Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer

Background:

In an earlier study, a 25-hydroxyvitamin D₃ (25(OH)D) score calculated from known predictors of vitamin D status significantly predicted plasma levels of 25(OH)D and the risk of colorectal cancer, but the influence of the 25(OH)D score on survival after diagnosis is unknown.

Materials and methods:

We prospectively examined the influence of post-diagnosis predicted 25(OH)D levels on mortality among 1017 participants in the Nurses'' Health Study and Health Professionals Follow-Up Study who were diagnosed with colorectal cancer from 1986 to 2004. Colorectal cancer-specific and overall mortality according to quintiles of predicted 25(OH)D levels were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) adjusted for other risk factors of survival.

Results:

Higher predicted 25(OH)D levels were associated with a significant reduction in colorectal cancer-specific (P trend=0.02) and overall mortality (P trend=0.002). Compared with levels in the lowest quintile, participants with predicted 25(OH)D levels in the highest quintile had an adjusted HR of 0.50 (95% CI, 0.26–0.95) for cancer-specific mortality and 0.62 (95% CI, 0.42–0.93) for overall mortality.

Conclusion:

Higher predicted 25(OH)D levels after a diagnosis of colorectal cancer may be associated with improved survival. Further study of the vitamin D pathway in colorectal cancer is warranted.     

Prospective analysis of vitamin D and endometrial cancer risk

BackgroundThis is the first prospective cohort analysis on the association between vitamin D and endometrial cancer incorporating time-varying predicted plasma 25-hydroxyvitamin D [25(OH)D].MethodsThe prospective cohort analysis of predicted 25(OH)D and total dietary vitamin D intake used the Cox proportional hazards model, and involved 644 incident endometrial cancer events from 1986 to 2006 in the Nurses' Health Study. Genotyping and unconditional logistic regression were carried out on 572 endometrial cancer cases and their matched controls on 12 single nucleotide polymorphisms (SNPs) in vitamin D-related genes.ResultsThere was no significant association between predicted 25(OH)D and endometrial cancer incidence, with the hazard ratio for the highest (versus the lowest) quintile of predicted 25(OH)D as 1.00 (95% CI 0.73–1.36) (p-trend = 0.33). There was also no significant association involving total dietary vitamin D. No significant associations between any of the vitamin D-related SNPs and endometrial cancer were observed.ConclusionBoth predicted 25(OH)D and total dietary vitamin D intake were not associated with endometrial cancer incidence. These results suggest that vitamin D may not protect against the development of endometrial cancer. However, the low and narrow vitamin D exposure range in the cohort may limit generalizability of the results.     

Serum vitamin D concentration,vitamin D-related polymorphisms,and colorectal cancer risk

Serum 25-hydroxyvitamin D (25(OH)D) has been demonstrated to be associated with risk of colorectal cancer (CRC). However, it remains unclear whether this association was modified by vitamin D-related polymorphisms. We evaluated association of serum 25(OH)D concentration with CRC risk among 403 170 participants from UK Biobank Project. Two variants of vitamin D binding protein (VDBP), rs4588 and rs7041, were included to estimate the binding affinity of 25(OH)D to VDBP, and three variants of vitamin D receptor (VDR), rs11568820, rs2228570 and rs1544410, which may influence VDR activity, were also investigated. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 4 957 677 person-years of follow-up, 5053 incident CRC cases were documented. Higher serum 25(OH)D concentrations were significantly associated with lower CRC incidence in a dose-response manner, with HR (95% CIs) being 0.94 (0.91-0.97) per 1 SD increment of serum 25(OH)D level (P_trend < .001). When separated by anatomic site, we observed a significant association between higher 25(OH)D and lower incidence of colon cancer (P_trend < .001), but not rectal cancer (P_trend = .880). The inverse associations between 25(OH)D level and CRC risk were demonstrated in almost all individuals carrying different GC or VDR genotypes, except for those with rs1544410 TT or rs4588 TT genotypes. There was no significant interaction between any single variant, or haplotypes of GC or VDR, and 25(OH)D level. Our findings suggest the potential benefits of maintaining adequate vitamin D for CRC prevention, particularly for tumors from colon.     

