The Circadian Rhythm of Breakthrough Pain Episodes in Terminally-ill Cancer Patients.

Opioid therapy must be adjusted to the rhythm of a cancer patient's pain to ensure adequate symptom control at the end of life (EOL). However, to-date no study has explored the rhythm of breakthrough pain (BTP) episodes in terminally-ill cancer patients. This prospective longitudinal study was aimed at verifying the existence of a circadian rhythm of BTP episodes in terminally-ill cancer patients. Consecutive adult cancer patients at their EOL treated with long-acting major opioids to control background pain (Numeric Rating Scale ≤ 3/10) were recruited from two Italian palliative care services. Using a personal diary, patients recorded the frequency and onset of BTP episodes and the analgesic rescue therapy taken for each episode over a 7-day period. Rhythms identified in BTP episodes were validated by Cosinor analysis. Overall, 101 patients were enrolled; nine died during the study period. A total of 665 BTP episodes were recorded (average of 7.2 episodes, mean square error 0.8) per patient, with 80.6% of episodes recorded between 8:00 a.m. and 12:00 a.m. At Cosinor analysis, a circadian rhythm of BTP episodes was observed, with a Midline Estimating Statistics of the Rhythm (MESOR) of 1.5, a double amplitude of 1.8, and an acrophase at 12:30 p.m. (p < 0.001). Oral morphine was the most frequent analgesic rescue therapy employed. In terminally-ill cancer patients, BTP episodes follow a circadian rhythm; thus, tailoring the timing of opioid administration to this rhythm may prevent such episodes. This circadian rhythm of BTP episodes in terminally-ill cancer patients should be confirmed in larger samples.

In-Hospital Palliative Care: Should We Need to Reconsider What Role Hospitals Should Have in Patients with End-Stage Disease or Advanced Cancer?

Traditionally, palliative care (PC) systems focused on the needs of advanced cancer patients, but most patients needing PC have end-stage organ diseases. Similarly, PC models focus on the needs of patients in hospices or at home; however, in most cases PC is provided in acute hospitals. Indeed, the symptom burden that these patients experience in the last year of life frequently forces them to seek care in emergency departments. The majority of them are admitted to the hospital and many die. This issue poses important concerns. Despite the efforts of attending healthcare professionals, in-hospital patients do not receive optimal care near the end-of-life. Also, evidence is emerging that delay in identifying patients needing PC have a detrimental impact on their quality of life (QoL). Therefore, there is an urgent need to identify, early and properly, these patients among those hospitalized. Several trials reported the efficacy of PC in improving the QoL in these patients. Each hospital should ensure that a multidisciplinary PC team is available to support attending physicians to achieve the best QoL for both PC patients and their families. This review discusses the role and the impact of in-hospital PC in patients with end-stage disease or advanced cancer.

Effects of serum testosterone levels after 6 months of androgen deprivation therapy on the outcome of patients with prostate cancer.

BACKGROUND: Controversy exists about whether testosterone serum levels at a cutoff point of < 50 ng/dL during luteinizing hormone-releasing hormone analogue (LHRHA) treatment are related to the outcome of patients with prostate cancer. We assessed the relationship between serum testosterone levels after 6 months of LHRHA therapy and disease outcome in a consecutive series of patients with prostate cancer. PATIENTS AND METHODS: Serum testosterone levels were measured prospectively in a cohort of patients given LHRHA for 6 months. End points were time to progression (TTP) and overall survival (OS). RESULTS: The study population was 153 patients: 54 with metastatic disease and 99 with biochemical failure. In multivariate analysis, adjustment for age, baseline serum prostatic specific antigen (PSA) levels, Gleason score, and disease stage, testosterone levels < 50 ng/dL failed to be associated with TTP and OS. A cutoff of < 20 ng/dL was associated with a nonsignificant lower risk of progression (adjusted hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.30-1.15; P = .12) and a significant lower risk of death (adjusted HR, 0.19; 95% CI, 0.04-0.76; P = .02). Only 25 patients attained serum testosterone levels < 20 ng/dL. Using a receiver operating characteristic curve (ROC), we found that a testosterone value of 30 ng/dL offered the best overall sensitivity and specificity for prediction of death. Serum testosterone levels < 30 ng/mL were associated with a significantly lower risk of death (adjusted HR, 0.45; 95% CI, 0.22-0.94; P = .034. CONCLUSIONS: Serum testosterone levels lower than the currently adopted cutoff of 50 ng/dL have a prognostic role in patients with prostate cancer receiving LHRHA and are a promising surrogate parameter of LHRHA efficacy.

