NCCN resource-stratified and harmonized guidelines: A paradigm for optimizing global cancer care
Abstract
Clinical practice guidelines in oncology lead to improved outcomes in care. However, the most frequently used guidelines are developed for highly resourced systems. Recognizing the significant and increasing burden of cancer in low- and middle-income countries, the National Comprehensive Cancer Network (NCCN) has developed resource-stratified framework and harmonization processes that allow the NCCN Guidelines to be tailored and optimized for specific geographical areas, resource levels, and settings. The critical need for local expertise and involvement in successful development and uptake is emphasized, and the promise of this collaboration for advancement in oncology programs is illustrated.
Introduction
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) provide evidence-based, consensus-driven, transparent, and contemporary algorithms that define the standard of cancer management and clinical practice, throughout the continuum of care, for more than 97% of all incident cancers in the United States. The NCCN Guidelines also furnish direction for supportive care, risk reduction, screening, and specially designated populations. The NCCN Guidelines are developed and continuously updated by expert multimodality representatives from each of the 28 academic cancer center member institutions that form the NCCN. Guideline-concordant care has consistently been shown to improve outcomes in oncology.1-5
The NCCN Guidelines specify appropriate cancer management in the United States and more specifically within the member institution cancer programs, which represent maximal resource settings. In these settings, there should be little or no resource impediment to obtaining the highest level of recommended care, although significant socioeconomic barriers continue to exist that prohibit access to care among vulnerable sectors of society.6, 7
In contrast, a significant proportion of cancer cases as well as the resultant morbidity and mortality occurs in low- and middle-income countries (LMICs), where barriers to care include economic, educational, structural, political, and cultural considerations.8 The incidence of cancer is disproportionately rising in LMICs in comparison with higher income regions, and it has been projected that 75% of all cancer deaths globally will occur in LMICs by 2030; this presents a formidable threat to national development and economic progress.9
Given the burgeoning incidence of cancer globally and aiming to make practice guidelines relevant in diverse areas of the world, the NCCN has embarked on a program to create resource-stratified and harmonized versions of its recommendations to focus on country- or region-specific needs and constraints.
NCCN Framework for Resource Stratification of NCCN Guidelines (NCCN Framework)
On the basis of a concept put forth by the World Health Organization for tailoring cancer care to the geographic-specific level of resource availability, the Breast Health Global Initiative (BHGI) pioneered the first set of resource-stratified, evidence-based oncology clinical practice guidelines addressing the detection, diagnosis, and treatment of breast cancer in LMICs.10 To establish a workable, systematic foundation for prioritizing standard cancer interventions, the BHGI divided resource settings and the associated management recommendations into 4 levels: basic, limited, enhanced, and maximal. The utility and uptake of the BHGI strategy provided a model from which new and expanded resource-stratified oncology guidelines could be developed by other organizations, including the NCCN.
- Basic resources: Basic resources include essential services needed to provide the basic minimal standard of care. Without such fundamental capacity, there can be no anticipated successful cancer management within that system.
- Core resources: Core resources include those provided in the Basic Resources Framework plus additional services that provide major improvements in disease outcomes (eg, survival) and that are not cost-prohibitive.
- Enhanced resources: Enhanced resources include those provided in the Core Resources Framework and additional services that provide lesser improvements in disease outcomes and/or services that provide major improvements in disease outcomes but are cost-prohibitive in lower resource settings.
- NCCN Guidelines: The parent NCCN Guidelines are evidence-based, consensus-driven recommendations made by the NCCN Guidelines panels. They include services from the Enhanced Resources Framework and additional services that provide minor improvements in disease outcomes, interventions that are cost-prohibitive in lower resource settings, and/or services that do not provide improvements in disease outcomes but are desirable services.
The resource-stratified guidelines are reviewed and revised by the entire associated NCCN panel as well as national and international disease-specific experts with experience in oncology care in low- and mid-resource settings.
The NCCN resource-stratified guidelines have been designed to maintain the underlying context of the complete NCCN Guidelines. Within each resource level, recommendations that are not applicable at that level are grayed out in comparison with the parent guidelines, whereas unique, necessary approaches in a low-resource setting that may not otherwise be considered appropriate in a higher means region are presented in blue text (see a similar schematic illustrated for the NCCN Harmonized Guidelines in Fig. 1). This format allow users in a given health care system to appreciate the differences in recommendations if resource constraints were less of, or not, an issue, and provides for education as well as advocacy efforts to improve oncologic capabilities.