Circulating 25-hydroxyvitamin D,vitamin D binding protein and risk of advanced and lethal prostate cancer

We previously found that higher total 25-hydroxyvitamin D [25(OH)D] levels were associated with lower risk of lethal prostate cancer. However, the relationships of bioavailable 25(OH)D and vitamin D binding protein (VDBP) with risk of advanced and lethal prostate cancer are unclear. In a prospective case–control study of 156 pairs of advanced prostate cancer cases and controls, we directly measured prediagnostic circulating 25(OH)D and VDBP and calculated bioavailable 25(OH)D using a validated formula. We examined the association of bioavailable 25(OH)D and VDBP levels with risk of advanced and lethal prostate cancer and whether total 25(OH)D levels interacted with VDBP levels to affect the risk. Conditional logistic models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to total 25(OH)D (p_trend = 0.02), bioavailable 25(OH)D levels were not more strongly associated with risk of advanced prostate cancer (p_trend = 0.14). Although VDBP levels were not associated with risk of advanced prostate cancer (p_trend = 0.16), we observed an interaction between total 25(OH)D levels and VDBP levels in relation to risk of advanced prostate cancer (p_interaction = 0.03). Compared to those with total 25(OH)D levels below the median and VDBP levels above the median (at highest risk), men with both levels above the median had a multivariable-adjusted OR of 0.31 (95% CI, 0.15–0.65) for advanced prostate cancer. We observed similar results when we restricted the analyses to 116 lethal prostate cancer cases and their controls. Our data suggest that VDBP levels may modify the association between total 25(OH)D levels and risk of advanced and lethal prostate cancer.     

Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case–control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 ± 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P _trend  = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30–0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.     

A prospective study of aromatase inhibitor therapy,vitamin D,C-reactive protein and musculoskeletal symptoms

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P _trend < 0.001), muscle (P _trend = 0.004), and bone pain (P _trend = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P _trend = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.     

Serum calcium improved systemic inflammation marker for predicting survival outcome in rectal cancer

BackgroundSystemic inflammation markers have shown prognostic values with variability in rectal cancer. Considering the association of serum calcium with inflammation, we aimed to examine whether it could improve systemic inflammation markers for survival prediction.MethodsWe enrolled 508 patients with stage I to III rectal cancer who underwent curative resection. The cohort was grouped by corrected serum calcium (cCa), platelet-to-lymphocyte ratio (PLR), and CaPLR (a score model combining cCa with PLR) for survival analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare models in survival prediction. The primary endpoint was disease-free survival (DFS).ResultsA total of 26.7% (136/508) patients reached recurrence after curative surgery. Both high cCa (HR 1.486; 95% CI, 1.018–2.171; P=0.040) and high PLR (HR 1.452; 95% CI, 1.059–1.991; P=0.021) were significantly associated with worse DFS. In model comparison, the AIC and LR were improved after cCa was added to PLR model in DFS prediction (AIC: 1,704.83 vs. 1,707.14 vs. 1,707.15; LR: 8.68 vs. 4.37 vs. 4.36; P=0.037). The CaPLR was developed for DFS prediction with adjusted HRs of 2.216 (95% CI, 1.256–3.909; P=0.006) and 1.679 (95% CI, 1.004–2.836; P=0.047) for high and intermediate score group respectively compared to low score group. A nomogram for predicting DFS was generated by using CaPLR and other clinical predictors, with a concordance index of 0.705 (95% CI, 0.620–0.789; P<0.001).ConclusionsSerum calcium could improve systemic inflammation markers in survival prediction for patients with rectal cancer.     

Surgical outcomes of gastrectomy with D1 lymph node dissection performed for patients with unfavorable clinical conditions

BackgroundGastric cancer (GC) patients with advanced age and/or multiple morbidities have limited expected survival and may not benefit from extended lymph node resection. The aim of this study was to evaluate the surgical outcomes of these GC patients who underwent gastrectomy with D1 dissection.MethodsWe retrospectively reviewed all GC patients who underwent gastrectomy with curative intent from 2009 to 2017. The decision to perform D1 was based on preoperative multidisciplinary meeting, and/or intraoperative clinical judgment.ResultsAmong 460 enrolled patients, 73 (15.9%) underwent D1 lymphadenectomy and 387 (84.1%) D2 lymphadenectomy. Male gender, older age, American Society of Anesthesiologists score (ASA) III/IV, higher neutrophil-to-lymphocyte ratio (NLR) and higher Charlson Comorbidity Index (CCI) were more common in the D1 group. Postoperative major complications were significantly higher in D1 group (24.7% vs 12.4%, p < 0.001) and mostly related to clinical complications. Locoregional recurrence was higher in the D1 group (53.8% vs 39.5%, p = 0.330) however, without statistical significance. No difference was found in disease-free survival (DFS) between D1 and D2 patients with positive lymph nodes (p = 0.192), whereas overall survival was longer in the D2 group (p < 0.001). Multivariate analysis showed a statistically significant impact on survival of age ≥70 years, CCI ≥5, total gastrectomy, D1 lymphadenectomy and advanced stages (III/IV).ConclusionsFrail patients had high surgical mortality even when submitted to D1 dissection. DFS was comparable to D2. Extent of lymphadenectomy in high-risk patients should take in account the expectation of a decrease in surgical risk with the possibility of impairment of long-term survival.     

