INTRODUCTION — Complementary and alternative medicine (CAM) is defined by the National Center for Complementary and Alternative Medicine as a group of diverse medical and health care systems, practices, and products that are not normally considered to be conventional medicine [1]. Included in this type of therapy are herbs, acupuncture, chiropractic, and massage, among others. Use of these therapies is common in the general population.
The use of CAM is widespread. Multiple studies have found that within one year, up to 90 percent of patients with cancer used a CAM approach for at least a part of their therapy [2-10]. However, patients may not reveal the use of CAM unless specifically asked. In one study, disclosure of the use of these therapies increased from 7 to 43 percent when directed questions were added to standard history taking [11]. Unfortunately, communication between oncologists and patients about CAM is poor, infrequent, and mostly initiated by patients or their kin [12].
Users of CAM are generally not dissatisfied with conventional medicine but find alternatives to be more congruent with their own values, beliefs, and philosophical orientations toward health and life [13]. Factors reported to be associated with use of CAM therapies in cancer patients include:
●Increased psychosocial stress (eg, anxiety, depression) [14]
●Being given a less hopeful prognosis [15]
●Having the feeling of "nothing to lose" [16]
●Attending support groups [17]
●Age (younger versus older) and gender (women more than men) [9]
Despite the current popularity of CAM, most mainstream oncologists have little understanding of these therapies [18], and fewer than one-half initiate discussions about their use with patients [19]. However, patients with cancer report feeling that their doctors "should be more interested in, more informed about, and more willing to discuss unconventional therapies" [20]. Although many patients assume that CAM is associated with beneficial effects, at least one Norwegian longitudinal study of 515 cancer patients suggests that CAM use may be associated with shorter survival [21].
A review of the available evidence regarding CAM in cancer therapy is presented here. The primary focus is on results from clinical trials; uncontrolled trials are considered in areas where controlled studies are not available. The use of complementary therapies for patients with cancer-related pain is addressed elsewhere. (See "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Integrative therapies'.)
ALTERNATIVE CANCER TREATMENTS — For the purpose of this discussion, alternative cancer treatments (ACTs) are defined as CAM therapies that are promoted for reducing tumor burden or prolonging the life of cancer patients. These are typically biologically active and promoted as replacements for, rather than adjuncts to, mainstream therapy. The use of ACTs dates back to the 1940s with the use of Koch antitoxins, and new therapies have been introduced each decade, including Hoxsey treatment in the 1950s, krebiozen in the 60s, laetrile in the 70s (which is again popular today [22]), immunotherapy in the 80s, and Di Bella therapy in the 90s [23].
All of these therapies have evolved through a strikingly similar life cycle; initially they were aggressively promoted by interested parties based on anecdotal evidence. Mainstream oncologists eventually succumbed to mounting pressure, conducting rigorous clinical trials. When these turned out to be negative, proponents claimed that the studies were flawed and that a conspiracy was underway to discredit a valuable therapy. In the end, each of these therapies submerged into a medical subculture, and cancer patients continued to be attracted to them despite negative scientific evidence.
The following ACTs are currently popular and will be discussed in more detail [23]:
●Dietary treatments
●Herbal medicinal products
●Nonherbal supplements
Dietary treatments — Diet can influence cancer outcomes. The influence of conventional dietary patterns on prognosis in cancer survivors is discussed separately. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Diet'.)
Proponents of "alternative" diets claim that prolongation of life through adherence to a specific diet is an achievable goal for cancer patients. However, a systematic review of the evidence found that none of the many dietary regimens has been convincingly shown to cure cancer or significantly prolong the life of cancer patients [24].
Gerson regimen — One retrospective comparative analysis reported a six-fold increase in five-year survival rates of melanoma patients treated with the Gerson diet (a low sodium, high potassium, lactovegetarian diet that emphasizes fresh vegetables, fruit juices, and vitamin supplements), but the flawed methodology limits the reliability of this study [25]. Therefore, no good evidence supports this approach.
Macrobiotic diets — Scientific evidence of benefit from a macrobiotic diet (a high-complex carbohydrate, low fat vegetarian diet) in cancer patients is limited to two methodologically flawed retrospective studies [26]; no controlled trials are available. In addition, one-third of cancer patients on a macrobiotic diet experience problems due to weight loss, the restrictive and unpalatable nature of the regimen, time spent preparing the food, and the expense and inaccessibility of some ingredients [27].
Kelley-Gonzalez regimen — The Kelley-Gonzalez regimen refers to a program of dietary restriction, intake of digestive aids (eg, pepsin and pancreatic enzymes), and a "detoxification" regimen that includes frequent coffee enemas. In one study that included 36 patients with unresectable or incompletely resected pancreatic cancer, only 11 were considered assessable for outcome for various reasons [28]. The median survival of treated patients was 17 months, compared with a literature control of four to six months. A trial comparing this therapy with gemcitabine for pancreatic cancer was underway at Columbia University, but accrual issues forced a redesign of the study, which now compares outcome in patients who elect to receive the Gonzalez regimen with an externally matched group who receive standard gemcitabine-based combination chemotherapy [29].
Selected vegetables and herb mix — Selected vegetables and herb mix (SV) is a blended, boiled, and freeze-dried product containing ingredients with purported immune-stimulatory and anticancer properties: soybeans, mushrooms, mung beans, red dates, scallion, garlic, lentils, leek, hawthorn fruit, onion, ginseng, angelica, dandelion, senega root, licorice, ginger, olives, sesame seeds, and parsley. Two small studies have been conducted in patients with cancer [30,31]. In a matched-control study involving patients with stage III/IV non-small cell lung cancer (NSCLC), median survival duration among the 11 patients who ingested SV daily was three-fold longer than that of 13 patients who did not receive the supplement (15 versus 4 months) [30]. A similar suggestion of prolonged survival was noted in a second study of 18 patients with stage III/IV NSCLC who had either rejected or failed to respond to conventional therapies [31]. The median survival was 33.5 months for the 12 patients who used SV for two months or longer, and at five years, 50 percent of the patients remained alive.
