The debate is global: how long can healthcare systems sustain the continually rising costs of care? Pharmaceutical and biotechnology companies are investing heavily in research to develop new molecules with improved efficacy and minimal adverse effects, novel drug delivery technologies, and diagnostic tests that can help personalize therapy as well as monitor response to therapy, especially in oncology.

Here’s the big picture: a report by the Pharmaceutical Research and Manufacturers of America (PhRMA) published last year indicated that it takes an average of 10 to 15 years to develop 1 drug molecule.

 Furthermore, drug development costs have experienced a steep rise over the past few decades: estimated at $140 million back in the 1970s, recent assessments reveal that the cost to develop 1 drug molecule now ranges from $1.3 to $11 billion.

 R&D spending, meanwhile, has also seen a steady increase—PhRMA projected its average per member cost, which was $2 billion in 1980, to be $48.5 billion for 2012.

 Like any other industry, the pharmaceutical sector seeks a return on its investments. So what does the spending translate into? Rising drug costs.

However, the discussion, especially in the oncology realm, is about whether the modest increase in benefit observed with some of the newer therapies—sometimes a few added weeks or months of life&mdash;justifies the cost (Figure 1). Back in 2012, Memorial Sloan Kettering Cancer Center took a stand and chose Avastin (which costs about $5000 per month) over Zaltrap (which costs about $11,000 per month) for treating patients with advanced metastatic colorectal cancer. Zaltrap, developed by Sanofi/Regeneron, was no more effective than Genentech’s Avastin. Subsequently, Sanofi was forced to reduce the price of Zaltrap by 50% in the United States.

There is no arguing that this tremendous investment in cancer care has paid dividends for patients. Since 1980, 83% of the improvement in the life expectancy of cancer patients has resulted from new treatments, which include novel medicines.1 Innovative approaches such as RNAi, cancer vaccines, and immunotherapy (both monoclonal antibodies and the new immunooncology inhibitors) are transforming the therapeutic spectrum. Screening and early detection have improved outcomes, at least for certain cancer types. The National Breast and Cervical Cancer Early Detection Program (NBCCEDP), run by the CDC following a Congressional directive, provides screening and diagnostic services to low-income and uninsured women throughout the country. Since 1991, the program has diagnosed more than 62,121 cases of breast cancer, 3458 cases of invasive cervical cancer, and 163,548 premalignant cervical lesions. Early detection in these 2 cancer types have definitely proved beneficial.

Drug development, of course, is just 1 variable in the equation of cancer care. Other treatment-associated costs, including doctor visits, hospitalization, and out-patient services such as laboratory tests, complete the picture.

The Affordable Care Act of 2010 supported the development of accountable care organizations (ACOs), with this objective: collaborative and coordinated care to improve quality, value, and health outcomes for patients. ACOs are expected to greatly impact Medicare spending. A feared potential drawback, however, is provider consolidation. This could drive up the cost of care, with the patient ultimately footing the bill (

However, providers can play a significant role in reducing these costs, as was argued during the session “Cancer Overdiagnosis and Overtreatment, or Appropriate Attention to Early Disease?” on June 1, 2014, at the annual meeting of the American Society of Clinical Oncology (ASCO) (see page SP285). To this end, ASCO’s Value of Cancer Care Task Force developed a list of opportunities for physicians to improve the quality and value of care delivered, as part of the Choosing Wisely campaign.

The debate will persist about choices made by physicians while treating an individual patient versus policies that govern the patient population as a whole. During a session that discussed the value of care (see page SP283), Daniel P. Sulmasy, MD, PhD, professor of medicine and associate director at the MacLean Center for Clinical Medical Ethics at the University of Chicago, said, “Population medicine cannot be practiced at the bedside. The goal is to improve the life of an individual patient and not the population. Bedside rationing and providing financial incentives can threaten the integrity of medicine and also undermine the patient’s trust.” 

1. 2013 profile: biopharmaceutical research industry. PhRMA website. http://www.phrma.org/sites/default/files/pdf/PhRMA%20Profile%202013.pdf. Accessed July 30, 2014.

2. Herper M. The truly staggering cost of inventing new drugs. Forbes website. http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of inventing-new-drugs/. Published February 2, 2012. Accessed July 30, 2014.

3. Boltz K. Cost challenges in developing new oncology drugs. OncLive website. http://www.onclive.com/publications/oncology-business-news/2013/november-2013/cost-challenges-in-developing-new-oncology-drugs/1. Published December 4, 2013. Accessed July 30, 2014.

4. National Breast and Cervical Cancer Early Detection Program (NBCCEDP). CDC website. http://www.cdc.gov/cancer/nbccedp/about.htm. Updated March 7, 2014. Accessed August 3, 2014.

5. Accountable care organizations. America’s Health Insurance Plans website. http://www.ahip.org/Issues/ACOs.aspx. Accessed July 31, 2014.

6. New ASCO Choosing Wisely list details five cancer tests and treatments routinely performed despite lack of evidence. Choosing Wisely website. http://www.choosingwisely.org/new-asco-choosing-wisely-list-details-five-cancer-tests-and-treatments-routinely-performed-despite-lack-of-evidence/. Accessed July 31, 2014.

Articles

Evidence-Based Oncology

Cancer Care in the United States: The Path Ahead

The epidermal growth factor receptor (EGFR), one of the many receptor tyrosine kinases that are targeted in cancer treatment, is frequently overexpressed or mutated in cancer, resulting in cell proliferation, survival, invasion, metastasis, and tumor-induced neoangiogenesis.

 The approach to targeting EGFR in cancer has included the use of small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, lapatinib, and afatinib, and monocloncal antibodies such as cetuximab, panitumumab, and matuzumab (

A session titled “Targeting EGFR: The Next 10 Years,” held May 31, 2014, on the second day of the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), provided a progress report on the successful targeting of the protein in non-small cell lung cancer (NSCLC).

The opening talk by Pasi A. Janne, MD, PhD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute and professor of medicine, Harvard Medical School, was titled “Clinical Activity of the Mutant-Selective EGFR Inhibitor AZD9291 in Patients With EGFR Inhibitor-Resistant NSCLC.” Janne presented results from a phase 1, open-label, multicenter clinical trial with a selective, third-generation EGFR-TKI by AstraZeneca, AZD9291, that has been found to be effective against both EGFR-TKI—sensitizing and resistance (T790M) mutations in preclinical models.

