There is a dramatic revolution under way in the treatment of advancedstage prostate cancer, which for many years consisted of systemic chemotherapy that offered only palliation of symptoms and no hope of improved survival. The last decade has witnessed the debut of a completely new arsenal of therapies that target prostate cancer—specific pathways that improve overall survival. These new medications include cabazitaxel (Jevtana), abiraterone acetate (Zytiga), enzalutamide (Xtandi), sipuleucel-T (Provenge), and radium-223 (Alpharadin). Denosumab (Xgeva or Prolia) represents another class of new drugs that can prevent bone-related complications. Prior to the advent of these new therapies, there was a well-defined therapeutic progression with available agents, but substantial changes are being felt by clinicians and their patients and new paradigms of sequencing are being developed. These advances aside, there are also considerations to be made for cost, not only those incurred by the patient but society as a whole.

Beyond survival improvements, research is also heavily focused on preventing skeletal-related events (SREs) which broadly represent the costly (>$10,000 per event) and painful sequelae of skeletal metastases common to men with late-stage prostate cancer including pathologic fractures, bone deformation, need for radiation or surgery to bone, and spinal cord compression.

While SREs represent a hard end point that can be quantified in trials, symptomatic benefit in the form of pain reduction and greater functional mobility may represent a better measure of overall efficacy of treatment as reported directly by patients. Therapies such as zoledronic acid (Zometa) and denosumab (Xgeva) exploit very different biochemical pathways that focus on preventing SREs (and in the case of radium-223, also targeting prostate cancer for destruction). Despite the focus on SRE prevention with many of these therapies, not all studies have borne out improvements in pain, quality of life, or overall survival.

Now, practitioners must grapple with the increased complexity of options, indications, cost, patient selection, and side effects, and determine how best to select therapies for patients with varied health statuses and preferences. The Table provides a quick look at these new agents, cost of treatment, and overall survival. This article will briefly examine newly approved treatments for castration- resistant prostate cancer (CRPC), their indications, toxicity profiles, and cost considerations, and evaluate their potential impact on quality of life, prevention of SREs, and overall survival.

Docetaxel (Taxotere) was approved in 2004, displacing mitoxantrone as one of the few therapeutics available for the treatment of CRPC. CRPC is diagnosed when prostate-specific antigen (PSA) progression occurs with or without metastasis in spite of androgen- deprivation therapy (ADT) and resultant castrate levels of serum testosterone (<50 ng/dL). Docetaxel provided a 2.4-month increase in overall survival compared with mitoxantrone while also providing improvements in reported pain levels. No differences in rates of progression or measurable disease were noted between the groups, however.

A second-line systemic chemotherapy, cabazitaxel (Jevtana), was approved in 2010 for men with metastatic CRPC who failed prior docetaxel use. When given every 3 weeks with prednisone, there was a significant improvement in overall survival of 2.4 months (15.1 vs 12.7 months) compared with mitoxantrone plus prednisone in men who were docetaxel resistant.

 Investigators noted a small improvement in progression- free survival (2.8 vs 1.4 months; 

 <.0001). Primary side effects included diarrhea, 7.5% rate of febrile neutropenia, and increased risk of death within 30 days of last dose of chemotherapy (5% in cabazitaxel vs 2% with mitoxantrone).

Abiraterone acetate (Zytiga) was approved by the US Food and Drug Administration (FDA) in April 2011 for the treatment of men with docetaxel-resistant metastatic CRPC. This compound is orally available and irreversibly inhibits the CYP17A enzyme, a key step in steroid biosynthesis. Traditional ADT suppresses gonadal sources of testosterone, but this compound shuts down virtually all sources, including gonadal, adrenal, and intratumoral sources of testosterone production. Therapy in the phase III trial that led to its approval was well tolerated.

 Adverse events typically include edema (31%), hypokalemia (17%), and hypertension (10%). Median overall survival improved 3.9 months over placebo (14.8 vs 10.9 months,

 <.001). Progression-free survival (PFS) also favored abiraterone acetate (5.6 vs 3.6 months). A second phase III trial of abiraterone acetate in metastatic, chemotherapy- naïve CRPC recently completed and revealed a significant difference in progression-free survival along with a trend in survival improvement.

Enzalutamide (previously known as MDV3100, trade name Xtandi) was approved by the FDA in September 2012. It is a potent second-generation antiandrogen that has an affinity for the androgen receptor 5 times greater than the affinity of bicalutamide.

Evaluated in the post-chemotherapy CRPC setting, it demonstrated a 4.8-month improvement in overall survival over placebo (18.4 vs 13.6 months).

 Importantly, quality of life was shown to be improved 43% versus 18%. Outcomes with respect to SRE, PSA progression-free survival, and radiographic progression-free survival were all markedly better in the treatment arm. The most serious adverse event attributed to enzalutamide was seizures, which occurred in about 0.5% of patients.

Sipuleucel-T (Provenge) represents a first-in-class immunotherapy against prostate cancer. A patient’s antigen-presenting cells are collected via leukapheresis, sent for processing, and loaded with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony—stimulating factor (GMCSF).This is cultured and infused back into the patient, initiating a beneficial immune response. A phase III trial of 512 men with asymptomatic or minimally symptomatic metastatic CRPC found improved overall survival of 25.8 versus 21.7 months for placebo, notwithstanding 64% of men in the placebo arm having crossed over during the trial.

Disease progression was not measurably different. Common reactions included chills, fever, and headache. The lack of PSA response as a marker of activity remains a challenge, particularly as sipuleucel-T is positioned at the forefront of current sequencing algorithms for CRPC (

) on the basis of clinical indications and the paucity of other low-toxicity therapies available to men in this disease category.

Therapeutic Sequencing—Current Realities and Future Potential 

Prior to the rapid introduction of the above-mentioned agents, prostate cancer was generally treated systemically with hormone ablation in the form of GnRH agonists/antagonists. If disease progression occurred (confirmed with 2 consecutive PSA rises despite castrate levels of serum testosterone >50 ng/dL), CRPC is diagnosed.

