RESUMEN
PURPOSE: This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. METHODS: Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m² in the first cohort. For subsequent cohorts, dose was increased by 20 g/m² until a maximum tolerated dose was found. RESULTS: Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m², respectively). C(max) and AUC values increased proportionately with dose between 0 and 70 g/m², but appeared to reach maximal values at 70 g/m² (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m² maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response. CONCLUSIONS: Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient's blood and was well tolerated. The recommended dose for future studies is 70-80 g/m².
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/efectos adversos , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Ácido Ascórbico/efectos adversos , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/uso terapéutico , Estudios de Cohortes , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/sangre , Neoplasias/metabolismo , Neoplasias/patología , Calidad de VidaRESUMEN
BACKGROUND: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer. METHODS: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months). RESULTS: We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain. CONCLUSIONS: These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better.
Asunto(s)
Ritmo Circadiano , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/psicología , Calidad de Vida , Actigrafía , Adulto , Anciano , Anciano de 80 o más Años , Ritmo Circadiano/fisiología , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Calidad de Vida/psicología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self-reported subjective sleep quality among patients with advanced lung cancer. METHODS: This cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patient's sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. RESULTS: The mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients. CONCLUSIONS: The correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality.
RESUMEN
BACKGROUND: Preclinical studies demonstrated that small chain RNA fragments accelerate the recovery of platelets numbers in animals exposed to high doses of chemotherapeutic drugs. There is anecdotal data supporting the same application in humans. The Phase I clinical trial described here was designed to investigate the relationship between the administration of small chain RNA fragments and the recovery in platelets following Chemotherapy-Induced Thrombocytopenia (CIT). METHODS: Cancer patients with solid tumors that experienced post chemotherapy thrombocytopenia with a nadir of < = 80,000 platelets/ml were eligible for this clinical trial. There were no exclusions based on ECOG status, tumor type, tumor burden or chemotherapeutic agents. Patients received a unique preparation of RNA derived from either E. coli or yeast. Ten patients per group received 20, 40, or 60 mg as a starting dose. Subjects self-administered RNA fragments sublingually on an every other day schedule while undergoing chemotherapy. The dose was escalated in 20 mg increments to a maximum dose of 80 mg if the nadir was < 80,000 platelets/ml at the start of the next cycle. Subjects were treated for three cycles of chemotherapy with the maximum effective dose of RNA fragments. Subjects continued on planned chemotherapy as indicated by tumor burden without RNA fragment support after the third cycle. Subjects kept a diary indicating RNA fragment and magnesium administration, and any experienced side effects. RESULTS: Patients receiving E. coli RNA fragments demonstrated a more rapid recovery in platelet count and higher nadir platelet count. None of the patients receiving the E. coli RNA fragments required a chemotherapy dose reduction due to thrombocytopenia. The optimal dose for minimizing CIT was 80 mg. Conversely, subjects receiving yeast RNA fragments with dose escalation to 80 mg required a chemotherapy dose reduction per American Society of Clinical Oncology guidelines for grade 3 and 4 thrombocytopenia. CONCLUSIONS: Patients receiving myelosuppressive chemotherapy experienced an improvement in the platelet nadir and shorter recovery time when receiving concurrent E coli RNA fragments, when compared to patients who received yeast RNA fragments. These data indicate that 60 and 80 mg doses of E. coli RNA accelerated platelet recovery. Further clinical investigations are planned to quantify the clinical benefits of the E. coli RNA at the 80 mg dose in patients with chemotherapy induced thrombocytopenia. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01163110.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , ARN/uso terapéutico , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Adulto , Anciano , Plaquetas/efectos de los fármacos , Dacarbazina/efectos adversos , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Escherichia coli/metabolismo , Femenino , Humanos , Ifosfamida/efectos adversos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVES: We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep-activity patterns in inpatients and outpatients with advanced non-small cell lung cancer (NSCLC) and determined whether cancer-associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities. METHODS: Equal numbers of inpatients (n=42) and outpatients (n=42) with advanced NSCLC were studied. Baseline depression and anxiety, assessed by the Hospital Anxiety and Depression Scale (HADS), and actigraphy were recorded before chemotherapy initiation. The effects of the presence and severity of chronic obstructive pulmonary disease (COPD) on depression, anxiety, and actigraphy were assessed only among the 42 outpatients. RESULTS: Anxiety occurred in 40% and depression in 25% of these lung cancer patients, equally among inpatients and outpatients. All patients suffer extremely disturbed daily sleep-activity cycles but each patient also maintains some degree of circadian organization. Outpatients maintain more robust daily activity patterns and longer, more consolidated nighttime sleep compared with inpatients. The more disrupted the daily sleep-activity rhythm, the worse the depression and/or anxiety scores for outpatients. These relationships are obscured among inpatients. COPD has no independent measurable effects on the daily organization of sleep-activity, depression, or anxiety. CONCLUSIONS: Lung cancer patients whose diurnal activity is disturbed by prolonged and frequent sedentary episodes and whose sleep is disturbed by frequent and prolonged waking are most anxious and depressed. These findings and relationships are masked by hospitalization. Since diurnal exercise improves both sleep and mood, it is reasonable to test whether enhancing daytime activity and nighttime sleep can diminish cancer-associated depression.