Complementary and Integrative Medicine in Lung Cancer: Questions and Challenges

Abstract

Lung cancer represents 13% of all cancers, making it the second most common type of malignancy in the United States. Lung cancer is the leading cause of cancer death in men and women in the United States and accounts for nearly 18% of all deaths from cancer. Because of its high mortality rate, lung cancer is associated with an increased rate of distress. Patients use various strategies to cope with this distress during and after cancer treatments, and complementary and integrative medicine (CIM) has become a common coping strategy. This review covers major questions and challenges of incorporating CIM during and beyond treatment for lung cancer. The questions revolve around determining the value of nutrition and nutritional supplements, assessing the role of exercise, addressing the mind–body connection, enhancing the benefit of immunotherapy, and determining the benefit of incorporating complementary therapies such as acupuncture and homeopathy. This review may provide a basis for discussion that can enhance patient–doctor dialogue regarding the use of CIM during and after treatment for lung cancer.

Introduction

Lung cancer is the most common cancer, comprising more than 13% of new cancer cases worldwide.^1,2 It is a highly lethal cancer because nearly 80% of cases are discovered in advanced stages. In the United States, lung cancer is the leading cause of cancer deaths in both men and women; the 5-year overall survival rate is 18.1% but can be up to 55.6% for localized disease.³

Because of its high mortality rate, lung cancer is associated with an increased rate of distress. Patients use various strategies to cope with this distress during and after cancer treatments, and complementary and integrative medicine (CIM) has become a common coping strategy. Most patients with lung cancer experience various symptoms related to either the disease or its treatment. The most commonly reported symptoms are pain, fatigue, weakness, depression, anxiety, nausea, and poor well-being.^4

–7 As a result, there is a constant search for additional options for care that can be incorporated into the treatment plan. This search may be associated with patients' core beliefs of how to restore their wellness and effectively manage their symptoms. The use of CIM falls into this category. Studies show that 23%–66% of lung cancer patients turn to CIM interventions such as the use of medicinal herbs, dietary supplements, and other complementary therapies in conjunction with conventional treatments.^4

–7 Patients use these interventions to reduce symptoms and the toxic effects of standard therapies and improve their ability to heal, as well as for an increased sense of autonomy and control.^5,8
–10

The use of CIM in patients with lung cancer raises multiple questions. Most of these questions surround six main areas of CIM: nutrition, nutritional supplements, physical activity, mind–body therapies, enhancing immunotherapy, and complementary therapies. Currently there is not enough evidence to support the use of any of these treatments in obtaining a cure. However, multiple studies suggest that CIM may be beneficial for patients with lung cancer. This review addresses the main questions and challenges related to the use of CIM, in its various forms, in patients with lung cancer. The authors anticipate that this information will be helpful to clinicians seeking to counsel their patients with lung cancer using a patient-centered and informed approach.

Nutrition

One of the main issues that patients affected by cancer request an integrative oncology consultation relates to the issue of nutrition.^6

–9 Although few studies have evaluated nutritional interventions in patients with active lung cancer, many studies have examined which foods and dietary patterns affect the risk of developing the disease. The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Report, “Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective,” which was first published in 1997, updated in 2007, and updated again in 2018, provides a comprehensive review of the relationship between certain food groups and lung cancer, in prevention as well as survivorship. In that document, the authors cited studies that discuss the role of fruits, vegetables, carotenoids, flavonoids, red meat, and others.¹¹ The main possible beneficial foods, as well as foods that have a possible detrimental effect as hinted in the research arena, are listed in Table 1.

Table 1.

Foods and Supplements That May Be Beneficial or Harmful in Patients with Lung Cancer

	Recommended	Avoid
Foods	Fruits^11,12 Nonstarchy vegetables (green leafy vegetables, nonstarchy root vegetables, tubers, and carrots)^11,12 Foods high in carotenoids (carrots, cantaloupe, sweet potatoes, tomatoes, pumpkins, spinach, apricots)^11,13 Foods high in selenium (Brazil nuts, cremini mushrooms, tuna, halibut, salmon, scallops, organic eggs, shiitake mushrooms, barley, grass-fed beef, turkey)¹¹ Foods high in quercetin (capers, dill, kale, buckwheat, sweet potatoes, apples)^14,15 Green tea⁸³ Spices: turmeric,⁸⁴ black cumin⁸⁵ Soy⁸⁶ Garlic⁸⁷ Pomegranate⁸⁸	Red meat^11,16 Processed meat^11,16 Diets high in Glycemic Index⁸⁹
Supplements	Astragalus^47,48 Omega 3 (EPA:DHA ≥4:1)^36 –41 Curcumin⁸⁴ Ginseng⁹⁰ Sun soup⁹¹ Trametes versicolor ^49,50 Homeopathic remedies^{73,78 –82} Melatonin^42 –46 Vitamin D (early stage)^30 –34 Probiotics^68 –71	Selenium¹¹ Vitamin A¹¹ β-carotene^11,22 Vitamin D (advanced stage)³⁵

Adapted with permission from the Integrative Oncology Consultants website: www.moshefrenkelmd.com (2018).

Fruits and vegetables

A recent systematic review and meta-analysis evaluated the impact of fruit and vegetable consumption on the risk of lung cancer. Across the 18 studies included, high intake of fruits and vegetables reduced the risk of lung cancer by 14% (relative risk [RR] = 0.86; 95% confidence interval [CI] = 0.78–0.94).¹² A dose–response association was observed, although consumption of more than 400 g (about 1 pound) per day did not confer additional protection. This beneficial effect was significant in current smokers, but not in former or never smokers.¹²

In terms of lung cancer prevention, fruits had a more beneficial effect than vegetables, with a risk reduction of 18% (95% CI = 0.76–0.89; n = 29 studies and 15,599 cases) when comparing the highest intake of fruits with the lowest intake.¹² A 15% reduction in lung cancer risk (95% CI = 0.78–0.93; n = 15 studies and 12,021 cases) was observed when examining citrus fruits in isolation, and a dose–response relationship was observed with intakes up to 70 g.¹²

