Rex B. Mowat

Dietary Glycemic Load and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings From CALGB 89803

BACKGROUND The influence of glycemic load and related measures on survival among colon cancer patients remains largely unknown. METHODS We conducted a prospective, observational study of 1011 stage III colon cancer patients reporting dietary intake during and 6 months after participation in an adjuvant chemotherapy trial. We examined the influence of glycemic load, glycemic index, fructose, and carbohydrate intakes on cancer recurrence and mortality using Cox proportional hazards regression; all tests of statistical significance were two-sided. RESULTS Stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted hazard ratio (HR) for disease-free survival of 1.79 (95% confidence interval [CI] = 1.29 to 2.48), compared with those in the lowest quintile (P (trend) across quintiles <.001). Increased glycemic load was associated with similar detriments in recurrence-free (P (trend) across quintiles <.001) and overall survival (P (trend) across quintiles <.001). These associations differed statistically significant by body mass index (BMI) (P (interaction) =.01). Whereas glycemic load was not associated with disease-free survival in patients with BMI < 25kg/m(2), higher glycemic load was statistically significant associated with worse disease-free survival among overweight or obese participants (BMI ≥ 25kg/m(2); HR = 2.26; 95% CI = 1.53 to 3.32; P (trend) across quintiles <.001). Increasing total carbohydrate intake was similarly associated with inferior disease-free, recurrence-free, and overall survival (P (trend) across quintiles <.001). CONCLUSION Higher dietary glycemic load and total carbohydrate intake were statistically significant associated with an increased risk of recurrence and mortality in stage III colon cancer patients. These findings support the role of energy balance factors in colon cancer progression and may offer potential opportunities to improve patient survival.

Predictive and Prognostic Analysis of PIK3CA Mutation in Stage III Colon Cancer Intergroup Trial

BACKGROUND Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer. METHODS We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided. RESULTS Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16). CONCLUSIONS Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.

Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial.

IMPORTANCE Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined. OBJECTIVES To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected. DESIGN, SETTING, AND PARTICIPANTS Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013. INTERVENTIONS One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year. MAIN OUTCOMES AND MEASURES Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events. RESULTS Among 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, -9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners. CONCLUSIONS AND RELEVANCE Among men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00931528.

Coffee Intake, Recurrence, and Mortality in Stage III Colon Cancer: Results From CALGB 89803 (Alliance)

PURPOSE Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown. PATIENTS AND METHODS During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression. RESULTS Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; Ptrend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; Ptrend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality. CONCLUSION Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.

Sugar-Sweetened Beverage Intake and Cancer Recurrence and Survival in CALGB 89803 (Alliance)

Background In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown. Methods We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. Results Patients consuming ≥2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04–2.68), compared with those consuming <2 servings per month (P trend = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index ≥25 kg/m2) and less physically active (metabolic equivalent task-hours per week <18) (HR = 2.22; 95% CI, 1.29–3.81, P trend = 0.0025). Conclusion Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.

Impact of Physical Activity After Cancer Diagnosis on Survival in Patients With Recurrent Colon Cancer: Findings From CALGB 89803/Alliance

BACKGROUND The impact of physical activity on survival outcomes in patients with recurrent colon cancer has not been studied. We tested the association between the level of postdiagnosis physical activity and survival outcomes of patients with recurrent colon cancer. PATIENTS AND METHODS We conducted a prospective observational study of 237 patients with stage III colon cancer who had recurrence of disease. Physical activity was measured approximately 6 months after the completion of therapy (14 months after surgical resection) but before detection of recurrent disease. The primary end point of the study was survival time after recurrence. RESULTS The hazard ratio comparing patients who reported at least 18 metabolic equivalent task (MET) hours per week of physical activity with those engaging in < 3 MET hours per week was 0.71 (95% confidence interval, 0.46-1.11). Increasing total MET hours of physical activity per week was associated with a borderline statistical significance trend for improved survival after recurrence (P = .052). The benefit of physical activity on survival was not significantly modified by sex, body mass index (BMI), number of positive lymph nodes, age, baseline performance status, adjuvant chemotherapy regimen, or recurrence-free survival period. CONCLUSION To our knowledge, this is the first study investigating the association of physical activity with survival outcome of patients with recurrent colon cancer. Although the association exceeded our predefined P trend < .05 for statistical significance, these findings warrant further studies of physical activity in patients with recurrent colorectal cancer.

Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance)

BACKGROUND Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients. PATIENTS AND METHODS A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy. RESULTS Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade ≥3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard. CONCLUSIONS Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens. CLINICALTRIALSGOV NCT00936702.

Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis: The CALGB 89803/Alliance Trial

Importance The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. Objective To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. Design, Setting, and Participants This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. Exposures We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. Main Outcomes and Measures Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free, recurrence-free, and overall survival. Results Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99; P = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06; P = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76; P = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84; P = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94; P = .05 for trend). Conclusions and Relevance Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. Trial Registration clinicaltrials.gov Identifier: NCT00003835

Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance)

Background Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown. Patients and methods We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards. Results Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status. Conclusion Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted. ClinicalTrials.gov Identifier NCT00003835.

Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance)

Purpose Observational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known. Patients and Methods We conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. Results After a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality. Conclusion Diets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer.