Limited financial and medical resources available to cancer treatment centers in developing nations often make it difficult for physicians there to follow best practices widely adopted in the United States and other highly affluent countries. The National Comprehensive Cancer Network (NCCN) is working to change that by developing modified guidelines for specific regions that offer less-costly and less—technologically intensive alternatives.

In developing these sets of Harmonized Guidelines, the NCCN has recognized the growing international use of its core set of guidelines on treating multiple cancer types. These were downloaded globally more than 10 million times in 2018, although not as frequently in less-developed countries. Overall usage is rising—downloads in 2018 were up 26% from 2017. Modified guidelines from the NCCN have already been developed for sub-Saharan countries and the Caribbean (Figure).

“We recognize that just having the guidelines on the web isn’t sufficient. They were initially developed for those with high resources at US comprehensive cancer centers. They need to meet the needs of patients and care providers at different locations where medical resources vary,” said Wui-Jin Koh, MD, the NCCN’s senior vice president and chief medical officer.

“We’re working on translations and with experts from around the world to adapt and harmonize the guidelines for [physicians’] specific regions, to give them novel ways of implementing guidelines-concordant care tailored to resource availability and to provide a platform for advocacy of improving care delivery systems with their governments,” he said.

NCCN care recommendations, determined by multidisciplinary panels from 28 leading academic cancer centers, cover about 97% of all cancers. They include recommendations for treatment of cancer by site and provide information on prevention and risk reduction and supportive care. There are also guidelines tailored to specific populations and patient educational products.

In addition to the Harmonized Guidelines already established in sub-Saharan Africa and the Caribbean, a related harmonization effort called the Middle East and North Africa (MENA) NCCN Adaptation Project was concluded in January. The NCCN also plans to update the Harmonized Guidelines to keep up with changes in the NCCN’s core guidelines.

The core guidelines are constantly refreshed. In 2018, for example, the NCCN’s “parent” breast cancer guidelines were updated 4 times and its non—small cell lung cancer (NSCLC) guidelines got 6 updates. Its Harmonized Guidelines are based on the parent guidelines but are modified to reflect the general standard of care (SOC) in specific regions of the world. In addition, less-sophisticated care options are provided for physicians who may not be able to provide regional SOC.¹

The NCCN is now working closely with experts in Latin America, the Pacific Basin, and Spain. In late April, for example, NCCN representatives met with health leaders in Bolivia to begin crafting guidelines that could be optimized for varying resources. The first 3 adaptations will focus on breast, cervical, and rectal cancers based on the highest incidences and greatest need for the region.

“We want to take advantage of every opportunity we have to advance the standard and accessibility of care globally,” said NCCN Chief Executive Officer (CEO) Robert Carlson, MD. “We have a process we’ve used in multiple settings, going through the guidelines page by page, decision by decision, to see what’s possible and what’s not for a specific setting. And if something’s not possible, we look at what pragmatic and evidencesupported alternatives can be used instead. Sometimes doctors don’t have access to a certain cancer drug, so we might have to find the next most successful drug.”

All versions of the NCCN Harmonized Guidelines come with 3 levels of recommendations: Black text indicates generally available SOC for that locale; gray text refers to care that may be costly, technically challenging, and/or have a lesser impact on oncologic outcome; and blue text provides regional options to consider when best practices aren’t available.

A Look at NCCN Harmonized Guidelines in Sub-Saharan Africa

Life expectancy in sub-Saharan Africa is rising partly due to better control of infectious diseases like HIV, malaria, and cholera. Cancer rates, however, are also increasing due to the longer life expectancy. The incidence of cancer is expected to double by 2040 to 1.6 million cases per year.² In this region, more than 50% of patients with cancer die within a year of diagnosis, as most patients—about 80%—seek care only when the disease is advanced, according to Abubakar M. Bello, MD.

Further complicating the situation is that few people have insurance and drug costs are high. Certain oncologic drugs may not be available. Residents also have limited access to cancer care centers, although that is improving. Not long ago, Bello, of the National Hospital in Abuja, Nigeria, was the sole oncologist serving about 16 million people. His slim cancer-fighting arsenal included an occasionally faulty 17-year-old linear accelerator.

Without “the privilege of specialization,” Bello said, he was expected to know how to diagnose and treat multiple cancers, “and you tend to be a bit confused if you don’t have something to fall back on.”

Bello and the NCCN worked with the African Cancer Coalition and Nigerian Health Minister Isaac Adewole, MBBS, an oncologist, on the creation of guidelines for sub-Saharan Africa that focused on how to achieve the best results with limited resources and provide a pathway for further development of cancer care systems.

They first determined which cancers were among the most prevalent in their area. In Nigeria’s case, this included breast, cervical, and prostate cancers. They then determined what treatments were available. There are now 19 NCCN Harmonized Guidelines for sub-Saharan Africa. The governments of Ethiopia, Nigeria, and Tanzania have formally endorsed the guidelines.

One example of sub-Saharan Africa— specific guideline harmonization is the treatment of cervical cancer. Pelvic external beam radiation therapy and brachytherapy are the NCCN’s primary recommendations for locally advanced cancer. But in recognition of limited resources in the area, the guidelines suggest the alternative of neoadjuvant chemotherapy followed by radical hysterectomy if there is no access to radiotherapy.

Another example can be found in breast cancer. A chest CT with contrast is the NCCN’s primary, or “black text,” recommendation for systemic staging, but because such technology may not be readily available, the guidelines in blue suggest using a pragmatic alternative of chest x-ray with abdominal ultrasound.

