Colorectal cancer in women

The lifetime risk of developing CRC is 5.12% in men and women. It is estimated that 142,570 men and women (72,090 men and 70,480 women) will be diagnosed with CRC in 2010, accounting for 10% of all new cancer cases in women. This figure translates to a 41.7 per 100,000 incidence rate in women per year. The cancer burden is sizeable; for example, on January 1, 2007, in the United States there were approximately 1,112,493 men and women alive who had a history of cancer of the colon and rectum, more than half of these being women.

The incidence rates of CRC have decreased from 1998 through 2004 in both men and women, likely from the increased use of colonoscopy driving the increase in CRC screening. Despite the decreased incidence rates, it is still the third most common cancer in the United States and the second leading cause of cancer death among men and women. An estimated 50,000 men and women die each year from CRC; 25,000 of these deaths occur in women, accounting for 9% of all cancer deaths in women. Data on cancer cases collected by the Surveillance Epidemiology and End Results (SEER) database and data on United States population collected by the US Census Bureau suggest that the incidence and mortality are slightly lower in women than in men, with a decline in mortality of 1.1% per year over 10 years in both men and women.

Since 1990, there has been a dramatic decline in mortality, by 32% in men and 28% in women. At the same time, there has been an increase in CRC screening among individuals 50 years of age and older. It is estimated that currently 50% of the population in the United States undergo screening. Other factors that may have contributed to a decrease in CRC mortality include hormone replacement therapy given to many women at the onset of menopause during the 1970s and 1980s (which might protect against CRC), and the increased use of aspirin for cardiovascular disease and nonsteroidal anti-inflammatory drugs for musculoskeletal disorders, which reduce the risk of colon polyps and CRC. The role of estrogen in the development of CRC is discussed later in the article.

Colon polyps in women

There are gender differences in the prevalence and location of colorectal polyps and tumors. There are reports noting a lower rate of colorectal adenomas in women as compared with men, with similar rates of colon cancer.

Several large studies have indicated that there is a significantly lower adenoma detection rate in women than men. A recent meta-analysis by Nguyen and colleagues that included 924,932 asymptomatic, average-risk adults undergoing screening colonoscopy reports that men had greater age-specific risk for advanced colorectal neoplasia than women, with a relative risk of advanced neoplasia in men versus women of 1.83 (95% confidence interval [CI] 1.69–1.97), Advanced neoplasia was defined as any adenoma equal to or greater than 10 mm, with any villous histology or high-grade dysplasia, or invasive adenocarcinoma. Given these findings, the aforementioned study also showed that the number needed to endoscope to detect one patient with advanced neoplasia in women is larger than in men. This finding has also been shown before in a study by Lieberman and colleagues, which showed that among patients younger than 50 years undergoing asymptomatic screening colonoscopy, 42 women and 28 men would need to be screened to identify 1 patient with a mass or polyp greater than 9 mm. After age 50, the risk of masses or polyps greater than 9 mm increases progressively with age in both men and women, with a decline in the number needed to endoscope in men from 18 (50–59 years) to 10 (>80 years); in women, the number needed to endoscope declines from 28 (50–59 years) to 14 (>80 years). Review of these data suggests that there is a lag time of about 7 to 8 years between risk in asymptomatic men and women, such that a 50-year-old man has roughly the same risk for CRC as a 58-year-old woman.

Gender differences in colorectal polyps and tumors are also seen in regard of location within the colon. Several retrospective studies have suggested that women have more right-sided tumors as compared with men. A recent retrospective analysis of a national endoscopic database showed that women had a greater risk of developing pure right-sided polyps and tumors (defined as located in the cecum, ascending, and hepatic flexure). However, this gender difference was lost with increasing age, with significant differences seen between the group aged 60 to 69 years and not those older than 69 years.

Does this location difference have clinical significance? A study by Elsaleh and colleagues published in 2000 compared response to chemotherapy in CRC; findings suggested that there were survival benefits for patients who had right-sided tumors and who received adjuvant chemotherapy (48% vs 27%), whereas those with left-sided tumors had only a minimal benefit.

Colon polyps in women

There are gender differences in the prevalence and location of colorectal polyps and tumors. There are reports noting a lower rate of colorectal adenomas in women as compared with men, with similar rates of colon cancer.