When these data were presented to the Cancer Advisory Panel for Complementary and Alternative Medicine, SV was judged worthy of further definitive research. Further information can be found at the NCI website (www.cancer.gov/about-cancer/treatment/cam).
Herbal medicinal products — Numerous herbal medicinal products (HMPs) are promoted as ACTs. The examples listed below represent only a brief selection. Additional information about many of these herbs is available through a free database About Herbs, which is maintained by the Integrative Medicine Service at Memorial Sloan Kettering Cancer Center.
Traditional Chinese medicine — Chinese herbal medicines are widely used in many areas of Asia to reduce the toxicity associated with conventional anticancer therapy; however, the efficacy of herbal therapy to minimize chemotherapy-related toxicity is unclear:
●This approach was assessed in a double-blind, placebo-controlled trial, in which 120 patients receiving adjuvant chemotherapy for breast or colon cancer were evaluated by a qualified Chinese herbalist [32]. Treatment was prescribed and the active herbs or a matched control were dispensed in a blinded fashion. There was no difference between the two groups in hematologic toxicity, which was the primary end point. Among 16 nonhematologic parameters assessed, the only statistically significant difference was a reduction in the severity of nausea with active treatment.
●A systematic review was conducted of four trials in which 270 patients with advanced or late stage gastric cancer were randomly assigned to the traditional Chinese medicinal herb Huachansu (wild toad extract) plus chemotherapy compared with the same chemotherapy alone [33]. The authors concluded that there was relatively weak evidence that Huachansu improved leukopenia when used together with chemotherapy, but it did not improve any other side effect or the short-term efficacy of chemotherapy.
Similar conclusions were reached in a later meta-analysis that pooled results from four trials of systemic chemotherapy with and without injectable traditional Chinese herbs (Huachansu, Aidi, Fufangkushen, or Shenqifuzheng); the addition of the herbs significantly improved treatment-related leucopenia, but did not increase short term remission rates [34].
Of note, several Cochrane and other reviews were unable to find convincing evidence from randomized trials supporting the benefit of Chinese herbal medicine as a treatment for esophageal or lung cancer; none of the trials that claimed to be randomized were actually randomized [35-37]. At least one rigorously performed randomized phase II trial of gemcitabine with or without Huachansu in patients with locally advanced or metastatic pancreatic cancer failed to demonstrate any benefit from combined therapy [38].
Green tea — Green tea is derived from the plant Camellia sinensis, and contains a number of biologically active polyphenols [5]. Herbal products are widely used as CAMs in cancer patients [5,39]. Green tea is the most widely used herbal product, used by 24 to 30 percent of all cancer patients.
The polyphenols in green tea have a variety of biologic activities that might influence tumor behavior [40-42]. There are only limited data on possible clinical efficacy:
●A single case control study from China suggested that consumption of large amounts of green tea may have a protective effect against the development of prostate cancer [43]. However, other case-control and cohort studies have not found a link between green tea intake and prostate cancer risk among Japanese men or Japanese-Americans living in Hawaii [44,45].
●A phase I study in lung cancer patients and a phase II study in prostate cancer patients showed no antitumor activity [46,47].
●Consumption of large amounts of green tea may correlate with improved survival in patients with ovarian cancer [48].
Green tea can interact in a variety of ways with conventional cancer treatments [5]. The polyphenols in green tea inhibit multiple cytochrome p450 enzymes that are important in drug metabolism; as a result, green tea could increase the plasma concentrations of a variety of chemotherapeutic agents (eg, anthracyclines and taxanes), possibly increasing drug toxicity. On the other hand, some drug-metabolizing enzymes are induced, which might lead to resistance to other chemotherapeutic agents.
In addition, preclinical studies suggest that the polyphenols contained in green tea may inhibit the induction of tumor cell death by the proteasome inhibitor bortezomib, which is used to treat multiple myeloma [49]. While it is not clear that patients receiving this drug should refrain from drinking any green tea, it might be prudent to avoid ingesting large quantities, until further information is available.
Essiac — Essiac is an herbal mixture originally formulated by a Canadian Ojibwa healer that has become popular in North America. The formula consists of burdock root (Arctium lappa), turkey rhubarb (Rheum palmatum), sheep or sheepshead sorrel (Rumex acetosella), and the inner bark of slippery elm (Ulmus fulva). Later, watercress, blessed thistle, red clover, and kelp were added.
In vitro studies of the individual components of this mixture have demonstrated some evidence of biological activity, including antioxidant, antiestrogenic, immunostimulant, and antitumor actions [50]. However, an attempted systematic review did not find a single published clinical trial testing this mixture in cancer patients [51]. The author concluded that there is no definitive evidence of its utility but that Essiac is unlikely to cause serious adverse effects [52].
Mistletoe — Mistletoe extracts (Iscador, Helixor) contain various lectins and viscotoxins (including viscum fraxini-2). Evidence from in vitro experiments and animal models suggests that these components have some anticancer activity [53,54].
Although dozens of matched pair cohort studies have largely supported a benefit for mistletoe extract in patients treated for cancer, randomized trials with various mistletoe preparations have given conflicting results [55-58]. Three independent systematic reviews of the clinical evidence concluded that there are insufficient data to support any benefit for mistletoe extracts [52,59,60]. A more recent meta-analysis suggested a modest survival benefit for cancer patients who received the mistletoe preparation Iscador [61]. However, benefit was observed only in nonrandomized studies (hazard ratio [HR] for death 0.33, 95% CI 0.17 to 0.65) and not in randomized trials (HR for death 1.24, 95% CI 0.79 to 1.92), and there was a high probability of publication bias skewing the results. Numerous adverse effects are on record; the most serious is anaphylactic shock [62].
