Follow-up care of cancer survivors: challenges and solutions

Series

Cancer survivorship in the USA 2 Follow-up care of cancer survivors: challenges and solutions Linda A Jacobs, Lawrence N Shulman

Attention to survivors of adult cancers formally began more than 30 years ago with the founding of the National Coalition for Cancer Survivorship by representatives from 20 organisations who envisioned an organisation that would address survivorship issues and include friends, family, and caregivers. Since then, progress has been made in cancer care delivery, which has created challenges for and barriers to provision of optimal follow-up care to patients and survivors living with cancer as a chronic illness. Focus on post-treatment cancer care, including monitoring for longterm and late effects, and concerns regarding the effect of a cancer diagnosis and treatment on quality of life have gained momentum in the past 10 years. This impetus is largely a result of the 2005 Institute of Medicine Report From Cancer Patient to Cancer Survivor: Lost in Transition. Although the issues raised in the report were hardly novel, they gave a new and powerful voice to the cancer survivorship movement that demanded a call to action. In this Series paper, we provide an overview of the issues surrounding provision of cancer survivorship and follow-up care in the USA and discuss potential solutions to these challenges.

Introduction The ongoing improved survival over the past 40 years for paediatric and adult cancers has resulted in populations of cancer survivors with many unique needs potentially at risk for many significant medical and psychosocial issues over the course of their lives. The National Coalition for Cancer Survivorship (NCCS) is a patientcentred US advocacy organisation that was founded in 1986, with the initial goal to replace the words “cancer victim” with “cancer survivor” to ultimately bring about a different perspective of the disease. Since then, the NCCS has had a major role in educating government agencies and policy makers in the USA about the need to provide quality care throughout the cancer survivorship continuum.1 The cancer survivorship movement in the specialty of adult oncology, the call for attention to the growing numbers of people living with cancer as a chronic illness, and the need for health-care professionals to provide careful systematic monitoring and mitigation of the side-effects of disease and treatment are attributed to the 2005 Institute of Medicine (IOM) report entitled From Cancer Patient to Cancer Survivor: Lost in Transition.2 However, in July, 1985, Fitzhugh Mullan, a cofounder of the NCCS, poignantly described the state of cancer care “…as if we have invented sophisticated techniques to save people from drowning, but once they have been pulled from the water, we leave them on the dock to cough and sputter on their own in the belief that we have done all we can…”.3 He went on to describe what he called the “seasons of survivorship”, which included acute survival or the period after diagnosis; extended survival, a time after completion of treatment; and permanent survival, when recurrence seems highly unlikely yet long-term effects of treatment continue. Several years later, comprehensive reviews of literature based on the physiological and psychosocial long-term and late effects of treatment were published.4,5 These publications suggested that the sequelae of cancer and its www.thelancet.com/oncology Vol 18 January 2017

treatment can affect any body system from months to years after treatment. They also showed that improved outcomes could be achieved when rehabilitation—a programme that might include a guide for physical activity, physical therapy, occupational therapy, and mental health support—was initiated as soon as possible after the initial cancer diagnosis. In 1991, an article6 entitled The Cancer Survivorship Movement was published in a special section on cancer survivorship. At that time, local organisations were emerging, publications on cancer survivorship in various journals were increasing, and networks and organisations were forming specifically to deal with survivorship issues. Much of this activity was attributed to the emergence of informed and assertive health-care consumers, working to unify and coordinate the different components of the early cancer survivorship movement.4 14 years later, the 2005 IOM report2 highlighted the importance of post-treatment care stating that the needs of cancer survivors are often not met. Along with many other organisations,7–10 the institute recommended that patients who complete primary treatment should be provided with a comprehensive, clear, and concise summary document of care and a follow-up plan, known as a survivorship care plan. Recommendations to guide provision of survivorship care were also summarised (panel 1). The Commission on Cancer has added patientcentred care to their programme accreditation standards in 2012, focusing on navigation, distress screening, and survivorship care.11 This addition requires cancer centres that are seeking Commission on Cancer accreditation to provide care plans to patients treated with curative intent who have completed active therapy. Cancer programmes have been scrambling to meet this standard, now effective as of 2015, despite the paucity of evidence supporting the actual efficacy of care plans. Cancer centres are moving forward to implement this costly endeavour, and this mandate is the first evidence of widespread use of survivorship care plans.

Lancet Oncol 2017; 18: e19–29 This is the second in a Series of five papers about cancer survivorship in the USA Director for Survivorship Clinical Programs, Research and Educational Initiatives (Prof L A Jacobs PhD), Deputy Director for Clinical Services (Prof L N Shulman MD), Abramson Cancer Center, Perelman Center for Advanced Medicine, Philadelphia, PA, USA Correspondence to: Prof Linda A Jacobs, University of Pennsylvania, Abramson Cancer Center, The Perelman Center for Advanced Medicine, 10-149 South Tower, Philadelphia, PA 19104, USA [email protected]

e19

Series

Panel 1: Institute of Medicine guide for the development of adult cancer survivorship programmes Recommendation 1 • Raise awareness of the needs of cancer survivors • Establish cancer survivorship as a distinct phase of cancer care • Ensure delivery of appropriate survivorship care Recommendation 2 • Provide every patient with a survivorship care plan that is clearly explained Recommendation 3 • Use of evidence-based clinical practice guidelines, assessment tools, and screening tests to help identify and manage late effects of cancer and of its treatment Recommendation 4 • Develop quality survivorship care measures • Implement quality assurance programmes to monitor and improve care for all cancer survivors Recommendation 5 • Test models of coordinated interdisciplinary survivorship care in diverse communities and across health-care systems Recommendation 6 • Develop comprehensive cancer control plans • Include survivorship care and promote implementation and assessment Recommendation 7 • Expand and coordinate efforts to provide educational opportunities to health-care providers • Equip providers to address health-care and quality of life issues facing cancer survivors Recommendation 8 • Work to eliminate discrimination and minimise adverse effects of cancer on employment • Support cancer survivors with short-term and long-term limitations in ability to work Recommendation 9 • Ensure that all cancer survivors have access to adequate and affordable health insurance with the assistance of insurers and health-care payers Recommendation 10 • Increase funding support for survivorship research • Expand mechanisms for research in an effort to guide survivorship care Adapted from the recommendations made in the 2005 Institute of Medicine report.2

