Strategiesto Improve Outcomes

Jeanne M. Wallace, PhD, CNC© 2017 Nutritional Solutions

www.Nutritional-Solutions.net

Radiation Therapy

cancer patientsundergo radiation therapy

50%of

Impact on 5-yr survival

Ann Surg Oncol 2007 Dec;14(12):3321-7.

Esophageal

Gastric

Pancreatic

Rectal

Breast10 20 30 40 50 60 70 80%

Hormonal TherapyChemotherapyRadiotherapy

META-ANALYSIS

WHY Doesn’t Radiation Always Work?

“

”

SO

IL

Why doaphids ‘attack’ plants?

EC

OS

YS

TE

M

While limiting damage to healthy cells

decrease cellSURVIVAL

increase cellDAMAGE

OvercomeHypoxia

SelectivelySensitize

Inhibit Tumor DNA

RepairBoost

Apoptosis

O₂

O₂

O₂

Increasingresistance

to therapy

Decreaseddelivery

of drugs & nutrients

Reduced

pO₂Tumor Hypoxia

Radiother Oncol 2011;100:22–32.

Meta-Analysis:Significant improved therapeutic benefit

Meta-Analysis:Significant improved therapeutic benefit

32 RCTs, n=4,805 HNSCC pts Tx: Normobaric O2 or Carbogen breathing

HBOT • Hypoxic Radiosensitizer

32 RCTs, n=4,805 HNSCC pts Tx: Normobaric O2 or Carbogen breathing

HBOT • Hypoxic Radiosensitizer

Improved local control OR: 0.71 ***

Disease-free survival OR: 0.73 ***

Overall survival OR: 0.87

Risk of metastases OR: 0.87

No difference in late side effects No difference in late side effects

Does itimprove outcomes

?TA

RG

ETIN

G H

YPO

XIA

Things to Consider...

Vascular Integrity

Anemia (HGB)

CirculationBlood viscosity

Boost O₂ Delivery

Oncologist 2002;7:492–508. PMID:12490737

GOALS

OXYGENATION

is the strongest predictor of

indicated by a robust hemoglobin level

successful response to radiation treatment

TUMOR

HNSCC Bladder Esophageal Rectal

1319

40

665554

65

86 HGB > 12HGB ≤ 12

n = 78 12 mo n = 61 24 mo n = 124 24 mo n = 94 36 mo

Am J Clin Oncol 2009;32, 587-91.Am J Clin Oncol

2009;32, 587-91.Asian Pac J Cancer Prev

2009;10:1151-7.Asian Pac J Cancer Prev

2009;10:1151-7.Cancer 2005;103:1740-6.Cancer 2005;103:1740-6.

Int J Radiat Oncol Biol Phys 2008;70:1087-93.Int J Radiat Oncol Biol

Phys 2008;70:1087-93.

LocalControlRatesHE

MO

GLO

BIN

＆%

Rectal NSCLC Glioma Esophageal

9

201617

35

465253 HGB > 12

HGB ≤ 12

n = 94 3 yr n = 56 2 yr n = 43 2 yr n = 124 2 yr

Int J Radiat Oncol Biol Phys 2008; 70:1087-93.

Int J Radiat Oncol Biol Phys 2008; 70:1087-93.

J Cancer Res Clin Oncol 2005; 131:261-9.

J Cancer Res Clin Oncol 2005; 131:261-9.

Strahlenther Onkol 2011; 187:778-83.Strahlenther Onkol 2011; 187:778-83.

Cancer 2005;103:1740-6.Cancer 2005;103:1740-6.

OverallSurvivalRatesHE

MO

GLO

BIN

＆%

Oncology 2005;68(1):3-11.

60%werenot treatedfor theiranemia

39%anemicpre-Tx

42%developanemiaduring Tx

HYPOXIA 30%

may decrease

A 20% increase in hemoglobin level

TUMORInt J Radiat Oncol Biol Phys 1988;15:391-7.