Several large studies have indicated that there is a significantly lower adenoma detection rate in women than men. A recent meta-analysis by Nguyen and colleagues that included 924,932 asymptomatic, average-risk adults undergoing screening colonoscopy reports that men had greater age-specific risk for advanced colorectal neoplasia than women, with a relative risk of advanced neoplasia in men versus women of 1.83 (95% confidence interval [CI] 1.69–1.97), Advanced neoplasia was defined as any adenoma equal to or greater than 10 mm, with any villous histology or high-grade dysplasia, or invasive adenocarcinoma. Given these findings, the aforementioned study also showed that the number needed to endoscope to detect one patient with advanced neoplasia in women is larger than in men. This finding has also been shown before in a study by Lieberman and colleagues, which showed that among patients younger than 50 years undergoing asymptomatic screening colonoscopy, 42 women and 28 men would need to be screened to identify 1 patient with a mass or polyp greater than 9 mm. After age 50, the risk of masses or polyps greater than 9 mm increases progressively with age in both men and women, with a decline in the number needed to endoscope in men from 18 (50–59 years) to 10 (>80 years); in women, the number needed to endoscope declines from 28 (50–59 years) to 14 (>80 years). Review of these data suggests that there is a lag time of about 7 to 8 years between risk in asymptomatic men and women, such that a 50-year-old man has roughly the same risk for CRC as a 58-year-old woman.

Gender differences in colorectal polyps and tumors are also seen in regard of location within the colon. Several retrospective studies have suggested that women have more right-sided tumors as compared with men. A recent retrospective analysis of a national endoscopic database showed that women had a greater risk of developing pure right-sided polyps and tumors (defined as located in the cecum, ascending, and hepatic flexure). However, this gender difference was lost with increasing age, with significant differences seen between the group aged 60 to 69 years and not those older than 69 years.

Does this location difference have clinical significance? A study by Elsaleh and colleagues published in 2000 compared response to chemotherapy in CRC; findings suggested that there were survival benefits for patients who had right-sided tumors and who received adjuvant chemotherapy (48% vs 27%), whereas those with left-sided tumors had only a minimal benefit.

Risk factors related to colorectal cancer in women

Several mechanisms have been suggested to account for the lag time in the development of polyps and tumors in women. One theory is that estrogen may have a protective role in prevention of polyp formation by mechanisms of estrogen receptor genes, decreased secondary bile acid production, and decreased serum levels of insulin-like growth factors. There is evidence that women have a relatively low risk of CRC until menopause, and might receive continued protection from hormone replacement therapy after menopause. When women age, reduced estrogen production may alter the bile acid composition, resulting in more toxic secondary bile acids, exposing the proximal colon to these neoplastic promoters.

In observational studies, postmenopausal hormone replacement therapy has been associated with a decreased incidence of CRC. A meta-analysis of 18 studies involving postmenopausal women showed a 20% reduction in the incidence of CRCs among women who had ever taken hormones and a 34% reduction among women who were taking them at the time of the study, as compared with women who had never taken hormones. In the Women’s Health Initiative, a randomized controlled trial of estrogen plus progestin in nearly 17,000 postmenopausal women, the results reported in observational studies were confirmed. After an average follow-up of 5.6 years, women in the hormone group had fewer large colorectal adenomas and CRCs than women in the placebo group; an overall 37% reduction in CRC risk was also seen. However, more women in the hormone group had lymph node involvement, advanced cancer stage, and metastasis at diagnosis. The benefit was not shown in estrogen-alone hormone replacement.

Other risk factors for the development of CRC such as diets high in fat and low in fiber have been extensively studied. Several large United States cohort studies (the Nurses’ Health Study [NHS] and the Health Professionals Follow-Up Study [HPFS]) found no benefit between fiber consumption and colon cancer risk. Data from the Women’s Health Initiative also failed to show a reduction in CRC in postmenopausal women on a low-fat diet. However, a diet high in red meat has been shown to increase the risk of CRC. Chao and colleagues studied a large cohort of patients enrolled in the Cancer Prevention Study II Nutrition Cohort, and found that prolonged consumption of red and processed meat increased the risk of CRC (relative risk [RR] = 1.41 and 1.33, respectively), with the highest association in distal cancers (RR = 1.75). The risk increased significantly with the amount of red meat consumed, with a 17-fold difference in women observed between the lowest and highest quintiles of red meat consumption. Subsequently, in one study of asymptomatic women undergoing colonoscopy, red meat consumption was associated with a higher rate of colorectal adenomas (odds ratio [OR] = 2.02).