Restless legs syndrome as a cause of sleep disturbances in cancer patients receiving chemotherapy.

CONTEXT: Sleep disturbances are frequent in cancer patients during chemotherapy; the contributory role of restless legs syndrome (RLS) in this setting has never been assessed. OBJECTIVES: This study investigated the role of RLS in causing sleep disturbances and altering the quality of life in cancer patients during chemotherapy. METHODS: Evaluation tools included the Pittsburgh Sleep Quality Index (PSQI), the RLS questionnaires, the Functional Assessment of Cancer Therapy-General, and the Hospital Anxiety and Depression Scale for quality of life and anxiety/depression assessment. The study population was 173 cancer patients. The questionnaires were administered during the third chemotherapy cycle. Patients positive for RLS were reassessed six months after the end of chemotherapy. RESULTS: In all, 58.8% of patients reported experiencing sleep disturbances (PSQI≥5) and 20% screened positive for RLS. Neither sleep disturbances nor RLS was associated with anemia, neurotoxic cytotoxic drugs, or benzamide treatment. A direct relationship was found between the PSQI and RLS (P=0.007); both PSQI and RLS scores were significantly associated with poor quality of life (P=0.008 and 0.01, respectively) and anxiety (P=0.0001 and 0.01, respectively). PSQI score also was associated with depression (P=0.0001). RLS persisted in four of the 25 RLS-positive patients reassessed at six months after chemotherapy. RLS recovery was associated with a significant reduction in sleep disturbances and improvement in quality of life. CONCLUSION: RLS can be a contributory factor in sleep disturbances in cancer patients undergoing chemotherapy. Screening for RLS could aid in tailoring a potentially more efficacious treatment of such disturbances.

Psychological distress in men with prostate cancer receiving adjuvant androgen-deprivation therapy.

OBJECTIVES: To compare the occurrence of depression, anxiety, self body image perception, sleep disturbances, and diminished quality of life in prostate cancer patients undergoing adjuvant androgen-deprivation therapy (ADT) as opposed to patients in follow-up alone. METHODS AND MATERIALS: Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, Restless Legs Syndrome Study Group essential diagnostic criteria, Body Image Scale and Functional Assessment of Cancer Therapy Prostate were administered to consecutive prostate cancer patients who underwent radical prostatectomy or radiation therapy and are presently either under adjuvant ADT or included in a follow-up program. RESULTS: Of the 103 patients enrolled, 49 (47.6%) were receiving adjuvant ADT and 54 (52.4%) were not. Compared with the controls, the patients undergoing ADT showed higher levels of depression (P = 0.002), worse self body image perception (P = 0.001), worse quality of life (P = 0.0001) and worse sleep quality (P = 0.04). ADT was significantly associated with depression at multivariate analysis after adjustment for age, stage, Gleason score, as well as demographic and social variables (P = 0.001). Depression scores showed a strong inverse correlation with quality of life scores (P < 0.01). CONCLUSIONS: Adjuvant ADT is associated with depression, worse quality of life, and altered self body image in prostate cancer patients.

Metronomic therapy concepts in the management of adrenocortical carcinoma.

Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.

Prognostic role of vitamin d status and efficacy of vitamin D supplementation in cancer patients: a systematic review.