Beginning with cervical, breast, and hepatobiliary cancers in 2015, the NCCN resource-stratified library has expanded to cover 16 cancer types as well as guidelines addressing breast cancer screening and diagnosis and recommendations for pain management and palliative care.
NCCN Harmonized Guidelines
The NCCN resource-stratified guidelines provide recommendations that, although useful in broad and generalized settings, may not be sufficiently specific and customized to the distinctive needs and capabilities of an individual country or region. It has also been recognized that at times, health care delivery systems do not readily fit into 1 of the 4 predetermined levels. For example, a cancer center in an LMIC may have access to reasonable surgical and medical oncology expertise and chemotherapy agents (at a “core” or “enhanced” level) but have no radiotherapy capability (“basic” level). Furthermore, this variability of resource availability is sometimes exacerbated by fluidity, such as when there is episodic availability of medical equipment, drugs, and personnel as well as shifting regulatory factors.
The NCCN harmonization process takes the resource-stratified methodology a step further and creates specific regional guidelines in collaboration with local experts that are relevant, optimal, and developed for the unique oncology ecosystems. In this regard, the resource-stratified guidelines provide not only content but more importantly a structure for the efficient development of specific harmonized guidelines that are unique to each region or country.
The NCCN harmonization process is initiated by a requesting body of experts who have reviewed the NCCN Clinical Practice Guidelines and/or NCCN Framework library and seek to work with the NCCN to develop region-specific guidelines that will enhance and optimize care within the level or levels of resource availability. These local delegates, who include health care professionals, regulatory agency representatives, and ministry of health officials, clarify the needs, resources, and capabilities of their sites and define the scope of harmonization (number of guidelines) desired. The active involvement and leadership of these regional partners are critical to the success of this enterprise.
In sub-Saharan Africa (SSA), providers and government officials sought a single, regional harmonized guideline document for each disease site or supportive care paradigm rather than the 4 separate resource-stratified versions found in the NCCN Framework. Local specialty working groups representing the countries involved were formed, and a working group chair was selected. With guidance and support provided by NCCN panel experts (typically the panel chair or cochair), an in-person meeting is held to generate a single harmonized guideline for a selected disease/supportive care topic.
Primary content is derived from the most recently published parent NCCN Clinical Practice Guidelines, with modifications informed by examples from the resource-stratification framework and incorporated with the specific needs and capabilities of the local cancer care system. The underlying context of the parent guidelines is preserved in this manner to provide education and an aspirational roadmap for advocacy and care advancement. To achieve this, recommendations within the NCCN Harmonized Guidelines are displayed with the system shown in Figure 1. As an example of a regional option that might otherwise not be considered a universal standard of care, the approach of concurrent chemoradiation for locally advanced cervical cancer may be substituted with neoadjuvant chemotherapy followed by hysterectomy if radiotherapy options are not available. The underlying principle of maintaining evidentiary support continues for substituted options: although neoadjuvant chemotherapy followed by surgery is considered inferior to concurrent chemoradiation for locally advanced cervical cancer, there are studies that do document curative potential for this alternative approach.12 The developmental process for harmonization of the NCCN Guidelines is illustrated in Figure 2.
Despite acknowledging the challenges presented by resource constraints, each harmonized guideline includes a general principle of cancer care section, as illustrated in Figure 3 for cervical cancer. This emphasizes the imperative to provide patients the highest level of care reasonably available, appropriate referrals when necessary, the importance of multidisciplinary management, and the need to minimize delays in diagnostic workup and treatment.
The preliminary modifications made for each harmonized guideline are carefully reviewed and reconciled by NCCN staff and then re-reviewed by the working group and the NCCN panel expert for final consensus before publication on the NCCN website (https://www.nccn.org/). Since the beginning of the harmonization process in SSA in April 2017, 46 guidelines have been evaluated for modification. As of November 2019, 34 harmonized guidelines have been fully completed and published, with an additional 12 expected by early 2020. Cumulatively, these harmonized guidelines provide coverage for more than 90% of incident cancer cases in SSA and also address risk reduction and screening, supportive care, and management considerations in specific populations. To maintain currency, each harmonized guideline will be updated on a minimum 2-year interval or earlier if fundamental diagnostic or therapeutic changes that would broadly affect care in SSA are reported.
