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June 2009 Meeting

Responses to Questions for Task Force Consideration:

Charlie Cleeland: Conceptual drawing of symptom burden
 

Pre-Meeting Reading Assignment

Bevans MF, Mitchell SA, Marden S. The symptom experience in the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT). Support Care Cancer 16(11): 1243-54, 2008.   [Link to PubMed]

ABSTRACT: Despite advances in allogeneic hematopoietic stem cell transplantation (HSCT), post-transplant complications are common, and patients' symptom experience has not been well documented. PURPOSE: To characterize the symptom experience of adult patients pre-transplantation and days 0, 30, and 100 after allogeneic HSCT. METHODS: Data from 76 participants enrolled in a prospective health-related quality of life (HRQL) study were used. Symptom occurrence, distress, and clusters were determined based on the 11 symptoms of the Symptom Distress Scale (SDS). RESULTS: Participants were on average 40 years old (SD +/- 13.5). The majority (54%) received reduced intensity conditioning. Prevalent symptoms included fatigue (68%) and worry (68%) at baseline, appetite change (88%) at day 0, and fatigue at days 30 (90%) and 100 (81%). Participants reported the following symptoms as severely distressing: worry (16%) [baseline], insomnia (32%) [day 0], appetite change (22%) [day 30], and fatigue (11%) [day 100]. The total SDS score was highest at day 0 (M = 26.6 +/- 7.6) when the highest number of symptoms were reported [median = 8 (1-11)]. Symptoms formed clusters comprised of fatigue, appearance change, and worry at baseline, and fatigue, insomnia, and bowel changes at days 0 and 30. Compared to those with low symptom distress, participants with moderate/severe symptom distress reported poorer HRQL. CONCLUSION: Allogeneic HSCT patients present for transplantation with low symptom distress yet experience multiple symptoms and high symptom distress after HSCT conditioning. Understanding the symptom experience of allogeneic HSCT patients can guide management strategies and improve HRQL.

Bezjak A, Lee CW, Ding K, Brundage M, Winton T, Graham B, Whitehead M, Johnson DH, Livingston RB, Seymour L, Shepherd FA. Quality-of-life outcomes for adjuvant chemotherapy in early-stage non-small-cell lung cancer: results from a randomized trial, JBR.10. J Clin Oncol 26(31):  5052-9, 2008.   [Link to PubMed]

ABSTRACT: Adjuvant chemotherapy for early stage non-small-cell lung cancer (NSCLC) is now the standard of care, but there is little information regarding its impact on quality of life (QOL). We report the QOL results of JBR.10, a North American, intergroup, randomized trial of adjuvant cisplatin and vinorelbine compared with observation in patients who have completely resected, stages IB to II NSCLC. PATIENTS AND METHODS: QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline and at weeks 5 and 9 for those who received chemotherapy and at follow-up months 3, 6, 9, 12, 18, 24, 30 and 36. A 10-point change in QOL scores from baseline was considered clinically significant. RESULTS: Four hundred eighty-two patients were randomly assigned on JBR.10. A total of 173 patients (82% of the expected) in the observation arm and 186 (85% of expected) in the chemotherapy arm completed baseline QOL assessments. The two groups were comparable, with low global QOL scores and significant symptom burden, especially pain and fatigue, after thoracotomy. Changes in QOL during chemotherapy were relatively modest; fatigue, nausea, and vomiting worsened, but there was a reduction in pain and no change in global QOL. Patients in the observation arm showed considerable improvements in QOL by 3 months. QOL, except for symptoms of sensory neuropathy and hearing loss, in those treated with chemotherapy returned to baseline by 9 months. CONCLUSION: The findings of this trial indicate that the negative effects of adjuvant chemotherapy on QOL appear to be temporary, and that improvements (with a return to baseline function) are likely in most patients.

Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, Ayoub J, Lago S, de Albuquerque Ribeiro R, Gerogianni A, Cyjon A, Noble J, Laberge F, Chan RT, Fenton D, von Pawel J, Reck M, Shepherd FA; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24(24): 3831-7, 2006.   [Link to PubMed]

ABSTRACT: This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain. RESULTS: Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01). CONCLUSION: Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.

Broderick JE, Schwartz JE, Vikingstad G, Pribbernow M, Grossman S, Stone AA. The accuracy of pain and fatigue items across different reporting periods. Pain 139(1): 146-57, 2008.   [Link to PubMed]

ABSTRACT: The length of the reporting period specified for items assessing pain and fatigue varies among instruments. How the length of recall impacts the accuracy of symptom reporting is largely unknown. This study investigated the accuracy of ratings for reporting periods ranging from 1 day to 28 days for several items from widely used pain and fatigue measures (SF36v2, Brief Pain Inventory, McGill Pain Questionnaire, Brief Fatigue Inventory). Patients from a community rheumatology practice (N=83) completed momentary pain and fatigue items on average of 5.4 times per day for a month using an electronic diary. Averaged momentary ratings formed the basis for comparison with recall ratings interspersed throughout the month referencing 1-day, 3-day, 7-day, and 28-day periods. As found in previous research, recall ratings were consistently inflated relative to averaged momentary ratings. Across most items, 1-day recall corresponded well to the averaged momentary assessments for the day. Several, but not all, items demonstrated substantial correlations across the different reporting periods. An additional 7 day-by-day recall task suggested that patients have increasing difficulty actually remembering symptom levels beyond the past several days. These data were collected while patients were receiving usual care and may not generalize to conditions where new interventions are being introduced and outcomes evaluated. Reporting periods can influence the accuracy of retrospective symptom reports and should be a consideration in study design.

Butt Z, Wagner LI, Beaumont JL, Paice JA, Peterman AH, Shevrin D, Von Roenn JH, Carro G, Straus JL, Muir JC, Cella D. Use of a single-item screening tool to detect clinically significant fatigue, pain, distress, and anorexia in ambulatory cancer practice. J Pain Symptom Manage 35(1): 20-30, 2008.   [Link to PubMed]

ABSTRACT: Fatigue, pain, distress, and anorexia are four commonly encountered symptoms in cancer. To evaluate the usefulness of a single-item screening for these symptoms, 597 ambulatory outpatients with solid tumors were administered a self-report screening instrument within the first 12 weeks of chemotherapy. Patients rated the severity of each symptom on a 0-10 scale, at its worst over the past three days, with higher ratings associated with higher symptom levels. From this sample, 148 patients also completed a more comprehensive assessment of these symptoms. Two criteria were used to determine optimal cut-off scores on the screening items: 1) the sensitivity and specificity of each screening item to predict clinical cases using receiver-operating characteristics analysis and 2) the proportion of patients at each screening score who reported that some relief of the target symptom would significantly improve their life. Optimal cut-off scores ranged from 4 to 6 depending on the target symptom (area under the curve range=0.68-0.88). Use of single-item screening instruments for fatigue, pain, distress, and anorexia may assist routine clinical assessment in ambulatory oncology practice. In turn, such assessments may improve identification of those at risk of morbidity and decreased quality of life due to excess symptom burden.

