# Presentation: 277041

## What is the Dose-Response Relationship between Vitamin D and Cancer?

- Cedric F. Garland1, Frank C. Garland1,
- Edward D. Gorham1, William B. Grant2
- and Sharif B. Mohr1

- May 7, 2007
- Lister Hill Auditorium
- NIH Campus

- 1University of California, San Diego CA
- 2Sunlight, Nutrition & Health Research Center (SUNARC),
- San Francisco CA

## 	15 oral intake studies of vitamin D and colon cancer 5 serum 25(OH)D and colon cancer studies2 serum 25(OH)D and breast cancer studies3 international comparisons of 177 countries cancer incidence rates vs estimated 25(OH)D serum levels2 randomized controlled clinical trials 

- Approach for Dose-Response Estimation

## 15 Dietary Studies of Vitamin D and Colon Cancer

**Garland CF, et al. Lancet. 1985;1(8424):307-9.**
**Benito E, et al. Int J  Cancer. 1991;49(2):161-7.**
**Peters RK, et al. Cancer Causes Control. 1992;3(5):457-73.**
**Ferraroni M, et al. Br J Cancer. 1994;70(6):1150-5.***
**Kearney J,  et al. Am J Epidemiol. 1996;143(9):907-17.**
**Martinez ME, et al. J Natl Cancer Inst. 1996;88(19):1375-82.**
**Pritchard RS, et al. Cancer Epidemiol Biomarkers Prev. 1996;5(11):897-900.**
**LaVecchia C, et al. Int J Cancer. 1997;73:525-30.**
**Marcus PM, et al. Int J Epidemiol. 1998;27(5):788-93.**
**Bostick RM, et al. Am J Epidemiol. 1999;149(2):151-61.**
**Pietinen P, et al. Cancer Causes Control. 1999;10(5):387-96.**
**Kampman E, et al. Cancer Causes Control. 2000;11(5):459-66.**
**Jarvinen R, et al. Eur J Clin Nutr. 2001;55:1000-7.***
**Terry P, et al. Nutr Cancer. 2002;43(1):39-46.***
**McCullough ML, et al. Cancer Causes Control. 2003;14(1):1-12.**
***Vitamin D intake < 250 IU/day**
** **

## Eight Oral Vitamin D Studies Combined

**Eight Oral Vitamin D Studies Combined**

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**Mean total oral vitamin D intake IU/day**

**Odds ratio**

- Source: Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005;97(1-2):179-94.

## Studies of Serum Levels of 25(OH)D and Colon Cancer

**Garland CF, et al.  Lancet. ****1989; 2:1176-8.**
**Braun MM, et al.Am J Epidemiol. ****1995;142(6):608-11.**
**Tangrea J, et al. Cancer Causes and Control. 1997;8(4):615-25.**
**Feskanich D, et al. Cancer Epidemiol Biomarkers Prev. 2004;13(9):1502-8**
**Wactawski-Wende J, et al. New Engl J Med 2006; 354:684-96.**

## Tangrea et al. 1997

**Tangrea et al. 1997**

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**Mean level of serum 25(OH)D ng/ml**

**Odds ratio**

## Slide 7

## Women’s Health Initiative 

**Women’s Health Initiative **
**Nested Study (N=295)**

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**Median level of serum 25(OH)D, ng/ml**

**Source: Wactawski-Wende J, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. New Engl J Med 2006; 354:684-96.**

*** ***

*** ***

**Odds ratio**

## Source: Gorham ED,  et al. Optimal vitamin D status for colorectal cancer prevention: A Quantitative Meta Analysis. Am J Prev Med March 2007; 32:210-6.

- Source: Gorham ED,  et al. Optimal vitamin D status for colorectal cancer prevention: A Quantitative Meta Analysis. Am J Prev Med March 2007; 32:210-6.

## Source: Gorham ED,  et al. Optimal vitamin D status for colorectal

- Source: Gorham ED,  et al. Optimal vitamin D status for colorectal

- cancer prevention: A Quantitative Meta Analysis. Am J Prev Med March 2007; 32:210-6.

## Studies of Serum Levels of 25(OH)D and Breast Cancer

## Data from: Lowe LC, et al. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 2005;41:1164-9. 

- Data from: Lowe LC, et al. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 2005;41:1164-9.

