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Chemotherapy

Lessening Chemotherapy Side Effects

Prevention and mitigation of chemotherapy side effects can avert the need to interrupt or stop treatment and allow for more aggressive dosing schedules, thus increasing the chance of treatment success. Toxic effects of chemotherapy are generally managed with drug dose adjustment (Janus 2010; CCS 2017; Griggs 2002; Verstappen 2003; Jansman 2001). However, a broad range of natural compounds may mitigate chemotherapy side effects as well (Ohkawa 1988; Liu 2012).

Although some physicins cite concern about possible harmful interactions between natural products and chemotherapy, several thorough reviews of published research have concluded that such concerns are only theoretical (Cheng 2010; Hart 2012; Ma 2014; Simone 2007a; Simone 2007b; Block 2004). It is important to note that anyone who utilizes the information contained within this protocol should do so in collaboration with their oncology team.

Research Summary: Integrative Interventions to Lessen Chemotherapy Side Effects

The following table outlines some integrative therapies that may be helpful in mitigating side effects of chemotherapy. This table briefly summarizes the research detailed in the text of this protocol. Human evidence is identified below as either from randomized controlled trials (RCT) or preliminary studies, which may or may not include an untreated control group. Animal studies are also included in this table and clearly identified as such.

Table 2. Integrative Therapies to Lessen Chemotherapy Side Effects

Chemotherapy Side Effect

Integrative Therapy

Evidence

Fatigue

Ashwagandha (Withania somnifera)

Positive findings in a preliminary trial (Biswal 2013)

Guarana (Paullinia cupana)

Positive findings in two preliminary trials (del Giglio 2013; de Oliveira Campos 2011); negative findings in one RCT (Martins 2016)

American ginseng (Panax quinquefolius)

Positive findings from a large RCT (Barton 2013)

Melatonin

Positive findings from multiple RCTs and confirmed in a meta-analysis (Wang 2012)

L-Carnitine

Positive findings from two preliminary trials in patients with carnitine depletion (Graziano 2002; Cruciani 2006); negative findings from one large RCT (Cruciani 2012)

IV Vitamin C

Positive findings from a preliminary trial (Hoffer 2015)

Turkey tail mushroom (Coriolus versicolor) polysaccharide peptide (PSP)

Positive findings from multiple RCTs (Piotrowski 2015; Fritz 2015)

Reishi (Ganoderma lucidum)

Positive findings from one small RCT (Zhao 2012)

Fermented soybean extract

Positive findings from one preliminary trial (Chi 2014)

Immunosuppression/Neutropenia

Eicosapentaenoic acid (EPA) from fish oil

Positive findings from a preliminary trial (Takagi 2001)

Fermented wheat germ extract (FWGE)

Positive findings from a preliminary trial in children (Garami 2004)

Probiotic

Supportive animal research (Salva 2014; Von Bultzingslowen 2003)

Zinc

Supportive animal research (Zhang 1992)

Quercetin

Supportive animal research (Merzoug 2014)

Ashwagandha (Withania somnifera)

Supportive animal research (Senthilnathan 2006; Gupta 2001)

Nausea/Vomiting

Ginger

Positive findings from one preliminary (Panahi 2012) and one RCT (Yekta 2012)

Taurine

Positive findings from one RCT (Islambulchilar 2014)

Peripheral Neuropathy

IV Calcium and Magnesium

Positive findings from multiple RCTs and confirmed in a meta-analysis (Xu 2013)

Vitamin E

Positive findings from multiple RCTs and confirmed in a meta-analysis (Eum 2013)

Glutathione

Positive findings from a RCT (Cascinu 1995)

N-Acetyl Cysteine

Positive findings from a preliminary trial (Lin 2006)

Omega-3 Fatty Acids

Positive findings from one RCT (Ghoreishi 2012)

Acetyl-L-Carnitine

Positive findings from two preliminary trials (Bianchi 2005; Maestri 2005) and one RCT (Campone 2013)

Glutamine

Positive findings from several preliminary trials (Vahdat 2001; Wang 2007; Huang 2015)

Alpha-Lipoic Acid

Positive findings from one preliminary trial (Gedlicka 2003)

Cardiotoxicity

Coenzyme Q10

Positive findings from several preliminary trials (Conklin 2005)

Green Tea Extract/EGCG

Supportive animal research (Patil 2011; Khan 2014; Li, Nie 2010)

Grape Seed Extract

Supportive animal research (Ray 2000; Boghdady 2013)

Rhodiola

Positive findings from one preliminary trial (Shen 2010)

Vitamin E

Supportive animal research (Sonneveld 1978)

Cranberry, Bilberry, Hawthorne, Boswellia, Ginger, Onion, Panax notoginseng, Propolis, Glutamine

Supportive animal research; see text for references

L-Carnitine

Positive findings in RCT and preliminary trials (De Leonardis 1987; Lissoni 1993)

Kidney Toxicity

IV Magnesium

Positive findings from preliminary trials (Hirai 2013; Yoshida 2014) and RCTs (Bodnar 2008; Muraki 2012)

N-Acetyl Cysteine

Positive case reports (Sheikh-Hamad 1997; Nisar 2002) and supportive animal research (Chen 2008)

IV Glutathione

Positive findings from one RCT (Smyth 1997)

Milk Thistle

Supportive animal research (Shahbazi 2012)

Ginkgo

Supportive animal research (Song 2013; Gulec 2006; Fukaya 1999)

L-Carnitine (in various forms, see text)

Supportive animal research (Sayed-Ahmed 2004; Yurekli 2011; Sayed-Ahmed 2012)

Selenium

Positive findings from preliminary trials (Ghorbani, Omidvar 2013; Naziroglu 2004) and two RCTs (Hu 1997; Hemati 2012)

Lycopene, Melatonin, Carnosic Acid, Ellagic Acid, Fisetin, Alpha-Lipoic Acid, Taurine, Sulforaphane, EGCG, Capsaicin, Berberine

Supportive animal research; see text for references

Chemosensory Dysfunction

Zinc

A positive case report in a patient with low serum zinc (Nishijima 2011)

Synsepalum dulcificum (Miracle Fruit)

Positive findings in a preliminary trial (Wilken 2012)

Hand-Foot Syndrome

Vitamin E

Positive findings from preliminary trials (Bozkurt Duman 2011; Yamamoto 2010)

Vitamin B6

Positive preliminary findings (Chen, Zhang 2013)

Gastrointestinal Disturbances

Probiotics for Diarrhea

Positive findings from RCT and confirmed in a meta-analysis (Wang, Yao 2016)

Glutamine for Diarrhea

RCT and a meta-analysis show reduced duration, but not severity, of diarrhea in patients taking glutamine (Sun 2012)

Omega-3 Fatty Acids

Supportive animal research (Xue 2011)

Senna Extract for Constipation

Preliminary support (Tao 2012)

Poor Nutritional Status/Cachexia

Glutamine

Positive findings from preliminary trials (Kuhn 2010)

Omega-3 Fatty Acids

Positive findings from preliminary trials (Murphy 2012)

L-Carnitine

Positive findings from preliminary trials (Isenring 2013) and one RCT (Kraft 2012)

Oral Mucositis

Honey

Positive findings from RCT and confirmed in a meta-analysis (Xu 2016)

N-Acetyl Cysteine

Positive findings from one RCT (Moslehi 2014)

Selenium

Positive findings from one RCT (Jahangard-Rafsanjani 2013)

Glutamine

Positive findings from one RCT (Tsujimoto 2015)

Topical Vitamin E

Preliminary evidence (El-Housseiny 2007)

Fatigue

Chemotherapy-related fatigue can include exhaustion, extreme weakness, depression, loss of motivation, difficulty concentrating, and a general sense of being unwell. Fatigue is the most common side effect of chemotherapy, with up to 96% of patients suffering from fatigue during treatment (Iop 2004; Tierney 1991; Visovsky 2003).

Conventional treatments for fatigue. Anemia is an important cause of chemotherapy-induced fatigue, and treating chemotherapy-induced anemia may prevent or improve fatigue (Mahoney 2014). Erythropoiesis-stimulating agents promote red blood cell formation. An analysis of four clinical trials that evaluated an erythropoiesis-stimulating agent known as darbepoetin alfa (Aranesp) found that it increased hemoglobin levels and improved chemotherapy-induced fatigue (Revicki 2012). A literature review found that erythropoiesis-stimulating agents made a clinically relevant difference in symptoms of chemotherapy-induced anemia (Bohlius 2014).

Integrative interventions for fatigue. Ashwagandha (Withania somnifera) is an herb with adaptogenic, anti-inflammatory, and anticancer properties. In an open-label trial in 100 breast cancer patients receiving two different chemotherapy regimens, ashwagandha plus chemotherapy was compared with chemotherapy alone. The dosage in this study was two grams of ashwagandha root extract every eight hours throughout the course of chemotherapy. Patients receiving chemotherapy alone had significantly higher fatigue scores than those who received ashwagandha. Ashwagandha treatment also improved quality of life (Biswal 2013).

