The Evolution of Clinical Pathways for Oncology

Abstract: A substantial portion of total medication costs is represented by the cost of specialty drugs, which only continues to rise. Oncology, in particular, is one of the three most costly specialty therapeutic areas of medicine. Payers have begun to take a variety of approaches to manage their overall oncology spend. One such approach is the implementation of clinical pathways. Clinical pathways are intended to be used by a multidisciplinary health care team in order to achieve the Triple Aim of healthcare reform: improving outcomes and quality, improving the patient experience, and lowering cost. The author reviews a selection of pathways programs that have been implemented and discusses the innovations being used in order to promote adherence to the pathways and enable reporting of outcomes. Barriers to the implementation of clinical pathways, as well as the implications of the increasing number of provider-initiated clinical pathways programs, are also discussed.

Citation: Journal of Clinical Pathways. 2015;1(1):37–42. 

Received on August 16, 2015; accepted September 11, 2015.

Disclaimer: Dr. Wong, the journal’s Editor-In-Chief, was not involved in the editorial review or decision to publish this article.
_____________________________________________________________________________________________________________________________

From the payer perspective, total medication costs under the prescription and medical benefits can represent up to 40–45% of the total care costs.1 Of these total medication costs, up to 45% can be represented by specialty drugs.1 In the 2014 Express Scripts Medication Trends report,2 an overall trend of 13.1% growth in the cost of drugs was reported from 2013 to 2014, breaking down to 6.4% growth for non-specialty drugs and 30.9% growth for specialty drugs. Although the observed difference in trends between non-specialty and specialty drugs is significant, the industry trend difference may actually be greater, because the Express Scripts trend figures are driven mostly by the ambulatory prescription benefit utilization, and are not directly impacted by newly released oncology medications under the medical benefit.2

In the same Express Scripts report, oncology ranked as the third most costly specialty therapeutic areas, behind inflammatory conditions and multiple sclerosis.2 Most small to mid-size payer organizations have not approached the topic of managing their oncology spend. At a minimum, payer organizations rely upon their pharmacy benefit managers to administer a prior authorization program to control utilization of oral chemotherapy medications, as well as to control the distribution channel (ie, requiring medications go through a specialty pharmacy to ensure tighter monitoring and follow-up activity).3 For the most part, these prior authorization programs focus on ensuring “appropriate use” as defined by compendia listing or FDA approval. In addition to these prescription benefit–based prior authorization programs, a few payer organizations have minimally controlled the utilization of individual oncology medications through medical “pre-certification” programs, The pre-certification program also tends to be focused on appropriate use, as defined by compendia listing or FDA approval, but also is inclusive of comprehensive patient care, centered around the treatment regimen, supportive care, patient support, and end-of-life planning.4

One approach to the management of oncology costs being used by payers is the implementation of clinical pathways. Clinical pathways—also referred to as “treatment pathways,” “patient pathways,” or simply “pathways”—are multidisciplinary plans of best clinical practices.5 In some respects, clinical pathways can be viewed as algorithms, outlining the sequence of treatment decisions to be made and the care to be provided for a given patient in a given condition. These pathways are intended to be used by a multidisciplinary team in order to enhance quality, care coordination, and accountability. These goals are consistent with the Triple Aim of healthcare reform: improving outcomes and quality, improving the patient experience, and lowering cost.6

The term “clinical pathways” has been used variably to represent anything from treatment protocols to mandated treatment plans. The label of clinical pathways has even been used interchangeably with clinical guidelines for the treatment of cancer, such as those developed by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) or
the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines (http://jco.ascopubs.org/site/misc/specialarticles.xhtml). However, a clear distinction must be made between clinical guidelines and clinical pathways. OpenClinical, an organization created to promote decision support, clinical workflow, and other knowledge management technologies in patient care and clinical research, provides the standard definition of clinical guidelines as systematically developed statements to assist practitioners and patient decisions about appropriate health care for specific circumstances.7 Like clinical pathways, clinical guidelines are designed to support the decision-making processes in patient care, in order to improve and maintain quality and consistency of care. Also like clinical pathways, the content of a guideline is based on a systematic review of clinical evidence. However, whereas clinical guidelines simply delineate treatment options in any given clinical situation, clinical pathways are designed to support not only clinical management but also clinical and non-clinical resource management, clinical audit, and financial management.4

PAYER-INITIATED CLINICAL PATHWAY PROGRAMS FOR ONCOLOGY

One of the first noted insurance plan-sponsored pathway programs was implemented in 2008 by Care First Blue Cross Blue Shield, based in Owning Mills, MD.8 Facilitated by P4 Healthcare, now part of Cardinal Health, a steering committee made of key oncologists from the CareFirst network was tasked with developing and maintaining the pathways. P4 Healthcare was responsible for monitoring and reporting compliance to the pathways.