## Data from: Bertone-Johnson, E.R. et al. Plasma 25-hydroxyvitamin D

- and 1, 25-dihydroxyvitamin D and risk of breast cancer. Cancer
- Epidemiol. Biomarkers Prev. 2005; 14: 1991-7.

## Source: Garland CF, et al. Vitamin D and prevention of breast cancer: Pooled analysis, J Steroid Biochem Mol Biol. 2007;103:708-11 

- Source: Garland CF, et al. Vitamin D and prevention of breast cancer: Pooled analysis, J Steroid Biochem Mol Biol. 2007;103:708-11

## Source: Tworoger SS, Lee IM, Buring JE, Rosner B, Hollis BW, Hankinson SE. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of incident ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:783-8. 

- Source: Tworoger SS, Lee IM, Buring JE, Rosner B, Hollis BW, Hankinson SE. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of incident ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:783-8.

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**15**

**20**

**25**

**30**

**35**

**Median serum 25(OH)D, ng/ml**

**Odds ratio**

**25(OH)D and Ovarian cancer**

## Estimated dose-response curves 

- based on 177 countryecological cancer studies

## Colon WM

- Projected 25(OH)D concentration in ng/ml

- Annual  age-standardized incidence rate per 100,000 population, Colon Cancer, 2002

- Source: GLOBOCAN Database of the International Agency for Research on Cancer.
- http://www-dep.iarc.fr/globocan/database.htm.

## Colon WM

- Projected 25(OH)D concentration in ng/ml

- Annual  age-standardized incidence rate per 100,000 population, Breast Cancer, 2002

- Source: GLOBOCAN Database of the International Agency for Research on Cancer.
- http://www-dep.iarc.fr/globocan/database.htm.

**Breast Cancer**

## Colon WM

- Projected 25(OH)D concentration in ng/ml

- Annual  age-standardized incidence rate per 100,000 population, Ovarian Cancer, 2002

- Source: GLOBOCAN Database of the International Agency for Research on Cancer.
- http://www-dep.iarc.fr/globocan/database.htm.

- Ovarian Cancer

## Lifeguards’ 25(OH)D 

- Lifeguards’ 25(OH)D
- level is 60 ng/ml

## Randomized Controlled Trial of Vitamin D and Calcium Joan Lappe, Robert Heaney, et al.Source: American Journal of Clinical Nutrition, In Press(June 2007)

## Randomized Controlled Trial of Vitamin D and Calcium

- Four years, N = 1,179 healthy women in Omaha NE
- Mean age 66.7 ± 7.3 years
- N = 1,032 finished trial (87.5%)
- Baseline serum 25(OH)D: 29 ± 8 ng/ml (72 ± 20 nmol/L)
- Three treatment groups:
- Vitamin D3 (1,100 IU/day) and calcium (1450 mg/day)
- Calcium (1,450 mg/day)
- Placebo
- Outcome:  All cancers (mainly breast, lung and colon)

- Source:  Lappe et al. Am J Clin Nutr 2007 (in press)

**Notes:**
Since 25(OH)D was measured at 12-month intervals, there was no change in the two grps not getting vit D.  But the treated group had a rise of about 20nmol/L  (to about 93 nmol/L).
There were 50 cancers, overall, mostly breast, lung, colon, & marrow/lymphoma.

## Randomized Controlled Trial

- Source: Lappe et al. Am J Clin Nutr 2007 (in press)

**Time (yrs)**

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**Fraction Cancer-Free**

**0.90**

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**1.00**

**Calcium and Vitamin D**

**Placebo**

**Calcium only**

***P***** < 0.01**
**Relative Risk = 0.40**

**Notes:**
Cedric:  Note the new diagnoses within the first month of enrollment.  We presumed they represented pre-existing (but undetected) cancers.  The next slide restarts the clock (so to speak) at the 1-yr anniversary.  Note the “build” on the two-headed arrow.

## All Except First Year Cases

- Source: Lappe et al. Am J Clin Nutr 2007 (in press)

**Time (yrs)**

**0**

**1**

**2**

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**4**

**Fraction Cancer-Free**

**0.90**

**0.92**

**0.94**

**0.96**

**0.98**

**1.00**

**Calcium and Vitamin D**

**Calcium only**

**Placebo**

***P***** < 0.05**
**Relative Risk = 0.23**

**Notes:**
Cedric:  Note the new diagnoses within the first month of enrollment.  We presumed they represented pre-existing (but undetected) cancers.  The next slide restarts the clock (so to speak) at the 1-yr anniversary.  Note the “build” on the two-headed arrow.

