External validation of the colorectal cancer risk score LiFeCRC using food frequency questions in the HUNT study.

PURPOSE: To mitigate the increasing colorectal cancer (CRC) incidence globally and prevent CRC at the individual level, individual lifestyle information needs to be easily translated into CRC risk assessment. Several CRC risk prediction models exist and their clinical usefulness depends on their ease of use. Our objectives were to assess and externally validate the LiFeCRC score in our independent, unselected population and to investigate the use of simpler food frequency measurements in the score. METHODS: Incidental colon and rectal cancer cases were compared to the general population among 78,580 individuals participating in a longitudinal health study in Norway (HUNT). Vegetable, dairy product, processed meat and sugar/confectionary consumption was scored based on food frequency. The LiFeCRC risk score was calculated for each individual. RESULTS: Over a median of 10 years following participation in HUNT, colon cancer was diagnosed in 1355 patients and rectal cancer was diagnosed in 473 patients. The LiFeCRC score using food frequencies demonstrated good discrimination in CRC overall (AUC 0.77) and in sex-specific models (AUC men 0.76 and women 0.77) in this population also including individuals ≥ 70 years and patients with diabetes. It performed somewhat better in colon (AUC 0.80) than in rectal cancer (AUC 0.72) and worked best for female colon cancer (AUC 0.81). CONCLUSION: Readily available clinical variables and food frequency questions in a modified LiFeCRC score can identify patients at risk of CRC and may improve primary prevention by motivating to lifestyle change or participation in the CRC screening programme.

Colorectal cancer detected by liquid biopsy 2 years prior to clinical diagnosis in the HUNT study.

BACKGROUND: Colorectal cancer (CRC) is often diagnosed in advanced stages. Circulating tumour DNA (ctDNA) has been proposed as an early diagnostic biomarker. However, as a screening tool, ctDNA has mainly been studied in selected populations at the time of clinical diagnosis. The aim of this study was to detect CRC by known ctDNA markers up to 2 years prior to clinical diagnosis. METHODS: In this case-control study, methylated ctDNA markers were detected in plasma samples from 106 healthy controls and 106 individuals diagnosed with CRC within 24 months following participation in The Trøndelag Health Study. RESULTS: The most specific single markers were BMP3, FLI1, IKZF1, SFRP1, SFRP2, NPTX2, SLC8A1 and VIM (specificity >70%). When combining these into a panel, the CRC sensitivity was 43% (95% CI 42.7-43.4) and the CRC specificity was 86% (95% CI 85.7-86.2). The findings were reproduced in an independent validation set of samples. CONCLUSIONS: Detection of known methylated ctDNA markers of CRC is possible up to 2 years prior to the clinical diagnosis in an unselected population resembling the screening setting. This study supports the hypothesis that some patients could be diagnosed earlier, if ctDNA detection was part of the CRC screening programme.

Risk factors for right colon, left colon and rectal cancers differ between men and women: the population-based HUNT study in Norway.

AIM: The aim of this study was to assess established risk factors for colorectal cancer (CRC) separately for right colon, left colon and rectal cancer in men and women. METHOD: This was a prospective cohort study comparing incidental CRC cases and the general population participating in a longitudinal health study in Norway (the HUNT study). RESULTS: Among 78 580 participants (36 825 men and 41 754 women), 1827 incidental CRCs were registered (931 men and 896 women). Among men, the risk of cancer at all locations increased with age [HR 1.46 (1.40-1.51), HR 1.32 (1.27-1.36), HR 1.30 (1.25-1.34) per 5 years for right colon, left colon and rectal cancer, respectively] and the risk of left colon cancer increased with higher body mass index [HR 1.28 (1.12-1.46) per 5 kg/m2 ]. The risk of right colon cancer (RCC) increased with smoking [HR 1.07 (1.04-1.10) per 5 pack years]. Among women, the risk of cancer at all locations increased with age [HR 1.38 (1.34-1.43), HR 1.23 (1.19-1.27), HR 1.20 (1.16-1.24) per 5 years] and smoking [HR 1.07 (1.02-1.12), HR 1.07 (1.02-1.12), HR 1.10 (1.05-1.17) per 5 pack years] for right colon, left colon and rectal cancer, respectively. The risk of RCC increased with night shift work [HR 1.93 (1.22-3.05)]. CONCLUSION: The risk factors for developing CRC differ by anatomical location and sex. The relationship between risk factors and CRC may be more nuanced than previously known.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

OBJECTIVES: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. METHODS: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). RESULTS: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate. CONCLUSIONS: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC.

Here we provide the updated version of the guidelines of the European Association for Palliative Care (EAPC) on the use of opioids for the treatment of cancer pain. The update was undertaken by the European Palliative Care Research Collaborative. Previous EAPC guidelines were reviewed and compared with other currently available guidelines, and consensus recommendations were created by formal international expert panel. The content of the guidelines was defined according to several topics, each of which was assigned to collaborators who developed systematic literature reviews with a common methodology. The recommendations were developed by a writing committee that combined the evidence derived from the systematic reviews with the panellists' evaluations in a co-authored process, and were endorsed by the EAPC Board of Directors. The guidelines are presented as a list of 16 evidence-based recommendations developed according to the Grading of Recommendations Assessment, Development and Evaluation system.

Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations.