Based upon the available evidence, it cannot be concluded that there is benefit from mistletoe extract.
Whether mistletoe improves quality of life in patients with cancer is unclear. Meta-analyses of controlled trials have concluded that there were positive effects in favor of Iscador [63] and several European mistletoe extracts [64], but in general, the methodologic quality of the included studies has been poor.
PC-SPES — PC-SPES is an herbal dietary supplement consisting of seven Chinese and one American herbal extract [65]. The name of the product emphasizes its intention: PC stands for 'prostate cancer' and spes is Latin for 'hope'. The eight herbs were selected for their immune stimulating, cytotoxic, and cytostatic properties.
PC-SPES has potent estrogenic activity. In men with advanced prostate cancer, decreases in serum prostate specific antigen, improvement in bone scans, and objective shrinkage of soft tissue measurable disease have been reported with PC-SPES. However, adulteration and toxicity (an acquired bleeding diathesis) forced a recall of this compound by the United States Food and Drug Administration in February 2002 [66]. As a result, it is no longer commercially available.
Sho-saiko-to — Sho-saiko-to is a traditional Chinese herbal mixture that contains extracts of seven medicinal herbs. It is widely administered in Japan to patients with chronic hepatitis and cirrhosis. Sho-saiko-to inhibits stellate cell activation and reduces hepatic fibrosis in vitro and in vivo. It also inhibits chemical hepatocarcinogenesis in animals, acts as a biological response modifier, and suppresses the proliferation of hepatoma cells by inducing apoptosis [67].
A prospective study of 260 cirrhotic patients found that a daily oral dose of sho-saiko-to (7.5 g) in addition to conventional therapy reduced the cumulative incidence of hepatocellular carcinoma over five years of follow-up compared with controls (p = 0.071) [68]. The difference was significant in patients who were hepatitis B surface antigen (HBsAg) negative (p = 0.024). Survival was also improved with sho-saiko-to therapy (p = 0.053), and again, the difference was significant in those who were HBsAg negative. Based on these results, the use of sho-saiko-to seems promising, but more clinical trials are required to be sure.
St. John's wort — St. John's wort has primarily been used to treat depression (see "Clinical use of St. John's wort"). An extract of St. John's wort, hypericin, has been noted to have a cytotoxic effect on tumor cells after photoactivation [69,70]. In vitro studies and in vivo investigations in mice have demonstrated that intralesional hypericin has the potential for use in a number of tumors, including bladder, squamous cell, pancreatic, and prostate cancer [71-74].
The only human study has involved intralesional injection of hypericin into basal cell and squamous cell carcinomas of the skin [75]. Injection with the extract three to five times per week was followed by irradiation with visible light. The authors claim that hypericin displayed selective tumor targeting; penetration in the surrounding tissues did not induce necrosis or cell loss, and generation of a new epithelium at the surface of the malignancy was noticed. Clinical remissions were observed after six to eight weeks. These preliminary results require replication in a randomized trial.
Concerns have been raised about potential interactions of St John's wort with other medications and treatments in patients with cancer. (See 'Interactions of CAM with conventional treatment' below.)
Astragalus — The Chinese herb astragalus membranaceous is postulated to boost host immune function. A meta-analysis of randomized 34 trials found that the addition of astragalus to chemotherapy was associated with a reduced risk of death, an improved response rate, and a better performance status [76]. However, significant methodologic limitations in these trials prevented definitive conclusions about the efficacy of this herb.
Nonherbal supplements — Among the nonherbal supplements that have been evaluated are melatonin, shark and bovine cartilage, hydrazine, and thymus extracts.
Melatonin — Melatonin, a normal secretion of the pineal gland, has captured public attention because of its effects on mood, sleep, and jet lag. It has also been suggested that melatonin stimulates the immune system and has antioxidant, anticancer, and antiaging properties.
Although melatonin has been evaluated in a number of settings in patients with cancer, it does not have an established role. Examples of relevant studies include the following:
●Several studies have tested the efficacy of melatonin supplementation for slowing tumor progression [77]. One randomized, controlled trial suggested that patients with unresectable brain metastases from solid tumors who were treated with melatonin (20 mg daily by mouth, at 8 PM) experienced a significantly longer survival compared with those receiving supportive care only [78]. However, a second randomized trial in patients with brain metastases did not find any benefit from using melatonin in conjunction with radiation therapy [79].
●In an early trial, patients with untreatable metastatic solid tumors who were treated with melatonin experienced less weight loss that those treated with supportive care alone, despite similar caloric intake. However, a subsequent placebo-controlled trial of melatonin in patients with advanced lung or gastrointestinal cancer and weight loss ≥5 percent showed no benefit for melatonin in terms of appetite, weight gain, quality of life, or survival endpoints. (See "Management of cancer anorexia/cachexia", section on 'Melatonin'.)
●Melatonin has been evaluated in combination with aloe vera, which may have immunomodulating properties. In one report, 50 patients with advanced solid malignancies for whom no effective standard anticancer therapy existed, were treated either with melatonin (920 mg per day) or with melatonin and aloe vera tincture (1 mL twice daily) [80]. No response was seen in the former group while two partial responses were observed in the group treated with aloe vera. This result awaits confirmation through a more rigorous trial.
Shark and bovine cartilage — Shark and bovine cartilage are claimed to have anti-angiogenesis effects that might contribute to an inhibition of malignant growth [81,82]. Shark cartilage, in particular, is marketed aggressively with claims that it can cure cancer; such claims are invariably based upon anecdotal evidence at best.
Despite these claims, two randomized trials, one in patients with unresectable non-small cell lung cancer and the other in patients with advanced breast or colorectal cancer, have demonstrated no improvement in survival with regimens including a shark cartilage derivative [83,84].
