ABSTRACT
Background
It is unknown whether dietary supplementation with vitamin D or calcium prevents keratinocyte carcinomas, also known as nonmelanoma skin cancers.
Objectives
This study aimed to determine whether daily vitamin D or calcium supplementation alters the risk of basal cell carcinoma (BCC) or invasive cutaneous squamous cell carcinoma (SCC).
Methods
The Vitamin D/Calcium Polyp Prevention Study is a completed multicenter, double-blind, placebo-controlled, partial 2 × 2 factorial, randomized clinical trial of vitamin D, calcium, or both for the prevention of colorectal adenomas. During 2004–2008, a total of 2259 men and women, 45–75 y of age, recently diagnosed with a colorectal adenoma, were randomly assigned to 1000 IU/d of vitamin D3 or placebo and 1200 mg/d of calcium carbonate or placebo for 3 or 5 y, and followed after treatment ended. Reports of incident BCC or SCC were confirmed from pathology records.
Results
During a median follow-up of 8 y, 200 (9%) participants were diagnosed with BCC and 68 (3%) participants were diagnosed with SCC. BCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.96; 95% CI: 0.73, 1.26), calcium compared with no calcium (HR: 1.01; 95% CI: 0.74, 1.39), and both agents compared with neither (HR: 0.99; 95% CI: 0.65, 1.51). SCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.79; 95% CI: 0.49, 1.27), but there was suggestive evidence of beneficial treatment effects for calcium compared with no calcium (HR: 0.60; 95% CI: 0.36, 1.01) and both agents compared with neither (HR: 0.42; 95% CI: 0.19, 0.91).
Conclusions
Calcium alone or in combination with vitamin D may reduce the risk of SCC, but not BCC. This trial was registered at clinicaltrials.gov as NCT00153816.
Keywords: basal cell carcinoma, calcium, cutaneous squamous cell carcinoma, keratinocyte carcinomas, nonmelanoma skin cancer, vitamin D
Introduction
Basal cell carcinoma (BCC) and invasive cutaneous squamous cell carcinoma (SCC), together known as keratinocyte carcinomas (KCs) or nonmelanoma skin cancers, are diagnosed in >3 million Americans annually (1). Exposure to ultraviolet radiation (UVR) is the primary risk factor for both BCC and SCC, and incidence is highest among fair-skinned individuals, as well as those with a history of severe sunburns, family history of skin cancer, and long-term immunosuppression (2). Clinical management generally entails standard excision or ablation for low-risk lesions or Mohs micrographic surgery for high-risk lesions, particularly on the face, head, and neck (3, 4). Although mortality is low overall, ∼4% of SCC patients experience metastatic disease requiring local radiation or systemic therapy (5). Preventive efforts to constrain the economic (6) and quality of life (7) burden associated with KC treatment remain a top public health priority (8).
Preclinical evidence links low vitamin D status to KC development (9, 10), but epidemiologic studies of circulating 25-hydroxyvitamin D [25(OH)D] as a risk factor are conflicting (11). Interpretation of these observational studies is difficult, because sun exposure is responsible for both carcinogenesis and vitamin D synthesis in keratinocytes, and thus may generate intractable confounding (9, 10). Calcium intake has been associated with reduced risk of some cancers (12). Only 10%–15% of calcium can be absorbed without vitamin D, and thus both are often taken together as dietary supplements (13).
Dietary and supplemental intakes of vitamin D and calcium have not been extensively studied with regard to KC risk. A secondary analysis of a clinical trial of daily vitamin D and calcium supplementation found no treatment effect for KC incidence, but did not consider histologic subtype and could not distinguish effects for vitamin D from those for calcium (14). To clarify these issues, we conducted a secondary analysis in the Vitamin D/Calcium Polyp Prevention Study, a placebo-controlled randomized clinical trial permitting separate evaluation of study agents and incidence of BCC and SCC, the 2 histologic subtypes of KC (15).
