Besides conventional medicine, many patients with cancer seek complementary and alternative medicine (CAM) as an additional treatment option. Since the early 1970s, the use of CAM in cancer treatment has expanded worldwide. CAM, as a tempting option, was used by patients with cancer mainly due to easy accessibility. Patients with cancer used CAM to achieve better quality of life or to find a cure. As physicians are mainly unaware of CAM use by patients, doctor-patient communication about CAM use should be brought to a higher level. To identify circumstances in which CAM are preferred, further investigations are needed especially in biologically based therapies. Clinical-based evidence for mind-body therapies have been established, so this type of CAM can be recommended for patients with cancer during chemotherapy. Future studies are necessary to fill the gaps so that CAM users, as well as medical experts, are in position to clearly determine all the benefits and disadvantages of the mentioned therapy.
Background Cancer is presently one of the most widespread and feared diseases. For years, it is the leading cause of mortality worldwide. According to the American Cancer Society’s Cancer Statistics Center in USA, there will be 4,380 new cases of cancer and 1,660 cancer deaths daily in 2019 . The second leading cause of cancer death in women is breast cancer . Although presently many cancers are successfully treated, some patients are limited to palliative therapy. The fact that, currently, in the USA, there are more than 3.1 million breast cancer survivors and that new therapeutic and diagnostic approaches give hope that this number will continuously increase over time . It is known that the diagnosis of cancer and the whole pathway affects the psychological, physical, and emotional state of the patient and therefore the quality of life. Besides conventional effects, cancer therapy leads to a number of serious adverse events, and therefore, patients with cancer may turn to nonconventional therapies. This review summarized the reasons for the use of CAM and its potential adverse effects based on papers published in the last 18 years.
The definition of CAM Although it is considered that complementary and alternative medicine (CAM) use is beyond the scope of traditional medicine, researchers are mainly referring to the CAM definition provided by the National Center for Complementary and Integrative Health (NCCIH), USA. According to the NCCIH, CAM must be seen as "health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice" . Another more complex definition is derived from Ernst et al. who see CAM as a "group of diverse medical and health care approaches and products that are not typically part of conventional medical care" . "Complementary" therapy is usually considered as an adjunct to conventional treatment or supplemental therapy that can reduce some of the difficulties that the patient has. In contrast, "alternative" therapy is considered as an approach that will replace conventional therapy . Moreover, the present term "integrative medicine" that involves the use of evidence-based CAM in combination with conventional medicine is becoming more widespread. According to the NCCIH, CAM therapies are classified into five domains (Figure 1). Figure 1 Classification of CAM CAM, Complementary and alternative medicine. The time of decision making of CAM use by patients with cancer has not yet been accurately determined. Patients with cancer use CAM regardless of the stage of the disease . Usually, some patients with cancer start with CAM therapy 4-6 months after initiating conventional treatment or after disease progression . The most incautious reasons for resorting to CAM therapy are better quality of life, remediation of side effects, control of cancer symptoms, and end-of-life care . It is interesting that among BRCA (breast cancer type 2 susceptibility protein) mutation healthy women, the frequency of using CAM is comparable to that of patients and survivors with breast cancer .