Guarana (Paullinia cupana) is an Amazonian plant that contains catechins, epicatechins, and a small amount of caffeine (Subbiah 2008). In two small clinical studies, guarana improved chemotherapy-induced fatigue. In the first study, 40 cancer patients with solid tumors and increasing fatigue after one week of chemotherapy began receiving 37.5 mg guarana extract twice daily. After three weeks, 90% of participants showed improvement in fatigue scores (del Giglio 2013). The second study, which evaluated the effects of 50 mg guarana extract twice daily in 75 breast cancer patients experiencing chemotherapy-related fatigue, found guarana superior to placebo for relieving fatigue (de Oliveira Campos 2011).

American ginseng (Panax quinquefolius) is a close relative of the better-known Asian ginseng (Panax ginseng). It contains an array of biologically active compounds including ginsenosides and polysaccharides. American ginseng possesses adaptogenic and anti-inflammatory properties (Jia 2009; Wang 2009; Barton 2013). An 8-week randomized controlled trial found that 2000 mg of American ginseng improved cancer-related fatigue in 364 cancer patients. Participants in the trial had various types of cancer and were either receiving cancer treatment or had completed treatment. At the end of the trial, fatigue scores improved significantly more in the ginseng group compared with the placebo group. Participants in the ginseng group undergoing cancer treatment benefited more than those who had already completed cancer treatment (Barton 2013).

Melatonin is a hormone produced by the pineal gland; it helps regulate the sleep-wake cycle (Vural 2014; Brown 1994). Melatonin also has antioxidant properties and antitumor and immune-modulating effects. A review of eight randomized controlled trials, which included 761 patients with solid tumors, showed that 20 mg of melatonin per day significantly reduced chemotherapy-related side effects, including fatigue. Furthermore, melatonin use was associated with 40% reduced one-year mortality and did not cause any serious side effects (Seely 2012; Wang 2012).

L-carnitine is an amino acid that may benefit chemotherapy-related fatigue. Carnitine is involved in cellular energy metabolism and is often depleted in cancer patients, including as a result of chemotherapy (Fukawa 2016; Silverio 2011). A study evaluated the effects of L-carnitine in 50 fatigued patients with low plasma carnitine levels. These patients were undergoing treatment with either cisplatin or ifosfamide (Ifex) for stage IV cancer, but they were not anemic. The participants received four grams of oral L-carnitine daily. Within seven days, plasma carnitine levels normalized in all patients, and 45 patients experienced significant relief from fatigue. This improvement in fatigue lasted until the next cycle of chemotherapy (Graziano 2002). In a smaller study in 21 patients with advanced cancer who had carnitine deficiency and moderate-to-severe fatigue, supplementation with up to three grams daily of oral L-carnitine led to improvements in fatigue scores that correlated with increases in blood carnitine levels. No toxicity or significant side effects were noted (Cruciani 2006).

Certain mushrooms and mushroom extracts have immune-modulating properties and are used along with chemotherapy in China and Japan. A review of studies found that supplementation with polysaccharide peptide (PSP), a compound derived from the mushroom Coriolus versicolor, decreased side effects related to cancer treatment, including fatigue (Piotrowski 2015). In a randomized controlled trial in 48 breast cancer patients without anemia who were undergoing hormonal therapy, treatment with 3000 mg of Ganoderma lucidum (reishi) spore powder daily for four weeks resulted in significant improvements in fatigue and physical well-being, as well as in anxiety, depression, and overall quality of life (Zhao 2012).

Scores for fatigue and appetite significantly improved in a study of a fermented soybean extract in 143 patients undergoing chemotherapy (Chi 2014). Trials studying the effects of nutritional factors including glutamine and fish oil on cancer cachexia (weakness and weight loss) have also shown positive results with regards to improvement in fatigue (Schlemmer 2015; Cerchietti 2007). (These interventions are discussed further in the Nutritional Status and Cachexia section of this protocol.)

A rigorous study found that all tyoes of exercise (not just aerobic exercise) improved quality of life and fatigue in individuals undergoing cancer treatment, particularly when the exercise was moderate to vigorous in intensity (Mishra 2012). Other approaches that may be helpful include Qigong, yoga, acupuncture, massage and healing touch, mindfulness-based stress reduction, cognitive behavioral therapy, and other forms of stress-relieving or psychosocial support (Chien 2013; Mitchell 2014; Wang 2014; Taso 2014; Oh 2010).

Immunosuppression and Blood-Related Complications

Chemotherapy can damage the body’s blood-forming system. In fact, suppression of blood cell formation in the bone marrow (myelosuppression) is one of the most serious and common side effects of chemotherapy (Carey 2003; Zangemeister-Wittke 2009; Repetto 2009). Myelosuppression can result in low red blood cells (anemia), low white blood cells (leukopenia), or low platelets (thrombocytopenia). Rarely, production of all three types of cells is reduced. This is called pancytopenia (Zangemeister-Wittke 2009; Gayathri 2011).

In neutropenia, the most serious type of leukopenia, levels of infection-fighting neutrophils (a type of white blood cell) fall far below normal, often accompanied by fever (Bhatt 2004; Crawford 2004; Levenga 2007). Neutropenia raises the risk of life-threatening infection and can interrupt treatment schedules (Crawford 2004; Levenga 2007; Carey 2003). Myelosuppression leading to low platelets increases the risk of excessive bleeding (Carey 2003; Vadhan-Raj 2009).

Conventional treatments for blood-related and immunosuppressive complications of chemotherapy. Granulocyte-colony stimulating factor (G-CSF), antibiotics, and dose reduction are primary management strategies for the immunosuppressive effects of chemotherapy (Dale 2003; Aapro 2011). A rigorous study found that G-CSF use is associated with lower all-cause mortality in patients receiving chemotherapy, especially in those on intensive dosing schedules (Lyman 2013). Depending on the proposed chemotherapy regimen and pretreatment blood cell counts, preventive G-CSF and/or antibiotics may be administered to patients at high risk of neutropenia. These treatments may also be used for neutropenia (Timmer-Bonte 2006; Krzemieniecki 2014; Timmer-Bonte 2005; Choi, Solid 2014; Aarts 2013; Pfeil 2014). The combination of G-CSF plus antibiotics is more effective than either alone (Timmer-Bonte 2006). Patients with chemotherapy-induced thrombocytopenia may be candidates for platelet transfusion (Apelseth 2011).

A comprehensive discussion of strategies for addressing low levels of blood cells and platelets is available in the Blood Disorders protocol.

Integrative interventions for chemotherapy-associated immunosuppression. In 15 esophageal cancer patients scheduled to undergo surgery, perioperative supplementation with eicosapentaenoic acid (EPA), an omega-3 fatty acid found in fish oil, reduced immunosuppression caused by chemoradiation. Five subjects received 1.8 grams per day of EPA starting one week before their operation and continuing until hospital discharge; the other 10 did not take EPA. Subjects who had taken EPA exhibited more robust white blood cell proliferation in response to immune-stimulating chemicals and increased natural killer cell activity when compared with control subjects (Takagi 2001). Omega-3 fatty acid supplementation has been recommended for post-surgical and critically ill patients due to its anti-inflammatory and immune-enhancing effects (Calder 2004; Machon 2012; Goldfarb 2012; Moison 2001).

An extract of fermented wheat germ (FWGE) is approved in Europe, where it was developed, as a “dietary food for special medical purposes for cancer patients” (Demidov 2008). It is available in powdered form, has a favorable safety profile, and has been studied for a variety of conditions including cancer (Boros 2005). FWGE’s potential to prevent neutropenia was demonstrated in an early-stage open-label trial in 11 pairs of children being treated with standard chemotherapy for various cancers. One child in each pair received six grams of FWGE per square meter of body surface area, dissolved in water twice daily throughout the study, and the other did not. Counterparts in each pair were matched for age, gender, diagnosis, stage of disease, and previous chemotherapy exposure; however, two patients in the FWGE group had metastatic disease at the beginning of the study, while their paired counterparts did not. At the end of the study, the FWGE and control groups had undergone essentially the same degree of treatment in terms of chemotherapy and other therapies; however, the FWGE group experienced on average 80% fewer monthly episodes of neutropenia with fever compared with the control group. Furthermore, during neutropenic episodes, the total white blood cell and lymphocyte counts were not as low in the FWGE group as the control group (Garami 2004).