 Patients could attempt secondary hormonal manipulation with the use of another GnRH agonist/antagonist or non-specific inhibitors like ketoconazole that disrupt steroid biosynthesis. Beyond hormonal ablation, physicians turned to systemic chemotherapies such as docetaxel for patients with aggressive symptomatic disease. Other interventions, like radiotherapy to bone metastasis, serve a palliative role and can offer relief in a cost-effective manner.

Now, however, there are at least 5 new therapies that improve overall survival, each with specific indications for utilization in addition to the adjunctive therapies that mitigate SREs from metastases. The Figure outlines current disease states under which these new agents are currently approved for use. Also shown are new therapeutics in phase III trials, and possible new scenarios for currently available therapies, some of which are under study, such as abiraterone in patients with chemotherapy-naïve metastatic CRPC.

Unfortunately, no randomized controlled trials directly compare the activity of these new agents, so practitioners must instead rely on side effect profiles to guide patient selection. A rational approach to therapy selection is certainly called for and should take into account overall cost and significant improvements in quality of life (as measured by reduction in SREs, pain scores, functional mobility). Future trials are needed to address several important questions: whether earlier initiation of agents in the disease course affects outcomes, how combination or adjuvant therapies perform (are they additive, synergistic, or neither), can varied sequencing improve time to disease progression and overall survival, and what therapies offer the best cost-tobenefit ratio with regard to maintaining quality of life? Prostate cancer remains a very heterogeneous disease, even in advanced stages, and clinical trials initiated in earlier disease states take longer to assess such outcomes. In the past, PSA was considered a surrogate marker of disease outcomes; however, the FDA does not consider PSA-related markers of progression as evidence for activity, as the correlation with overall survival is quite variable.

Despite the huge advances made in the development of these targeted therapies, cost-effective oncologic care will most likely occur when physicians successfully prevent progression and they minimize side-effect profiles of treatment.

The dramatic changes afoot in prostate oncologic care have created new opportunities to lengthen overall survival, increase quality of life, and reduce disease burden, and to alter the incidence of SREs. Physicians will need to consider each patient’s performance status and disease state in order to effectively choose beneficial treatments. Future studies will need to examine these agents head-to-head in order to best determine sequencing, and examine their use, particularly those with small side effect profiles in earlier disease states, and determine their effect on overall survival. Combinations of these agents should be studied. The elusive cures for many cancers will be formulated by attacking concurrent pathways using multiple agents.

 From the University of Colorado (EDC, KOR), Aurora, CO.

Dr Crawford has received consultancies from Poinard, Indevus, honoraria from UBM Medica, and lecture fees from sanofi-aventis, Poinard, AstraZeneca, GlaxoSmithKline, and Ferring. Dr Rove has received honoraria from Turner White Communications and UBM Medica.

 Concept and design (EDC, KOR); analysis and interpretation of data (EDC, KOR); drafting of the manuscript (KOR); and critical revision of the manuscript for important intellectual content (EDC, KOR).

 E. David Crawford, MD, Division of Urology, University of Colorado, Anschutz Medical Campus, PO Box 6510, Mailstop F743, Aurora, CO 80045. E-mail: david.crawford@ucdenver.edu.1. Lage MJ, Barber BL, Harrison DJ, Jun S. The cost of treating skeletal-related events in patients with prostate cancer. Am J Manag Care. 2008; 14(5):317-322.

2. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.

3. Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol. 2006;17(6):986-989.

4. Petrylak DP, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15): 1513-1520.

5. Tannock IF, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.

6. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 Study. J Clin Oncol. 2008;26(2):242-245.

7. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747): 1147-1154.

8. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21): 1995-2005.

9. Clinical trial NCT00887198: Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer. US National Institutes of Health. http://clinicaltrials.gov/ct2/show/record/ NCT00887198. Accessed October 21, 2012.

10. Tran C, Ouk S, Clegg N, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790.

11. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187- 1197.

12. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel- T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411- 422.

13. Crawford ED, Flaig TW. Optimizing outcomes of advanced prostate cancer: drug sequencing and novel therapeutic approaches. Oncology (Williston Park, NY). 2012;26(1):70-77.

14. Antonarakis E and Paller. Cabazitaxel: a novel second-line treatment for metastatic castrationresistant prostate cancer. DDDT 2011:117.

15. Timmerman L. Dendreon sets Provenge price at $93,000, says only 2,000 people will get it in first year. Xconomy. www.xconomy.com/ seattle/2010/04/29/dendreon-sets-provengeprice-at-93000-says-only-2000-people-will-get-itin-first-year/. Published 2010. Accessed October 22, 2012.

Articles

Evidence-Based Oncology

Advanced Prostate Cancer: Therapeutic Sequencing, Outcomes, and Cost Implications

In response to the billions of dollars wasted each year in the United States on fragmented, ineffective, and uncoordinated care, some healthcare reform efforts have focused on integrating the delivery of healthcare.

Today, millions of Americans receive their healthcare from integrated delivery networks (IDNs).

However, just what is an IDN? Today, there really is no single answer.

“The phrase covers a spectrum of scenarios; it has not been defined and is actually used as a catchall phrase to cover a variety of types of healthcare arrangements,” explained health economist Mark Hornbrook, PhD, researcher with the Cancer Research Network and senior investigator and chief scientist at the Kaiser Permanente Center for Health Research in Portland, Oregon. Integration might take place vertically, across different levels of care, or horizontally, such as occurs with hospital mergers.

In practice, an IDN might coordinate and standardize clinical care, disease management, financial management, and human resources across all of its providers and facilities. Some IDNs develop and employ patient care strategies with the end goals of costeffective improvements in health outcomes, quality of care, and efficiency.

 Evidence demonstrates that patient care strategies are more likely to be used by IDNs than solo practitioners.

According to the 2012-2013 National Committee for Quality Assurance (NCQA) private health insurance plan rankings, half of the nation’s top 10 ranked plans (N = 474) are IDNs that provide insurance and employ the doctors who serve their clients.

 The rankings are published in the November 2012 issue of Consumer Reports, which states,“Unlike traditional, independent fee-for-service doctors and hospitals that make money by doing as many treatments and procedures as possible, whether needed or not, integrated plans prosper by keeping their customers healthy and avoiding wasteful care.”