Historical background of CAM The use of CAM plays an important role in the prevention and treatment of diseases since the ancient times. In the 16th-11th century B.C.E., there were earliest notes of tumors and their treatment methods were described by traditional Chinese practitioners . It is believed that aromatherapy establishments were established in Egypt around 1600 B.C.E. . Aromatherapy was also used in Chinese and Greek medicine. Aromatherapy is based on the use of oils obtained from various plants with the enhancement of the physical and emotional state of the user [3, 9]. Aromatics massage is also one of the fundamental aspects of traditional Indian medicine known as "Ayurveda" or "medicine of the Gods." The roots of Ayurveda as a special Hindu medical system date back to the 6th century, and presently, it is used globally. Ayurvedic medicine can include various therapeutic approaches such as use of special diets, specific Ayurvedic medications that may contain some heavy metals such as mercury or arsenic, various herbal therapies, meditation, yoga, or urine therapy . As an integral part of Ayurveda yoga has been practiced for years to promote psycho-physical health, but it cannot be disputed that recently it has become more popular. Numerous studies point to the benefits of yoga in patients with cancer, stressing that this type of CAM drastically improve quality of life . When it comes to traditional Chinese medicine (TCM), which is practiced by millions of people, acupuncture takes a significant place. Acupuncture is actively used for more than 4700 years, but in 1971, there was a boom worldwide. According to the Chinese tradition, it is believed that the benefits of acupuncture are due to a constant energy flow. Numerous studies and clinical trials suggested that acupuncture has been beneficial in controlling vomiting and pain in patients with cancer . Moxibustion and acupressure that are based on the principles of acupuncture also have a foothold in TCM . It has also been shown that reflexology, which was practiced for years by followers of Chinese, Egyptian, and Indian medicine, has been successfully used to relieve pain in patients with cancer . Judging by the results of the recently published study, after diagnosis, patients with cancer usually prefer herbal-based CAM type . The herbal medicine used today is based on "traditional Chinese herbalism, Ayurvedic herbalism, Western herbalism (came from Greece and Rome) and Arab traditional medicine" . An ancient book of medicine Shengnongbencaijing, which laid the foundations of herbal medicine in China in 2700 B.C.E., describes the therapeutic effects of more than 300 plants . Dioscorides, a Greek physician, wrote De Materia Medica. This pharmacopoeia was widely read for 1500 years and is considered as standard reference of herbal medicine . Greek medicine used diluted opium as anesthetic/pain killer, while Indian medicine considered belladonna a medication of choice for the relief of pain. Among patients with cancer, especially women with breast cancer, most used herbal medicines are Echinacea, garlic, Jianghuang (Curcuma longa L.), green tea, Renshen (Panax ginseng C. A. Mey) flax seed or oils, ginger, and others [12, 14].
Patterns of CAM use Since the early 1970s, the use of CAM in cancer treatment has expanded worldwide . Of patients with cancer, 30% to even 80% use some form of CAM in order to relieve treatment-related symptoms [16-22]. The enormous variability in the prevalence of CAM use is a consequence at least partly due to the methodological variability of published studies and inconsistent definition of CAM. Some authors questioned only the use of herbal preparations, while others included it in their body-based practices. Even today, CAM use is rapidly expanding. Various systematic reviews concluded that the use of CAM has been increasing from 25% of patients with cancer in 1990 to 49% in 2000-2009  and 51% in 2009-2018 . Additionally, CAM use is determined by geography . It has been hypothesized that geography-related CAM use may be a result of different cultural viewpoints toward health and most of all accessibility of conventional and CAM therapies [17, 25-30]. For example, it is well known that Kampo medicine and acupuncture are covered by public health insurance in Japan unlike in Western countries. In contrast, chiropractic and osteopathy, which are known to be widespread in the USA, are not recognized in Japan . Moreover, in Taiwan, TCM is highly adopted and available mainly because it is covered by the insurance program . In some countries, such as Nigeria, CAM is used as primary healthcare . Furthermore, several studies indicate that German-speaking countries have a high prevalence of CAM use compared to other European countries. The main stronghold of this hypothesis lies in the fact that homeopathy, anthroposophic medicine, and naturopathy have their bassinet in these countries . Moreover, different cultural viewpoints indicate that various patients have a different idea of what CAM may be. For example, Turkish patients with cancer did not regard indigenous herbal remedies as CAM unlike Indo-Asian patients with cancer [35, 36]. When it comes to dietary supplements, it is well known that, in USA, using Yinxing (Ginkgo biloba L.), echinacea, garlic, Renshen (Panax ginseng C. A. Mey), soybean, St John’s wort, valerian, green tea, and ginger is extremely popular , while, in Japan, Agaricus blazei, beer yeast, propolis, Japanese plum, and chlorella are highly used . Since 1991, mushroom Agaricus blazei has been mostly used in Japan but is currently in the first phase of the clinical trial in patients with cancer . Interestingly, Danggui (Angelica sinensis), with its immunomodulatory effects, is still a dietary supplement in USA, while it is considered as a medicine in Japan .