Hydrazine — Hydrazine is a chemical with a variety of actions. It is an inhibitor of the enzyme phosphoenolpyruvate carboxykinase, a key enzyme in mammalian gluconeogenesis, a metabolic pathway that is thought to play a role in cancer cachexia. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)
Four controlled trials have been reported [85-88]. The first study, which randomly assigned 64 patients with lung cancer to receive chemotherapy with or without hydrazine (60 mg three times daily) failed to show a significant difference in survival between the two groups [85]. Three subsequent trials, two in lung cancer, and one in colorectal cancer, also failed to demonstrate a positive impact of hydrazine on survival [86-88].
Coenzyme Q10 — Coenzyme Q10 (also known as Vitamin Q10, ubiquinone, or ubidecarenone) has been widely promoted for patients undergoing treatment for cancer, based upon the suggestion that it might improve tolerance for chemotherapy [89]. However, in a double-blind placebo-controlled trial in patients with newly diagnosed breast cancer, there was no benefit from the use of coenzyme Q in self-reported cancer treatment-related fatigue [90].
Previous randomized clinical studies have not supported any benefit from this molecule in patients with heart failure. (See "Investigational therapies for management of heart failure" and "Investigational therapies for management of heart failure", section on 'Coenzyme Q10'.)
Several studies evaluated coenzyme Q10 for possible cardioprotective effects in association with anthracycline therapy [91,92]. Two of these suggested a possible cardioprotective effect [91,93], but all had serious design flaws, and no definitive conclusions could be drawn [89]. Although there were no adverse effects with coenzyme Q10, the molecule has procoagulant activity and may interfere with warfarin therapy [94].
Thymus extracts — Several in-vitro studies have demonstrated that thymus extracts restore lymphocyte function, improve immunological variables, activate natural killer cells, and increase cytotoxic activity as well as mitogen-induced interferon levels in human lymphocytes. In addition, animal experiments have suggested that thymus extracts inhibit tumor growth [95].
A systematic review located 26 randomized, controlled trials of thymus extracts for various human cancers [96]. There was no evidence that the addition of purified thymus extracts or synthetic thymic peptides to antineoplastic treatment significantly reduced the risk of death or tumor progression, or improved tumor response rates.
Shiitake and Reishi mushrooms — Shiitake mushrooms are among the most consumed mushrooms in the world, and they have been used in traditional Asian medicine for over 2000 years [97]. In vitro, several polysaccharide components exhibit antitumor activity [98]. The antitumor efficacy of a shiitake mushroom extract was tested in an open-label study in which 62 men with advanced prostate cancer received oral extracts of shiitake mushroom daily for six months [99]. The clinical endpoint was the tumor marker, serum prostate specific antigen (PSA). By six months, 23 patients had a rising PSA, while 38 remained stable. No patient had a conventional PSA response, defined as a reduction of ≥50 percent of serum PSA over baseline. The authors concluded that shiitake mushroom extract alone was an ineffective treatment for men with clinical advanced prostate cancer.
Reishi mushrooms (Ganoderma lucidum) are also widely used and recommended by Asian physicians and naturopaths for their supporting effects on the immune system. Antitumor activity is less certain. A Cochrane analysis of five randomized trials (373 subjects) comparing the antitumor efficacy of G. lucidum against an active or placebo control concluded that there were marginal benefits (enhanced host immune function, higher likelihood of an antitumor response, better quality of life) when the mushroom was used in conjunction with chemotherapy and/or radiation therapy compared with chemotherapy and/or radiation therapy alone, and no major toxicity was reported [100]. However, methodologic quality was very low, all studies were conducted in the Chinese population, and there was no information on prolongation of overall survival. The data are insufficient to justify use of G. lucidum as a first-line treatment for cancer.
Lycopene — Multiple studies have suggested that the carotenoid lycopene, which is particularly rich in tomatoes, may have a role in preventing prostate cancer [101,102], although this has not been established in controlled clinical trials. (See "Overview of cancer prevention", section on 'Fruits and vegetables'.)
A detailed review of the available evidence by the United States Food and Drug Administration found that there was no credible evidence to support a relationship between lycopene intake and a reduced risk of cancer [103].
Vitamin C — A number of studies have examined the hypothesis that antioxidants such as vitamin C can prevent cancer by augmenting the body's ability to dispose of toxic free radicals, thereby retarding oxidative damage. Although there is little evidence to support an important role for vitamin C in cancer prevention, many patients who have cancer take supplemental vitamin C, often at high doses [104]. Double-blind trials of oral vitamin C have failed to demonstrate any benefit in terms of cancer outcomes [105,106]. High-dose intravenous (IV) vitamin C is widely used by practitioners of CAM [107]. To date, at least four phase I trials have been conducted to evaluate high dose IV vitamin C in patients with advanced cancer [108-111]; no trial has adequately addressed antitumor efficacy. (See "Vitamin intake and disease prevention", section on 'Antioxidants'.)
While high-dose vitamin C is relatively nontoxic because excess doses of this water-soluble vitamin are excreted in the urine, concerns have been raised as to a potentially detrimental impact of vitamin C intake on the antitumor efficacy of cytotoxic chemotherapeutic agents [112], including bortezomib [113]. Patients taking bortezomib should refrain from taking supplemental doses of vitamin C.
Modified citrus pectin — Modified citrus pectin (MCP) is a form of pectin (a carbohydrate that is found in most plants and is particularly plentiful in the peels of apples, citrus fruits, and plums) that has been broken down into small molecules to facilitate absorption in the digestive tract. MCP inhibits metastases in animal models of prostate cancer and melanoma [114-116]. One small uncontrolled clinical study of MCP demonstrated a significant slowing of the prostate-specific antigen (PSA) doubling time in 7 of 10 men in men with metastatic treatment-refractory prostate cancer [117]. However, no study has demonstrated a reduction in solid tumor growth or enhanced survival with MCP. Randomized trials of larger groups of patients using conventional endpoints and an untreated control group are needed before any firm conclusions as to the benefit of MCP can be reached.