The trial, conducted in 199 EGFR mutant (T790M+) NSCLC patients with acquired resistance to EGFR-TKIs, conducted a dose escalation and expansion study of oral AZD9291. Among all the evaluable patients, the confirmed+unconfirmed overall response rate (c+uORR) was 51% (91/177). Response Evaluation Criteria in Solid Tumors (RECIST) responses were observed at all dose levels and in brain metastases. Of 132 patients with centrally confirmed T790M, the c+uORR in 89 EGFR T790M+ patients was 64% (95% CI: 53%-74%), and in 43 EGFR T790M patients was 23% (95% CI: 12%-39%). The overall disease control rate in T790M+ patients was 96% (85 of 89). Among the 60 patients with a confirmed response, 97% (58 of 60) were ongoing at data cutoff and the longest duration of response was greater than 8 months. AZD9291 did not present any dose-limiting toxicities, maximum tolerated dose (MTD) was not defined, and the most common adverse events (AEs) were diarrhea, rash, and nausea. Very few grade 3 or higher AEs were observed in any of the cohorts. The overall response rate (ORR) was 53% and the overall disease control rate was 83%. A progression-free survival (PFS) benefit was observed in T790M+ patients. The results of this study have helped establish the dose for the phase 2 trials.

The phase 1 study demonstrated that T790M+ NSCLC patients with acquired resistance to EGFR-TKIs respond very well to AZD9291 and have a higher ORR compared with the EGFR T790M patients. Further clinical developments directed at the T790M+ patient population are ongoing.

The subsequent presentation was a dose-finding study for Clovis Oncology’s CO-1686, a molecule that targets the EGFR T790M mutation in NSCLC patients, which recently received the FDA’s “breakthrough therapy” designation.

 Designed to target mutant EGFR, CO-1686 does not bind wild-type EGFR, thus increasing specificity and reducing adverse effects, which makes it eligible as first-line therapy in patients with activating EGFR mutations.4 Clovis wants to develop CO-1686 as an oral treatment for NSCLC patients who have failed EGFR-directed therapy, such as Tarceva (Genentech) or Iressa (AstraZeneca), and have also developed the T790M mutation, which is the dominant resistance mechanism to Tarceva/Iressa.

The results were presented by Lecia V. Sequist, MD, MPH, Massachusetts General Hospital. The first-in-human dose-finding study was conducted in 88 patients with EGFR-mutated advanced NSCLC. The formulation, a hydrogen bromide salt form of CO-1686, was administered to patients who were previously treated with EGFR TKI and had a tumor biopsy in screening for central EGFR genotyping. The patients had previously received a median of 3 therapies, with 40% having had more than 1 prior line of EGFR TKI. Related AEs, which were mild and observed in about 10% of patients, included nausea, fatigue, and hyperglycemia (managed with oral hypoglycemic agents such as metformin, with or without dose reduction). A recommended phase 2 dose of 750 mg twice a day was selected.

ORR was 58% in biopsy-proven, heavily pretreated, centrally confirmed T790M+ patients, and the responses deepened over time with longer follow-up. Median PFS was not reached at the time the data was presented, but was projected at more than 12 months. The trial also observed central nervous system responses with the drug.

CO-1686 proves promising in T790M+ EGFR mutant NSCLC patients, and the phase 1 study provided proof of concept that targeting the mutant form of EGFR can reduce AEs like diarrhea and rash. The phase 2/3 program initiated this year called TIGER (third generation inhibitor of mutant EGFR in lung cancer) is actively recruiting patients for 3 registration studies.

The subsequent presentation by Gideon Michael Blumenthal, MD, Holy Cross Hospital, who is also a clinical team lead with the FDA, was entitled “Overall Response Rate (ORR) as a Potential Surrogate for Progression-Free Survival (PFS): A Meta-Analysis of Metastatic Non-Small Cell Lung Cancer (mNSCLC) Trials Submitted to the FDA.” There is an ongoing debate about the appropriate end points in clinical trials—they hold immense importance in oncology trials&mdash;and the FDA has guidelines for same.

 The use of surrogate markers has stemmed from the accelerated drug approval process, whereby drug manufacturers often use surrogate end points to speed up drug launch, to save or extend lives. These surrogate end points include ORR, PFS, disease-free survival (DFS), time to progression (TTP), and patient-reported outcomes.

Targeted therapies (TT) administered as single agents in molecularly defined mNSCLC subsets are yielding high ORRs. Additionally, large improvements in PFS with favorable benefit-to-risk ratio have served as the basis of drug approval in mNSCLC. However, the relationship of ORR with PFS or OS in mNSCLC is not established. The FDA conducted a meta-analysis using data from 15 mNSCLC trials that were submitted to the agency, which enrolled 12,534 patients, including 3 trials of TT in molecularly enriched populations with high (HR) and OS HR versus the estimated odds ratio (OR) of ORR on the log scale was calculated.

On a trial level, the meta-analysis of randomized, active-controlled trials indicated a strong correlation between ORR and PFS (R2 = .89), especially for head-to-head trials, which means ORR could be an acceptable surrogate for PFS. A correlation between ORR or PFS and OS is not established and may be confounded by crossover in the TT trials. This might either be the result of a weak relation or no relation or a high crossover, under-power, or long post program survival, in the 3 small targeted therapy trials in the enriched population, which may confound the analysis. At the trial level, a TT in a molecularly defined subset of mNSCLC with a large magnitude of effect on ORR will likely have a large effect on PFS.

Lawrence H. Schwartz, MD, a diagnostic radiologist at Columbia University Medical Center and at NewYork-Presbyterian Hospital, concluded the session with his talk titled “Getting the Right Drug to the Right Patient Faster,” wherein he provided his critique on the current treatment protocols that analyze response versus progression of disease.

“It’s critical to distinguish response and progression as 2 distinct events,” said Schwartz. Response rate is objective, measurable, and reproducible. Additionally, there’s a long history—more than 30 years&mdash;of standardization and measurement of response. But the definition of response needs to be challenged and modified, he said. RR can be strongly correlated with median survival time, but the question remains—– what is “optimal” RR?