In the United States, substandard, heterogeneous, and excessive cancer care adversely affects a number of important short- and long-term outcomes including survival, quality of life, and cost.

The complex and multidisciplinary nature of cancer care makes it prone to system failures, such as inadequate hand-offs, poor communication, and lack of accountability between providers. 

Additionally, the cost of cancer treatments—especially medical oncology and specialty pharmacy drugs&mdash;is notoriously high. Hence, strategies to promote their cost-effective use have become key elements of cost-reduction efforts (

In the 2012 market intelligence report, Academic Cancer Centers: Trends Impacting Key Account Management, Inside Oncology, LLC, predicted that by 2016, the majority of patients with cancer will be treated at IDNs and cancer institutions (

Factors contributing to this trend include Medicare reimbursement rate reductions for community practices, loosened 340B drug pricing qualification criteria, and pressure to meet new quality and performance requirements of the Centers for Medicare & Medicaid Services (CMS).

 “CMS has put in quality programs that are really stimulating and motivating people to become more aware of quality of care and integrating care,” stated David Guy, managing partner of Inside Oncology.

Well-established cancer centers have been delivering integrated cancer care for years. Most of them offer patient care teams comprising a range of specialists, as well as a breadth of services at a single location. In this setting, however, care is generally limited to the cancer episode, not pre-diagnosis or post-treatment. Primary care of survivors commonly reverts back to a primary care physician who is not affiliated with the cancer care center. Albeit, many cancer centers have begun to take a more proactive role in survivor care as its importance has gained recognition.

Perhaps the truest form of integrated cancer care is the type delivered by the large full-service IDNs at the top of the NCQA rankings. These institutions offer care that extends beyond cancer diagnosis and treatment to targeted detection, prevention, and survivorship care.

 This version of integrated care is in accordance with the Commission on Cancer’s (COC’s) 

Cancer Program Standards 2012: Ensuring Patient-Centered Care

, which mandates care throughout the cancer continuum, from prevention through end-of-life care or survivorship.8 Cancer centers may provide prevention and screening services, but often these services are offered at the community level and not targeted to specific patients. These stand-alone interventions, while beneficial, may not be as effective overall as those delivered as part of an organized program integrated into comprehensive longterm patient encounters.

In other models of integrated care delivery, community oncologists are banding together into statewide or regional conglomerates such as the Regional Cancer Care Associates (RCCA) of New Jersey, formed in January 2012. According to RCCA president Andrew Pecora, MD, by the end of 2012, the group will provide care for about half of patients newly diagnosed with cancer in the state of New Jersey. Among the initiatives being implemented by the group are cost-conscious protocols, networkwide integration of electronic medical record (EMR) systems, real-time overall and progression-free survival tracking software, and survivorship care planning in collaboration with local primary care physicians. “If I was to do this as a single doctor inmy individual practice, it might be interesting; if we are doing it in an entire state…we will move the needle,” said Dr Pecora.

In another model aimed at community oncology, McKesson Specialty Health offers tools to support delivery of integrated cancer care by practices belonging to The US Oncology Network, which is one of the nation’s largest networks of communitybased oncology physicians. “For more than 15 years our affiliated practices have been pulling together resources our patients need into a single building in the community setting,” said Matt Brow, vice president of public policy and reimbursement strategy for McKesson Specialty Health. Brow said it is important to distinguish this type of quality- and value-driven initiative by oncologists from the trend of hospital systems buying up everything in their vicinity. For radiation oncologist Gregory Patton, MD, practice president, Compass Oncology in Portland, Oregon, being part of The US Oncology Network has been beneficial in terms of the resources and skilled professionals it offers. “The strength of The Network is that its leadership and initiatives evolve from the practices,” he commented.

J. Russell Hoverman, MD, PhD, medical director of managed care for The US Oncology Network, discussed the challenges of delivering truly integrated care in the community setting. “We have a lot of things in our network that would fit into IDN but they are not all in the same place,” said Dr Hoverman. Moving forward toward integration that is more complete will require cooperation with groups outside of their network, platforms for communication, incentives, and perhaps, payment change. “We are continuously looking at models in which we could do all this; I think we all agree this is the direction we need to head.” He also discussed how he would like to form long-term relationships with payers, rather than 1- or 2-year relationships, so they can collaboratively learn from and build on existing pathways and integrated care processes.

Well-designed, integrated cancer care systems are positioned to provide the types of services increasingly being recognized as essential to good cancer care by performance monitoring groups like the COC.8 Proponents of healthcare systems that integrate care throughout a cancer patient’s life journey talk about the benefits of team care, quick response, accountability, research integration, and systematic implementation of medical evidence, as well as the facilitation of screening and early detection programs.

 Ultimately, the benefits of integration should improve survival outcomes for patients. Cancer care delivery organizations are beginning to look beyond surrogate quality indicators to primary health outcomes. Kaiser Permanente’s most recently reported 5-year cancer survival rates were higher than the national average—in some cases 10% higher&mdash;for nearly every disease state (see Figure 3 for melanoma survival rates).

 “It is not just that we have great oncologists, but also because we do a lot of screening, prevention, and proactive patient support,” said Joanne Schottinger, MD, assistant medical director for Quality at Kaiser Permanente in Southern California. “Our patients are with us an average of 17 years; these people do well not only because they saw us as a cancer patient, but also because of the care they received outside of that phase. Everything else that needs to be done is being supported. It is an integrated network that leads to results like that.”

With a heavy focus on early detection, Kaiser Permanente has set an organizational goal of having the lowest number of stage 3 and 4 cancers in the country. Its fully integrated EMR system was customized to fit its oncology needs and features tools that make every single patient visit, for any purpose, an opportunity to deliver clinical prevention services or to schedule a screening. Through its organized colon- cancer screening program, which includes mailed fecal screening kits, the number of colon cancers detected at the treatable stages of 0 or 1 has improved to 41%, which is a 28% increase. Likewise, the number of late-stage colon cancers detected has decreased by 32% to just 13%. This work extends to other cancers as well (eg, breast and cervical), in which similar results have been garnered. According to Dr Schottinger, they also attribute positive outcomes to robust prevention programs that focus on smoking cessation, alcohol use reduction, and overall wellness.