Within the CareFirst market, the physician participation rate by practice type was 88% of community-based oncologists, 44% of hospital-based oncologists, and 6% of academic-based oncologists; together, these practices drove ~75% of the total oncology costs to CareFirst.8 During the first year of its pathway program, CareFirst rewarded oncology practices that achieved a 70% rate of compliance with the pathways by granting them a reimbursement rate more favorable than the standard fee schedule. Oncology practices that did not achieve the required level of compliance were reimbursed at the standard fee schedule. Thus, the only potential financial impact to participating practices was a positive one, if the compliance threshold was met. In subsequent years, oncology practices were required to achieve a higher compliance rate of at least 80% in order to receive the higher reimbursement rate.8

During the first 17 months of the program, CareFirst saw savings of more than $7 million for treatment of breast, colon, and lung cancers. Additional savings were achieved in supportive care and service costs, bringing the total savings for these three types of cancer to more than $10.5 million.9 This represents an estimated 15% savings. Later analysis showed that ~50% of the cost-savings could be attributed to prescribing practice changes, which resulted in less variability in treatment regimens, reduced use of high-cost medications, and increased use of generics. The remaining 50% of the savings resulted from decreased emergency room visits and decreased inpatient hospitalizations.10 These outcomes were attributed to improved patient care follow-up and coordination, which occurred as a result of compliance with the supportive care pathway.10

In a similar program, BlueCross BlueShield of Michigan (BCBSM) partnered with Oncology Physician Resource (OPR), a physician-owned practice management entity created by the Michigan Society of Hematology and Oncology, to launch a pathways program.4 Oncologists initially resisted the program due to concerns about the potential impact to the practice workflow and to the practice’s profits.8 In order to address these concerns, OPR and BCBSM agreed on three ways to reward physicians for using the pathways. First, each oncologist who agreed to participate in the program from its launch in January 2010 received a $5,000 participation fee. Physicians who enrolled in the program after this date received a participation fee of a prorated amount. Second, the reimbursement rate for generic medications was substantially inflated, while still remaining below the cost of the branded counterpart. The rationale for increasing the reimbursement for generics was to remove the incentive for physicians to use a more expensive brand name drug. The use of generic drugs instead of brand-name drugs benefits all stakeholders: the oncology practice benefits from not having the liability of higher-cost inventory; the payers benefit from paying for a less expensive drug than the brand-name drug; and the patient benefits from paying significantly lower copayments.8 Third, BCBSM committed to compensate the oncology practice a certain percentage of any overall savings realized in its expenditures for chemotherapy and supportive medications.

The BCBSM/OPR pathway program successfully recruited 80% of Michigan oncologists to participate in its program.11 OPR developed clinical pathways for breast, colon, and lung cancers, later adding pathways for lymphoma, myeloma, and ovarian and prostate cancers. BCBSM funded the development and updating of the pathways, monitoring adherence, and funding the incentives to oncologists for participation in the pathway program.

In the first 2 years of the program, paid claims for branded chemotherapy medication decreased by 44%, with a 10% decrease in the variability of treatment regimens administered. Costs savings estimates were not reported.12 BCBSM noted the difficulty of analyzing the program data in order to evaluate outcomes, because claims data does not include information on staging or lines of therapy, both of which are essential for determining compliance with pathways and outcomes associated with their use.12

The BCBSM oncology management program was updated in 2014 to integrate with two other oncology management collaboration programs. In order to better track compliance with the pathways, an interactive web portal was implemented to provide practitioners with point-of-service decision support. The portal presents the information necessary to select treatment and supportive care regimens compliant with the pathways, and it also collects data that makes it possible to evaluate the outcomes associated with using the pathway.12