Animal and human research suggests probiotic lactobacilli may decrease chemotherapy-induced immunosuppression. In mice treated with cyclophosphamide, a drug known to cause neutropenia, the probiotics Lactobacillus casei CRL431 and Lactobacillus rhamnosus CRL1506 increased the number of certain types of blood stem cells in the bone marrow and induced faster recovery of neutrophil levels (Gold Standard 2016b; Salva 2014). In addition, the mice that recieved the probiotics were less susceptible to infection with Candida albicans, a yeast that is part of the normal microbial community but can become pathogenic in immunocompromised individuals (Naglik 2003). The scientists who carried out these experiments remarked “…probiotic lactobacilli have the potential to be used as alternatives for lessening chemotherapy-induced immunosuppression in cancer patients” (Salva 2014). A rigorous literature review found that probiotics reduced the odds of moderate-to-severe antibiotic- and chemotherapy-associated diarrhea in cancer patients by 68% (Redman 2014).

In an animal model, zinc supplementation reduced several aspects of immune system suppression caused by cyclophosphamide. Mice that received zinc were resistant to cyclophosphamide-induced reductions in numbers of white blood cells and mature T lymphocytes, suppression of IgM antibody production, and reduction of thymus weight (Zhang 1992). Quercetin, a flavonoid, was found in one study to modestly diminish doxorubicin-induced immunosuppression in rats. Quercetin treatment also resulted in lower levels of brain oxidative stress and fewer behaviors believed to indicate anxiety and depression (Merzoug 2014; Reagan-Shaw 2008).

Ashwagandha (Withania somnifera) helped control paclitaxel-induced immunosuppression in mice with lung cancer (Senthilnathan 2006). In another animal study, ashwagandha reversed paclitaxel-induced neutropenia in mice when administered for four days before paclitaxel treatment and continued for 12 days after treatment. The authors concluded that ashwagandha may be useful during cancer chemotherapy for the prevention of bone marrow suppression (Gupta 2001).

In a randomized controlled trial in 40 young adults with acute lymphoblastic leukemia, undergoing maintenance chemotherapy, supplementation with two grams of the amino acid taurine daily, compared with placebo, significantly reduced the number of episodes of fever and infection and increased white blood cell counts (Islambulchilar 2015).

Additional strategies for supporting healthy immune system function are reviewed in the Immune Senescence protocol.

Nausea and Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a burden for many cancer patients (Grunberg 2013). It can lead to malnutrition because patients with CINV may have diminished appetite (Marx 2016; Davidson 2012). CINV can also cause weight loss, fatigue, anxiety, treatment non-compliance, and poor treatment outcome (Janelsins 2013; Grunberg 2013). Cisplatin, doxorubicin, and cyclophosphamide are agents known to cause CINV (Janelsins 2013).

Conventional treatments for chemotherapy-induced nausea and vomiting. CINV can be prevented in almost 80% of patients with prescription antiemetics (ie, drugs to reduce nausea and vomiting) (Jordan 2014). Antiemetic drugs used to mitiagte CINV include (Viale 2005; Vrabel 2007; Gold Standard 2014; Gold Standard 2016a):

  • palonosetron (Aloxi), a 5-HT3 receptor blocker
  • oral aprepitant or intravenous fosaprepitant (Emend), a neurokinin-1 receptor blocker
  • ondansetron (Zofran)

Typically, a single intravenous dose of palonosetron is given 30 minutes prior to chemotherapy to prevent nausea and vomiting; this medication has a favorable safety profile (Gold Standard 2014; Popovic 2014; Schwartzberg 2014). Alternatively, a three-day regimen of oral aprepitant may be used, 125 mg one hour prior to chemotherapy on day one and 80 mg one hour prior to chemotherapy on days two and three (Gold Standard 2016a).

The steroid dexamethasone (Decadron) can also be combined with antiemetics to control CINV (Gralla 2016; Gao, Liang 2013). In addition, clinical studies show olanzapine (Zyprexa), an antipsychotic drug, may be helpful as a co-treatment for CINV prevention (Hocking 2014). Gabapentin (Neurontin), which is mainly used to treat neuropathic pain, has recently been found to have antiemetic effects and may be used for the treatment of CINV (Guttuso 2014). Another drug that may be used to treat CINV in some cases is megestrol acetate (Megace), a synthetic progesterone derivative. In one study, individuals undergoing chemotherapy were given megestrol acetate along with two other antiemetic medications, metoclopramide (Reglan) and granisetron (Kytril), or a combination of the two standard antiemetics without megestrol acetate. Complete protection against nausea and vomiting was observed in 45% of the megestrol acetate group versus only 17% of the group that did not receive megestrol acetate (Zang 2011).

Dronabinol (Marinol) is an oral form of delta-9-tetrahydrocannabinol, a cannabanoid from Cannabis sativa (marijuana), that has been FDA approved since 1985 to treat CINV that does not respond to usual treatment (May 2016). Among the more common possible side effects of dronabinol are drowsiness, dizziness, euphoria, paranoia, abnormal thoughts, and nausea and vomiting. One case study reported that a patient with end-stage ovarian cancer and peritoneal carcinomatosis whose nausea and vomiting did not respond to other treatments had a dramatic response to dronabinol (Hernandez 2013).

Integrative interventions for chemotherapy-induced nausea and vomiting. Several integrative strategies have been shown to mitigate chemotherapy-induced nausea and vomiting:

Ginger is a botanical antiemetic that has been used in traditional medicine for over 2000 years (Yekta 2012; Montazeri 2013; Palatty 2013; Lee 2013). The antiemetic effects of ginger are thought to involve the phytochemicals 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol. Interestingly, ginger may function via mechanisms similar to palonosetron (5-HT3 receptor blocker) and aprepitant (neurokinin-1 receptor blocker) (Gold Standard 2016a; Gold Standard 2014; Haniadka 2012).

In a randomized controlled trial, 744 cancer patients were given either 0.5 grams, 1.0 gram, or 1.5 grams of ginger root extract, or placebo, twice daily for six days, starting three days before their first day of chemotherapy. All doses of ginger supplementation resulted in significantly reduced severity of acute chemotherapy-induced nausea (Ryan 2012). In another controlled clinical trial, 80 women with breast cancer undergoing chemotherapy and suffering from chemotherapy-induced vomiting were given one gram of ginger root extract per day or placebo for six days, starting three days prior to chemotherapy. Those taking ginger had significantly less vomiting (Yekta 2012). A randomized trial involving 100 women with advanced breast cancer found the combination of standard antiemetic treatment plus 500 mg of dry powdered ginger root three times daily reduced nausea after chemotherapy significantly better than standard treatment alone (Panahi 2012).

The amnio acid taurine helped reduce CINV in leukemia patients in a clinical trial. This study randomized 40 subjects aged 16 - 23 with acute lymphoblastic leukemia who were undergoing chemotherapy to receive either one gram of taurine twice daily or placebo six hours after each chemotherapy treatment for six months. Thirty-two subjects completed the study. Those who took taurine were less likely to experience CINV; they also had greater improvement in chemotherapy-related taste and smell disturbances, appetite, and fatigue (Islambulchilar 2014).

Concord grape juice was shown in early research to reduce the frequency and duration of nausea and vomiting when consumed before meals following chemotherapy cycles (Ingersoll 2010). In a randomized clinical trial, acupressure at the P6 point (located on the wrist) using an acupressure wrist device was found to reduce the amount and intensity of delayed CINV, which begins 24 hours or more after chemotherapy, in women undergoing chemotherapy for breast cancer (Rice 2011; Dibble 2007). Use of an acupressure wristband, called Sea Band, is one way of applying pressure to the P6 point (Dundee 1990).

Peripheral Neuropathy

The nervous system consists of two primary parts: the central nervous system includes the brain and spinal cord; the peripheral nervous system includes nerves that emanate from the brain and spinal cord, along with their sensory and motor endings (O'Rahilly 2008). Chemotherapy can damage peripheral nerves, leading to symptoms such as tingling, pain, and numbness, especially in the extremities. This is called chemotherapy-induced peripheral neuropathy (CIPN). Other organ systems, such as the digestive and cardiovascular systems, also contain peripheral nerves, so CIPN can lead to symptoms such as constipation and arrhythmias (Kolak 2013). CIPN occurs in as many as 70% of individuals who undergo chemotherapy. Some drugs associated with CIPN are platinum compounds, taxanes, vinca alkaloids, thalidomide (Thalomid), and bortezomib (Velcade) (Argyriou 2014; Gewandter 2014).

Conventional treatments for chemotherapy-induced peripheral neuropathy. Unfortunately, there is no effective treatment for CIPN. As of early 2017, no medications are approved for the treatment of CIPN. There are also no preventives, and a rigorous review of literature found insufficient evidence to conclude that antidepressants or anticonvulsants reduce CIPN (Chu 2015; Majithia 2016; Park 2014; Cavaletti 2015).