Methods
Study design
Details of the Vitamin D/Calcium Polyp Prevention Study (NCT00153816) have been described previously (15, 16). In brief, men and women, 45–75 y of age, were recruited from 11 medical centers and associated clinical practices in the United States between July 2004 and July 2008. All participants provided written informed consent and institutional review boards at each center approved study protocols.
Eligible participants underwent polypectomy for ≥1 colorectal adenoma within 120 d before enrollment. Individuals with inflammatory bowel disease, familial colorectal cancer syndromes, history of any cancer (except KC) in the past 5 y, or medical conditions that precluded treatment with calcium or vitamin D were ineligible. In total, 2259 participants were randomly assigned to 1000 IU/d vitamin D3 (cholecalciferol), 1200 mg/d elemental calcium as carbonate, both, or placebo. The study used a partial 2 × 2 factorial design, allowing women to elect to receive the active calcium study pill while being randomly assigned to active vitamin D or placebo for vitamin D (2-group randomization), because of ethical concerns about withholding calcium from women. All other participants were randomly assigned to 1 of 4 treatments: only vitamin D, only calcium, both vitamin D and calcium, or placebo (full-factorial randomization). Thus, all 2259 participants were randomly assigned to vitamin D or a vitamin D placebo, but only 1675 were also randomly assigned to calcium or a calcium placebo; 584 women underwent 2-group randomization.
Randomization using permuted blocks was stratified by clinical center, sex (for full-factorial randomization), anticipated treatment period (3 or 5 y), and randomization type (full factorial or 2-group). A 3-mo placebo run-in was used to exclude noncompliant participants. Participants agreed to limit dietary intake of vitamin D to ≤400 IU/d and of calcium to ≤1200 mg/d. Nonprotocol use of study agents was discouraged, and those interested in taking a multivitamin were supplied a preparation without vitamin D and calcium.
Baseline assessment
Health history ascertained at baseline included age, sex, race, ethnicity, smoking status, dietary supplement use, time spent in outdoor activities during daylight hours, and use of sunscreen. Dietary intakes of vitamin D and calcium were measured from a semiquantitative FFQ (Block Brief 2000; NutritionQuest). Previous diagnoses of KC or melanoma any time before enrollment were self-reported and neither adjudicated from medical records nor classified by histologic subtype. Individuals diagnosed with any invasive cancer (including melanoma but excluding KC) within the past 5 y were ineligible to enroll in the study. Skin cancer history was defined as any report of KC or melanoma any time before enrollment (except melanoma within the past 5 y).
A blood specimen was collected before randomization. Those with circulating calcium outside of the sex-specific normal range, with creatinine ≥20% above the upper limit of the sex-specific normal range, or with 25(OH)D <12 ng/mL or >90 ng/mL were excluded from the study. Another blood specimen was collected before the end of study treatment to assess treatment compliance. Serum 25(OH)D concentrations were measured by liquid-phase RIA from Immunodiagnostic Systems Inc. (17). Values of 25(OH)D were adjusted for season of blood draw based on the month-specific mean and overall mean for all participants. Adjusted values were defined as the participant's measured value plus the difference between the overall mean and the month-specific mean for the given month. Baseline and end-of-treatment values were adjusted for season separately. In analyses, serum 25(OH)D was categorized as <20 ng/mL, 20 to <30 ng/mL, and ≥30 ng/mL (18). Serum calcium was not evaluated as a marker of calcium treatment compliance because changes in circulating calcium concentrations are usually short-lasting after calcium supplementation (19), and in this study blood draws were not timed with respect to daily supplementation.
Follow-up
Study tablets were mailed to participants every 4 mo. Treatment continued for 3 or 5 y according to the surveillance interval recommended by each participant's gastroenterologist. The treatment period ended in August 2013, and participants were invited to be followed observationally afterward until June 2016. Participants were contacted every 6 mo while on treatment and annually thereafter to report major medical events including diagnoses of any malignancy. During the treatment period, this interview also ascertained adherence to study agents by asking participants to report how many tablets they had taken per week on average since their last contact. The proportion of participants who had taken ≥80% of expected tablets on average during the treatment period was calculated from this self-reported information.