The CareFirst BCBS and BCBSM programs demonstrated that plans could collaborate with oncology practices to work towards controlling the cost of cancer care; however, these programs were very resource-intensive, especially at a time when technology and automation were not as developed as they are today. Therefore, pathways were only developed for a few cancer types and stages. In contrast, two of the largest pathway programs in place today—Anthem BlueCross BlueShield’s Cancer Care Quality Program and Humana’s Oncology Quality Management Program—offer broader coverage of cancer types and stages, and have automated systems for monitoring and reporting of pathway compliance and outcomes.13,14 Additionally, payers now delegate the administration of their clinical pathways program to medical review support administrators—such as AIM Specialty Health, New Century Health, Eviti, and CareCore—under the umbrella of a pre-certification program. Administering pathways as an extension of the pre-certification program under the medical benefit allows for tighter management of the in-office infused treatment regimens, as opposed to the prior authorization program under the pharmacy benefit used to manage the oral medications.

In July 2014, Anthem BlueCross BlueShield launches its Cancer Care Quality Program, one of the largest payer pathway programs in place today, with fourteen states scheduled to participate by the end of 2015. The program currently includes clinical pathways for fourteen different cancer types and stages. The breadth of their pathway program was intended to be applicable for 80–90% of their population of beneficiaries with the most common types of cancer. The pathways are based upon the type and stage of cancer, biomarker or specific genetic profile, and the clinical presentation of the patient.13

The program is administered by Anthem’s subsidiary, AIM Specialty Health, which operates as a medical support vendor. Treatment plans are to be submitted online into the AIM provider portal by the treating oncologist. Treatment regimens are processed, evaluated against the preferred pathway, and notification is provided immediately. If the regimen is designated as a preferred regimen, an “S-Code” is issued for a care management fee to be billed as part of the claim. The care management fee payment is $350 per month of treatment. The $350 per month fee was determined to “essentially equalize the difference” between what the practice would be making between the preferred regiment and the non-preferred regimen.14 If a treatment plan is received from a provider that is determined to not match the referred pathway regimen, a request can be made to have the regimen reviewed, and the regimen may be designated as a preferred regimen for that patient.12 Thus, providers are not penalized for non-preferred regimen treatments; however, submission is mandatory to receive the incentive.

Anthem released preliminary results15 on provider participation and adherence to their cancer treatment pathways at the American Society of Clinical Oncology meeting, held June 3–7, 2015. They reported that, between July and December 2014, 616 practices registered 5538 patients in the program. Among registered patients, pathway adherence was 63% for breast cancer, 72% for colon cancer, and 63% for non-small cell lung cancer (NSCLC).15 The results of the first year of the program have not yet been reported, but are expected soon.

Humana has partnered with New Century Health16 and Oncology Analytics17 to administer their Oncology Quality Management Program. Similar to Anthem’s pathways program, the pathways are evidence-based, incorporating a peer-to-peer counseling model into a traditional pre-certification program. The scope of their program is expected to be active in 32 states by the end of 2015. All treatment regimens are required to be submitted through the physician portal. Treatment regimens are processed, and evaluated against the approved treatment regimens. Treatment regimens meeting the approved criteria are immediately authorized for reimbursement. Regimens not meeting criteria can be appealed through a peer-to-peer consultation. Ultimately, regimens not meeting criteria for authorization will not be reimbursed. Unlike the Anthem model, providers will not be reimbursed for non-approved regimen treatments. Results of the program have not yet been reported.14

BARRIERS TO THE SUCCESS OF PAYER PATHWAY PROGRAMS

Payers have developed pathway programs with the goal of greater standardization of treatment regimens and sequencing, in order to improved clinical outcomes, quality of life, patient experience, and cost control. Genentech’s 2015 Oncology Trends Report18 states that 40% of managed care organizations (MCOs) have initiated a pathways program to guide cancer treatment decisions, up from 31.1% in 2013. Of the 42 surveyed MCOs that have initiated a pathways program, most have developed their own pathways in collaboration with a network or with their own oncologists, whereas some use pathways developed by network oncologists independent of the MCO. Ten MCOs use the NCCN Value Pathways, and ten use the P4 Pathways program. Most of the 42 MCOs with a treatment pathways program (59.5%) manage them internally. However, local oncologists manage the pathways program for 16.7% of the 42 MCOs. Voluntary use of pathways by oncologists is also the standard for 45.2% of the 42 MCOs, though 35.7% incentivize voluntary use and 16.7% link reimbursement to mandatory use of pathways, which represents an increase from the previous study period. The 22 MCOs that incentivize oncologists to follow treatment pathways primarily reward their use by giving oncologists a share of the cost savings (n=8), bonus payments (n=7), improved/higher evaluation and management reimbursements (n=7), and reductions in prior authorization or precertification requirements (n=7).18