Cella D. The Functional Assessment of Cancer Therapy-Lung and Lung Cancer Subscale assess quality of life and meaningful symptom improvement in lung cancer. Semin Oncol 31(3 Suppl 9): 11-5, 2004.   [Link to PubMed]

ABSTRACT: Treatment options for patients with advanced lung cancer who have received prior chemotherapy are largely palliative, with little hope for cure. Current therapies may provide only modest survival benefits to patients while potentially adding treatment-related toxicities to lung cancer-related symptoms. However, new treatments have been developed that may improve disease-related symptoms and quality of life with only mild toxicities. The Functional Assessment of Cancer Therapy-Lung, a validated, disease-specific quality-of-life instrument, effectively correlates quality-of-life changes with clinical outcomes in patients with non-small-cell lung cancer. In a large randomized trial from the Eastern Cooperative Oncology Group study 5592, a change of two to three points in the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung was found to be clinically meaningful and correlated well with patient symptom differences at baseline, changes in symptoms after treatment, tumor response, and time to disease progression. Results from trials that include symptom improvement and quality of life as end points, in addition to the more standard outcomes of tumor response and survival, will provide meaningful information in evaluating the clinical benefits of new cancer treatments.

Cella D, Herbst RS, Lynch TJ, Prager D, Belani CP, Schiller JH, Heyes A, Ochs JS, Wolf MK, Kay AC, Kris MG, Natale RB. Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial. J Clin Oncol 23(13): 2946-54, 2005.   [Link to PubMed]

ABSTRACT: Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.

Cleeland CS. Symptom burden: multiple symptoms and their impact as patient-reported outcomes. J Natl Cancer Inst Monogr 37: 16-21, 2007.   [Link to PubMed]

ABSTRACT: Cancer and its treatment produce multiple symptoms that significantly distress patients and impair function. Symptoms caused by treatment may delay treatment or lead to premature treatment termination, and residual treatment-related symptoms often complicate posttreatment rehabilitation. When treatment is no longer possible, symptom control becomes the focus of cancer care. Patient ratings of symptom severity and impact are important patient-reported outcomes (PROs) in cancer clinical trials and comprise a subset of a larger domain of PROs generally referred to as health-related quality of life (HRQOL). Symptoms rarely occur in isolation; rather, there is now ample evidence that symptoms frequently occur in clusters. The impact of these multiple symptoms upon the patient can be described as "symptom burden," a concept that encompasses both the severity of the symptoms and the patient's perception of the impact of the symptoms. The distress caused by symptoms is a subject of much investigation, and several validated measures of the severity and impact of multiple symptoms are now available. Symptom measures are generally brief, thereby reducing respondent burden, and can be administered repeatedly during a trial to give a relatively fine-grained picture of the patient's status across time. In many instances, information on trial-related changes in symptom burden, or comparison of symptom burden between arms in a clinical trial, may provide sufficient self-report data for clinical trial consumers (patients, clinicians, and regulators) to make treatment choices or to evaluate new therapies, without measuring other HRQOL domains.

Gabrilove JL, Perez EA, Tomita DK, Rossi G, Cleeland CS. Assessing symptom burden using the M. D. Anderson symptom inventory in patients with chemotherapy-induced anemia: results of a multicenter, open-label study (SURPASS) of patients treated with darbepoetin-alpha at a dose of 200 microg every 2 weeks. Cancer 110(7): 1629-40, 2007.   [Link to PubMed]

ABSTRACT: Patients with cancer who are receiving chemotherapy often experience chemotherapy-induced anemia (CIA), which is associated with symptoms that reduce quality of life. The M. D. Anderson Symptom Inventory (MDASI) is a brief, self-rating assessment scale that measures the severity of core symptoms and symptom interference with function. The current study used the MDASI to prospectively assess the correlation between hemoglobin and self-perceived cancer-related symptoms in a large patient population with CIA who were receiving darbepoetin-alpha at a dose of 200 mug every 2 weeks. METHODS: Eligible patients enrolled in this multicenter, open-label study were age > or =18 years, had a nonmyeloid malignancy, were receiving multicycle chemotherapy, and were anemic (hemoglobin < or = 11 g/dL). Hemoglobin was measured every 2 weeks; the MDASI was administered weekly. For hemoglobin-based endpoints, patients were stratified by baseline hemoglobin (< 10 g/dL or > or =10 g/dL). RESULTS: Of 2422 enrolled patients, 2401 received > or =1 dose of darbepoetin-alpha. Eighty percent of patients (95% confidence limit, 78-82 patients) achieved target hemoglobin levels (> or =11 g/dL) during the study. Patients with a baseline hemoglobin < 10 g/dL had a greater increase in hemoglobin, took longer to achieve the target hemoglobin, and received more red blood cell transfusions than patients with a baseline hemoglobin > or =10 g/dL. The percentage of patients with moderate to severe MDASI scores (> or =5 points) for fatigue, distress, loss of appetite, disturbed sleep, and interference with function was reduced during the study. Improvement in symptom burden was associated with an increase in hemoglobin concentration. CONCLUSIONS: Treatment with darbepoetin-alpha at a dose of 200 mug every 2 weeks is associated with improvement in symptom burden as measured by the MDASI, a simple tool that may improve symptom management for cancer patients with CIA.

