors is at least partly successful in mitigating the resistance in advanced melanoma to BRAF inhibition alone that occurs over time. Dabrafenib and trametinib given to patients at their full singleagent doses proved to be safe and effective when combined, the clinicians stated. This trial, they concluded, supports the effectiveness of using a combination regimen of BRAF-MEK inhibitors for treating patients with advanced melanoma.

Flaherty KT, Infante JR, Daud D, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-1703.

The Effect of Ipilimumab on Health-Related Quality of Life in Patients With Unresectable Advanced Melanoma

Patients diagnosed with melanoma are typically affected psychologically. Treatment usually causes impaired physical functioning and fatigue. Researchers summarized health-related quality of life (HRQOL) during the 12-week ipilimumab induction period in previously treated patients diagnosed with advanced stage III or IV melanoma.

Patients in the study were randomized to receive 1 of 3 treatments: ipilimumab plus gp100 vaccine, gp100 vaccine plus placebo, or ipilimumab plus placebo. The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORT QLQ-C30) was utilized to assess HRQOL. This tool entails global health status, and physical, emotional, role, cognitive, and social functioning. Higher scores are indicative of better functioning. Differences in scores were subgrouped into 4 categories (eg, “no change” [0-5 points], “a little” [5- 10 points], “moderate” [10-20 points], and “very much” [>20 points]). A score differential of 0 to 10 points was interpreted as no or minimal impact on patient HRQOL.

The researchers reported that after 12 weeks, most patients reported that changes to HRQOL outcomes were no greater than minimal. The only statistically significant difference in score was for constipation, in a comparison of the ipilimumab plus gp100 and the gp100 alone groups. Scoring indicating “moderate” function and global health status score were role function in the ipilimumab alone group and role function and global health in the gp100 group. Symptom scoring rating a “moderate” were fatigue in the ipilimumab plus gp100 group; fatigue, sleep disturbances, and appetite loss in the ipilimumab alone group; and fatigue, pain, sleep disturbances, appetite loss, and constipation in the gp100 alone group.

Patients older than 65 years tended to have more “moderate” changes in health status than the patients younger than 65 years. The greatest differences, albeit moderate, were observed for role function, social function, global health, dyspnea, sleep disturbance, appetite loss, and diarrhea. It is difficult to fully appreciate the importance of the findings owing to the small sample size of the >65 years group, as the mean age was 55.6 years to 57.4 years across all of the study groups.

Treatment within all 3 treatment groups resulted in minimal changes in HRQOL. Therefore, the authors conclude that HRQOL changes should not be a concern for those patients with advanced melanoma and their physicians considering ipilimumab treatment.

 Revicki DA, van den Ertwegh AJM, Lorigan P, et al. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012;10:66.

Is Daily Sunscreen Use Cost-Effective for Preventing Skin Cancer?

Exposure to ultraviolet radiation is an important risk factor for the development of skin cancers. A major study previously demonstrated the benefit of sunscreen as an effective strategy, both clinically and economically, for reducing the burden of squamous-cell carcinoma. However, the study did not investigate the long-term benefit of using sunscreen to prevent melanoma, the least prevalent but more often fatal skin cancer.

To evaluate the economic effects of sunscreen use to prevent melanoma, investigators evaluated data from the Nambour Skin Cancer Prevention Trial conducted in Queensland, Australia, from 1992 to 2006. In this trial, the intervention group was encouraged to apply daily a sunscreen with an SPF rating of at least 15, which was provided free of charge at designated study clinics. The study group was instructed to apply the sunscreen daily to their head, neck, arms, and hands, and the control group was instructed to apply sunscreen at their discretion. The decision model tracked multiple cohorts to examine the health and cost outcomes of participants with different profiles. Key measures included time since diagnosis, costs, number of melanomas, QALYs, and life-years lived.