In the Genentech Oncology Trends Report, the majority of MCOs (71%) reported that pathways were effective in enabling their organization to improve the quality of care and decrease the cost of care.18 Unfortunately, to date, few published results regarding the effects on cost savings, clinical outcomes, or patient satisfaction associated with these programs have been reported.3

In a 2014 presentation, a representative from the National Pharmaceutical Council reported research showing that information technology limitations was cited by 77% of survey respondents as a major barrier to the development and implementation of clinical pathways.19 Information technology limitations most likely account for the paucity of data to demonstrate improvements in patient outcomes and a return on investment for payer-provided clinical pathway initiatives. An adequate information technology infrastructure is an absolute requirement for a successful practice. Practices usually incorporate the clinical pathways into a decision support tool or process, which is usually embedded into their electronic medical records system, decision support system, or some other workflow system. Without some type of decision-support system, analysis capability would be limited to claims, which only contains fields essential for claims processing and payment. Necessary clinical indicators, i.e. tumor staging, treatment sequence, etc. are not included, which significantly impacts the accuracy of the reporting of compliance and clinical outcomes, as well as financial impact. Decision support systems are key to reinforce and monitor compliance to the clinical pathway, as well as to measure the impact of clinical pathways upon clinical outcomes and cost of care.

In the same National Pharmaceutical Council report, the number one barrier to the development and implementation of clinical pathways identified was physician resistance.19 It is possible that providers view treatment pathways as “cookbook medicine,” limiting their ability to provide the best and most appropriate care for their patients.8 Because clinical pathways are developed to incorporate treatments found to be the most clinically appropriate and cost-effective on a population-wide, multi-disciplinary level, clinical pathways can seem antithetical to personalized medicine.20 MCOs and oncologists cite balancing treatment standardization with personalization as being a major challenges facing cancer care today.18 It should be mentioned, however, that personalized medicine approaches can easily be integrated into clinical pathways. Genomic profiling, in its most simplest view, is merely identifying a subpopulation in which a positive clinical outcome for a given treatment option is more likely. Thus, genomic profiling can be used within the clinical pathway to determine the most appropriate treatment option on an even more granular level.

THE RISE OF PROVIDER-INITIATED PATHWAY PROGRAMS

Despite the slow acceptance of payer-initiated clinical pathways by practitioners, many large group oncology practices are starting to embrace treatment pathways as a foundation for the comprehensive care of their patients. From the perspective of practice managers, the incorporation of treatment pathways into practice workflows can enable the provision of smarter, more efficient, and higher quality care to patients. Smarter and more efficient prescribing results in cost control, which, coupled to a higher quality of care through patient follow-up, better positions the practice to assume financial risk for their patient population. In some respects, practice-driven pathways represent an option for providers to improve quality and control cost, as opposed to allowing the payers to drive the solution. It also allows the practice to be competitive with institutional and other community-based health care programs.

US Oncology, now owned by McKesson Specialty Health, implemented one of the first noted practice-driven pathways programs in their Level 1 Corporate Partner Practices. US Oncology’s pathway program is designed to be appropriate for 80% of the patient population, allowing for other mitigating factors, such as toxicity or comorbidities, to influence treatment decisions for the other 20% of patients.21 Key to the success of the US Oncology program was incorporation of the pathway into their electronic medical record decision support system.22 By having the treatment regimen embedded into the decision support system, non-pathway treatment decisions are identified immediately. Non-pathway treatment decisions are reviewed by the practice CMO for authorization.22 Although fully integrated into the Level 1 Corporate Partner Practices, the US Oncology pathways are available to all US Oncology affiliated network practices.8