Over the last decade with the increased incidence of obesity in the United States, there have been many studies showing an increased risk for gastrointestinal diseases such as nonalcoholic fatty liver disease. Multiple studies have now shown obesity as a risk factor for the development of both CRCs and adenomas. The Framingham Study showed that a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared, ie, kg/m ² ) of 30 or more led to a 50% increase in CRC in middle age (30–54 years) and a 2.4-fold increase in older (55–79 years) adults; however, the effect was stronger for men than for women. This was confirmed by the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which showed BMI as a risk factor (RR = 1.55) for men but not for women. However, both the Framingham and EPIC studies demonstrated that waist circumference, an indicator of central obesity, was strongly associated with colon cancer risk in both men and women. The risk increased linearly with increasing waist size and was evident for both proximal and distal cancers. More recently, Anderson and colleagues reported a significant correlation between BMI and colonic adenomas in women. This cross-sectional study of 2493 asymptomatic patients undergoing screening colonoscopy found the highest risk patients were women with a BMI greater than 40 (OR = 4.26). In this group of women, almost one-quarter had significant colorectal neoplasia (polyp ≥1 cm, villous tissue, high-grade dysplasia).

It has been postulated that insulin resistance and hyperinsulinemia is the common pathway for environmental risk factors such as obesity, increased waist-to-hip ratio, sedentary lifestyle, and a diet high in meat and saturated fats to promote the development of CRC. Insulin is a growth factor that has been shown to promote proliferation of colon cancer cells in vitro and to promote colonic tumors in experimental animals. A cross-sectional analysis by Elwing and colleagues focused on the impact that type 2 diabetes mellitus may have on the risk of colorectal adenoma in women. A total of 600 estrogen-negative women were included in the analysis (100 diabetic, 500 nondiabetic). The study showed an increased prevalence of adenomas (37% vs 24%; OR = 1.82, 95% CI 1.16–2.87, P = .009) and advanced adenomas (defined as villous or tubulovillous features, size >1 cm, or high-grade dysplasia) in women with diabetes (14% vs 6%; OR = 2.38, 95% CI 1.22–4.65, P = .009). Several observational studies in large cohorts of women have also supported that there is an increased risk of CRC with type 2 diabetes and hyperinsulinemia.

Lifestyle factors such as tobacco, alcohol, and exercise have all been studied with varying results. Initial studies of tobacco did not find an increased risk for CRC. However, several meta-analyses have found statistically significant results with an approximate 20% risk increase, although the association appears stronger for rectal cancers. Analysis of 8 prospective cohort studies showed a multivariate risk of CRC of 1.24 with alcohol consumption of 30 g or more per day. In the HPFS, men who drank more than 2 drinks per day had twice the risk of developing CRC than men who drank less than 0.25 drinks per day, and there was an increased risk of colorectal adenomas with heavy alcohol use. Lastly, physical activity has been shown in both the HPFS and NHS to be inversely associated with the risk of CRC, decreasing the risk approximately twofold between those in the lowest quintile and those in the highest quintile of activity.

Studies have shown that women diagnosed previously with gynecologic cancers may have an increased risk for the development of CRC. Hereditary nonpolyposis CRC (HNPCC), a familial CRC syndrome with the early development of CRC, is associated with the development of both endometrial and ovarian cancer. Forty percent of women with HNPCC are affected with endometrial cancer and 10% develop ovarian cancer, which is 4 times that of women without HNPCC. Weinberg and colleagues evaluated the risk for CRC after gynecologic cancer in women enrolled in the SEER registry. In total 21,222 patients with cervical cancer, 51,680 patients with endometrial cancer, and 28,832 patients with ovarian cancer were evaluated for subsequent incidence of colon or rectal cancer from 1974 to 1995 and then compared with the general female population. Women who were diagnosed with endometrial or ovarian cancer before age 50 years were more than 3 times more likely to have subsequent CRC (RR = 3.39 and 3.67, respectively). Women aged 50 to 64 years with ovarian cancer also had an increased risk of CRC (RR = 1.52). Cervical cancer did not increase the risk of CRC.

Whether the occurrence of colon tumors is increased in women with a history of breast cancer is controversial. The SEER registry failed to show an increase in CRC risk in those women with a previous history of breast cancer. Similarly, no increase in CRC was found in relatives of Ashkenazi Jews with BRCA1 and BRCA2.

Should we screen women with gynecologic cancers earlier or more often for CRC? Official guidelines exist to begin screening earlier and perform surveillance every 1 to 2 years for individuals with a diagnosis of or who are at increased risk for HNPCC. However, there are no guidelines or recommendations for women with gynecologic cancers. Given the data presented here, it would be reasonable to screen more often. Some experts advocate colonoscopy every 3 to 5 years for women with a history of ovarian or endometrial cancer diagnosed before age 50 years, even without a history of HNPCC. If the cancer is diagnosed after age 50 or if there is history of breast cancer alone, these women should be screened according to recommendations for the average risk population.