All participants were melanoma free at the start of the data collection period. Individuals who developed melanoma and were diagnosed and treated were characterized further by whether they remained in remission, had a recurrence, were diagnosed with additional tumors or distant metastases, or died, as well as by an age-specific all-cause mortality risk.

Health outcomes in the model included QALYs, counts of melanomas and squamous-cell carcinoma, and melanoma-related deaths. Resources and costs included both those of government health providers (monitoring participants, cost of sunscreen, diagnosis, treating, and following suspicious skin lesions) and household members (time and out-of-pocket costs for applying sunscreen, attending clinic visits, and a discounted lifetime cost following a diagnosis of melanoma. The cost of melanoma was taken from a previous study and inflated to 2010 prices.

Literature Review: Melanoma

At SABCS 2012, experts in the field provided an update on the use of molecular testing to guide treatment selection for in situcarcinoma of the breast, early-stage intermediate-risk estrogen-receptor-positive and triple-negative breast cancer, and metastatic disease.Molecular oncology has brought a new understanding of carcinogenesis and has revolutionized the way we think about treating cancer.

Oncologists believe they are at a turning point in terms of how to use molecular assays now and in the not-toodistant future. “We are beginning to realize that we have only just scratched the surface,” said Peter Ravdin, MD, PhD, UT Health Science Center San Antonio, who chaired an educational session titled

 The Practical Use of Molecular Profiling

 at the 2012 CTCR-AACR San Antonio Breast Cancer Symposium (SABCS). “It is pretty exciting, actually.” The field is moving away from making decisions based on qualitative, descriptive prognostic information and moving toward precision medicine that is based on quantitative predictions.

Lawrence Solin, MD, Albert Einstein Medical Center, talked about molecular profiling of in situ carcinoma. Recent studies suggest that in situ disease is relatively advanced in its molecular progression to invasion, despite its distinct histologic appearance. National Comprehensive Cancer Network guidelines do not recommend molecular profiling for ductal carcinoma in situ (DCIS) or lobular carcinoma in situ, although estrogen receptor (ER) status is recognized as a tumor marker for DCIS.

Whole breast irradiation (XRT) is known to reduce local recurrence among women who undergo lumpectomy for DCIS. Randomized trial data have demonstrated that radiation plus tamoxifen reduces risk for patients with estrogen receptor (ER)-positive tumors. In practice, it is difficult to distinguish low-risk patients using clinical and pathological factors. “These are aggressive treatments for low-risk patients who rarely die of this disease,” said Dr Solin.

Researchers who have developed a 12-gene signature assay for DCIS hope their system will address the problem of who to treat with adjuvant XRT. Initial results of their findings were presented at the 2011 SABCS and are under review for publication.

 Investigators anticipate that this type of assay, once incorporated into widespread use, will support individualized treatment decision making and identification of molecular biology underlying DCIS.

Dr Solin participated in an analysis that compared the costeffectiveness of basing decisions of whether to use adjuvant XRT on the 12-gene score versus routine clinical practice. Results of the analysis were presented as a poster at the 2012 SABCS.

The average cost of the 12-gene assay was lower than that of standard clinical assessment by approximately $1000 per patient. Changing strategy from using the assay to clinical assessment was associated with an incremental cost-effectiveness ratio of approximately $95,000 per quality-adjusted life-year. Estimates assumed that XRT benefits were independent of biology and that ≥75% of patients would not receive XRT.

For early-stage breast cancer, decisions regarding the use of adjuvant chemotherapy have considered hormone status of the tumor. With respect to tumor markers for breast cancer, the American Society of Clinical Oncology recommends ER and progesterone receptor (PgR) testing for decisions on endocrine therapy, and human epidermal growth factor (HER2) testing for decisions regarding anti-HER2 and anthracycline therapy.