The objectives were to review the existing literature on management of opioid-induced nausea and vomiting in cancer patients and summarize the findings into evidence-based recommendations. Systematic searches of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were performed, using free text and MeSH/EMTREE search terms. The searches were limited to articles published in English from each database set-up date to 31 July 2009. Reference lists and relevant international conference proceedings were hand-searched. Fifty-five studies were identified, providing data on 5741 patients. The studies were classified into: (A) studies in which treatment of nausea/vomiting was the primary outcome (a total of 18 studies, of which eight studies specifically addressed opioid-induced emesis); and (B) studies in which nausea/vomiting were secondary or tertiary outcomes (37 studies). The existing evidence had several limitations, there was a lack of consistency and the overall quality was grade D. By applying the principles of the Grading of Recommendations Assessment, Development and Evaluations (GRADE) system, three weak recommendations were formulated. The current evidence is too limited to give evidence-based recommendations for the use of antiemetics for opioid-induced nausea or vomiting in cancer patients. The evidence suggests that nausea and vomiting in cancer patients receiving an opioid might be reduced by changing the opioid or opioid administration route. The evidence was also too limited to prioritize between symptomatic treatment and adjustment of the opioid treatment.

Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids.

BACKGROUND: This study investigates whether demographical, disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain. METHODS: Cancer patients receiving opioids were included from 17 centres in 11 European countries. Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales. In stratified regression models including demographical and disease-related factors as covariates, 96 single nucleotide polymorphisms (SNPs) in 16 candidate genes related to opioid- or nausea/vomiting signalling pathways (ABCB1, OPRM1, OPRK1, ARRB2, STAT6, COMT, CHRM3, CHRM5, HRH1, DRD2, DRD3, TACR1, HTR3A, HTR3B, HTR3C, CNR1) were analysed for association with nausea and vomiting. FINDINGS: Age, body mass index, Karnofsky Performance Status, gender, use of antiemetics, type of opioid, type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids (p<0.01). The SNPs were rs1176744, rs3782025 and rs1672717 in HTR3B; rs165722, rs4680 and rs4633 in COMT; rs10802789 and rs685550 in CHRM3. Only the SNP rs1672717 in HTR3B passed the Benjamini-Hochberg criterion for a 10% false discovery rate. INTERPRETATION: Clinical characteristics and SNPs within the HTR3B, COMT and CHRM3 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids. This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain.

Inadequate symptom control in advanced cancer patients across Europe.

PURPOSE: The purpose of this study is to examine the adequacy of treatment for constipation, nausea, depression and poor sleep and the factors associated with inadequate symptom control in cancer patients receiving opioids. METHODS: Patients receiving strong opioids for cancer pain were recruited from 17 centres in 11 European countries. By using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30, 1,938 patients reported their symptoms at four-point scales. Health care providers assessed symptoms at corresponding four-point scales and registered use of medications, demographic and disease-related variables. Symptomatic treatment was scored as 1 if not administered during the past 24 h and as 2 if administered. Adequacy of treatment was evaluated by subtracting the patients' symptom score from the treatment score. Negative scores, caused by either no treatment or ineffective treatment of a symptom, were interpreted as inadequate treatment. RESULTS: Approximately 60% of patients with constipation, depression or poor sleep and 45% of nauseated patients were inadequately treated. Numbers of inadequately treated patients varied between countries. In general, underestimation of symptom intensity by health care providers (p < 0.001), low performance status (p < 0.05) and recent initiation of opioids (p < 0.05) increased the risk of inadequate treatment. The subset of demographic- and disease-related factors associated with inadequate treatment varied between the symptoms investigated. CONCLUSIONS: Inadequate treatment, either no treatment or ineffective treatment, was frequent in cancer patients. There were subgroups of patients at particular risk for inadequate treatment, which might need additional attention from health care providers for achievement of adequate symptom control.

Health care providers underestimate symptom intensities of cancer patients: a multicenter European study.

BACKGROUND: Many patients with advanced cancer depend upon health care providers for symptom assessment. The extent of agreement between patient and provider symptom assessments and the association of agreement with demographic- and disease-related factors was examined. METHODS: This cross-sectional study included 1933 patient-health care provider dyads, from 11 European countries. Patients reported symptoms by using the four-point scales of the European Organization of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3, and providers used corresponding four-point categorical scales. Level of agreement was addressed at the group level (Wilcoxon Signed-Rank test), by difference scores (provider score minus patient score), at the individual level (Intraclass Correlation Coefficients, ICCs) and visually by Bland-Altman plots. Absolute numbers and chi-square tests were used to investigate the relationship between agreement and demographic-, as well as disease-related factors. RESULTS: The prevalence of symptoms assessed as moderate or severe by patients and providers, respectively, were for pain (67 vs.47%), fatigue (71 vs. 54%), generalized weakness (65 vs. 47%), anorexia (47 vs. 25%), depression (31 vs. 17%), constipation (45 vs. 30%), poor sleep (32 vs. 21%), dyspnea (30 vs. 16%), nausea (27 vs. 14%), vomiting (14 vs. 6%) and diarrhea (14 vs. 6%). Symptom scores were identical or differed by only one response category in the majority of patient-provider assessment pairs (79-93%). Providers underestimated the symptom in approximately one of ten patients and overestimated in 1% of patients. Agreement at the individual level was moderate (ICC 0.38 to 0.59). Patients with low Karnofsky Performance Status, high Mini Mental State-score, hospitalized, recently diagnosed or undergoing opioid titration were at increased risk of symptom underestimation by providers (all p < 0.001). Also, the agreement was significantly associated with drug abuse (p = 0.024), provider profession (p < 0.001), cancer diagnosis (p < 0.001) and country (p < 0.001). CONCLUSIONS: Considerable numbers of health care providers underestimated symptom intensities. Clinicians in cancer care should be aware of the factors characterizing patients at risk of symptom underestimation.