It is noteworthy that the number of SSA harmonized guidelines exceeds those of the NCCN Framework: The generalized concept and structure of resource stratification informed and facilitated the development of harmonized guidelines, even when the NCCN Framework was not available for a specific clinical topic. Select examples of harmonized guideline pages for cervical and breast cancer are illustrated in Figures 4 and 5.13 In the cervical cancer harmonized guidelines for SSA (Fig. 4), recommendations for costly imaging modalities such as magnetic resonance imaging and positron emission tomography as well as advanced surgical techniques such as laparoscopic node dissection, which are not routinely available, are grayed out. Regional treatment approaches that are considered when standard-of-care capabilities such as radiotherapy do not exist are added in blue text. For breast cancer (Fig. 5), the SSA experts determined that lumpectomy, as characteristically defined, is infeasible in most centers because of a lack of imaging localization, and they modified the recommended surgical approach accordingly.
A similar process was undertaken with partners in the Caribbean, who also requested single harmonized guideline documents for selected disease sites. The experience in the Caribbean has been quite different from that in SSA. The Caribbean generally enjoys a higher level of resources than SSA but has challenges related to transportation and access because of the island-based geography. At present, this effort has led to published Caribbean-specific harmonized guidelines for breast, cervical, colorectal, non–small cell lung, and prostate cancer as well as multiple myeloma.
The unique needs and characteristics of each geographic region mandate flexibility and customization of recommendations and delivery of care. In NCCN's most recent harmonization collaboration with Bolivia, the local delegates requested 4 resource-stratified versions for each of the breast, cervical, and rectal cancer guidelines. In this situation, the Bolivian harmonized guidelines more closely resemble the NCCN Framework for these tumor types but had specific adaptations to each level for the distinct Bolivian health care system and environment.
Role of Harmonized and Resource-Stratified Guidelines in Program Evaluation, Capacity Building, and Shared Resources for Cancer Programs
Beyond providing clinical guidance and decision support, the NCCN Framework and Harmonized Guidelines permit oncology stakeholders to realistically evaluate and build their programs in an integrated and judicious manner, identifying stepwise incremental resources that can have the broadest impact. The review of multiple guidelines in parallel can help to prioritize funding for initiatives that provide the greatest benefit across the most common cancer types. The critical role of pathology expertise and appropriate reporting is emphasized throughout all treatment guidelines and underpins rational oncologic management. Improved laboratory and radiologic diagnostic technologies would benefit patients broadly. New access to radiotherapy capacity would enhance treatment outcomes in multiple malignancies, including breast, cervical, rectal, lung, head and neck, and prostate cancers. Such broad-based approaches to resource sharing and capacity building across tumor types avoid siloed decision making and allow for cost-effective advancements in a cancer program.
The harmonized and resource-stratified guidelines are used widely as educational tools for health care providers, trainees, and students. The algorithms outline management approaches throughout the continuum of care in a given patient's cancer journey, and the discussion section that accompanies each guideline provides excellent textual synthesis of the background and rationale for multiple aspects of cancer care and is accompanied by an extensive, continually curated bibliography.
Phased Implementation and Opportunities
The NCCN Framework and Harmonized Guidelines serve as a basis for tangible current and future advances in multiple aspects of regional cancer control programs.
Within each geographic area, the process of resource stratification and harmonization has brought together previously uncoordinated and often isolated regional health care providers in developing consensus and collaboration and in collectively adapting and building on contemporary NCCN algorithms as an unbiased source of evidence-based content without having to expend the significant time and resources required to create de novo guidelines. Such amalgamation and professional camaraderie have led to an increased sense of agency, with enhanced presence and recognition of these regional groups within the arena of global oncology. For example, the nascent effort in SSA has grown over two and a half years into a network of more than 100 oncologists and other health care providers representing 13 countries, who are now collectively identified as the African Cancer Coalition (ACC). This is facilitated by their shared success in the development of the harmonized guidelines. The consortium actively communicates knowledge and information among its members and has held joint sessions at international forums such as the International Union Against Cancer and the African Organisation for Research and Training in Cancer. Within SSA and the Caribbean, there has been discussion of appropriate patient referrals and shared resources across national borders, which may include expert surgical expertise, specialized pathology and diagnostics, and radiation therapy capabilities. Previously detached sites of clinical practice have also begun discussing collaborative research to address region-specific questions and collectively advance cancer care. The harmonization initiative has also aligned and melded the efforts of multiple international organizations that collectively seek to support global cancer care, such as the NCCN, the American Cancer Society, IBM, and the Clinton Health Access Initiative in SSA.
