vitamin d status and survival of metastatic colorectal cancer … · 2018-06-01 · vitamin d...

Vitamin D Status and Survival of Metastatic Colorectal Cancer

Patients: Results From CALGB/SWOG 80405 (Alliance)

Ng K, Venook AP, Sato K, Hollis BW, Niedzwiecki D, Ye C,

Chang I-W, O’Neil BH, Innocenti F, Lenz H-J, Blanke CD, Mayer RJ,

Fuchs CS, Meyerhardt JA

Abstract 507

Background: Vitamin D and Colorectal Cancer

• Vitamin D inhibits cell proliferation and angiogenesis, induces

cell differentiation and apoptosis, and has anti-inflammatory

effects

• Vitamin D receptor (VDR) and 1-α-hydroxylase are expressed

in colorectal cancer (CRC) cells

– Anti-proliferative effects greatest in cell lines with high

VDR1

• Treatment of APCmin mice with vitamin D decreases tumor

burden,2 whereas adenoma numbers and size are increased in

VDR-null APCmin mice3

• Low plasma 25(OH)D levels associated with risk of CRC

1. Evans SR, et al. Clin Cancer Res. 1998;4(11):2869-2876. 2. Huerta S, et al. Cancer Res. 2002;62(3):741-746. 3. Zheng W, et al. Int J Cancer.

2011;130(1):10-19. 4. Ma Y, et al. J Clin Oncol. 2011;29(28):3775-3782.

.

Ng K, et al. J Clin Oncol. 2015;33(suppl 3): Abstract 507.

Prospective Cohort Study of 304 CRC Patients Suggests Association Between Prediagnosis 25(OH)D and Survival

Ng, K et al. J Clin Oncol. 2008;26(18):2984-3991.

Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity

Survival benefit

may be greater in

stage III and IV

patients

1.0

0.81 [0.49 – 1.35]

0.81 [0.48 – 1.37]

0.52 [0.29-0.94]

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

<22.8 22.8-27.1 27.2-33.1 >33.1

Hazard

Rati

o f

or

Death

P trend = .02

Plasma 25(OH)D (ng/mL)

People with highest

level of vitamin D have

48% improvement

in outcome


Study Objective

Are higher vitamin D levels associated

with improved survival in patients with

metastatic CRC?


CALGB/SWOG 80405: Final Design

n = 1140

Primary endpoint: Overall Survival

Chemo + cetuximab

Chemo + bevacizumab

mCRC

first line

KRAS wild type (WT)

(codons 12,13)

Strata: • FOLFOX/FOLFIRI

• Prior adjuvant

chemo

• Prior radiotherapy

FOLFIRI or

FOLFOX

MD choice

Chemo + bevacizumab and

cetuximab


CALGB/SWOG 80405: Final Design

n = 1140

Primary endpoint: Overall Survival

Chemo + cetuximab

Chemo + bevacizumab

mCRC

first line

KRAS wild type

(codons 12,13)

Strata: • FOLFOX/FOLFIRI

• Prior adjuvant

chemo

• Prior radiotherapy

FOLFIRI or

FOLFOX

MD choice

Chemo + bevacizumab and

cetuximab

2334

Original


Study Cohort

Randomized

(n = 2334)

Bevacizumab

(n = 899)

Cetuximab

(n = 902)

Both

(n = 533)

RAS WT

(n = 256)

RAS mutant (mut)

(n = 167)

Unknown

(n = 476)

Plasma 25(OH)D Available (n = 1043)

n = 172 n = 126 n = 123

RAS WT

(n = 270)

RAS mutant

(n = 180)

Unknown

(n = 452)

n = 173 n = 121 n = 124

RAS WT

(n = 0)

RAS

mutant

(n = 124)

Unknown

(n = 409)

n = 0 n = 62 n = 142


Statistical Methods

• Preplanned, prospective, observational cohort study

• Primary endpoint: Overall survival

– Kaplan-Meier method

– Log rank test

• Plasma 25(OH)D measured by radioimmunoassay prior to

treatment

• Validated diet and lifestyle questionnaires prior to treatment

• Multivariable analyses using Cox proportional hazards models

• All P values two-sided and considered significant at the .05 level


Vitamin D Cohort vs Final Trial Cohort

Vitamin D

(n = 1043)

Final Trial

(n = 1137)

Median age, years 60 59

Male, % 58 61

ECOG PS 0 / 1, % 61 / 39 58 / 42

Primary tumor in place, % 25 28

Palliative intent, % 82 84

FOLFOX / FOLFIRI, % 77 / 23 73 / 27

All P values >.05


Baseline Characteristics (1)

Q1

(n = 208)

Q2

(n = 209)

Q3

(n = 208)

Q4

(n = 210)

Q5

(n = 208) P

Median

25(OH)D,

ng/mL (range)

8.0

(2.2-10.8)

13.6

(10.9-15.4)

17.2

(15.4-19.2)

21.4

(19.3-24.0)

