Introduction

The global incidence of childhood cancer has observed

a steady increase in the past decade likely due to increased

access to treatment and improved reporting of childhood

cancer.1 Survival rates exceed 90% for the most common

childhood malignancy, acute lymphoblastic leukemia (ALL),

whereas overall survival of all pediatric malignancies is 70%.2

The scientific advances for the treatment of childhood cancer

have led to significant controversy over the use of understudied

and less well-known treatments that comprise integrative

medicine. Several surveys have reported that the combined use

of integrative medicine in children undergoing treatment for

malignancies is high in several countries3,4; however, there is a

general consensus that the evidence supporting its efficacy

remains unclear for most indications. The lack of demonstrated safety and efficacy, the potential for adverse interactions with prescribed therapy, delays in seeking conventional

treatment, and the risk of diminishing the high cure rate obtained for several pediatric malignancies have raised concerns

about the use of integrative medicine and have created barriers

to its integration into pediatric cancer care.

Ketogenic diet

The relationship between carbohydrates and cancer has

been supported by preclinical experimental studies, prospective observational studies, and small pilot studies.16 The

role of sugar in cancer growth is fostered from the early

work of Otto Warburg who discovered that cancer cells  preferentially underwent glycolysis for energy production,

even in the presence of oxygen,16 an observation that has

become one of the most consistent hallmarks of cancer.17

The efficacy of the ketogenic diet among children and adolescents receiving cancer treatment has not been tested in a

randomized trial. One case series described the administration of a ketogenic diet (60% medium chain triglycerides,

20% protein, 10% carbohydrate, and 10% dietary fat) for a

period of 8 weeks to two children with astrocytoma.18 The

authors found that the ketogenic diet promoted weight gain

and improved quality of life, suggesting a beneficial effect

among children with a brain tumor. Importantly, no adverse

events were associated with the ketogenic diet. The ability

of patients to adhere to a diet that is significantly different

than typical dietary regimens may be difficult to test in a

randomized study. Additional research evaluating its feasibility and effectiveness in childhood cancer is necessary

before its incorporation into cancer care

Lifestyle Interventions (Diet and Physical Activity)

Lifestyle interventions aimed at improving dietary intake

and physical activity have a beneficial effect on reducing the

risk of several adult cancers.19 Despite the high incidence of

nutritional-related late effects among survivors of childhood

cancer,20–22 there remains a paucity of data on the effect of

lifestyle behaviors and risk of subsequent cancers or development of late effects. The clinical implications of unhealthy diets on the risk of cancer among adolescents are

limited and focus primarily on dietary intake during adolescence and risk of breast cancer.23 A limited number of

dietary studies have evaluated single nutrients or food

groups; few studies have reported on comprehensive indices

of dietary intake (e.g., Healthy Eating Index).24,25 Moreover, the majority of studies have been observational rather

than interventional studies. For physical activity, the existing studies have evaluated physical activity as an intervention during and after treatment.

In one of the largest observational dietary studies

among survivors of childhood cancer, the diet of 170

survivors was evaluated. The authors found that improved

adherence to national dietary guidelines was significantly

associated with improved quality of life and reduced fatigue.26 Moreover, this study identified at-risk groups of

survivors who may be more vulnerable to the effects of

suboptimal dietary practices. The authors observed that

females, adolescence and young adults, and survivors of

tumors of the central nervous system or lymphoma may be

at higher risk of following poor dietary patterns than other

groups of survivors. Tonorezos et al. reported that with

greater adherence to the Mediterranean diet, the odds of

developing metabolic syndrome fell by 31% (odds ratio

0.69; 95% CI 0.50–0.94; p = 0.019),27 lending preliminary

support for the role of dietary behaviors for the prevention

of late effects of childhood cancer. Other cross-sectional

surveys have reported positive associations between adherence to dietary recommendations and a higher frequency of

physical activity, suggesting that healthy dietary behaviors

may also promote the adoption of other healthy lifestyle

behaviors.