Vegetable intake is also helpful for lung cancer prevention, with a summary RR estimate of 0.92 (95% CI = 0.87–0.97; n = 25 studies and 19,095 cases) between the highest and lowest intake, although this association was statistically significant only for current smokers. A dose–response association was observed for vegetables; the risk was decreased by 18% for intakes of up to 300 g (two-thirds of a pound) per day.¹² The 2018 report suggests that there is limited but generally consistent that lung cancer risk is decreased with increased intake of nonstarchy vegetables (specifically green leafy vegetables) and nonstarchy root vegetables, such as tubers and beets, carrots, artichokes, asparagus, avocados, beans, and others. Data extracted from 10 studies showed a significant inverse association per 80 g of vegetables consumed per day, but this was a nonlinear dose response for intakes of up to 300–400 g/day.¹¹ Regarding particular types of vegetables, green leafy vegetables reduced the risk by 15% (95% CI = 0.75–0.96; n = 9 studies and 5783 cases), slightly more than the 13% reduction seen for cruciferous vegetables (95% CI = 0.79–0.97; n = 11 studies and 11,467 cases).¹²

Carotenoids

A substantial amount of evidence shows that food containing carotenoids (e.g., sweet potatoes, carrots, tomatoes, pumpkins, spinach, cantaloupe, and apricots) has a protective effect against lung cancer.¹¹ Fruits and vegetables high in β-carotene provide a 23.2% reduced risk of lung cancer (95% CI = 0.675–0.874; n = 18 studies and 9372 cases) when comparing the highest with the lowest dietary intake, according to a 2015 meta-analysis.¹³ A clear dose–response relationship is evident from cohort studies. The more one consumes dietary carotenoids, the more the risk of developing lung cancer is reduced. Data extracted from several studies with a total of 400,000 participants, including 3100 lung cancer patients, with a follow-up period of 7–16 years, suggest that those who consumed the most carotenoids had a 24% decreased risk of developing lung cancer.¹¹

Supplements of β-carotene, however, are not recommended. Findings from the new edition of WCRF/AICR document reveal that high-dose beta carotene supplements are a convincing cause of lung cancer in current and former smokers.¹¹ The protective effect of dietary intake of carotenoids may be lost or reversed by the higher doses that pharmacologic supplementation provides.¹¹

Flavonoids

Flavonoids, which are phytochemicals in food products derived from plants, often contribute to the color of the foods. Foods such as berries, dill, buckwheat, red onions, kale, cranberries, sweet potatoes, apples, and others contain flavonoids. Flavonoid intake has been shown to be associated with a decreased risk of lung cancer, particularly for current smokers. A 2013 meta-analysis of dietary flavonoid intake showed a marginally significant reduction in lung cancer risk of 16% (95% CI = 0.71–1.00; n = 8 studies),¹⁴ which differs from a prior meta-analysis that showed a statistically significant 24% risk reduction with a dose–response association.¹⁵ For flavonoid subclasses, lung cancer risk appears to be most significantly reduced by the flavonols quercetin (34% risk reduction; 95% CI = 0.47–0.92; n = 5 studies) and kaempferol (22% risk reduction; 95% CI = 0.64–0.95; n = 5 studies).¹⁵

Red meat and processed meat

In the 2018 WCRF report, there was limited but consistent evidence that consumption of red meat and processed meat increases risk of lung cancer. The dose–response meta-analysis showed a significantly increased risk of lung cancer per 100 g of red meat and 50 g of processed meat.¹¹

Other studies suggest that among current and former smokers (the COSMOS screening study), there is a significant 73% increased risk (CI = 1.15–2.61; p = 0.002; n = 178 cases) of lung cancer for those with the highest meat consumption.¹⁶

Mediterranean diet

In terms of overall dietary patterns, the Mediterranean diet is well established for the prevention of cardiovascular disease¹⁷ and likewise appears promising for lung cancer prevention. The COSMOS screening study of 4336 heavy smokers revealed an 80% lower risk of lung cancer diagnosis among participants with a strong adherence to the Mediterranean diet.¹⁸ That study also suggested that a high dietary inflammatory index increases the risk. An earlier case–control study of individual components of the Mediterranean diet showed protective effects with high consumption of carrots, tomatoes, and white meat and statistically significant protection with high consumption of sage and the exclusive use of olive oil.¹⁹

Additional beneficial foods are listed in Table 1.

Nutritional Supplements

Nutritional supplements include herbal remedies, minerals, vitamins, and certain other substances. Supplements are one of the easiest type of CIM therapies for cancer patients to use, and 20%–90% of patients affected by cancer use supplements.²⁰ Patients tend to use nutritional supplements as a type of psychologic support; they want to feel hopeful or have a sense of control in the decision-making process, so that they feel they are doing everything possible.^20,21 Patients also use supplements to help reduce side effects of conventional treatments and enhance their quality of life. Typically patients are not seeking a cure for their disease with supplements.²¹

Although foods high in vitamins and minerals appear to reduce the risk of lung cancer, studies of micronutrient supplements thus far have not shown convincing evidence for the prevention of lung cancer. A 2012 Cochrane review of randomized controlled trials of vitamin A, vitamin C, vitamin E, and selenium supplementation found no significant risk reduction for the general population and a small but significant increased risk with β-carotene supplementation in smokers and individuals exposed to asbestos.²² However, a few other studies suggest that adding nutritional supplements could reduce the risk of lung cancer or improve the benefit of conventional care during and after treatment.^23

–29

A meta-analysis from 2014 showed a 17% lung cancer risk reduction (95% CI = 0.734–0.937; n = 21 studies and 8938 cases) when comparing highest and lowest intake of vitamin C, with a linear 7% dose–response reduction with every 100-mg increase per day, but the analysis did not distinguish between dietary and supplemental intake.²³ In addition, a 2017 meta-analysis of vitamin E intake showed a 16% lung cancer risk reduction (95% CI = 0.76–0.93; n = 11 studies and 4164 cases), with a dose–response decrease in risk of 5% for every 2-mg increase per day in dietary vitamin E intake.²⁴