The structure of the harmonized and resource-stratified guidelines, which highlight what is currently generally feasible but are set within the retained contextual background of the NCCN parent guidelines, serves as a basis for advocacy and capacity building. In SSA, clinicians and select patient groups have used the harmonized guidelines in dialogues with ministries of health to emphasize the need for improvement in cancer care, which is made even more urgent by the expected dramatic rise in cancer incidence in the near future.14 Encouragingly, the NCCN Harmonized Guidelines for SSA have now been endorsed as national standards of care by the ministries of health or national cancer centers of 6 countries—Ethiopia, Malawi, Nigeria, Tanzania, Uganda and Zambia—which together represent 43% of the population of SSA (excluding South Africa), or a total of 450 million lives. In the two and a half years since the SSA NCCN Harmonized Guidelines process was initiated, several nations have increased investments in facilities, technologies, and personnel training. This has led to changes in the harmonized guidelines that reflect greater access to cancer care. For example, the original SSA harmonized guidelines for breast cancer in 2017 (Fig. 6) considered that breast-conserving therapy for early-stage invasive breast cancer was not generally feasible because of the lack of radiotherapy facilities, and all radiation options were grayed out in favor of mastectomy. However, by 2019, there was felt to be sufficiently increased capability that the updated harmonized guideline now includes routine options of radiotherapy for breast-conserving therapy (shown as black text in Fig. 5), even though the specific specialized technique of accelerated partial breast radiotherapy has remained generally unavailable.
A consensus around harmonized guidelines provides a basis for determining cancer medication requirements within a hospital, a city, a nation or across a region. This, in concert with developing tumor registries and in combination with tools created by the American Cancer Society and IBM for estimating quantities of chemotherapy needed, has been used to negotiate more affordable bulk pricing for many medications with the help of the Clinton Health Access Initiative. For example, cisplatin is a commonly used cytotoxic that is effective in lung, testicular, cervical, head and neck, and ovarian cancers, and realistic estimates of use based on incidence and guidelines will permit more efficient ordering and inventory management.
To foster enhanced ease of utilization by the ACC members, IBM has partnered with the NCCN on a Clinical Guidelines Navigator tool for tablets and smartphones and has begun to digitize some of the harmonized guidelines to create a portable decision support tool at the point of care. Health care providers can enter key patient/cancer characteristics into the program, which will then generate specific management recommendations based on the NCCN Harmonized Guidelines.
A forthcoming goal is the opportunity to quantify uptake and concordance with harmonized guideline recommendations and to assess outcome impact both on patient-related variables such as tumor control, survival, and toxicity/quality of life and on broader health care system measures such as quality and cost. This will again be predicated on a multifaceted approach: the initiative and commitment of the ACC members, necessary improvements in tumor registries and clinical data collection, and partnerships with organizations that have proficiency in health outcomes research. Multiple large cancer organizations and groups, including many NCCN member institutions, have dedicated efforts and active personnel seeking to improve care in resource-constrained settings, and their proficiency in implementation processes and evaluation may be leveraged through collaboration in specific global regions.
In conclusion, the NCCN Framework and Harmonized Guidelines provide a flexible, dynamic, and responsive platform that can affect cancer care on multiple levels. Although the primary role is to provide management guidance to providers that optimizes care within the realities and potential constraints of a system, they can also underpin efforts in education, advocacy, capacity building, resource allocation, and research. The process is tailored to the unique needs of a specific region or health care system, and its success and sustainability are dependent on the leadership and engagement of committed local stakeholders. Based on lessons learned to date, the NCCN Framework and Harmonized Guidelines will be continually improved and will evolve to accommodate the spectrum of cancer care requirements globally.
Funding Support
The Breast Health Global Initiative Global Summit was funded by grants from the Fred Hutchinson Cancer Research Center, Susan G. Komen (GSP18BHGI001), the National Comprehensive Cancer Network, the US National Institutes of Health (1R13CA224776-01A1), the National Cancer Institute's Center for Global Health, the American Society of Clinical Oncology, the American Society of Clinical Pathology, the Journal of Global Oncology, the National Breast Cancer Foundation, pH Trust, the Seattle Cancer Care Alliance, the Union for International Cancer Control, and the University of Washington Department of Global Health. Support from unrestricted educational grants came from Cepheid, GE Healthcare, Novartis, Pfizer, and UE LifeSciences. Additional funding to cover publication costs was provided by GE Healthcare and Novartis.
Conflict of Interest Disclosures
The authors made no disclosures.