Nutritional Supplements

The use of nutritional supplements is one of the most

controversial areas in integrative oncology care due to the

potential interaction with conventional therapy. A recent

systematic review of clinical trials evaluating the use of

nutritional supplements for supportive care indications

found several studies with a range of evidence.36 The authors reported on 32 studies that investigated the use of

dietary supplements for several supportive care indications, including mucositis (N = 12),37–48 treatment-related

toxicities (N = 5),49–53 appetite and weight management

(N= 3),54–56 hepatic toxicity (N= 3),57–59 fever and neutropenia (N= 3),60–62 neuropathy (N= 2),63,64 chemotherapyinduced nausea and vomiting (N= 2),65,66 bone mineral

density (N= 1),67 and gastrointestinal symptoms (N= 1).68

Mixed, but encouraging, findings were reported for glutamine

and honey for mucositits, zinc for the prevention of weight

loss and infections, essential fatty acids for weight loss, and

milk thistle for the treatment of hepatoxicity 

Homeopathy

There have been trials investigating a single homeopathic

agent in pediatric oncology. TRAUMEEL S is a homeopathic remedy that contains extracts from several plants and

minerals, all of them highly diluted (10-1–10-9 of the stock

solution).41 TRAUMEEL S has been investigated in both a

small pilot study and large randomized clinical trial with

conflicting results. TRAUMEEL S was administered to 32

pediatric patients undergoing a bone marrow transplant and

was associated with significant reductions in the severity and

duration of stomatitis ( p < 0.01).41 No adverse events were

reported. However, a double-blind randomized trial conducted through the Children’s Oncology Group in patients

undergoing myeloablative stem cell transplantation did not

find a benefit with the administration of TRAUMEEL S.43

The study found no statistical difference in incidence or severity of mucositis in the TRAUMEEL S group compared

with placebo. However, adherence to 100% of the days was

poor, adherence was 37% and 35% in the TRAUMEEL S and

placebo groups, respectively. A trend toward less narcotic

usage for the management of mucositis was observed in the

TRAUMEEL S patients. It is unknown whether fewer administrations delivering the same dose of TRAUMEEL S

would have improved adherence.

Complementary Therapies

Acupuncture

A white paper published by the National Cancer Institute

presented the evidence on the role of acupuncture in cancer

care.73 Overall, acupuncture appears to be safe in the context of cancer care, even in the pediatric population. A

safety study performed in children and adolescents undergoing chemotherapy including stem cell transplantation

found that acupuncture was safe among those with severe

thrombocytopenia.74,75 Although limited in pediatrics, two

clinical studies have evaluated the role of acupuncture for

the prevention/treatment of chemotherapy-induced nausea

and vomiting.76,77 Each study reported a significant decline

in the use of antiemetics. One study reported a significant

decrease in episodes of retching and/or vomiting. 

Aromatherapy

One good quality study investigated aromatherapy among

children undergoing HSCT.78 This trial examined the effects

of bergamot essential oil on anxiety in 27 children undergoing HSCT for a variety of diagnoses. The authors found

increased nausea and anxiety in the aromatherapy group

than in the control group.

Massage

Massage therapy is a supportive care treatment that can

be readily applied, either by credentialed massage therapists

or by parents who have learned massage techniques with a

licensed therapist. Parents of children with cancer and adults

with cancer have consistently reported that massage therapy

provides benefit during anticancer therapy. There have been

several studies evaluating the efficacy of massage therapy in

the setting of pediatric oncology.36 The available evidence

suggests that massage therapy may be beneficial for several

symptoms, which concurs with a recent consensus statement

on nonpharmacologic approaches.79 Evidence-based nonpharmacologic massage therapy may be a cost-effective

approach to advance the provision of supportive care

throughout the spectrum of pediatric cancer care.

Summary

There remains a significant interest in approaching pediatric cancer care from an integrative perspective, especially

for symptom management. Despite sustained interest among

conventional practitioners in researching promising integrative therapies, such as acupuncture and massage, there is

insufficient evidence to guide most discussions related to

nutritional or biological therapies during conventional treatment. However, some integrative therapies, such as acupuncture and massage, are beneficial and have little risk of

interfering with conventional treatment or increasing the risk

of an adverse event. The International Society of Pediatric

Oncology developed guidelines to guide the assimilation of

integrative oncology into cancer care, including open nonjudgmental discussions with families and the need for bidirectional educational opportunities.80 The authors advocate

for more research as this will pave the way for integration of

the two medicinal approaches into pediatric cancer care.