Preliminary studies suggest that the use of antioxidant vitamins and minerals following a diagnosis of cancer reduces chemotoxicity and radiotoxicity during treatment; positive findings were observed in 34 of 46 trials in a 2016 systematic review.²⁵ However, there remains a concern that antioxidant supplementation could reduce the therapeutic effects of free radical-generating radiotherapy or chemotherapeutic agents such as the platinum compounds (e.g., cisplatin), and current evidence regarding treatment outcomes is not definitive.²⁵

For lung cancer specifically, two preliminary Mayo Clinic cohort studies showed improved survival in patients with small-cell lung cancer (SCLC; RR = 0.65; 95% CI = 0.43–1.00; p = 0.05; n = 178) and non-SCLC (NSCLC; RR = 0.74; 95% CI = 0.44–0.65; p < 0.01; n = 1129) who used vitamin or mineral supplements, along with improved quality of life in the NSCLC cohort.^26,27 An early study of 18 patients with SCLC showed improved survival with supplementation of vitamins, trace elements, and fatty acids,²⁸ and a randomized controlled trial of 136 patients with advanced NSCLC showed improved survival with supplementation, although this was not statistically significant.²⁹ More research is needed to determine whether antioxidant supplementation is appropriate during curative regimens, although use in palliative settings is likely worth consideration.

Nutritional supplements that have a possible benefit are listed in Table 1. Leading nutritional supplements such as vitamin D, fish oil, Astragalus, and melatonin are discussed in more detail.

Vitamin D

Three meta-analyses published in 2017 examined the relationship between vitamin D and lung cancer. Regarding the prevention of lung cancer, high serum 25-hydroxyvitamin D levels were associated with a 16% risk reduction (95% CI = 0.74–0.95; n = 17 studies and 4368 cases), and each 10 nmol/L increase in 25(OH)D levels conferred an 8% reduction in lung cancer risk and a 7% reduction in lung cancer mortality.³⁰ One meta-analysis showed a nonsignificant correlation between overall survival in patients with lung cancer and low circulating 25(OH)D levels (adjusted hazard ratio = 1.25; p = 0.13; n = 8 studies),³¹ and another showed no relationship at all (RR = 1.01; 95% CI = 0.88–1.16; p < 0.001; n = 5 studies).³⁰ Finally, high vitamin D intake was associated with a 28% reduced risk of lung cancer (95% CI = 0.61–0.85; p < 0.001), particularly in nonsmokers.³²

One group of researchers took another approach to the question of vitamin D supplementation: they found that the stage of disease was an important factor. In their studies, in the early stages of the disease, surgery combined with dietary vitamin D intake was associated with significantly improved survival rates in patients with NSCLC.³³ In addition, levels of circulating vitamin D in the early stages of disease were directly correlated with survival in these patients.³⁴ In patients with advanced-stage NSCLC, the situation was more complex. The C/C genotype of the FokI polymorphism, which is thought to have increased vitamin D receptor activity, was associated with improved survival. However, the G-T-C (Cdx-2-FokI-BsmI) polymorphism, which is thought to have reduced vitamin D receptor activity, was associated with poor survival. This suggests that in patients with certain types of advanced disease, supplementation with vitamin D might increase mortality and those patients should avoid the use of vitamin D. Thus, caution is needed. Researchers concluded that further studies are needed to confirm vitamin D's role in improving outcomes in patients with advanced lung cancer.³⁵

Fish oil

Multiple in vitro studies have shown that omega-3 polyunsaturated fatty acids (fish oil) have activity against lung cancer cell lines.^36
–38 There is also some evidence that adding fish oil in clinical care carries some benefit. Lung cancer patients who used fish oil supplements during chemotherapy showed significantly higher rates of response and objectively longer overall survival. These benefits were not accompanied by any increase in dose-limiting toxicities.³⁹

In a double-blind experiment with 40 patients with stage III NSCLC, patients were randomized to receive an oral nutritional supplement containing n-3 polyunsaturated fatty acids (2.02 g eicosapentaenoic acid +0.92 g docosahexaenoic acid per day) or an isocaloric control supplement during multimodality treatment. Patients in the intervention group reported a significantly higher quality of life, physical and cognitive function, global health status, and social function than those in the control group.⁴⁰ In a small multicenter, randomized, double-blind trial with 33 patients diagnosed with advanced inoperable NSCLC and undergoing chemotherapy, eicosapentaenoic acid + docosahexaenoic acid supplementation was associated with a significant increase in weight, as well as anti-inflammatory and antioxidative effects.⁴¹

Melatonin

Melatonin is a hormone produced within the pineal gland from tryptophan, which is converted to 5-hydroxytryptophan and finally to melatonin. Numerous recent in vitro studies have shown promise for the use of melatonin in the treatment of lung cancer.^42
–44 Earlier human studies by Lissoni et al. showed significantly increased survival and quality of life among lung cancer patients who used melatonin supplementation.⁴⁵ However, a 2014 randomized controlled trial of 151 patients with NSCLC that showed improved quality of life with treatment with melatonin (either 10 or 20 mg) revealed no significant difference in median survival.⁴⁶

Astragalus

Astragalus is a unique herbal remedy that has been used in Traditional Chinese Medicine for thousands of years. Astragalus is an adaptogenic herb that is thought to play a role in protecting the body against various stressors, including physical, mental, or emotional stress. The Astragalus root has antioxidant effects and also affects the immune system. It contains a variety of components, including saponins such as astragaloside, polysaccharides, multiple trace minerals, flavonoids, and amino acids.⁴⁷

A 2016 meta-analysis of Astragalus use in patients with advanced NSCLC showed improved overall survival (hazard ratio = 0.61; 95% CI = 0.42–0.89; p = 0.011; n = 17 studies and 1552 patients), improved performance status (RR = 0.43; 95% CI = 0.34–0.55; p < 0.001), and tumor overall response rate (RR = 0.7982; 95% CI = 0.715–0.89; p < 0.001), and fewer side effects compared with platinum-based chemotherapy alone.⁴⁸

Trametes versicolor (Coriolus versicolor)

