Prediction of Erectile Function Following Treatment for Prostate Cancer. Part 2
Individual characteristics, such as pretreatment erectile function, that influence posttreatment sexual outcome are known to vary at diagnosis, yet tools to predict posttreatment erectile dysfunction based on pretreatment sexual HRQOL at baseline have been limited. Treatment refinements, such as nerve-sparing techniques, can mitigate erectile dysfunction consequences of prostate cancer treatment, while other treatment variations, such as use of neoadjuvant hormone therapy, can adversely affect sexual outcome. Although associations of these and other factors with patient-reported sexual outcome have been studied, information regarding how the combination of pretreatment patient characteristics and treatment factors relate to individualized sexual outcome remains limited.
We sought to determine whether an individual man's sexual outcomes after the most common treatments for early-stage prostate cancer (radical prostatectomy, external radiotherapy, or brachytherapy) can be predicted accurately based on baseline characteristics and treatment planning details.
Study Patients and Measures
The Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment (PROSTQA) is a prospective, longitudinal, multicenter cohort comprising men with previously untreated clinical stage T1 to T2 prostate cancer who had elected prostatectomy, external beam radiotherapy, or brachytherapy as primary treatment and were enrolled from 2003 to 2006 at 9 US university-affiliated hospitals into an institutional review board–approved protocol after providing written informed consent.
Patient demographic, race/ethnicity, and clinical data were collected (because such factors have known associations with prostate cancer aggressiveness) by research coordinators via direct patient contact, eg, clinical visits supplemented by medical record review. Details of treatment, such as plan for nerve sparing during prostatectomy or neoadjuvant hormone therapy with radiation, were collected prior to treatment to enable predictive models based on pretreatment information. Patient-reported outcome measures, including the Expanded Prostate Cancer Index Composite (EPIC-26) and information regarding use of medications or devices for erectile dysfunction, were collected by third-party telephone interview before treatment and at 2, 6, 12, and 24 months after treatment; men who completed a pretreatment evaluation (1201/1371 eligible patients who had agreed to be contacted) comprised the PROSTQA cohort.
Among the 1201 men registered for follow-up, 1027 (86%) completed the 24-month interview and are the focus of this study. Their primary treatment included either prostatectomy (n = 524), external beam radiotherapy (n = 241), or brachytherapy (n = 262).
Prediction of Erectile Function Following Treatment for Prostate Cancer
Context Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking.
Objective To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics.
Design Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n = 1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort.
Main Outcome Measures Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment.
Results Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%-52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%-56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74-0.80] for prostatectomy; 0.87 [95% CI, 0.80-0.94] for external radiotherapy; and 0.90 for brachytherapy).
Conclusion Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer.
Because most patients survive early-stage prostate cancer after treatment, health-related quality of life (HRQOL) outcomes have emerged as a major emphasis in treatment decisions. Erectile dysfunction is commonplace after prostate cancer treatment and has significant consequences for HRQOL. Among urinary, bowel, vitality, and sexual HRQOL domains—outcomes commonly impaired by prostate cancer treatment—sexual function in previously potent men is the most commonly impaired and is closely related to outcome satisfaction.
Proximal and Distal Colon Cancer, and Rectal Cancer. Part 4
Our findings add to the limited prospective data on meat consumption in relation to rectal cancer. Consumption of red meat, as reported in 1992/1993, was more strongly associated with rectal than colon cancer in our study, as has been reported in some but not all case-control studies. One recent case-control study found no association between rectal cancer and red meat, poultry and fish, or processed meat consumption but reported increased risk associated with greater doneness of red meat among men. In our study, the positive association and significant dose-response relationship was observed mostly with tumors of the rectosigmoid junction rather than the rectum. Taken together with the higher risk of cancer observed in the distal colon, our results suggest that tumors in the distal portion of the large intestine may be particularly associated with meat consumption. It is possible that concentration of stool in the distal portion of the large intestine may contribute to higher cancer risk by increasing exposure to carcinogens as a result of water resorption during transit through the large intestine.