One randomized controlled trial of the antidepressant duloxetine (Cymbalta) in 231 patients taking oxaliplatin, paclitaxel or other taxanes, found those receiving duloxetine were significantly more likely to experience a 30% or 50% reduction in pain than those in the placebo group (Smith 2013). Other studies have also shown a modest benefit for venlafaxine (Effexor), topical amitriptyline, and oxcarbazepine (Trileptal) (Chu 2015).

In a pilot trial, intravenous mangafodipir (Teslascan), a drug composed of a vitamin B6 derivative bonded to manganese, eased oxaliplatin-induced peripheral neuropathy (Coriat 2014). Vitamin B6 helps maintain normal nerve function and has neuroprotective activity (Zysset-Burri 2013; Yu 2014).

Integrative interventions for chemotherapy-induced peripheral neuropathy. Several integrative interventions with neuroprotective and neuroregenerative effects hold promise in the prevention and treatment of CIPN (Argyriou 2014; Wolf 2008).

Calcium and magnesium infusions may prevent CIPN (Piccolo 2014). A rigorous analysis of 16 studies involving 1765 patients with gastrointestinal cancers found that calcium and magnesium infusions significantly reduced the incidence of low- or moderate-grade oxaliplatin-induced neuropathy without interfering with the anticancer effect of chemotherapy (Xu 2013).

Glutathione has been shown to reduce neuropathy associated with cisplatin-based chemotherapy in gastric cancer patients (Cascinu 1995). N-acetyl cysteine (NAC) was shown in one study on colon cancer patients to mitigate neuropathy caused by oxaliplatin (Lin 2006). A randomized controlled trial in breast cancer patients undergoing chemotherapy with paclitaxel found that supplementation with omega-3 fatty acids reduced the incidence and severity of peripheral neuropathy. The subjects took 640 mg of omega-3 fatty acids three times daily during chemotherapy and for one month after chemotherapy completion (Ghoreishi 2012).

A meta-analyis of five randomized controlled trials involving 319 patients found that 333–900 IU of supplemental vitamin E daily reduced the risk of CIPN by 57%; vitamin E was particularly effective for patients on cisplatin therapy, reducing CIPN risk by 74%. No adverse effects of vitamin E were reported in any of the trials included in this analysis (Eum 2013).

In a double-blind placebo-controlled clinical trial in patients with ovarian cancer or prostate cancer, administration of intravenous sagopilone (a chemotherapy drug in development) along with 1000 mg acetyl-L-carnitine (at a dosage of 1000 mg every three days) significantly reduced the incidence of severe neuropathy without diminishing response to treatment (Campone 2013). An 8-week trial assess the effects of three daily oral doses of 1000 mg of acetyl-L-carnitine in 25 patients with severe CIPN. The subjects were undergoing paclitaxel or cisplatin therapy during the trial, or had moderate CIPN persisting for at least three months after discontinuing chemotherapy. Sensory neuropathy severity improved in 60% of subjects, and motor neuropathy improved in 79%. The total neuropathy score improved in 92% of subjects. Symptomatic improvement was maintained in 12 of 13 patients who were followed for an average of 13 months (Bianchi 2005). In a trial on 26 individuals with CIPN due to paclitaxel or cisplatin treatment, a daily intravenous dose of 1000 mg acetyl-L-carnitine for a minimum of 10 days resulted in reduced severity of neuropathy in 73% of subjects (Maestri 2005).

Several studies have found that the amino acid glutamine reduced the severity of CIPN resulting from oxaliplatin or high-dose paclitaxel treatment (Amara 2008). In one trial, 12 patients were given 10 grams oral glutamine three times daily beginning 24 hours after completing treatment with high-dose paclitaxel. The severity of their neuropathy was significantly lower than in 33 patients undergoing the same treatment without glutamine (Vahdat 2001). In a trial in patients with metastatic colorectal cancer treated with oxaliplatin, those receiving 15 grams oral glutamine, twice daily for seven consecutive days every two weeks, beginning on the day of oxaliplatin treatment, had a lower incidence of moderate and severe neuropathy compared with those receiving oxaliplatin alone. The glutamine group experienced less interference with normal activities and was less likely to have to reduce their oxaliplatin dosage. Glutamine did not interfere with the response to chemotherapy (Wang 2007).

Alpha-lipoic acid may reduce the risk of peripheral neuropathy in patients undergoing chemotherapy (Melli 2008). An early-phase trial was conducted in 14 cancer patients with moderate or severe peripheral neuropathy, which developed during or after docetaxel plus cisplatin chemotherapy. Subjects received 600 mg alpha-lipoic acid intravenously once per week for three to five weeks, followed by 1800 mg oral alpha-lipoic acid three times daily, for a maximum of six months or until they completely recovered from neurological symptoms. Eight (57%) participants had improvement in their neuropathy within four months (Gedlicka 2003).

Balance retraining has been shown to improve measures of balance in patients with peripheral neuropathies (Stubblefield 2012). Patients with CIPN have reported that exercise, mindfulness, and occupational therapy were helpful self-management strategies in reducing the impact of CIPN symptoms (Speck 2012).

Cardiotoxicity

Cardiotoxicity (toxic damage to the heart and blood vessels) is a common complication of chemotherapy, particularly with anthracyclines such as doxorubicin, epirubicin, and daunorubicin (van Dalen, Caron 2011). Other chemotherapy agents, including 5-FU and its prodrug, capecitabine (Xeloda), cisplatin, paclitaxel, and docetaxel, can also cause cardiotoxicity (Molinaro 2015; Stewart 2010). Cardiotoxicity can appear soon after or long after chemotherapy, and may vary from subclinical heart muscle dysfunction to heart failure (Stewart 2010; Kalam 2013; Lenihan 2012). Oxidative stress is a central mechanism underlying the cardiotoxicity of many chemotherapy agents (Sterba 2013).

Conventional treatments for cardiotoxicity. Published reviews have concluded that dexrazoxane (Zinecard, an iron-chelating agent), carvedilol (Coreg, a beta-blocker), valsartan (Diovan, an angiotensin receptor blocker), statins (a class of cholesterol-lowering medications), and enalapril (Vasotec, an angiotensin-converting enzyme inhibitor [ACE]-inhibitor), are effective in preventing heart muscle dysfunction and reducing cardiac events in patients treated with anthracyclines (Kalam 2013; Lenihan 2012).

Dexrazoxane is highly effective in reducing anthracycline-induced cardiotoxicity (Wang, Zhang 2013). Anthracyclines such as doxorubicin produce damaging reactive oxygen species via iron-dependent mechanisms, which are thought to be responsible for their cardiotoxicity (Xu 2005). Dexrazoxane is metabolized into a compound that binds free iron and protects the heart by preventing iron-related oxidative damage in cardiac tissue. This protection is particularly notable against anthracyclines (Sterba 2013; Hasinoff 2007). However, dexrazoxane can cause bone marrow suppression (Jordan 2009), and the manufacturer of this medication reported one clinical trial in which dexrazoxane may have interfered with the clinical response to doxorubicin (Gold Standard 2012).

Metformin, the most frequently prescribed antidiabetic drug, has been shown to mitigate doxorubicin-induced cardiotoxicity in several animal models (Ashour 2012; Argun 2016; Kelleni 2015). Two of these studies further examined the animals’ cardiac cells and found metformin inhibited doxorubicin’s oxidative and inflammatory effects (Ashour 2012; Kelleni 2015).

Enalapril is an ACE-inhibitor often used to treat heart failure (Sacks 2014; NLM 2017). In a trial in anthracycline-treated patients at high risk for cardiac side effects, early treatment with enalapril was found to prevent the development of late cardiotoxicity (Cardinale 2006).

Statin drugs may protect against late cardiotoxicity. In a study in 628 breast cancer patients who had been treated with anthracycline-based chemotherapy and were monitored for an average of just over 2.5 years, those taking a statin medication throughout the follow-up period had a 70% lower risk of developing heart failure (Seicean 2012).

Integrative interventions for cardiotoxicity. Coenzyme Q10 (CoQ10), a natural substance present in every cell in the body, is essential for cellular energy metabolism (Zheng 2008; Singh 2007). Evidence from preclinical and clinical studies suggests that cardiotoxicity caused by anthracycline drugs, such as doxorubicin and daunorubicin, may be preventable with CoQ 10 supplementation. Indeed, a review of the literature found that CoQ10 protects against cardiotoxicity (Roffe 2004). Because cardiotoxicity is a dose-limiting side effect of anthracyclines, CoQ10’s cardioprotective activity might enable higher dosages of anthracycline chemotherapy, and thus more effective cancer treatment, if administered along with treatment. Heart cell mitochondria contain a unique enzyme (an NADH dehydrogenase) on their inner mitochondrial membrane that is not present in other non-cardiac mitochondria. This enzyme converts anthracyclines to substances that cause severe oxidative stress, irreversible damage to mitochondrial DNA, and disruption of mitochondrial energy metabolism. This damage leads to death of heart cells, accounting for anthracyclines’ cardiotoxicity. CoQ10 appears to prevent damage to cardiac mitochondria, protecting against anthracycline-induced cardiomyopathy. Doses of CoQ10 used in clinical studies in the context of doxorubicin toxicity have ranged from 30 mg to approximately 200 mg daily (Conklin 2005).