Serum vitamin D,vitamin D binding protein,and lung cancer survival

ObjectivesVitamin D may prolong cancer survival by inhibiting tumor progression and metastasis, however, there are limited epidemiologic studies regarding the association between circulating 25-hydroxyvitamin D (25(OH)D) and lung cancer survival. The aim of this study was to examine the relationship between serum 25(OH)D and lung cancer specific survival and to evaluate whether vitamin D binding protein (DBP) concentration modified this association.Materials and methods25(OH)D and DBP were measured in fasting serum samples from 500 male lung cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer related death according to quartiles of season-specific 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D.ResultsComparing highest to lowest quartiles, serum 25(OH)D (HR = 1.18; 95% CI: 0.89–1.56) and DBP (HR = 0.95; 95% CI: 0.71–1.26) were not associated with lung cancer survival and DBP concentration did not modify the association with 25(OH)D (p for interaction = 0.56). There was suggestion of an association between higher serum 25(OH)D and better survival from adenocarcinoma (HR = 0.64; 95% CI: 0.17–2.45) and small cell carcinoma (HR = 0.55; 95% CI: 0.21–1.45), but these estimates were based on a relatively small number of cases.ConclusionSerum 25(OH)D was not associated with overall lung cancer survival regardless of DBP concentration, however, these findings should be examined in other studies that include women and subjects with higher 25(OH)D levels.     

Optimal adjuvant chemotherapy completion time for stage III colon cancer: a cohort study

BackgroundAdjuvant chemotherapy for 6 months following surgery is the standard treatment plan for stage III colon cancer. The aim of the present study was to determine whether the adjuvant chemotherapy completion time for stage III colon cancer had an effect on prognosis and cut-off time that affected the prognosis.MethodsThis was a retrospective study of stage III colon cancer patients who completed adjuvant chemotherapy at Guangzhou Red Cross Hospital from January 2010 to December 2017. Univariate and multivariate analyses were used to determine the association between adjuvant chemotherapy completion time and the 3-year disease-free survival (DFS). The restricted cubic spline model was used to analyze the cut-off time that affected the 3-year DFS.ResultsA total of 431 patients were included in the study. The 3-year DFS was associated with a combination of obstruction or perforation, preoperative serum carcino-embryonic antigen (CEA) concentration, T stage, N stage, pathological stage, and adjuvant chemotherapy completion time in the univariate analysis (P<0.05). A combination of obstruction or perforation, preoperative serum CEA concentration, N stage, and adjuvant chemotherapy completion time were independent prognostic factors in the multivariate analysis (P<0.05). The cut-off time was 28 weeks for adjuvant chemotherapy completion time in the restricted cubic spline model analysis. For those whose adjuvant chemotherapy completion time was >28 weeks, the risk of 3-year recurrence was 1.428 times higher compared with those whose adjuvant chemotherapy completion time was ≤28 weeks. [P=0.032, 95% confidence interval (CI): 1.034–2.055].ConclusionsThe 3-year DFS of stage III colon cancer was related to the adjuvant chemotherapy completion time. For those who completed adjuvant chemotherapy >28 weeks, the risk of 3-year recurrence increased.     