HE

MO

GLO

BIN

What’s the

IdealRange

?WOMEN MEN

Cervical (n=142) HNSCC (n=104)

The Oncologist 2008;13:21–6.

Int J Radiat Oncol Biol Phys 2000;46:459–66.

9 10 11 12 13 14 15 16

g/dL HGB

20

15

10

5

Median Tumor pO₂

(mm/Hg)

How NOT toAddressHypoxia

EPOErythropoeitin

OK for HGB ≤ 11 to ↑ to 12mg/dl Risky if used outside indicated

range: ↑1.6-fold risk DVT, ↑adverse events & risk of death

The Oncologist 2008;13: 33–36.

CMAJ 2009;180:E62-71.

Trans-fusion

Causes cycling hypoxia (not steady HGB levels) and ↑ aggressive phenotype;

↑ adverse events, no change survival

Cancer Chemother Pharmacol

2008;62:1-9.

IronUse only if Fe deficient, ↑ iron may promote more

aggressive disease

Eur J Cancer Prev1996;5:19-36.

IL-6

InflammatoryStimulus

↓ Enterocyte Fe release

Trap Fe in macrophages, hepatocytes, & enterocytes

↓ Transferrin saturation

↑ Ferritin

↓ Fe avail for erythropoiesis

Anemia of Chronic Inflammation

TNFα

IL-6

suppresshematopoiesis

Hepcidin

Assessingthe Type ofAnemia

Anemia of Chronic Disease

Iron-DeficientAnemia

Ferritin > 100 < 30

Fe Sat < 24 < 20

Sed Rate > 20 < 20

CRP > 0.8

NEJM 2005;352(10):1011-23.Am J Clin Pathol 2001;115(1):112-8.

HemoglobinboostingFOODS

Protein foods Leafy greensMicro-greensBeetsGoji berriesSea buckthornJujube

LactoferrinWheyAstragalusRhodiola Angelica

HemoglobinboostingOPTIONS

Lactoferrin, better than iron

prospectiveopen-label

RCTn=148

Advanced Stage(Gyn, BrCa, Lung,Prostate, GastricColon & Bladder)

HGB ≤ 10ferr>100ng/ml

CHANGE Fe GLUCONATE125mg iv

LACTOFERRIN200mg/d po

HGB at 4 wks ↑ 0.55 ↑ 0.90

HGB at 8 wks ↑ 1.12 ↑ 1.60

HGB at 12 wks ↑ 1.6 ↑ 1.8

Serum iron ↓ 9.7 ↑ 13.6

Ferritin ↑ 278.2 ↓ 82.5

CRP ↑0.69 ↓1.3

Oncologist 2010;15:894-902.

Things to Consider...Boost O2 Delivery

RBC DeformabilityCoagulabilityCirculationBlood viscosity

TemperatureHydration

GOALS

Fibrinogen FBG > 310 mg/dl

d-Dimer DD < 0.5 µg/ml< 500 ng/ml

Hematocrit HCT F > 44%M > 48%

Hemoglobin HGB > 14 g/dl

Platelets PLT > 300 µ/l

Sed Rate ESR >20 mm/h

AssessingViscosity &Coagulability

FIB

RIN

OG

EN

＆Hepatogastroenterology 2011;58, 1507-10.

Complete Response Overall Survival 2yr

30

5

71

27

FBG < 400FBG ≥ 400

%

Locally advanced Rectal Ca Tx CRT (n=53)

Post-CRTResponse& Survival

Co

agu

lab

ilit

y

＆Post-TxOutcomeData

Sarcomas

66

93

Lung Cancers

9

15

No Mets at 23 mo (n=85)D-Dimer | 0.41 µg/ml

BMC Musculoskelet Disord 2011;12:250-6.