Johansson E, Bill-Axelson A, Holmberg L, Onel÷v E, Johansson JE, Steineck G; for the Scandinavian Prostate Cancer Group Study No 4. Time, Symptom Burden, Androgen Deprivation, and Self-Assessed Quality of Life after Radical Prostatectomy or Watchful Waiting: The Randomized Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) Clinical Trial. Eur Urol, e-pub ahead of print, 2008.   [Link to PubMed]

ABSTRACT: Quality-of-life outcomes are important in the choice of treatment strategy for men with localized prostate cancer. OBJECTIVE: To evaluate how follow-up time, number of physical symptoms, and presence of androgen deprivation affected quality of life among men randomized to radical prostatectomy or watchful waiting. DESIGN, SETTING, AND PARTICIPANTS: The study group was composed of all 376 living men included in the Swedish part of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) [1] between January 1, 1989, and February 29, 1996. Quality-of-life data were collected after a mean follow-up time of 4.1 yr. INTERVENTION: All patients were randomly assigned to radical prostatectomy or watchful waiting. Forty-five men were androgen deprived. MEASUREMENTS: Data of specific symptoms, symptom-induced stress, sense of well-being, and self-assessed quality of life were obtained by means of a questionnaire. Psychological symptoms were assessed using seven-point visual digital scales. RESULTS AND LIMITATIONS: In analyses stratified on the basis of the numbers of physical symptoms, anxiety and depressed mood were less common, and sense of well-being and self-assessed quality of life were better throughout in the radical prostatectomy group than in the watchful waiting group. As the number of physical symptoms increased, all psychological variables became worse and more prominent in the watchful waiting group. After a follow-up time of 6-8 yr, a significant decrease in quality of life (p=0.03) was seen in the watchful waiting group. Twenty-four percent of androgen-deprived patients assigned to watchful waiting reported high self-assessed quality of life compared with 60% in the radical prostatectomy group. Eighty-eight percent of patients had clinically detected tumors. CONCLUSIONS: Androgen deprivation negatively affected self-assessed quality of life in men assigned to watchful waiting. The number of physical symptoms was associated with the level of quality of life. Quality of life was lower with longer follow-up time in both groups and was statistically significant in the watchful waiting group (p=0.03).

Kirkova J, Davis MP, Walsh D, Tiernan E, O'Leary N, LeGrand SB, Lagman RL, Russell KM. Cancer symptom assessment instruments: a systematic review. J Clin Oncol 24(9): 1459-73, 2006. Erratum in: J Clin Oncol 24(18): 2973, 2006.   [Link to PubMed]

ABSTRACT: A variety of assessment instruments have been created to identify cancer symptoms. We reviewed systematically cancer symptom assessment instruments published in English. METHODS: A systematic search of the MEDLINE database, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and EMBASE was performed. Non-peer-reviewed articles were identified through BIOSIS. Articles were accessed through the related article links in PubMed and references were searched by hand. Studies were included if the instrument had symptom assessment as the primary outcome. Quality-of-life instruments were excluded. RESULTS: We identified 21 instruments; some had undergone modification or validation. An additional 28 studies examined symptom prevalence and interrelations; many involved symptom checklists. Studies varied in design, patient characteristics, symptoms, and outcome. Meta-analysis was not possible due to heterogeneity in design, study outcomes, and validation. Seventy-six articles and two conference abstracts (derived from MEDLINE, Cochrane, CINAHL, EMBASE, BIOSIS, related articles link in PubMed, and search by hand) met inclusion/exclusion criteria. The electronic search (without related links) yielded only 26% of those articles and conference abstracts that met inclusion criteria. Searches by hand of related articles identified 59% of studies. CONCLUSION: Twenty-one instruments were identified as appropriate for clinical use. The instruments vary in symptom content and extent of psychometric validation. Both comprehensive and shorter instruments have been developed, and some instruments are intended for specific symptom assessment or symptoms related to treatment. There is no ideal instrument, and the wide variety of instruments reflects the different settings for symptom assessment. Additional research is necessary.

Natale RB. Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. Semin Oncol 31(3 Suppl 9): 23-30, 2004.   [Link to PubMed]

ABSTRACT: Patients with advanced non-small cell lung cancer (NSCLC) who fail to respond to cytotoxic chemotherapy or who cannot tolerate chemotherapy have limited treatment options. In addition, patients with advanced NSCLC often experience disease-related symptoms that impact their quality of life. Treatment goals in this setting include palliation of symptoms and improvement in quality of life, in addition to tumor response or disease stabilization and increased survival. ZD1839 (Iressa, gefitinib) is an orally active, small-molecule, epidermal growth factor receptor-tyrosine kinase inhibitor that has shown single-agent efficacy for previously treated advanced NSCLC. In phase I clinical trials, ZD1839 provided relief from symptoms often associated with lung cancer, including fatigue, shortness of breath, and chest pain. The IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 clinical trials evaluated ZD1839 treatment at 250 mg/day and 500 mg/day in patients with advanced NSCLC for objective tumor response and safety, as well as for improvements in NSCLC-related symptoms and health-related quality of life. The majority of patients enrolled in these studies had received multiple prior treatments. Rapid, sustained symptom improvement was documented for many patients receiving ZD1839 at 250 mg/day or 500 mg/day in both IDEAL trials and was positively associated with clinical benefits, such as tumor response and increased survival.

Osoba D, Hsu MA, Copley-Merriman C, Coombs J, Johnson FR, Hauber B, Manjunath R, Pyles A. Stated preferences of patients with cancer for health-related quality-of-life (HRQOL) domains during treatment. Qual Life Res 15(2): 273-83, 2006.   [Link to PubMed]

ABSTRACT: It is postulated that patients with different cancer diagnoses, stages of disease and treatments will exhibit different individual preferences for health-related quality-of-life (HRQOL) functional domains and symptoms. METHODS: A stated-preference (SP) instrument incorporating all functional domains and symptoms of the EORTC Quality of Life Questionnaire (QLQ-C30) was administered to 400 patients with either breast (n = 150); colorectal (n = 150) or non-small cell lung cancer (n = 100) who had previously experienced chemotherapy. The SP survey asked patients to make choices between a series of hypothetical functional/symptom pairs defined by combinations of HRQOL attributes, and depicted by levels of functioning and symptomatology. RESULTS: In the 400 patients, considered as one group, role, cognitive, and social functioning, fatigue, nausea/vomiting, pain, appetite loss, diarrhea and financial difficulties were most important, whereas physical and emotional functioning, dyspnea, constipation and insomnia were less important. The four effects that patients with breast cancer most wished to avoid were nausea and vomiting, pain, and decreases in emotional and role functioning. Patients with colorectal cancer listed diarrhea as the second most important effect to avoid (after nausea/vomiting, but before pain and role functioning), whereas those with non-small cell lung cancer listed dyspnea as the fourth most important effect to avoid. CONCLUSION: These results provide more precise information regarding patient treatment concerns than that provided by the usual measurement of HRQOL. This information can be used by clinical trial investigators to design more precise interventions to improve HRQOL in the domains of greatest importance to patients and by all health care professionals to improve counseling of patients.