Moving on to analyzing progression, Schwartz asked, “How accurate a gold standard is progression?” Alternate methods to assess response and progression to find effective therapies earlier are needed. To this end, the FNIH-sponsored VOL-PACT trial is under way, which considers an entire spectrum of metrics, not just RR. “The value proposition of these simulations is that combining metrics with imaging would provide much improved results,” said Schwartz.

He concluded the session by saying that there is a need to combine smarter trials and smarter trial end points, including imaging, to derive optimal results and responses. 

1. Ciardiello 1, Tortora G. EGFR antagonists in cancer treatment. 

2. Chanprapaph K, Vachiramon V, Rattanakaemakorn P. Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management [published online March 2, 2014]. 

3. Clovis Oncology receives breakthrough therapy designation for CO-1686 for the treatment of second-line EGFR mutant non-small cell lung cancer (NSCLC) in patients with the T790M mutation. Business Wire website. http://www.businesswire.com/news/home/20140519006502/en/Clovis-Oncology-Receives-Breakthrough-Therapy-Designation-CO-1686#.U76NarH93Z0. Accessed July 10, 2014.

4. CO-1686. Clovis Oncology website. http://www.clovisoncology.com/products-companion-diagnostics/co-1686/. Accessed May 31, 2014.

5. Guidance for industry clinical trial endpoints for the approval of cancer drugs and biologics. FDA website. http://www.fda.gov/download/drugsGuidanceComplianceRegulatoyInformation/Guidance/UCM071590.pdf. Published May 2007. Accessed May 31, 2014.

6. McCain JA. The ongoing evolution of endpoints in oncology. Manag Care. 2010;19(5 suppl 1). http://www.ptcommunity.com/supplements/1005_CB_endpoint/CB_endpoints.pdf. Accessed May 31, 2014.

The EGF Receptor (EGFR) Continues to Be a Promising Target in NSCLC

The beta cell lymphoma-2 (BCL-2) protein family—key regulators of apoptosis in human cells&mdash;includes both proapoptotic and antiapoptotic/prosurvival proteins. Cancer cells use prosurvival proteins to evade apoptosis, and inhibitors of these proteins have been in development for some time now. ABT-199, the result of a collaboration between AbbVie and Genentech, is a selective, potent, orally available BCL-2 inhibitor (

 ABT-199 is being developed for the treatment of acute myelogenous leukemia and chronic lymphocytic leukemia (CLL).

The following posters presented at the meeting provided the current status of this promising drug moiety.

ABT-199 in the treatment of diffuse B-cell and follicular lymphoma

The objectives of this phase 1 dose-escalation study included evaluation of safety, pharmacokinetics (PK), and preliminary efficacy in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). ABT-199 was administered on week 1, day 1, followed by continuous, once-daily dosing from week 1, day 7, until the disease progressed or unacceptable toxicity was observed. A 2- to 3-week lead-in period with stepwise dose titration was implemented. As of April 2014, 20% or more of 62 patients presented with all-grade adverse events (AEs) of nausea, vomiting, anemia, and fatigue, while 5% or more presented with grade 3/4 AEs of anemia, neutropenia, and thrombocytopenia. A case study presented showed anti tumor activity of ABT-199 in a stage 2 mantle cell lymphoma patient who had previously undergone 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin, and prednisone) and 2 cycles of R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) and IFRT (involved-field radiation therapy). A 6-week treatment with ABT-199 showed complete clinical resolution of node after 6 weeks. The overall response rate was 48% in the evaluated NHL patients. The authors are in the process of conducting biomarker studies with ABT-199.

Interim results from a phase 1b trial of ABT-199 plus rituximab in CLL

The objective of this trial was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of ABT-199 with rituximab in patients with relapsed/refractory (R/R) CLL, and to determine a recommended phase 2 dose. The most common treatment-emergent AEs, observed in more than 25% patients, were neutropenia (43%), nausea (38%), and diarrhea (30%). The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%), and anemia (11%). Two dose-limiting toxicities were observed with ABT-199 + rituximab: thrombocytopenia and hemophagocytic syndrome. The addition of rituximab to ABT-199 identified no new toxicities. The combination was active in R/R CLL with a substantial complete response (CR) rate. Best CR of 89% was observed in R/R patients and 39% achieved CR/CR with inadequate recovery (CRi). Absence of minimal residual disease was observed in 6 of 8 patients tested who had achieved CR/CRi, along with 5 patients who had a partial response. A fatal episode of tumor lysis syndrome (TLS) occurred during the ABT-199 lead-in period, but dosing modifications and increased monitoring prevented the occurrence of any further TLS events. Rituximab did not seem to influence ABT-199 exposure.

A phase 3 trial is ongoing in previously treated CLL patients, to evaluate ABT-199 plus rituximab versus bendamustine plus rituximab.

Phase 1 study of ABT-199 in CLL and SLL patients: determine safety, PK, efficiency

The primary objectives of this phase 1 study were to evaluate the safety and PK and to determine the maximum tolerated dose and a recommended phase 2 dose of ABT-199 in patients with CLL and small lymphocytic leukemia (SLL). A secondary objective was to assess preliminary efficacy. Following early events of TLS, a weekly ramp-up period to the final cohort dose (150-1200 mg) was implemented. Patients are currently being enrolled in the safety expansion (SE) cohort. Most common AEs observed were diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 AEs (≥3 patients) were neutropenia (32%), anemia (8%), TLS (8% including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). Twenty-eight patients discontinued the study: 18 for disease progression, 8 for AEs, and 2 for other reasons. ABT-199 monotherapy was active in patients with R/R CLL with a 77% RR. Patients with high-risk CLL showed similar efficacy, with OR above 75%. ABT-199 monotherapy and combination therapy in CLL are currently enrolling. This includes a phase 3 trial evaluating the combination of ABT-199 and rituximab compared with bendamustine/rituximab in patients with relapsed CLL4 and combination studies with bendamustine/rituximab and obinutuzumab in patients with relapsed CLL. 

1. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. 

2. Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) Promising Results in Leukemia From a BCL-2 Inhibitor at higher cohort doses. 

3. Ma S, Seymour JF, Lanasa MC, et al. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): interim results of a phase 1b study. 

4. A study of GDC-0199 (ABT-199) plus MabThera/Rituxan (Rituximab) compared with bendamustine plus MabThera/Rituxan (Rituximab) in patients with relapsed or resistant chronic lymphocytic leukemia. ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT02005471. Accessed July 10, 2014.

5. Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high completeresponse rate and durable disease control. 

Promising Results in Leukemia From a BCL-2 Inhibitor

May 31, 2014, the second day at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), ended with a session entitled “Health Care in America in 2014: Current and Future Implications of the Patient Protection and Affordable Care Act” (ACA). The presenters provided an overview of the recent and anticipated changes related to the ACA as well as its timeline. The panelists also explored how federal budget sequestration might affect reimbursement, Medicare, and funding of research and drug development.

Rena M. Conti, PhD, a health economist and assistant professor in the section of hematology/ oncology at the University of Chicago, opened the session with, “Bracing

for the Future: Impact of Changes in Healthcare Policy on Drug Development.” Healthcare spending in the United States is already 17.7% of current gross domestic product (GDP), and is projected to rise to 22% in 6 years, she said. About 1 of every 20 healthcare dollars is spent on cancer care, said Conti, although estimates vary among

Conti affirmed that cancer care costs are rising faster than overall healthcare and cancer care is outpacing all other healthcare spending, with the current costs estimated at $125 billion. The ACA will increase that level of spending, and a population that is increasingly older will add to the financial burden.

So where is the problem? It manifests in the skirmish between the average value of new innovations and their application to individual patients. There result: although improvements in survival benefit are observed (due to various contributing factors such as improved screening techniques, treatment advances, and behavioral changes) (

), there is overuse and misuse of therapies. This is in addition to the off-label and unapproved use of drugs.

There is no argument that drug costs have seen a substantial increase, although the newer molecules have improved precision and thus response to therapy. But are these costs sustainable?

“So the fundamental question remains, how do we improve access and cost-effectiveness of these therapies while maintaining innovation?” asked Conti.

Conti laid out the political economy of reform. The cost of a drug is 2-pronged: if patients are well insured, they don’t face very steep bills. Additionally, co-payment assistance is widely available for branded therapies. This, however, acts as a lever to inflate prices.

Consequently, physician practices face significant pressures to find deep discounts on acquisition prices of these therapies, and the 340B drug pricing program, which requires drug manufacturers to provide outpatient drugs to eligible healthcare organizations or covered entities at significantly reduced prices

resulted in a major consolidation of practices.

Conti highlighted the “how” of reform:

1. Change drug reimbursement policy: maintain the current system but make efforts to closely match reimbursements with acquisition costs.

2. Change the locus of risk bearing from physicians and hospitals to pharmacy benefit managers and insurers.

3. Change reimbursement models to include novel drugs.

Use of generic therapies is an obvious opportunity to exploit, she said. For example, Gleevec is going off-patent in 6 months, and replacing it with a generic will cause a drastic drop in drug price. “Each stakeholder—the provider, the payer, and the manufacturer&mdash;has a role to play in bringing about this payment reform,” concluded Conti.

Lawrence N. Shulman, MD, chief of staff and senior vice president for medical affairs at Dana-Farber Cancer Institute, and associate professor, department of medicine, Harvard Medical School, presented his perspective on “The Impact of Accountable Care Organizations on Oncology Practice.” He explained what accountable care

organizations (ACOs) are and what can be done to best position oncologists in that environment.

He started off with the CMS definition of an ACO.

 ACOs are groups of doctors, hospitals, and other healthcare providers who come together voluntarily to deliver coordinated high-quality care to their Medicare patients.

The goal of coordinated care is to ensure that patients, especially the chronically ill, get the right care at the right time, while avoiding unnecessary duplication of services and preventing medical errors. When an ACO succeeds, both in delivering high-quality care and spending healthcare dollars more wisely, it will share in the savings it achieves for the Medicare program.

Shulman then delineated the characteristics of an ACO. Patients participate in an ACO if their primary care physician (PCP) is enrolled in it. Patients are not restricted to

seeking care from predetermined providers, although PCPs may try to direct care. Although the payment is fee-forservice, the actual cost is still determined by CMS.

The question remains, though, “What do patients want? Access to treatment for best chance of survival, an improved quality of life, high ficiently, and of course affordable care,” said Shulman. Payers are interested in high-quality care, at a reasonable cost, and they want affordable premiums that are acceptable to their clients. The third stakeholder in the equation, the oncologist, wants freedom to provide the best care, fair compensation, and freedom from administrative burdens to be better able to focus on care.

Shulman then said that cancer care is different with regard to ACOs. PCPs manage or co-manage patients with diabetes, heart failure, and other ailments with specialists, and influence the cost of care. But they cede care of the cancer patient to a specialist and so are out of the cost equation. However, PCPs would share the risk and benefit of ACO performance when employed by a hospital or by multi specialty practices.

The challenges with cost include noninformed decision making. Oncologists are not very good at measuring patient outcomes, managing cost of care, and factoring in cost of treatment during care. Much of what they do daily in the clinic only provides weak evidence to help decide between treatments. “But,” emphasized Shulman, “that cost must be factored in when making treatment decisions.” Pathways, he said, must include the total cost of care, and the oncologist must carefully evaluate the cost of imaging, the selection of a testing laboratory, and other factors, based on what is absolutely needed.

Shulman’s concluding remarks were that pathway developers need to make tough decisions. Partnerships between providers and payers can control costs and improve

care. “We should aspire to do these things with the patient in mind,” said Shulman. “The current system is not patient centered.”

How oncology practices will fit into and interact with ACOs is not very clear yet. Oncology practices should play an active role in the control of cancer care costs to fit into the quality metrics of care.

“Healthcare Reform 101: Summary of the Recent and Planned Changes Related to the Patient Protection and Affordable Care Act” was presented by Blase N. Polite, MD, MPP. Polite, an assistant professor of medicine in the section of hematology/oncology at the University of Chicago and chair of the ASCO Government Relations Committee, offered an overview of the impact of the PPACA on patients and providers.

Polite discussed ASCO’s policy on Medicaid expansion, which has been the source of controversy in some states due to the US Supreme Court ruling that upheld ACA but allowed states to opt out of extending Medicaid to Americans in the low-income tier just above the poverty level. ASCO’s policy, Polite said, is that “All states should expand their Medicaid program to provide coverage, at least for individuals with incomes below the poverty level, or should come up with an alternate strategy that provides comprehensive subsidized health coverage that ensures, among other benefits, access to high-quality cancer care, measured by cancer-specific quality metrics, delivered by a cancer specialist.”