Trametes (Coriolus) versicolor is a mushroom, also known as turkey tail, that contains several polysaccharides, including polysaccharide peptide and polysaccharide krestin, both shown to have antitumor and immunomodulating effects.⁴⁹ A 2015 systematic review of polysaccharide K from T. (C.) versicolor showed supportive evidence for activity against lung cancer in 15 of 17 preclinical studies, improved survival in 5 nonrandomized clinical trials, and objectively improved quality of life and survival in 6 randomized controlled trials.⁵⁰

Physical Activity

Physical activity is known to improve quality of life during and after cancer therapy. These effects include alleviating physical and mental fatigue, reducing anxiety, increasing cognitive function, improving self-esteem, increasing muscle tone and balance, helping manage weight, enhancing the immune system, and even reducing the chances for other illnesses such as heart disease, adult-onset diabetes, and osteoporosis.^11,51 In a systematic review of 45 U.S. National Cancer Institute-designated comprehensive cancer center websites, researchers found that the most common CIM therapy, that is being discussed, is exercise (97.8%).⁵²

Evidence from prospective and case–control studies has shown that the risk of lung cancer is reduced with increasing levels of physical activity. The 2007 WCRF/AICR report mentioned 5 cohort studies investigating the relationship between total physical activity and lung cancer, 2 cohort studies investigating nonrecreational activity, and 11 cohort studies and 4 case–control studies investigating recreational activity as it relates to lung cancer risk. Overall, most studies showed a decreased risk with increased physical activity.¹¹ Extrapolating from other studies investigating different types of cancer, clinicians often suggest 150 min of walking per week at a speed of 2–2.9 miles/h (3.2–4.6 km/h).⁵³

Exercise training can be beneficial at all stages of treatment for lung cancer. Before surgery, after surgery, during treatment, and even during palliative anticancer therapy in patients with advanced (inoperable) lung cancer who have compromised lung function, supervised exercise-based pulmonary rehabilitation is thought to improve cardiorespiratory fitness and functional capacity.⁵⁴ A recent randomized controlled study examined the effects of a 12-week exercise intervention on sleep and quality of life in 111 patients with lung cancer. In that study, the intervention included home-based walking exercise and weekly exercise counseling. Researchers found that sleep in the exercise group was significantly improved at 3 and 6 months after the intervention. The researchers concluded that walking is an effective intervention for improving subjective and objective sleep quality in patients with lung cancer and can be considered an additional element of lung cancer rehabilitation.⁵⁵

Mind–Body Therapies

Mind–body therapies, including stress reduction, meditation, yoga, massage, and music therapy, are commonly used in most comprehensive cancer centers in the United States. This increased use reflects the current understanding that these therapies have an essential role in approaching cancer patients in general.⁵² Stress, when experienced chronically, leads to the activation of neuroendocrine pathways, including the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis. Biologic mechanisms identified as having potential direct carcinogenic effects on the sympathetic nervous system include DNA repair, oncogene activation, inflammation and immune response, hematopoiesis, angiogenesis, survival, and apoptosis.⁵⁶

In a recent study, researchers found that prolonged employment in a stressful job was associated with increased odds of developing cancers of the lung.⁵⁷ In addition to stress being a possible etiologic factor in lung cancer development, the diagnosis of lung cancer by itself is a cause for emotional reactions such as anxiety, stress, depression, and fear.⁵⁸ Untreated mood disorders can negatively affect a patient's quality of life, level of pain, and response to chemotherapy. Reducing negative emotions, such as depression, may increase survival.^59,60

Animal studies also support this observation; psychologic distress was shown to be associated with faster tumor growth and spread in mice.^61,62 Because most patients are diagnosed with lung cancer in the advanced stage, when the prognosis is poor, the stress and anxiety that these patients experience are quite high. Most CIM practitioners agree that integrating mind–body therapies in cancer care is an essential element in caring for patients with cancer, especially in patients with a poor prognosis.⁶³

Some argue that current research includes a limited number of controlled studies in oncology populations, and thus, no clear conclusions can be drawn. However, the few published trials appear to show that mind–body therapies have promising effects on the immune system, health-related quality of life, functional capacity, and mood. As a result, most cancer centers do combine mind–body therapies into their CIM care plan. In a study of 265 patients, including those with lung cancer, conducted at The University of Texas MD Anderson Cancer Center, patients' distress was shown to be relieved by using a patient-centered communication style and integrating mind–body therapies into the patients' care.⁶⁴

A recent review of the literature suggested that mind–body modalities as part of a multidisciplinary approach can help reduce anxiety, mood disturbance, pain, nausea, vomiting, sleep disturbance, and general well-being in patients with lung cancer.⁵⁴ Most of the research on mind–body therapies such as meditation, mindfulness-based stress reduction, yoga, massage, t'ai chi, qigong, and others suggests that these therapies are safe and beneficial for patients with lung cancer if performed by skilled practitioners.⁵⁴ The authors of the American College of Chest Physicians guidelines expanded on this idea and suggested that for lung cancer patients whose anxiety or pain is not adequately controlled by usual care, the addition of massage therapy performed by trained professionals can be helpful in reducing anxiety and improving well-being, as part of a multimodality cancer supportive care program.⁵⁴

Enhancing Immunotherapy

Immunotherapy is the use of medicines to stimulate a patient's own immune system to recognize and destroy cancer cells. Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials of PD-1/PD-L1 axis blockade in solid tumors. This type of approach is becoming one of the leading new advances in treating some forms of NSCLC.⁶⁵ However, despite improvements in tumor response leading to the initial excitement about immunotherapy, these therapies also induce a range of responses that are hard to predict, accompanied with multiple toxic effects in the skin, gastrointestinal tract, lungs, and endocrine system.⁶⁶

Information about the benefits of incorporating CIM to reduce these toxic effects and improve therapeutic coverage is limited because this field is still in its infancy. One recent study examined the safety of adding treatment with Viscum album (European Mistletoe), a botanical commonly used in Europe to improve quality of life during cancer treatment, to immune checkpoint inhibitors. This herbal therapy neither altered nor increased the toxic effects of the immune checkpoint inhibitors.⁶⁷