## RR = 0.69,  p = 0.09

- RR = 0.69,  *p* = 0.09

## Dose-response relationships from cohort studies were used to estimate the number and percent of cancer cases that could be prevented worldwide by vitamin D3 supplementation

- Global Impact

## Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage prevention of COLON CANCER cases (bars) with 2,000 IU/day of Vitamin D3 or modest suberythemal UVB (typically 1 minute)

**Central and Eastern Europe**
**35,017**

**Eastern Asia**
**82,791**

**North America**
**48,609**

**Northern Europe**
**5,500**

**Western Europe**
**61,255**

**Australia/New Zealand**
**4,191**

**South Central Asia**
**4,585**

**Western Asia**
**3,841**

**South America**
**5,534**

**27%**

**19%**

**12%**

**28%**

**10%**

**26%**

**28%**

**29%**

**27%**

**32%**

**Southeast Asia**
**1,338**

**3%**

**Central America**
**1,444**

**Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage prevention of ****COLON CANCER**** cases (bars) with ****2,000**** IU/day of Vitamin D3 or modest suberythemal UVB (typically 1 minute)**

## Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage reduction in BREAST CANCER incidence (bars) 2,000 IU/day of Vitamin D3 or modest suberythemal UVB (typically 2 minutes)

**Central and Eastern Europe**
**27,112**

**Eastern Asia**
**47,272**

**North America**
**58,165**

**Northern Europe**
**5,577**

**Western Europe**
**46,992**

**Australia/New Zealand**
**3,336**

**South Central Asia**
**12,304**

**Western Asia**
**6,327**

**South America**
**8,077**

**25%**

**21%**

**11%**

**25%**

**9%**

**26%**

**23%**

**26%**

**21%**

**28%**

**Southeast Asia**
**2,042**

**3%**

**Central America**
**2,945**

**Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage reduction in ****BREAST CANCER**** incidence (bars) ****2,000**** IU/day of Vitamin D****3**** or modest suberythemal UVB (typically 2 minutes)**

## Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage reduction in BREAST CANCER incidence (bars) with 4,000 IU/day of Vitamin D3 or modest suberythemal UVB (typical 4 minutes)

**Central and Eastern Europe**
**47,208**

**Eastern Asia**
**69,154**

**North America**
**91,330**

**Northern Europe, 22,251**

**Western Europe**
**74,362**

**Australia/New Zealand**
**6,018**

**South Central Asia**
**17,534**

**Western Asia**
**17,534**

**South America**
**12,522**

**40%**

**29%**

**16%**

**45%**

**10%**

**41%**

**41%**

**36%**

**27%**

**41%**

**Southeast Asia**
**2,193**

**4%**

**Central America**
**4,079**

- Estimated 25(OH)D serum levels (color coded, ng/ml) and projected percentage reduction in **BREAST CANCER** incidence (bars) with 4,000 IU/day of Vitamin D3 or modest suberythemal UVB (typical 4 minutes)

## Source: Vieth R. et al., Annals Epidemiol  (in press)

- Source: Vieth R. et al., *Annals Epidemiol*  (in press)

## Conclusions

-  Universal oral intake of vitamin D3 in  North America, Europe, and Northern Asia:
-  2,000 IU per day for men
-  2,000-4,000 IU/day for women
-  Children 400-600 IU/day
-  Adequate calcium intake: 800-1,000 mg/d for males; 1,200-1,500 mg/d for females

## Conclusions

-  25(OH)D blood test yearly. Vitamin D adjusted, if needed, to maintain 40-60 ng/ml (“lifeguard” level).
-  Vitamin D3 for all cancer patients, except those with hypercalcemia.
-  More research on dose-response gradients for cancers other than colon, breast, and ovarian

## The End

## Discussion Slides

## Garland et al., 1985

- N = 49
- cases

- N = 1,905
- noncases

- Cohort of N = 1,954 men

- Length:  19 years

- Location: Chicago

- Garland C, Shekelle RB, Barrett-Connor E, Criqui M,
- Rossof A, Paul O.  Dietary vitamin D and calcium and
- risk of colorectal cancer:  a 19-year prospective study in men.
- Lancet 1985; 1: 307-9.