Pectasides D, Mylonakis N, Farmakis D, Nikolaou M, Koumpou M, Katselis I, Gaglia A, Kostopoulou V, Karabelis A, Kosmas C. Irinotecan and gemcitabine in patients with advanced non-small cell lung cancer, previously treated with cisplatin-based chemotherapy. A phase II study. Anticancer Res 23(5b): 4205-11, 2003.   [Link to PubMed]

ABSTRACT: To evaluate the efficacy and tolerability of irinotecan plus gemcitabine administered every two weeks in patients with advanced non-small cell lung cancer (NSCLC) previously treated with cisplatin-based chemotherapy. Fifty patients with advanced NSCLC, refractory or resistant to cisplatin derivatives, were treated on an out-patient basis with irinotecan 150 mg/m2 intravenously (i.v.) and gemcitabine 1,800 mg/m2 i.v. on days 1 and 15, every two weeks. The response to treatment was evaluated every two cycles. The patients' median age was 59 years, 44 were men and 92% had a performance status (PS) of 0-1. On an intent-to-treat analysis, 8 (16%) patients, [95% confidence interval (CI), 7.2% to 29.1%] achieved partial response (PR), 19 (38%) stable disease (SD) and 23 (46%) progressive disease (PD). The median time to tumor progression (TTP) was 5.5 months (range, 0.1 to 16.5 months), the median survival time was 8.1 months (range, 0.8 to 22.1 months) and the 1-year survival 36% (95% CI, 22.9% to 50.8%). Clinical benefit response, including improvement of PS, dyspnea, anorexia and fatigue, cessation of hemoptysis and fever and reduction of cough and pain, was observed in 10% to 44% of patients. No patient experienced grade 3/4 anemia. Grade 3/4 neutropenia and thrombocytopenia occurred in 7 (14%) and 8 (16%) patients, respectively. Five (10%) patients were hospitalized due to febrile neutropenia and were successfully treated with broad-spectrum antibiotics and G-CSF support. One (2%) patient experienced grade 4 fatigue and discontinued treatment. Other grade 3/4 adverse events included diarrhea (3 cases, 2 of whom required hospitalization), alopecia (5 cases), asthenia (2 cases) and allergy (2 cases). Eight (16%) patients required a dose reduction. There were no treatment-related deaths. The combination of irinotecan and gemcitabine, administered every two weeks, demonstrated rather modest activity in advanced NSCLC patients who had previously been treated with cisplatin-based chemotherapy. It was well tolerated with mild toxicity and was associated with significant 1-year survival rate and symptomatic benefit response.

Rosenthal DI, Mendoza TR, Chambers MS, Burkett VS, Garden AS, Hessell AC, Lewin JS, Ang KK, Kies MS, Gning I, Wang XS, Cleeland CS. The M. D. Anderson Symptom Inventory-head and neck module, a patient-reported outcome instrument, accurately predicts the severity of radiation-induced mucositis. Int J Radiat Oncol Biol Phys 72(5): 1355-61, 2008.   [Link to PubMed]

ABSTRACT: PURPOSE: To compare the M. D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) module, a symptom burden instrument, with the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) module, a quality-of-life instrument, for the assessment of mucositis in patients with head-and-neck cancer treated with radiotherapy and to identify the most distressing symptoms from the patient's perspective. METHODS AND MATERIALS: Consecutive patients with head-and-neck cancer (n = 134) completed the MDASI-HN and FACT-HN before radiotherapy (time 1) and after 6 weeks of radiotherapy or chemoradiotherapy (time 2). The mean global and subscale scores for each instrument were compared with the objective mucositis scores determined from the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: The global and subscale scores for each instrument showed highly significant changes from time 1 to time 2 and a significant correlation with the objective mucositis scores at time 2. Only the MDASI scores, however, were significant predictors of objective Common Terminology Criteria for Adverse Events mucositis scores on multivariate regression analysis (standardized regression coefficient, 0.355 for the global score and 0.310 for the head-and-neck cancer-specific score). Most of the moderate and severe symptoms associated with mucositis as identified on the MDASI-HN are not present on the FACT-HN. CONCLUSION: Both the MDASI-HN and FACT-HN modules can predict the mucositis scores. However, the MDASI-HN, a symptom burden instrument, was more closely associated with the severity of radiation-induced mucositis than the FACT-HN on multivariate regression analysis. This greater association was most likely related to the inclusion of a greater number of face-valid mucositis-related items in the MDASI-HN compared with the FACT-HN.

Sawicki GS, Sellers DE, Robinson WM. Self-reported physical and psychological symptom burden in adults with cystic fibrosis. J Pain Symptom Manage 35(4):372-80, 2008.   [Link to PubMed]

ABSTRACT: Symptom burden is a key component of health-related quality of life in patients with cystic fibrosis (CF). To examine symptom prevalence and characteristics of adults with CF, we administered the Memorial Symptom Assessment Scale (MSAS), a previously validated measure of symptom burden, to CF patients enrolled in the Project on Adult Care in CF. The mean age of the 303 respondents (response rate 91%) was 32.8 years (range, 19-64); 58% were female, and their mean baseline pulmonary function (FEV(1) % predicted) was 69% (SD 28%). The median number of symptoms reported was 10, and there was no difference in the number of symptoms reported based on age, gender, or FEV(1). The most prevalent symptoms were cough (94%), shortness of breath (77%), and lack of energy (77%). Lack of energy and irritability caused the highest level of distress. MSAS symptom subscales were only moderately correlated with symptom status domains from existing CF health-related quality of life measures. Factor analysis led to the development of three distinct MSAS CF-symptom subscales, each with high internal validity. These findings show that adults with CF have a high symptom burden, particularly with respiratory and psychological symptoms, and that the new MSAS CF-specific subscales are a reliable measure of symptom distress in the CF population.

Williams LA, Wang XS, Cleeland CS, Mobley G, Giralt S. Assessment of symptoms and symptom burden before and after engraftment during allogeneic blood or marrow transplant (BMT) [abstract]. American Society of Hematology 47th Annual Meeting, Atlanta GA. Blood 106(11): 384A, 11/2005; 1323.   [Link to full text]

Additional Suggested Reading

Armstrong TS, Gilbert MR. Net clinical benefit: functional endpoints in brain tumor clinical trials. Curr Oncol Rep 9(1): 60-5, 2007.   [Link to PubMed]

ABSTRACT: Primary brain tumors are associated with a poor prognosis and recognized impact on physical and neurologic function. In an effort to improve poor prognosis, novel therapeutic approaches have been pursued. The impact of therapy on function has not been fully evaluated in the past, with clinical trials focused on traditional survival endpoints. Therapies to date have been associated with incremental improvements in survival that may not have been associated with improvement in functional status. Methods for evaluating this impact include health-related quality of life symptom burden and evaluation of neurocognitive function. Each approach has associated benefits and limitations based on the type of treatment and the potential impact on functional status. An essential component of trial design evaluating functional endpoints is the development of clear hypotheses, specific aims, and predefined metrics of functional change related to each measure. This paper reviews these three approaches and discusses their potential use in evaluation of therapies for patients with primary brain tumors.