Inroads have been made in the identification of risk factors for long-term and late effects of cancer treatment, and in understanding the psychosocial problems that might occur between treatment and these effects, such as marital, financial, interpersonal, and employment issues, as well as psychiatric issues.12 Screening guidelines for follow-up care after cancer treatment have been outlined by professional organisations including the National Comprehensive Cancer Network (NCCN)7 and the American Society of Clinical Oncology (ASCO).8 Additionally, ASCO released a statement13 in 2013 on achieving high-quality cancer survivorship care noting the urgency of an understanding of the needs of survivors e20

and of development of models of comprehensive and coordinated care. Substantial progress has been made in cancer care in the past few decades. This progress has created challenges and barriers to provision of optimal follow-up care to patients and survivors living with cancer as a chronic illness. In this Series paper, we discuss the issues affecting care delivery, and the current approaches to provision of care within the rapidly changing oncology care delivery system. We also examine and propose solutions to the barriers to care delivery for cancer survivors.

The needs of cancer survivors Unmet needs of cancer survivors have been defined as “…[survivors’] needs which lack the level of service or support an individual perceives are necessary to achieve optimal wellbeing”.14 The needs of cancer survivors have been documented and assessed using well-established survey methods that are designed to measure physical, psychosocial, resource, and informational needs,15 and are discussed in detail by Mayer and colleagues.16 An understanding of these needs is central to the development of strategies to address them and to create models of survivorship care delivery. Such models have been developed and refined over time in response to the identification of these needs. These models vary and depend on the setting—whether urban or rural, wellresourced or resource-poor, or community-based versus academic-based health-care systems.17–24 The largest qualitative dataset14 from cancer survivors was done by the American Cancer Society and investigated responses of cancer survivors using openended questions about current unmet needs related to cancer. Responses to the question “Please tell us about any needs you have now as a cancer survivor that are not being met to your satisfaction” were examined from 1514 survivors across six cancer types (breast, prostate, colorectal, bladder, uterine, and melanoma) encompassing survivor cohorts of 2 years, 5 years, and 10 years after diagnosis. The goal of this project was to describe how the themes outlined in survivors’ responses compared with themes of unmet needs explored in previous research.14 The patterns of unmet needs across subgroups such as age, disease type, and time since completion of treatment were described. Although the patterns and themes identified provide important information about which specific groups’ interventions could be targeted, the unmet needs identified in the study were consistent with those recognised in previous and ongoing research (figure 1).18–24 The needs of cancer survivors can differ substantially as a result of many factors, including specific cancer diagnosis and treatment provided. Consequently, followup care of many cancer survivors can be complicated and, therefore, these patients should not be cared for solely by non-cancer care providers. www.thelancet.com/oncology Vol 18 January 2017

Series

Models for delivering cancer survivorship care

Risk stratification model

Established models

One of the models proposed and currently being tested is an oncology and primary care risk-stratified shared care model for cancer patients and survivors,26 which includes an outline of the roles and responsibilities of oncologists and primary care providers (PCPs) from diagnosis to long-term follow-up care.27 In this model, patients are stratified into low, moderate, or high-risk on the basis of either the type of chemotherapy they received, whether or not they were treated with radiotherapy, and whether or not they had a bone marrow or stem-cell transplant. The toxic effects from treating agents are also considered (panel 3).27,28

The term model has been used to describe the process for delivery of survivorship care, and many survivorship care models have been developed, described, and researched in the past 10 years (panel 2).25 However, despite the work that has been done in the examination and testing of models for provision of survivorship care, little data exist on how effective these models are. Each model comes with its own set of difficulties, supporting the notion that no universal model of care exists that will work for all cancer survivors. Other models have been proposed in addition to those in panel 2. These developing models show promise with regard to their use during the survivorship and follow-up phase of care, and in some cases throughout the entire cancer care continuum. Potential long-term and late effects of treatment Effect on cancer survivor

Chronic care model The chronic care model, which uses self-management interventions, is used for many chronic diseases—such Pain

Cognitive impairment

Fatigue

Psychosocial issues

Bowel or bladder dysfunction

Role disruption

Sexual dysfunction

Economic problems

Cancer survivor

Social isolation

Sleep problems

Spiritual issues

Loss or change in employment status

Struggle for meaning

Fear of recurrence

Anxiety or depression

Osteoporosis

Lymphoedema

Hot flashes

Peripheral neuropathy

Figure 1: Potential long-term and late effects of treatment and how they affect cancer survivors Potential long-term and late effects of treatment, any and all of which can affect the personal characteristics of the cancer survivor.

www.thelancet.com/oncology Vol 18 January 2017

e21

Series

Panel 2: Cancer survivorship models of care Paediatric follow-up care model Multidisciplinary • Several providers available to provide care the same day • Resource intense, not disease specific Adult follow-up care models Multidisciplinary • Resource intense, not disease specific Disease specific • Separate survivorship clinics for each disease Consultative service • One visit in a survivorship clinic setting • Can be disease specific or not disease specific Integrated care model • Extension of the cancer care continuum • Nurse practitioner or physician’s assistant visits • Survivorship care-focused visits Risk-stratified and shared care • Low, moderate, and high risk of developing long-term and late effects of treatment or cancer recurrence • Coordination between oncologists and primary care provider • Transition to primary care Description of models of care developed, tested, and most frequently used in the clinical setting.25

Panel 3: Summary of proposed solutions recommended by the American Society of Clinical Oncology for survivorship care delivery challenges Clinical guidance • Develop, standardise, and disseminate long-term evidence-based guidelines for follow-up care of adult cancer survivors • Make guidelines accessible to oncologists and primary care providers • Use general health guidelines beyond oncology Models of survivorship care • Promote successful survivorship care models and tools for the transition process between oncology and primary care • Promote a shared care model and communication between providers • Use a risk-stratified approach for care and transition • Partner to test models of coordinated multidisciplinary care in diverse communities and across systems of care Assure high-quality survivorship care • Establish standardised ways to monitor and improve the quality of survivorship care • Strategies to ensure that every survivor receives a written coordinated treatment summary and follow-up plan • Encourage all settings to implement quality improvement programmes • Develop quality of survivorship care measures through public–private partnerships and quality assurance programmes (Continues on next page)

e22

as diabetes, depression, asthma, and congestive heart failure—and is a good model to consider for cancer follow-up care (panel 4).29–33 This model fosters productive interactions between informed patients who actively participate in their care and experienced providers, resulting in a more broadly applicable, higher quality, and possibly more cost-effective patient care continuum than traditional models where healthcare providers manage all aspects of a patient’s care. Use of the chronic care model across the cancer care continuum requires a change in approach towards planning for long-term care beyond acute care for the cancer survivor.29,34,35 McCorkle and colleagues35 described cancer as a chronic illness, and cancer care as occurring on a continuum that extends from prevention to the end of life, interspersed by early detection, diagnosis, treatment, and survivorship. A care model based on self-management could, therefore, be a useful model that could apply to all stages of cancer care.