L-carnitine is involved in energy production from fatty acids in the mitochondria of cells. There is a high concentration of carnitine in muscle cells, and in particular, cardiac cells. Certain chemotherapy regimens can result in a carnitine deficiency that may be reversible with carnitine supplementation (Sayed-Ahmed, Al-Shabanah 2010).

Clinical studies support the efficacy of carnitine in reducing or preventing chemotherapy-induced cardiotoxicity. In a randomized trial in 30 cancer patients undergoing immunotherapy with interleukin-2 (IL-2), there were significantly fewer cardiac complications in those who received 1000 mg oral L-carnitine daily in addition to IL-2 compared with those who received IL-2 alone (Lissoni 1993). In a study of 15 patients with breast or lung cancer undergoing treatment with doxorubicin or the doxorubicin-related compound epirubicin, subjects were divided into three treatment groups: doxorubicin, doxorubicin plus L-carnitine, or epirubicin. Twenty-five healthy individuals served as controls. Left ventricular function of the heart was assessed by echocardiogram. After six chemotherapy treatment cycles, the group that received L-carnitine had preserved systolic left ventricular function (De Leonardis 1987).

Green tea extract and the green tea flavonoid epigallocatechin-3-gallate (EGCG) show promise in preclinical studies in reducing cardiac damage resulting from treatment with doxorubicin (Zheng 2011; Li, Nie 2010; Khan 2014; Patil 2011). Laboratory and animal studies have shown green tea extract and EGCG can decrease oxidative stress and prevent cardiac tissue damage (Khan 2014; Patil 2011; Li, Nie 2010). In one of these studies, the addition of 100 mg/kg/day of green tea extract to doxorubicin treatment normalized blood pressure and restored normal electrocardiogram results in the test animals, compared with those treated with doxorubicin alone (Patil 2011). In another study, animals that received doxorubicin alone showed signs of tissue damage and increased free radical activity, while those that also received green tea extract had increased free radical scavenging enzymes in their heart tissue (Khan 2014).

Proanthocyanidins are phytochemicals found in a wide range of foods and medicinal plants. In an animal model, pretreatment with a grape seed extract rich in proanthocyanidins significantly reduced doxorubicin-induced cardiotoxicity (Bagchi 2002). In a similar study, mice given proanthocyanidin-rich grape seed extract for 7–10 days before receiving doxorubicin injections were almost completely protected from the drug’s toxic effects on blood chemistry and heart tissue; DNA damage was also reduced (Ray 2000). Findings from another study in which grape seed proanthocyanidins suppressed doxorubicin-related cardiotoxicity in rats indicated that the cardioprotective effects were mediated through antioxidant, anti-inflammatory, and antiapoptotic mechanisms (Boghdady 2013). A cell culture study found that proanthocyanidin-rich grape seed extract protected heart muscle cells from doxorubicin-induced toxicity without interfering with the antiproliferative effect of doxorubicin on breast cancer cells (Li, Liu 2010).

Rhodiola, an herbal adaptogen, was shown to improve cardiac function in cancer patients who received epidoxorubicin chemotherapy (Shen 2010). Cranberry (Elberry 2010), hawthorn (Shatoor 2014), and bilberry (Ashour 2011) extracts, which are known sources of free-radical-scavenging polyphenols (Dixon 2005; Kirakosyan 2003), have also prevented doxorubicin-induced cardiotoxicity in animal models. Animal research has found other compouds capable of combatting doxorubicin cardiotoxicity, including boswellia (Uma Mahesh 2013), onion extract (Alpsoy 2013), the Chinese herb Panax notoginseng (Liu 2008), the ginger phytochemical 6-gingerol (El-Bakly 2012), and a polyphenol-rich extract of the honeybee product propolis (Alyane 2008). In addition, the amino acid glutamine protected rats from cyclophosphamide-induced cardiotoxicity (Todorova 2009).

Vitamin E also has protective capacity aginst chemotherapy-induced cardiotoxicity. An animal model found that giving d-alpha-tocopherol, a form of vitamin E, to rats 24 hours before a high dose of doxorubicin reduced cardiotoxicity without interfering with the chemotherapeutic effects of doxorubicin on leukemia (Sonneveld 1978). In another study, rats that received seven weekly injections of doxorubicin in addition to a diet supplemented with alpha-tocopherol had 2- to 4-fold higher vitamin E concentrations in their cardiac mitochondrial membranes and reduced protein oxidation in their heart tissue (Berthiaume 2005).

Kidney Damage (Renal Toxicity/Nephrotoxicity)

Several chemotherapy drugs can cause kidney damage, notably cisplatin and methotrexate (Ries 1986; Widemann 2006; Miller 2010). Cisplatin causes acute kidney toxicity in about 25% of patients; kidney toxicity often necessitates treatment discontinuation (Solanki 2014). Two likely mechanisms for cisplatin-induced kidney damage are increased oxidative damage (dos Santos 2012) and altered metabolism of magnesium in the kidneys (Solanki 2014). High-dose methotrexate has been shown to cause kidney impairment in 2–10% of patients (Widemann 2014).

Conventional treatments for chemotherapy-associated nephrotoxicity. Kidney damage caused by methotrexate therapy is typically treated with hydration, alkalinization, and leucovorin (calcium folinate) (Holmboe 2012; Takimoto 1996; Widemann 2006). Glucarpidase (Voraxaze), a bacterial enzyme that cleaves methotrexate to form inactive metabolites, was FDA approved in 2012 for the treatment of toxic methotrexate concentrations caused by impaired kidney clearance. Toxic levels of methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase, which has been shown to induce a 99% or greater sustained reduction of serum methotrexate levels (Widemann 2014). Glucarpidase has rare and relatively mild adverse effects, including tingling, itchiness, flushing, nausea, vomiting, and headache (Green 2012).

Pentoxifylline (Trental, Pentoxil) is an anti-inflammatory and free radical scavenger that may provide kidney protection by improving cellular antioxidant activity, as well as by down-regulating tumor necrosis factor-alpha (TNF-α). An animal study demonstrated a protective effect of pentoxifylline on the kidney after methotrexate administration (Asvadi 2011).

The antioxidant drug amifostine (Ethyol) has been shown in preclinical and clinical studies to reduce the nephrotoxicity of cisplatin without interfering with antitumor activity (Akbulut 2014; Capizzi 1999). In a clinical trial involving 31 cancer patients who had solid tumors, amifostine plus chemotherapy (cisplatin and ifosfamide plus either etoposide or paclitaxel) was compared with chemotherapy alone. The subjects who received amifostine maintained a normal glomerular filtration rate (GFR), a measure of kidney function, after two chemotherapy cycles, whereas a 30% reduction in GFR occurred in subjects who did not receive amifostine (Hartmann 2000).

Avoid dehydration. Avoiding dehydration helps prevent kidney toxicity caused by chemotherapy (Sato 2011; Tiseo 2007). It is critical to maintain sufficient intake of fluid and electrolytes.

Integrative interventions for chemotherapy-associated nephrotoxicity. In a randomized controlled trial in ovarian cancer patients undergoing treatment with cisplatin plus paclitaxel, participants received either magnesium or placebo. Five grams of magnesium sulfate was administered intravenously every three weeks before each course of chemotherapy. Participants also took 500 mg of magnesium subcarbonate orally three times daily between treatments. Kidney function was better preserved in the magnesium-supplemented group (Bodnar 2008). Another trial compared traditional intravenous hydration therapy to hydration therapy with magnesium in patients with non-small cell lung cancer. The participants were treated with cisplatin and pemetrexed (Alimta), a folate antimetabolite with a mechanism of action similar to methotrexate. Thirty patients received traditional hydration therapy, consisting of saline, mannitol (Osmitrol), and the diuretic furosemide (Lasix), and 20 patients received modified hydration therapy, consisting of saline, mannitol, and magnesium, but not furosemide. The magnesium-treated group showed significantly greater creatinine clearance, a measure of kidney function (Muraki 2012).

A small two-week trial of intravenous magnesium sulfate administered before cisplatin and 5-FU chemotherapy was undertaken in patients with esophageal and hypopharyngeal cancer. Compared with those who did not receive magnesium (13 patients), subjects who received magnesium (10 patients) exhibited significantly less kidney toxicity (Hirai 2013). A 2014 study compared magnesium treatment prior to cisplatin chemotherapy for thoracic malignancies (161 patients) to cisplatin alone (335 patients). Kidney toxicity was considerably less common in the magnesium-treated group (Yoshida 2014).