• expand the list of cancer risk syndromes covered

• clarify that follow-up testing should be covered without cost sharing

• clarify that coverage for risk-reducing surgeries is covered

The clinical trial provisions under ACA state that health plans cannot:

• deny an individual participation in a clinical trial

• deny, limit, or impose additional conditions on the individual associated with participation in a trial

• discriminate against the individual for participation in a trial

However, these provisions are not yet backed by strong regulations. They do not apply to Medicaid patients or those covered by “grandfathered” health plans, and they do not allow out-of-network coverage. Polite emphasized that oncologists need to monitor the implementation of these policies by health plans.

Polite concluded by saying that the ACA-implemented provisions are good news for cancer patients overall, although there are a few concerns with regard to coverage and penalties on physicians caring for the poorest and sickest patients. 

1. 340B Drug Pricing Program. HHS website. http://www.hrsa.gov/opa/. Accessed June 1, 2014.

2. Accountable care organizations. CMS website. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ACO/. Accessed May 31, 2014.

Impact of the Affordable Care Act on Cancer Care

Earlier this year, the American Society of Clinical Oncology (ASCO) brought together the pharmaceutical industry, payers, providers, and patient advocacy groups to initiate a conversation on the challenges of defining value in cancer care. Annual costs in cancer care are escalating with no end in sight; estimated at $125 billion in 2010, treating cancer patients is predicted to cost the United States a staggering $175 billion in 2020.

 While the cost of newly improved drug molecules and drug delivery systems accounts for a significant part of these totals, several other factors contribute. Quality improvement measures (such as QOPI) and participation in the Choosing Wisely campaign adopted by ASCO can help develop and promote high-quality, evidence-based care.

Healthcare providers play an extremely important role in choosing the right treatment and care option without compromising the quality of care. On the second day of the 50th Annual Meeting of ASCO, “The Value of Cancer Care and the Professional and Ethical Obligations of the Practicing Oncologist: A Debate” delved into the ethical issues raised by the economic reality of the rising costs of cancer care for the practicing oncologist. The presenters discussed the potential conflict between costs and

value in cancer care, as well as affordability issues and how they may come into conflict with respecting the patient’s individual wishes and needs.

The 3 physicians who participated in this session co-authored an article that was published online by ASCO: Value of Cancer Care: Ethical Considerations for the Practicing Oncologist.

Beverly Moy, MD, MPH, clinical director of the breast oncology program at the Massachusetts General Hospital, Harvard Medical School, opened the discussion with her talk, “‘Value’ and ‘Values’ in Cancer Care: Can We Balance Our Duties to Patients and Society?” Moy began with an example of a 32-year-old woman with HER2+ breast cancer without metastatic disease. The dilemma in this case was, in addition to adjuvant chemotherapy and trastuzumab, could she be administered pertuzumab? Pertuzumab is priced at $4890 to $6000 per cycle.

Pertuzumab was granted accelerated approval by the FDA as neoadjuvant therapy for HER2+ early-stage breast cancer; however, there are no data demonstrating improved overall survival or event-free survival. Additionally, no data demonstrating its efficacy in the adjuvant setting are available.

Another example was of a 38-year-old woman, with ALK+ lung cancer. She had stage T2aN1 non-small cell lung cancer (NSCLC) with ALK rearrangement but no metastasis. The dilemma with this patient: Is there a role for crizotinib in the adjuvant setting? Crizotinib, which costs $9200 to $12,000 per month, improves response rate and progression-free survival with ALK rearrangements, but there are no data on adjuvant treatment.

The cost of cancer care is skyrocketing. The National Institutes of Health estimated the total cost for cancer care for the year 2009 at $216.6 billion, and cancer therapy takes up 5% to 11% of the national healthcare budget. Asked Moy, “Where is the major spending? Technology and drugs account for most of the costs, and chemotherapy takes up a major chunk of the drug cost.” Moy went on to emphasize that practicing oncologists are the gatekeepers of chemotherapy and patient care, and so in some way are responsible for the cost. Six of the 8 drugs approved by the FDA in 2013 cost $10,000 per month. Alarmingly, most of these failed to show improved survival, and even if they did, the results were modest. “Where’s the value? The response to this question will vary based on the stakeholder who’s asked. There’s no consensus,” said Moy.

Moy ended her talk by echoing the thoughts that were expressed in the value session on the first day of the meeting—no consensus has yet been reached in defining value.

“The ethical dilemma arises because the oncologist’s duty is split between the patient and the society, and choosing a side is extremely difficult. The cost of this dilemma—patient deprivation of lifesaving therapy.”

Daniel P. Sulmasy, MD, PhD, professor of medicine and associate director at the MacLean Center for Clinical Medical Ethics at the University of Chicago, took the stage next to discuss “Advocating for the individual patient’s good should be the oncologist’s priority.” His research interests include end-of-life decision making, ethics education, and spirituality in medicine.

As the speaker before him, Sulmasy began the discussion by stating that costs in oncology have spun out of control, and oncologists are responsible for controlling the

costs. However, he argued that this cost control cannot be implemented at the patient’s bedside. Economics and public policy do not control bedside medicine—it’s about treating an individual patient and not the population. In the art of medicine, the individual patient is of interest: “Will this drug be useful to this patient under a particular

circumstance?” However, science is concerned with population effects and not an individual patient. Clinical medicine is a blend of both, he said—it involves science directed to an individual patient.

“Population medicine cannot be practiced at the bedside. The goal is to improve the life of an individual patient and not the population,” said Sulmasy. Medicine has historically been treated as a business. However, given the necessity of access to medicine, it should be considered a public good and not a business. Patients should trust that the physicians are practicing medicine to improve their lives.

The question that arises, therefore, is: How can we control healthcare costs without compromising on quality?

“Bedside rationing and providing financial incentives can threaten the integrity of medicine,” said Sulmasy. “They also undermine the patients trust: is the CT scan ordered

to increase personal income or do I really need it? Additionally, financial incentives disrupt the balance between the professional, the state, and the market.”

In the absence of transparent and universally applicable rules, treatment will become unpredictable and idiosyncratic, and it will not achieve the goals of those who are advocating it.