Transition models Models of cancer care that involve a transition to other oncology, specialty, or PCPs create many challenges. Paucity of knowledge, and preparation for care for patients with cancer after they have completed treatment by non-oncology providers, and inadequate communication between providers, have been cited as challenges and barriers in many studies36–38 exploring differences between oncology and non-oncology care delivery. Patient and provider preferences, skillset differences, satisfaction, and real and perceived communication patterns also present challenges. As cancer treatment becomes more complex, with new treatments evolving rapidly, PCPs and other non-oncology providers will find the short-term and long-term effects of new and old drugs, and other aspects of treatment, increasingly difficult to understand.

Miscellaneous models Several other survivorship programmes have been established throughout the USA at comprehensive and community cancer centres and in free-standing clinics. These programmes vary in structure and many are based on versions of the models presented in panels 2 and 3. In addition to these models, survivorship programmes have been established that do group visits to address issues common to all survivors, while others offer educational programmes rather than clinic visits. Telemedicine visits are another format for providing survivorship care. This format attempts to meet the needs of a population of survivors independent of sex, age, socioeconomic strata, or geographical location.34,39,40 Notably, no universal solution to survivorship care exists. There are different challenges and barriers present in different settings, and solutions that might be appropriate in one setting might not be appropriate in another. www.thelancet.com/oncology Vol 18 January 2017

Series

Challenges and barriers to survivorship care Provision Studies published both before and since the 2005 IOM report2 have been consistent in stating that cancer survivors need health care that addresses many different medical and psychosocial concerns.41–43 Data from qualitative and quantitative studies have guided research examining models to address these concerns and challenges to provision of care in various settings. Among the challenges identified are time and resource restraints in oncology and primary care settings, patient and provider preferences, financial concerns, and reimbursement issues.42,44 Inadequate knowledge from many oncologists, PCPs, and specialty care providers with regards to cancer treatment and follow-up care also posed substantial barriers to provision of high-quality care for cancer survivors, irrespective of their risk category. Observations have shown that oncology providers provide suboptimal non-oncology care, and PCPs provide suboptimal oncology follow-up care.30,38,45–48 These observations are realities that will worsen as general medical technology and oncology care become increasingly complex. As new cancer drugs are developed and become available, the gap in oncology knowledge by the PCPs will widen. Additionally, long-term effects of new cancer drugs are not yet known.49

Care coordination Care coordination is a frequently noted challenge in health care and has often been described as being inadequate yet essential to improving the care of cancer survivors.44,45 Findings from many studies have shown differences in the type and intensity of follow-up care received by patients comparing type and quality of care. Survivor and provider satisfaction have also been examined by investigators comparing follow-up of primary or oncology care, or both, in a survivorship programme or in the general practice setting.45–47,50,51 Findings from some studies have shown that survivors are managed better when followed up by both oncology and PCPs compared with when they are followed up by only one of these providers. However, data are scarce for the roles that different providers have and the extent to which providers share responsibility.48,52,53

(Panel 3 continued from previous page) Provider education • Expand survivorship-related education and training opportunities and promote interdisciplinary shared care models • Promote evidence-based use of survivorship care plans and other methods to increase communication, coordination, and confidence in provision of shared care • Advocate increased medical education curriculum funding for all providers and access to adequate tools, resources, and knowledge Education for survivors and families • Increase educational offerings with regard to survivorship issues • Identify and promote action-oriented messages via the internet on health, wellness, secondary disease prevention, and psychosocial coping • Help to identify expert, reputable survivor referral resources for all practices • Survivors and families capable of advocating for own self-interests Research • Increase survivorship research and expand funding mechanisms • Assess research portfolios: federal, state, and private • Identify knowledge gaps in under-represented patient populations and health-related outcomes of interest, and build strategies to address knowledge gaps • Leverage NCI cooperative group organisation to advance agenda within NCI-sponsored clinical trials Policy and advocacy • Ensure the full range of resources are available by promoting policy to support patients and families • Advocate federal and state-affordable health insurance • Improve Medicare reimbursement for survivorship services related to surveillance, prevention, management of late effects, and care coordination • Define essential health benefits for cancer survivors and advocate for coverage • Educate policymakers and advocate for legislation to enhance survivorship care and funding research • Advocate for Congress to push for US states to develop comprehensive cancer control plans that include survivorship care, and promote implementation, assessment, and refinement of existing cancer control programmes • Advocate for increased funding for survivorship research to help in the creation of evidence-based comprehensive survivorship care guidelines NCI=National Cancer Institute. Adapted from McCabe and colleagues,13 with permission from the American Society of Clinical Oncology.

care (eg, those that are required by cancer survivors). This approach to care delivery could be based on risk stratification categories as described in figure 2.

