Cielito C. Reyes-Gibby

Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene

Abstract Pain is a complex human trait. It is likely that the interaction of multiple genes, each with a small individual effect, along with the effect of environmental factors, influences the clinical efficacy of opioids rather than a single gene alone. Polymorphisms in genes coding for the mu‐opioid receptor (A118G) and catechol‐O‐methyl transferase (Val158Met) may be important modulators of opioid efficacy. We assessed joint effects of the OPRM1 and COMT genes in predicting morphine dose for cancer pain relief. We used genotype and clinical data from a pharmacokinetic study of morphine in 207 inpatients treated with stable morphine dose for at least 3 days by Palliative Medicine Specialists. Results showed significant variation in morphine dose requirement by genotype groups: carriers of COMT Val/Val and Val/Met genotype required 63% and 23%, respectively, higher morphine dose compared to carriers of Met/Met genotype (p = 0.02). Carriers of OPRM1 GG genotype required 93% higher morphine dose compared to carriers of AA genotypes (p = 0.012). When we explored for joint effects, we found that carriers of the OPRM1 AA and COMT Met/Met genotype required the lowest morphine dose to achieve pain relief (87 mg/24 h; 95%CI = 57,116) and those with neither Met/Met nor AA genotype needed the highest morphine dose (147 mg/24 h; 95%CI = 100,180). The significant joint effects for the Met/Met and AA genotypes (p < 0.012) persisted, even after controlling for demographic and clinical variables in the multivariable analyses. Future studies are needed to further characterize the joint effects of multiple genes, along with demographic and clinical variables, in predicting opioid dose.

Fatigue and Sleep Disturbance in Patients with Cancer, Patients with Clinical Depression, and Community-Dwelling Adults

This study compared the severity of fatigue in patients with cancer to the fatigue reported by depressed psychiatric patients and community-dwelling adults. Data were collected for this study during the process of validating a new fatigue assessment tool, the Brief Fatigue Inventory (BFI). The sample included 354 cancer patients, 72 psychiatric patients, and 290 non-patient volunteers. Study subjects reported severity of fatigue and the degree to which fatigue interfered with various aspects of life. Data were also collected on sleep disturbance and demographic variables that might correlate with fatigue. The psychiatric patients reported significantly higher levels of fatigue and fatigue-related interference than the cancer patients, who reported more severe fatigue and interference than the community subjects. The sleep disturbance scores of the cancer patients and the community subjects were significantly correlated with fatigue severity. Although the majority of the psychiatric patients reported sleep disturbance, their sleep disturbance scores were not significantly associated with fatigue severity.

Impact of a Palliative Care Consultation Team on Cancer-Related Symptoms in Advanced Cancer Patients Referred to an Outpatient Supportive Care Clinic

CONTEXT Patients with advanced cancer may develop severe physical and psychosocial symptoms. There are limited data on the impact of an outpatient palliative consultation (PC) team on cancer-related symptoms. OBJECTIVES To study the impact of the PC on symptoms in patients with advanced cancer receiving outpatient palliative care. METHODS Four hundred six consecutive patients referred to a supportive care outpatient center (OPC) from January 2006 to June 2007 with complete Edmonton Symptom Assessment Scale (0-10 scale) at the initial and follow-up visits were reviewed. Patient characteristics, change of symptoms at follow-up visit, and response rate were analyzed. Using logistic regression models, the predictors of improvement of pain and fatigue were assessed. RESULTS Median age was 59 years; 53% were female. Median interval between visits was 15 days. Mean scores at baseline and follow-up visits were fatigue 6.8 and 5.3 (P<0.0001), pain 5.3 and 4.1 (P<0.0001), depression 3.2 and 2.5 (P<0.0001), anxiety 3.7 and 2.8 (P<0.0001), dyspnea 2.7 and 2.5 (P=0.05), sleep 5 and 4 (P<0.0001), and well-being 5.2 and 4.4 (P<0.0001). Dyspnea (odds ratio and P-value, 0.90, 0.03), nausea (0.92, 0.06), and depression (0.91, 0.04) were associated with improvement in fatigue; drowsiness (1.10, 0.04), and feeling of well-being (0.87, 0.02) were associated with improvement in pain. CONCLUSION The initial consult by PC achieved significant symptom improvement in patients receiving treatment in the OPC. Further prospective studies are needed.