A rodent and cell culture study showed that magnesium deficiency significantly increased markers of cisplatin-induced kidney damage. Magnesium treatment reversed these effects. Magnesium deficiency increased platinum accumulation in the kidney, which altered the expression of important kidney transport proteins, another effect reversed by magnesium replacement. Tests using ovarian, breast, and lung cancer cells found that magnesium treatment did not diminish cisplatin's effectiveness as a chemotherapeutic agent (Solanki 2014).

N-acetyl cysteine (NAC) can help replenish stores of the antioxidant glutathione (Matera 2016; Rushworth 2014). Both NAC and glutathione have been studied as preventives for kidney toxicity and neurotoxicity. In a phase III trial in 151 women with ovarian cancer being treated with cisplatin, 74 women were given intravenous glutathione before chemotherapy and 77 were given sterile saline as a placebo. The glutathione dose was three grams per square meter of body surface area. The women who received glutathione maintained better kidney function than those who did not, as evidenced by preservation of creatinine clearance rates. The glutathione group also had less depression, vomiting, peripheral neuropathy, hair loss, shortness of breath, and difficulty concentrating. Because of the reduction in side effects and improved quality of life, they were also more likely to tolerate all six cycles of cisplatin without a dose reduction (Smyth 1997).

Case reports demonstrate improvement in kidney function with NAC in individuals with cisplatin-induced kidney toxicity (Sheikh-Hamad 1997; Nisar 2002). NAC has also been found to protect against ifosfamide-induced kidney toxicity in experiments on cultured cells and in a study in rats (Chen 2007; Chen 2008). In addition, NAC does not appear to interfere with ifosfamide’s antitumor effect (Chen 2011).

Silybum marianum, or milk thistle, is well known for its liver-protective properties and has also been shown to protect the kidneys from chemotherapy-induced damage in rodent and cell studies. The active constituent silymarin has anti-inflammatory and antioxidant activity. Several studies indicate that silymarin rmitigates the nephrotoxic effects of cisplatin without compromising its antitumor effect (Shahbazi 2012). Milk thistle offers more pronounced kidney protection when used before rather than after chemotherapy (Karimi 2005; Shahbazi 2012).

Ginkgo biloba is a medicinal plant with a long history of use in traditional Chinese medicine. It is typically used to support cognitive function. Ginkgo’s antioxidant and anti-inflammatory properties may contribute to its ability to protect against cisplatin-induced kidney toxicity.

In a rodent model, a standardized ginkgo extract prevented cisplatin kidney toxicity. Serum levels of blood urea nitrogen (BUN) and creatinine, indicators of kidney function, improved in rodents given ginkgo compared with rats given cisplatin alone (Song 2013). Other studies in rats have demonstrated that ginkgo can provide kidney protection from cisplatin toxicity without interfering with the anticancer effect of the drug (Gulec 2006; Fukaya 1999).

L-carnitine has been shown in preclinical studies to protect against kidney toxicity from cisplatin and ifosfamide (Sayed-Ahmed 2010; Sayed-Ahmed 2012; Jafari 2013). Animal studies have shown that multiple forms of carnitine, including L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine, can protect against cisplatin-induced kidney toxicity (Yurekli 2011; Tufekci 2009; Aleisa 2007). A study in rodents identified carnitine deficiency as a risk factor for cisplatin-induced kidney damage. This study also found L-carnitine injections normalized markers of kidney function (Sayed-Ahmed 2004). Daily injections of L-carnitine in rats treated with ifosfamide resulted in less oxidative stress and kidney damage compared to treatment with ifosfamide alone (Sayed-Ahmed 2012).

In a trial involving 46 cancer patients, those who received selenium (200 mcg) and vitamin E (400 IU) had less cisplatin-induced kidney toxicity than those who received placebo (Hemati 2012). In a separate trial involving 122 cancer patients, a daily dose of 400 mcg oral selenium prevented cisplatin-induced acute kidney injury when added to hydration therapy (Ghorbani, Omidvar 2013). Other studies have shown selenium supplementation may help reduce kidney toxicity and bone marrow suppression caused by cisplatin (Ghorbani 2013; Naziroglu 2004; Hu 1997).

Hair Loss (Alopecia)

Hair loss caused by chemotherapy is common and distressing (Randall 2005; Choi, Kim 2014). Chemotherapy drugs disrupt the rapidly proliferating cells responsible for hair growth, resulting in weakening of the hair shaft with subsequent breakage and hair loss (Yeager 2011).

Conventional treatments for chemotherapy-associated hair loss. Topical minoxidil (Rogaine) is an effective therapy to accelerate hair regrowth after chemotherapy (Yeager 2011). If a non-drug treatment is preferred, one such modality is scalp cooling. Cooling the scalp during chemotherapy can help prevent hair loss and has been shown to be safe and well tolerated. This approach uses a cooling cap placed snugly over the patient’s scalp during chemotherapy infusion (Ekwall 2013). The cooling causes a reduction in blood flow to the scalp, so less of the chemotherapeutic drugs reach the hair follicles (van den Hurk 2013). Side effects, such as headache, dizziness, coldness, and claustrophobia, sometimes occur with scalp cooling (Komen 2011).

Chemosensory Dysfunction

Chemosensory functions, such as taste, smell, and hearing, are often distorted during chemotherapy. Platinum-based chemotherapies (eg, cisplatin, carboplatin) are notorious for causing chemosensory dysfunction. Fortunately, recovery typically occurs after treatment ends (Steinbach 2012; Bernhardson 2008). Currently, there is no approved treatment for chemotherapy-induced chemosensory dysfunction. However, strategies such as increasing the use of spices or flavoring agents during food preparation may be helpful (Steinbach 2012).

Integrative interventions for chemosensory dysfunction. Disorderd taste sensation, such as altered taste or metallic taste (termed dysgeusia), is associated with poor nutrition and can reduce quality of life (Sánchez-Lara 2010; Mattes-Kulig 1985).

Some early evidence suggests that zinc suopplementation may help alleviate taste distrubances in cancer patients receiving chemotherapy, though the evidence is not strong (Nishijima 2013; Asano 2012; Nishijima 2011).

Miracle fruit (Synsepalum dulcificum) contains a protein, miraculin, which produces a sweet taste in an acidic environment, thereby masking unpleasant tastes and increasing the palatability of foods for a short time. A preliminary clinical study on eight cancer patients undergoing chemotherapy found that consumption of miracle fruit improved chemotherapy-associated taste disturbances, which might then lead to better nutrition (Wilken 2012).

Hand-Foot Syndrome (HFS)

Hand-foot syndrome (HFS) is a reaction of the skin to certain chemotherapy agents, including 5-FU, capecitabine, cytarabine (Depocyt), and pegylated liposomal doxorubicin (Doxil, Caelyx). The symptoms of HFS include tingling, pain, redness, swelling, and blistering (Qiao 2012; Bartal 2011).

Conventional treatments for hand-foot syndrome. Supportive treatments include topical wound care, elevation of the affected body part, cold compresses, and avoiding clothing and activities that put pressure on hands and feet (Mayo Clinic 2013). The anti-inflammatory drug celecoxib (Celebrex) is a promising intervention to prevent HFS. However, celecoxib is not recommended for those with heart disease because it increases heart attack risk (De Vecchis 2014; Macedo 2014; Caldwell 2006; Zhang 2012; El-Rayes 2006).

Integrative interventions for hand-foot syndrome. In a randomized controlled trial, 106 patients with colorectal or breast cancer were given 50 mg vitamin B6 (as pyridoxine) or placebo three times daily in addition to palliative treatment with capecitabine. In the pyridoxine group, there was a trend toward better capecitabine dosage maintenance and fewer high-grade HFS adverse effects (Corrie 2012). Pyridoxine has a history of successful use, at doses ranging from 50 to 800 mg per day, for the prevention and treatment of HFS caused by sorafenib (Nexavar), doxorubicin, 5-FU, docetaxel, or etoposide. Evidence suggests that 400 mg per day of pyridoxine may be more effective than lower dosages (Chen, Zhang 2013).

Vitamin E was used in a clinical study involving liver cancer patients treated with the chemotherapy agent sorafenib, which is known to cause HFS. Vitamin E at a dose of 333 to 450 IU per day controlled HFS after 10 to 12 days (Bozkurt Duman 2011). Another study described a positive effect of 100 to 600 IU of vitamin E daily in breast cancer patients experiencing HFS caused by capecitabine. Supplementation with vitamin E reduced skin complications within seven days, and the effects lasted throughout treatment. Neurological symptoms, skin peeling, and pain were reduced. Moreover, among those receiving vitamin E, the median time to cancer progression was 10.2 months, while those not taking vitamin E exhibited a median time to cancer progression of 6.1 months (Yamamoto 2010).