Through their EMR systems, IDNs share standardized point-of-care decision support, protocols, and patient information among all healthcare personnel within a network. “Being within an organized IDN offers opportunity for better care for patients and better communication through EMRs. These systems are organized so that providers can manage cases together,” said Guy. New health information technologies will allow organizations such as RCCA to share patient electronic health information across multiple disparate EMR platforms, avoiding the need for groups who have already made an investment in an EMR system to make changes.

EMRs have contributed greatly to standardization of cancer care across large provider networks through incorporation of continuously updated evidence-based treatment pathways. The US Oncology Network, a pioneer in this area, has published studies documenting maintained outcomes with improved practice standardization and reduced costs through the use of costconscious pathways that are disseminated networkwide via their proprietary electronic health record system.

IDNs that use EMRs in conjunction with a team-based approach have also been able to enhance quality assurance and reduce chemotherapy-related error rates. Oncology pharmacists at Kaiser Permanente who monitor and manage patient safety have prevented 99.7% of patients with poor renal function from getting worse and 95.9% of patients on chemotherapy from developing anemia.

Furthermore, EMRs have advanced the power of clinical research programs within the IDNs. Dr Hornbrook explained that the benefits have been tremendous in terms of increases in the availability, accessibility, and amount of data, as well as reduced workload (eg, chart abstractions). “We can do translational research out of (our EMRs),” said Dr Schottinger. “That is really an exciting part for us…we get to look at how real people are responding to these regimens in the real world and build in the support that they need.” IDNs are capable of rapidly disseminating and deploying not only their own research-based safety responses, but also any externally issued medication or device safety alerts.

Nonetheless, not all efforts at integrated health delivery are going to be effective. As discussed in a recent report by the US Government Accountability Office, the delivery of highquality care must be the mission at the outset.

 At this point, clear documentation associating cost and quality outcomes with IDN-provided care is not available.

 The variations in the extent of clinical and financial integration of existing IDNs make evaluation, comparison, and meta-analyses difficult. “The field is still in its infancy in terms of measuring what integrated care is, what it should be, and what expectations should be,” said Dr Hoverman.

Growing evidence suggests that consolidation of healthcare providers and hospitals in a market opens the door for the resulting health system to charge payers more for their services and reduces market pressure to provide patients with value-based, highquality care.

 “When cancer doctors are employed by hospitals, costs go up in spades,” said Brow. He based this statement on reports prepared by healthcare consulting firms Avalere Health and Milliman that analyze site-of-service—related costs of cancer care.

 “The bigger a health system gets, the more leverage it has against the payer, the more indispensable it is to the payer,” said Brow.

Hospital systems argue that the higher reimbursement rates they receive for delivering chemotherapy are offset by other services they provide that are not available at private oncology practices and by the fact that they are required to care for larger numbers of uninsured and underinsured patients. On the other hand, said Guy, the current fee-for-service model also incentivizes community oncologists to use the most expensive drugs to maximize reimbursement.

A 2010 report by AcademyHealth cited some of the potential clinical benefits and elimination of duplicate services that can result from integrating services for patients within a single organization.

Nonetheless, some motivations for integration may be geared toward increasing volume and revenue, not cost containment or quality improvement.

 Evidence suggests that consolidation motivated by reasons other than efficiency will not garner efficiency.

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. United States Government Accountability Office. Health care delivery: features of integrated systems support patient care strategies and access to care, but systems face challenges. GAO-11-49. http://www.gao.gov/products/GAO-11-49. Published 2010. Accessed October 10, 2012.

2. Bach P. How many doctors does it take to treat a patient? The Wall Street Journal. June 21, 2007:A17.

3. Kelley R. Where can $700 billion in waste be cut annually from the US healthcare system? Thomson Reuters; 2009.

4. Enthoven AC. Integrated delivery systems: the cure for fragmentation. Am J Manag Care. 2009;15(10 suppl):S284-S290.

5. National Commission for Quality Assurance. NCQA’s health insurance plan rankings 2012- 2013: private plan details. http://www.ncqa.org/Portals/0/Report%20Cards/Rankings/hpr2012privatedet.pdf. Published September 20, 2012. Accessed October 10, 2012.

6. Health Insurance. Consumer Reports. November 2012:40-49.

7. Hewitt ME, Simone JV; National Cancer Policy Board (US). Ensuring Quality Cancer Care. Washington, DC: National Academies Press; 1999. http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&db=nlabk&AN=14721. Accessed October 5, 2012.

8. Commission on Cancer. Cancer program standards 2012: ensuring patient-centered care v1.0. American College of Surgeons. http://www.facs.org/cancer/coc/standards.html. Published 2012. Accessed October 10, 2012.

9. Clauser SB, Wagner EH, Aiello Bowles EJ, Tuzzio L, Greene SM. Improving modern cancer care through information technology. Am J Prev Med. 2011;40(5 suppl 2):S198-S207.

10. Bickell NA, LePar F, Wang JJ, Leventhal H. Lost opportunities: physicians’ reasons and disparities in breast cancer treatment. J Clin Oncol.

Is Our Healthcare System Ready to Integrate Cancer Care?

Over the last few years there has been a marked decrease in the number of independent oncology practices. The Practice Impact Report, a recently released study by the Community Oncology Alliance (COA), shows that 241 clinics have closed over a 4.5- year time period ending in 2011.

“The key driver of consolidation in oncology is financial strain,” said David Eagle, MD, president of COA. “While there are some concerns about business and professional changes, the key driver is almost purely financial. All of the others are secondary to payment issues.”

The reimbursement changes began with the Medicare Modernization Act of 2003 (MMA). Congress moved payments from a profit margin above the average wholesale price to an average sales price. They hoped this would better match payments with the services provided by oncologists.

“The problem is that Congress overdid it,” said Eagle. “The money they took away from chemotherapy and supportive drugs was more than they put toward infusion services. In addition, Medicare has been cutting payments for infusion services every year since MMA was implemented.”