“It’s a bit early, but we do know this is a step in the right direction. There’s a lot of enthusiasm to follow the guidelines, and practices are changing because of the guidelines,” Bello said. “Patients are properly staged before starting treatment because doctors are downloading the guidelines and trying to follow them.

“In a few years, maybe 5, we hope to have cancer centers that are NCCN-accredited so we can use all of that expertise to lower the death rates of patients in sub-Saharan Africa,” Bello said. “We’re getting cancer care, and it’s becoming more affordable, and it’s almost on par with developing nations, even if it’s not [on par with] the United States.”

NCCN Harmonized Guidelines for the Caribbean

Marisa Nimrod, MD, chair and CEO of the Caribbean Association of Oncology and Hematology (CAOH), said adaptation and implementation of the NCCN guidelines will be a regional goal this year. There are currently 7 NCCN Harmonized Guidelines for the Caribbean.

“The Caribbean Harmonized Guidelines present a more hand-in-glove fit for the resources available within this area,” said Owen Gabriel, MD, a consultant oncologist at Victoria Hospital in Saint Lucia and chair of an NSCLC guideline initiative. “Although there is no formal adoption, these guidelines are being promoted via their use as the backbone of multidisciplinary tumor boards as well as individualized patient care.”

Still, the changes were not extensive, according to Gilian Wharfe, MD, clinical chair of the NCCN CAOH guideline development initiative. “Most of the changes made were related to lacking certain technology [and] skilled surgeons and, most of all, the unavailability/affordability of the medications used in the treatment of these conditions,” she said. “The cost of medication has a huge impact on how we treat our patients.”

One example of how the guidelines have been harmonized for the Caribbean is a recommendation for neoadjuvant platinum- based chemotherapy in advanced cervical cancer if initiation of SOC chemoradiation must be delayed.

Figure. Sample of NCCN Harmonized Guidelines for Sub-Saharan Africa: Version 2.2017, Breast Cancer^a,b

“The NCCN Caribbean Harmonized Guidelines afforded the evidence and justification for this option, which is not typical for the more advanced stages of disease,” Gabriel said. “The results have been astounding, with generally no difference in outcome when compared with patients who underwent the [SOC] option.” In Jamaica, Sophia Edwards-Bennett, MD, chair of the NCCN/CAOH guideline harmonization initiative, said the guidelines were modified to “reflect the current technologies available in Jamaica at this juncture.” Thus, clinical practice generally aligns with the new construct. “Although not empirically determined, the gap between aspiration and reality has been largely addressed,” she said.

Physicians in Jamaica are preparing to distribute the guidelines electronically and via pamphlets, a process that will be complemented by medical conferences.

Edwards-Bennett echoed Wharfe’s comment about the high cost of anticancer drugs in Jamaica, noting that “this challenge is not only applicable to novel targeted therapies, such as immunotherapy, but [includes] conventional regimens as well.”

The MENA NCCN Adaption Project

Abdul-Rahman Jazieh, MD, MPH, chairman of the MENA NCCN Adaptation Project, said doctors in this region turn to the NCCN guidelines because they cover most common cancer and clinical scenarios, are continuously undated to incorporate recent evidence, and are easy to access and understand. Harmonization, he said, required minimal changes, “as our aim is to practice medicine similar to US oncologists. We kept changes at a high level as resource-stratified guidelines give choices to oncologists to choose adaptation at different levels.”

One example of a MENA-adapted guideline is for the treatment of NSCLC. Lung cancer has the highest incidence among cancers in 7 of 13 Arab countries, and data indicate that NSCLC is on the rise.³

Primary NCCN guidelines recommend molecular testing for metastatic NSCLC. The MENA adaptation recommends establishing an independent molecular tumor board (MTB) or including experts in thoracic MTB meetings to carefully assess the need for, and results from, molecular testing.

Primary NCCN guidelines also recommend either completing or interrupting systemic therapy in patients who are found to have molecular biomarkers, such as EGFR mutations or ALK rearrangements, during first-line chemotherapy. The MENA adaptation clarifies that chemotherapy should be interrupted in the event of serious adverse events and appropriate tyrosine kinase inhibitor therapy should be initiated.

The rollout of the adapted guidelines has encouraged many cancer care centers in the region to enhance their practices, Jazieh said. “They accelerated the adoption of the latest treatment options, especially when it comes to precision medicine, including workup and management,” he said. “We use the NCCN guidelines to convince hospital leaders to have access to medications on formulary” or that are not on formulary but are part of the NCCN guidelines.

References

1. National Comprehensive Cancer Network Harmonized Guidelines for sub-Saharan Africa: breast cancer, version 2.217. NCCN website. Updated November 3, 2017. Accessed May 1, 2019. www.nccn.org/ professionals/physician_gls/pdf/breast_harmonized-africa.pdf.
2. Dent J, Manner CK, Milner D, et al. Africa’s emerging cancer crisis: a call to action. BIO Ventures for Global Health website. bvgh.org/ wp-content/uploads/2017/07/Africas-Emerging-Cancer-Crisis-ACall- to-Action.pdf. Published June 2017. Accessed May 1, 2019.
3. Salim EI, Jazieh AR, Moore MA. Lung cancer incidence in the Arab League countries: risk factors and control. Asian Pac J Cancer Prev. 2011;12(1):17- 34. researchgate.net/publication/51074223_Lung_Cancer_Incidence_ in_the_Arab_League_Countries_Risk_Factors_and_Control.