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is a potentially life-threatening disorder that occurs when tumor cells undergo rapid lysis (breakdown), either spontaneously or in response to chemotherapy. TLS most often occurs after the start of cytotoxic therapy in patients with high-grade lymphomas (particularly the Burkitt lymphoma subtype) and acute leukemias, or after treatment of large or fast-growing tumors. These are highly metabolically active cancers that tend to have a strong response to cytotoxic chemotherapy—that is, large numbers of cancer cells die rapidly. The dying cancer cells release potassium, phosphorus, and nucleic acids into the bloodstream (Wilson 2012). Breakdown of nucleic acids to uric acid leads to a significant increase in uric acid excretion, which can result in acute kidney injury (Mughal 2010), while hyperkalemia (high levels of potassium), hyperphosphatemia (high levels of phosphorus), and secondary hypocalcemia (low levels of calcium) can quickly progress to medical emergencies (Wilson 2012).

Prevention of TLS is critical and requires identification of patients at risk of developing TLS during chemotherapy. Factors that affect TLS risk include tumor type (particularly hematologic malignancies), specific tumor characteristics (eg, bulky tumor, high cellular proliferation rate), and baseline creatinine (Wilson 2012). For intermediate-risk patients, hydration plus the uric acid-lowering drug allopurinol (Zyloprim) or rasburicase (Elitek), is recommended to prevent TLS. For those at high risk, hydration plus rasburicase is recommended for prevention (Coiffier 2008). When allopurinol is administered along with purine-based chemotherapy drugs such as mercaptopurine (Purinethol) or azathioprine (Imuran, Azasan), reduction of the chemotherapy dosage is required. Allopurinol is contraindicated for use with capecitabine (Mughal 2014; Held-Warmkessel 2010).

Conventional treatments for tumor lysis syndrome. Treatment of TLS requires vigorous intravenous hydration (Mughal 2014; Coiffier 2008). Monitoring of electrolyte abnormalities and therapy with uric acid-lowering drugs (allopurinol or rasburicase) are important in treating TLS (Coutsouvelis 2013; Lam 2013; Mughal 2014). Phosphate binders, such as aluminum hydroxide, or calcium acetate or carbonate may be used. Hemodialysis may be required in some cases (Held-Warmkessel 2010).

“Chemo Brain” or “Chemo Fog”

“Chemo brain” and “chemo fog” refer to problems with cognitiino and memory following chemotherapy. The condition can last months to years (Raffa 2013). 5-FU is frequently associated with chemotherapy-associated cognitive impairment. What makes patients susceptible to chemo brain, and precisely what biologic mechanisms are involved, are not clearly established (Wigmore 2010; Taillibert 2010).

Cognitive problems associated with cancer chemotherapy may be related to elevation of inflammatory cytokines such as IL-6 and TNF-α, as well as to structural and functional brain changes (Kesler 2013). Systemic inflammation has been linked to impaired cognitive function and aberrations in brain structure in many settings (refer to the Age-Related Cognitive Decline protocol for a more thorough discussion of the role of inflammation in cognitive dysfunction).

Another theory posits that the distress associated with a cancer diagnosis may contribute to altered cognitive function and eventually lead to depression and anxiety (Hess 2007). Thus, taking steps to manage stress may benefit individuals who experience cognitive deficits during cancer treatment. A comprehensive discussion about coping with stress is available in the Stress Management protocol.

Gastrointestinal Disturbances

Chemotherapy can cause a range of adverse gastrointestinal effects ranging from nausea and vomiting to diarrhea, constipation, and loss of appetite (ACS 2015; NCI 2007; DeBoer 2008).

Conventional treatments for gastrointestinal disturbances. Conventional management of nausea and vomiting is covered in the section on chemotherapy-induced nausea and vomiting. It may be possible to manage some cases of chemotherapy-induced diarrhea with supportive measures (NCI 2012). Loperamide (Imodium) and diphenoxylate (Lomotil), an opioid agonist, are first-line medical treatments for chemotherapy-induced diarrhea. Octreotide (Sandostatin) may be used in persistent cases; hospitalization along with rehydration, antibiotics, and octreotide may be indicated in severe cases, and chemotherapy dose reduction is sometimes necessary (Kadowaki 2011; Maroun 2007).

Constipation is frequent in patients who undergo cancer treatment (Davila 2008). Often, constipation is not a result of the chemotherapy drug, but is secondary to drugs given to control chemotherapy side effects or relieve cancer symptoms, such as anti-nausea drugs and pain relievers (Gibson 2006). Other medications used in cancer care that are capable of causing constipation include vinca alkaloids, antidepressants and anti-anxiety medications, iron supplements, cardiovascular drugs, nonsteroidal anti-inflammatory drugs, antacids, anti-nausea drugs, and antispasmodics (Avila 2004). Stool softeners and laxatives, such as the osmotic agents lactulose (Generlac) and sorbitol, may be prescribed for constipation (Davila 2008; Avila 2004).

Integrative interventions for gastrointestinal disturbances. In a case study, a patient with stage IV breast cancer and severe chemotherapy-induced diarrhea with incontinence and abdominal cramping was successfully treated for diarrhea with a multispecies combination probiotic (Abd El-Atti 2009). The combination probiotic consisted of eight strains of live, freeze-dried lactic acid bacteria, but the specific strain swere not described in the paper that reported this case study. A review of studies in patients with abdominal and pelvic cancers concluded that probiotics may have a beneficial role in preventing moderate-to-severe chemotherapy-induced diarrhea (Wang, Yao 2016).

A meta-analysis found the amino acid glutamine significantly reduced duration of chemotherapy-induced diarrhea (Sun 2012). Other studies found glutamine helpful in ameliorating the gastrointestinal toxicity of chemotherapy (Kuhn 2010). In one study where glutamine was used along with chemoradiotherapy for non-small cell lung cancer, the nutrient did not interfere with treatment efficacy and helped prevent weight loss and unplanned treatment delays (Topkan 2012). Omega-3 fatty acids from fish oil may also prevent adverse gastrointestinal toxicity related to chemotherapy (Xue 2011).

Senna extract can be effective and is safe in treating chemotherapy-induced constipation (Tao 2012). Daily exercise, adequate hydration, and dietary fiber may also help prevent and alleviate chemotherapy-induced constipation (Lederle 1995). For more information on integrative management of constipation, please consult the Constipation protocol.

Nutritional Status and Cachexia

Cancer patients often become malnourished, either because of their disease or as a side effect of cancer treatment. Maintaining adequate nutritional status and body weight, as well as avoiding cachexia (wasting of muscle and fat tissue), is critically important for cancer patients, as these factors have been associated with reduced quality of life and greater chemotherapy toxicity (Fearon 2013). Maintaining adequate nutrition allows the patient to continue treatment and avoid further complications. Chemotherapeutic regimens that cause gastrointestinal disturbances such as nausea and vomiting, diarrhea, and constipation may impair nutritional status and worsen prognosis (Xue 2011; NCI 2014b).

Cachexia is more than just a nutritional problem. This condition is a complex side effect of cancer itself, in which tissues are broken down and protein synthesis decreases. Proinflammatory cytokines produced by the patient’s tumor(s), such as TNF-α, IL-1, and IL-6, contribute to this process, and central nervous system and hormonal signaling may also be involved (Nicolini 2013; Fearon 2013; Chabner 2013b).

Medications and integrative interventions can aid in maintaining nutritional status. When food and caloric intake is reduced, nutritional support is important (Fearon 2013). A literature review found that megestrol acetate, a synthetic progesterone derivative, improved appetite and helped cancer patients gain weight (Ruiz Garcia 2013). However, megestrol acetate can cause significant side effects such as fluid retention, depression, and blood clots (Gold Standard 2016c). Dronabinol, a synthetic cannabinoid, may also be used in the treatment of chemotherapy-related weight loss; however, the evidence supporting the use of dronabinol for appetite remains preliminary, and one study found megestrol acetate was more effective (Jatoi 2002; Walsh 2005).

The conditionally essential amino acid glutamine, which is especially vital for the severely ill, has been shown to improve clinical status of cancer patients, aiding in the provision of adequate nutrition, without increasing tumor burden (Lacey 1990; Kuhn 2010). Omega-3 fatty acids in fish oil may help with cancer cachexia, preserving muscle mass and functional ability, and improve chemotherapy tolerance and response, leading to greater clinical benefit (Murphy 2012; Laviano 2013). L-carnitine is a promising integrative intervention for fatigue associated with cachexia. In one placebo-controlled study, L-carnitine helped maintain body weight, body fat, and nutritional status (Isenring 2013; Kraft 2012). A growing body of research points to multiple modality treatments that use nutrition, medication, and side-effect management to address cachexia in cancer (Solheim 2012).