Payments for infusion services have declined by a total of 35% since 2004—a figure that rises to nearly 50% after factoring in medical inflation. An analysis of oncology practice expenses by COA and Avalere Health showed Medicare payments covered only 57% of the cost of providing these services.

“Over time, private payers have also begun migrating to the same system,” said Eagle. “That is one of the reasons that a law enacted in 2003 is just hitting its apex.”

COA’s latest Practice Impact Report suggests the trend away from community practices may be accelerating. There was a 20% increase in the number of physician-owned community oncology practices impacted in the 12 months since the release of the previous report. Additionally, there was a 21% year-overyear increase in clinics closed.

Passage of the Patient Protection and Affordable Care Act (ACA) may stimulate another round of consolidation in oncology practices. This time, however, other specialties may be impacted, as well.

“When the ACA passed, it launched another increase in efforts to buy out physician practices,” said Vivian Ho, PhD, James A. Baker III Institute Chair in Health Economics at Rice University in Houston, Texas. “Some hospitals believe strongly that we are moving toward more accountable care, either the Medicare or other models. They are preparing by acquiring physician practices to bring as much care in-house as they can.”

Another driver of oncology practice consolidation is that Medicare seems to be moving toward a payment model geared toward rewarding large organizations. Some of the programs require a minimum of 5000 patients for entry.

Both the federal programs and private insurers are looking to shift risks from them to the practicing physician. Thus, they are moving toward more bundling of treatment payments, episodic care, large accountable care organizations, and the like.

“There are many names for the changes being made, but the bottom line is a realignment of people and providers,” said Kenneth Hertz, FACMPE, a principal with the MGMA Health Care Consulting Group. “These changes in who has the risk exposure tend to drive people to work together so they can reduce costs, provide better compensation to the providers, spread the risk over more people, and obtain more and easier access to financial resources.”

Governmental payers have already moved toward bundled payment for some cardiovascular disease codes to cover not only the hospitalization, but all services up to 30 days after discharge. The National Cancer Institute estimates that the total US cost for cancer care is $125 billion, and that figure is projected to go as high as $158 billion (in 2010 dollars) by 2020. Because of this “target-rich environment,” Medicare is looking at putting a target on the backs of oncologists next.

One frequently overlooked change in the oncology landscape is how radically the definition of what constitutes good cancer care has evolved over the last 2 decades.

“Medical oncology, and to a degree radiation oncology, is very different than it was when I went into practice 20 years ago,” said Therese Mulvey, MD, physician chief, South Coast Center for Cancer Care, New Bedford, Massachusetts. “At that time you basically saw a patient with cancer, you determined the correct treatment plan, administered that therapy, and then followed the patient for a period of time. Patients, and the entire healthcare industry, are now expecting that we will be able to provide far more services to the individual patient.”

Counseling and social work services, nutritional support, integrative medicine, patient navigation, outreach and support groups, and genetic screening are now part of what most consider standard care. Smaller practices have problems providing all of the needed resources in this environment.

“Some of the migration to hospital employment or to larger practice entities has to do with being able to provide all the services that we now believe to be part of high quality care,” said Mulvey. “The expectations are completely different, yet reimbursement has only gone down during that time. This quality of care standard is hard for smaller practices to deliver unless there is some link to the resources of a larger organization.”

She stressed that although much of the talk on this subject focuses on how reimbursement changes are causing problems throughout oncology, a lot of the impact on the financial stability of practices is driven by patients’ wants and needs. “It has crossed the line where oncologists are no longer being asked to do the same with less, we are now being asked to do significantly more with less,” she said. “It is combining increasing responsibilities with lower reimbursements that really drove oncologists to look for partners. Those who could help them achieve high-quality patient care in a way that did not bankrupt everybody.”

 Mr. Ullman reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design; acquisition of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.1. Community Oncology Alliance practice impact report. Community Oncology Alliance. http://goo.gl/9FgbA. Published April 4, 2012. Accessed August 31, 2012.

2. Providing high quality care in community oncology practices: an assessment of infusion services and their associated costs. Avalere Health, LLC. www.avalerehealth.net. Accessed August 30, 2012.

3. The cost of cancer. National Cancer Institute. http://goo.gl/nC5mU. Published January 12, 2011. Updated February 18, 2011. Accessed August 30, 2012.

Oncologist Practice Consolidation Continues

Cancer of the lung comprises both small cell and non-small cell lung cancers (NSCLCs), with NSCLC being the more common of the 2 types, accounting for 85% of all lung cancers.

 NSCLC can be further classified into various types depending on the type of cells and what they look like under the microscope.

 The most common of these types are squamous cell, large cell, and adenocarcinoma NSCLC.

 Lung cancer, including small cell and NSCLC, has the highest mortality rate of all the cancers in the United States for both men and women.

 In 2012, lung cancer was estimated to be the cause of death in 160,340 people, roughly 28% of all cancer deaths.

Numerous trials are under way investigating whether newer agents and regimens may improve overall survival.

The treatment of NSCLC has changed drastically over the past decade with a trend toward personalized medicine and targeted therapy, especially in those with metastatic disease. For patients with early stage, resectable lung cancer, surgery is the treatment of choice. If the patient cannot tolerate resection or if the tumor is non-operable, radiation is recommended. For those with stage II or IIIA disease who undergo surgery, adjuvant chemotherapy with cisplatin and vinorelbine is recommended with or without radiation. Stage IIIB patients should receive concurrent chemoradiation with a cisplatin doublet. For stage IV, or metastatic disease, treatment depends upon multiple factors, including tumor histology and epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein- like 4/anaplastic lymphoma kinase (EML-ALK) mutation status. Patients who have certain EGFR mutation should receive erlotinib. Crizotinib, an ALK inhibitor, should be used in patients who are ALK positive. Non-squamous NSCLC should receive platinum doublet therapy with or without bevacizumab. Of note, cisplatin with pemetrexed has shown an increased survival compared with cisplatin with gemcitabine in the non-squamous population. Once patients have received 4 to 6 cycles of the platinum doublet, maintenance therapy is recommended, with options including continuation or switching to single-agent bevacizumab, cetuximab, pemetrexed, gemcitabine, or erlotinib. For squamous cell NSCLC, a platinum doublet is recommended with possible maintenance therapy of continuation or switching to cetuximab or gemcitabine. Treatment of relapsed/refractory NSCLC is patient specific depending on previous therapy and may include single or multi-agent chemotherapy as mentioned previously.