Our study had several limitations in addition to the measurement error inherent in studies based on FFQs. The 1982 questionnaire did not assess the number of servings of meat per day and could not differentiate persons who ate multiple servings from those who ate meat only once per day; we were also unable to estimate total energy intake from the 1982 diet questionnaire. We had no information on meat cooking methods to estimate exposure to heterocyclic amines or other specific carcinogens produced from pyrolysis of meat; our reliance on self-reported data on preference for doneness of meat was likely a crude proxy of the relevant exposures. Although heterocyclic amines are potent mutagens in the Ames assay and are carcinogenic in animal studies, the impact of these compounds on colorectal carcinogenesis in humans is less clear,81-83 primarily due to the difficulties in measuring exposure and possible interactions between meat and other dietary constituents or genetic susceptibility. We had no information on family history of colorectal cancer from the 1992/1993 questionnaire to update this important variable, which could potentially modify the association between meat intake and risk of colorectal cancer. No information was collected on examination by sigmoidoscopy, colonoscopy, or fecal occult blood test in either the 1982 or 1992/1993 questionnaires. However, in 1997, persons who reported long-term high consumption of red meat were less likely (23%) to have had endoscopy for screening than those persons who reported long-term low intake of red meat (34%). It is difficult to predict the net effect of endoscopy on colorectal cancer incidence. On the one hand, endoscopic removal of precancerous lesions could contribute to lower risk; however, endoscopy could accelerate the diagnosis of some tumors that might not otherwise have been identified during the follow-up period.
Proximal and Distal Colon Cancer, and Rectal Cancer. Part 3
The higher risk associated with prolonged consumption of red meat but not poultry and fish is consistent with other epidemiological studies. The cytotoxic effect of dietary heme has been proposed as a potential mechanism by which red meat increases colorectal cancer risk because of higher heme content in red meat compared with poultry and fish. Heme damages the colonic mucosa and stimulates epithelial proliferation in animal studies. Both ingestion of red meat and heme iron supplementation have been shown to increase fecal concentrations of N-nitroso compounds and DNA-adducts in human colonocytes.
We found that consistently high consumption of processed meat was associated with increased risk of distal colon cancer. Results of prospective studies of colorectal cancer and processed meat have been more consistently positive in Europe than in the United States. Processed meat includes foods preserved by salting, smoking, or the addition of nitrites or nitrates, and high consumption of these foods can increase exposure to nitrosamines and their precursors. The amount of these substances in processed meat likely varied by region and over time but we had no information to assess the impact of these differences in our study results.
Several prospective studies have reported an inverse association between colon cancer risk and prolonged high consumption of poultry and fish. However, other studies have found either no association or increased risk associated with poultry and fish consumption. The lower risk associated with high consumption of poultry and fish or a low ratio of red meat-to-poultry and fish could be attributed to a displacement of red meat in the diet, but in our study high consumption of poultry and fish remained independently associated with lower risk of colon cancer even when controlling for red meat intake. It is also possible that poultry and fish contain factors that may protect against colon cancer. Poultry contains small amounts of nutrients such as selenium and calcium that have been associated with lower risk of colorectal neoplasia, but it is a relatively minor source of these nutrients. Fish is a primary source of omega-3 fatty acids and high intake of fish or fish oil has been inversely associated with colorectal cancer risk in some epidemiological studies. In experimental studies, omega-3 fatty acids have been shown to inhibit tumor growth and to modulate the expression of proinflammatory genes. However, the poultry and fish consumed by CPS II Nutrition Cohort participants consisted mostly of chicken.
Proximal and Distal Colon Cancer, and Rectal Cancer. Part 2
Red meat consumption was marginally associated with higher risk of rectal cancer (RR, 1.43; 95% CI, 1.00-2.05); this association was somewhat stronger for cancers of the rectosigmoid junction (RR, 1.75; 95% CI, 1.04-2.96) than for cancer of the rectum (RR, 1.31; 95% CI, 0.79-2.15). The relationship between long-term consumption of red meat, poultry and fish, and risk of colon or rectal cancer remained unchanged when all were included in the same model (data not shown).