Outcomes associated with using the Level 1 Pathways for NSCLC were reported in 2010.23 Overall, outpatient costs were 35% lower for on-pathway versus off-pathway patients (average 12-month cost, $18,042 vs. $27,737, respectively). Costs remained significantly less for patients treated on pathway versus off pathway in the adjuvant and first-line settings, whereas no difference in overall cost was observed in patients in the second-line setting. No difference in overall survival was observed overall or by line of therapy. In the net monetary benefit analysis, after adjusting for potential confounders, treating patients on pathway was cost-effective across a plausible range of willingness-to-pay thresholds.23 In 2011, another study reported clinical outcomes and the economic impact of adherence to Level I Pathways for the treatment of colon cancer.24 Overall costs from the national claims database—including total cost per case and chemotherapy costs—were lower for patients treated according to Level I Pathways compared with patients not treated according to Level I Pathways. Use of pathways was also associated with a shorter duration of therapy and lower rate of chemotherapy-related hospital admissions.

In a similar practice model to the Level 1 US Oncology practices, Via Oncology Pathways evolved out of the University of Pittsburg Medical Center (UPMC) Cancer Center in 2005.22 Since 2005, Via Oncology has grown from a single institution, to a nationally recognized leader in oncology pathways, covering more than 90% of cancer types and all major modalities and phases of care, including surgical and radiation oncology.22 Their pathways have been demonstrated to improve the consistency of care across oncology practices and to generate health care savings across their network.25 Today, Via Oncology clinical pathways are currently in use by oncologists practicing in many of the major cancer programs across the United States.26 Thirty-three separate disease committees maintain their pathways. A pathway portal and decision support tool was implemented in 2007, providing access to the pathways, references, and dose modification guidelines.22

Finally, the growing acceptance of clinical pathways by oncologists is seen by the use of clinical pathways by Oncology Patient Centered Medical Home (OPCMH) programs. In the longest running OPCMH program, Consultants in Medical Oncology and Hematology, P.C., pathways are seen as one of the foundations of achieving improved quality while controlling costs.27 Compliance to clinical pathways has been measured at over 80%.27 The use of clinical pathways by Consultants in Medical Oncology and Hematology was complimented by their improvement in care coordination and follow-up, leading to a reduction in emergency room visits and inpatient hospitalizations, with an increase in office visits.27

CONCLUSIONS

Because of their ability to support evidence-based treatment decisions that include considerations of value, clinical pathways will likely continue to be integrated into the management of oncology care, from the perspectives of both the payer and the oncology practice. As payers actively seek alternative methods to manage oncology care costs and improve the overall value of treatments provided, the concept of clinical pathways is starting to gain momentum. Oncology practices also are embracing the concept of pathways as a means to standardize treatment decisions, which they believe will allow them to achieve the goals of the Triple Aim of healthcare reform.5 Although “preferred regimens” or “pathways” are commonly said to be based upon efficacy, safety and tolerability, cost must be given significant weight as well. Clinical pathways are a means for practices to respond to alternative financial models, and provide leverage to negotiate with payers for higher reimbursement. Similar to payer-driven clinical pathways, cost is a determining factor in assigning value to a particular treatment approach, along with efficacy, safety, and tolerability. In short, providers will need pathways to assist them in responding to the call of payers to lower and control costs, thus balancing between the cost of providing quality care and reimbursement. The next question is whether this gain in acceptance of clinical pathways will extend to their implementation in a more collaborative setting; ie, their incorporation into alternative financial models such as bundled payments or episodes of care. Whichever model prevails, clinical pathways will likely play a role. 

-----

References

1.    Care First Blue Cross Blue Shield. Data on file.

2.    The Express Scripts Lab. The 2014 Drug Trend Report. http://lab.express-scripts.com/~/media/PDFs/Drug%20Trend%20Report/ExpressScripts_DrugTrendReport.ashx. Published March 1, 2015. Accessed August 10, 2015.

3.    Tu HT, Samuel DR. Limited options to manage specialty drug spending. http://www.hschange.com/CONTENT/1286/. Center for Studying Health System Change Research Brief No. 22. Published April 2012. Accessed September 21, 2015.

4.    EMD Serono Specialty Digest, 10th Edition. Managed Care Strategies for Specialty Pharmaceuticals, Stern D, ed. 2014.