For prognosis, the 21- gene recurrence score (Oncotype DX breast cancer assay, Genomic Health, Inc), urokinase plasminogen activator, and plasminogen activator inhibitor for prognosis are recommended. The 21-gene recurrence score may also be used to help make treatment decisions; patients identified with a highrisk recurrence score are more likely to benefit from chemotherapy. This is not surprising, explained Antonio Wolff, MD, Johns Hopkins Kimmel Cancer Center, because nearly one-third of the non-reference genes in the assay are markers of proliferation, a trait that makes tumors particularly vulnerable to chemotherapy.

Gene expression array analyses have further refined tumor classifications. As additional molecular information is emerging, it is becoming clear that breast cancer should be viewed as a biologic continuum, not as discrete categories. “We know that [these categories] are not enough,” said Dr Wolff. The validated predictive biomarkers have a strong negative predictive value; if the markers are not expressed, targeted therapy is not indicated. With a modest positive predictive value, however, they don’t specifically ensure that patients who have receptor-positive tumor markers will benefit. “They also don’t tell us in absolute terms whether to give it. For prognostic utility, you have to incorporate clinicopathologic measures of prognosis such as tumor size and node status for baseline assessment of risk.”

At this point, clinicians and researchers are realizing that standard clinical measures and molecular assays do not provide the same information. “One assay, one method, is not necessarily better than the other,” said Dr Wolff, emphasizing that clinical context matters. “The question is whether they can be complementary. What we need now are exercises where we are able to combine both molecular and clinical standard information and try to improve on the prediction of what to do.”

To answer some questions about how to use these assays, the field is awaiting the results of 2 completed prospective randomized trials: the Trial Assigning IndividuaLized Options for Treatment (Rx) (TailoRX) and the Microarray for Node-Negative Disease may Avoid Chemotherapy (MINDACT).

 TailoRX will attempt to answer the question of whether adding adjuvant chemotherapy to endocrine therapy will improve outcomes of patients with ERpositive, node-negative breast cancer and an intermediate-risk recurrence score (by the 21-gene assay). MINDACT will examine outcomes when chemotherapy is added to endocrine therapy in patients with discordant tumor risk assessments as determined by Adjuvant! Online and the 70-gene signature (MammaPrint, Agendia).

Tumor classification will improve with continued research. Building on established molecular information, the Cancer Genome Atlas recently reported the molecular portrait of over 800 breast tumor tissue samples, incorporating a host of biological factors, including phenotype, genotype, proteomics, epigenetics, copy number variation, and mRNA expression.

 The analyses confirmed the existence of 4 major molecular subtypes of breast cancer: HER-2 enriched, luminal A, luminal B, and basal-like. “Much of the prognostic variability seems to be happening within these groups,” said Dr Wolff. Yet, the usefulness of the data set is limited without a correlation to clinical outcomes. “As we move into the era of precision medicine, I think we need to begin to correlate this kind of information with clinical outcomes so that we can begin to make decisions,” he said. Along with other studies, this study is also beginning to tease out different molecular subtypes underlying triple-negative breast cancer.

Multiple studies have been examining how and to what extent available assays are being put into practice. One of the largest of these studies used the NCCN registry database to assess the adoption of gene expression profiling (GEP) and use of chemotherapy for women with hormone-receptorpositive breast cancer at 17 centers.

 They found an absolute increase of 12% in GEP use (P <.01) from 2006 to 2008 and an absolute decrease of about 5% in chemotherapy use (

<.01) over the same time period (N = 7375). Testing was associated with lower odds of chemotherapy use (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.62- 0.80), overall. However, Dr Wolff noted an interesting observation: physicians might have ordered the 21-gene assay to help confirm their underlying intent. Patients with node-positive and large node-negative cancers were less likely to receive chemotherapy (OR, 0.11; 95% CI, 0.07-0.17) while those with small, node-negative cancers were more likely to receive chemotherapy after GEP testing (OR, 11.1; 95% CI, 5.39-22.99). This suggested an underlying assumption by the clinician that one test might be more informative than the other. Patient factors also may have influenced GEP test ordering; the odds of being tested were lower for blacks versus whites (OR, 0.70; 95% CI, 0.54-0.92) and for those with high school education or lower versus those with a higher education (OR, 0.63; 95% CI, 0.52-0.76).