Effect Modification
No statistically significant interaction was observed between meat consumption and other known risk factors for colon or rectal cancer on a multiplicative scale.
The association between processed meat consumption and colon cancer risk was independent of other covariates only when intake was measured at 2 time points during a 10-year interval. Moreover, the association was observed consistently only for cancers of the distal colon. Prolonged high consumption of red meat was associated with higher risk of rectal cancer, particularly cancers of the rectosigmoid junction. Prolonged high consumption of poultry and fish was marginally associated with lower risk of proximal and distal colon cancer but not rectal cancer.
A strength of our study was the ability to control for several factors known to influence colon cancer risk. Inadequate control for potential confounding may partly explain the inconsistently observed positive associations between red meat and colon cancer risk in other studies, since some positive articles included in the quantitative reviews have adjusted for only age and energy. In our analyses, the association between colon cancer risk and high intake of red (RR, 1.41; 95% CI, 1.12-1.78) and processed meat (RR, 1.33; 95% CI, 1.08-1.64) measured at a single time point is consistent with meta-analysis results, adjusting for age and energy intake. However, the association was substantially attenuated with further adjustment for educational attainment, cigarette smoking, physical activity, and other lifestyle factors associated with red meat intake.
To our knowledge, no study has addressed the relationship between long-term meat consumption and risk of colon and rectal cancer. The association with distal colon cancer was stronger among persons who reported greater consumption of processed meat at 2 time points during a 10-year interval, as was the risk of cancer of the rectosigmoid junction among those persons who consistently reported high red meat intake. It is possible that true high consumers of red or processed meat were better defined with less measurement error when assessed twice during a 10-year period. It is also plausible that long-term high consumption of red and processed meat may be more strongly associated with colorectal carcinogenesis than short-term or sporadic consumption of meat. Certain components of red meat may affect both early and late stages in the development of neoplasia. Animal studies show that diets high in red meat tend to affect the early aberrant crypt stage of carcinogenesis. To our knowledge, no study has evaluated the importance of continued high exposure to red meat in animal models.
Proximal and Distal Colon Cancer, and Rectal Cancer
Higher consumption of poultry and fish was inversely associated with colon cancer risk in women but not men. Further adjustment for additional covariates other than energy attenuated the association. Among women, the inverse relationship remained statistically significant (P = .03 for trend). The positive association between colon cancer risk and ratio of red meat-to-poultry and fish intake was also stronger in women than men. The trend test for the ratio of red meat-to-poultry and fish intake was statistically significant in men, women, and both sexes combined. The inverse, marginally significant, association between high consumption of poultry and fish and colon cancer risk in men and women remained unchanged when adjusting simultaneously for red meat (data not shown).
Proximal and Distal Colon Cancer, and Rectal Cancer
After covariate adjustment, no consistent association was observed between consumption of red meat, poultry and fish, or processed meat as reported at a single time point and cancer of either subsite of the colon. Men and women in the second to fifth quintiles of red meat intake had higher risk of rectal cancer compared with those in the lowest quintile, particularly those individuals in the highest quintile (RR, 1.71; 95% CI, 1.15-2.52; P = .007 for trend). This association was observed primarily with cancers of the rectosigmoid junction (RR, 2.40; 95% CI, 1.30-4.43) with risk increasing significantly with the amount of red meat consumed (P = .002 for trend). No significant association was observed between red meat consumption and cancers of the rectum (data not shown). No clear association was observed between rectal cancer risk and other measures of meat consumption reported in 1992/1993.