Workforce shortage There is an anticipated shortage of oncologists and PCPs projected for the year 2020, as well as an exponential increase in direct medical cost associated with cancer care. The direct medical cost associated with the ever growing number of therapeutic treatments is calculated to be more than US$173 billion per year. These factors are among the growing concerns that directly affect the care of cancer survivors.54–57 As patient loads increase for both oncologists and PCPs, both groups will be forced to prioritise patients with urgent medical problems over those seeking routine medical www.thelancet.com/oncology Vol 18 January 2017

Cost and quality of care Treatment options for different types of cancers and follow-up care continue to expand, and with them so does cost. Many factors contribute to rising costs, such as an ageing population, new and improved treatments for all chronic diseases, regulatory demands, inefficient delivery of care, inconsistencies in treatment by different physicians of patients with the same disease, and outdated computer systems.44,58 These and other factors result in substantial variations in practice patterns between medical oncologists managing e23

Series

Panel 4: Components of the chronic care model and proposed interventions Self-management • Educational: provision of information alone • Behavioural support: provision of tools for behaviours • Motivational support: linkage of specific goals for behavioural changes to clinical information Delivery system design • Interventions that provide advanced access to medical care • Provide access to care 24 h per day and 7 days per week for participants • Implement practice teams to coordinate preventive measures for chronic care Decision support • Use or implement evidence-based guidelines • Integrate specialty expertise: referrals for management of comorbidities • Identify barriers to care • Undertake performance reviews Clinical information system • Clinical registries: population information databases • Clinical reminders • Provider feedback (eg, from physicians, nurses, or pharmacists) Components of the chronic care model with proposed interventions used with patients who have obstructive pulmonary disease.29

patients at any point on the cancer care continuum. Additionally, choice of drugs and of referrals for radiotherapy, surgery, palliative, end-of-life, and other follow-up and supportive care (including care provided in the survivorship period) have historically had an absence of any type of algorithms or pathways. Despite an increasing number of health-care options and rising costs, however, quality and outcomes are not improving.54,59–64 In the past decade, strategies such as decreasing fee schedules and demanding prior authorisation from health-care insurance providers for any number of services have been implemented in an attempt to decrease or at least slow down the rising costs of cancer care and follow-up. However, practice variances have not been addressed with these strategies, and their benefit has been inadequate and brief at best.65 Access to care, high cost, and the many barriers to survivorship care are in fact the same barriers seen across the cancer care continuum at all points of care. The variability in cancer care from diagnosis to end of life is one of the most important factors contributing to the high cost of care. Consequently, many institutions and groups are hesitant to invest resources in developing survivorship care programmes that operate without a set of data-driven guidelines for the follow-up care provided.13,58 e24

Despite substantial activity devoted to survivorship care worldwide, little has been published with regards to the quality of care delivered, which is in most cases expensive.13 Issues in cancer and in cancer survivorship and follow-up care, including cost and financial burden, access, inadequate treatment protocols, poorly delineated surveillance schedules, inadequate preparation and knowledge on the part of providers, poor communication, workforce issues including the current and projected shortage of oncologists and PCPs, and uncertainty regarding the best approach to provision of survivorship care,57,66–68 are barriers to high-quality care in oncology and the delivery of health care in general. Challenges for and barriers to planning and provision of care across the entire cancer continuum exist, including the care provided during the cancer survivorship phase. Although models of survivorship care have been proposed, tested, and implemented successfully in in communal, academic, and clinical settings, no established framework of optimal care has been recognised. The challenges of health-care delivery are changing constantly as treatment and other advances are made, and this moving target requires that ongoing assessment is done and new strategies are used.

Proposed solutions Tools for survivorship care A comprehensive and carefully considered approach to potential solutions for the challenges and barriers should be used in the delivery of cancer follow-up and survivorship care. Development and testing of survivorship care models, examination of survivors’ needs, assessment of provider knowledge, and other areas of research in the past few decades have provided some understanding of the barriers to and possible solutions necessary for delivery of high-quality survivorship care. In March, 2013, the NCCN issued its first version of clinical practice guidelines for survivorship.7 These guidelines noted that an accurate assessment of survivors’ needs and concerns is crucial to good survivorship care, and provided evidence-based and consensus guidelines for screening, assessment, and treatment of common consequences of cancer and cancer treatment. Guidance about health promotion and disease prevention encompassing the survivor’s physical and emotional health, health behaviours, and psychosocial needs is also provided. In the 2016 update of these guidelines,69 the fact that clinicians might not have the expertise that they need to address many possible issues reported by survivors was highlighted. Consequently, algorithms for many survivorship topics were suggested to include information designed to increase clinicians’ awareness of issues, and appropriate screening questions or methods for the provider to access when caring for a survivor, followed by the option for early referral to specialists. The revised guidelines also provide guidance that is appropriate for oncology, www.thelancet.com/oncology Vol 18 January 2017

Series

Cancer diagnosis

Primary treatment

Patients at low risk of developing long-term and late effects of treatment All of the following: • Surgery only • Non-alkylating chemotherapy • No radiotherapy • Low risk of recurrence • Mild or no persistent toxicity of therapy

Follow-up care after treatment

Survivorship and follow-up care

Patients at moderate risk of developing long-term and late effects of treatment Any of the following: • Low or moderate-dose alkylating agent • Low or moderate-dose radiotherapy • Autologous stem-cell transplantation • Moderate risk of recurrence • Moderate persistent toxicity of treatment

Long-term follow-up care

End-of-life care

Patients at high risk of developing long-term and late effects of treatment Any of the following: • High-dose alkylating agent • High-dose radiotherapy • Allogeneic stem-cell transplantation • High risk of recurrence • Multi-organ persistent toxicity of therapy

Figure 2: Risk-stratified and shared care model In this model, cancer care is delivered at any timepoint along the continuum by different providers on the basis of risk category and patient and provider preferences and skillsets.

primary care, or specialty care providers for assessment, treatment, and follow-up care for various physiological and psychosocial issues. ASCO has been partnering with other organisations in the oncology community to develop a compendium of survivorship tools and resources for providers. The plan is for these processes to capture the advantages and disadvantages of models used by oncologists, and the lessons learned in the process. Metrics are also necessary to investigate, for example, adherence to surveillance guidelines, assessment of appropriate testing, coordination of care with non-cancer providers, cost of services, and satisfaction when comparing different programmes and models of care. The quality of care programmes put into place by ASCO are frameworks that build an evidence base for treatment and follow-up guidelines, and for assessment of models of care by leveraging data in the medical record.13 Additionally, ASCO outlined the items needed to achieve high-quality survivorship cancer care, and in doing so, identified solutions for many barriers that have been noted (panel 3).13 These solutions are general and do not offer implementation strategies; however, they are a good starting point and provide a succinct summary of the many challenges for, barriers to, and solutions for achievement of the best possible cancer follow-up and survivorship care.