Median Survival (n=100)D-Dimer | 500 ng/dL

Tumori 2011;97:743-8.

mo

%LowHigh

Survival at 2 years78% / 30%low / highD-Dimer

Haematologica 2012;97:1158-64.

0%

20%

40%

60%

80%

100%

0 6 12 18 24

Months

d-DIMER< 0.340.34-0.710.71-0.1.33> 1.33 µg/mL

AN

TI-

CO

AG

UL

AN

TS

J Clin Oncol 2012;30:3540-4.

ProstateCancerSpecificMortality

➜

57%

ViscosityreducingFOODS

SardinesGarlic/onionGingerNattoBerriesBrazil nutsSpices/curriesJicamaOlive oil

Ginkgo bilobaFish oilMagnesiumSeleniumNicotinamide

ViscosityreducingOPTIONS

v,art(mm/s)

Arzneim-Forsch/Drug Res 1990;40:589–93.

0.5

1.0

1.5

0 50 150 250

Time(minutes)

GinkgoPlacebo

320 mg57%boostRBCvelocityat 1 hr

RB

C n

ail

be

dv,

art

(m

m/s

)

Ginkgo boosts circulation

Radiother Oncol 1996;41:163-7.

Control RT alone RT+GBE

12

9

7

Days Until 2.3-fold ↑ in Fibrosarcoma

RT & GinkgoHypoxic area reduced from 10% to < 3%

Permitted 50%dose reductionNo increased damageto normal tissues

Br J Cancer 1994;70:330-4.

α-Linolenic ω-3 DHA Linoleic ω-6 Arachidonic

1920

11

7

1515

2528

Below medianAbove median

%

% p

ts d

evel

opin

g m

ets

Breast Cancer Treatment Efficacy & Adipose Fatty Acids

Gan To Kagaku Ryoho 2008;35:437-40.

600ml enteral formula providing 10g ω-3

EsophagealCancer &High Dose Fish OilDuring ChemoRT

Neutropenia LESS

Diarrhea LESS

Somatitis/pharyngitis REDUCED

Thrombocytopenia SIMILAR

Clin Cancer Res 2012;18(20):5585-94.

HYPOXIA

↑ HIF-1α

FosterInvasion

Metabolic Shift

Promote Angiogenesis

ApoptosisResistance

↑ Glycolysis↑ LACTATE↑ LDH

VEGFVEGFR2Leptin

IGF-1, NOS2TGF-α, EPO↓BAX, ↑Bcl-2

AMF, MetRUPARCathD

↑ RONS EGFR→PI3K/AKT/

mTOR

High HIF1-α expressioncorrelates with poor locoregional control and increased riskof tumor-related mortality

Clin Cancer Res 2012;18(20):5585-94.

AssessingHIF-1αActivation

Proton MR Spectroscopyor C¹³-NMR scan

Proton MR Spectroscopyor C¹³-NMR scan ✓

LDH > 300 U/l ?

CO₂ > 28 mg/dl ?

Lactate:Pyruvate RatioLactate:Pyruvate Ratio ?

Overall Survivalafter WBRT forBrain MetsLac

tate

Deh

ydro

gen

ase

＆Scientific World Journal 2012:609323.

0 6 12 18 24 30

Months

100%

75%

50%

25%

LDH< 307.5 ≥ 307.5 U/l

(n=100)

Suppressing

HIF-1αOPTIONS

Soy isoflavones Salvia miltiorrhizaGrape seed extractGreen tea EGCGGuggulsterones SilybininPanax ginseng

Mechanisms of EnhancedRadiosensitivitySOY

Isof

lavo

nes •Induce G₂/M cell

cycle arrest

•Inhibit DNA repair enzymes

•Inhibit RT-induced ↑HIF1α & NFkβ

•Boosts apoptosis: ↑BAX, ↓Bcl and survivin

Free Radic Biol Med 2011;51:289–98.

＆

Radiother Oncol 2011;101:329-36.

SOY

Isof

lavo

nes Day 1 Day 20-22 Day 23-48 Day 49

iv lung cacells A549

Nodes +SOY (1mg/d)

Day 22

RT 12Gy SOY (1mg/d) Sacrificeanimals

# Tumors

1

4

2

4

% Viable

15

5545

90

Area of Tumors

2

9

5

20 ControlRT aloneSoyRT+SOY

Soy, RT & Prostate Cancer

Free Radic Biol Med 2011;51:289–98.SOY

Isof

lavo

nes

23

0

88

43

1521

28

PlaceboIsoflavone 200mg

UrinaryIncontinence

DiarrheaCramping

ErectileDysfunction

Pain w/BM

0.9

3.7

2.0

4.9

PSAPre-RT

PSApost-RT(4-6mo)

%

Am J Clin Nutr 2012 Jul;96(1):123-32.

Meta-Analysis:Significant improved therapeutic benefit

Meta-Analysis:Significant improved therapeutic benefit

n=9,514 ER+ BrCa pts U.S. and Asian cohorts

pre- and post-menopausal

n=9,514 ER+ BrCa pts U.S. and Asian cohorts

pre- and post-menopausal

Improved local control OR: 0.71 ***

Disease-free survival OR: 0.73 ***

Overall survival OR: 0.87

Risk of metastases OR: 0.87

No difference in late side effects No difference in late side effectsIs SoySafe

?SO

Y &

ER

+ C

AN

CER

S

Rodents metabolizesoy differently:less isoflavone conjugationleads to 20 to 150-fold highercirculating levels than are found in humans eating soy

Am J Clin Nutr 2011;94:1284-94.

Wait a minute here,what about antioxidants?

AN

TIO

XID

AN

TSHelpful

NEUTRAL orHarmful

?

•RT relies on oxidation to kill cancer cells

•↑ O₂ improves outcome

•Antioxidants “quench” free radicals, might interfere

•Antioxidants have other important jobs: immune support, apoptosis, differentiation

•Many studies show no interference

oxid

atio

n

AVOIDAntioxidant

Camp

anti

oxid

ants

anti

oxid

ants

PROAntioxidant

Camp

oxid

atio

n

Cancer Lett 2006;238:240–7.

3-yr Survival HNSCC post-RT

27

79

GSH > medianGSH < median

-79%

-65%-70%

β-caroteneα-CaroteneLutein

Nutr Cancer 2010;62:322–8.

HR PFS HNSCC by post-RT Total Plasma Carotenoids

corrected for BMI/energy intake

1-yr Survival GBM (n=30)

6

43

RT+MLT 20mgRT alone

Oncology 1996;53:43–6.

CR PR (↓50%) Wks/Progression

2724

20

414040

Lycopene 8mgPlacebo

High-Grade Glioma RT Response at 6-mo MRI (n=50)

Neurol India 2010;58:20–3.

%

wk

%

• “Pharma” model of antioxidant supplementation — synthetic forms β-carotene and vitamin E — fractionated forms (e.g., 1 of 8 toco’s) — standardized vs individualized dosing — “single agent” antioxidants vs network

• Fail to measure intended effect. Did intervention... — similarly ↑ blood levels of nutrient or TAC? — actually reduce ROS? to what level?

SHORTCOMINGS IN THE RESEARCH

4 Biomarkers ofOxidative Stress

Hydroperoxides (d-ROMS) γ-Glutamyl transpeptidase

8-Isoprostagladin F2α FRAP (ferric reducing antiox power)

Ratio oxidized/total ascorbic acid

BMC Cancer 2009;9:458-69.

15 AntioxidantBiomarkersAscorbic acid 6 Carotenoids4 Tocopherols

Total antioxidant capacity GSH redox potential

Total GSH Total cysteine

HNSCC (n=60) pre-RT levels [cf healthy controls (n=100)], retest last wk of RT

Adapted from BMC Cancer 2009;9:458-69.