Despite a great deal of exciting investigational activity on molecular profiling of metastatic disease, relatively little has carried over to actual routine clinical use. “Sadly enough, there is no genomic test that is used routinely in the management of metastatic breast cancer today,” lamented Lajos Pusztai, MD, Yale Cancer Center. More often, for metastatic breast cancer, molecular markers are being used as patient selection criteria or to enrich a specific population in clinical trials.

In some select cases, repeating ER, PgR, or HER2 tests can be justified; for example, when the diagnosis of a solitary nodule is in doubt, on technical grounds, in clinical trial, or when the clinical course of disease suggests different biology than the original receptor test result indicates. Considering test results in the clinical context is critically important. “For example, if a patient originally diagnosed with ERnegative breast cancer has recurrence 5 or more years after original diagnosis, this would be atypical,” explained Dr Pusztai. “In this setting, repeating a biopsy could be very important. If the patient turns out to be hormone receptor— positive on repeat testing, you could extend the life of that patient by years by offering hormone therapy.”

It is important to understand that a single repeat of the same test does not improve accuracy of the result. A 90% accurate test repeated twice on the same sample yields concordant results about 81% of the time (0.9 x 0.9) because 10% of the 90% of correct classifications from the first round will be misclassified in the second round and vice versa.

Because there is a cognizance bias to act on the most recent results, discordant results can be problematic and potentially dangerous, said Dr Pusztai. Yet, outside of a known technical error in the first test, there is no reason why the most recent test would be more accurate than the first. He recommends that if a patient has at least 1 positive result, at least 1 targeted agent should be tried.

Circulating tumor cells appear promising as a prognostic indicator for metastatic breast cancer, but are not of clinical utility in treatment selection. “One of the most important future challenges is to design experimental and informatics tools that could guide how to combine targeted agents to match the multiple abnormalities that individual cancers have that we can now readily measure,” said Dr Pusztai.

Clinical studies, as well as private and grant-funded entities, are now bringing high-throughput genomic analysis to cancer care with the goal of therapy tailored to a tumor’s molecular abnormalities.

 In practice, however, clinicians are faced with the problem of what to do with the results.

In an interview after the session, Dr Pusztai talked about a hypothetical scenario with a patient who has metastatic disease, has tried all available established therapies, has a molecular profile showing an epidermal growth factor receptor (EGFR) mutation, and is asking for an additional line of treatment with an EGFR inhibitor. “It would be great to know if that worked,” said Dr Pusztai. “It would be great to have a means to collect information on this— whether patients in those types of scenarios responded to a certain drug.” But, these therapies are expensive, most patients cannot afford them, and insurance companies are not likely to be willing to pay for these types of offlabel treatment.

From a systems perspective, it is currently hard to prospectively collect outcomes data of this type of molecularly directed treatment approach in academic centers, explained Dr Pusztai. “At this point, off-label use of molecularly targeted drugs is too expensive without proper funding. Individual molecular abnormalities (eg, EGFR mutation in breast cancer) are rare; access to many different off-label drugs would be needed in order to offer some therapy for most molecularly tested patients and learn from their experience,” he explained. Dr Pusztai would like to see insurance companies and the Centers for Medicare & Medicaid Services explore reimbursement for approved molecularly targeted drugs administered in the context of clinical studies that collect outcome information systematically. That type of information could provide grounds to build subsequent large definitive clinical trials to follow up on drugs that show activity in molecularly selected patient populations. “Molecular analysis of tumors to find intriguing potential targets is readily available; the real bottleneck of progress is how to prove or disprove the clinical utility of these technologies,” said Dr Pusztai.

The author reports receiving payment for involvement in the preparation of this manuscript with no associated conflicts of interest.

 Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or logistic support; and supervision.1. National Comprehensive Cancer Network. NCCN Guidelines Breast Cancer Version 3. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published 2012. Accessed December 26, 2012.

2. Solin LJ, Gray R, Butler S, et al. A quantitative multigene RT-PCR assay for predicting recurrence risk after surgical excision alone without irradiation for ductal carcinoma in situ (DCIS): a prospective validation study of the DCIS Score from ECOG E5194 [Abstract S4-6]. Presented at: 2011 CTCR-ACCR San Antonio Breast Cancer Symposium; December 6-10; San Antonio, Texas.

3. Alvarado MD, Harrison BL, Solin LJ, Ozanne EM. Cost-effectiveness of gene expression profiling for ductal carcinoma in-situ (Oncotype DCIS Score) [Abstract P5-15-01]. Poster presented at: 2012 CTCR-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas.

4. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007;25(33):5287-5312.

5. Clinicaltrials.gov website. www.clinicaltrials.gov. Accessed December 20, 2012.

6. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors [published online September 23, 2012]. Nature. 2012;490(7418):61-70.

7. Metzger-Filho O, Tutt A, de Azambuja E, et al. Dissecting the heterogeneity of triple-negative breast cancer [published online March 26, 2012]. J Clin Oncol. 2012;30(15):1879-1887.

8. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer [published online May 14, 2012]. J Clin Oncol. 2012;30(18):2218- 2226.

9. Pusztai L, Yelensky R, Wang B, et al. Use of next-generation sequencing to detect high frequency of targetable alterations in primary and metastatic breast cancer [abstract 10559]. J Clin Oncol. 2012;30(15S):670S.

10. SantarpiaL, Qi Y, Stemke-Hale K, Wang B, et al. Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers [published online April 27, 2012]. Breast Cancer Res Treat. 2012;134(1):333-343.

11. Foundation Medicine website. www.foundationmedicine.org. Accessed December 20, 2012.

12. My Cancer Genome website. www.mycancergenome.org/. Accessed December 20, 2012.

Crossroads in Breast Cancer: The Intersection of Clinical Uncertainty and Molecular Profiling

Newly Discovered Biomarkers Predict Response in AML

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and most patients with AML relapse after achieving complete remission with induction therapy. Most patients with AML die from relapsed disease. Therefore, biomarkers that accurately predict outcome in AML are needed so patients can be matched to the most appropriate therapies, according to presenters at the American Society of Hematology 54th Annual Meeting.

Extensive mutational testing can be used to refine prognostication in AML and inform therapeutic approaches, said Ross L. Levine, MD, Memorial Sloan- Kettering Cancer Center, New York, NY. Novel disease alleles in AML are mutations in TET2, ASXL1, IDH1 and IDH2, PHF6, and DNMT3A. Integrated genetic analysis from 502 patients with AML enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 clinical trial revealed several genes with prognostic importance. Mutations in IDH2 R140, but not IDH2 R172 or IDH1, were associated with improved survival. Mutations in ASXL1 and PHF6 were associated with worse overall survival.

Risk can be further refined in patients with intermediate-risk AML by more extensive mutational analysis, said Dr Levine. Three distinct risk groups can be identified in FLT3-ITDnegative intermediate-risk AML based on mutational status; TET2, ASXL1, PHF6, and partial tandem duplications in MLL are poor-risk mutations associated with worse survival in the group of intermediate-risk patients with wild-type internal tandem duplications in FLT3.

In the ECOG E1900 trial, a post hoc analysis of mutational status found that high-dose daunorubicin improved outcomes markedly for patients with DNMT3A mutations. Patients with NPM1 or DNMT3A mutations, or MLL translocations, had a 3-year overall survival rate of 44% with high-dose daunorubicin induction chemotherapy compared with 25% rate when treated with standarddose daunorubicin.