27.5

(24.1-72.7) --

Median age,

years 59 60 60 61 61 .07

Male, % 48 64 58 64 55 .004

Black, % 25 12 6 7 2 <.0001

ECOG 0 / 1, % 49 / 50 64 / 36 58 / 42 63 / 37 70 / 30 .002

RAS WT / mut /

unknown, %

33 / 30 /

37

31 / 30 /

39

26 / 39 /

35

38 / 29 /

33

37 / 21 /

42 .02

Median 25(OH)D = 17.2 ng/mL


Baseline Characteristics (2)

• No significant difference in chemotherapy backbone, history of

prior adjuvant therapy, or assigned biologic between quintiles of

25(OH)D

• Significantly lower 25(OH)D seen in:

– Patients living in the north and northeast (P<.0001)

– Patients with blood drawn in winter and spring (P = .03)

– Obese patients (P = .0006)

– Less physically-active patients (P = .004)

– Patients not reporting vitamin D supplement use (P<.0001)


Higher Vitamin D Levels Associated With Better Survival

417 328 227 117 56 27 5 1

418 332 237 125 64 34 11 2

208 171 137 76 41 22 1

Quintiles 1 & 2

Quintiles 3 & 4

Quintile 5

No. at Risk

0

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7

Time (years)

Ove

rall

Su

rviv

al P

roba

bili

ty

Log-rank P = 0.01

Quintile

5

3

2

mOS (months)

30.0

28.4

32.6

1 24.5

95% CI

21.7-28.6

4 27.2

25.8-32.2

24.2-31.0

25.0-31.5

27.7-36.9


Time (Years)

Higher Vitamin D Levels Also Associated with Better Progression-Free Survival (PFS)

417 163 55 19 10 4 3 1

418 196 72 34 19 13 3

208 96 37 17 6 4

Quintiles 1 & 2

Quintiles 3 & 4

Quintile 5

No. at Risk

0

0

0

4

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 5 6 7

Time (Years)

Pro

gre

ssio

n-F

ree S

urv

ival P

robabili

ty

Log-rank P = .02

Quintile

5

3

2

mPFS (months)

10.9

11.4

12.2

1 10.1

95% CI

9.2-11.3

4 12.7

9.6-11.6

9.7-12.9

11.1-13.6

10.8-14.2


Multivariate Analysis • Final model adjusted for:

– Age

– Sex

– Race

– ECOG performance status

– Chemotherapy backbone

– Previous adjuvant therapy

– Assigned biologic

– RAS mutation status

– Season of blood draw

– Geographic region of residence

– Body-mass index

– Physical activity


Multivariate Hazard Ratios: Overall Survival

1.0

0.83

[0.66-1.03]

0.81

[0.65-1.02]

0.65

[0.51-0.83]

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

2.2-10.8 10.9-15.4 15.5-19.2 >24.1

Haza

rd R

ati

o f

or

Dea

th

P trend = .001


Pa ti e n ts w i th th e h i g h e s t

l e v e l s o f v i ta m i n D h a v e

a 3 5 % i m p r o v e m e n t

in overall survival

19.3-24.0

0.79

[0.63-1.00]


Multivariate Hazard Ratios: PFS

1.0 0.99

[0.80-1.23]

0.84

[0.67-1.05] 0.79

[0.63-0.99]

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

2.2-10.8 10.9-15.4 15.5-19.2 >24.1

Ha

za

rd R

ati

o f

or

Pro

gre

ss

ion

or

De

ath

P trend = .01


Pa ti e n ts w i th th e h i g h e s t

l e v e l s o f v i ta m i n D h a v e

a 2 1 % i m p r o v e m e n t

i n PF S

19.3-24.0

0.83

[0.67-1.04]


Subgroup Analyses of

Overall Survival, Comparing

Extreme Quintiles of 25(OH)D

Adjusted HR:

Age (years)

<60

>60

Race

White

Black

Sex

Male

Female

ECOG performance status

0

1

Planned chemotherapy

FOLFIRI

FOLFOX

Assigned treatment arm

Bevacizumab

Cetuximab

Both

RAS mutation status

Wild-type

Mutant

Body mass index (kg/m2)

<25

≥25

Physical activity (MET-hours/wk)

<3

≥3

P interaction

0.27

0.10

0.09

0.85

0.32

0.90

0.20

0.78

0.50

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

Favors Higher 25(OH)D


Randomized Double-Blind Phase II Trial of Vitamin D in Metastatic CRC

Participating sites:

DFCI

MGH

BIDMC

DF/HCC satellites

DF/HCC affiliates

Northwestern

Vanderbilt

MSTI (Boise, ID)


n = 120

Conclusions

• Metastatic CRC patients are frequently vitamin D

deficient

• Higher vitamin D levels are associated with significantly

improved overall survival and PFS

• This association persists across all patient subgroups

and after adjusting for multiple prognostic factors

• A phase II randomized trial to evaluate the impact of

vitamin D supplementation as an adjunct to

chemotherapy is currently ongoing


vitamin d status and survival of metastatic colorectal cancer … · 2018-06-01 · vitamin d...

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