So the big question is: How can costs be contained in a morally appropriate manner, and what’s the oncologists role? “Diagnostic elegance and therapeutic parsimony are the call of the hour. Diagnostic elegance translates into using only those tests necessary to diagnose a patient, while therapeutic parsimony means using adequate treatment, not overtreatment.”

The session was wrapped up by Reshma Jagsi, MD, DPhil, associate professor of radiation oncology, University of Michigan. Jagsi’s clinical practice and research are

focused on breast cancer, but she is also actively involved in social, political, and ethical aspects of medical care. In her talk, “The Oncologist’s Duty to Society,” Jagsi stated that physicians have a moral duty to society and they have a privileged professional role. They have an obligation to serve not only their individual patient, but also the society in general.

It has been proved that healthcare spending crowds out other spending in social services that are essential to promote health. Additionally, the rising cost of care limits access by limiting the affordability of care. Rationing is no longer an issue of whether, but how. Resources are finite and allocation must happen. “Physicians owe it to society to help ensure that resources are allocated in a way that is congruent with broad moral intuitions, as well as to reduce waste to maximize the value of our interventions,” said Jagsi.

She affirmed that physicians must be stewards to lead an evidence-based assessment of value, including studies to identify situations of overdiagnosis and overtreatment in healthcare. Eliminating waste is absolutely essential, and it could be initiated at the level of the easy low-hanging fruit. For example, a shorter course of radiotherapy for preventing bone metastases or for adjuvant treatment of breast cancer. Embracing such an approach could reduce cost and improve outcome as well. Another easy fruit to pick is utilizing cheaper therapy with the same outcomes. Jagsi believes it’s not just about financial incentives—oncologists are a little nervous about adopting cost-saving changes when they lack a clear understanding. An example of a more difficult decision to make would involve a patient who is unlikely to benefit from a treatment with high costs for society, but who demands to be administered the drug. This would create a conflict for the provider, who would have to balance his obligation to society with obligation to his patient.

The Choosing Wisely campaign by the American Board of Internal Medicine is engaging professional societies like ASCO to obtain therapeutic parsimony and diagnostic

elegance. ASCO in turn has issued top 5 lists of opportunities to improve the quality and value of care.

Jagsi left the audience with the following words of wisdom from Howard Brody, MD, PhD, director of the Institute for the Medical Humanities:

“The myth that physicians are innocent bystanders merely watching healthcare costs zoom out of control cannot be sustained.”

Her own final thoughts were, “We must eliminate the cases of obvious waste, and we must be leaders in engaging our society in public deliberation over what constitutes meaningful benefit and value in healthcare.” 

1. ASCO holds leadership summit to address value in cancer care, cost of cancer drugs and technologies. American Society of Clinical Oncology website. http://www.asco.org/advocacy/asco-holds-leadership-summit-address-valuecancer-care-cost-cancer-drugs-and-technologies. Accessed June 1, 2014.

2. Jagsi R, Sulmasy DP, Moy B. Value of cancer care: ethical considerations for the practicing oncologist. American Society of Clinical Oncology website. http://meetinglibrary.asco.org/content/ 11400146-144. Accessed June 1, 2014.

3. The University of Chicago website. http:// www.uchospitals.edu/physicians/daniel-sulmasy.html. Accessed June 1, 2014.

The Oncologist Defines Value of Care

Velcade (bortezomib), developed by Millenium Pharmaceuticals Inc, is a proteasome inhibitor (

) currently approved for the treatment of multiple myeloma and relapsed mantle cell lymphoma.

 Several abstracts, presented on May 31, 2014, and June 1, 2014, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago set forth data from trials that are under way to evaluate bortezomib for other indications.

Bortezomib and rituximab in the treatment of iNHL

This study, conducted at multiple trial centers and led by clinicians at Northwestern University, Chicago, was designed to assess the tolerability of bortezomib and rituximab in patients with high tumor burden (HTB) non- Hodgkin’s lymphoma. Treatment in this multicenter phase 2 study consisted of 3 induction cycles of bortezomib and

rituximab, followed by an abbreviated consolidation. All outcomes were analyzed by intent to treat. All 42 patients enrolled in the trial were evaluable. The therapy was well tolerated, with few grade 3/4 toxicities and minimal neurotoxicity. Grade 3 adverse events (AE) included fever, infusion reaction, infection, cardiac, fatigue, diarrhea, hypokalemia, and bowel obstruction; the only grade 4 AEs were neutropenia and thrombocytopenia. Overall response rate (ORR) at the end of therapy was 70%, with a 40% complete remission (CR) rate (follicular lymphoma [FL]: ORR 76%, CR 44%). At a median follow-up of 50 months, 4-year progression-free survival (PFS) was 44%, with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Interestingly, 4-year OS was superior for FL compared with non-FL histologies (97% vs 43%, respectively, P = .003). Altogether, bortezomib/rituximab is a targeted therapeutic regimen that was very well tolerated and resulted in long-term survival rates comparable to prior HTB FL rituximab/chemotherapy series.

Replacing vincristine with bortezomib in R-CHOP regimen in treating mantel cell lymphoma

R-CHOP—rituximab, cyclophosphamide, doxorubicin (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone&mdash;is standard therapy for newly diagnosed, bone-marrow transplant (BMT)-ineligible mantle cell lymphoma (MCL) patients. Bortezomib is approved in the United States for relapsed MCL. This study, registered as a collaborative trial between Millennium Pharmaceuticals and Johnson & Johnson Pharmaceuticals, evaluated whether replacing vincristine with bortezomib in R-CHOP

improves outcomes in newly diagnosed, BMT-ineligible MCL patients. Adults with treatment-naïve, measurable stage 2 through 4 MCL and ECOG PS 0 to 2 were

randomized to VR-CAP (velcade, rituximab, cyclophosphamide, doxorubicin, prednisone) or R-CHOP. The primary end point was PFS and secondary end points included time to progression, time to next treatment, OS, response by modified international lymphoma workshop response criteria (LWRC), and safety. Of the 487 patients, 244 were randomized to the R-CHOP arm and 244 to the VR-CAP arm, and were administered a median of 6 cycles. After 40 months median follow-up (298 PFS events), median

PFS was 14.4 months (R-CHOP) vs 24.7 months (VR-CAP). Rates of grade 3 or higher AEs were 85% (R-CHOP) versus 93% (VR-CAP), serious AEs were 30% versus 38%, discontinuations due to AEs 7% versus 9%, and on-treatment drugrelated deaths 3% versus 2%. This trial showed that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy end points versus R-CHOP in newly diagnosed, BMT-ineligible MCL patients, with additional but manageable toxicity.