For reported KC occurrences after randomization (termed nonmelanoma skin cancer on questionnaires), BCC or SCC histology and diagnosis date were confirmed by centralized blinded adjudication of pathology reports or physician notes after biopsy. Histology was confirmed for 94% of reported diagnoses. Unverified diagnoses and those found to be precancerous lesions such as SCC in situ (Bowen's disease) or actinic keratoses were excluded as endpoints. Pathology findings from resections performed within 60 d were combined and counted as occurring on the date of the earliest diagnosis in order to capture updated information for re-evaluations of persistent issues. Melanoma was not considered as an endpoint in this analysis. The incidence of any cancer after randomization according to treatment assignment was previously documented as part of adverse events analyses for the treatment period (15) and posttreatment period (16), but did not include KC.
Statistical analysis
Separate analyses considered time to the first BCC diagnosis and time to the first SCC diagnosis after randomization. Whether within 60 d or not, participants diagnosed with both BCC and SCC were included as having both follow-up to a first BCC and follow-up to a first SCC after randomization. HRs with 95% CIs were estimated from proportional hazards regression adjusted for the variables involved in the stratified randomization. However, in order to limit the degrees of freedom in our models, we dichotomized clinical center by geographic UVR exposure (with centers located in Iowa, Minnesota, New Hampshire, and Ohio grouped together and centers in California, Colorado, Georgia, North Carolina, Puerto Rico, South Carolina, and Texas grouped together), used a 3-level variable for sex and type of randomization (male, female with full-factorial randomization, female with 2-group randomization), and did not adjust for the anticipated treatment period (3 or 5 y).
We considered 3 intention-to-treat contrasts that accommodated the trial design: 1) vitamin D compared with no vitamin D among all 2259 participants who were randomly assigned to vitamin D (full-factorial randomization and 2-group randomization); 2) calcium compared with no calcium among the 1675 participants who underwent full-factorial randomization that included random assignment to calcium; and 3) calcium and vitamin D compared with no calcium and no vitamin D among the 836 participants who underwent full-factorial randomization and were assigned to 1 of those 2 treatment combinations. The HR for vitamin D compared with no vitamin D was not adjusted for calcium assignment and the HR for calcium compared with no calcium was not adjusted for vitamin D assignment.
In sensitivity analyses, we calculated the HR for vitamin D compared with no vitamin D and for calcium compared with no calcium with mutual adjustment, both among the 1675 participants who underwent full-factorial randomization and among all 2259 participants by including in the calcium group the 584 women who underwent 2-group randomization. We also report the P value for treatment interaction among the 1675 participants who underwent full-factorial randomization from a regression model with a main effect for vitamin D assignment, a main effect for calcium assignment, and a multiplicative interaction term between treatments.
Subgroup analyses were performed according to skin cancer history and baseline circulating 25(OH)D. As a test of the proportional hazards assumption, separate HRs were estimated for the treatment and posttreatment periods using a product interaction term between treatment assignment and a time-dependent indicator variable for treatment period defined according to the date of stopping treatment for each participant. A sensitivity analysis was performed not counting KC diagnoses during the first year after randomization, because these lesions may have been prevalent but undiagnosed at baseline and unaffected by the study treatment. Two-sided P values ≤0.05 were considered statistically significant. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc.) and R version 3.5.2 (R Project for Statistical Computing).
Results
Skin cancer risk factors including age, race, time spent outdoors, sunscreen use, and skin cancer history were similarly distributed across treatment arms (Table 1). In total, 1137 (50%) participants were scheduled to be treated during a 3-y surveillance interval and 1122 (50%) participants were scheduled to be treated during a 5-y surveillance interval. As documented previously (15), 76% of participants took ≥80% of study tablets during the treatment period, and <5% reported nonprotocol use of substantial amounts of vitamin D (≥1000 IU/d) or calcium (≥400 mg/d). The mean ± SD increase in circulating 25(OH)D was 8.3 ± 9.9 ng/mL among those assigned to vitamin D compared with 0.5 ± 9.0 ng/mL among those assigned to no vitamin D during 3.9 ± 1.3 y of treatment. As reported previously, no treatment effects for either agent were observed for the primary colorectal adenoma endpoints, both during the treatment period (15) and during the posttreatment period (16).