Survivorship care plans In the 2005 IOM report,2 the survivorship care plan was promoted as a method to help coordinate survivorship care by supporting communication between providers, including the oncology and primary care teams, and the patient. This plan was viewed as a potential guide for provision of survivorship care and a solution to meeting the needs of cancer survivors. However, little success has occurred in implementation of survivorship care plans in oncology practices because of several barriers.70–74 The barriers to implementation of survivorship care plans in practice have been well documented in the literature. They include the time needed for preparation of the plans, role clarity as to who is responsible for preparing the document, no reimbursement for this www.thelancet.com/oncology Vol 18 January 2017

preparation, poor communication and collaborations between providers, and importantly, the paucity of data regarding the association between use of survivorship care plans and patient outcomes.30,38,43–48,52,53 The inadequate compatibility of existing survivorship care plan templates with electronic health records is pushing vendors to develop functionality of electronic health records, which might be the most reasonable solution to effective survivorship care plan implementation.75 Additionally, the Commission on Cancer Standard 3.3,11 which states that survivorship care plans should be developed for all patients completing treatment with curative intent, continues to be mandated and promoted in centres across the USA, supporting delivery of high-quality survivorship care.

Clinical pathways Clinical pathways have begun to be adopted by many oncology practices as a mechanism to streamline care, increase efficiency, improve quality of care, and reduce costs. Ideally, pathways guide both the patient and the provider from diagnosis to primary and ongoing treatment, post-treatment, and end-of-life care. Clinical pathways are evidence-based, detailed processes for delivery of cancer care.76 Oncology practices throughout the USA are working to integrate pathways into their models of cancer care. Also known as care pathways, critical pathways, integrated care pathways, or care maps, they are one of the main approaches used to manage the quality in health care in terms of the standardisation of care processes.77 In early 2016, ASCO released a policy statement78 on clinical pathways in oncology. One of their recommendations was the call for pathways to “address the full spectrum of cancer care and include imaging, laboratory testing, survivorship and end-of-life care” and, in doing so, maximise opportunities for improved medical outcomes. These recommendations further suggested that oncology pathways should define aspects of care beyond selection of anticancer agents and treatment methods to enhance patient care. Use of clinical pathways along the cancer care continuum could provide a solution to the barriers to or challenges in provision of cancer care follow-up, and lead e25

Series

Cancer diagnosis

Primary treatment

Follow-up care after treatment

Survivorship and follow-up care

Long-term follow-up care

End-of-life care

Supported self-management (patients at low risk for developing long-term and late effects of treatment): • Patients are given the knowledge and skills to self-manage their care Shared care (patients at moderate risk for developing long-term and late effects of treatment): • Patients have regular contact with health-care professionals Complex case management (patients at high risk for developing long-term and late effects of treatment): • Patients need intensive support from health-care services to meet their needs

Figure 3: Risk-stratified model of the National Cancer Survivorship Initiative This model is developed by the National Cancer Survivorship Initiative79 in the UK using patient-reported outcome measures integrated into eHealth platforms to help risk stratify patients.

to more seamless survivorship care than exists at present. Pathways developed for patients completing primary treatment or for outlining surveillance schedules on the basis of individual risk stratification could help to assure quality care for cancer survivors who might appropriately remain in oncology practices, transition to primary care, or be followed up in a survivorship programme. Pathways are developed for specific diseases, by stage, and often by biological subtype. The short-term and long-term effects of cancer and cancer treatment vary greatly by diagnosis and treatment rendered, which provides a particularly good opportunity for pathways to tailor survivorship care to specific clinical scenarios. A team in the UK has proposed pathways for cancer survivors using patient-reported outcome measures integrated into eHealth platforms.79 This care model was developed by the National Cancer Survivorship Initiative,80 and it stratified patients into three broad categories: supported self-management, shared care, and complex case management (similar to those described earlier). Because further development and research is needed before this vision becomes a reality, the investigators carefully selected patient-reported outcome measures for initial assessment of cancer survivors at the end of treatment to inform an individualised care plan, to help with risk stratification, and to ultimately ensure assignment to the appropriate care pathway. In this model, support for selfmanagement is provided by offering advice on the basis of patient-reported outcome scores, which direct survivors to appropriate resources (figure 3).79 Although in the early stages of development for patients’ post-treatment care, clinical pathways in oncology care are being used as a way to improve patient care by limiting undesirable variability in treatment and surveillance, and by reducing costs. New scientific information is rapidly accelerating progress in oncology, making pathway development important. However, pathway development is also generating criticism. The number of pathways has created administrative burdens; for example, some oncology practices report that they are being required to adhere to numerous pathways for the same type and stage of cancer as a result of different requirements of different payers that are covering patients in clinical practice.78 e26

The ASCO recommendations for clinical pathway development and implementation in the oncology setting maintain that the ultimate goal of oncology pathways is the provision of high-quality care to all patients.

Workforce solutions The 2005 and 2009 IOM reports2,57 as well as the 2007 ASCO workforce report81 called for a change in traditional care models, and the integration and expansion of the roles of physicians’ assistants and nurse practitioners within the collaborative and team-based care model. Integration and expansion could counter the effects of the anticipated shortage of primary care physicians and oncologists. Numerous models for providing follow-up and survivorship care have evolved, and in each of these models, care is provided by a physician (primary care or oncology), or more recently, by nurse practitioners or physicians’ assistants.26,82–85 Many aspects of survivorship care exist; however, the authors of a 2012 review86 suggested that few high-quality intervention studies have been done that involve randomised comparisons of different models and programmes. Additionally, the authors identified only six trials that assessed nurse-led follow-up care. However, a few descriptive studies have been done examining or testing (or both) different models of nurse-led follow-up in cancer care that also support the feasibility, acceptability, and safety of nurses providing survivorship care—previously a viable alternative to oncologist-led follow-up.87–96 Widespread use of nurse practitioners and physician assistants to provide cancer follow-up care could be one feasible solution to the workforce shortage, and has the potential to be a vehicle for providing long-term, sustainable, high-quality followup and survivorship care.

Conclusion The rapidly changing world of drug discovery, advances in genetic technology, sophisticated diagnostic tests, earlier diagnoses, more effective treatments, improved supportive care, and people living longer with a better quality of life after a cancer diagnosis have contributed to cancer being viewed as a chronic disease, and have also led to an increased number of cancer survivors. Ongoing changing issues and challenges continue to www.thelancet.com/oncology Vol 18 January 2017

Series

Search strategy and selection criteria We searched MEDLINE, Index Medicus, CINAHL, and PubMed for articles published in English between Jan 1, 1970, and Sept 1, 2016. We used the following search terms: “cancer survivorship”, “cancer survivorship care”, “survivorship care planning”, “models of survivorship care”, “cancer survivorship movement”, “oncology workforce”, “barriers to survivorship care”, “culture of oncology survivorship care”, “chronic care model”, “self-management”, “patient reported outcomes”, “clinical pathways”, and “oncology clinical pathways”. This search generated hundreds of articles, including intervention and descriptive studies and review articles. Consequently, we reviewed the abstracts to select the articles most relevant to the focus of this Series paper.

