Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer.

PURPOSE: The aim of this study was to evaluate the safety and tolerability of escalating doses of flavopiridol/ paclitaxel/carboplatin in patients with advanced-stage non-small-cell lung cancer (NSCLC) as well as the pharmacokinetics and activity of flavopiridol when used in combination with paclitaxel/carboplatin. PATIENTS AND METHODS: Eligible patients aged 18-75 years with previously untreated stage IIIB/IV NSCLC received paclitaxel 175 mg/m2 over 3 hours followed by carboplatin area under the curve (AUC) 5 over 1 hour and flavopiridol 30-85 mg/m2 over 24 hours every 3 weeks for 3 cycles. RESULTS: Eighteen patients were enrolled at 4 sites in the United States and received flavopiridol 30 mg/m2 (n = 3), 50 mg/m2 (n = 6), 70 mg/m2 (n = 3), or 85 mg/m2 (n = 6). No dose-limiting toxicities (DLTs) occurred at the 50-mg/m2 or 70-mg/m2 dose levels. Two patients treated at the 85-mg/m2 dose level experienced cardiovascular events that did not meet the criteria for DLT but were fatal in 1 case, prompting no further flavopiridol dose escalations and establishment of 70 mg/m2 as the maximum tolerated dose. The most frequently reported adverse events across all dose levels combined were nausea (89%), asthenia (67%), and diarrhea (56%). Flavopiridol concentrations increased rapidly, reached a plateau, and showed a multiphasic decline after the 24-hour infusion. Of 12 patients evaluable for efficacy, 8 achieved a partial response, and 4 had stable disease. CONCLUSION: Flavopiridol in doses

Prediction of survival for advanced cancer patients by recursive partitioning analysis: role of Karnofsky performance status, quality of life, and symptom distress.

We performed an exploratory recursive partitioning analysis (RPA) in 429 metastatic cancer patients who had completed a Functional Assessment of Cancer Therapy-General (FACT-G) and a Memorial Symptom Assessment Scale-Short Form (MSAS-SF) to define survival prognostic groups. The Cox model analysis also was performed. Both RPA and Cox models included Karnofsky performance status (KPS), age, FACT-G subscales, and MSAS-SF subscales as survival predictors. Of 429 patients, 348 patients (81.1%) had expired at time of analysis. The median age was 67 years (27-89), with median length of survival of 147 days. The RPA identified four distinct survival groups (p < .0001) with three variables: KPS, physical well-being, and physical symptom distress. The most significant split was KPS of 50%, followed by physical well-being score of 25 and physical symptom distress score of 0.6. The median survival time was 29 days for patients with KPS < 50%; 146 days for patients with KPS > or = 50% and physical well-being < 25; 292 days for patients with KPS > 50%, physical well-being > or = 25, and physical symptom distress score > 0.6; and 610 days for patients with KPS > or = 50%, physical well-being > or = 25, and physical symptom distress score < or = 0.6. The Cox model found, in addition to KPS (p < .0001) and physical well-being (p = .08), different predictors: psychological symptom distress (p = .0007), global distress index (p = .02), and age (p < .0001). We concluded that the KPS, quality of life, and symptom distress scores can be combined to define prognostic groups. Such models may be helpful for clinical decision making.

Study of unmet needs in symptomatic veterans with advanced cancer: incidence, independent predictors and unmet needs outcome model.

Veteran patients possess distinctive characteristics such as a higher mortality rate, lower socioeconomic status and poorer health status. We report the prevalence and predictors of unmet needs and examine the association between unmet needs and quality of life (QOL). Two hundred ninety-six male cancer patients who presented with distressing symptom(s) completed the following instruments: a 14-item multidimensional unmet needs questionnaire, Functional Assessment of Cancer Therapy (FACT-G), Memorial Symptom Assessment Scale-Short Form (MSAS-SF) and other validated measurements of function, depression, health and social support. Multiple linear regression models were used to identify independent predictors of each unmet needs domain and of total unmet needs. The relationships between total unmet needs, QOL and multidimensional variables were also explored. The median number of total unmet needs was three, and the most frequently reported unmet needs areas were physical (80.0%), activities of daily living (53.3%), nutrition (46.1%) and emotional (32.5%). Different predictors of each unmet needs domain were identified. Younger age was associated with a higher risk of unmet needs in physical, economic and medical domains. Higher psychological symptom distress was associated with more unmet needs in the emotional/social, economic and medical domains. Physical symptom distress, extent of disease and health measure were only significant in the physical unmet needs domain. The depression, psychological and physical symptom distress scores, confident and affective social support scores, total unmet needs and age independently predicted FACT-G total QOL score (R(2)=63%, P < 0.00001). Patients with higher psychological, physical symptom distress and depression scores, younger age, lower functional status and metastatic disease were more likely to report more unmet needs. The total number of unmet needs was predictive of QOL. The unmet needs and QOL outcomes model was developed but needs further validation.