Molecular epidemiology, cancer-related symptoms, and cytokines pathway

The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalized and more effective therapies for persistent symptoms.

Depressive symptoms and health-related quality of life in breast cancer survivors

BACKGROUND Breast cancer diagnosis and treatment can have a profound influence on a womans physical, psychosocial, and overall well-being. We examined the prevalence of depressive symptoms and its association with health-related quality of life (HRQOL) in women who are survivors of breast cancer. We also assessed if factors, including metastasis, cancer recurrence, diagnosis of new primary cancers, and comorbid conditions, are associated with depressive symptoms. METHODS The Patient Health Questionnaire (PHQ-8) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were mailed to assess depressive symptoms and HRQOL, respectively, in breast cancer patients who received cancer treatment in a large tertiary cancer center. RESULTS Two hundred forty patients participated (56% response rate and 6-13 years since treatment). The mean score on the PHQ-8 scale was 4 points (standard deviation [SD] 4.8, median 2.0). Sixteen percent had PHQ-8 score ≥10 and were categorized as depressed. Depression was inversely associated with HRQOL subscales for functioning, financial, and global health and positively associated with symptoms. Logistic regression showed that younger age (odds ratio [OR] age in years 0.92, 95% confidence interval [CI] 0.86- 0.99, p<0.02), rheumatoid arthritis (OR 8.4, 95%CI 1.3-57.4, p<0.03), and years from treatment (OR 0.70, 95% CI 0.46-0.99, p<0.05) were significant correlates of depression. CONCLUSIONS Depression is a significant health concern for breast cancer survivors and is associated with lower HRQOL. The results suggest the need to monitor women with breast cancer for depression and provide resources for treating depression during the survival period.

Rapid improvement in pain management: the Veterans Health Administration and the institute for healthcare improvement collaborative.

BackgroundPoor pain management persists in health care. Although common practice errors in pain management have been identified and standards and guidelines for pain management have been published, improvement has been modest. With the goal of rapid improvement in pain management, a joint Collaborative (Veterans Health Administration and Institute for Healthcare Improvement) was conducted from May 2000 to January 2001. ObjectiveTo improve delivery of pain management to VHA patients and to compare team process and patient report data on key goals from selected study units. MethodsCharts were reviewed for outcome and process measures. Measures included changes in percentage of patients with (1) moderate to severe pain, (2) documentation of a pain assessment, (3) documentation of a pain care plan, and (4) documentation that the patient received pain education. ResultsSeventy teams from 22 Veterans Integrated Service Networks throughout the U.S. participated. Moderate or severe pain on study units dropped from 24% to 17%; pain assessment increased from 75% to 85%; pain care plans for patients with at least mild pain increased from 58% to 78%; and number of patients provided with pain educational materials increased from 35% to 62%. DiscussionSignificant progress toward the target goals was reported during the Collaborative period. This improvement needs to be viewed in the context of a VHA system-wide effort to improve pain management. Data suggest that a program of team formation, goal identification, testing and adaptation of recommended system changes, sharing and feedback of process and outcome information can produce significant change in pain management in a major health care organization.

Chemotherapy-Induced Peripheral Neuropathy as a Predictor of Neuropathic Pain in Breast Cancer Patients Previously Treated With Paclitaxel

UNLABELLED Neuropathic pain (NP) remains difficult to control for a significant number of patients with cancer. Chemotherapy-induced peripheral neuropathy (CIPN) has been postulated as an initial stage in the development of NP. To assess whether CIPN (defined as National Cancer Institute Common Toxicity Criteria grade 2 or higher) was associated with NP, we conducted a survey of breast cancer patients who had participated in clinical trials of paclitaxel. Of the 430 potential respondents, 240 responded to the survey. Results showed that 64% experienced CIPN during paclitaxel treatment. Follow-up survey data revealed that 27% of those with CIPN were subsequently diagnosed with NP. Logistic regression analyses showed that those who had experienced CIPN were 3 times more likely to develop NP (95% confidence interval = 1.2-7.2; P < .001), which persisted in the multivariate logistic model. In addition, NP patients reported twice as many visits to their health care provider (P = .02) and had taken more prescription (50% vs 19%; P = .001) and over-the-counter medications (62.5% versus 45%; P = .08) for pain than those without NP. The results of this study confirm that CIPN is a predictor of NP, suggesting that survivors treated with paclitaxel should be regularly monitored for NP beyond treatment. PERSPECTIVE The survival rates of breast cancer patients have steadily improved over recent years; thus, research into symptoms that persist after treatment is important. We found CIPN as a predictor of NP. Understanding the epidemiology of NP in breast cancer patients has high clinical and public health significance.

Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study.

CONTEXT In pancreatic cancer, the presence of obesity or weight loss is associated with higher mortality. OBJECTIVES To explore the relationships among body mass index, longitudinal body composition alterations, and clinical outcomes in pancreatic cancer patients. METHODS Records of 41 patients with inoperable locally advanced pancreatic cancer who participated in a prospective chemoradiation study were reviewed. Body composition was analyzed from two sets of computed tomography images obtained before and after radiation treatment (median interval 104 days). RESULTS Median age was 59 years and 56% of patients were female. Twenty-four (59%) patients were either overweight (22%) or obese (37%). Sarcopenia was present in 26 (63%) patients. At follow-up, weight loss was experienced by 33 (81%) patients. The median losses (%) before and after treatment were weight 5% (P<0.001), skeletal muscle (SKM) 4% (P=0.003), visceral adipose tissue (VAT) 13% (P<0.001), and subcutaneous adipose tissue 11% (P=0.002). SKM loss positively correlated with age (P=0.03), baseline body mass index (P<0.001), and VAT (P=0.04) index. Obese patients experienced higher losses in weight (P=0.009), SKM (P=0.02), and VAT (P=0.02). Median survival was 12 months. In univariate analysis, age, baseline obesity, sarcopenic obesity, and losses (%) in weight, SKM, and VAT were associated with worse survival. In multivariate analysis, only age (hazard ratio=1.033, P=0.04) and higher VAT loss (hazard ratio=2.6 and P=0.03) remained significant. CONCLUSION Our preliminary findings suggest that obese patients experience higher losses in weight, SKM, and VAT, which may contribute to poorer survival in these patients.

Cytokine Genes and Pain Severity in Lung Cancer: Exploring the Influence of TNF-α-308 G/A IL6-174G/C and IL8-251T/A

Introduction: Cytokines, aberrantly produced by cancer cells, have recently been implicated in the severity of cancer-related pain. We explored if polymorphisms in candidate cytokine genes could explain variability in self-reported pain in lung cancer patients of all stages. Methods: Pain, clinical, and demographic variables were assessed at presentation and before any cancer treatment in 446 Whites, 125 African-Americans, and 35 Hispanics with newly diagnosed non–small cell lung cancer. We genotyped functional single nucleotide polymorphisms in tumor necrosis factor-α (TNF-α -308 G/A), interleukin-6 (IL-6) -174G/C, and IL-8 -251T/A and determined their associations with pain severity. Results: More African-Americans (35.5%) reported severe pain (score ≥7 on a 0-10 scale) relative to Hispanics (20%) and Whites (17%; P < 0.001). We did not observe any significant association between genotypes in TNF-α, IL-6, and IL-8 and severe pain for either African-Americans or Hispanics, possibly due to small sample sizes. However, we observed that IL-8 (TT, 13%; TA + AA, 87%; P = 0.04) was significantly associated with severe pain among White patients. Logistic regression analyses showed that after controlling for epidemiologic (age and sex), clinical (stage of disease, comorbidities), and symptom (depressed mood and fatigue) variables known to influence pain severity, variant alleles in IL-8 -251T/A [odds ratio (OR), 2.35; 95% confidence interval (95% CI), 1.10-5.03; P = 0.03] persisted as a significant factor for severe pain for White patients. Conclusions: In this preliminary analysis, we found evidence of the influence of cytokine genes on pain in White patients with lung cancer. Additional larger studies are needed to validate our findings. The long-term application is to tailored pain therapies. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2745–51)

The influence of tumor necrosis factor-α -308 G/A and IL-6- 174 G/C on pain and analgesia response in lung cancer patients receiving supportive care

Introduction: We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non–small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-α (TNF- α-308 G/A), interleukin (IL)-6 −174G/C, and IL-8 −251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment. Methods: Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine. Results: Forty-one percent (57 of 140) of the patients reported severe pain (score >7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFα −308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 −174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes. Conclusions: We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3262–7)