8

9

10

11

12

13

14

be encountered at all points of the cancer care continuum, including the follow-up and survivorship phases of care. We have explored these challenges and barriers, and identified and discussed the potential solutions in this Series paper. Survivorship care, like all of cancer care, is a moving target that necessitates ongoing assessment, development, testing, and implementation of oncology care models. These care models should keep pace with new technology and approach the challenges that present with potential solutions to assure provision of optimal follow-up and survivorship care, and of care at other points throughout the cancer care continuum. Contributors LAJ did the literature search, reviewed articles and abstracts, and drafted, revised, and finalised the report. LNS reviewed abstracts, edited and contributed to the draft report, and reviewed and edited the revised text, panels, and figures.

15

16

17

18

19 20

21

22

Declaration of interests We declare no competing interests. Acknowledgments We thank Abigail N Blauch for her assistance with the submission of this manuscript, who formatted the submission, helped with the literature search and reference list, and worked with the authors to develop the panels and figures. References 1 The National Coalition for Cancer Survivorship. History of the National Coalition for Cancer Survivorship. 1995–2011. http://www.canceradvocacy.org/about-us/our-history/ (accessed May 4, 2016). 2 Hewitt M, Greenfield S, Stovall E. From cancer patient to cancer survivor: lost in transition. Washington, DC, USA: National Academies Press, 2005. 3 Mullan F. Seasons of survival: reflections of a physician with cancer. N Engl J Med 1985; 313: 270–73. 4 Welch-McCaffrey D, Hoffman B, Leigh SA, Loescher LJ, Meyskens FL Jr. Surviving adult cancers. Part 2: psychosocial implications. Ann Intern Med 1989; 111: 517–24. 5 Loescher LJ, Welch-McCaffrey D, Leigh SA, Hoffman B, Meyskens FL Jr. Surviving adult cancers. Part 1: physiologic effects. Ann Intern Med 1989; 111: 411–32. 6 Leigh S, Logan C. The cancer survivorship movement. Cancer Invest 1991; 9: 571–79. 7 Ligibel JA, Denlinger CS. New NCCN guidelines for survivorship care. J Natl Compr Canc Netw 2013; 11 (suppl 5): 640–44.

www.thelancet.com/oncology Vol 18 January 2017

23

24

25 26 27

28

29

30 31

Mayer DK, Shapiro CL, Jacobson P, McCabe MS. Assuring quality cancer survivorship care: we’ve only just begun. Am Soc Clin Oncol Educ Book 2015; e583–91. Irwin M, Klemp JR, Glennon C, Frazier LM. Oncology nurses’ perspectives on the state of cancer survivorship care: current practice and barriers to implementation. Oncol Nurs Forum 2011; 38: e11–19. American Cancer Society. Survivorship care plans. 2016. http://www.cancer.org/treatment/ survivorshipduringandaftertreatment/survivorshipcareplans/index (accessed accessed May 4, 2016). Commission on Cancer. Cancer program standards 2012: ensuring patient-centered care. Chicago: American College of Surgeons, 2012. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst 2011; 103: 117–28. McCabe MS, Bhatia S, Oeffinger KC, et al. American Society of Clinical Oncology statement: achieving high-quality cancer survivorship care. J Clin Oncol 2013; 31: 631–40. Burg MA, Adorno G, Lopez ED, et al. Current unmet needs of cancer survivors: analysis of open-ended responses to the American Cancer Society Study of Cancer Survivors II. Cancer 2015; 121: 623–30. Palmer S, DeMichele A, Schapira M, et al. Symptoms, unmet need, and quality of life among recent breast cancer survivors. JCSO 2016; 14: 2–9. Mayer DK, Nasso SF, Earp JA. Defining cancer survivors, their needs, and perspectives on survivorship health care in the USA. Lancet Oncol 2016; 18: e11–18. Boyajian RN, Grose A, Grenon N, et al. Desired elements and timing of cancer survivorship care: one approach may not fit all. J Oncol Pract 2014; 10: e293–98. Lavoie Smith EM, Skalla K, Li Z, et al. Assessing cancer survivors’ needs using web-based technology: a pilot study. Comput Inform Nurs 2012; 30: 71–81. Stewart DE. Physical symptoms of depression: unmet needs in special populations. J Clin Psychiatry 2003; 64 (suppl 7): 12–16. Sanson-Fisher R, Girgis A, Boyes A, Bonevski B, Burton L, Cook P. The unmet supportive care needs of patients with cancer. Supportive Care Review Group. Cancer 2000; 88: 226–37. Ream E, Quennell A, Fincham L, et al. Supportive care needs of men living with prostate cancer in England: a survey. Br J Cancer 2008; 98: 1903–09. Koopman C, Angell K, Turner-Cobb JM, et al. Distress, coping, and social support among rural women recently diagnosed with primary breast cancer. Breast J 2001; 7: 25–33. Hodgkinson K, Butow P, Hunt GE, et al. The development and evaluation of a measure to assess cancer survivors’ unmet supportive care needs: the CaSUN (Cancer Survivors’ Unmet Needs measure). Psychooncology 2007; 16: 796–804. Degner LF, Kristjanson LJ, Bowman D, et al. Information needs and decisional preferences in women with breast cancer. JAMA 1997; 277: 1485–92. Jacobs LA, Vaughn DJ. In the clinic. Care of the adult cancer survivor. Ann Intern Med 2013; 158: ITC6–1. Oeffinger KC, McCabe MS. Models for delivering survivorship care. J Clin Oncol 2006; 24: 5117–24. McCabe MS, Partridge AH, Grunfeld E, Hudson MM. Risk-based health care, the cancer survivor, the oncologist, and the primary care physician. Semin Oncol 2013; 40: 804–12. Salz T, Baxi SS, Raghunathan N, et al. Are we ready to predict late effects? A systematic review of clinically useful prediction models. Eur J Cancer 2015; 51: 758–66. Adams SG, Smith PK, Allan PF, Anzueto A, Pugh JA, Cornell JE. Systematic review of the chronic care model in chronic obstructive pulmonary disease prevention and management. Arch Intern Med 2007; 167: 551–61. Bodenheimer T. Primary care—will it survive? N Engl J Med 2006; 355: 861–64. Coleman K, Austin BT, Brach C, Wagner EH. Evidence on the chronic care model in the new millennium. Health Aff 2009; 28: 75–85.