0.8

0.6

0.4

0.2

Effect of RT on Antioxidant Status

GSH α-Tocoϒ, β, δToco’s Vit C

β-Carotene Lycopene Lutein Zeaxanthin

He

alth

y

Pre-RTLast wk RT

HNSCC I-IV, n=78

Can youguess the outcome?

Progression-FreeSurvival Correlates to

oxid

atio

nAVOID

AntioxidantCamp

anti

oxid

ants

anti

oxid

ants

PROAntioxidant

Camp

oxid

atio

n

BMC Cancer 2009;9:458-69.

10 20 30 40 50

High CarotenoidsLow Carotenoids

mo

1.0

0.8

0.6

0.4

0.2

Pts with above mediantotal carotenoids before radiotherapy62% increase in overall survival

BMC Cancer 2009;9:458-69.

10 20 30 40 50

High ↑ Total peroxidesLow ↑ Total peroxides

mo

1.0

0.8

0.6

0.4

0.2

Pts with above medianoxidative stress during radiotherapy70% reduced riskof progression

In those with BOTH

Pts with above medianoxidative stress during radiotherapy

Pts with above mediantotal carotenoids before radiotherapy

risk of progression80%reduced

BMC Cancer 2009;9:458-69.

risk of death at 2 yr87%reduced

oxid

atio

n

ANTIAntioxidant

Camp

anti

oxid

ants

anti

oxid

ants

PROAntioxidant

Campox

idat

ion

NewUnderstanding

oxid

atio

n

anti

oxid

ants

HIGH

Antioxidant Status

HIG

H

LOW

LOW

Oxi

dati

ve S

tres

s

Time forOpposingCampsto JOINForces

WHY?•Dietary antioxidants not

powerful enough to quench ↑↑oxidation of RT

•Differential uptake of antioxidants

•ReDox impact on cell cycle•Antioxidants’ non-Redox

functions•Redox Adaptation (glycolysis)

HIF1α-inducedmetabolic shiftleads tumors to increase theirendogenousantioxidantcapacity, blockingRT-inducedoxidative stress

Clin Cancer Res 2012;18(20):5585-94.

Low pO2reduces ROS generation

HYPOXIA

ReduceROS-mediatedfixation of DNA

damage

Metabolic Shift: accumulation of

endogenous antioxidants

Int J Radiat Biol 2009;85(11):963-71.

Redox imaging with quantitativebioluminescence

The conclusion that more research on the redox stateof cancer cells would be desirable lead us to develop

a technique for the quantitative assessment of theredox metabolism of solid malignant tumours. Sincetumours often represent an irregular arrangement ofviable and necrotic cancer cell areas, normal stromaand host defense cells, an imaging method was

Figure 4. The relationship between respiration, glycolysis and glutathione metabolism in cancer cells. The differences in boldness of the

arrows are to indicate the more or less preferential pathways in transformed cells. (1) LDH; (2) pyruvate dehydrogenase; (3) glucose-6-

phosphate dehydrogenase; (4) GSH reductase; GSH peroxidase.

Figure 5. Representative array of serial cryosections through a snap-frozen hSCC xenografted in a nude mouse. The upper two sections were

stained with hematoxylin and eosine (H&E) or with anti-mouse antibodies (stromal tissue). This is followed by the lower four colour-coded

metabolite concentration distributions measured with induced bioluminescence with the colour-code given in mmol/g in the upper right-

hand part of the figure. The two holes (distance 2 mm) allow for the exact overlay of the sections; they are generated by driving two parallelchannels through the frozen tissue specimen perpendicular to the prospective sectioning plane. Such an overlay can be used for metabolic

analysis in selected tissue areas, such as viable tumour regions (upper part of the specimen) versus tumour-adjacent cutaneous and

subcutaneous tissue (lower part of the specimen). Furthermore, the overlay makes it possible to derive ratios of corresponding pixelconcentration values from different metabolites. Since the lactate/pyruvate (L/P) ratio is considered a measure of the cellular redox state, the

generation of L/P maps can be used for quantitative redox imaging in solid tumours.