Laparoscopic approach for T4 colon cancer can be associated with poor prognosis in right-sided T4b tumours

IntroductionAlthough recent studies have demonstrated the safety of laparoscopic surgery in T4 colon cancer, some patients could have poor prognosis. In this study, we aimed to analyse the risk factors affecting oncologic outcome of laparoscopic surgery.Materials and methodsAmong the 1033 T4 colon cancer patients collected from a multicentre database (2004–2017), 584 patients (458 T4a and 126 T4b) underwent laparoscopic approach for radical surgery. Risk factors associated with 3-year disease-free survival (DFS) and overall survival (OS) were evaluated through multivariate analysis. In addition, subgroups were classified using a combination of risk factors, and the survival rate was evaluated.ResultsDuring this period, 188 (32.2%) had recurrence, and 151 (25.9%) died. In the multivariate analysis for oncologic outcome, elevated carcinoembryonic antigen level (hazard ratio [HR] 1.37) and absence of adjuvant chemotherapy (HR 1.60) were associated with poor DFS. T4b (HR 1.56, 1.46), right-sided location (HR 1.52, 1.42), and open conversion (HR 2.70, 2.12) were independently associated with both poor DFS and OS. When four subgroups were analysed through the combination of tumour location and T stage, the DFS and OS rates were significantly lower in patients with right-sided T4b cancer than in other groups (log-rank p < 0.001).ConclusionRight-sided T4b colon cancer for laparoscopic surgery may lead to poor oncologic outcome. This approach could be a caution in suspected cases preoperatively.     

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502

BackgroundWhile adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer.Patients and methodsPatients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety.ResultA total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group.ConclusionEighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer.Clinical trial numberUMIN-CTR C000000245.     

Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset

BackgroundThe prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.Patients and methodsWe analyzed the pronostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.ResultsKRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35–2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85–1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51–2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00–2.56; P = 0.051).ConclusionKRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.Clinical trial numberThis is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.     

Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer

BackgroundIdentifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage III colon cancer who are more likely to benefit from adjuvant chemotherapy. The present study analyzed a subset of 10 polymorphisms within eight genes involved in the tumor angiogenesis pathway and their impact on prognosis in stage III colon cancer patients treated with adjuvant chemotherapy.Patients and methodsBlood samples were obtained from 125 patients with locally advanced colon cancer at University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR–restriction fragment length polymorphism and 5′-end [γ-³³P] ATP-labeled PCR protocols.ResultsPolymorphisms in vascular endothelial growth factor (VEGF) (C+936T; P = 0.003, log-rank test) and interleukin-8 (IL-8) (T-251A; P = 0.04, log-rank test) were independently associated with risk of recurrence in stage III colon cancer patients. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of VEGF C+936T and IL-8 T-251A were associated with a higher likelihood of developing tumor recurrence (P < 0.001).ConclusionHigh expression variants of VEGF C+936T and IL-8 T-251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.     

Tumor Sidedness,Recurrence, and Survival After Curative Resection of Localized Colon Cancer

BackgroundRight-sided primary tumor location is associated with worse prognosis in metastatic colon cancer, but the effect of sidedness on recurrence and prognosis for non-metastatic disease is less understood. The purpose of this study was to examine the relationship between sidedness, recurrence, and survival among patients with localized colon cancer.Patients and MethodsConsecutive patients who underwent curative resection of colon cancer (2006-2013) were identified from a prospective database and retrospectively analyzed. Risk for recurrence, overall survival, and survival after recurrence (SAR) were compared between left- and right-sided tumors using the log-rank test, and multivariable Cox proportional hazards regression.ResultsWe evaluated 673 patients (347 right-sided). There was no difference in overall recurrence rates (adjusted hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.54-1.55; P = .75) or overall survival (HR, 1.22; 95% CI, 0.75-1.97; P = .42) between right- and left-sided primary tumors. However, right-sided tumors were more likely to develop multi-focal and poor prognostic site recurrence (P = .04). Among the 71 patients who developed recurrence, those with right-sided tumors had significantly lower SAR (HR, 3.88; 95% CI, 1.42-10.62; P = .008).ConclusionsAmong patients with colon cancer who underwent curative resection, tumor sidedness was not associated with recurrence risk. However, among patients who developed recurrence, right-sidedness was associated with unique recurrence patterns and inferior SAR. For patients presenting with localized disease, treatment stratification should not be based on tumor sidedness alone.     