Small molecule tyrosine kinase inhibitors (TKIs) are a hot area of research and development for drug manufacturers, with multiple targets having been identified.

 While some of these agents have very focused receptor targeting, others have a wide range of activity on multiple targets.

 Currently, there are 2 small molecule TKIs approved by the US Food and Drug Administration (FDA) for use in the treatment of NSCLC: crizotinib and erlotinib.

 Research has shown that the primary benefit with erlotinib is limited to certain subpopulations of patients with sensitive EGFR mutations, which will be discussed in more detail later.

 The recent approval of crizotinib was limited to patients positive for ALK.

 While promising results have been seen in progression-free survival (PFS), these agents have so far been unable to improve overall survival (OS), as resistance develops via multiple mechanisms.

 Irreversible inhibition of the target kinase has been one strategy in drug development to overcome such resistance.

 Other strategies have been to develop agents that can impact multiple targets and redundant pathways, or to use multiple TKIs in combination.

Most toxicities seen have been mild, with fatigue, nausea, rash, and diarrhea being common within the class; however, some drug-specific toxicities have been identified, such as cholecystitis with motasenib.

 Further, TKIs that target the VEGF pathway have shown common yet not always consistent themes regarding adverse effects, including hypertension, gastrointestinal toxicities, and thromboembolism.

Afatinib is an oral dual irreversible EGFR/HER2 TKI which has promise in dealing with resistance seen with reversible EGFR-TKIs.

 Preliminary results of the LUX-lung 3 randomized phase III trial comparing afatinib with pemetrexed and cisplatin as first-line treatment in patients with EGFR mutation— positive lung cancer showed better PFS results with afatinib (11.1 vs 6.9 months; hazard ratio [HR] 0.58 [0.43- 0.78]; 

 Several other studies (including phase III studies) are currently ongoing.

KD019/XL647 is a small-molecule TKI that targets multiple receptors, including EGFR, vascular endothelial growth factor receptor 2, HER2, and Ephrin type-B receptor 4. A phase II study evaluating 2 dosing regimens demonstrated a confirmed objective response rate (ORR) of 20% and a PFS of 5.3 months (90% confidence interval, 3.7-6.7). In patients with an EGFR mutation the ORR was 57% and PFS was 9.3 months (90% confidence interval, 5.5-11.7).16 A phase III study investigating the effect on prolonging survival with KD019 versus erlotinib in patients with NSCLC who have progressed after first- or second-line chemotherapy is currently open to accrual.

BIBF 1120 is an oral indoline derivative which potently blocks VEGFR, plateletderived growth factor receptors (PDGFRs), and fibrolast growth factor receptors (FGFRs).

Currently, 2 phase III trials are under way evaluating BIBF 1120 in NSCLC. One is a multinational study with advanced or recurrent NSCLC investigating PFS in patients receiving BIBF 1120 with or without docetaxel.

 The second ongoing multinational study is evaluating pemetrexed/folic acid with or without BIBF 1120 as second- line therapy in patients with nonsquamous NSCLC.20

EGFR, one of the 4 HER family receptors, is expressed in 80% to 85% of patients and mutated in approximately 10% of Caucasians and 50% of Asians with NSCLC.21 This mutation in the tyrosine kinase portion of the receptor causes EGFR to become constantly active. This leads to an increase in downstream cancer cell growth, invasion, differentiation, and proliferation.

EGFR mutations are more commonly found in patients who are non-smokers, of Asian descent, women, and those who have adenocarcinoma NSCLC. While EGFR mutations do not have an effect on prognosis, these patients may potentially benefit from an EGFR inhibitor, particularly NSCLC with deletions on exon19 or mutations on exon 21.

 Currently, only 1 EGFR tyrosine kinase inhibitor, erlotinib, is available in the United States.

 Drug development targeting the HER family receptors in NSCLC is ongoing in phase I-III clinical trials.

Unlike erlotinib, which only targets EGFR, dacomitinib (PF-00299804) is a TKI with activity against EGFR as well the HER2 and HER4 receptors.

In a published phase II trial, dacomitinib was compared with erlotinib in 188 patients with progressive NSCLC after treatment with 1 or 2 chemotherapy regimens. The primary end point, median PFS, was 2.86 months in the dacomitinib arm compared with 1.91 months in the erlotinib arm (

 = .012). Median OS was non-significant at 9.53 months and 7.44 months, respectively (

 = .205). The most common adverse effects were acneiform rash, diarrhea, oral mucositis, and infections of the nails.25 Phase II and III trials are currently being conducted; specifically, the phase III trial, ARCHER 1009, is comparing dacomitinib with erlotinib in patients with relapsed or refractory NSCLC or intolerance to prior treatment regardless of EGFR mutation status.

Another EGFR inhibitor in clinical trials is necitumumab (IMC-11F8), a fully humanized IgG monoclonal antibody. Compared with cetuximab, a chimeric monoclonal antibody which has a 20% rate of hypersensitivity reactions, necitumumab has a much lower risk. Also, the immunoglobulin (Ig) G1 monoclonal antibody should be more likely to have an antibody-dependent cell-mediated cytotoxicity compared with IgG2 agents, such as panitumumab.27 In February of 2011, a phase III trial (INSPIRE) of cisplatin and pemetrexed with or without necitumumab for newly diagnosed patients with stage IV non-squamous NSCLC was halted due to rates of thromboembolism in the necitumumab arm.

 No thromboembolic events had been reported previously in the phase I and II trials.

 The SQUIRE trial, a phase III trial in newly diagnosed metastatic squamous NSCLC being treated with cisplatin and gemcitabine for up to 6 cycles with or without necitumumab, has completed enrollment but results have not been reported.

The most common toxicities seen in trials were dermatologic, including dry skin (14%) and acneiform rash (52%).