TABLE 1.
Baseline characteristics of Vitamin D/Calcium Polyp Prevention Study participants according to treatment assignment1
| Full-factorial randomization | 2-Group randomization | |||||
|---|---|---|---|---|---|---|
| Baseline characteristics | Placebo (n = 415) | Calcium (n = 419) | Vitamin D (n = 420) | Calcium + vitamin D (n = 421) | Calcium + placebo (n = 295) | Calcium + vitamin D (n = 289) |
| Age, y | 58 ± 7 | 59 ± 7 | 58 ± 7 | 59 ± 7 | 57 ± 6 | 57 ± 7 |
| Sex | ||||||
| Female | 60 (14) | 63 (15) | 62 (15) | 67 (16) | 295 (100) | 289 (100) |
| Male | 355 (86) | 356 (85) | 358 (85) | 354 (84) | 0 (0) | 0 (0) |
| Race | ||||||
| White | 357 (89) | 354 (88) | 364 (90) | 350 (87) | 238 (87) | 237 (87) |
| African American or black | 27 (7) | 33 (8) | 25 (6) | 46 (11) | 28 (10) | 25 (9) |
| Asian or Pacific Islander | 10 (2) | 10 (2) | 12 (3) | 6 (1) | 8 (3) | 7 (3) |
| Other | 8 (2) | 7 (2) | 3 (1) | 2 (1) | 1 (<1) | 2 (1) |
| Ethnicity | ||||||
| Non-Hispanic | 395 (95) | 395 (94) | 396 (94) | 394 (94) | 267 (91) | 263 (91) |
| Hispanic | 19 (5) | 23 (6) | 24 (6) | 26 (6) | 28 (9) | 26 (9) |
| BMI, kg/m2 | 29 ± 5 | 29 ± 5 | 29 ± 5 | 29 ± 5 | 29 ± 6 | 28 ± 5 |
| Cigarette smoker | ||||||
| Never | 187 (45) | 212 (51) | 217 (52) | 204 (49) | 205 (69) | 169 (58) |
| Former | 193 (47) | 174 (42) | 164 (39) | 169 (40) | 62 (21) | 88 (30) |
| Current | 35 (8) | 33 (8) | 39 (9) | 48 (11) | 28 (9) | 32 (11) |
| Serum 25-hydroxyvitamin D,2 ng/mL | 24 ± 8 | 25 ± 8 | 25 ± 8 | 24 ± 8 | 25 ± 9 | 24 ± 8 |
| Dietary vitamin D, IU/d | 138 ± 97 | 146 ± 96 | 131 ± 102 | 130 ± 92 | 124 ± 96 | 134 ± 98 |
| Supplemental vitamin D, IU/d | ||||||
| None | 204 (52) | 203 (51) | 209 (52) | 210 (52) | 84 (31) | 71 (26) |
| <400 | 5 (1) | 11 (3) | 5 (1) | 5 (1) | 14 (5) | 17 (6) |
| ≥400 | 187 (47) | 186 (47) | 189 (47) | 191 (47) | 176 (64) | 183 (68) |
| Dietary calcium, mg/d | 672 ± 313 | 718 ± 326 | 643 ± 286 | 652 ± 303 | 604 ± 295 | 656 ± 313 |
| Supplemental calcium, mg/d | ||||||
| None | 202 (51) | 199 (50) | 207 (52) | 212 (52) | 64 (24) | 56 (21) |
| <200 | 65 (17) | 57 (14) | 66 (16) | 70 (17) | 27 (10) | 38 (14) |
| ≥200 | 127 (32) | 139 (35) | 128 (32) | 125 (31) | 181 (67) | 174 (65) |
| Study center3 | ||||||
| Low UVR location | 217 (52) | 218 (52) | 221 (53) | 221 (52) | 131 (44) | 126 (44) |
| High UVR location | 198 (48) | 201 (48) | 199 (47) | 200 (48) | 164 (56) | 163 (56) |
| Time spent outdoors,4 h/wk | ||||||
| ≤7 | 118 (29) | 118 (28) | 111 (26) | 122 (29) | 137 (46) | 133 (46) |
| >7 | 296 (72) | 301 (72) | 308 (74) | 299 (71) | 158 (54) | 155 (54) |
| Sunscreen use5 | ||||||
| Never or rarely | 222 (53) | 230 (55) | 258 (62) | 236 (56) | 129 (44) | 120 (42) |