Reasons for CAM use It is also clear that patient’s conception of CAM therapies may be different from those of health care professionals. CAM treatments are poorly used by conventional healthcare experts . Literature suggests on the fact that physicians discuss CAM use to patients with cancer [41-43]. This is probably the consequence of several associated barriers: the use of CAM is not their field of interest [44, 45]; they believe that the CAM use does not have support in evidence-based medicine , or time is inadequate for CAM use during patients’ checkups . However, the crucial moment in decision making regarding the use of CAM in patients with cancer is the time of cancer diagnosis . For patients with cancer, increased psychosocial stress and less hopeful prognosis remain the main reasons for using this kind of therapy. Most users believe that CAM use can provide hope and psycho-spiritual well-being and improve the quality of life . Mainly, patients with cancer want to achieve faster recovery, strengthen the immune system, reduce the side effects of conventional therapies, and silence the fear that the disease will not be under control [48, 50]. Anxiety disorders, chronic pain, and metastatic form of disease are also associated with CAM use. According to literature, female sex, younger age, and high education level are strongly associated with CAM use [51-55]. Study results indicate that women use CAM more frequently than men . High education level and younger age are often associated with easier use of social platforms, media, internet, and medical information. Another theory is based on the economic side of CAM use. It is known that, in most countries or cultures, patients purchase CAM by themselves. This information suggests that patients with higher education level are also patients with higher incomes, which can afford continuous CAM cost.
Economic insight of CAM use The most commonly used types of CAM are dietary supplements and mind-body practices. Dietary supplements include use of vitamins, minerals, herbal and/or botanical supplements/medicines, and other over-the-counter natural products, while other groups mainly include yoga, meditation/spiritual healing, acupuncture, massage, and reiki [3, 57]. Dietary supplements are often registered as over-the-counter products indicating that economical cost of this type of CAM goes to the user’s expense . In Thailand, patients with cancer need to spend about 200 USD/month for CAM use , between 100 to 300 Euros/month in Italy , and 50 to 150 USD/month in rural Australia . The allocation for this type of therapy is different and reported primarily from the health system. In 1997, in the USA, the total cost of CAM for patients was 27 billion USD , and they are followed by the costs in Europe as the second largest market in 2001 . Besides that, the total budget of the NCCIH increased from 50 million USD in 1999 to 120 million USD in 2006 to 146.5 million USD in 2019, reflecting the interest in CAM use at all levels of the beneficial chain . It is very clear that economic impact of CAM use is huge. If we exclude phytomedicine, which has been shown to be pharmacoeconomically justified , in 2017, Huebner et al. concluded that they "did not find any arguments in the literature that were directed at the economic analysis of CAM in oncology" .
