Nutritional modulation of the

efficacy and toxicity of

chemotherapyVickie E Baracos, PhD

Department of Oncology

University of Alberta, Canada

Outline

• Therapeutic index - definition

• Types of chemotherapy

• Chemotherapy toxicity

• Nutritional modulation of therapeutic index

– Fish oil, glutamine, Vitamin E

• Interpretations

Cancer treatment, toxicity & efficacy

• cancer treatment approaches combine surgery,

cytotoxic or targeted chemotherapy and

radiation, multiplying nutritional risk.

• systemic antineoplastic agents have characteristic

toxicities, limiting the dose and duration of

cancer therapy

• Specific nutrients are proposed to improve the

therapeutic index of cancer treatments by

increasing their efficacy, reducing toxicity or both.

Efficacy and Toxicity:Therapeutic index

Efficacy and Toxicity

• Treatment at Maximum Tolerated Dose (MTD)

• Narrow therapeutic index of most cancer tx

Toxicity outcomes

• Patients experience limitations in their

chemotherapy treatment:

– dose reductions

– delays in therapy

– discontinuation of therapy.

• Toxicities also worsen malnutrition and

wasting

Types of chemotherapy

• Grouped into different classes based on mechanism of action.

• Drugs of different classes are combined to increase antitumor effects.

• Drugs in different classes have different side effect profiles

– Combination therapy often based on avoiding overlapping toxicities.

•act on rapidly dividing

cancer and normal cells

•Alkylating agents

interfere with DNA base

pairing, leading to strand

breaks.

•Topoisomerase inhibitors

prevent DNA uncoiling.

•Taxanes and vinca

alkaloids interfere with

microtubule function

required for mitosis.

•Antimetabolites block the

formation and use of

nucleic acids.

Mechanisms of cytotoxic

chemotherapy

•Receptor tyrosine kinases and

downstream RAS/RAF/MAPK and

PI3K/AKT/mTOR signaling pathways

are activated for proliferation and

invasion by tumor cells

•Molecular cancer therapeutics target

these pathways

•Some drugs (e.g., sorafenib [Nexavar],

sunitinib [Sutent], imatinib [Gleevec])

have multiple targets

EGFR = epithelial growth factor

receptor; VEGF = vascular endothelial

growth factor.)

Mechanisms of targeted

therapies

Chemotherapy side

effects and toxicities

Target of rapamycin (TOR) is a kinase

that integrates signals from nutrients

(amino acids and energy) and growth

factors to regulate cell growth, cell

cycle progression and protein

synthesis in tissues such as skeletal

muscle.

Nutrient utilization and the pathways

affected by targeted therapies

Glass DJ. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.

Curr Top Microbiol Immunol. 2010;346:267-78. Review.

Sorafenib causes muscle

wasting independent of disease

progression

Mean loss ~ 2.1 kg muscle

during 1 y on sorafenib

Cisplatin, carboplatin, oxaliplatin

• Binds to guanine residues in DNA, inhibits replication

• Cell-cycle nonspecific, kills all dividing cells

• Common uses

– Gastrointestinal tumors, Lung, Germ Cell, Ovarian cancer

Toxicities:

• Severe nausea/vomiting

• Nephropathy

• Chronic, cumulative sensory neuropathy

• Ototoxicity, high-frequency hearing loss

• Alopecia

• Myelosuppression

• Dysgeusia

Irinotecan

• DNA Topoisomerase inhibitor

• Used in metastatic colorectal cancer, pancreatic, gastric cancers

Toxicities:

• Diarrhea as major side effect

• Late diarrhea (>24 hours) may be insensitive to loperamide

• Incidence of severe diarrhea: 31-39%

• Life-threatening for 8% of patients

Can diet make a difference? Nutritional

modulation of therapeutic index

Glutamine,

Vitamin E

Reduced

toxic effect ?

N-3 fatty

acid

increase

therapeutic

effect ?

Widening the

therapeutic

index

Quantity and quality of evidence for dietary

alteration of therapeutic index

• Animal studies

• Small number of studies

• Heterogeneous design

• Low ability to translate to clinical setting

• Human studies

• Small number of studies

• Low n

• Non-randomized

• Heterogeneous design and outcomes

• Lack of dose-finding studies

• Contamination between treatment arms (patients self-treat)

Clinical studies n-3 polyunsaturated fatty acids

Bougnoux P, et al. Improving outcome of chemotherapy of metastatic breast cancer

by docosahexaenoic acid: a phase II trial Br J Cancer. 2009 ;101(12):1978-85

•Metastatic breast cancer

•FEC 75 chemotherapy regimen (5-fluorouracil, epirubicin,

cyclophosphamide) , the standard first-line chemotherapy in

a metastatic setting

•Prospective open-label phase II trial

•1.8g/day of purified DHA

Differential incorporation of DHA

Time to tumor progression by DHA incorporation

Overall survival by DHA incorporation

Murphy RA et al. Supplementation with fish oil increases first-line

chemotherapy efficacy in patients with advanced nonsmall cell lung cancer.

Cancer 2011 , 117: 3774–3780

•Non-small cell lung cancer patients stage IIIB/IV

receiving 1st line platinum-based chemotherapy

•Matched fish oil supplemented (n=14) patients

compared with standard of care controls (n=31).