e27

Series

32

33

34

35

36

37

38

39 40

41

42 43 44

45

46

47

48 49

50

51

52

53

54

55

e28

Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness: the chronic care model, part 2. JAMA 2002; 288: 1909–14. Katon W, Von Korff M, Lin E, Simon G. Rethinking practitioner roles in chronic illness: the specialist, primary care physician, and the practice nurse. Gen Hosp Psychiatry 2001; 23: 138–44. Kvale EA, Huang CS, Meneses KM, et al. Patient-centered support in the survivorship care transition: outcomes from the patient-owned survivorship care plan intervention. Cancer 2016; 122: 3232–42. McCorkle R, Ercolano E, Lazenby M, et al. Self-management: enabling and empowering patients living with cancer as a chronic illness. CA Cancer J Clin 2011; 61: 50–62. Lawrence RA, McLoone JK, Wakefield CE, Cohn RJ. Primary care physicians’ perspectives of their role in cancer care: a systematic review. J Gen Intern Med 2016; 31: 1222–36. Nyarko E, Metz JM, Nguyen GT, Hampshire MK, Jacobs LA, Mao JJ. Cancer survivors’ perspectives on delivery of survivorship care by primary care physicians: an internet-based survey. BMC Fam Pract 2015; 16: 143. Mao JJ, Bowman MA, Stricker CT, et al. Delivery of survivorship care by primary care physicians: the perspective of breast cancer patients. J Clin Oncol 2009; 27: 933–38. Trotter K, Schneider SM, Turner BS. Group appointments in a breast cancer survivorship clinic. J Adv Pract Oncol 2013; 4: 423–31. University of Colorado Cancer Center. Care for cancer survivors. 2016. http://www.ucdenver.edu/academics/colleges/medicalschool/ centers/cancercenter/cancercare/survivors/Pages/survivors.aspx (accessed May 4, 2016). Hudson SV, Chubak J, Coups EJ, et al. Identifying key questions to advance research and practice in cancer survivorship follow-up care: a report from the ASPO Survivorship Interest Group. Cancer Epidemiol Biomarkers Prev 2009; 18: 2152–54. Earle CC. Long term care planning for cancer survivors: a health services research agenda. J Cancer Surviv 2007; 1: 64–74. Aziz NM. Cancer survivorship research: state of knowledge, challenges and opportunities. Acta Oncol 2007; 46: 417–32. Chubak J, Tuzzio L, Hsu C, et al. Providing care for cancer survivors in integrated health care delivery systems: practices, challenges, and research opportunities. J Oncol Pract 2012; 8: 184–89. Klabunde CN, Han PK, Earle CC, et al. Physician roles in the cancer-related follow-up care of cancer survivors. Fam Med 2013; 45: 463–74. Khan NF, Ward A, Watson E, Austoker J, Rose PW. Long-term survivors of adult cancers and uptake of primary health services: a systematic review. Eur J Cancer 2008; 44: 195–204. Snyder CF, Earle CC, Herbert RJ, Neville BA, Blackford AL, Frick KD. Preventive care for colorectal cancer survivors: a 5-year longitudinal study. J Clin Oncol 2008; 26: 1073–79. Earle CC, Neville BA. Under use of necessary care among cancer survivors. Cancer 2004; 101: 1712–19. Dawes AJ, Hemmelgarn M, Nguyen DK, et al. Are primary care providers prepared to care for survivors of breast cancer in the safety net? Cancer 2015; 121: 1249–56. Snyder CF, Earle CC, Herbert RJ, Neville BA, Blackford AL, Frick KD. Trends in follow-up and preventive care for colorectal cancer survivors. J Gen Intern Med 2008; 23: 254–59. Haggstrom DA, Arora NK, Helft P, Clayman ML, Oakley-Girvan I. Follow-up care delivery among colorectal cancer survivors most often seen by primary and subspecialty care physicians. J Gen Intern Med 2009; 24 (suppl 2): S472–79. Snyder CF, Frick KD, Kantsiper ME, et al. Prevention, screening, and surveillance care for breast cancer survivors compared with controls: changes from 1998 to 2002. J Clin Oncol 2009; 27: 1054–61. Potosky AL, Han PK, Rowland J, et al. Differences between primary care physicians’ and oncologists’ knowledge, attitudes and practices regarding the care of cancer survivors. J Gen Intern Med 2011; 26: 1403–10. Feinberg BA, Lang J, Grzegorczyk J, et al. Implementation of cancer clinical care pathways: a successful model of collaboration between payers and providers. J Oncol Pract 2012; 8 (suppl 3): e38s–43s. Nelson L. Lesson’s from Medicare’s demonstration projects on disease management, care coordination, and value-based payment. Washington, DC, USA: Congressional Budget Office, Health and Human Resources Division, 2012.