968 U. G. A. Sattler & W. Mueller-Klieser

Downloaded By: [Mueller-Klieser, W.] At: 08:13 4 November 2009

GlycolysisInducesRedoxAdaptation

LDH

G6PD

GSH peroxidase

Int J Radiat Biol 2009;85(11):963-71.

↑10-20x

direct ROSscavengingO₂﹣& OH●

↑10x

GSH reductase

GOALSPrevent Tumor Protection

Carb Restriction

Selective GSHDepletion

HIF1α Inhibitors

Reduce Lactate

Ketogenic Diet+RT in Animal Model of Glioma

PLoS ONE 2012;7:e36197.

0 50 100 150 200 250

Keto+RT SD+RT

p<0.0001

100%

75

50

25

Time (days)

apparently cured of their implanted tumor (Figure 1B). The in vivoimaging data from one representative animal treated withradiation alone and one treated with radiation and KC is shownin Figure 2. After an initial period of slower growth (Figure 2B,inset), there was rapid tumor growth in the animals fed SD andtreated with radiation until the animal succumbed to the tumor(Figure 2A, B) with a final photon count of 6.9956109 p/sec/cm2/sr on day 39 following tumor implantation. In the animaltreated with radiation and KC the presence of growing tumor canbe seen for the first 1.5–2 weeks following implantation, reaching amaximum bioluminescent signal of 1.2586107 p/sec/cm2/sr onday 9 following tumor implantation. This was followed by a nearexponential decline that approaches background levels 60 daysfollowing implantation. Bioluminescence remained undetectableand on day 104 post-implantation the 9 surviving animals treatedwith radiation and KC were switched from KC to the standardrodent chow. There was no detectable recurrence of tumor asdemonstrated by the continued absence of detectable biolumines-cent signal. The animals were sacrificed on day 299. Histologicalevidence upon necropsy using hematoxylin and eosin (H&E)staining of brain tissue from the apparently cured KC plusradiation animals showed no evidence of tumor cells in or near thearea of implantation (data not shown).Survival data from SD alone, KC alone, SD+radiation, and

KC+radiation were examined for interaction effects using CoxProportional Hazards. The p-value for radiation and KC isp = 1.03610211 vs. SD. The implication being that there is aprofound enhancing (by mean survival) effect of radiation with KCvs. SD alone. There is also an enhancing effect of radiation withSD (p= 8.3861022) but the effect is many orders of magnitudeless. Thus, we propose that a more than additive and highly

positive survival effect is seen through the KC diet and adjuvantradiation therapy.

Animals Fed KetoCalH Exhibit Elevated bHB levelsAnimals fed KC had a statistically significant increase in blood

bHB levels (Figure 3A) both 6 and 13 days post-implantation. Thegreatest increase in bHB levels was seen in animals given adjuvantradiation therapy. However, increased bHB levels did notcorrelate with a decrease in blood glucose levels. Glucose levelswere significantly lower in the KC and KC plus radiation groupson day 6 (p,0.0001) than SD and SD plus radiation; and only inthe KC group on day 13 (p,0.001) when compared to SD.KC diet itself had very little effect on the animal’s body weight,

indicating that the diet itself was tolerable. Body weight remainedvery close to the starting weight in animals that were changed toKC three days following implantation. Eighteen days followingimplantation, body weights for SD and KC fed animals start todecline slowly as symptoms began to present (Figure 4A). Weightloss just prior to death is a function of the onset of symptoms dueto tumor burden and not KC treatment.Animals fed KC and treated with radiation saw a noticeable dip

in weights 3–6 days following treatment (Figure 4B), indicatingthat combination therapy had an effect on body weight. Theseanimals rapidly gained their weight back and there was nodifference between the 2 groups by day 15. This treatment groupalso had a slightly higher level of blood BHB and a slightly lowerlevel of blood glucose on day 6 compared to day 13. While wecannot rule out the possibility that the transient drop in weight andslightly lower glucose on day 6 contributed to the survival benefitseen when radiation and KC were combined, it is unlikely that thisplayed a major role since tumor shrinkage continued well after the