Study of hormone refractory prostate cancer: hospital care and palliative care resource use at a VA medical center.

Palliative care plays a central role in the management of hormone refractory prostate cancer patients (HRPC), yet little is known about palliative care resource use. Computerized medical records of a retrospective cohort of 89 consecutive HRPC patients seen at a VA medical center from 1994 to 1999 were reviewed for hospital and palliative care resource use in the last 6 months of life. There were 51 Caucasian and 38 African American patients; 95% of patients were admitted to the hospital for symptom management (median of 2 admissions); 98% visited clinics (median 19 visits); 35% went to the emergency room (median of 1 visit); 60% died in the hospital (median length of last hospitalization of 22 days); 49% received palliative radiation; 52% used rehabilitation; 57% received blood transfusion (median 2 units). Thirty-five patients (40%) received hospice care (median stay 35 days). The most frequently prescribed medications included opioids (90%), laxatives (89%), H2-blockers (57%), antiemetics (55%), diuretics (49%), and corticosteroids (43%). The prevalence of patients receiving opioids, as well as the dose of opioids increased over time. There was no difference in categories of palliative care resource use or survival by race. The median survival for all patients was 13 months. The results begin to highlight the extent of care and resources needed by patients with end-stage HRPC. This information will be of importance in planning palliative care for patients with HRPC and in designing future prospective studies.

Longitudinal quality of life in advanced cancer patients: pilot study results from a VA medical cancer center.

To document quality-of-life (QOL), symptom distress and Karnofsky Performance Status (KPS) over time, 67 advanced cancer patients completed the Functional Assessment of Cancer Therapy (FACT-G) and Memorial Symptom Assessment Scale - Short Form (MSAS-SF) from the time of determination of no active anti-cancer treatment to death at 3-6 week intervals. The KPS was determined at each time point. Statistical analyses with mixed effects models were performed to examine the association between changes in QOL, symptom distress and KPS at selected time points in the advanced cancer trajectory. Median survival for the population was 115 days, and a median of 5 interviews was completed per patient. Slow steady changes in KPS, MSAS-SF and FACT-G QOL parameters started 6 months prior to death, with accelerated decline in the last 2 to 3 months and dramatic increase in psychological symptoms during the last month. Different domains changed at different rates at different selected time points. The correlation between changes in KPS, FACT-G parameters and MSAS-SF subscales at enrollment and near death suggests that when patients were stable, changes in KPS correlated significantly with changes in sum FACT-G QOL and physical well being, and with changes in the MSAS-SF subscales. However, when patients were near death, changes in KPS did not correlate with any other changes, and only emotional well being reflected changes in physical and psychological symptom distress. The sequence of changes, and how determinants of symptom distress and QOL change over time, may help clinicians assess the prognosis of terminally ill patients and plan appropriate interventions.

Caregiver unmet needs, burden, and satisfaction in symptomatic advanced cancer patients at a Veterans Affairs (VA) medical center.

OBJECTIVES: Caregiver outcomes among those caring for symptomatic advanced cancer patients at VA Medical Centers have not been well reported. The purposes of this study were (1) to identify the caregiver characteristics and their unmet needs; (2) to examine the association between caregiver unmet needs, caregiver burden, and caregiver satisfaction; and (3) to identify the independent predictors of different caregiver outcomes. METHODS: One hundred caregivers completed three caregiver outcomes instruments: Family Inventory of Needs (FIN), Care Strain Index (CSI), and Family Satisfaction with Advanced Cancer Care (FAMCARE). The caregivers' demographics and their function, depression, health status, and social support status as well as the caregivers' perception of the patients' unmet needs (PPUN) were obtained. Principal component analysis was performed to examine the underlying dimensions of caregiver outcome measures. Pearson correlation and stepwise multivariate regression analyses were performed. RESULTS: The median number of unmet needs was 2 and the median CSI score was 4. Most of unmet needs were related to information needs (needing more information related to home care, finding help with the problems at home, and disease prognosis) and symptom management. The majority of caregivers were satisfied or very satisfied by the care patients received. Spouse caregivers (N = 60, 60%) were significantly older (p = 0.006) with higher unemployment rates (p = 0.001), higher depression scores (p = 0.04), and lower social support scores (p < 0.0001) than nonspouse caregivers (N = 40, 40%). The PPUN predicted caregiver burden and the presence of caregiver unmet needs independently. The presence of caregiver unmet needs was the only independent predictor of caregiver satisfaction. Caregivers with a high PPUN and higher depression score experienced a higher burden. SIGNIFICANCE OF THE RESEARCH: The caregiver outcome model is proposed and needs to be further validated in a new cohort of caregivers.