Another CIM treatment of interest in immunotherapy is probiotics. According to mouse studies and some early human studies, the gut microbiome helps to enhance the efficacy of immunotherapy. Two recent studies revealed that gut microbiota may enhance the antitumor immune responses to checkpoint inhibitors, resulting in tumor regressions.⁶⁸ In patients who were treated with antibiotics or were germ free, immune checkpoint inhibitors lost their therapeutic efficacy.⁶⁹

Researchers have found that certain gut bacteria increase the therapeutic benefit of CTLA-4 blockade (Bacteroides) in melanoma,⁶⁹ whereas others enhance the effect PD-1 blockade (Clostridiales)⁷⁰ and PD-L1 blockade (Bifidobacterium).⁶⁸ These individual differences in microbiome composition may be one of the reasons that immunotherapies work better in some patients than others. Understanding this principle can lead to innovative approaches that may improve the efficacy of immunotherapy.

Current evidence already suggests that optimizing the gut microbiome might improve the therapeutic coverage of immune checkpoint inhibitors.⁷¹ These studies suggest that manipulating the microbiome by adding a specific probiotic might lead to improvement in immunotherapy but requires further research, specifically in the context of lung cancer. Additional research is needed to provide an educated answer to this question.

Complementary Therapies

In a recent guideline document from the American College of Chest Physicians on the use of CIM in lung cancer patients, the reviewed evidence revealed that CIM therapies can be beneficial to patients during and after treatments.⁵⁴

Acupuncture

In acupuncture, a technique derived from Traditional Chinese Medicine, trained practitioners stimulate specific points on the body by inserting thin needles into the skin. Acupuncture has been in use in various forms for more than 3000 years. In the past decade, acupuncture has become one of the most common CIM therapies used by patients affected by cancer. This technique is considered safe for use in the general population when practiced by an experienced practitioner.^52,72
–74

In response to the severity and persistence of symptoms related to cancer care, patients usually try acupuncture in conjunction with standard treatments. This use is generally considered safe when conventional treatment fails or has intolerable side effects.^72
–74 In a set of American College of Chest Physicians guidelines, which are backed by clinical evidence, acupuncture was suggested as an adjunct treatment option for patients experiencing nausea and vomiting caused by chemotherapy or radiotherapy, as well as for patients with cancer-related pain and peripheral neuropathy that are poorly controlled.⁵⁴

A more recent article, summarizing the current state of knowledge related to acupuncture use in cancer care, concluded that research has yielded promising evidence for the role of acupuncture in the management of several challenging symptoms for which existing standard options remain limited. These symptoms include pain, fatigue, hot flashes, nausea/vomiting, and xerostomia.⁷⁴ To evaluate the effectiveness of acupuncture as a potential treatment modality in symptomatic lung cancer patients, a cancer center in Canada conducted a prospective observational study. Researchers combined acupuncture with the conventional best care for that center and observed statistically significant improvement in pain, appetite, nausea, anxiety, and well-being. These effects were obtained with a minimum of six acupuncture sessions. The researchers concluded that acupuncture may be an effective approach for improving symptoms, especially pain and well-being, in lung cancer patients.⁷⁵

Since then, additional studies have emerged suggesting that acupuncture might have a beneficial effect in other situations in cancer care. In a small randomized, double-blind, placebo-controlled pilot trial that aimed to evaluate the clinical effect of acupuncture on cancer-related fatigue in lung cancer patients, researchers found that Brief Fatigue Inventory scores were significantly reduced in participants who received active acupuncture compared with those receiving the placebo.⁷⁶

In another study that investigated acupuncture for the relief of breathlessness in lung cancer, researchers performed a single-center, randomized phase II study of 173 patients with NSCLC or mesothelioma with a dyspnea score of >4 on the visual analog scale. In that study, patients were randomized to receive acupuncture alone, morphine alone, or both. Acupuncture was found to be effective in relieving dyspnea, and the changes in visual analog scale scores were not significantly different between treatment arms. In addition, acupuncture, alone and combined with morphine, reduced anxiety, with a significant improvement in visual analog scale relaxation scores. Morphine alone increased anxiety. The effects of acupuncture were evident at 90 min and maximal at 4 h, but the effects were sustained for up to 2 weeks.⁷⁷

Homeopathy

Homeopathy is a health system of care that is commonly practiced in Europe, Asia, and South America, mostly for minor ailments. Homeopathic remedies have appeared to be safe and free of adverse effects in multiple clinical trials.^73,78

–81 However, it is unclear if homeopathy has any clinical effect in cancer patients, and until recently, homeopathy has not received attention as a possible option for care.

In a survey of 123 cancer centers across Europe, 47.5% of the centers provided CIM treatments. The leading CIM treatments in those centers were acupuncture (55.3%) and homeopathy (40.4%).⁷³ In another cross-sectional survey across eight European countries that specifically targeted lung cancer patients who use CIM, researchers found that homeopathy was also one of the leading CIM treatments.⁵

Data from multiple research disciplines, ranging from studies evaluating the effect of homeopathic remedies on cancer cell lines to scientifically valid animal and clinical studies, suggest that homeopathy may have a role in improving quality of life in selected cancer patients.⁷⁸ In a recent study of an integrative oncology service in a large comprehensive cancer center in Israel, homeopathy was found to be successfully incorporated as a supportive care modality. Review of 124 files of cancer patients who received homeopathy for symptom relief revealed that nearly three-quarters of these patients reported a beneficial effect when they used homeopathic treatment for symptom relief.⁷⁹

In another pragmatic randomized controlled trial in a comprehensive cancer center in Austria, with 410 cancer patients who were randomized to receive or not receive classic homeopathic adjunctive therapy in addition to standard therapy, researchers found that the subjective well-being of these patients improved significantly when they received adjunct classic homeopathic treatment in addition to conventional therapy.⁸⁰

Some might argue that the intensive homeopathic interview conducted at baseline may have influenced the findings.

