November 4, 2015

Coffee May Reduce Colon Cancer Recurrence

Should a daily cup of coffee be part of the colon cancer recovery plan?
In this prospective, observational study, drinkers of caffeinated and decaffeinated coffee who also survived colon cancer were found to be 41% less likely to have their cancer recur than non‒coffee drinkers.


Guercio BJ, Sato K, Niedzwiecki D, et al. Coffee intake, recurrence, and mortality in stage III colon cancer: results from CALGB 89803 (Alliance). J Clin Oncol. 2015 Aug 17. [Epub ahead of print]


Prospective, observational study embedded in a randomized trial


Participating were individuals with colon cancer (N=953) already enrolled in a separate National Cancer Institute‒sponsored randomized clinical trial comparing 2 chemotherapy regimens. All patients had stage III colon cancer, underwent complete surgical resection, had no evidence of distant metastasis, and were in relatively good health overall (0 to 2 on the Eastern Cooperative Oncology Group Scale). All eligible participants also had adequate bone marrow, kidney, and liver function. Exclusion criteria included improper/incomplete questionnaire results, recurrence of cancer or death from any cause within 3 months of filling out questionnaire, and extremely high or extremely low caloric intakes (<600 or >4200 cal/d for men; <500 or >3500 cal/d for women).

Outcome Measures

A food frequency questionnaire was given midway through adjuvant treatment for colon cancer (Q1, approximately 4 months after surgery) and 6 months after completion of treatment (Q2, 14 months after surgery). Participants were queried about intake of caffeinated coffee, decaffeinated coffee, nonherbal tea, herbal tea, caffeinated soft drinks, and chocolate. There were 5 frequency categories for total coffee, caffeinated coffee, and tea (0, <1, 1, 2-3, and >4 c/d). Decaffeinated coffee had 3 frequency categories (0, <1, 1, and >2 c/d) to conserve statistical power. 
Primary endpoint was disease-free survival, which was defined as time from completion of Q1 to recurrence, occurrence of a new primary colon cancer lesion, or death from any cause. Secondary outcome measures included overall survival (OS), which was defined as the time from completion of Q1 to death from any cause. Recurrence-free survival, which was the time from completion of Q1 to recurrence or occurrence of a new primary colon cancer lesion, was also assessed.
The original clinical trial in which this observational study was performed found no difference in outcome between the arms, so all patients could be pooled for this analysis without concern for treatment as a confounder. Median follow-up time from Q1 to completion was 7.3 years.

Key Findings

Overall, increasing total coffee intake was associated with a significant reduction in the risk of recurrence or mortality after adjusting for other predictors of cancer recurrence.
During this time, 329 of the 953 participants had a recurrence or new primary colon cancer lesion. Of these, 288 died of their disease. Thirty-six participants died of other causes and without evidence of colon cancer.  
Compared to abstainers, those consuming more than 4 cups of coffee per day (caffeinated plus decaffeinated) had a 41% reduction in their risk of recurrence (hazard ratio [HR]:0.59; P=0.003). Increasing total intake of coffee was also associated with a significant improvement in OS (P=0.008).
Caffeinated coffee, in particular, showed an even more profound reduction in risk. Compared to abstainers, those consuming more than 4 cups of caffeinated coffee per day had a 51% reduction in their risk of recurrence or mortality (HR:0.49; P=0.003).
Total caffeine intake was also associated with benefit. There was a 35% reduction in recurrence and mortality in the highest vs the lowest quintile of caffeine intake (HR:0.65, P=0.005).
Neither nonherbal tea nor decaffeinated coffee intake was associated with patient outcomes. Results were unchanged when adjusted for sugar-sweetened beverages, dietary glycemic load, Western vs prudent dietary patterns, or physical activity.

Practice Implications

It is estimated that 1 in 20 Americans will develop colorectal cancer his/her lifetime.1 It is second to lung cancer as the leading cause of cancer deaths overall. (When parsed by gender, prostate and breast cancers are the second leading cause and colorectal cancer is third.)  
Despite these dismal facts, colorectal cancer has a commendable distinction within oncology: Deaths from colorectal cancer have been falling for over 20 years.2 This is largely due to earlier detection via colonoscopies along with better access to treatment. As of January 2014, there were approximately 1.3 million people with a history of colorectal cancer in the United States.3 The chance that primary care clinicians will see patients with a history of colorectal cancer in their practices is fairly high and growing.
The chance that primary care clinicians will see patients with a history of colorectal cancer in their practices is fairly high and growing.
The publication under review appears to be the first prospective study on coffee intake and colon cancer recurrence or survival. Systematic reviews on incident colon cancer and coffee intake have been inconsistent, suggesting either an inverse association4 or no statistically significant relationship.5 The current publication suggests there is an inverse association between coffee intake and both recurrence of colon cancer and OS.
If coffee does lower the recurrence rate, what is the mechanism? There are 2 broad possibilities. Either there are systemic effects, such as coffee’s influence on insulin and glucose control, or there are phytochemicals in the coffee bean that have direct action on cancer and/or immune cells. 
Colorectal cancer is strongly associated with excess energy balance, in particular obesity, insulinemia, and type 2 diabetes.6 Coffee is known to reduce the risk of type 2 diabetes7,8 to lower insulin,9 and increase adeponectin levels.10 The authors of the study under review hypothesized that these favorable effects of coffee on insulin and energy balance may affect outcome in those with a history of colon cancer. While the study did not assess blood sugar parameters per se, it is plausible that coffee’s apparent benefit on outcome is due to its well-known effects on improved energy control and utilization.
However, excess energy balance is largely influenced by diet and exercise. It is intriguing that sugar-sweetened drinks, glycemic load, and exercise did not change outcomes in this study. This implies there may be another mechanism at work. Indeed, phytochemicals found in coffee beans may have direct anticancer actions in colorectal cancer specifically.
In a mouse model of colon cancer, the phenolic phytochemicals from coffee (caffeic acid and chlorogenic acid) were determined to lessen metastasis to the lungs.11 In the same study, using resected colon cancer tissue from 20 participants (10 coffee drinkers, 10 non‒coffee drinkers), there was inhibition of the requisite growth pathway involving ERK in those consuming coffee. This implies that there is a direct inhibition of intracellular growth signals by coffee constituents. In this study, the effect was independent of caffeine content, as 6 of the 10 coffee drinkers consumed decaffeinated coffee.
In a case-control study that sought to identify relevant biomarkers for coffee consumption, 251 colorectal cancer patients and 247 matched controls were compared. There were 29 serum metabolites that most closely correlated with coffee consumption. Three metabolites in particular—theophylline, caffeine, and paraxathine—were inversely associated with colorectal cancer.12
As always, in observational studies any associated risk and/or benefit can be a surrogate for other behaviors that influence outcome. What is interesting in the study under review is that those consuming the most coffee were more likely to be smokers with higher-calorie diets and a lower prudent dietary pattern. However, they were also more physically active and tended to eat lower glycemic diet. Taken together, these confounders strengthen the conclusion that it is indeed the coffee/caffeine consumption that confers benefit. 
As with all interventions, the risks of coffee consumption must be weighed against the benefits. Stomach ulcers, hypertension, or anxiety are a few conditions in a patient’s history that may preclude caffeinated coffee consumption. However, given the apparent benefit suggested from this study, we should not discourage patients who enjoy coffee without apparent consequences. While establishing with each patient the difference between use and abuse of caffeine or coffee, we should relay the current state of the evidence for all possible measures that may lessen risk of recurrence. Our advice on coffee may run counter to presumptions by many patients, but conveying the evidence, especially if unexpected, is a valuable part of our service as practitioners.

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