Phase 3 trial for myeloma comparing different iMiDs

Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade, with triple drug combinations proving more effective than double or single agents. This trial, Myeloma XI—a collaborative study between the University of Leeds, Celgene Corportation, and Merck Sharp and Dohme Corporation&mdash;was a phase 3 randomized trial for newly diagnosed patients of all ages, which compared induction treatment with cyclophosphamide/lenalidomide/dexamethasone (CRD) to cyclophosphamide/thalidomide/dexamethasone (CTD), given to maximum response or intolerance. To evaluate the role of pretransplant consolidation with a proteasome inhibitor, patients achieving less than a very good partial response (VGPR) were randomized to additional cyclophosphamide/bortezomib/dexamethasone (CVD) versus no treatment. Fit patients went on to receive melphalan + autologous stem cell transplant. Of the 1939 patients analyzed, 1104 were on the intensive pathway arm (540 CRD vs 564 CTD) and 835 were on the nonintensive arm (411 CRDa vs 424 CTDa); 274 patients received additional bortezomib. The preplanned intent-to-treat analysis of combined CR+VGPR rates presented a significant difference between CRD and CTD treatment on multivariate analysis in favor of CRD, with odds ratio of 1.27 (95% CI 1.06-1.52, P = .009). Additional bortezomib therapy&mdash;for those with a suboptimal response&mdash;upgraded response in 51% of the patients, demonstrating that PI therapy can be effective in patients intrinsically resistant to IMiDs. Treatment with both IMiDs was well tolerated. The trial demonstrated an important difference in response between the IMiDs thalidomide, and lenalidomide; however, further follow-up is required to see whether this translates into prolonged PFS and OS. 

1. How Velcade (bortezomib) works. Velcade website. http://www.velcade.com/Understanding-velcade/About-velcade. Accessed June 1, 2014.

2. Evens AM, Smith MR, Lossos IS, et al. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumor burden (HTB) indolent non-Hodgkin lymphoma

3. Cavalli F, Rooney B, Pei L, Van De Velde H, Robak T; on behalf of the LYM-3002 Investigators. Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VRCAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT). 

4. Pawlyn C, Davies FE, Cairns DA, et al. Optimizing induction and pretransplant consolidation for myeloma: results of Myeloma XI, a phase III trial comparing different IMiDs. 

Velcade: A Progress Report in Various Cancers

Some experts argue that overdiagnosis (OD) and overtreatment (OT) of cancer is common and increasingly costly. Others argue that current cure rates are high because of the screening processes that are in place. Both viewpoints were debated during the session “Overdiagnosis and Overtreatment in Cancer: Point/Counterpoint,” conducted on June 1, 2014, the third day of the annual meeting of the American Society of Clinical Oncology (ASCO) held in Chicago.

“Cancer overdiagnosis and overtreatment, or appropriate attention to early disease?” was the question posed by Barbara L. Smith, MD, PhD, director of the breast program at Massachusetts General Hospital, codirector of the Gillette Center for Women’s Cancers, and associate professor of surgery at Harvard Medical School. So far, the goals of cancer care have been minimizing mortality, prolonging life, reducing morbidity of treatment, preventing primary cancers, and providing access to quality care for all. Of late, the discussion has widened to include cost effectiveness and avoiding excess treatment.

“For several years now, death rates from cancer have seen a dip and cancer incidence rates have plateaued—an indicator that the strategy is working. The cornerstones of success of modern care include earlier detection, improved treatments (multimodality care op-tions), a combination of early detection and better treatment, and also

improvement in overall population health. Healthier patients can work through the toughest treatments,” said Smith.

Smith questioned whether diminishing returns could be resulting in overkill. “Are cancer patients being administered more treatment than needed?” More importantly,

can comparable success be achieved with lighter treatment?

She provided an example of the increasing use of bilateral mastectomy in early-stage breast cancer. The numbers were at 3% back in 1998 but are up to 18% in 2007. The question to pose: Is it necessary? Patients want the procedure for peace of mind—to reduce their chances of recurrence. But what about the oncologist?

This is a challenge being discussed across a spectrum of disease states such as hypertension and cholesterol. Some of the questions that oncologists need to ask include:

• What is the optimal way to screen (sensitivity/specificity goals, cost, and limitations of diagnostic technologies)?

• What should the threshold for treatment be?

• What are the morbidity and mortality goals?

An ideal example is that of the recent debate about using the Papanicolaou (Pap) test cytology versus human papillomavirus (HPV) DNA testing. Pap has proved successful in reducing cervical mortality, but the role of HPV in disease has been recognized, and recently the cobas test was approved as a primary HPV screen.

The sensitivity of the screening is ideal—the problem lies in the fact that 10% of patients who are Pap-positive have precancerous lesions, but some cancers are HPV-negative. Additionally, there may be cancer-independent transient HPV infections that could result in falsepositive results. Only 10% of women with high-risk HPV develop persistent infection. The result: unnecessary colposcopies and biopsies following HPV testing.

However, a recent study showed that patients are the ones who want screening and would even overrule their physician in wanting to be screened.

Can improved treatment reduce the need for screening? Not yet, said Smith. We still cannot reliably distinguish between patients with indolent and aggressive cancer. “Cost is the elephant in the room—an unsustainable and sensitive topic that comes up with death panels, rationing, etc,” she said.

The other elephant in the room is liability for malpractice. Delays in diagnosis are common claims in malpractice lawsuits, and variations in guidelines (eg, annual vs biennial screening for breast cancer) can increase a physician’s exposure to such litigations.

What will it take to change practice? A change in physician perspective and a change in patient expectations may be the answer. Additionally, cost constraints need to be modified, guidelines need to be standardized, and medicolegal issues need to be addressed.

Smith concluded by saying that implementing small changes can lead to the bigger goals of:

Rinaa S. Punglia, MD, MPH, associate professor, Department of Radiation Oncology, Harvard Medical School, presented “The Case Against Overdiagnosis and Overtreatment of Cancer.”