Minimal residual disease (MRD) after treatment in AML predicts failure to maintain a morphologic complete response and negatively affects survival. Elisabeth Paietta, PhD, professor, department of medicine (oncology), Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, reviewed approaches to monitoring MRD, noting that the best method is still a matter of debate and that MRD assessment assays need to be standardized. They are either immunophenotypic, done by multiparameter flow cytometry, or done by polymerase chain reaction to detect recurrent gene mutations or leukemia fusion transcripts. Very sensitive assays, perhaps next generation sequencing, are needed to find minor clones present at diagnosis that may lead to relapse. Even with detection of MRD, therapeutic options at present are limited, she said. Intensive therapeutic approaches have not worked in MRD-positive patients, said Dr Paietta.

Relapsed AML remains a clinical challenge, said Jeffrey Szer, MBBS, professor/ director, department of clinical haematology and BMT service, The Royal Melbourne Hospital, Parkville, Australia. Novel approaches to the treatment of relapse include clofarabine, a novel purine analogue, with or without cytarabine; tosedotat, an orally available aminopeptidase inhibitor that has shown significant clinical activity in a phase I/ II study; and FLT3 inhibitors, which may have a role as a bridge to transplantation. Inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus and sirolimus, have potential utility given the role of the mTOR pathway in cytarabine activity. Hypomethylating agents are being studied as maintenance therapy after allo-stem cell transplant (SCT). Allo-SCT has the potential to cure relapsed or refractory disease, but only after patients have achieved a second complete remission or MRD.

Evidence-Based Approaches to Cytopenias Discussed

Diagnostic approaches to cytopenias require an understanding of their etiology, said presenters during the American Society of Hematology 54th Annual Meeting.

Neutropenia is often a secondary finding “to a far more significant underlying hematologic disorder, placing the patient at risk for infectious complications,” said Laurence A. Boxer, MD, a pediatric hematologist-oncologist at the University of Michigan Heath System, Ann Arbor.

In the case of severe congenital neutropenia (SCN), which is characterized by recurrent severe infections during the first months of life, bone marrow examination characteristically shows a myeloid “maturation arrest” at the promyelocyte-myelocyte stage of development. Mutations in the ELANE gene have been observed in 40% to 60% of patients with congenital neutropenia, and neutropenia caused by the ELANE mutation is associated with the most severe infectious complications, Dr Boxer said.

An autosomal-recessive subtype of SCN is Kostmann disease, in which mutations of the HAX1 gene are observed. Patients with both isoform A and isoform B HAX1-spliced variants can suffer from neurologic impairment that ranges from developmental delay to severe epilepsy.

Uncovering the cause of chronic anemia relies on a complete blood count (CBC), said Mark J. Koury, MD, professor of medicine, division of hematology/oncology, Vanderbilt University, Nashville. The 4 patterns encountered frequently in CBCs associated with chronic anemia are anemia with abnormal platelets and/or leukocyte counts, anemia with increased reticulocyte counts, a lifelong persistence of an abnormal CBC, and anemia with inappropriately low reticulocytes.

Diseases affecting early-stage hematopoietic progenitors, such as liver disease, will likely affect platelets and leukocytes. Underlying causes can include chronic alcohol intake and antiviral treatments for hepatitis C. The absence of an enlarged spleen usually indicates a primary bone marrow disease, including myelodysplasia or malignant invasion of the bone marrow, such as with multiple myeloma.

An increased number of reticulocytes with chronic anemia indicates lowgrade hemolysis or blood loss (possibly from upper gastrointestinal lesions or menorrhagia). Erythrocyte fragmentation on the blood smear is often associated with malignant tumors, large hemangiomas, prosthetic heart valve defects, or direct external trauma, said Dr Koury. Spherocytes suggest hereditary spherocytosis or immune hemolysis, the latter of which can be diagnosed by surface antibodies and/or complement components on erythrocytes in the direct antiglobulin test.

Bone marrow events responsible for low reticulocyte production include apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated elF2-alpha kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.