Colonoscopy issues in women

Colonoscopy is considered the gold standard screening test for CRC, yet colonoscopy may be technically more difficult in women than in men. One of the main differences documented in several studies is longer colonic length in women as compared with men. A longer colonic length likely leads to more looping of the colonoscope and more difficult examinations. Saunders and colleagues looked at a barium enema series from 183 female and 162 male patients. Mean colonic length was 155 cm for women and 145 cm for men ( P ≤.005). The transverse colon was the primary area found to have a longer length, and extended into the true pelvis more often in women than in men (62% vs 26%, P <.001). In a study cohort of 505 computed tomographic colonography examinations, women had significantly longer colons than men ( P <.002) and the transverse colon was again shown to be the section that was primarily longer. Older age ( P <.001) and female gender ( P <.01) were also more likely to have incomplete conventional colonoscopy. General factors associated with incomplete colonoscopy included greater colonic length, tortuosity, and advanced diverticular disease. Rowland and colleagues used a technique with magnetic drive coils to visualize the path of a colonoscope, and found longer colon length and significantly more looping in the sigmoid colon in women than in men ( P <.05).

Other anatomic features can make colonoscopy more difficult, including previous abdominal surgeries (particularly hysterectomy), pelvic irradiation, diverticulosis, and BMI. Postsurgical pelvic adhesions can lead to a more fixed sigmoid colon, which may be hard to traverse. A study evaluating flexible sigmoidoscopy in women cited hysterectomy and women younger than 70 years as more likely to have incomplete procedures. In a prospective study comparing women with and without hysterectomy, sigmoidoscopy in those with hysterectomy was more difficult ( P <.001), painful ( P <.001), and less complete ( P <.0001). Church found adjusted completion rates of colonoscopy to be lower in women after hysterectomy (92.8% vs 98.3%). Takashi and colleagues found that the two factors predictive of pain and difficult cecal intubation in a series of consecutive unsedated colonoscopies were female gender and previous hysterectomy. There was, however, an overall high completion rate in this study (99.6%). Of interest, one study has shown that women who have had hysterectomy had significantly longer procedures, lower completion rates (89.2% vs 98.1%), and higher sedation requirements with benzodiazepine (88.7% vs 43%) than women who had a hysterectomy and sigmoid resection in the past ( P <.05). Anderson and colleagues found lower adjusted completion rates for colonoscopy in women (94.8%) than in men (98.2%) ( P <.005). Lower BMI and diverticular disease were predictive of more difficult examinations with longer times to cecal intubation ( P <.001) in this study.

All the aforementioned features make colonoscopy more challenging to do, leading not only to lower completion rates but also reduced patient comfort. Procedures can require more time, leading to the use of more air insufflation, more external abdominal pressure, and thus a greater risk for procedural pain and complications. More medications may be used for sedation and analgesia for these reasons, and can also be associated with complications, particularly cardiopulmonary adverse events. Several studies have found that women experience more pain with colonoscopy than men. One study prospectively looked at the incidence of minor complications and time lost from normal activities after screening or surveillance colonoscopy. Of 504 patients, 34% reported complications before day 7 and 6% between days 7 and 30. The most common complications were bloating (25%) and abdominal pain (11%), and were reported significantly more often in women than men ( P = .0020).

Various ways to improve colonoscopy in women have been studied. The use of thinner-diameter scopes with more flexibility, such as pediatric colonoscopes, can traverse fixed angulations in the colon more easily. In a study of 100 randomized colonoscopies in women, cecal intubation was shown to be higher with pediatric colonoscopes than with standard colonoscopes (96.1% vs 71.4%; P <.001), although procedure time and use of meperidine and midazolam were no different. Other methods used to obtain higher completion rates for those with a previous incomplete colonoscopy include use of push enteroscopes, upper endoscopes, overtube placements, external stiffeners, and the use of propofol sedation. Most recently, double-balloon colonoscopy and double-balloon enteroscopy have been shown to achieve full colonoscopy in previously incomplete procedures. In a series of 29 patients with previous incomplete colonoscopies, 28 of 29 were able to have repeat procedures reaching cecum with a double-balloon retrograde technique. Reasons cited for higher completion rates with a double balloon included smaller scope diameter and improved flexibility, better loop fixation and control by overtubes, and greater tip deflection through angles.