Introduction

Cancer is a global health challenge that knows no boundary. Over the next 2 decades, the number of new cancer cases is expected to rise approximately 50% worldwide.1 Many obstacles stand in the way of successful global cancer care, particularly in low- and middle-income countries (LMICs). In these regions, access to quality affordable care, including cancer screening facilities, trained medical professionals, availability of conventional treatment (such as surgery, chemotherapy, and radiation therapy), and supportive care services, can be extremely limited.2

Patients have been using culturally salient, lower cost traditional medicine practices, such as acupuncture, yoga, meditation, and herbal medicine, along their cancer journeys. Collectively, these modalities are classified as part of complementary and alternative medicine (CAM) in the West.3 Since 2002, the traditional medicine strategy of the World Health Organization (WHO) has encouraged and strengthened the insertion, recognition, and use of traditional, complementary, and integrative medicines (TCIMs) in national health systems at all levels: primary health care, specialized care, and hospital care.4 Therefore, we use the term TCIM in this article to refer to these practices.

Although TCIM is widely used among populations in high-income countries (HICs)5 as an adjunct to conventional medicine, TCIM may be considered primary health care in LMICs such as Chile, Brazil, and rural India.6-8 With economic development and international engagement, growing numbers of LMICs have initiated efforts to provide conventional cancer screening, treatment, and supportive care. Despite the increased use of both TCIM and conventional medicine globally, tension and conflicts between these approaches exist, and systematic integration remains extremely limited. It is precisely for this reason that the growing field of integrative oncology can contribute solutions for patients, families, and practitioners to navigate between the 2 health care paradigms. The Society for Integrative Oncology (SIO) defines this field as a patient-centered, evidence-informed approach to cancer care that uses lifestyle modifications, mind and body therapies, and natural products from different traditions in tandem with conventional cancer treatments.9 Integrative oncology offers both a bridge and path forward to help deliver culturally sensitive, high-quality care in LMICs.

In October 2020, over 700 participants virtually joined global leaders, researchers, and scholars to learn more about the opportunities and challenges of integrative oncology at the Trans–National Cancer Institute (NCI)-National Institutes of Health (NIH) Conference, International Perspectives on Integrative Medicine for Cancer Prevention and Cancer Patient Management. In this review, we have drawn upon the meeting procedures and summarized the key themes that emerged from the presentations and discussions on global integrative oncology, with a particular focus on LMICs. In addition, we performed a scoping review of current clinical guidelines that included integrative oncology treatments. Furthermore, selected conference presenters and moderators formulated recommendations based on the meeting summary. This review includes 6 sections: 1) a synthesis of the global cancer burden and cancer control challenges; 2) a review of the conceptual challenges between TCIM and conventional medicine in cancer care and examples in specific regions, eg, Latin America, Africa, and Asia (China and India); 3) the current evidence base for integrative oncology; 4) research challenges and opportunities in integrative oncology; 5) examples of global integrative oncology research collaborations to increase the evidence base; and 6) the formulation of policy, research, and practice recommendations to advance the global impact of integrative oncology.

Global Cancer Burden Human and Societal Costs of Cancer

Over 19 million people around the world were diagnosed with cancer and almost 10 million died from cancer in 2020.10 By 2040, new case and death totals are expected to reach approximately 28 million and 16 million, respectively.11, 12 Cancer treatment alone costs the world approximately US$1.2 trillion annually—nearly 2% of the global gross domestic product in 2019.13 LMICs account for 80% of the global cancer burden; yet, with only 5% of the global spending to combat this disease, LMICs will continue to fall behind in efforts to provide quality cancer care to their citizens.14 Furthermore these countries will not remain aligned to achieve the WHO Sustainable Development Goal Target 3.414 for the year 2030, which aims to reduce by one-third premature mortality from noncommunicable diseases, including cancer, compared with rates from 2015.15 Countries with a low human development index (a summary measure of key dimensions affected by sustainability and equity) experience significantly higher premature mortality because of delayed diagnosis and access to therapeutic services as well as limited availability of quality treatment.16 Furthermore, a constellation of dynamics surrounding issues, such as lack of infrastructure, health policies, properly trained professionals to perform evidence-based screening and treatment, trust in providers, and continuity of care across services, underlies and exacerbates these global challenges in cancer care delivery (Fig. 1). For example, premature deaths from noncommunicable diseases that could be prevented through effective policies and public health interventions have increased nearly 50% over a few decades, from 23 million deaths in 1990 to over 34 million deaths in 2017, with one-third of those being cancer-related.17

Worldwide Challenges in Cancer Care Delivery.