BACKGROUND: Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D (vitD) supplementation improves outcome remain controversial. DESIGN: Studies evaluating the prognostic role of vitD and vitD receptor (VDR) in cancer patients and trials evaluating the efficacy of vitD administration on patient outcome were identified by a search of MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library through June 2010. RESULTS: Twenty-five studies were included. A negative prognostic role for low serum vitD level was observed in five cohort studies including patients with breast cancer (one study), colon cancer (two studies), prostate cancer (one study), and melanoma (one study), but not in two studies on non-small cell lung cancer and one study on breast cancer. Three of four studies showed that VDR(+) tumors carry a better prognosis than VDR(-) tumors, whereas VDR polymorphisms were significantly associated with prognosis in five of 10 studies. A significant interaction between serum vitD level and VDR polymorphism was observed in one study. Three randomized trials involving advanced prostate cancer patients explored the prognostic role of vitD supplementation. A meta-analysis of these trials showed no effect on survival (pooled risk ratio, 1.07; 95% confidence interval, CI, 0.93-1.23), with strong heterogeneity among studies. CONCLUSION: Hypovitaminosis D seems to be associated with a worse prognosis in some cancers, but vitD supplementation failed to demonstrate a benefit in prostate cancer patients. The currently available evidence is insufficient to recommend vitD supplementation in cancer patients in clinical practice.

Prevalence of complementary/alternative medicines (CAMs) in a cancer population in northern Italy receiving antineoplastic treatments and relationship with quality of life and psychometric features.

PURPOSE: To explore the use of CAM (Complementary/Alternative Medicine) in a population of cancer patients undergoing antineoplastic therapy, and to compare differences in sociodemographics, quality of life, and psychological features between CAM users and non-users. METHODS: The study population was consecutive cancer patients undergoing antineoplastic treatment in three Piedmont cancer centers. Data were collected from anonymous questionnaires investigating CAM use or not, and what type if used, and sociodemographics, and through validated psychometric instruments to assess psychological features: Functional Assessment of Cancer Therapy-General, the Hospital Anxiety and Depression Scale, and the Mini Mental Adjustment to Cancer Scale. RESULTS: Of the 288 evaluable patients, 52 (18.1%) reported using one or more types of CAM; the most often cited were herbs, special diets and body-based practices, such as plantar reflexology, chiropractic application, and massage. On quality of life assessment, CAM users scored lower than CAM non-users for physical wellbeing (P = 0.006); no significant differences emerged for anxiety and depression and coping styles. CONCLUSIONS: CAM use is less prevalent in northern Italy than in most other European countries. CAM users were found to have a lower quality of life than CAM non-users.

Restless legs syndrome and its relationship with anxiety, depression, and quality of life in cancer patients undergoing chemotherapy.

OBJECTIVE: Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by uncomfortable and unpleasant sensations in the legs that are relieved by movement. This study evaluated the prevalence of RLS in a consecutive series of cancer patients during chemotherapy and examined the relationship between presence of RLS and quality of life, anxiety, and depressive symptoms in these patients. METHODS: RLS was assessed according to the International RLS Study Group essential diagnostic criteria in two stages: a screening questionnaire first, followed by a sleep specialist-conducted structured diagnostic interview. The following questionnaires were administered: Functional Assessment of Cancer Therapy-General (FACT-G) for Quality-of-life (QoL) assessment; Hospital Anxiety and Depression Scale (HADS) to evaluate the levels of anxiety and depression; and Mini Mental Adjustment to Cancer Scale (Mini-MAC) to assess coping styles. RESULTS: A total of 257 patients were evaluated. Among them 56 were identified by the screening questionnaire to meet the criteria for RLS and 47 of whom were confirmed as affected by RLS after a structured interview, rendering a prevalence rate of 18.3%. RLS was significantly more frequent in women than men (23.7 vs. 11.8%; P = 0.01), and in patients receiving antineoplastic therapies for more than 3 months than their counterpart (21.8 vs. 10.8%; P = 0.03). Compared with those without RLS, patients with RLS had higher levels of anxiety (P = 0.0009) and depression (P = 0.001) and lower quality of life (P = 0.006). Sex-chemotherapy-duration-adjusted odds ratios of anxiety and physical well-being associated with RLS were 1.1 (95% CI 1.00-1.19; P = 0.04) and 0.7 (95% CI 0.43-1.01; P = 0.04), respectively. CONCLUSIONS: The prevalence of RLS in cancer patients undergoing chemotherapy is 18.3%, about double of that expected in the general population. The occurrence of RLS is much more frequent in female patients and with longer-term chemotherapy. Cancer patients afflicted by RLS have significantly higher levels of anxiety and depression, and poorer quality of life especially in the physical well-being dimension. Recognition and treatment of RLS in cancer patients is an important target in clinical management and may improve quality of life and overall health outcomes in these patients.