| Sometimes | 86 (21) | 87 (21) | 80 (19) | 92 (22) | 60 (20) | 45 (16) |
| Usually | 43 (10) | 40 (10) | 22 (5) | 35 (8) | 23 (8) | 40 (14) |
| Almost always or always | 64 (15) | 62 (15) | 59 (14) | 58 (14) | 83 (28) | 83 (29) |
| History of any skin cancer6 | ||||||
| No | 373 (90) | 367 (88) | 374 (90) | 357 (86) | 266 (90) | 266 (92) |
| Yes | 40 (10) | 50 (12) | 43 (10) | 60 (14) | 28 (10) | 22 (8) |
| Anticipated treatment period,7 y | ||||||
| 3 | 206 (50) | 213 (51) | 214 (51) | 217 (52) | 145 (49) | 142 (49) |
| 5 | 209 (50) | 206 (49) | 206 (49) | 204 (48) | 150 (51) | 147 (51) |
Values are means ± SDs or n (%). Numbers missing are as follows: race (n = 99), ethnicity (n = 3), BMI (n = 3), dietary vitamin D (n = 165), supplemental vitamin D (n = 109), dietary calcium (n = 165), supplemental calcium (n = 122), time spent outdoors (n = 3), sunscreen use (n = 2), and history of skin cancer (n = 13). KC, keratinocyte carcinoma; UVR, ultraviolet radiation.
Adjusted for season of blood draw.
Low-UVR study centers were located in Iowa, Minnesota, New Hampshire, and Ohio. High-UVR study centers were located in California, Colorado, Georgia, North Carolina, Puerto Rico, South Carolina, and Texas.
Time spent in outdoor activities during daylight hours during the consecutive 3-mo period when participants spent the most time outdoors in the past year.
Typical use of sunscreen during the consecutive 3-mo period when participants spent the most time outdoors in the past year.
Includes any diagnosis of KCs (histologic subtype not ascertained) or melanoma any time before enrollment. Individuals diagnosed with cancer (including melanoma, but not KCs) within the past 5 y were ineligible to enroll in the study.
The anticipated treatment period was the 3- or 5-y colonoscopic surveillance interval after initial polypectomy as determined by each participant's gastroenterologist.
During a median follow-up of 8.3 y, 200 (9%) participants were diagnosed with BCC and 68 (3%) with SCC, including 26 with both BCC and SCC (Supplemental Figure 1). Vitamin D and calcium supplementation, alone or together, were unrelated to overall BCC risk (Table 2, Figure 1). However, the treatment effect for both agents together differed according to skin cancer history, with a lower HR of BCC among those without prior skin cancer (Supplemental Table 1). Trends of lower HRs with higher serum 25(OH)D at baseline were not statistically significant (Supplemental Table 2). The HR of BCC for calcium compared with no calcium was lower during the posttreatment period than during the treatment period (Supplemental Table 3).
TABLE 2.