Growing Inequality in Cancer Prevention

Suboptimal implementation of highly effective cancer prevention strategies, such as tobacco-control interventions and vaccination against hepatitis B virus (HBV) and human papillomavirus (HPV) in LMICs, has widened global cancer inequality. More than 80% of global smokers live in LMICs,18 and many of these countries have not satisfactorily enforced the 6 evidence-based measures identified by the WHO Framework Convention on Tobacco Control.19 Although the current prevalence of tobacco use is comparatively low in Africa, concerns have been expressed about the impact of lifestyle changes, weak tobacco-control measures, and intensified marketing by tobacco companies. A significant increase in smoking prevalence among men has already been documented in some African countries like Congo.20 Infection-related cancers constitute disproportionally high rates in LMICs where effective prevention and treatment strategies exist. Chronic HBV infection was responsible for 55% of the hepatocellular cancers occurring in 2018.21 Coverage of the birth dose of HBV vaccine is <40% globally, with huge disparities across countries.22 Only 40% of Asian countries and 31% of African countries have introduced HPV vaccination programs as of 2020, although the majority of the global cervical cancer burden is shared by these countries.23

Western Lifestyle Contributes to Growing Cancer Incidence

LMICs face additional challenges in responding to the rise of cancer incidence and premature death caused by undesirable lifestyle trends. Cancer incidence changes when people from Asia or Africa migrate to Western countries. Immigrants experience increased obesity and a spike in Western lifestyle-associated diseases, including cancer incidence rates higher than those observed in their home countries. Several epidemiological studies found that immigrant cancer rates can match those of their newfound home in as quickly as one generation for Africans and South Asians.24-26

In addition, cancer incidence trends in those LMICs that have experienced recent economic development are starting to mirror the trends in Western countries.27 Whereas breast cancer rates used to be low in China, India, and Brazil, metropolitan areas of these countries now have rates similar to the West because of changes in lifestyles as well as delays in pregnancy and changes in breast-feeding practices.28-30 Highly processed fast-food diets are common Western exports to LMICs, and obesity rates are increasing alongside Western diseases. In Brazil, for example, almost one-half of people who, in the recent past, were underweight and struggling to consume sufficient calories because of poverty are now overweight, which is linked to physical inactivity and an increased consumption of fast and processed foods that are low in nutrition.31

Limited Access to Cancer Treatment

It is well established that lack of resources and fragmented care contribute to global cancer treatment disparities. Despite the rapid development of novel cancer therapies like targeted treatment and immunotherapies in HICs, these treatments are not available to the majority of the population in LMICs. Furthermore, access to older and effective cancer treatment remains extremely limited in the majority of regions in Africa, rural Asia, and rural Latin America.32 The median density of radiotherapy machines per million population in 2020 was virtually nonexistent at only 0.0 (range, 0.0-0.4) in low-income countries compared with 5.1 (range, 0.4-11.6) in HICs.33

A recent Lancet Oncology article reported a 25-times difference between LMICs and HICs (3.5% vs 87%) in 5-year survival among women diagnosed with breast cancer. Those authors further estimated that, by implementing a conventional package of screening and treatment (imaging, surgery, radiation, and medical oncology), improving the quality of care delivery can improve survival from 3.5% to 55.3% in LMICs.34 Inadequate health care coverage systems can also lead to limitations in cancer treatment.35 Patients in LMICs often cannot afford conventional medicine options, and out-of-pocket payments dominate health care financing in many of these countries.36 This has led to elevated risks for adverse financial outcomes, such as medical impoverishment and death, especially in lower income households.37

In addition to cost, mistrust of conventional medicine further complicates cancer care in LMICs. More than one-half of patients with cancer in sub-Saharan African countries consulted a traditional healer because of access problems, high cost, stigma, and myths associated with Western cancer treatment.38 However, an overall lack of cancer education among TCIM practitioners may lead to delayed diagnosis and poor outcomes. For those who do have access to modern cancer advances, early detection and treatment contribute to increases in survival.