Knowledge and attitudes toward end-of-life care in veterans with symptomatic metastatic cancer.

OBJECTIVES: The purposes of this study were to study symptomatic metastatic cancer patients' knowledge and attitudes toward end-of-life (EOL) care and to examine how patient-perceived health status affects attitudes toward EOL care and survival. METHODS: From 1999 to 2002, 254 symptomatic metastatic cancer patients at the VA New Jersey Health Care System completed the Vermont Voices on Care of the Dying Questionnaire. Survival status and location of death were obtained. Descriptive statistics and the chi square method were used to assess the differences between African Americans (N=109) and Caucasians (N=135), and between different patient-perceived health status groups. A log-rank test was performed to assess for differences in median survival length between different patient-perceived health-status groups. RESULTS: Veterans' responses to the Vermont questionnaire showed knowledge deficits regarding EOL care. There was wide variation in self-rankings of health status: 45.6% of patients rated their illness as serious and life threatening, 18.9% considered their health problem significant but not life threatening, 2.8% thought they were in good health, and one-third of patients were unsure about their health status. Most patients (86.2%) preferred physician frankness when communicating bad news and 61.8% preferred family involvement in EOL discussions. African American patients were less likely to have completed advance directives (p < 0.0001), to have knowledge about hospice programs (p < 0.00001), and to feel capable of assessing their health situation (p = 0.04). Patient-rated health status affected completion rates of advance directives and survival. SIGNIFICANCE OF THE RESEARCH: These findings demonstrate knowledge deficits and racial differences in attitudes and values toward EOL care in veterans with cancer. The Vermont questionnaire enables patients to state their EOL preferences but may not be detailed enough for clinical applications. Patient-rated health status may be an important explanatory variable for EOL preferences and length of survival.

Clinical relevance of fatigue levels in cancer patients at a Veterans Administration Medical Center.

BACKGROUND: The correlation of fatigue levels with functional interference, symptom distress, and quality of life may help determine clinically significant fatigue levels. METHODS: One hundred eighty consecutive patients with cancer completed the Functional Assessment of Cancer Therapy (FACT) General and Fatigue subscales (FACT-G and FACT-F, respectively), the Memorial Symptom Assessment Scale-Short Form (MSAS-SF), the Depression Scale (Zung), and the Brief Fatigue Inventory (BFI). The Karnofsky performance status (KPS) was determined for each patient. Multivariate analyses of variance were performed to compare fatigue models with different cut-off points to categorize fatigue levels. Cox proportional hazards analysis was performed to assess the association between fatigue severity and survival. RESULTS: Increased fatigue levels were associated with greater symptom distress and decreased quality of life. A model with usual fatigue cut-off points of 0 (no fatigue), 1-2 (mild fatigue), 3-6 (moderate fatigue), and 7-10 (severe fatigue) was optimal in relation to functional interference items (Wilks lambda, 0.36; F = 11.61; P < 0.0001), symptom distress scores (Wilks lambda, 0.52; F = 10.41; P < 0.0001), and quality-of-life scores (Wilks lambda, 0.50; F = 0.50; P < 0.0001). Fatigue severity predicted survival in univariate analysis (chi-square test, 25.42; P < 0.0001). The KPS, stage of disease, and number of symptoms independently predicted survival in patients with fatigue. CONCLUSIONS: Clinically relevant fatigue levels are correlated with symptom and quality-of-life measurements. Patients with a usual fatigue severity > 3 or a worst fatigue severity > 4 on a 1-10 scale may require further assessment.