Most researchers seem to agree that given its low toxicity, homeopathy is a possible option for symptom management and supportive care. Whether these remedies have direct effects on the tumor or survival is a more complex issue. In Austria, researchers from the Medical University of Vienna collected survival data on 538 patients with fatal disease and poor prognosis who used homeopathy in addition to conventional cancer care. The study included patients with glioblastoma, lung cancer (both SCLC and NSCLC), metastatic renal cell carcinoma, and others.⁸² Median overall survival was compared with experts' predictions of survival outcomes by specific cancer type. The researchers found that patients who received homeopathy survived longer than the expected prognosis, across all observed cancer types. Patients with SCLC and metastatic renal cell carcinoma had the best results. The expected median overall survival was 11.3 months for SCLC and 26.4 months for metastatic renal cell carcinoma, but the observed median overall survival was 47 months for patients with SCLC who received homeopathy and 61.4 months for patients with metastatic renal cell carcinoma who received homeopathy. Although these results were promising, the authors stressed the need for further study of homeopathic care in cancer patients.⁸² These European studies suggest that there is an urgent need for homeopathic clinical trials in lung cancer.

Summary

Most patients with lung cancer are diagnosed late in their disease process and thus have a poor prognosis and increased distress. As a result, a large percentage of these patients tend to use CIM. Patients use CIM therapies to reduce symptoms, lower the toxicity of conventional therapies, improve their ability to heal, and increase their sense of autonomy and control. Communicating openly with these patients and their families about the use of CIM is important for improving patients' quality of life and empowering them during the disease trajectory. A growing number of studies support the use of CIM interventions such as nutrition and dietary supplements, exercise, acupuncture, homeopathy, and mind–body approaches. These interventions reduce the severity of symptoms that relate to the disease and its treatment, increase well-being, improve quality of life, and may even improve the survival of these patients.

Footnotes

Acknowledgment

The authors acknowledge Ms. Erica A Goodof, from MD Anderson Department of Scientific Publications, for her editorial review of the articles and helpful comments that increased the quality of this article.

Author Disclosure Statement

No competing financial interests exist.

References

Ferlay

, Soerjomataram

, Ervik

, et al. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer, 2014. Online document at: www.globocan.iarc.fr, accessed January 1, 2018 .

World Cancer Research Fund International. Cancer Facts and Figures: Worldwide Data. Online document at: www.wcrf.org/int/cancer-facts-figures/worldwide-data, accessed January 1, 2018 .

SEER Cancer Stat Facts: Lung and Bronchus Cancer. Bethesda, MD: National Cancer Institute. Online document at: www.seer.cancer.gov/statfacts/html/lungb.html, accessed January 1, 2018 .

Yates

, Mustian

, Morrow

, et al. Prevalence of complementary and alternative medicine use in cancer patients during treatment. Support Care Cancer, 2005; 13:806–811.

Molassiotis

, Panteli

, Patiraki

, et al. Complementary and alternative medicine use in lung cancer patients in eight European countries. Complement Ther Clin Pract, 2006; 12:34–39.

Wells

, Sarna

, Cooley

, et al. Use of complementary and alternative medicine therapies to control symptoms in women living with lung cancer. Cancer Nurs, 2007; 30:45–55.

Micke

, Buntzel

, Kisters

, et al. Complementary and alternative medicine in lung cancer patients: A neglected phenomenon?. Front Radiat Ther Oncol, 2010; 42:198–205.

Bauml

, Langer

, Evans

, et al. Does perceived control predict complementary and alternative medicine (CAM) use among patients with lung cancer? A cross-sectional survey. Support Care Cancer, 2014; 22:2465–2472.

Sierpina

, Levine

, McKee

, et al. Nutrition, metabolism, and integrative approaches in cancer. Semin Oncol Nurs, 2015; 31:42–52.

10.

Mao

, Cohen

. Advancing the science of integrative oncology to inform patient-centered care for cancer survivors. J Natl Cancer Inst Monogr, 2014; 2014:283–284.

11.

World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Expert Report 2018. Diet, Nutrition, Physical Activity and Lung cancer. Online document at: dietandcancerreport.org, accessed June 1, 2018 .

12.

Vieira

, Abar

, Vingeliene

, et al. Fruits, vegetables and lung cancer risk: A systematic review and meta-analysis. Ann Oncol, 2015; 27:81–96.

13.

, Su

, Wang

, et al. Association of dietary vitamin A and β-carotene intake with the risk of lung cancer: A meta-analysis of 19 publications. Nutrients, 2015; 7:9309–9324.

14.

Woo

, Kim

. Dietary flavonoid intake and smoking-related cancer risk: A meta-analysis. PLoS One, 2013; 8:e75604.

15.

Tang

, Zhou

, Wang

, et al. Flavonoids intake and risk of lung cancer: A meta-analysis. Jpn J Clin Oncol, 2009; 39:352–359.

16.

Gnagnarella

, Maisonneuve

, Bellomi

, et al. Red meat, Mediterranean diet and lung cancer risk among heavy smokers in the COSMOS screening study. Ann Oncol, 2013; 24:2606–2611.

17.

Martínez-González

. Benefits of the Mediterranean diet beyond the Mediterranean Sea and beyond food patterns. BMC Med, 2016; 14:157.

18.

Maisonneuve

, Shivappa

, Hébert

, et al. Dietary inflammatory index and risk of lung cancer and other respiratory conditions among heavy smokers in the COSMOS screening study. Eur J Nutr, 2016; 55:1069–1079.

19.

Fortes

, Forastiere

, Farchi

, et al. The protective effect of the Mediterranean diet on lung cancer. Nutr Cancer, 2003; 46:30–37.

20.

Frenkel

, Abrams

, Ladas

, et al. Integrating dietary supplements into cancer care. Integr Cancer Ther, 2013; 12:369–384.

21.

Frenkel

. Is there a role for nutritional supplements in cancer care?. Future Oncol, 2015; 11:901–904.

22.

Cortés-JofrÉ

, Rueda

, Corsini-Muñoz

, et al. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev, 2012; 10:CD002141.

23.