Lack of Survivorship and Palliative Care

Growth of the aging population also factors into the rise in cancer survivorship globally, with the WHO reporting that the number of people older than 60 years will increase approximately 2-fold by 2050.39 The intersection of aging and cancer survivorship can be particularly difficult to navigate for people affected by cancer. Despite progress in supportive care for survivors, gaps still exist in addressing complex symptoms such as anxiety, pain, fatigue, insomnia, neuropathy, and cognitive dysfunction.40, 41 Moreover, the physical, emotional, and social ramifications of cancer may linger years after treatment,42 further challenging the infrastructure and resources of health care systems.43

Early integration of palliative care, which is considered an essential component of universal health care by the WHO to improve quality of life,44 is also not easily accessible worldwide. For example, only 29% of patients with cancer in middle-income countries and 10% of those in low-income countries have access to oral morphine for pain relief.45 India and China do not have national policies or government funding that support palliative care,46, 47 and only 12 African countries reported having a stand-alone, nationwide palliative care policy.48 Therefore, culturally and socioeconomically sustainable solutions are especially needed to support patients and families with advanced disease in LMIC cancer populations.

Challenges of Integrating TCIM Into Conventional Cancer Care

In many LMICs, TCIM practices are deeply rooted in societal cultures and traditions. When used appropriately, TCIM may offer some solutions to address global cancer challenges6; however, tensions exist between TCIM and conventional cancer care.

Key differences between conventional cancer care and TCIM perspectives hinder collaboration and integration. Conventional medicine uses a bottom-up, micro-to-macro approach to understand health and disease, examining how structure leads to function. Conversely, TCIM embraces a top-down, macro-to-micro approach, examining how function necessitates structure.49 Conventional medicine and TCIM have distinct philosophies and treatment approaches (Fig. 2). The conventional oncology paradigm focuses on treating cancer as a biologic disease with identifiable mutations and targets. Treatments have clear, basic science mechanisms and are evaluated through rigorous clinical trials with well defined end points. As a result, modern anticancer approaches such as surgery, chemotherapy, radiation, hormonal treatment, targeted therapy, and immunotherapy have increased survival for many types of cancer. TCIM, instead, often relies on ancient theory and wisdom as well as thousands of years of empirical practice with people of a particular culture and community. The treatment focuses on the person with the illness rather than the disease itself and embraces the holistic nature of health as the interplay among body, mind, and spirit. The therapeutic approaches, including herbs, acupuncture, touch therapies, and spiritual practices, achieve harmony in the patient regardless of disease status.

Tensions Between Traditional, Complementary, and Integrative Medicine (TCIM) and Conventional Medicine in Low- and Middle-Income Countries.

Examples of Progress and Challenges of Integrating TCIM and Conventional Medicine in LMICs

Recognizing the tension between TCIM and conventional medical practice, many LMICs are working to integrate their traditional healing practices with conventional cancer care. Below, we provide the examples of Latin America, Africa, and Asia (India and China) to highlight some unique approaches and challenges in health care delivery, research structures, and funding.

Latin America

TCIM is widely used by patients with cancer in Latin American countries.50-54 It is estimated that between 50% and 90% of adult or pediatric patients with cancer use TCIM.53, 55-62 Natural products and nutritional supplements are most frequently used, followed by spiritual practices. More recognized mind and body therapies, such as meditation, yoga, tai chi, acupuncture, massage, music therapy, dance therapy, mandalas, and horticultural therapy, are also used across Brazil, Argentina, and Chile.50, 53, 56, 58, 59, 61, 63