Safety of CAM use An interesting fact is that about 65% of users in Ireland had a "might help, can not hurt" attitude toward CAM . It is clear that CAM use can help patients with cancer in different ways but can also carry certain risks especially when it comes to dietary supplements and herbal remedies. Dietary supplements and herbal remedies are ingested substances that increase the risk of certain adverse effects and interactions with conventional chemotherapy. Berretta et al. reported that, in Italy, 86% of CAM users were unaware of the possible side effects of CAM use . If we add to this the fact that most patients (43% in Berretta’s study  or 50% in Davis’  do not tell their physician about the use of CAM, it is quite certain that they are at higher risk of developing adverse events . Sometimes, the side effects of CAM use, such as vomiting, nausea, abdominal pain, and diarrhea, may be perceived as adverse effects of conventional therapy. The scenario that follows is that a physician discontinues using conventional therapy because of the side effects. According to the American Cancer Society in 2012, more than 2800 adverse events of dietary supplements were reported . For example, it has been reported that echinacea, soybean, or St. John’s wort caused anaphylaxis . Garlic, Renshen (Panax ginseng C. A. Mey), ginger, and kava kava (Piper methysticum) caused gastrointestinal side effects. Valerian caused hepatotoxicity. Obstruction of the sigmoid colon has been reported after treatment with grape seed . Moreover, probiotic sepsis has been observed in immunocompromised patients soon after probiotics have been used by patients with cancer to relieve chemotherapy-induced diarrhea [69, 70]. Furthermore, it has been observed that garlic, aloe vera, aromatherapy, Yuejiancao (Oenothera biennis), and cod liver oil caused vomiting in patients with cancer [43, 71]. Flu-like syndrome has also been noted in patients with cancer after using St. John’s wort or cod liver oil . Pain and inflammation were reported by these patients after massage, chiropractic, or use of valerian products . Moreover, due to possible interactions, some CAM may potentially affect the metabolism of chemotherapy agents, causing more toxic or either subtherapeutic effects of conventional drugs [72, 73]. There are two most common mechanisms of interaction formation at the pharmacokinectic level: P-glycoprotein and cytochrome P450 CYP enzyme interactions [74-83]. It is well known that green tea, Yinxing (Ginkgo biloba L.), reishi mushroom, and grape seed are CYP3A4 inhibitors, so they can easily increase the risk of toxicity of dasatinib, imatinib, docetaxel, or vinca alkaloids. In contrast, CYP3A4 inducers include echinacea and St John’s wort so they can interact with cyclophosphamide and other previously mentioned chemotherapeutic agents. Cannabinoids seem to be a CYP2C9 inducer, so they can easily increase the risk of overdose of prodrugs cyclophosphamide and tamoxifen [74-83]. Curcumin and milk thistle are CYP2C9 inhibitors. Ginger can also increase bleeding risk during warfarin therapy. Another problem in herbal medicine is the belief that it is better to use original plant tissues instead of isolated individual active ones . In most cases, it is not possible to isolate all active ingredients from different plants and monitor their metabolism, so a problematic interaction may occur between unknown secondary constituents of herbal medicines and standard cancer treatment [85, 86].
CAM use in patients with breast cancer The use of CAM was highest in patients with breast cancer. The prevalence of CAM use in patients with breast cancer varies from 30% to > 90%. It is known that women are the most frequent users of CAM, including biologically based CAM (vitamins, minerals, herbal medicine), followed by some types of mind-body medicine-prayer, meditation, and spiritual healing (Table 1). Women with breast cancer are less likely to be defined in energy medicine. In addition to the fact that many researchers use different classifications of CAM in their studies, they are usually omitted from changes in diet of patients. As information sources, patients with breast cancer seek guidance from family and friends, self-help groups, health professionals, and CAM providers [87-114]. Interestingly, it has been shown that patients consult their preferred physician if they desire to use herbal medicine. On the contrary, they did not report use of body-based practices, massage spiritual healing, hypnosis, or acupuncture to a physician . This may increase the awareness of women about potential adverse reactions of CAM. According to previous insights, younger women with higher education level seemed to be more attracted to CAM use. Younger women with breast cancer also were more easily accommodated in spiritual techniques. There are indications that income stage, marital status, and private health insurance are predictors of CAM use among these patients. The main reasons for CAM use among patients with breast cancer were promotion of emotional health, reduction of conventional medicine side effects, and healing. Contrasting opinions were available on correlations between the use of CAM and poorer emotional functioning [113, 114]. It has been reported that patients with breast cancer were more likely to use CAM if they were depressed . On the contrary, anxiety and depression were not related to CAM use in patients with breast cancer . Different contradictions and lack of awareness suggest the need to appropriately increase evidence-based medicine information on CAM.