Bellizzi KM, Latini DM, Cowan JE, DuChane J, Carroll PR. Fear of recurrence, symptom burden, and health-related quality of life in men with prostate cancer. Urology 72(6): 1269-73, 2008.   [Link to PubMed]

ABSTRACT: To examine the contributions of fear of recurrence and the more commonly examined treatment-related symptoms to the health-related quality of life (HRQOL) of men treated for localized prostate cancer. A total of 730 men with localized disease were identified from the Cancer of the Prostate Strategic Urologic Research Endeavor, a national, prospective study of men with prostate cancer. Pre- to post-treatment changes in fear of recurrence, treatment-specific symptoms and burden, comorbidities at diagnosis, number of new symptoms, and post-treatment HRQOL data were analyzed. Linear regression, adjusted for clinical and demographic characteristics, showed that improved fear of recurrence (P <0.01), higher number of post-treatment symptoms (P <0.01), and improved bowel function (P <0.01) significantly predicted better mental health scores. For physical health, improved urinary bother (P <0.01) and lower number of post-treatment symptoms (P <0.01) were associated with better physical health. Understanding men's fears about cancer recurrence and how these fears influence physical and mental health are important components of providing care to this growing population.

Breen SJ, Baravelli CM, Schofield PE, Jefford M, Yates PM, Aranda SK. Is symptom burden a predictor of anxiety and depression in patients with cancer about to commence chemotherapy? Med J Aust 190(7): S99-S104, 2009.   [Link to PubMed]

ABSTRACT: OBJECTIVES: To assess the prevalence, severity and distress from physical symptoms and the prevalence of anxiety and depression in patients about to undergo chemotherapy for potentially curable cancers; and to explore the presence of symptom clusters and investigate their relationships with anxiety and depression. DESIGN, PARTICIPANTS AND SETTING: Cross-sectional survey of 192 patients with breast or gastrointestinal cancers or lymphoma before first ever chemotherapy treatment with curative intent. MAIN OUTCOME MEASURES: Hospital Anxiety and Depression Scale to assess anxiety and depression and the Chemotherapy Symptom Assessment Scale to measure physical symptom prevalence, severity and distress ("bother"). RESULTS: Prevalence of anxiety was 45% and depression 25%. The most prevalent physical symptoms were pain (48%), feeling unusually tired (45%) and difficulty sleeping (45%). Physical symptoms rated as most severe were pain (28%), difficulty sleeping (26%) and feeling unusually tired (19%). Physical symptoms causing the most distress were pain (39%), constipation (18%) and nausea (16%). Factor analysis of symptom distress scores indicated that five factors explained 36.7% of the variance and included: gastrointestinal (nausea, vomiting, pain), general malaise (tiredness, feeling weak, headaches), emotional (feeling depressed, feeling anxious), nutritional (changes to appetite, weight loss or gain) and general physical (mouth/throat problems, shortness of breath). Regression analysis indicated that symptom distress for the malaise (beta = 1.46; P < 0.001), nutritional (beta = 0.70; P < 0.05) and gastrointestinal (beta = 0.73; P < 0.05) factors were independent predictors of depression. CONCLUSIONS: Before commencing chemotherapy, patients are already experiencing distressing symptoms and have high scores for anxiety and depression, partially explained by physical symptom distress. Patients should be routinely screened for both emotional and physical needs and appropriate interventions should be developed.

Butt Z, Wagner LI, Beaumont JL, Paice JA, Straus JL, Peterman AH, Carro G, Von Roenn JH, Shevrin D, Cella D. Longitudinal screening and management of fatigue, pain, and emotional distress associated with cancer therapy. Support Care Cancer 16(2): 151-9, 2008.   [Link to PubMed]

ABSTRACT: Fatigue, pain, and emotional distress are common symptoms among patients with cancer. We sought to learn about patient perceptions of these symptoms and their treatment. MATERIALS AND METHODS: At a baseline assessment and two monthly follow-up assessments, we asked a diverse sample of patients with solid tumor or lymphoma (N = 99) about their fatigue, pain and distress, their treatment for these symptoms, and their satisfaction with treatment via standardized questionnaires and semistructured interviews. MAIN RESULTS: In this observational study, patients reported fatigue, pain, emotional distress, and general quality of life at expected levels. Across all assessments, at least half of our sample experienced at least some fatigue, pain, or distress. On the whole, patients and providers do communicate about these concerns, and at least 75% of patients found these discussions helpful when they occurred. CONCLUSIONS: Improved symptom identification and communication may optimize the detection of those at risk of morbidity and decreased quality of life because of excess symptom burden.

Chen L, Antras L, Duh MS, Neary M, O'Brien ME. Symptom assessment in relapsed small cell lung cancer: cross-validation of the patient symptom assessment in lung cancer instrument. J Thorac Oncol 3(10): 1137-45, 2008.   [Link to PubMed]

ABSTRACT: Lung cancer symptoms can be burdensome for patients with small cell lung cancer (SCLC). Patient Symptom Assessment in Lung Cancer (PSALC), a self-report scale for assessing SCLC symptom burden, was developed and validated previously using intravenous topotecan clinical trial data. This study cross-validates the PSALC using oral topotecan (OT) trial data. METHODS: Data were analyzed from a randomized, open-label, multicenter trial including 71 patients with relapsed SCLC receiving OT with best supportive care and 70 patients receiving best supportive care alone. PSALC and EQ-5D were administered at baseline and at 3-week intervals. Internal consistency, reliability, construct validity, and responsiveness were evaluated. RESULTS: Only one factor was indicated in factor analysis, hence PSALC total score (PSALC-TS) was used for psychometric analysis. Internal consistency was supported by Cronbach's alpha of 0.78. Construct validity was supported by significant associations of higher PSALC-TS (higher symptom burden) with worse Eastern Cooperative Oncology Group performance status and by correlations of PSALC-TS with EQ-5D utility index and visual analog scale score (all p < 0.001). Reliability was supported by intraclass correlation coefficient of 0.68 (using PSALC-TS before clinical status change) and concordance correlation coefficient of 0.69 (using PSALC-TS at baseline and before first visit). PSALC-TS was responsive to clinical status change from baseline to tumor response (responsiveness statistic = -0.99) and to tumor progression (responsiveness statistic = 0.94). CONCLUSIONS: Consistent with prior psychometric results, this cross-validation study using OT trial data showed acceptable validity, reliability, and responsiveness of the PSALC scale, further supporting its use to measure symptom burden in previously treated SCLC.