Although widespread use has led to more official recognition, implementation has been mixed. In Argentina, Garrahan Pediatric Hospital and FUNDALEU (Foundation to Fight Leukemia) are 2 examples of health centers that apply TCIM in the clinical setting with medical recommendation. In Chile, the Clinica Alemana, the Arturo Lopez Perez Foundation, the National Cancer Institute, and the Calvo Mackenna Hospital also offer TCIM services integrated with Western conventional therapies to patients with cancer.64, 65 Several Brazilian medical centers have established integrative oncology programs with an academic focus on clinical care, teaching, and research: Hospital Israelita Albert Einstein in Sao Paulo and the Brazilian NCI-Designated Cancer Centers (the National Cancer Institute in Rio de Janeiro and the university hospitals of Sao Paulo and Fortaleza).66-70 Brazil has a national policy that integrates TCIM within the United Health System, which now includes 29 practices.71-73 Despite recognition of its policy, these practices are not routinely provided for oncology patients in conventional health centers. In addition, health professionals do not often inquire whether patients are using TCIM; therefore, the extent of benefits or safety issues such as herb-drug interactions are unknown.59, 74, 75

Similarly, the current evidence on TCIM used in Latin America is nascent. Almost all research is preclinical investigation involving plants. Several native and exotic species of Annonaceae, Loranthaceae, and Lamiaceae have been extensively studied.76-81 Several early phase clinical trials have found preliminary efficacy that plants from the Amazon region, such as Uncaria tomentosa and guarana, may help manage adverse effects of cancer treatment (eg, neutropenia, anorexia, fatigue) and improve quality of life.82-86 The Ministry of Health in Brazil has charged the Brazilian Academic Consortium for Integrative Health, along with the Latin American and Caribbean Center on Health Sciences Information/Pan American Health Organization, with generating clinical guidelines based on systematic reviews that evaluate clinical evidence and treatment outcomes related to cancer symptoms such as fatigue, pain, nausea, and vomiting.67

Africa

For most people in Africa, contemporary cancer care is unavailable, inaccessible, or unviable. This is because of the shortage of skilled medical professionals in oncology and scarcity of the required infrastructure. These resources, when available, are concentrated around the few urban centers (mostly national capitals) of the respective countries. The insufficient infrastructure and supply of radiology, diagnostic pathology, therapeutic surgery, chemotherapy, and radiotherapy make conventional cancer care extremely expensive and unviable for the majority of the population. Therefore, TCIM providers are often the first line of health care providers when individuals present with symptoms of cancer, and, for a large segment of the population, they may be the only source of health care that is available and affordable to patients with cancer.87-90

African traditional medicine delivered to the community can be classified as divination, spiritualism, and herbalism. Often it is seen as a mixture of these 3 in different proportions, varying from one practitioner to another.91 In a recent systematic review and meta-analyses, the use of herbs by patients with cancer in Africa was reported to be approximately 40%, the highest of all continents.92 Because of limited conventional treatment options, many patients with cancer receive herbal medicine alone as monotherapy. Because of a lack of population-based screening and diagnostic capacity, cancer often presents at an advanced and incurable stage. For these patients, TCIM interventions provide symptom relief and solace until death. Therefore, in the context of Africa, we often find traditional medicine as the first line of treatment for cancer, which is accessible and is introduced as soon as the disease is identified.90 In urban settings where there are conventional cancer care resources, several hospital-based survey studies in Nigeria, Tunisia, and Morocco found that the use of TCIM treatments among patients receiving treatment was common, which raises the potential for drug-herb interactions.93-95 TCIM treatments can have side effects and can contribute to renal and hepatic toxicities, which can be a detriment to patients' health; despite common use, physicians rarely inquire about them.93, 94 Considering these drawbacks and the extensive exposure of the African population to TCIM for cancer management and care, it is essential that well defined and focused clinical and experimental investigations are conducted into the safety and effectiveness of these practices to determine their appropriate use in various stages of the cancer care continuum.87-89

India

The pluralistic health care system of India offers patients access to TCIM known in the country as AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, Sowa Rigpa, and Homeopathy). Published estimates of TCIM use among patients who have cancer in India range from 24% to 39%,96-98 with Ayurveda being the most common.97 However, these estimates are based on small sample sizes and may not represent behavior of their larger population of patients with cancer. Underreporting raises the possibility of unnoticed harms and benefits and concerns about potential interactions with chemotherapeutic agents. The use of TCIM has been associated with delays in seeking help from oncologists,96 potentially contributing to delayed diagnosis and treatment and, thus, higher mortality rates. Conversely, benefits from the integration of TCIM therapies into cancer care go unnoticed and are underreported as well.