Luo

, Shen

, Zheng

. Association between vitamin C intake and lung cancer: A dose-response meta-analysis. Sci Rep, 2014; 4:6161.

24.

Zhu

, Bo

, Liu

, Qiu

. Association of dietary vitamin E intake with risk of lung cancer: A dose-response meta-analysis. Asia Pac J Clin Nutr, 2017; 26:271–277.

25.

Yasueda

, Urushima

, Ito

. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: A systematic review. Integr Cancer Ther, 2016; 15:17–39.

26.

Jatoi

, Williams

, Marks

, et al. Exploring vitamin and mineral supplementation and purported clinical effects in patients with small cell lung cancer: Results from the Mayo Clinic lung cancer cohort. Nutr Cancer, 2005; 51:7–12.

27.

Jatoi

, Williams

, Nichols

, et al. Is voluntary vitamin and mineral supplementation associated with better outcome in non-small cell lung cancer patients? Results from the Mayo Clinic lung cancer cohort. Lung Cancer, 2005; 49:77–84.

28.

Jaakkola

, Lähteenmäki

, Laakso

, et al. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res, 1992; 12:599–606.

29.

Pathak

, Bhutani

, Guleria

, et al. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer. J Am Coll Nutr, 2005; 24:16–21.

30.

Feng

, Zhang

, Dong

, et al. Circulating 25-hydroxyvitamin D and lung cancer risk and survival: A dose-response meta-analysis of prospective cohort studies. Medicine (Baltimore), 2017; 96:e8613.

31.

Huang

, Dong

, Shao

, et al. Circulating 25-hydroxyvitamin D level and prognosis of lung cancer patients: A systematic review and meta-analysis. Bull Cancer, 2017; 104:675–682.

32.

Liu

, Dong

, Lu

, et al. Meta-analysis of the correlation between vitamin D and lung cancer risk and outcomes. Oncotarget, 2017; 8:81040–81051.

33.

Zhou

, Suk

, Liu

, et al. Vitamin D is associated with improved survival in early stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev, 2005; 14:2303–2309.

34.

Zhou

, Heist

, Liu

, et al. Circulating 25-hydroxyvitamin D levels predict survival in early stage non-small cell lung cancer patients. J Clin Oncol, 2007; 25:479–485.

35.

Heist

, Zhou

, Wang

, et al. Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. J Clin Oncol, 2008; 26:5596–5602.

36.

Yang

, Cartwright

, Chan

, et al. Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation. Mol Carcinog, 2014; 53:566–577.

37.

D'eliseo

, Velotti

. Omega-3 fatty acids and cancer cell cytotoxicity: Implications for multi-targeted cancer therapy. J Clin Med, 2016; 5 pii: E15.

38.

Yin

, Sui

, Meng

, et al. The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K/Akt pathway. Lipids Health Dis, 2017; 16:87.

39.

Murphy

, Mourtzakis

, Chu

, et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer, 2011; 117:1775–1782.

40.

van der Meij

, Langius

, Smit

, et al. Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J Nutr, 2010; 140:1774–1780.

41.

Finocchiaro

, Segre

, Fadda

, et al. Effect of n-3 fatty acids on patients with advanced lung cancer: A double-blind, placebo-controlled study. Br J Nutr, 2012; 108:327–333.

42.

Yun

, Kim

, Lee

, et al. Melatonin sensitizes H1975 non-small-cell lung cancer cells harboring a T790 M-targeted epidermal growth factor receptor mutation to the tyrosine kinase inhibitor gefitinib. Cell Physiol Biochem, 2014; 34:865–872.

43.

Zhou

, Gui

, Zhou

, Wang

. Melatonin inhibits the migration of human lung adenocarcinoma A549 cell lines involving JNK/MAPK pathway. PLoS One, 2014; 9:e101132.

44.

Plaimee

, Weerapreeyakul

, Barusrux

, Johns

. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif, 2015; 48:67–77.

45.

Lissoni

, Chilelli

, Villa

, et al. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: A randomized trial. J Pineal Res, 2003; 35:12–15.

46.

Sookprasert

, Johns

, Phunmanee

, et al. Melatonin in patients with cancer receiving chemotherapy: A randomized, double-blind, placebo-controlled trial. Anticancer Res, 2014; 34:7327–7337.

47.

Upton

, ed. Astragalus Root: Analytical, Quality Control, and Therapeutic Monograph. Santa Cruz, CA: American Herbal Pharmacopoeia, 1999:1–25.

48.

Wang

, Wang

, Jiao

, et al. Astragalus-containing traditional Chinese medicine, with and without prescription based on syndrome differentiation, combined with chemotherapy for advanced non-small-cell lung cancer: A systemic review and meta-analysis. Curr Oncol, 2016; 23:e188–e195.

49.

Hayakawa

, Mitsuhashi

, Saito

, et al. Effect of Krestin as adjuvant treatment following radical radiotherapy in non-small cell lung cancer patients. Cancer Detect Prev, 1997; 21:71–77.

50.

Fritz

, Kennedy

, Ishii

, et al. Polysaccharide K and Coriolus versicolor extracts for lung cancer: A systematic review. Integr Cancer Ther, 2015; 14:201–211.

51.

Brown

, Ligibel

. The role of physical activity in oncology care. J Natl Cancer Inst Monogr, 2017; 2017:lgx017.

52.

Yun

, Sun

, Mao

. Growth of integrative medicine at leading cancer centers between 2009 and 2016: A systematic analysis of NCI-designated comprehensive cancer center websites. J Natl Cancer Inst Monogr, 2017; 2017:lgx004.

53.

Holmes

, Chen

, Feskanich

, et al. Physical activity and survival after breast cancer diagnosis. JAMA, 2005; 293:2479–2486.

54.

Deng

, Rausch

, Jones

, et al. Complementary therapies and integrative medicine in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 2013; 143(5 Suppl):e420S–e436S.

55.

Chen

, Tsai

, Wu

, et al. Effect of walking on circadian rhythms and sleep quality of patients with lung cancer: A randomised controlled trial. Br J Cancer, 2016; 115:1304–1312.

56.