Ganetespib (STA-9090) is a non-geldanamycin heat shock protein 90 (HSP90) inhibitor currently being studied in multiple malignancies. Heat shock proteins are molecular chaperones which are activated with elevated temperatures.

 In particular, HSP 90 is essential in the development and stabilization of proteins. In cancer cells, compared with normal cells, HSP 90 is constantly active.

 Geldanamycin inhibitors of HSP 90 have shown to be active against cancer cell lines, but patient tolerability was poor due to gastrointestinal and liver toxicities. This led to the development of non-geldanamycin compounds such as ganetespib.

 Ganetespib is currently being studied in phase I-III trials alone or combined with docetaxel or crizotinib in patients with relapsed or refractory stage IIIB or IV NSCLC.

 In early reports of phase II outcomes, out of 73 participants 1 had a partial response and 7 had stable disease. The majority of toxicities were either grade 1 or 2 and included nausea, constipation, diarrhea, and dyspnea.

Eribulin, also known as E7389, is a microtubule inhibitor derived from the Japanese sea sponge Halichondria okadai. Unlike traditional taxanes which inhibitmicrotubule depolymerization, eribulin suppresses microtubule polymerization, which prevents mitotic spindles from forming and causes subsequent cell death.

 Currently eribulin (Halaven) is FDA-approved in the third-line treatment of metastatic breast cancer,

but this agent is involved in multiple trials for previously treated, advanced or metastatic non-small cell lung cancer as a single agent or combined with other active agents such as pemetrexed or erlotinib.

 Two published phase II trials have studied the effects of single-agent eribulin in a total of 139 patients with stage IIIB or IV non-small lung cancer who have relapsed or have refractory disease during or after receiving traditional platinum doublet chemotherapy. The ORR for eribulin was 4.5% to 11.7% with a median OS of approximately 8.9 to 12.6 months. The most common adverse effect was neutropenia, with neuropathy being the main cause of eribulin discontinuation.

Solvent-based paclitaxel (sb-paclitaxel) plus carboplatin is a commonly utilized regimen in lung cancer.

 Unfortunately, this combination is associated with a high incidence of adverse effects, including fatal hypersensitivity reactions, neutropenia, and anemia. Because of the hypersensitivity reactions, premedication with a steroid, diphenhydramine, and an H2 antagonist is recommended.

Two agents being investigated are nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and paclitaxel poliglumex (PPX). Nab-paclitaxel is a unique protein formulation of paclitaxel that may reach the tumor microenvironment more efficiently and may be preferentially taken up by cancer cells while also decreasing toxicities associated with paclitaxel and its solvent.

 Of particular note was the decrease seen in neuropathy in the nab-paclitaxel treatment arm, including a decrease in recovery time from grade 4 neuropathy after the treatment was finished. Additionally, grade 4 neutropenia was significantly less in the nabpaclitaxel group; however, there was an increase observed in the amount of anemia and thrombocytopenia in study subjects. Despite increases in cumulative dosages administered and improvements in PFS, OS was not improved with the use of nab-paclitaxel. Although the results were not as promising as expected, subgroup analysis indicates that patients with squamous cell cancer may experience a greater benefit from nab-paclitaxel. Despite the advantageous adverse effect profile with PPX, no improvements in overall survival or time to progression was seen in studies. 

 No recent information can be found regarding FDA approval or marketing by the manufacturer.

Lactoferrin, most commonly found in breast milk,

 when given orally causes maturation of dendritic cells in the gut-associated lymphoid tissue which counteracts anti-tumor effects produced by malignant cells.

A recombinant lactoferrin, talactoferrin alfa, has been studied in phase I and II trials in patients with locally advanced or metastatic NSCLC who have failed firstline chemotherapy.

 In early August, a phase III trial of talactoferrin alfa as third line in the treatment of NSCLC (FORTIS-M) was closed to accrual due to not meeting its primary end point of OS, which was a median of 7.5 months in the talactoferrin groups compared with 7.7 months in the placebo group (

 A phase III trial, FORTIS-C, for the treatment of newly diagnosed, stage IIIB or IV lung cancer of talactoferrin or placebo in combination with carboplatin and paclitaxel is still ongoing.

The goal of vaccination in NSCLC is to mount a targeted immune response specifically against the NSCLC cells. In the past, outcomes in vaccine and immunologic research for NSCLC were disappointing. The majority of current phase III research is focused on implementing vaccine therapy after successful response to standard therapy, or as a maintenance phase of treatment.

Melanoma-associated antigen A3 (MAGE A3), a tumor-specific antigen that can be identified by cytotoxic T cells, is overexpressed in 35% to 50% of NSCLC.50,51 This antigen, which is expressed in early carcinogenesis, is most commonly found in squamous NSCLC and is associated with more aggressive disease.50,52 A vaccine, astuprotimut-R, consisting of a recombinant MACE A3 fused with protein D of H influenza, has undergone phase I and II trials in early stage NSCLC.53,54 A randomized phase II trial assigned 182 patients with MAGE A3 expressing stage IB or II NSCLC to astuprotimut-R or placebo following curative surgery. The HR for disease-free interval was 0.74 and OS was 0.66, both non-signficant.

A randomized, double-blind phase III trial, MAGRIT, including patients with stage IB, II, and IIIA NSCLC receiving astuprotimut- R or placebo after surgery or chemotherapy, is ongoing.

Emepepimut-S (Liposomal BLP25 or Stimuvax)

Emepepimut-S is a vaccine with a synthetic MUC-1 peptide core and a liposomal delivery system.

 MUC-1 is a glycoprotein overexpressed on cancer cells necessary for tumor cell growth, anti-apoptosis, and chemotherapy resistance. 

 In animal models, emepepimut- S has produced a T-cell mediated response against NSCLC cells.

A total of 171 patients with a response or stable disease after first-line treatment for advanced or metastatic disease NSCLC were randomized to maintenance emepepimut-S, given with cyclophosphamide prior to vaccination, or placebo, which was continued until disease progression. There was no difference in median OS (17.2 months vs 13 months), but a non-significant trend of improved survival was seen in patients with stage IIIB NSCLC without malignant pleural effusions (30.6 months vs 13.3 months). Only 21% of patients mounted a specific T-cell response against MUC-1.