Correct identification of the cause of thrombocytopenia is crucial for proper management, said Roberto Stasi, MD, PhD, department of haematology, St. George’s Hospital, London, UK. Thrombocytopenia may be the initial manifestation of infections (ie, HIV and hepatitis C virus). Examination of the peripheral blood smear remains the most important investigation to guide diagnostic approaches. Liver and renal function tests, a clotting screen with D-dimers, and measurement of lactate dehydrogenase are part of the basic laboratory evaluation.

A bone marrow aspirate and biopsy may be performed if the etiology of the thrombocytopenia is unclear, said Dr Stasi.

Primary immune thrombocytopenia (ITP) remains a diagnosis of exclusion, he said, with no consensus on the set of investigations. The role of the bone marrow biopsy and aspirate in ITP are controversial.

Thrombocytopenia in the hospitalized patient has many possible etiologies; special consideration should be given to drug-induced thrombocytopenia considering its frequency in this setting, said Dr Stasi. Heparin-induced thrombocytopenia is often a clinical emergency and typically develops after 5 to 10 days of exposure to heparin.

Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

ASH Conference Coverage 

Across specialties, prior authorization (PA) is the bane of physicians and their office staff. Once employed as a utilization management tactic primarily for more benign therapeutic classes, it is now a ubiquitous force in oncology management—one that is expected to become even more targeted beyond US Food and Drug Administration (FDA) indication alone.

Recent research conducted by HRA (Healthcare Research & Analytics, a market research consultancy based in Parsippany, New Jersey) reveals that 93% of the 47 major health plans included in its recent study routinely employ PA to manage utilization of oncology agents. Over three-fourths of these payers, which cover over 100 million lives in total, place at least some reliance on rigid PA that links approval with product efficacy at specific milestones, or rely on PA to ensure that the appropriate biomarker tests are conducted prior to approval of specific agents. In the future, the use of more stringent PA criteria is expected to increase significantly—with nearly 90% of the plans intending to link PA to specific treatment milestones and even more planning to link PA with genetic testing (

“Any specialty other than oncology, this is the way you’d do it—fairly rigid according to what the evidence has shown,” states one key opinion leader participating in the research who is employed by a major US payer organization. “Oncologists want a separate set of guidelines for how they manage patients. The problem is you’re dealing with expensive drugs, and we have a fiduciary responsibility to make sure what the employer is paying for is appropriate, and to keep the physicians honest.…When you have a third party paying for it, they have a right to a say on how it’s being spent.”

 Changing Paradigms in Managed Care— Oncology Management

, surveyed oncologists and oncology nurse navigators clearly are not pleased with the trends toward increased PA use.

“Who’s going to be calling for all these approval[s]?…I’ve got somebody that’s got metastatic cancer. They need to be treated now—not a month from now, not 3 months from now,” stated an oncologist participating in HRA’s study.

“We spend a lot of time in trying to do the best…for our patients [to get treatments] approved and it basically delays care.”

In fact, the use of more stringent prior authorization guidelines will lead about half of the 100 medical oncologists participating in the research to reconsider their first-choice oncolytic agent due to the hassle factor that PA presents (

). PA based on product efficacy at select milestones or on the number of treatment cycles, as well as step therapy requirements enforced via PA, serve as the primary deterrents, whereas oncologists are less fazed by the idea of payers requiring specific biomarker/genetic tests before approving the associated agents. Fortunately, for the oncologists and the patients they treat, widespread use of PA beyond FDA indication alone is not occurring—yet.

Although managed care is including general PA as a requirement for over two-thirds of oncology agents, on average, more stringent PA is just emerging. PA based on patient response to specific treatments, on biomarker/ genetic testing, and as a means to enforce step therapy is currently in place for one-fifth or less of agents, though significant increases in prevalence are expected over the next few years (Table).