Energy-Adjusted Meat Intake
Analyses using energy-adjusted meat intake reported in 1992/1993 yielded results similar to those using meat intake (g/wk) with few exceptions. Compared with risk estimates derived from nonenergy-adjusted meat intake, the association between colon cancer and consumption of processed meat (RR, 1.35; 95% CI, 1.04-1.77; highest to lowest quintile, P = .02 for trend) became stronger in men, although the association between rectal cancer and red meat intake (RR, 1.31; 95% CI, 0.96-1.79; P = .03 for trend) was attenuated in men and women combined. Other risk estimates for red meat, poultry and fish, and processed meat remained unchanged.
Long-term Meat Consumption
Prolonged high consumption of red meat was associated with a statistically nonsignificant increased risk of distal colon cancer (RR, 1.29; 95% CI, 0.88-1.89). The most consistent associations were observed between distal colon cancer and prolonged high intake of processed meat (RR, 1.50; 95% CI, 1.04-2.17), and ratio of red meat to poultry and fish (RR, 1.53; 95% CI, 1.08-2.18) compared with persons with prolonged low intake. These associations were not observed with cancer of the proximal colon. The association between distal colon cancer and consumption of processed meat was stronger in analyses based on long-term consumption than on that reported only in 1982 (data not shown). Long-term high intake of poultry and fish was marginally associated with lower risk of proximal (RR, 0.77; 95% CI, 0.59-1.02) and distal (RR, 0.70; 95% CI, 0.50-0.99) colon cancer.
Participant Characteristics by Meat Consumption. Part 2
We tested the proportional hazard assumption for each meat intake variable in relation to colon or rectal cancer using the likelihood ratio test, comparing models with and without product terms for meat consumption (quintiles) and follow-up time (years). We evaluated effect modification of the RR for colon and rectal cancer in relation to meat consumption by other covariates using the likelihood ratio test comparing models with and without interaction terms. The Wald statistic was used to test for homogeneity of the RR for proximal and distal colon cancers.63 All P values were 2-sided and considered significant at P<.05. All analyses were conducted using SAS version 9.0 (SAS Institute Inc, Cary, NC).
Participant Characteristics by Meat Consumption
Men and women reported a wide range in consumption of red and processed meat in 1992/1993. A 10-fold difference was observed between the lowest and highest quintiles of red meat in men and a 17-fold difference in women (Table 1). Men reported greater consumption of red and processed meat than did women; median intake was 427 g/wk and 274 g/wk for red meat among men and women, respectively, and 95 g/wk and 43 g/wk for processed meat, respectively. There was little variation in the consumption of poultry and fish by quintiles of red meat intake. Men also reported substantially higher intake of red and processed meats in 1982 than did women (data not shown). Approximately half of the men and women in the top tertile for consumption of red or processed meat in 1982 were also in the highest tertile in 1992/1993 (data not shown). The absolute levels of meat consumption in 1982 could not be compared with consumption in 1992/1993 due to differences in the questionnaires.
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Men and women who reported higher intake of red meat in 1992/1993 were more likely to report lower educational attainment, no recreational physical activity, higher body mass index, current cigarette smoking, beer and liquor drinking, higher total daily energy intake, low fruit intake in 1992/1993, and little or no intake of vegetables or high-fiber grain foods in 1982 compared with those with lower red meat intake. Men and women who reported lower red meat intake tended to report multivitamin use in 1982, wine drinking, and (in women) use of hormone therapy in 1992/1993.
Meat Consumption and Colon Cancer Incidence
Table 2 shows the relationship between colon cancer incidence and meat consumption as reported in 1992/1993. Higher intake of red and processed meat was associated with higher colon cancer risk in men and women in models that adjusted only for age and energy intake. However, the positive associations were attenuated in analyses that further adjusted for nondietary factors, including education, body mass index, cigarette smoking, recreational physical activity, use of multivitamins or aspirin, and (in women) use of hormone therapy. Further adjustment for dietary factors had little effect on the RR estimates. No association was observed between colon cancer incidence and consumption frequency of beef, pork, or lamb as a main dish, or with reported preference for red meat doneness (data not shown).