COMPLEMENTARY SUPPORTIVE CARE — Complementary therapies are adjuncts to mainstream care that may be used to manage cancer symptoms, adverse effects of therapy or improve quality of life or even quality of death. In contrast to alternative therapies, many complementary therapies have been shown to be of benefit in patients with cancer.
Acupuncture and related therapies — Acupuncture has been studied in patients with cancer to reduce chemotherapy and radiation therapy-induced nausea and vomiting, for pain control, to reduce vasomotor symptoms in women receiving antiestrogen treatment for breast cancer as well as in men treated with gonadotropin analogs for prostate cancer, to diminish cancer–related fatigue, and to improve and prevent xerostomia in patients who have received radiation for head and neck cancer. Unfortunately, interpretation of the results of randomized trials is hampered by a high risk of bias in most studies, and lack of standardization of treatment methods and comparison groups [118]. (See "Side effects of androgen deprivation therapy", section on 'Alternative strategies' and "Cancer-related fatigue: Treatment", section on 'Acupuncture' and "Rehabilitative and integrative therapies for pain in patients with cancer" and "Management of late complications of head and neck cancer and its treatment", section on 'Acupuncture'.)
Nausea and vomiting — Several different techniques have been used to stimulate the pericardium 6 (P6 or neiguan) site, which is commonly thought to be useful in the management of chemotherapy-induced nausea and vomiting [119], and possibly radiation therapy-induced nausea and vomiting [120]. These include manual stimulation with the insertion of fine needles [121], electrostimulation through needles [122] or percutaneously [123-125], and noninvasive pressure on the skin over the P6 pressure point (ie, acupressure) [120,126-128].
The potential benefits and limitations of these approaches are illustrated by two of the larger randomized trials:
●In a randomized trial, 739 patients beginning chemotherapy with a cisplatin or doxorubicin-containing regimen were randomly assigned to acupressure bands, an acustimulation band, or a no-band control in addition to standard antiemetics [126]. Patients who used the acupressure bands had significantly less nausea on day one than did controls, but there were no differences in acute vomiting or in rates of delayed nausea or emesis among the groups.
●Low frequency noninvasive electroacupuncture at classic antiemetic acupuncture points was evaluated in a trial in which 104 women with breast cancer were randomly assigned to the active intervention, mock electrostimulation on the same schedule, or no intervention [122]. All patients received concurrent three drug antiemetic pharmacotherapy and highly emetogenic chemotherapy. The number of emesis episodes occurring during the five days was significantly lower for patients receiving electroacupuncture compared with those receiving the mock procedure or antiemetic pharmacotherapy alone (median number of episodes, 5, 10, and 15, respectively). The observed effect had a limited duration, and by day 9, there were no differences between the two groups.
A year 2013 systematic review of acupuncture in cancer care included 11 randomized trials in which nausea and vomiting were assessed; eight were considered to have a high risk of bias [118]. Only one trial [122] had a low risk of bias and was positive for short term benefit of electroacupuncture after chemotherapy for breast cancer; two other trials (one addressing benefit after chemotherapy and the other after radiation therapy) had unclear risk of bias [129,130], and one was positive, the other negative. All other trials were considered uninterpretable because of high risk of bias. The authors concluded that based upon the single positive study with low risk of bias that acupuncture could be considered an appropriate adjunctive treatment for chemotherapy-induced nausea and vomiting but that additional studies are needed.
Pain control and xerostomia — Although some trials have suggested that acupuncture can be useful in ameliorating cancer pain, a systematic review concluded that the value of acupuncture has not been established [131]. (See "Rehabilitative and integrative therapies for pain in patients with cancer".)
On the other hand, benefit for acupuncture has been suggested in patients being treated for head and neck cancer:
●At least four randomized trials suggest that acupuncture and acupuncture-like electrical nerve stimulation improve treatment-related xerostomia [132-135]. In a representative trial, 70 patients with pain and salivary dysfunction three or more months after neck dissection and irradiation for head and neck cancer were randomly assigned to four weekly acupuncture treatments or usual care (physical therapy, analgesia, antiinflammatory drugs); the use of sialagogues was not described [132]. Acupuncture was associated with a significant reduction in pain and dysfunction as well as a greater improvement in patient-reported xerostomia as compared with usual care. The duration of benefit was not stated. These data are discussed in more detail elsewhere. (See "Management of late complications of head and neck cancer and its treatment", section on 'Salivary gland damage and xerostomia'.)
●More recently, two small randomized trials of patients undergoing treatment for nasopharyngeal cancer suggested that prophylactic use of acupuncture may prevent radiation-induced xerostomia [136,137]. In the larger of the two, 86 patients in the treatment arm received acupuncture three times weekly during radiation therapy, while those in the control group received standard care only without sham acupuncture. Xerostomia questionnaire scores for the acupuncture group were significantly lower than for controls starting week 3 and continuing through six months. Significant differences in salivary flow favoring the acupuncture arm were seen as early as three weeks into treatment and persisted at six months.
While intriguing, interpretation of these data is limited by the lack of a sham acupuncture control group in any of the trials. At least in the setting of chronic pain, both acupuncture and sham acupuncture have been shown to have much greater efficacy than no treatment, suggesting a strong placebo effect. (See "Acupuncture", section on 'Summary'.)
Independent confirmation of these data in appropriately controlled trials is needed before acupuncture can be considered a standard approach to treatment or prevention of xerostomia in patients undergoing treatment for head and neck cancer.
Vasomotor symptoms — Acupuncture has been studied as a potential therapy for hot flashes, but its value is unproven. In a meta-analysis of five trials comparing acupuncture to sham acupuncture in menopausal women with vasomotor symptoms, reductions in severity and frequency of hot flashes were seen with both therapies, but there were no significant differences between the two groups. (See "Menopausal hot flashes", section on 'Role of complementary and alternative therapies'.)