 Adverse effects included mild flu-like symptoms, infections, and injection reactions. Currently, 2 phase III trials, START (closed to accrual) and INSPIRE, are being conducted in stage IIIB patients who have had a response or stable disease to concurrent chemoradiotherapy.

Unlike emepepimut and astuprotimut, belagenpumatucel-L includes 4 irradiated NSCLC cell lines—2 adenocarcinoma, 1 squamous cell, and 1 large cell. An antisense gene plasmid, or inhibitor, of transforming growth factor β2 (TGF- β2) is incorporated into these cells for additional efficacy.

 TGF- β2 inhibits T-cell activation and maturation and increased levels have been linked to a worse prognosis in patients with NSCLC.

 Seventy-five patients with stage II-IV NSCLC and a tumor burden of ≤125 mL were randomized into a phase II trial to receive 3 different doses of belgenpumatucel- L every 4 or 8 weeks for up to 16 doses following standard chemotherapy. OS was higher in the patients in the 2 higher-dosing groups compared with patients in the lower-dosing group, with an estimated 1-year survival of 68% in the higher-dosing groups (≥25 x 106 cells) compared with 39% in the lowerdosing group. There was no difference in toxicity between the 3 dosing schema, with the most common toxicities being pain, fatigue, cough, and breathing problems.

The STOP trial, a randomized, placebo-controlled, phase III study, is currently comparing belagenpumatucel-L (25 x 106 cells) with placebo in stage IIIA-IV disease following standard chemotherapy. 

Several cancers have been linked to mutations in the mesenchymal—epithelial transition (MET) gene including NSCLC.

 Hepatocyte Growth Factor Receptor (HGFR) or MET is a protein encoded within the MET gene that supports oncogenesis through a wide variety of mechanisms including cell proliferation, cell survival, invasion of surrounding tissue, metastasis, and angiogenesis.

 Tivantinib is an orally administered HGFR-selective TKI, which is also the most clinically advanced c-MET inhibitor to date. A randomized controlled phase II study investigating dual EGFR and MET inhibition using erlotinib plus tivantinib or placebo in patients with advanced NSCLC not previously treated with an EGFR inhibitor did not significantly improve PFS (16.1 vs 9.7 weeks) using an intention to treat population (HR 0.81 [95% CI 0.57-1.15; 

After using a Cox regression model to adjust for prognostic factors including histology and genotype, significant PFS improvement was noted (HR 0.68 [95% CI 0.47- 0.98; 

 <.05]). Heightened PFS improvement was observed in patients with nonsquamous histology, EGFR wild-type status, and k-RAS mutations.

A phase III study closed to accrual but which is still ongoing is evaluating the tivantinib plus erlotinib combination in non-squamous NSCLC.

A second phase III study is investigating the combination in wildtype EGFR patients who have received 1 or 2 prior systemic treatments; however, this study was suspended August 29, 2012.

On the Horizon for Non-Small Cell Lung Cancer

The care and management of patients with oncologic disorders is highly complex, often requiring combinations of surgical, radiologic, and chemotherapeutic interventions. Supportive measures are usually needed when patients utilize these primary and adjunctive treatments. Several layers of health professionals are involved in the care and treatment of patients with cancer, which leads to the need for a strong scientific basis for the treatments prescribed.

Health professionals and managed care executives know well that cancer management is not straightforward— it is not like peptic ulcers, not like hepatitis C, and not even like the autoimmune disorders. Myriad cancer treatments, including chemotherapies, biologics, and immunotherapies, have been approved for use, some with multiple indications. Not every drug&mdash;and there are many more in the pipeline&mdash;works for every patient, and the extent to which they work varies patient by patient. This lends itself to much experimentation by individual providers to try to optimize an individual patient’s clinical outcome and quality of life. It is then unsurprising that a paper from the American Society of Clinical Oncology found that 50% or more of prescribing of cancer agents is for unapproved indications.

The magnitude of off-label prescribing of oncology agents makes it difficult for payers—health plans, insurers, selfinsured employers, and governments&mdash; to address what should be covered and what should be excluded from coverage. In the 1990s and early 2000s, managed care organizations had been wary of applying traditional utilization management tools to the oncology category of medications. Part of this hesitation is related to the acute nature of the disease. Part is related to the fact that a specific medication may not work for everyone with lung cancer, for example. However, much of this reluctance can be traced back to Fox v HealthNet, in which a jury awarded Nellie Fox’s family $89 million in 1993 for the California health plan denial of coverage for an experimental treatment (high-dose chemotherapy followed by bone marrow transplant) to this patient with metastatic breast cancer.

 (Ms Fox’s family obtained the investigational treatment and she passed away soon afterward.) Since then, managed care has been wary of the medico-legal implications of not covering investigational cancer treatments.

An additional concern may now have arisen, partly owing to managed care’s caution in using its tool box to manage oncology costs. In a survey conducted for this article, one health plan medical director said that the biggest concern he faced in off-label prescribing was not the legal implications of withholding coverage, but “the medico-legal risk for the plan for allowing unproven treatments with high risk for toxicity or mortality.”

December

Advanced Prostate Cancer: Therapeutic Sequencing, Outcomes, and Cost Implications

Is Our Healthcare System Ready to Integrate Cancer Care?

Oncologist Practice Consolidation Continues

On the Horizon for Non-Small Cell Lung Cancer

The Complexity of Covering Off-Label Use for a Multitude of Oncology Regimens

Strategies to Increase the Value of Colon Cancer Medications

Breast Cancer: Will Treatment Costs Outpace Effectiveness?

Exploring New Ways to Broaden the Reach of Molecular Tumor Testing

Precision Medicine and the Rapidly Approaching Future of Cancer Management

Clinical Pathways: An Evolutionary Approach to Cancer Care

Oncology Enters the Informatics Era

Initial Success, Frequent Recurrence

Trends in the 2012 Eisai Oncology Digest: Insurance and Cost Obstacles in Cancer Treatment