Post-diagnostic coffee and tea consumption and breast cancer survival

Background We examined the role of post-diagnostic coffee and tea consumption in relation to breast cancer-specific and all-cause mortality among women with breast cancer in prospective cohort studies.Methods We identified 8900 women with stage I–III breast cancer from 1980 through 2010 in the Nurses’ Health Study (NHS) and from 1991 through 2011 in the NHSII. Post-diagnostic coffee and tea consumption was assessed by a validated food frequency questionnaire every 4 years after diagnosis.Results During up to 30 years of follow-up, we documented 1054 breast cancer-specific deaths and 2501 total deaths. Higher post-diagnostic coffee consumption was associated with a lower breast cancer-specific mortality: compared with non-drinkers, >3 cups/day of coffee was associated with a 25% lower risk (hazard ratio (HR) = 0.75, 95% confidence interval (CI) = 0.59–0.96; P_trend = 0.002). We also observed a lower all-cause mortality with coffee consumption: compared with non-drinkers, >2 to 3 cups/day was associated with a 24% lower risk (HR = 0.76, 95% CI = 0.66–0.87) and >3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.63–0.87, P_trend < 0.0001). Post-diagnostic tea consumption was associated with a lower all-cause mortality: compared with non-drinkers, >3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.58–0.95; P_trend = 0.04).Conclusions Among breast cancer survivors, higher post-diagnostic coffee consumption was associated with better breast cancer and overall survival. Higher post-diagnostic tea consumption may be related to better overall survival.Subject terms: Breast cancer, Outcomes research     

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy

BackgroundThis multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.Patients and methodsPatients were assigned to 24 weeks of capecitabine 1250 mg/m² twice daily on days 1–14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS).ResultsThe intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77–1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74–1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand–foot syndrome may be associated with better outcomes in capecitabine recipients.ConclusionOral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.     

Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study

Introduction

Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent.

Methods

We conducted a case-control study nested within two prospective cohorts, the New York University Women''s Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH)D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.

Results

No association was observed between circulating levels of 25(OH)D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, p_trend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH)D > 0.70). An inverse association between 25(OH)D levels and breast cancer risk was observed among women who were ≤ 45 years of age (OR_Q5-Q1 = 0.48, 95% CI = 0.30-0.79, p_trend = 0.01) or premenopausal at enrollment (OR_Q5-Q1 = 0.67, 95% CI = 0.48-0.92, p_trend = 0.03).

Conclusions

Circulating 25(OH)D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention.     

Vitamin D and colon cancer

Calcitriol, 1α, 25-dihydroxyvitamin D3(1,25(OH)2D3), the most active form of vitamin D, is a pleotropic hormone with a wide range of biological activities. Due to its ability to regulate calcium and phosphate metabolism, 1,25D3 plays a major role in bone health. In addition, 1,25D3 binds to the vitamin D receptor and thereby regulates the expression of a number of genes which control growth, differentiation and survival of cancer cells. In agreement, the levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models. Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Several studies confirmed that increasing vitamin D3 lowers colon cancer incidence, reduces polyp recurrence, and that sufficient levels of vitamin D3 are associated with better overall survival of colon cancer patients. Vitamin D regulates the homeostasis of intestinal epithelium by modulating the oncogenic Wnt signaling pathway and by inhibiting tumor-promoting inflammation. Both activities contribute to the ability of 1,25D3 to prevent the development and progression of colon cancer.     

Locoregional recurrence following nipple-sparing mastectomy with immediate breast reconstruction: Patterns and prognostic significance

IntroductionThere are limited available data on the prognostic implications of locoregional recurrence (LRR) after nipple-sparing mastectomy (NSM) and immediate reconstruction. In this study, we investigated the patterns and prognosis associated with LRR following this treatment approach for breast cancer.MethodsA total of 1696 patients with primary breast cancer who underwent NSM with immediate reconstruction from March 2003 to December 2016 were retrospectively analyzed. Post-recurrence disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards model were performed to evaluate the prognostic factors associated with the DFS and DMFS.ResultsAfter a median follow-up period of 84 months, we identified 172 patients (10.1%) with an LRR as the first event. The 5-year post-recurrence DFS rates for the nipple-areola complex recurrence (NCR), skin or subcutaneous recurrence/chest wall recurrence (SCR/CWR), and regional recurrence (RR) groups were 89.1%, 73%, and 59.4%, respectively (P = 0.009), and the 5-year post-recurrence DMFS rates for the NCR, SCR/CWR, and RR groups were 96%, 82.8%, and 59.7%, respectively (P < 0.001). In multivariate analysis, a time to LRR ≤2 years (P = 0.016) and the site of LRR (P = 0.022) were significantly associated with the post-recurrence DFS.ConclusionsNCR is more likely to be detected as a non-invasive recurrence and is associated with more favorable overall outcomes than other LRR types. The interval to LRR and its site of onset seem to be associated with the prognostic outcomes.