Treatment effects for BCC and SCC1
| BCC | SCC | ||||||
|---|---|---|---|---|---|---|---|
| Treatment assignment | At risk, n | BCC, n (%) | HR2 (95% CI) | P | SCC, n (%) | HR2 (95% CI) | P |
| No vitamin D3 | 1129 | 101 (9) | 1 (Ref) | 0.76 | 37 (3) | 1 (Ref) | 0.33 |
| Vitamin D3 | 1130 | 99 (9) | 0.96 (0.73, 1.26) | 31 (3) | 0.79 (0.49, 1.27) | ||
| No calcium4 | 835 | 78 (9) | 1 (Ref) | 0.93 | 39 (5) | 1 (Ref) | 0.05 |
| Calcium4 | 840 | 80 (10) | 1.01 (0.74, 1.39) | 24 (3) | 0.60 (0.36, 1.01) | ||
| No calcium + no vitamin D5 | 415 | 42 (10) | 1 (Ref) | 0.95 | 20 (5) | 1 (Ref) | 0.03 |
| Calcium + vitamin D5 | 421 | 44 (10) | 0.99 (0.65, 1.51) | 9 (2) | 0.42 (0.19, 0.91) | ||
BCC, basal cell carcinoma; SCC, cutaneous squamous cell carcinoma; UVR, ultraviolet radiation.
HR from proportional hazards regression adjusted for age, study center (low compared with high UVR), and a 3-level variable for sex and type of randomization (male, female with full-factorial randomization, female with 2-group randomization). Low-UVR study centers were located in Iowa, Minnesota, New Hampshire, and Ohio. High-UVR study centers were located in California, Colorado, Georgia, North Carolina, Puerto Rico, South Carolina, and Texas.
Among all 2259 participants who underwent randomization.
Among the 1675 participants who underwent full-factorial randomization.
Among the 836 participants who underwent full-factorial randomization and were randomly assigned to calcium and vitamin D or to placebo and placebo.
FIGURE 1.
Cumulative incidence of BCC and SCC in the Vitamin D/Calcium Polyp Prevention Study. Treatment assignments shown are (A) vitamin D compared with no vitamin D, (B) calcium compared with no calcium, and (C) calcium and vitamin D compared with no calcium and no vitamin D. BCC, basal cell carcinoma; SCC, cutaneous squamous cell carcinoma.
Risk of SCC was 40% lower among those assigned to calcium, with or without vitamin D, than among those assigned to no calcium (HR: 0.60; 95% CI: 0.36, 1.01), and 58% lower for those assigned both agents compared with neither (HR: 0.42; 95% CI: 0.19, 0.91) (Table 2, Figure 1). No effect modification or time-dependence was noted for these treatment effects (Supplemental Tables 1–3).
For both BCC and SCC, joint modeling the vitamin D and calcium treatment effects without interaction did not materially alter the results (Supplemental Tables 4, 5). In models that included a multiplicative interaction term between the treatments calculated among those who underwent full-factorial randomization, the interaction did not achieve statistical significance (P = 0.20 for BCC; P = 0.44 for SCC). Exclusion of 20 BCC events and 5 SCC events occurring within 1 y after randomization yielded similar results (data not shown).
Discussion
Evidence from this secondary analysis of the Vitamin D/Calcium Polyp Prevention Study suggests 1200 mg Ca/d, alone or with 1000 IU vitamin D3/d for 3 or 5 y, may reduce the risk of SCC, but not BCC. To our knowledge, the only previous randomized clinical trial of vitamin D and/or calcium to investigate KC risk in secondary analyses was the Women's Health Initiative (WHI) trial of both agents together for the prevention of hip fractures among postmenopausal women (14, 20). In the WHI, there was no treatment effect for KC with a twice-daily supplement containing 500 mg Ca and 200 IU vitamin D3 over 7 y of follow-up (14).
Comparisons of our secondary analysis with that of the WHI should consider several important differences in trial design and conduct. Whereas the daily calcium dose was similar in the WHI and the Vitamin D/Calcium Polyp Prevention Study (1000 compared with 1200 mg/d), the vitamin D dose was 2.5 times lower in the WHI (400 compared with 1000 IU/d), and adherence was slightly lower in the WHI (63% at 3 y compared with 76% at end of treatment). The WHI used medical record–based adjudication of diagnoses of melanoma, but not KC (14). Unlike in our study, nonprotocol use of vitamin D and calcium was not actively discouraged in the WHI and, consequently, more than half of women, including those assigned to placebo, reported nonprotocol use of calcium and vitamin D supplements after randomization (14, 21, 22). Secondary analyses restricted to WHI women who avoided using nonprotocol vitamin D and calcium suggested reduced risk of fractures and total cancer (21, 22), in contrast to the primary analyses that included all randomly assigned women (20). Such analyses were not reported for their evaluation of KC (14). Based on the different effects we observed for BCC and SCC, it is possible any treatment effect for KC in the WHI, which was likely dominated by BCC, may have been obscured by not considering tumor histology.