Fortner B, Baldwin S, Schwartzberg L, Houts AC. Validation of the Cancer Care Monitor items for physical symptoms and treatment
side effects using expert oncology nurse evaluation. J Pain Symptom Manage 31(3): 207-14, 2006.   [Link to PubMed]

ABSTRACT: The Cancer Care Monitor (CCM) is a tablet computer-based multidimensional measure of symptom burden and quality of life. This study examined individual item validity for 42 items measuring general physical symptoms and treatment side effects. Patients (40 females and 20 males) completed the CCM and a blinded nurse interview. In general, patient self-reported symptoms on the CCM corresponded well to nurse-verified evaluations. There was excellent agreement between the patient-reported CCM items and nurses' ratings on whether the symptom was present or absent and on the severity of a given symptom. Additionally, the results suggested that the majority of items had high sensitivity, specificity, positive predictive value, negative predictive value, and Youden's Index score. Taken together, the results suggest that the CCM can provide an efficient method for collecting information about symptom presence and symptom burden at the point of care.

Fortner BV, Schwartzberg LS, Stepanski EJ, Houts AC. Symptom burden for patients with metastatic colorectal cancer treated with first-line FOLFOX or FOLFIRI with and without bevacizumab in the community setting. Support Cancer Ther 4(4): 233-40, 2007.   [Link to PubMed]

ABSTRACT: FOLFOX (oxaliplatin/leucovorin/5-fluorouracil) and FOLFIRI (irinotecan/leucovorin/5-fluorouracil) with or without bevacizumab have become standard-of-care regimens in first-line treatment of metastatic colorectal cancer. However, there is a paucity of symptom burden information regarding these regimens from the patient perspective in community oncology. Patients and Methods: This retrospective chart review and telephone interview study examined patients with first-line metastatic colorectal cancer from 5 community oncology centers treated with FOLFOX or FOLFIRI with and without bevacizumab. Patientreported outcomes were taken from the Patient Care Monitor 1.0 Revised, a validated tablet computer-based questionnaire that measures symptom burden and several scales of functioning and quality of life. A subset of patients completed structured telephone interviews about the impact of treatment on practical activities and income. Results: Eighty-eight patients with an average age of 62 years were included. Patients completed a median of 8 cycles of treatment. The most common moderate to severe symptom complaint was fatigue. Gastrointestinal symptoms were common but did not cluster in one regimen versus another. Neuropathyrelated symptoms were also common across all regimens except FOLFIRI without bevacizumab. Nausea and neutropenia were common indications for concomitant medications. One third reported work and other activity interference, and care produced outof- pocket expenditures in excess of $1000. Conclusion: Although sample size was small in the FOLFIRI-based regimens, patient reports and chart records suggested that there was not a systematic difference between FOLFOX and FOLFIRI regimens in type of symptom. The addition of bevacizumab did not appear to increase symptom burden.

Gwede CK, Small BJ, Munster PN, Andrykowski MA, Jacobsen PB. Exploring the differential experience of breast cancer treatment-related symptoms: a cluster analytic approach. Support Care Cancer 16(8): 925-33, 2008.   [Link to PubMed]

ABSTRACT: Cancer patients experience multiple concurrent symptoms. This exploratory analysis assessed symptom burden among patients undergoing chemotherapy for breast cancer to identify distinct subgroups of patients who experience differential symptom burden and assessed whether the patient subgroups were associated with deleterious quality of life (QOL) outcomes. MATERIALS AND METHODS: Women (N = 133) with stage I and II breast cancer undergoing adjuvant chemotherapy after primary surgery were evaluated at baseline and at the end of chemotherapy using the Memorial Symptom Assessment Scale (MSAS) and the SF-36 QOL questionnaire. Post treatment MSAS symptoms were included in hierarchical cluster analysis. Two patient subgroups were identified that corresponded to a high-symptom prevalence group and a low-symptom group. RESULTS AND DISCUSSION: No marked, statistically significant differences were found between groups on demographic, symptoms, QOL, or treatment variables at baseline. Patients in the high-symptom cluster were more likely to have stage I disease (p < 0.05). The two groups of patients showed significant differences in end-of-treatment symptoms and QOL scores (p < 0.05). The high-symptom burden group was more likely to report greater symptom prevalence and poorer QOL. CONCLUSIONS: Future research needs to examine why these differences occur despite similarities in treatment and how symptom burden can be reduced for the high-symptom prevalence group.

Kenne Sarenmalm E, OhlÚn J, OdÚn A, Gaston-Johansson F. Experience and predictors of symptoms, distress and health-related quality of life over time in postmenopausal women with recurrent breast cancer. Psychooncology 17(5): 497-505, 2008.   [Link to PubMed]

ABSTRACT: The purpose of this study was to explore the symptom experience and predictors of distress and quality of life over time in women with recurrent breast cancer. Fifty-six women completed questionnaires at the diagnosis of recurrence, 1 month, 3 and 6 months after recurrence. A majority of women reported multiple, concurrent and distressing symptoms such as lack of energy, difficulty sleeping, pain, worry and problems with sexual interest or activity during the recurrent breast cancer trajectory. The highest level of symptom burden and distress and decreased quality of life was reported 3 months after recurrence. Although distress declined and quality of life improved over time, patients reported persistent symptoms. Of the patients at increased risk of vulnerability to distress were women who experienced multiple and concurrent symptoms. Other risk factors were co-morbidity, prehistory of anxiety and depression and progressive or terminal disease. Fatigue, pain and depression explained 68-72% of the variance in distress. Distress explained 44-46% of the variance in quality of life. These findings suggest that symptoms are important contributors to the distress experience, and that distress has a severe impact on quality of life. The care of women with recurrent breast cancer must be based upon the awareness of critical factors that exacerbate the vulnerability to distress throughout the disease trajectory.