5.    openclinical.org/clinicalpathways.html

6.    Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood). 2008;27(3):759-69.

7.    openclinical.org/guidelines.html

8.    Gesme DH, Wiseman M, Strategic Use of Clinical Pathways. JOP 2010;7(1):54-56.

9.    Blue Cross Blue Sheild Blue Care Network of Michigan. BCBSM Physician Group Incentive Program 2014 Program Year: Michigan Oncology Clinical Treatment Pathways Program. pmcpo.com/sites/pmcpo.com/files/filepicker/1138/2014%20Pathways%20Initiative%20Plan.pdf. Published 2014. Accessed August 10, 2015.

10.    Kreys ED, Kim TY, Delgado A, Koeller JM. Impact of cancer supportive care pathways compliance on emergency department visits and hospitalizations. J Oncol. Pract. 2014; 10(3):168–173.

11.    Butcher L. State Oncology Groups Advance Clinical Pathways. Oncology Times 2011; 33(16):14–16.

12.    Wong W: Partnering with oncology providers to manage oncology care. Presented at eValue8 National Users’ Conference, July 13, 2010, Chicago, IL. nbch.org/nbch/files/ccLibraryFiles/Filename/000000001041/Wong,%20Winston.pdf

13.    Anthem Cancer Care Quality Program – Treatment Pathways Revised. https://anthem.aimoncology.com/ Published April 2015. Accessed September 21, 2015.

14.    Anderson J. Insurers, Providers Experiment with New Oncology Payment Models, Health Business Daily, April 2, 2015, downloaded from AISHealth.com

15.    Malin J, Nguyen A, Ban SE, et al. Impact of enhanced reimbursement on provider participation in a cancer care quality program and adherence to cancer treatment pathways in a commercial health plan. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2015; Chicago, IL. freepdfhosting.com/4cabfc650b.pdf.

16.    Humana. Chemotherapy – New Century Health. https://www.humana.com/provider/medical-providers/education/referral/chemotherapy-new-century. Accessed August 10, 2015.

17.    Humana. Chemotherapy – Oncology Analytics. https://www.humana.com/provider/medical-providers/education/referral/chemotherapy-oncology-analytics. Accessed August 10, 2015.

18.    The 2015 Genentech oncology trend report: perspectives from managed care, specialty pharmacies, oncologists, practice managers, and employers. 7th ed. South San Francisco, CA: Genentech; 2015.

19.    Dubois RW, Kolodziej M, Nguyen A, Wong W. Navigating Clinical Pathways. Poster presented at: Academy of Managed Care Pharmacy 27th Annual Meeting and Expo; April 7–10, 2014; San Diego, CA. 

20.    Shelley S. Bending the cost curve in oncology. Pharmaceutical Commerce. http://pharmaceuticalcommerce.com/brand_communications?articleid=27192. Published April 28, 2014. Accessed September 21, 2015.

21.    DeMartino JK, Larsen JK. Equity in cancer care: pathways, protocols, and guidelines. JNCCN 2012; 10(suppl 1):S1–S9.

22.    Neubauer M, Gosse N, Verrilli D, et al. Clinical pathways: are we there yet? J Community Support Oncol. 2013; 10:96–98.

23.    Neubauer MA, Hoverman JR, Kolodziej M, et al. Cost Effectiveness of Evidence-Based Treatment Guidelines for the Treatment of Non–Small-Cell Lung Cancer in the Community Setting. J Oncol Pract. 2010; 6(1):12-18.

24.    Hoverman JR, Cartwright TH, Patt DA, et al. Pathways, Outcomes, and Costs in Colon Cancer: Retrospective Evaluations in Two Distinct Databases. J Oncol Pract. 2011; 7(3S):52s–59s.

25.    Rajagopalan MS, Flickinger JC, Heron DE, Beriwal S. Changing practice patterns for breast cancer radiation therapy with clinical pathways: An analysis of hypofractionation in a large, integrated cancer center network. Pract Radiat Oncol. 2015; 5(2):63–69.

26.    Via Oncology website. http://viaoncology.com.

27.    Sprandio JD, Oncology patient-centered medical home and accountable cancer care, Commun Oncol. 2010;7:565–572.