A few previous observational studies have investigated the association of dietary and supplemental intake of vitamin D with KC risk. A case-control study conducted among members of Kaiser Permanente Northern California found no association between supplemental vitamin D intake and SCC risk (23). The Nurses’ Health Study and Health Professionals Follow-up Study prospective cohort studies identified incident cases of KC, with medical record–based adjudication for SCC but not BCC, and found higher dietary and supplemental vitamin D intake was associated with higher BCC risk, but not with SCC risk (24). Earlier reports from these cohorts found no association between vitamin D intake and BCC risk based on shorter follow-up (25, 26). Calcium intake was not specifically evaluated.
Our analysis was prompted by the fact that previous placebo-controlled randomized clinical trials of vitamin D and/or calcium supplementation evaluating overall cancer risk as an endpoint excluded KC (27). Previous randomized clinical trials of vitamin D supplementation, with or without calcium, have been inconsistent with respect to overall cancer risk (28–34). A trial of postmenopausal women from Nebraska testing 2000 IU vitamin D3/d and 1500 mg Ca/d reported a 30%–35% reduced risk of any cancer over 4 y (29, 32), and the Physicians’ Health Study II trial of men testing a multivitamin containing 400 IU vitamin D3/d and 200 mg Ca/d among 2 dozen other vitamins and minerals reported an 8% reduced risk of any cancer over 11 y (35). However, other trials found no effect on total cancer incidence (28, 30, 31, 33, 34). In addition, no treatment effects for overall cancer risk have been reported in randomized clinical trials of calcium alone (36–40).
Strengths of the Vitamin D/Calcium Polyp Prevention Study include the randomized design, separate evaluation of vitamin D and calcium, excellent adherence, limited nonprotocol use of study agents, and histology verification for incident KC diagnoses. The randomized design helped balance unmeasured variables such as skin type and pre-existing actinic keratoses by treatment assignment. It is also unlikely that more intense sun exposure, skin cancer screening, or uncontrolled use of study agents occurred in any particular treatment arm compared with another. Patients with inflammatory bowel disease, who may be at increased risk of BCC from certain immunosuppressive treatments (41), were ineligible for the study, and the overall cumulative incidence of KC was consistent with nationwide estimates (1).
The Vitamin D/Calcium Polyp Prevention Study was not originally designed to investigate skin cancer. History of skin cancer before baseline was ascertained but diagnoses and histologic subtype were not verified. We did not consider lesion size or anatomic location and so did not distinguish low-risk from high-risk BCCs and SCCs (3, 4). Treatment effects involving calcium suggestive of reduced BCC risk were apparent only after the treatment period ended. It is possible that supplementation for >3 or >5 y may be needed to observe any chemopreventive effect given the relatively long latency period for cancer development. Follow-up after the end of the 3- or 5-y treatment period was included in analyses, and participant dropout and personal use of vitamin D and calcium after treatment ended may have affected our results. However, as described previously (16), we did not find that average dietary and supplemental use of vitamin D and calcium after the end of treatment differed by treatment assignment among those who participated in the observational follow-up.
The study design permitted separate evaluation of treatment effects for vitamin D alone, calcium alone, and both agents together. We tested for a treatment interaction in sensitivity analyses, and for both BCC and SCC there was insufficient evidence to conclude that the overall treatment effects for vitamin D and calcium differed. This supported our choice to employ in primary analyses a marginal approach (without interaction) in the context of a partial factorial design. However, a specific test of the effect of both agents compared with neither provided statistically significant evidence of reduced risk of developing SCC. Although this particular comparison resulted in the strongest observed treatment effect for SCC, this estimate was also based on a smaller sample size and was thus less precise than for other contrasts. We did not adjust the type I error probability to account for the multiple statistical testing of 3 treatment contrasts and 2 KC subtypes as endpoints. Consequently, caution should be exercised in interpreting our findings.