Oi-Ling K, Man-Wah DT, Kam-Hung DN. Symptom distress as rated by advanced cancer patients, caregivers and physicians in the last week of life. Palliat Med 19(3): 228-33, 2005.   [Link to PubMed]

ABSTRACT: To study the symptom distress as rated by patients with advanced cancer during their last week of life, and to compare patients' ratings with those perceived by caregivers and physicians. This was a prospective study on all patients admitted to the Hospice Unit of the Caritas Medical Centre with an estimated life expectancy of two weeks or less from May 2002 to September 2002. A questionnaire with a list of 13 symptoms, including pain, dyspnoea, nausea, vomiting, dry mouth, cough, fatigue, cachexia, anorexia, constipation, diarrhoea, insomnia and haemoptysis, was administered to assess the distress. Distress was rated by a verbal rating scale consisting of five grades (grade 0 to grade 4). Patients, caregivers and physicians completed the questionnaire weekly until the patient died. Only the questionnaires completed in the last week of life were included for analysis. Of 82 patients who were recruited in the study, 30 patients were able to complete the questionnaire within the last week of life. Their median age was 69 years and the gender ratio was 1:1. Lung cancer was the most common primary tumour. Fatigue, cachexia and anorexia caused distress of all grades in nearly all 30 patients and caused significant distress of grade 3 and above in two-thirds of patients. Neither the caregivers nor the physicians gave congruent distress scores for these three symptoms (kappa<0.4). Caregivers' ratings agreed well with those of patients for five symptoms (kappa>0.4, P<0.005), including dyspnoea, cough, dry mouth, constipation and insomnia. For physicians, good agreement was found for three symptoms only, including pain, dyspnoea and cough. Moreover, physicians tended to underrate the distress. Fatigue, cachexia and anorexia were the three most distressful symptoms in the last week of life in this group of patients, but caregivers and physicians failed to rate them in agreement with patients.

Opasich C, Gualco A, De Feo S, Barbieri M, Cioffi G, Giardini A, Majani G. Physical and emotional symptom burden of patients with end-stage heart failure: what to measure, how and why. J Cardiovasc Med (Hagerstown) 9(11): 1104-8, 2008.   [Link to PubMed]

ABSTRACT: Much of our understanding about symptom burden near the end of life is based on studies of cancer patients. The aim of this study was to explore physical and emotional symptom experience among end-stage chronic heart failure patients, looking for those symptoms mostly related to their global health status. Forty-six patients with end-stage heart failure compiled the following: Edmonton Symptom Assessment Scale (ESAS) and Kansas City Cardiomyopathy Questionnaire (KCCQ). End-stage heart failure patients have many complaints and poor global health status. The most distressing symptoms reported were general discomfort and tiredness followed by anorexia and dyspnea. The KCCQ summary scores were highly correlated with ESAS (r = -0.78; P = 0.0001). Among the domains explored by the KCCQ, social functioning and self-efficacy showed the lowest correlation coefficients with ESAS (r = -0.50; P = 0.001 and r = -0.31; P = 0.003, respectively); concerninng the physical limitation domain, the symptom score and the quality-of-life domain, the correlation coefficients were as follows: r = -0.71 (P = 0.0001), r = -0.75 (P = 0.0001) and r = -0.74 (P = 0.0001), respectively. In the multiple regression analysis of ESAS and KCCQ scores, general discomfort, depression and anxiety were the symptoms that mostly related with the results in the domains explored by the KCCQ. No independent predictor was found among symptoms and quality of life. General discomfort together with depression and anxiety were the symptoms that were mostly related with the physical limitation domain of global health status, but did not influence the social functioning and the self-efficacy domains. When ESAS is used together with KCCQ, comprehensive and quantitative information on a patient's physical, emotional and social distress is provided.

Rosenthal DI, Mendoza TR, Chambers MS, Asper JA, Gning I, Kies MS, Weber RS, Lewin JS, Garden AS, Ang KK, Wang XS, Cleeland CS. Measuring head and neck cancer symptom burden: the development and validation of the M. D. Anderson Symptom Inventory, head and neck module. Head Neck 29(10): 923-31, 2007.   [Link to PubMed]

ABSTRACT: The aim of this study was to develop and validate a symptom inventory for patients with head and neck cancer and to assess the occurrence and severity of symptoms, the overall symptom burden, and the interference the symptoms cause in daily life. METHODS: Items were generated from a comprehensive literature review, our prior work, and focus groups with head and neck cancer patients, symptom researchers, and a multidisciplinary group of head and neck cancer health care workers. We selected 11 provisional head and neck cancer-specific items for addition to the core M. D. Anderson Symptom Inventory (MDASI), and conducted a cross-sectional validation study among patients with head and neck cancer. RESULTS: Construct validity was established using principal axis factoring with direct oblimin rotation, and tests of concurrent and known-groups validity were conducted. Two items were dropped because of low severity scores and low frequency of complaint, leaving 9 final head and neck cancer-specific items. The coefficient alpha reliabilities were 0.88, 0.83, and 0.92 for the 13 core MDASI items, the 9 head and neck cancer-specific items, and the 6 interference items, respectively. The most prevalent severe symptoms were problems with mucus, mouth/throat sores, tasting food, difficulty with chewing or swallowing, dry mouth, pain, and fatigue. CONCLUSIONS: The M. D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) is a reliable and valid instrument to measure head and neck cancer symptom burden, and the interference symptoms cause in the major aspects of a patient's daily life. A subset of specifically distressing symptoms was identified, many of which are not included in commonly used head and neck cancer quality of life instruments.

Saini T, Murtagh FE, Dupont PJ, McKinnon PM, Hatfield P, Saunders Y. Comparative pilot study of symptoms and quality of life in cancer patients and patients with end stage renal disease. Palliat Med 20(6): 631-6, 2006.   [Link to PubMed]

ABSTRACT: Patients with advanced renal failure are increasingly opting for conservative treatment, yet little is known of their palliative care needs. METHODS: We performed a cross-sectional study, examining symptom burden and quality of life in patients with advanced renal failure (estimated GFR < 17 mL/min; n = 11). A contemporary cohort with terminal malignancy acted as comparators (n = 11). Symptom burden was scored using an extended Memorial Symptom Assessment Scale Short Form questionnaire. Quality of life was assessed using the Euroqol-5Q questionnaire. Demographic and pathological data, performance status and co-morbidity were also recorded. RESULTS: Baseline characteristics were similar for the two groups. Symptom burden (renal 17; cancer 15; P =NS) and quality of life scores (renal 60; cancer 60; P =NS) were remarkably similar. Both groups reported high levels of psychological distress. CONCLUSIONS: Patients with advanced renal failure experience a symptom burden and impairment of quality of life similar to that of patients with terminal malignancy.

Sarna L, Brecht ML. Dimensions of symptom distress in women with advanced lung cancer: a factor analysis. Heart Lung 26(1): 23-30, 1997.   [Link to PubMed]

ABSTRACT: OBJECTIVE: To explore the structure of symptom distress in women with advanced lung cancer. DESIGN: Descriptive. SETTING: Oncology clinics and private offices. SUBJECTS: Sixty women with advanced lung cancer (71% non-small-cell); the majority received palliative treatment (88%). OUTCOME MEASURES: Symptom Distress Scale and Karnofsky Performance Status Scale. METHOD: Factor analytic techniques (principal components, varimax rotation) to investigate combinations of all symptoms in the Symptom Distress Scale and combinations of serious symptoms. RESULTS: Fatigue, disruptions in outlook, frequent pain, and difficulties in sleeping were rated the most distressing and were the most prevalent serious disruptions. A four-factor solution for the symptom distress ratings explained 63.3% of the variance and revealed groups of items representing emotional and physical suffering, gastrointestinal distress, respiratory distress, and malaise. Symptoms with a rating of serious distress were represented by five factors with emotional and physical suffering as separate factors. Symptoms were significantly related to Karnofsky Performance Status. CONCLUSIONS: Multiple symptoms formed distinct congregations of distress. Symptom control requires consideration as a multivariate approach.