Despite pluralistic health care systems in India, policies to facilitate cooperation and integration between TCIM and conventional medicine do not exist. Practitioners of these different systems work independently, and integration is challenging because of fundamental distrust in the other.99 For this reason, integrative oncology is not well developed in India. There have been many scattered and isolated attempts to integrate AYUSH treatments for cancer care in public and private hospitals. For example, several conventional oncology hospitals have established adjunct Ayurveda/AYUSH clinics to integrate relevant treatments with the goals of improving quality of life among patients with cancer. In addition, an Ayurvedic cancer care hospital in Pune, India integrates Ayurvedic drugs in coordination with modern oncology treatments such as chemotherapy, with some reported preliminary benefit.100

Research of AYUSH and cancer is predominantly preclinical and focuses on anticancer properties of herbs and formulations, with Curcuma longa and Withania somnifera being the most studied.101, 102 Some Ayurvedic formulations appear to have chemopreventive, antimetastatic, antiproliferative, chemosensitizing, and radiosensitizing activities.103-107 To translate any of these findings into effective clinical interventions at the point of care, well designed and rigorous clinical trials are needed. One study of 36 patients with cancer who were undergoing chemotherapy and radiation showed that the Ayurvedic formulation Rasayana Avaleha could reduce adverse events such as vomiting, mucositis, alopecia, and ageusia when used as an adjuvant.108 Limited funding opportunities, lack of research training, and ethical issues are just some of the challenges faced by researchers in India studying the role of TCIM in cancer management.

China

Traditional Chinese medicine (TCM) is deeply rooted in Chinese culture and everyday life is and held as a symbol of the nation.109 Approximately 75% to 80% of patients in China use TCM after a cancer diagnosis, with Chinese herbal medicine (55%-75%) used most often and tai chi/qi gong (7%) and acupuncture (1%-5%) used less frequently.110-112 TCM is widely integrated in oncology departments within China's hospitals in conjunction with conventional cancer treatment.113 Furthermore, conventional oncology diagnosis (eg, pathology, imaging) and treatment (eg, surgery, chemotherapy, radiation, and hormonal treatment) are available in elite TCM hospital oncology departments in addition to TCM approaches. One medical insurance analysis of oncology inpatients in China showed that 42% used TCM herbs and 25% combined herbs with conventional cancer drugs.114 In addition, traditional herbal formulas and TCM cancer drugs are listed in China's National Basic Medical Insurance Drug Catalog.

In Hong Kong in 2014, the hospital authority of the Special Administrative Region launched the Integrated Chinese-Western Medicine Pilot Program in 3 public hospitals, which included the integration of acupuncture and Chinese herbal medicine for inpatients with late-stage cancer.115 The results showed that the practices were safe and feasible, and the program was expanded to 8 hospitals in 2017. Clinical trials conducted in Hong Kong also demonstrated acupuncture benefits in cancer care, including reduced need for postoperative analgesics and improvements in cancer-related cognitive impairment and chemotherapy-induced peripheral neuropathy.116-118

In mainland China, with rapid economic growth, government and industry have invested in basic, clinical, and outcomes research of TCM in oncology.119 For example, in a prospective cohort study, the use of a physician-prescribed TCM formula was associated with improved survival in patients with stage II or III colorectal cancer.120 In a phase 2 clinical trial, the TCM formula Renshen Yangrong Tang reduced cancer-related fatigue.121 A systematic review and meta-analysis found that acupuncture was associated with moderate evidence for reducing pain in patients with cancer.122 Despite progress, TCM often involves complex herbal formulas or individualized prescriptions based on a patient's presentation; therefore, there is a need to increase the quality of TCM clinical trials by developing standardized diagnostic criteria, treatment approaches, and outcome measures according to defining TCM characteristics.123