OD/OT are inherent in breast cancer screening, and OD is central to the mammography debate in breast cancer. “OD usually leads to OT. A treatment does not necessarily alter outcomes,” said Punglia.

The solution to this problem, she believes, lies in informed decision making (IDM), which is made possible by opening a dialogue. Decision to screen can lead to false positives, but also to early diagnosis and improved outcomes. IDM can be used to reduce OT.

For example, ductal carcinoma in situ (DCIS) has historically been treated with mastectomy, but that approach may be too drastic. Today, patients undergo breast preservation surgery, which can leave patients at risk for a second breast event in the preserved breast, but can be followed with radiation therapy (RT). Meaningful outcomes for a patient after RT include recurrence, treatment of recurrence, and breast preservation. However, on the downside, RT can be expensive.

So how does one decide if a patient receives RT? DCIS overestimates a patient’s risk of recurdrence, and making a decision is difficult for patients. Therefore, individual decision making is key—lay the options down and help patients make the right choice. Punglia shared knowledge on a decision-making tool being actively used at Dana-

Farber (www.onlineDeCISion.org), which helps patients and providers alike.

The final viewpoint in this debate, “The Case for Overdiagnosis and Overtreatment of Cancer,” was presented by Laura Esserman, MD, MBA, director, Carol Franc Buck

Breast Care Center; and coleader, breast oncology program, UCSF Helen Diller Family Comprehensive Cancer Center.

In March 2012, the National Cancer Institute convened a workshop to generate ideas for a research agenda around OD. According to Esserman, a critical shift in philosophy is needed to explain that the previous approach of OD saves lives.

The old paradigm of cancer was of inexorable progression—or of every patient having the same rate of disease progression. That has changed, and we know today that it is far from true. Oncologists recognize that there is variable progression in patients and that there are IDLE (indolent lesions of epithelial origin) lesions that may not affect mortality. Therefore, understanding the biology of the cancer is extremely important.

Although the spectrum of disease has been realized and understood, the definition of cancer has not evolved. If a patient thinks “cancer,” they think they will die if they are not treated.

“A very important question is: what do you know, when do you know, and how do you act on what you know?” said Esserman.

The need of the time is a new approach to cancer treatment rather than arguments on 30-year-old guidelines, Esserman emphasized. However, it is extremely important to understand outcomes before changing guidelines. “Increased detection saves lives” is way too simple: the concept is much more complex, she said.

Recognizing and gaining an improved understanding of IDLE disease is important said Esserman—for example, does a tumor with little potential for metastasis and with little chance of progression or death require aggressive treatment? “IDLE tumor gene signatures could help define ultra-low—risk tumors. This could be validated in various cohorts and used to stratify patients with high- and lowrisk tumors,” according to Esserman.

Esserman closed her argument by recommending that a better-tailored definition replace the word “cancer,” companion diagnostics be coupled with treatment, and observational registries be created to identify IDLE disease. 

Overdiagnosis and Overtreatment: The Cancer Paradigm

On June 1, 2014, the penultimate day of the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), the discussion on value in cancer care was rekindled, but this time on a global scale. The session, “ASCO/European CanCer Organisation (ECCO) Joint Session: Value and Cancer Care,” saw participation from physicians and economists from around the world, with individual perspectives on defining value and the programs being developed to address the issue. Regulatory approval does not guarantee patient access to efficient therapies. So where lies the problem?

The first talk was “ESMO-EONS: Value and the Exchange Between Physicians, Nurses, and Patients” by Elisabeth De Vries, MD, PhD, University Medical Center Groningen, Netherlands, a member of the Magnitude of Clinical Benefit Scale task force.

De Vries began with an overview on cancer drug use in Europe, and discussed how the cancer drug development process is influenced by the European Society for Medical Oncology (ESMO).

Similar to what has been demonstrated in the United States, the 5-year relative cancer survival rate in Europe increased between 1999 and 2007. However, the cost of treatment is only burgeoning.

So what is the relevance of the cost of cancer drugs? Using imatinib as an example, De Vries presented a pricing plot that showed that the drug costs the most in the United States, but costs substantially less in Europe and other countries elsewhere around the globe.

She went on to state that there are differences in access to relevantly new anticancer drugs in Europe—differences in price, differences in healthcare costs, and differences in time to access following approval by the European Medicines Agency (EMA). These disparities are associated with various issues, one of which is the cost of the drug and reimbursement.

Among European nations, a 1.8-fold difference in the cost of trastuzumab has been identified. Additionally, a difference in time to availability after EMA approval has been observed. The bottom line: the lack of timely access to anticancer drugs can result in major disparities in cancer outcomes.

With the hope of standardizing policies and easing patient access to novel treatments, ESMO is developing the Magnitude of Clinical Benefit Scale. How will the scale be used? EMA-approved drugs will be scaled by the task force, and drugs with the highest value will then be promoted.

Various factors that contribute to the scale include quality of life (QOL), overall survival (OS), progression-free survival (PFS), prognosis of condition, toxicity, hazard ratio, long-term survival, and rate of response. These factors will be used to determine the magnitude of clinical benefit. “We did not factor costs into the equation due to the heterogeneity that exists across Europe,” clarified De Vries. “We believe the ESMO scale will be constantly evolving with the availability of increasing efficacy and toxicity data as the treatment is used by the wider population.”

The scales, she noted, are distinct for curative versus palliative settings. PFS, for example, can never qualify for a grade 4 score as a primary end point, but could be a secondary end point to be considered concurrent with OS, toxicity, and QOL.

The American Society of Clinical Oncology Annual Meeting, 2014

Cancer Care in the United States: The Path Ahead

The EGF Receptor (EGFR) Continues to Be a Promising Target in NSCLC

Promising Results in Leukemia From a BCL-2 Inhibitor

Impact of the Affordable Care Act on Cancer Care

The Oncologist Defines Value of Care

Velcade: A Progress Report in Various Cancers

Overdiagnosis and Overtreatment: The Cancer Paradigm

The Global Perspective on Value in Cancer Care

Clinical Pathway Adherence and Barriers to Coverage

Achieving Value in Cancer Care-the Case of Low- and Middle-Income Countries

In Conversation With ASCO President Peter Paul Yu