•Patient’s choice of supplementation with:

1) 4 capsules/d (2.5 g EPA + DHA) OR

2) 1.5 tsp/d fish oil liquid (2.5 g EPA +DHA)

Median 2.75%

High EPA incorporators

N=9

Low EPA incorporators N=7

Incorporation of EPA into plasma phospholipid was variable

0

10

20

30

40

50

60

Fish Oil

Std Care

%

Chemotherapy outcomes

Fish oil favoring

Increase partial

response

Decreased progressive

disease, p= 0.008

Witte TR et al RBC and WBC fatty acid composition following consumption of

an omega 3 supplement: lessons for future clinical trials. Lipids Health Dis.

2010 Mar 22;9:31

Interpretation

• Potentially interesting findings

• Still needed:

– Essential fatty acid status of patients throughout

the cancer trajectory

– A basis for dose; target levels in plasma? Cells?

– Purified DHA or EPA versus fish oil unclear

– Randomized designs needed

– Individual drug or regimen interaction with diet

Clinical studies glutamine

Li Y, et al Clinical trial: prophylactic intravenous alanyl-glutamine reduces the

severity of gastrointestinal toxicity induced by chemotherapy--a randomized

crossover study. Aliment Pharmacol Ther. 2009 ;30(5):452-8.

Gastric or colorectal cancer patients receiving

FAM (5-FU, doxorubicin, mitomycin) or FOLFOX

(5FU, oxaliplatin, folinic acid)

Randomized double blind crossover study n=44

Intravenous alanyl-glutamine dipeptide 20 g / day

N=44

grade II

toxicity

PLACEBO

GLUTAMINE PLACEBO

GLUTAMINE

Also noted reduced plasma endotoxin levels in glutamine – treatment

period.

Vahdat L et al. Reduction of paclitaxel-induced peripheral neuropathy with

glutamine. Clin Cancer Res. 2001 May;7(5):1192-7.

•Metastatic breast cancer

•High dose paclitaxel as part of a regimen to ablate bone

marrow (followed by haematopoetic stem cell replacement)

•Successive cohorts without (n=33) and with (n=12)

glutamine treatment

•30 g/ d glutamine orally

Also improved by glutamine: motor weakness (p=0.04), gait

(p=0.0016), activities of daily living (p=0.001). No difference in nerve

conduction studies (amplitude and conduction velocity of motor or

sensory nerves)

Wang WS et al. Oral glutamine is effective for preventing oxaliplatin-induced

neuropathy in colorectal cancer patients Oncologist. 2007 Mar;12(3):312-9.

•Metastatic colorectal cancer

•FOLFOX regimen (5Fluorouracil, oxaliplatin, folinic acid)

•Randomized but not blinded or placebo controlled n=42

glutamine, 44 control

•30 g/ d glutamine orally

Incidence of neuropathy assessed according to Common Toxicity Criteria

Clinical outcomes of oral glutamine supplementation

Interpretation

• Potentially interesting findings suggesting

clinical benefit for GI toxicity and neuropathy

• Requires randomized, placebo controlled

designs

• Reproducible / objective quantification of

peripheral neuropathy is a challenge

Clinical studies Vitamin E and

chemotherapy – induced neuropathy

• Solid tumors, cumulative dose of cisplatin > 300

mg/m2

• Randomized, blinded and placebo controlled

n=17 supplemented, n=24 placebo

• Alpha tocopherol 400 mg/d

Pace A et al Vitamin E neuroprotection for cisplatin neuropathy: a randomized,

placebo-controlled trial. Neurology. 2010;74(9):762-6

Improved by Vitamin E 400 mg/ d

• Incidence and severity of

neurotoxicity (p<0.01)

• % grade 3 sensory

neuropathy (p<0.01)

• Vitamin E prevented fall in

sensory median nerve

amplitude (p<0.01)

0

10

20

30

40

50

Vit E Placebo

5,9

41,7

• Mixed patients on neurotoxic chemotherapy

(taxanes, cisplatin, carboplatin, oxaliplatin or

combination)

• Phase III Randomized, blinded and placebo

controlled n=96 supplemented, n=93 placebo

• Alpha tocopherol 600 mg/d

Kottschade LA The use of vitamin E for the prevention of chemotherapy-induced

peripheral neuropathy: results of a randomized phase III clinical trial. Support Care

Cancer. 2010 Oct 9. [Epub ahead of print] PMID: 20936417

• No significant effects : % grade 2 or greater

sensory neuropathy

• No significant effects: Time to onset or duration of

neuropathy

• No significant effects: Numbness, tingling, pain,

difficulty walking, working

No significant findings

Interpretation

• Randomized placebo controlled

• Single agent cisplatin vs mostly taxanes;

• ? glutamine is effective for taxane – neuropathy and Vitamin E is effective for cisplatin neuropathy

• Further discussion regarding objective and subjective assessment of neuropathy interventions: Albers JW et al Interventions for

preventing neuropathy caused by cisplatin and

related compounds Cochrane Database Syst Rev. 2011 Feb 16;(2):CD005228

Nutritional modulation of therapeutic index

• N-3 fatty acids may left-shift therapeutic effect

• Glutamine and Vitamin E may right-shift toxic effect

Glutamine,

Vitamin E

Reduced

toxic effect

N-3 fatty

acid

increase

therapeutic

effect

Widening the

therapeutic

index

Conclusions

• Specific individual nutrients are proposed to improve the therapeutic index of cancer treatments by increasing their efficacy, reducing toxicity or both

• Nutrition intervention might need to be specific to chemotherapy type / regimen

• Promising candidates include n-3 fatty acids (increased therapeutic efficacy), Vitamin E and glutamine (decreased toxicity)