The growing presence of step therapy poses a disadvantage for new oncology agents—logistically as well as conceptually&mdash; as oncologists maintain strong perceptions that new oncolytic agents are very likely to be subject to PA. Agreement with this concept is noted among over 80% of oncologists in the research. Further, nearly 2 out of 3 oncologist participants point to PA as a deterrent to prescribing new agents (

“[There will be] a lot more prior authorization, a lot more attempt to engage oncologists around pathway adherence, and end-of-life discussions earlier in the course of therapy,” said a key opinion leader participating in the research, “because these are felt to be the biggest variables that contribute the most to cost.”

Increased PA, the development of clinical pathways programs, and high copays/ co-insurance levels are leading oncologists toward perceptions of oncology as now being a “heavily managed” category. While over half of oncologists currently perceive payers as providing hands-on management of oncology, 8 in 10 oncologists predict that active management will be the norm 2 or 3 years from now (

). Further, those oncologists who have more negative perceptions of payers and their involvement in oncology are more inclined to suggest that payers will be more stringent in both the short and long term (

“There is a new intensity of scrutiny from the payer side, a significant increase in protocols and other management constraints on oncology,” said one of the key opinion leaders participating in the research. “Across all lines of business, saying ‘We’re not going to pay for everything, and if we are, we need to have some understanding of medical necessity, and the rationale around morbidity, mortality, and patient improvement.’”

By 2015, oncolytic agents are predicted to be the second- or third-greatest driver of total drug spend, an increase from seventh place in 2011.

 By 2020, total cancer costs are projected to reach $158 billion.

 To ensure their own fiscal survival, payers may be left with little choice but to increase controls in oncology, despite the potential backlash.

So the question remains—which direction will payers take in exerting greater control over the oncology category? Will novel approaches such as clinical pathways programs provide enough specific direction and incentive to control spend, or will payers need to resort to the more traditional mainstay of prior authorization to manage utilization? If prior authorization in oncology continues to evolve, just how far will payers be willing to go in the stringency of their requirements, without risking major repercussions among oncologists? And, will oncologist and payer affiliations in integrated delivery networks help enforce these approaches?

As one payer respondent participating in the research states, “We have a number of prior auth requirements on most of these agents, but are limited in our effectiveness by the strong public pressure and some special legal protections they enjoy.”

Balancing the need for fiscal soundness with public policy considerations as well as—most importantly&mdash;the need to provide patients with the most effective treatments is a fine line for payers, one that continues to fray with each new expensive oncology treatment that comes to market.

 From Healthcare Research & Analytics, Parsippany, NJ.

 Ms Fox reports employment with HRA—Healthcare Research & Analytics, the company that produced this research. HRA is owned by MJH & Associates, which also owns The American Journal of Managed Care.

Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

 Lisa A. Fox, Vice President, Research Strategy, Healthcare Research & Analytics, 400 Lanidex Plaza, Parsippany, NJ 07054. E-mail: lfox@hra research.com.1. Study by Express Scripts, via Real Endpoints Advisory Services. www.valueandinnovation.com/research/cancer-pathways-provide-leverage-for-payers-hurting-biopharma/. Accessed December 10, 2012.

2. Cancer’s growing burden—the high cost of care. USA Today website. www.usatoday.com/news/health/story/health/story/2012-02-27/Cancers-growing-burden-the-high-cost-ofcare/53271430/1. Published February 27, 2012. Accessed December 10, 2012.

January/February

Lessons From an Oncology Medical Home Collaborative

Literature Review: Chronic Myeloid Leukemia

Literature Review: Melanoma

Crossroads in Breast Cancer: The Intersection of Clinical Uncertainty and Molecular Profiling

ASH Conference Coverage

Managed Care Restrictions: Barriers to Product Use in Cancer Care

Partial Fill Strategies for Oral Oncolytics to Reduce Waste and Drive Persistency

From Bench to Bedside: Promising Colon Cancer Clinical Trials

The Future of Oncology? COME HOME, the Oncology Medical Home

Focusing on Clinical and Economic Outcomes-Not Guidelines

The Role of Companion Diagnostic Testing in Payer Decision Making