In men receiving gonadotropin analogs for prostate cancer, a small pilot study suggested that acupuncture decreases hot flashes, but there are no data from randomized trials [138]. (See "Side effects of androgen deprivation therapy", section on 'Vasomotor symptoms'.)
Hypnotherapy — Several (mostly small) randomized, controlled trials have demonstrated the usefulness of hypnotherapy in palliative cancer care, with efficacy in controlling pain and nausea/vomiting in various settings. A systematic review of hypnosis may be particularly useful for reducing the anticipatory emesis associated with chemotherapy [139]. In addition, hypnosis can be useful in children for preventing anxiety and pain due to procedures such as lumbar puncture or bone marrow aspiration [140]. (See "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Clinical hypnosis'.)
The use of hypnotherapy has also been evaluated as an adjunct to radiation therapy in a randomized study [141]. In a study of 69 patients undergoing curative radiation therapy for a variety of cancers, benefit could not be documented with formal instruments assessing anxiety and quality of life, although patients reported an improved sense of both overall and mental wellbeing.
It is unclear to what extent these effects are due to specific or nonspecific (placebo) effects. An older review that summarized published clinical trials of hypnotherapy concluded that there is encouraging, albeit not compelling, evidence to suggest that hypnotherapy is helpful for controlling anxiety and pain as well as nausea and vomiting in cancer patients [142]. A later systematic review of randomized trials of self-care strategies for managing common chemotherapy-related adverse effects concluded that randomized trials of reasonable quality provided limited support for the benefit of hypnosis in reducing nausea and vomiting [143].
Behavioral intervention — Behavioral intervention encompasses a number of techniques, which have been applied separately and in combination. Evidence of benefit for these psychoeducational strategies is provided by the following examples:
In a randomized trial with 115 patients, a structured multidisciplinary program including cognitive, emotional, physical, social, and spiritual interventions was useful in patients receiving radiation therapy for advanced cancer [144]. Those receiving the active intervention were able to maintain their quality of life during the four week treatment period, while the control group who did not receive this adjunctive treatment had a significant decrease in quality of life. Six months after the intervention, quality of life was similar in the two groups.
In a randomized trial conducted in 229 women after completion of surgery, chemotherapy, and/or radiation therapy for breast cancer, an eight-week program of mindfulness-based stress reduction significantly improved mood, breast and endocrine-related quality of life, and well-being [145]. The beneficial effects on fatigue and depression seen at eight weeks were no longer apparent at 12 weeks.
The systematic review discussed above concluded that there was limited evidence to support the benefit of psychoeducation to reduce chemotherapy-related fatigue [143]. (See "Cancer-related fatigue: Treatment", section on 'Cognitive-behavioral and psychosocial interventions'.)
The data on cognitive-behavioral therapy to reduce chronic cancer and cancer treatment-associated pain are discussed elsewhere. (See "Rehabilitative and integrative therapies for pain in patients with cancer".)
Relaxation therapy — Relaxation techniques such as imagery [146-148], breathing exercises [146], manual massage [149-152], music therapy [153], art therapy [154], yoga [155,156], medical Qigong [157-159], Tai Chi [160,161], and reflexology [162,163] have been used to reduce symptoms (such as nausea and vomiting, pain, fatigue) and improve mood, sleep, physical function, and quality of life in cancer patients. The systematic review discussed above concluded that there was limited evidence to support a benefit for relaxation and exercise to reduce nausea and vomiting, with some benefit for this practice seen in 10 of 13 published randomized trials [143]. The benefit of yoga for reducing fatigue and improving sleep quality has been demonstrated in a randomized trial [156]. (See "Cancer-related fatigue: Treatment", section on 'Yoga'.)
The impact of relaxation therapy on mood and quality of life are less certain, as evidenced by the following data:
●In one randomized study, 96 women receiving chemotherapy for newly diagnosed breast cancer were assigned to receive either regular relaxation training and imagery or standard care only [147]. The experimental group experienced better quality of life than the control group.
●Another trial of relaxation therapy in women with early breast cancer and hot flashes found no benefits in terms of anxiety or quality of life [164].
●A meta-analysis of 11 randomized trials compared creative arts therapies (music, art, dance/movement) with a control condition (no treatment, waiting list, or usual care) as an add-on treatment in over 500 patients with cancer (primarily breast or blood) [165]. There was a significant but clinically modest improvement in anxiety, depression, and pain, and increased quality of life favoring the active intervention during treatment, but some of the benefits were transient. (See "Rehabilitative and integrative therapies for pain in patients with cancer" and "Management of psychiatric disorders in patients with cancer".)
●Manual massage therapy with or without aromatic oils (aromatherapy) can convey intensive relaxation to both the body and the mind, but benefits are usually transient [149-152]. A Cochrane review concluded that there was a lack of evidence on the clinical effectiveness of massage with or without aromatherapy for symptom relief in patients with cancer [166]. The quality of evidence was very low, and most studies were small and considered to be unclear or at high risk of bias because of underreporting.
Relaxation and massage therapy for management of chronic cancer and cancer treatment-associated pain are discussed elsewhere. (See "Rehabilitative and integrative therapies for pain in patients with cancer" and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Massage therapy'.)
Therapeutic touch — Several clinical trials have tested the effectiveness of therapeutic touch (Reiki) to reduce anxiety [167], improve wellbeing or quality of life [168,169], or reduce pain in cancer patients. Some of these studies have yielded positive results. Due to weaknesses in study design, however, it is unclear whether the observed effects were due to specific therapeutic or nonspecific (placebo) effects [170]. The use of therapeutic touch as a treatment for cancer pain is addressed in more detail elsewhere. (See "Rehabilitative and integrative therapies for pain in patients with cancer".)
Self-help and support groups — There is a trend for increasing participation in support groups among cancer patients. Although patients attending these groups do so mainly for psychosocial support, the data are conflicting as to whether these interventions prolong survival. Some reports have suggested a survival benefit [171-174]. However, these benefits were not confirmed in larger randomized trials, and a meta-analysis showed no significant effect on survival [175-181].