56

57

58

59

60 61 62 63 64

65

66

67

68

69

70

71

72

73

74

75

76 77

78

79

Rauh SS, Wadsworth EB, Weeks WB, Weinstein JN. The savings illusion—why clinical quality improvement fails to deliver bottom-line results. N Engl J Med 2011; 365: e48. National Cancer Policy Forum of the Institute of Medicine. Ensuring quality cancer care through the oncology workforce: sustaining care in the 21st century. Washington, DC: National Academies Press, 2009. Hanly P, Ceilleachair AO, Skally M, et al. How much does it cost to care for survivors of colorectal cancer? Caregiver’s time, travel and out-of-pocket costs. Support Care Cancer 2013; 21: 2583–92. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009; 27: 2758–65. Elkin EB, Bach PB. Cancer’s next frontier: addressing high and increasing costs. JAMA 2010; 303: 1086–87. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs. N Engl J Med 2009; 360: 626–33. Smith TJ, Hillner BE. Bending the cost curve in cancer care. N Engl J Med 2011; 364: 2060–65. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol; 12: 933–80. Advisory Board Company. Defining accountable cancer care: unclear return on today’s cancer care investment. 2011. http://www.advisory.com/Research/Oncology-Roundtable/ Resources/2011/Posters/~/media/Advisory-com/Screenshots/ Posters/OR_HVCC_Infographic_Poster_big.jpg (accessed May 4, 2016). Holcombe D. Oncology management programs for payers and physicians: evaluating current models and diagnosing successful strategies for payers and physicians. J Oncol Pract 2011; 7 (suppl 3): e46s–49s Guy GP Jr, Yabroff KR, Ekwueme DU, et al. Healthcare expenditure burden among non-elderly cancer survivors, 2008–2012. Am J Prev Med 2015; 49 (suppl 5): S489–97. Guy GP Jr, Ekwueme DU, Yabroff KR, et al. Economic burden of cancer survivorship among adults in the United States. J Clin Oncol 2013; 31: 3749–57. Yabroff KR, Lamont EB, Mariotto A, et al. Cost of care for elderly cancer patients in the United States. J Natl Cancer Inst 2008; 100: 630–41. Denlinger CS, Ligibel JA, Are M, et al. NCCN guidelines insights: survivorship, version 1. 2016. J Natl Compr Canc Netw 2016; 14: 715–24. Birken SA, Deal AM, Mayer DK, Weiner BJ. Following through: the consistency of survivorship care plan use in United States cancer programs. J Cancer Educ 2014; 29: 689–97. Birken S, Deal A, Mayer D, et al. Prevalence and barriers to survivorship care plan use in United States cancer programs. J Cancer Educ 2014; 4: 689–97. Forsythe L, Parry C, Alfano C, et al. Gaps in survivorship care plan delivery and potential benefits to survivorship care. J Clin Oncol 2013; 1 (suppl): abstr 9594. Salz T, Oeffinger KC, McCabe MS, Layne TM, Bach PB. Survivorship care plans in research and practice. CA Cancer J Clin 2012; 62: 101–17. Stricker CT, Jacobs LA, Risendal B, et al. Survivorship care planning after the institute of medicine recommendations: how are we faring? J Cancer Surviv 2011; 5: 358–70. Mayer DK, Nekhlyudov L, Snyder CF, Merrill JK, Wollins DS, Shulman LN. American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning. J Oncol Pract 2014; 10: 345–51. Gesme DH, Wiseman M. Strategic use of clinical pathways. J Oncol Pract 2011; 7: 54–56. Panella M, Marchisio S, Di Stanislao F. Reducing clinical variations with clinical pathways: do pathways work? Int J Qual Health Care 2003; 15: 509–21. Zon RT, Frame JN, Neuss MN, et al. American Society of Clinical Oncology policy statement on clinical pathways in oncology. J Oncol Pract 2016; 12: 261–66. Warrington L, Absolom K, Velikova G. Integrated care pathways for cancer survivors—a role for patient-reported outcome measures and health informatics. Acta Oncol 2015; 54: 600–08.

www.thelancet.com/oncology Vol 18 January 2017

Series

80

81 82

83 84

85

86

87 88

Department of Health, Macmillan Cancer Support, NHS Improvement. London: The National Cancer Survivorship Initiative Vision; 2010. Hortobagyi GN. A shortage of oncologists? The American Society of Clinical Oncology workforce study. J Clin Oncol 2007; 25: 1468–69. McCabe MS, Baker S, Huffman C, Miller K. Optimizing survivorship care: academic and community clinic models. New York: Springer, 2011: 223–238. McCabe MS, Jacobs LA. Clinical update: survivorship care—models and programs. Semin Oncol Nurs 2012; 28: e1–8. Lewis R, Neal RD, Williams NH, et al. Nurse-led vs conventional physician-led follow-up for patients with cancer: systematic review. J Adv Nurs 2009; 65: 706–23. Watts SA, Gee J, O’Day ME, et al. Nurse practitioner-led multidisciplinary teams to improve chronic illness care: the unique strengths of nurse practitioners applied to shared medical appointments/group visits. J Am Acad Nurse Pract 2009; 21: 167–72. Sussman J, Souter L, Grunfeld E, et al. Models of care for cancer survivorship. 2012. http://www.cancercare.on.ca/common/pages/ UserFile.aspx?fileId=258056 (accessed May 4, 2016). NHS Confederation. Co-ordinated cancer care: better for patients, more efficient. London: NHS Confederation, 2010. Moore S, Wells M, Plant H, Fuller F, Wright M, Corner J. Nurse specialist led follow-up in lung cancer: the experience of developing and delivering a new model of care. Eur J Oncol Nurs 2006; 10: 364–77.

www.thelancet.com/oncology Vol 18 January 2017

89

90

91

92

93

94 95 96

Koinberg IL, Fridlund B, Engholm GB, Holmberg L. Nurse-led follow-up on demand or by a physician after breast cancer surgery: a randomised study. Eur J Oncol Nurs 2004; 8: 109–17; discussion 18–20. Helgesen F, Andersson SO, Gustafsson O, et al. Follow-up of prostate cancer patients by on-demand contacts with a specialist nurse: a randomized study. Scand J Urol Nephrol 2000; 34: 55–61. Ferrell BR, Virani R, Smith S, Juarez G. The role of oncology nursing to ensure quality care for cancer survivors: a report commissioned by the National Cancer Policy Board and Institute of Medicine. Oncol Nurs Forum 2003; 30: e1–11. Davies N, Batehup L. Cancer follow-up: towards a personalised approach to aftercare services. A review of current practice and selected initiatives. London: Macmillan Cancer Support, 2009. Buswell LA, Ponte PR, Shulman LN. Provider practice models in ambulatory oncology practice: analysis of productivity, revenue, and provider and patient satisfaction. J Oncol Pract 2009; 5: 188–92. Gates P, Krishnasamy M. Nurse-led survivorship care. Cancer Forum 2009; 33: 1–4. John C, Armes J. Developing a nurse-led survivorship service for patients with lymphoma. Eur J Oncol Nurs 2013; 17: 521–27. Beaver K, Tysver-Robinson D, Campbell M, et al. Comparing hospital and telephone follow-up after treatment for breast cancer: randomised equivalence trial. BMJ 2009; 338: a3147.

e29