Figure 2. KetoCalH plus radiation treated animals experienced a loss of bioluminescence. (A) Radiation and KetoCalH plus radiationanimal imaged every three days. Color scheme represents signal intensity with red representing the highest intensity photon count. (B) (C)Bioluminescent signal plotted as in vivo photon count versus days post-implantation.doi:10.1371/journal.pone.0036197.g002

Ketogenic Diet as an Adjuvant to Radiation Therapy

PLoS ONE | www.plosone.org 3 May 2012 | Volume 7 | Issue 5 | e36197

82% of theKetoCal+RT treated groupwere cured

PLoS ONE 2012;7:e36197.

SelectivelyDepleteTumor GSH

Carb restriction Whey proteinDHA omega-3 fatPropolis (CAPE) Parthenolide

SuppressTumor DNARepair Enzymes

CaffeineSoy isoflavonesVitamin ACurcuminResveratrolSoy isoflavones

J Oncol 2012:370481.

DNA DSBDNA Double Strand Breaks

ATR ATM

CheckpointActivation HRRNHEJ

✖✖✖=Caffeine effect

Cancer Biol Ther 2009;8:665-70. Toxicology 2003;193:153-60.

GOALSBoost Tumor Die-off

Optimize p53Foster apoptosis

Immune support

Cell Cycle 2012 Dec 1;11(23):4436-46.

Carb restrictedbut calorie adequatediet depletes mutated p53but not wild type p53

Garlic/onionGreen teaSoy foodsCruciferous vegBrazil nutsSpices/curries

ApoptosisInducingFOODS

Exp Biol Med (Maywood) 2006;231:117-29.

ApoptosisInducingOPTIONS

Low carb diet SeleniumSoy isoflavonesResveratrolCurcuminEllagic Acid

J Gastrointest Cancer 2012 Jun;43(2):236-43.

Lymphocyte-mediatedimmune responseis important for suppression of recurrence

IMM

UN

E S

UP

PO

RT

J Gastrointest Cancer 2012 Jun;43(2):236-43.

0 500 1000 1500 2000 2500

> 1.8 ≤ 1.8

100%

75

50

25

Time (days)

Dx

-Fre

e S

urv

ival

p<0.01

Lymph#PredictsOutcome

1.8

IMM

UN

E S

UP

PO

RT

Breast Cancer Res 2007;9:212.

Consider TimingCarefully

↑ HIF-1α

Metabolic Shift

↑ Glycolysis↑ LACTATE↑ LDH

IMMUNE ESCAPE↓ Motility monocytes/macrophages↓ Dendritic cell differentiation↓ DC & T-cell cytokine secretion (IL-6, TNFa)↑ Inflammation↑ IL-17A and Treg cells activity

Tumor LACTATEcorrelates with reduced survival and increased ratesof metastasis

Cancer Res 2011 Nov;71:6921-35.

Low GL dietBone brothsCultured foodsGarlicMushroomsBrazil nuts

ImmuneboostingFOODS

AstragalusFish oilMelatonin MushroomsSeleniumVitamins C&E

ImmuneboostingOPTIONS

Address Side EffectsGOALS

Enteritis

MucositisDermatitisPneumonitis

Proctitis

Int J Radiat Oncol Biol Phys 1995;33:99-109. Cancer Metastasis Rev 2008;27:363-74.