Ginseng and guarana for fatigue — A beneficial effect of American ginseng (2000 mg daily) on cancer-related fatigue was suggested in a double-blind, placebo controlled trial conducted by the North Central Cancer Treatment Group. A similar degree of benefit was suggested with Asian (Korean red) ginseng in a separate placebo-controlled trial conducted in patients with colorectal cancer undergoing chemotherapy.
Guarana is a stimulant derived from an extract of seeds from a plant in the Amazon (Paullinia cupana). In a small, double-blind, placebo-controlled study of breast cancer patients receiving chemotherapy, oral guarana at a dose of 100 mg daily significantly improved fatigue scores (p<0.01) at the end of 21 days of treatment. Further studies are needed to confirm these results and to evaluate their generalizability to chronic cancer-related fatigue and to other types of cancer.
These trials are all described in greater detail elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Ginseng and guarana'.)
Fish oil for symptom control — Fish oil, which contains alpha-3 omega fatty acids, has been studied as a pharmacologic treatment for cancer-related anorexia/cachexia. (See "Management of cancer anorexia/cachexia".)
At least one trial has examined the benefit of fish oil for control of cancer-related symptoms in addition to anorexia. Sixty patients with a variety of cancers were randomly assigned to fish oil capsules or placebo in addition to their conventional treatments [182]. Among the 60 patients who both began and completed two weeks of their allotted therapy (27 dropped out during treatment because they could not tolerate the regimen), supplemental fish oil did not influence appetite, fatigue, nausea, weight loss, caloric intake, nutritional status or sense of wellbeing.
SAFETY ISSUES WITH COMPLEMENTARY AND ALTERNATIVE TREATMENTS — While many forms of complementary and alternative medicine (CAM) for cancer are associated with minimal or no risk, this is not true for all such therapies. Potential toxicities include direct toxicity of CAM medications and procedures, indirect effects of CAM due to interactions with other medications, and also the risk to the patient who uses CAM to avoid or delay established, effective treatment in the management of malignant disease [183,184]. (See "Overview of herbal medicine and dietary supplements".)
Direct toxicity of CAM medications and procedures — A variety of herbal medications may produce serious side effects. (See "Overview of herbal medicine and dietary supplements" and "Hepatotoxicity due to herbal medications and dietary supplements" and "Nephropathy induced by aristolochic acid (AA) containing herbs".)
Quality control of these preparations can be a major concern. Pertinent issues include variability in biologic potency in different crops, the realistic possibility of fungal or bacterial contamination, the use of incorrect plant species, and consumer fraud [185]. One of the most severe examples of the potential for harm with herbal preparations is the development of renal failure and urothelial cancer in individuals who thought they were using the herbal preparation Stephania tetrandra for weight loss but who actually received the Chinese herb Aristolochia fangchi because of a manufacturing error [186,187]. Numerous examples of potential side effects associated with the more commonly used herbal and other types of CAM are provided in the table (table 1) [47,188-195]. Adverse events due to herbal remedies should be reported to the United States Food and Drug Administration (800-FDA-1088).
Reported adverse effects of acupuncture include transmission of an infectious agent through needle insertion, broken, forgotten, or misapplied needles, pneumothorax, transient hypotension, minor bleeding, contact dermatitis, and pain [196]. Therapeutic deep massage can result in hematoma, particularly in anticoagulated or thrombocytopenic patients, and other serious complications have been reported [197-199]. Finally, severe complications of enema therapy include infection with enteric pathogens, severe dehydration and electrolyte imbalance, and death [200-202].
Interactions of CAM with conventional treatment — Many botanical agents are pharmacologically active, raising concerns about potential interactions with conventional therapy, both cytotoxic agents, and other medical therapies [203-208].
Many common chemotherapy agents are metabolized through the cytochrome p450 system and the specific isoenzymes responsible for their metabolism are listed in the individual drug monographs section on Metabolism/Transport Effects. What follows are selected examples of potential interactions:
●St John's wort induces CYP3A4 [209], which can lead to subtherapeutic levels of chemotherapeutic agents that are metabolized by CYP3A4 (eg, taxanes, irinotecan, imatinib) as well as other drugs such as oxycodone. (See "Clinical use of St. John's wort", section on 'Drug interactions'.)
●Essiac consists of multiple biologically active ingredients, which may act synergistically with chemotherapeutic agents by its inhibition of CYP3A or through the cytotoxic or immunosuppressive activities of anthraquinones present in this mixture [5].
●As noted previously, the polyphenols in green tea inhibit multiple cytochrome p450 enzymes, which are important in drug metabolism and induce other drug-metabolizing enzymes (see 'Herbal medicinal products' above). Several components of green tea and green tea extract can antagonize the effectiveness of bortezomib [49].
●Because it can inhibit the cytochrome p450 system, milk thistle has the potential to decrease the metabolism of some cytotoxic agents such as paclitaxel [210,211] and doxorubicin [212].
●Panax ginseng and ginkgo biloba increase the functional activity of several drug-metabolizing enzymes of the CYP family and should be avoided in patients receiving cytotoxic agents metabolized by CYP3A4 or CYP2C19 [203].
●Others have shown that pretreatment of cancer cells with some botanical agents (eg, berberine, a constituent of huang lian) reduces the sensitivity of these cells to chemotherapy-induced apoptosis [213].
●PC-SPES, which is no longer commercially available in the United States, has been associated with elevations in the prothrombin time, which may promote bleeding in patients with drug or disease-induced thrombocytopenia. (See "Alternative endocrine therapies for castration-resistant prostate cancer".)