Cole

, Nagaraja

, Lutgendorf

, et al. Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer, 2015; 15:563–572.

57.

Blanc-Lapierre

, Rousseau

, Weiss

, et al. Lifetime report of perceived stress at work and cancer among men: A case-control study in Montreal, Canada. Prev Med, 2017; 96:28–35.

58.

Holland

. Psycho-Oncology, Second Edition. New York: Oxford University Press, 2010.

59.

Giese-Davis

, Collie

, Rancourt

, et al. Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: A secondary analysis. J Clin Oncol, 2011; 29:413–420.

60.

Spiegel

. Mind matters in cancer survival. JAMA, 2011; 305:502–503.

61.

Thaker

, Han

, Kamat

, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med, 2006; 12:939–944.

62.

Sloan

, Priceman

, Cox

, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res, 2010; 70:7042–7052.

63.

Ben-Arye

, Schiff

, Zollman

, et al. Integrating complementary medicine in supportive cancer care models across four continents. Med Oncol, 2013; 30:511.

64.

Frenkel

, Cohen

, Peterson

, et al. Integrative medicine consultation service in a comprehensive cancer center: Findings and outcomes. Integr Cancer Ther, 2010; 9:276–283.

65.

Balar

, Weber

. PD-1 and PD-L1 antibodies in cancer: Current status and future directions. Cancer Immunol Immunother, 2017; 66:551–564.

66.

Rapoport

, van Eeden

, Sibaud

, et al. Supportive care for patients undergoing immunotherapy. Support Care Cancer, 2017; 25:3017–3030.

67.

Thronicke

, Steele

, Grah

, et al. Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer. BMC Complement Altern Med, 2017; 17:534.

68.

Sivan

, Corrales

, Hubert

, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 2015; 350:1084–1089.

69.

Vetizou

, Pitt

, Daillere

, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 2015; 350:1079–1084.

70.

Gopalakrishnan

, Spencer

, Nezi

, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2018; 359:97–103.

71.

Pitt

, Vetizou

, Waldschmitt

, et al. Fine-tuning cancer immunotherapy: optimizing the gut microbiome. Cancer Res, 2016; 76:4602–4607.

72.

Sierpina

, Frenkel

. Acupuncture: A clinical review. Southern Med J, 2005; 98:330–337.

73.

Rossi

, Vita

, Baccetti

, et al. Complementary and alternative medicine for cancer patients: Results of the EPAAC survey on integrative oncology centres in Europe. Support Care Cancer, 2015; 23:1795–1806.

74.

Zia

, Olaku

, Bao

, et al. The National Cancer Institute's Conference on Acupuncture for Symptom Management in Oncology: State of the Science, Evidence, and Research Gaps. J Natl Cancer Inst Monogr, 2017; 2017:lgx005.

75.

Kasymjanova

, Grossman

, Tran

, et al. The potential role for acupuncture in treating symptoms in patients with lung cancer: An observational longitudinal study. Curr Oncol, 2013; 20:152–157.

76.

Cheng

, Chen

, Ning

, et al. Acupuncture for cancer-related fatigue in lung cancer patients: A randomized, double blind, placebo-controlled pilot trial. Support Care Cancer, 2017; 25:3807–3814.

77.

Minchom

, Punwani

, Filshie

, et al. A randomised study comparing the effectiveness of acupuncture or morphine versus the combination for the relief of dyspnoea in patients with advanced non-small cell lung cancer and mesothelioma. Eur J Cancer, 2016; 61:102–110.

78.

Frenkel

. Is there a role for homeopathy in cancer care? Questions and challenges. Curr Oncol Rep, 2015; 17:467.

79.

Samuels

, Freed

, Weitzen

, et al. Feasibility of homeopathic treatment for symptom reduction in an integrative oncology service. Integr Cancer Ther, 2017; 17:486–492.

80.

Frass

, Friehs

, Thallinger

, et al. Influence of adjunctive classical homeopathy on global health status and subjective wellbeing in cancer patients—A pragmatic randomized controlled trial. Complement Ther Med, 2015; 23:309–317.

81.

Banerji

, Campbell

, Banerji

. Cancer patients treated with the Banerji protocols utilizing homoeopathic medicine: A Best Case Series Program of the National Cancer Institute USA. Oncology Rep, 2008; 20:69–74.

82.

Gaertner

, Müllner

, Friehs

, et al. Additive homeopathy in cancer patients: Retrospective survival data from a homeopathic outpatient unit at the Medical University of Vienna. Complement Ther Med, 2014; 22:320–332.

83.

Arts

. A review of the epidemiological evidence on tea, flavonoids, and lung cancer. J Nutr, 2008; 138:1561S–1566S.

84.

Howells

, Mahale

, Sale

, et al. Translating curcumin to the clinic for lung cancer prevention: Evaluation of the preclinical evidence for its utility in primary, secondary, and tertiary prevention strategies. J Pharmacol Exp Ther, 2014; 350:483–494.

85.

Attoub

, Sperandio

, Raza

, et al. Thymoquinone as an anticancer agent: Evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol, 2013; 27:557–569.

86.

, Liu

. Soy food consumption and lung cancer risk: A meta-analysis using a common measure across studies. Nutr Cancer, 2013; 65:625–632.

87.

Myneni

, Chang

, Niu

, et al. Raw garlic consumption and lung cancer in a Chinese Population. Cancer Epidemiol Biomarkers Prev, 2016; 25:624–633.

88.

Turrini

, Ferruzzi

, Fimognari

. Potential effects of pomegranate polyphenols in cancer prevention and therapy. Oxid Med Cell Longev, 2015; 2015:938475.

89.

Melkonian

, Daniel

, Ye

, et al. Glycemic Index, Glycemic Load, and Lung Cancer Risk in Non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev, 2016; 25:532–539.

90.

Majeed

, Malik

, Ahmed

, et al. Ginseng phytochemicals as therapeutics in oncology: Recent perspectives. Biomed Pharmacother, 2018; 100:52–63.

91.

Sun

, Ostadal

, Ryznar

, et al. Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer, 1999; 34:62–69.