In addition, subgroup analyses were limited by relatively low statistical power. Despite apparent trends, there was insufficient evidence to conclude that treatment effects differed according to vitamin D status as measured by serum 25(OH)D concentrations at baseline. Those with 25(OH)D <12 ng/mL were ineligible for study participation, and so our results may not be generalizable to populations with severe hypovitaminosis D. We considered treatment effects according to previous history of skin cancer, given those with such history would be of high priority for chemopreventive interventions. For BCC, the direction of effects for both calcium and vitamin D supplementation appeared to differ according to history of skin cancer. Future investigations of these supplements conducted among high-risk populations should thus carefully consider the potential for increased BCC risk for some individuals. As for any potential chemopreventive agent, long-term assessment of harms is needed before use in a clinical setting (42). For calcium supplementation, in particular, adverse cardiovascular disease risks have been suggested (43, 44), although aggregate evidence is inconclusive (45).
Our findings suggest calcium supplementation, with or without vitamin D, may be a preventive factor for SCC. Although exposure to UVR is the primary risk factor for both BCC and SCC, there are known environmental and lifestyle risk factors more strongly associated with SCC than BCC risk, such as exposure to arsenic (46), infectious agents including human papillomaviruses (47) and HIV (48), long-term immunosuppression (49), and cigarette smoking (50). Whether the effects of calcium supplementation on hormonal mechanisms related to vitamin D receptor and calcium-sensing receptor activity in keratinocytes would differ for SCC and BCC incidence remains unclear (51, 52). We speculate that parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), which regulate circulating calcium, may elucidate a potential SCC-specific effect of calcium supplementation. Both PTH and PTHrP are involved in growth and angiogenesis of skin and hair follicles (53–55), and SCCs are more likely to secrete PTHrP than BCCs (56). Studies evaluating circulating PTH or PTHrP as a risk factor for KC are lacking, but the hypothesis is not new (57). Such studies may also be informed by findings from investigations of patients with psoriasis, a KC risk factor found to be more strongly associated with SCC than BCC (58), and for which calciotropic hormones have been effective treatments (59).
In summary, this analysis of a placebo-controlled randomized clinical trial suggests 3–5 y of calcium supplementation at a dose of 1200 mg/d may prevent the occurrence of SCC, but not BCC. Potential chemopreventive effects of vitamin D were most apparent when taken with calcium.
Supplementary Material
Acknowledgments
The authors’ responsibilities were as follows—JAB: designed the research; LAM, JRR, ELB, and JAB: conducted the research; MNP and LAM: analyzed the data or performed the statistical analysis; MNP and JAB: wrote the manuscript and had primary responsibility for the final content; and all authors: critically revised the manuscript and read and approved the final manuscript. Together with the Trustees of Dartmouth College, JAB holds a patent for the chemopreventive use of calcium for colorectal cancer. All other authors report no conflicts of interest.
Notes
Supported by NIH National Cancer Institute grant R01CA098286 (to JAB) and NIH National Institute of General Medical Sciences grant P20GM104416 (to MNP). Study tablets were provided by Pfizer Consumer Healthcare.
Supplemental Figure 1 and Supplemental Tables 1–5 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/ajcn/.
De-identified data described in the article, code book, and analytic code will be made available upon request pending approval of an application for data use with the Polyp Prevention Study Group and execution of a data use agreement and/or material transfer agreement with Dartmouth College.
Abbreviations used: BCC, basal cell carcinoma; KC, keratinocyte carcinoma; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; SCC, cutaneous squamous cell carcinoma; UVR, ultraviolet radiation; WHI, Women's Health Initiative; 25(OH)D, 25-hydroxyvitamin D.
Contributor Information
Michael N Passarelli, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Margaret R Karagas, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Leila A Mott, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Judy R Rees, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Elizabeth L Barry, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
John A Baron, Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
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