Radiation-InducedPerpetual Cascadeof CytokinesCONTINUUM

↑ROS

↑free Fe

↑Nfkβ

↑IL-6

↑TGFβ₁↑TXA₂

↑IL-1↑FGF2

VEGF

↑PDGF

PredictSideEffects

Side Effect BioMarker Reference

Fatigue ↓HGB Oncol Nurs Forum

2003;30: E33-9.Fatigue ↑BMI, ↑CRP,

↑FBG,↑Neutro#Int J Radiat Biol Phys

2004 May 1;59(1)160-7.

SkinReactions ↑blood viscosity Radiother Oncol 2009;

90:136–140.

Mucositis ↑CRP, ↑Sed Rate Head Neck 2012;34:985-93.

GI Enteritis ↑blood viscosity↑thrombosis

Int J Radiat Oncol Biol Phys 2009;74:942-8.

Proctitis ↓HGB, ↑IL-6, ↑Ferritin

J Cancer Res Clin Oncol 2007;133:297-304.

Radionecrosis & Fibrosis ↑blood viscosity Anticancer Res

1999;19:5583-6.BIO

MA

RK

ER

S

BRAIN RT &Radionecrosis

Anticancer Res 1999;19:5583–6.

405 pts brain mets: lung, breast, melanoma

262 standard risk (controls)143 high risk

Fish oil (2,450mg/d)Milk thistle (200mg/d)

x 5 mo

Survival (wks) Necrosis

14

54

4

89Fish oilControls

SID

E EF

FEC

TS

Pycnogenol 50mg tidSI

DE

EFFE

CTS

Rx Required

Mucositis

Edema

Fatigue

Dry mouth/eyes

DVT/SVT 4

25

45

45

53

57

19

40

61

65

70

77

PlaceboPycnogenol

Panminerva Med 2008;50:227–34.

%

SID

E EF

FEC

TS

✔

✔

Calendula topically, ad lib [PMID: 15084618]

Curcumin 6g/d orally [ASCO 2012:#9027]

Proteolytic enzymes 3 tab (8-10x), TID [11561868]

Aloe vera gel topically [12464836, 8892458]

]

HelpfulNEUTRAL orHarmfulSupportStrategies

?X

✔

Dermatitis & Erythema

SID

E EF

FEC

TSOral Mucositis

✔

✔

HelpfulNEUTRAL orHarmfulSupportStrategies

? ✔

✔

Zinc 60-90mg/d [PMID: 16751063, 14697435]

Proteolytic Enzymes 3 tab (8-10x), TID [11561868]

Honey 20 ml, 15 min pre-, 15 min & 6 hr post-RT [12673463]

Selenium 300-500mcg/d [20592387]

✖

✔

EnteritisSI

DE

EFFE

CTS

HelpfulNEUTRAL orHarmfulSupportStrategies

? ✔

✔

Selenium 300-500mcg/d [PMID: 20133068]

Berberine 300mg, TID [19757213]

Fish oil 2 gm/d [1940579, 2912146]

Probiotics 50 bill cfu/d [20682502]

✔

✔

HelpfulNEUTRAL orHarmfulSupportStrategies

?✔

Vitamin A 10,000iu/d [PMID: 15690650,19690489]

Soy isoflavone 200mg/d[20924975]

Butyrate enema 80 mL qd [11072942, 19107351]

SID

E EF

FEC

TSProctopathy

Coordinating Integrative CareCoordinating Integrative CareCoordinating Integrative CareCoordinating Integrative CareCoordinating Integrative CareCoordinating Integrative CareCoordinating Integrative Care

Optimize HGB

NormalizeViscosity,

Boost Circulation

SuppressHIF-1a

DepleteTumorGSH

InhibitTumor DNA

repairFoster

Apoptosis

BolsterTh1

ImmuneEffect

Diet/NutritionBotanical Agents

Lifestyle

NaturopathyMind-Body-Spirit

TCM Acupuncture

AyurvedaHomeopathy

AromatherapyMassage

ChiropracticPharmaceuticals

HOWwould yourModality