Specific herbal remedies to discourage or avoid during chemotherapy are shown in the attached table (table 2) [214]. This list is not comprehensive. Specific interactions of herbs and herbal mixtures with medications, including chemotherapy drugs, may be determined using the Lexicomp drug interactions tool (Lexi-Interact) included in UpToDate. Additional information on drug-herb interactions is available through the About Herbs website, which includes a database on herbal and dietary supplements maintained by the Integrative Medicine Service of Memorial Sloan Kettering Cancer Center.
An extensive, although not all-inclusive, listing of herbs and their actions that may interact with certain drugs is found in the following tables. As examples, herbs with laxative properties may interact with antidiarrheal drugs, while those having anticoagulant effects may interact with warfarin.
●Allergenic herbs (table 3)
●Amine, alkaloid, and sympathomimetic herbs (table 4A-B)
●Anticoagulant and coagulant herbs (table 5)
●Cardioactive herbs (table 6)
●Diuretic herbs (table 7)
●Herbs affecting blood sugar (table 8)
●Herbs affecting lipids (table 9)
●Hormonally active herbs (table 10)
●Hypertensive herbs (table 11)
●Hypotensive herbs (table 12)
●Immunostimulating herbs (table 13)
●Irritant herbs (table 14)
●Laxative herbs (table 15)
●Sedative herbs (table 16)
Delay or avoidance of conventional therapy of known benefit — Although not a direct "toxic" effect, the use of CAM may result in a significant delay in instituting conventional treatment that is of documented benefit for a specific condition [215-218].
Furthermore, it is often required or "recommended" that only natural substances be ingested for the duration of the CAM treatment, as non-natural products are alleged to negate the benefit of the therapy [202]. This strategy of care can lead to the rejection of effective medical therapies such as opioid analgesics, regardless of the severity of pain [183].
Although data are limited, there is an adverse impact of refusing/delaying standard treatments in favor of alternative therapies [219,220]:
●In an early report of 61 patients with breast cancer who were identified in a community surgical practice over a 10-year period, at a median follow-up of 54 months, among the 26 patients who omitted or delayed surgery, 96 percent experienced disease progression, and one-half died of their disease [219]. Of the 35 patients who were nonadherent to adjuvant therapy recommendations, only 14 percent remained relapse free, and 20 percent died of disease.
●In a second report, 258 patients diagnosed with nonmetastatic breast, prostate, lung, and colorectal cancer in the National Cancer Database between 2004 and 2013 who underwent alternative medicine treatment as the sole therapy (identified as those coded as "other unproven cancer treatments administered by nonmedical personnel") and who also did not receive conventional cancer treatment were compared with a matched cohort of 1032 patients who received conventional cancer therapy [220]. Patients who chose alternative therapy had higher refusal rates for surgery (70 versus 0.1 percent), radiation therapy (53 versus 22 percent), chemotherapy (34 versus 3 percent), and hormone therapy (34 versus 3 percent). Alternative medicine use was associated with worse five-year overall survival (82.2 versus 86.6 percent). While use of alternative treatment was independently associated with a greater risk of death (hazard ratio [HR] 2.08, 95% CI 1.50-2.90) in a multivariate model that did not include treatment delay or refusal, there was no significant association between use of alternative treatment and survival once treatment delay or refusal was included in the model. These data suggest that the mortality risk associated with use of alternative treatments was mediated by the refusal of conventional cancer therapy.
Important limitations of this study are its observational nature and the reliance on medical diagnosis coding at a single facility, which may have underascertained the use of conventional cancer treatment for patients who received treatment at a different facility or those who initially received alternative medicine prior to presenting to the facility that was reporting data.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Complementary and alternative medicine (The Basics)" and "Patient education: Nausea and vomiting with cancer treatment (The Basics)")
SUMMARY
●There is no compelling evidence that any alternative therapy is effective in patients with cancer. Nevertheless, outlandish and irresponsible claims continue to be published in the medical literature: "With classic homeopathy it is possible to treat people suffering from cancer. The patients can be helped palliatively as well as curatively" [221]. (See "Homeopathy".)
●Thus, it is understandable that oncologists are concerned about the high level of acceptance of alternative therapies by cancer patients. On the other hand, outright rejection of these treatments might be counter-productive for the following reasons:
•Every now and then impressive case reports emerge from credible sources. An open mind toward plausible CAM options might therefore be a good general policy [222].
•Outright rejection alienates patients and negatively affects the therapeutic relationship.
●Proponents of these therapies argue that it would be inhumane not to provide such treatments if patients want them. Oncologists should certainly not hinder patients from seeking such help. On the other hand, one should still insist that the usefulness of these therapies be demonstrated beyond reasonable doubt. The use of ineffective supportive treatments is ethically problematic; for instance, it might lead to a situation where such therapies replace others with proven effectiveness. An important point is that claims of efficacy should be supported with acceptable evidence by those who make these claims, rather than rejected through research carried out by those who doubt them. (See 'Alternative cancer treatments' above.)
●In the interest of our patients, we should discuss the (lack of) evidence for alternative therapies openly and objectively. This includes the fact that some treatments carry considerable risks and many are neither associated with prolongation of life nor an enhanced quality of life. Information must be reliable and from reputable sources [223].
●The role of complementary therapies in palliative and supportive cancer is a different matter and seems more promising. Several of these therapies have at least some potential for improving quality of life. The common denominator in achieving this goal may turn out to be the promotion of relaxation. (See 'Complementary supportive care' above.)
●The often emotional conflicts between opponents and proponents of CAM are, to a large degree, a regrettable artifact caused by the lack of reliable evidence in this area. If more convincing data existed, there would be far less room for disagreement. It follows that more research efforts (and research funds) should be directed towards creating reliable evidence.
In the United States, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) and the National Cancer Institute are supporting well designed studies of alternative medicine. Information on CAM is available through the NCCIH website and the NCI website, and in registry of systematic reviews of CAM (not limited to cancer) produced by a CAM field group within the Cochrane Collaborative (http://cam.cochrane.org/).