Oral Mucositis

Oral mucositis is a very painful condition marked by ulcerative lesions on the oral surfaces. It is a common complication of cancer treatment, occurring in 40‒80% of patients undergoing chemotherapy, and can predispose to infections of the oral mucosa (Campos 2014; Chaveli-Lopez 2016). Pain and risk of secondary infections from oral mucositis are generally managed with oral hygiene practices, local anesthetics, mouthwashes, and other agents with anti-inflammatory, analgesic, and antimicrobial properties (Campos 2014; Zhang 2011; Chaveli-Lopez 2016).

Conventional treatments for oral mucositis. Oral cryotherapy, which involves sucking on small ice cubes for about 30 minutes, provides relief of pain caused by mucositis. In addition, the application of ice for 5‒10 minutes before, 15‒35 minutes during, and 30 minutes after chemotherapy significantly reduces mucositis (Chaveli-Lopez 2016; Campos 2014). Low-intensity laser therapy is sometimes used as a pretreatment to reduce mucositis severity in patients undergoing chemotherapy; however, its use is limited due to the requirement for expensive equipment and specially trained operators. Oral mucosal protectant gels that form a barrier on the surface of the affected mucous membrane, protecting it against irritation from food and liquids, are also sometimes used (Campos 2014). Topical steroids, applied to surfaces of the oral cavity, may be used to treat mucositis (Raeessi 2014). Prescription mouthwashes, variably containing antibiotics, antihistamines, antifungals, corticosteroids, and antacids, are also frequently used to treat chemotherapy-induced oral mucositis. These formulations are colloquially referred to as “magic mouthwash” (Moynihan 2014).

Integrative interventions for oral mucositis. In an intriguing double-blind randomized clinical trial, researchers divided 75 adults with chemotherapy-induced oral mucositis into three groups. The first group received a syrup-like solution containing a steroid; the second group received a similar solution containing honey; and the third group received a solution with honey plus coffee. The study participants sipped 10 mL of the prescribed solution every three hours for one week. Although all three groups benefited from treatment, the group that received honey plus coffee showed the most improvement (Raeessi 2014). A meta-analysis of published studies concluded that honey could effectively prevent chemotherapy- and radiation therapy-induced oral mucositis (Xu 2016).

In a randomized controlled trial, leukemia patients undergoing bone marrow transplant, preceded by high-dose chemotherapy, were given 100 mg/kg N-acetyl cysteine (NAC) or placebo daily for 15 days after the procedure. The incidence of severe oral mucositis was significantly lower, and the duration shorter, in the NAC-treated group (Moslehi 2014).

Selenium protects cells through its participation in the glutathione peroxidase system, and prevents toxic effects caused by some chemotherapy drugs. A clinical study evaluated the efficacy of selenium for the prevention of oral mucositis in 77 leukemia patients undergoing bone marrow transplant. Thirty-seven patients received 200 mcg oral selenium twice daily while 40 matched patients received placebo from the first day of chemotherapy until 14 days after transplantation. The incidence of severe oral mucositis and the duration of moderate-to-severe symptoms were significantly lower in the selenium-treated group (Jahangard-Rafsanjani 2013).

Glutamine has been used topically, as an oral supplement, and intravenously to prevent and treat chemoradiotherapy-induced oral mucositis, with mixed results (Chaveli-Lopez 2016). In one randomized controlled trial, 40 previously untreated patients with head and neck cancer received either placebo or 10 grams of glutamine three times daily over the course of six weeks, during which time they were treated with radiation plus cisplatin and docetaxel. One-quarter of subjects in the placebo group, and none in the glutamine group, developed severe mucositis. From week four to six, mucositis severity was reduced and pain scores were lower in subjects taking glutamine (Tsujimoto 2015).

Topical vitamin E and natural mouthwashes containing herbs with antimicrobial activity such as chamomile, sage, and myrrh (a tree resin) have also been investigated as possible treatment aids for oral mucositis, but more research is needed (Campos 2014).

Vitamin D Insufficiency

Vitamin D has numerous beneficial effects throughout the body. It is especially pertinent in the context of immune system health, calcium metabolism, and cancer prevention (Dimitrov 2014; Feldman 2014). With regard to cancer, vitamin D helps regulate cell proliferation and slows growth of malignant cells in several tissue types (Moukayed 2013). Furthermore, laboratory studies suggest vitamin D can sensitize some types of cancer to the toxic effects of chemotherapy. For instance, pretreatment with vitamin D enhanced the cytotoxicity of doxorubicin on breast cancer cells in a laboratory study (Ravid 1999). In another study, vitamin D combined with all-trans retinoic acid lowered the threshold at which paclitaxel and doxorubicin were able to kill breast cancer cells (Wang 2000).

It appears that undergoing chemotherapy may decrease vitamin D levels. In a study on women with locally advanced breast cancer, over 79% of subjects had vitamin D insufficiency (25-hydroxyvitamin D levels below 30 ng/mL) before chemotherapy, and that number increased to over 97% after chemotherapy (Jacot 2012). A study of 50 colorectal cancer patients found that people undergoing chemotherapy had a markedly attenuated rise in vitamin D blood levels in response to vitamin D supplementation compared with people not undergoing chemotherapy (Fakih 2012).

Mitigating Chemotherapy Side Effects with Intermittent Fasting

Fasting induces an array of biochemical and physiological changes that may delay aging and the onset of chronic degenerative diseases, including cancer (Lee 2011; Brandhorst 2015; Stipp 2015; Safdie 2012). Some forms of fasting or caloric restriction may also protect animals and cancer patients from some chemotherapy side effects and sensitize cancer cells to the effects of chemotherapy (Lee 2011; Brandhorst 2013; Horne 2014; Stipp 2015; Safdie 2012). Interestingly, preliminary reports suggest that fasting for several days followed by normal food consumption may protect patients against chemotherapy toxicity without causing long-term weight loss (Lee 2011).

In a randomized early-stage trial, a 48-hour fast reduced chemotherapy immunotoxicity in women with breast cancer. Thirteen women with HER2-negative stage II or III breast cancer participated in the study. Seven women fasted for 24 hours before and after receiving neo-adjuvant chemotherapy, while the remaining women ate normally. The women received a chemotherapy regimen that included docetaxel, doxorubicin, and cyclophosphamide. Laboratory studies of subjects’ blood 30 minutes after chemotherapy revealed significantly less DNA damage in lymphocytes and monocytes in blood samples from the fasting women compared with those from the women who ate normally. This protective effect was still detectable seven days after chemotherapy treatment (de Groot 2015).

There are several potential mechanisms by which fasting may interfere with tumor progression and protect healthy cells against chemotherapy toxicity, but reductions in levels of glucose and insulin-like growth factor-1 (IGF-1) are often cited as important mediators of these benefits (Lee 2010; Hine 2014; Safdie 2009; Cheng 2014; Brandhorst 2013). In a chemotherapy toxicity study, one group of mice underwent a 48-hour fast, while another group underwent a 48-hour fast but also received injections of IGF-1. Both groups received injections of the cytotoxic agent doxorubicin. In the fasting-only group, the survival rate after injection of doxorubicin was 100%; in the group who fasted and received IGF-1 injections, the survival rate was only 38% (Lee 2010).

Fasting triggers healthy cells to switch into a “protected mode” that confers resistance to toxins, including chemotherapy. In cancer cells, pro-cancer genes called oncogenes prevent this switch. In other words, under fasting conditions, healthy cells are protected against toxicity from chemotherapy but cancer cells are not. This phenomenon has been called differential stress resistance (Raffaghello 2010).

In a report on 10 cases, subjects with various types of cancer voluntarily fasted for 48–140 hours before receiving chemotherapy and/or 5–56 hours after chemotherapy. Six of the patients underwent chemotherapy in both a fed and a fasted state at different times; they reported reduced fatigue, weakness, and gastrointestinal side effects while fasting. The other four subjects underwent all of their chemotherapy treatments while fasting; the severity of most side effects was reported to be low relative to typical experience. In cases in which cancer progression could be assessed, fasting did not reduce the efficacy of chemotherapy (Safdie 2009).

Abundant preclinical evidence indicates fasting itself may retard cancer growth. A series of studies in cancer cell lines showed cycles of fasting were as effective as chemotherapy in delaying the progression of various tumors. Moreover, fasting increased the ability of chemotherapy to kill several types of cancer cells. The researchers who conducted this investigation concluded “These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers” (Lee, Raffaghello 2012).

To learn more about the health benefits of caloric restriction, refer to the Caloric Restriction protocol.