- 96%
- follow-up

## Garland et al., Colon Cancer Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- 1.4

- 50

- 120

- 200

- 250

**Dietary Vitamin D IU/day**

**Relative Risk**

## Pritchard et al., 1996

- N = 569
- cases

- N = 512
- Pop. controls

- Population
- Registry

- Length 2 years

- Location: Stockholm

- Pritchard R, Baron J, Gerhardsson de Verdier M. Dietary
- calcium, vitamin D, and the risk of colorectal cancer in
- Stockholm, Sweden. *Cancer Epidemiology, Biomarkers and*
*Prevention* 1996; 5: 897-900. (FFQ5Y, NS, CR)

- 98%
- ascertainment

## Prichard et al., Colon Cancer Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- 110

- 140

- 220

- 250

**Total vitamin D intake IU/day**

**Odds ratio**

*P*

- trend = 0.08

**50% projected reduction**
**with 250 IU/day**

## Bostick et al., 1993

- N = 212
- cases

- N = 35,004
- noncases

- Cohort of N = 35,216 women

- Length 5 years

- Location: Iowa

- 95%
- follow-up

- Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. *Am J Epidemiol* 1993; 137 (12): 1302-17.

## Bostick et al. 

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- 100

- 200

- 340

- 520

- 795

**Quintiles of total Vitamin D intake, IU/day**

**Relative Risk**

- Bostick et al.

- Bostick et al., Colon Cancer Results

**50% projected reduction**
**with 750 IU/day**

## Martinez et al., 1996

- N = 351
- Cases

- N = 89,097
- Noncases

- Cohort of 89, 448 women

- Length: 13 years

- Location: USA

-       Martinez ME, Giovannucci EL, Colditz GA, Stampfer MJ, Hunter DJ, Speizer FE, Wing A, Willett WC. Calcium, vitamin D, and the occurrence of colorectal cancer among women. J Natl Cancer Inst 1996;88:1375-82.

- 94%+
- ascertainment

## Martinez et al., Colon Cancer Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- < 92

- 125

- 205

- 370

- 580

- Total vitamin D intake IU/day

- Relative risk

**40% projected reduction**
**with 560 IU/day**

## Kearney et al., 1996

- N = 203
- cases

- N = 47,732
- noncases

- Cohort of N = 47,935 men

- Length 7 years

- Location: USA

- Kearney et al.  Calcium, vitamin D, and dairy foods and the
- occurance of colon cancer in men. *Am J Epidemiol* 1996;
- 143(9): 907-17.

- ~ 95%
- follow-up

## Kearney et al, Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- <161

- 161 - 246

- 247 - 373

- 374 - 612

- > 612

**Quartiles, total vitamin D, IU/day**

**Relative Risk**

*P*

- trend = 0.02

## Marcus et al., 1998

- N = 678
- women cases

- N = 47,732
- controls

- Madison WI
- population

- Length 6 years

- Location: Madison WI

- Marcus et al. The association of calcium and vitamin D, and
- colon and rectal cancer in Wisconsin women. *International *
*Journal of Epidemiology* 1998; 27: 788-93. (FFQ2, CR, CaR)

- ~ 95%
- ascertainment

## Marcus et al., Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- <148

- 148 - 233

- 234 - 372

- 373 - 556

- >556

**Quintiles, total vitamin D intake, IU/day**

**Odds ratio**

*P*

- trend = 0.05

## Lieberman et al., 2003

- N = 329
- Cases - A/N

- N = 1,441
- controls

- Cohort of 3,121 VA members

- Length 3 years

- Location: 13 Centers

- Lieberman et al. Risk factors for advanced colonic neoplasia
- and hyperplastic polyps in asymptomatic individuals. JAMA
- 2003; 290(22): 2959-67. (FFQ, AdvNeo)

- Colonoscopic
- ascertainment

## Lieberman et al., Results

- 0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- <179.5

-    179.5 –
-    270.2

-    270.3 –
-    417.7

-    417.8 –
-    644.9

- > 644.9

**Total dietary vitamin D, IU/day**

**Odds ratio**

*P*

- trend = 0.02