Despite extensive TCM use in China and its surrounding regions, challenges in delivering comprehensive and equitable services exist. One survey of patients that identified barriers to care cited TCM treatment concerns (42%), such as side effects, its hindrance of conventional treatments, and lack of scientific evidence for its use, along with logistical difficulties (42%), including herb decoction, locating a good TCM physician, concerns over treatment cost, and adherence to longer treatments.124 Furthermore, patients aged 60 years or younger with localized disease had more concerns, and those actively employed reported more logistical difficulties.124 These findings highlight the need for more basic, clinical, and health services research on TCM treatments, better evidence-based education, and more patient-centered and convenient TCM treatment approaches for patients with cancer.124

Current State and Evidence of Integrative Oncology

As shown by the examples above, despite numerous challenges, the practices of conventional medicine and TCIM do not need to be mutually exclusive. By appropriately incorporating specific, evidence-informed TCIM therapies alongside conventional medicine, the field of integrative oncology can overcome tensions and create an inclusive environment in which both philosophies and treatment approaches effectively coexist to produce better patient outcomes. With this goal in mind, it is useful to review the current state of integrative oncology and how it might be used to advance solutions to persistent global challenges in cancer prevention and patient management. Over 20 years ago, leading North American academic cancer institutions, including Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and The University of Texas MD Anderson Cancer Center, developed clinical, educational, and research integrative oncology programs in response to the growing demand from patients with cancer to incorporate TCIM into conventional cancer treatment and survivorship care. The NCI also established the Office of Cancer Complementary and Alternative Medicine (OCCAM) to coordinate and enhance activities in TCIM research as it relates to the prevention, diagnosis, and treatment of cancer, cancer-related symptoms, and side effects of conventional cancer treatment.125 By 2016, the majority of 45 US NCI-designated cancer centers provided integrative medicine information to patients on their websites, including acupuncture/massage (73% each), meditation/yoga (69% each), nutrition consultations (91%), dietary supplements (84%), and herbs (67%), and most also offered these services.126 Building on 20 years of clinical research, including data from high-quality randomized controlled trials (RCTs), both the SIO and the American Society of Clinical Oncology (ASCO), a leading oncology organization, recommend integrative medicine for supportive care of various disease-related and treatment-related symptoms.127-129 Furthermore, guidelines from the National Comprehensive Cancer Network (NCCN) include acupuncture, massage, meditation, yoga, music therapy, exercise, and nutrition among their recommendations for alleviating common symptoms, such as fatigue, pain, nausea, hot flashes, and sleep disorders (Table 1).130-136 A brief summary of the evidence of selected integrative medicine approaches follows.

TABLE 1. National Comprehensive Cancer Network Clinical Practice Guidelines for the Use of Integrative Medicine for Supportive Cancer Care SYMPTOMS ACUPUNCTURE MASSAGE MEDITATION/MBSR YOGA MUSIC THERAPY EXERCISE NUTRITION Adult cancer pain X X X X X Cancer-related fatigue X X X X X X Sleep disorders X X Distress (anxiety/depression) X X X X X Cancer-associated cognitive dysfunction X X Hot flashes/night sweats X X X Sexual dysfunction X X Nausea/vomiting X X X Anorexia X X Abbreviation: MBSR, mindfulness-based stress reduction. a Derived from the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for supportive cancer care (NCCN 2021,130 Denlinger 2021,131 Swarm 2021,132 Berger 2021,133 Ettinger 2021,134 Riba 2021,135 Dans 2021136). Lifestyle Management

Promotion of healthy lifestyles is a key component of integrative oncology and a critical component of cancer prevention. Smoking cessation has been a crucial strategy for cancer prevention on a population level.137-139 Studies that have examined poor diet, insufficient physical activity, and being overweight or obese have been largely observational. However, consistent associations have been demonstrated over time, and it is now well accepted that up to 50% of cancers could be prevented by modifying common lifestyle factors.140 Reducing alcohol consumption will lower the risk of more than 12 different cancers because alcohol has long been known as a carcinogen.141 Strategies such as safe sex and vaccinations can decrease the risk of virally mediated cancers caused by HPV, and healthy sun protection practices can reduce the risk of melanoma or other skin cancers.