Sherr L, Lampe F, Norwood S, Leake-Date H, Fisher M, Edwards S, Arthur G, Anderson J, Zetler S, Johnson M, Harding R. Successive switching of antiretroviral therapy is associated with high psychological and physical burden. Int J STD AIDS 18(10): 700-4, 2007.   [Link to PubMed]

ABSTRACT: HIV treatment and management is constantly evolving. This is as a result of more treatment options coming on stream, tolerance changes and progress in treatment management. HIV infection today, in resource-rich countries and in the presence of combination therapies, is experienced as lifelong treatment punctuated by adjustments to antiretroviral therapy (ART) regimens. People who are diagnosed as HIV positive face a number of challenges and changes around the decision to commence treatment, responses to treatment and changes in treatment regimens. This study was set up to examine the experience of switching treatments and the impact of such switches on psychological parameters. The method used was a cross-sectional questionnaire study. A group of 779 HIV-positive clinic attendees at four clinics in London and South East England participated in the study (86% response rate). They provided detail of their treatment switching experiences as well as demographic details, risk and optimism evaluations, quality of life, symptom burden, adherence and disclosure information. The sample (n=779) comprised 183 (24%) females, 76 (10%) heterosexual males and 497 gay males (66%). Self-reported ethnicity was 67% white, 25% black, 3% Asian and 5% mixed/other ethnicity. One hundred and fifty-five (21%) were ART-na´ve and 624 (79%) were ART experienced; 161 (22%) were receiving their first regimen, 135 (18%) had experienced one regimen switch, 196 (26%) had multiple switches and 99 (13.3%) had stopped treatment. Treatment na´ve, non-switchers and single switchers generally reported lower symptom burden and higher quality of life. Multiple switchers reported higher physical symptom burden and higher global symptom distress scores. Those who had stopped treatment had significantly lower quality-of-life scores than all other groups. Suicidal ideation was high across the groups and nearly a fifth of all respondents had not disclosed their HIV status to anyone. Reported adherence was suboptimal -- 79% of subjects were at least 95% adherent on self-report measures of doses taken over the preceding week. In conclusion, nearly half this clinic sample will have switched treatments. A holistic approach is needed to understand the psychological effects of such switches if lifelong treatment is to be maintained and those on antiretroviral treatment are to attain good quality of life and minimize symptom burden.

Teunissen SC, de Graeff A, Voest EE, de Haes JC. Are anxiety and depressed mood related to physical symptom burden? A study in hospitalized advanced cancer patients. Palliat Med 21(4): 341-6, 2007.   [Link to PubMed]

ABSTRACT: Anxiety and depressed mood are common symptoms in hospitalized advanced cancer patients. It is often presumed that anxiety and depression affect the occurrence and experience of physical symptoms. PURPOSE: To analyse the relation between anxiety, depressed mood and the presence and intensity of physical symptoms. PATIENTS AND METHODS: Anxiety and depressed mood were assessed in a hospitalized advanced cancer population (n = 79) primarily by the Hospital Anxiety and Depression Scale (HADS), and also by a single-item question ;Are you anxious and/or depressed?' and by the Edmonton Symptom Assessment System (ESAS). Physical symptoms were assessed by a semi-structured interview and by the ESAS. RESULTS: Thirty-four percent of the patients reported anxiety, 56% depressed mood and 29% both, as assessed by the HADS. The correlations between HADS, the single-item question and the ESAS were low. No association was found between anxiety or depressed mood and the presence of physical symptoms. Patients who were anxious or depressed had higher ESAS scores for insomnia and drowsiness; scores for pain, anorexia, asthenia, nausea and dyspnea were independent of anxiety and/or depressed mood. CONCLUSION: The relationship between anxiety, depressed mood and the presence and intensity of physical symptoms in hospitalized advanced cancer patients is very limited.

Wang XS, Shi Q, Williams LA, Cleeland CS, Mobley GM, Reuben JM, Lee BN, Giralt SA. Serum interleukin-6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation. Cancer 113(8): 2102-9, 2008.   [Link to PubMed]

ABSTRACT: During the time of lowest white blood cell count (nadir) of allogeneic hematopoietic stem cell transplantation (allo-HSCT), cancer patients suffer from tremendous symptom burden related to therapy that requires intensive patient care. However, the mechanism underlying the development of multiple symptoms has not been established. METHODS: To explore the role of inflammatory cytokines in the development of treatment-related symptoms, we studied dynamic changes in symptoms and in serum concentrations of inflammatory cytokines (interleukin [IL]-6, IL-8, soluble tumor necrosis factor receptor 1 [sTNF-R1], IL-1 receptor antagonist, and IL-12p40p70) from pretherapy throughout the first 30 days of allo-HSCT in 30 patients with acute myelogenous leukemia or myelodysplastic syndrome. We measured multiple symptoms repeatedly using the M. D. Anderson Symptom Inventory. Mixed-effects modeling was used to analyze longitudinal data. RESULTS: In response to conditioning and stem-cell infusion, serum levels of IL-6 and the severity of multiple symptoms increased rapidly and peaked at nadir. From baseline to nadir (approximately Day 8 post-transplantation), increase in IL-6 was significantly associated with worsening of the most severe symptoms (fatigue, poor appetite, pain, drowsiness, dry mouth, and disturbed sleep; P< .01). During the first 30 days after transplantation, increases in IL-6 (P< .001) and sTNF-R1 (P< .05) significantly predicted the increasing severity of these symptoms. CONCLUSIONS: These results suggest that release of systemic inflammatory cytokines, mainly IL-6, corresponds to an increase in treatment-related multiple-symptom burden during the nadir period of allo-HSCT.

Williams LA, Ault P, Wang XS, Cleeland CS, Mendoza TR, Mobley GM, Cortes JE. The symptom burden of chronic myeloid leukemia (CML) [abstract]. American Society of Hematology 50th Annual Meeting and Exposition, San Francisco CA, Dec 6-9, 2008. Blood 112(11), 11/2008; 2408.   [Link to full text]