Chromogranin A expression in patients with hormone naïve prostate cancer predicts the development of hormone refractory disease.

PURPOSE: We assessed chromogranin A as a tissue biomarker in prostate needle biopsies or as a plasma biomarker, a risk factor for hormone refractory prostate cancer. MATERIALS AND METHODS: A total of 211 patients with newly diagnosed prostate cancer treated with luteinizing hormone releasing hormone analogues constituted the study cohort. Univariate and multivariate Cox regression analyses were used to assess the predictive role of tissue and plasma chromogranin A expression. RESULTS: Chromogranin A expression in less than 30% or in 30% or more tumor cells was significantly associated with a shorter time to hormone refractory disease on univariate analysis (HR 2.0, 95% CI 1.3-3.1 and HR 6.0, 95% CI 2.7-12.9), or on multivariate analysis after adjusting for Gleason score, serum prostate specific antigen and disease stage (HR 1.7, 95% CI 1.0-2.8 and HR 3.9, 95% CI 1.7-9.0), respectively. Plasma chromogranin A measured at baseline (HR 3.0, 95% CI 1.8-5.2), and after 1 year (HR 5.8, 95% CI 3.1-10.1) and 2 years (HR 3.5, 95% CI 1.6-7.6), was predictive of hormone refractory risk confirming the tissue results. Plasma as well as tissue chromogranin A expression negatively correlated with overall survival. CONCLUSIONS: Chromogranin A expression in prostate cancer biopsies is an independent predictive factor of hormone refractory disease in patients with newly diagnosed prostate cancer on early androgen deprivation therapy. Plasma chromogranin A is also a reliable predictive marker and the predictive significance is maintained over time. These results deserve validation in another data set.

Pharmacoeconomic comparison between chronochemotherapy and FOLFOX regimen in the treatment of patients with metastatic colorectal cancer: a cost-minimization study.

AIMS AND BACKGROUND: The addition of oxaliplatin to the widely employed De Gramont schedule (FOLFOX regimen) in patients with metastatic colorectal cancer improved their outcome with a moderate toxicity pattern. The adaptation of the delivery rate of 5-fluorouracil, leucovorin and oxaliplatin to circadian rhythms (chronotherapy) resulted in a very high drug tolerability with clinical results at least comparable to those achieved with the FOLFOX regimen. However, chronomodulated infusion seemed to be more expensive, requiring dedicated electronic pumps and several disposable materials. The present study aimed to compare the direct costs of the two regimens and to determine whether chronotherapy was effectively more expensive than the FOLFOX regimen. STUDY DESIGN: The direct costs of drug delivery devices derived from various publicly available sources and of toxicity management as extrapolated from two published studies considering comparable patient subsets were added and compared. RESULTS: Pump, central venous system and disposable materials for a single chronotherapy cycle were Euro 193 or Euro 212 according to whether the pumps were bought or rented, compared to Euro 58 for the FOLFOX regimen. Toxicity management costs were Euro 144 vs Euro 288 for the two schemes, respectively. Globally, a single course of chronotherapy cost Euro 337 or Euro 356, whereas a single FOLFOX cycle cost Euro 346. CONCLUSIONS: Direct costs for a single chronotherapy cycle appeared to be comparable to a single course of the FOLFOX regimen. In fact, the major material cost of chronochemotherapy devices was balanced by a better tolerability profile. The overall improvement in quality of life with chronochemotherapy affecting indirect costs, such as reduction of work, and intangible costs is worthy of further pharmacoeconomic attention.

Cytokine detection in HIV-1/HHV-8 co-infected subjects.

In a previous work we have evaluated some immunologic and haematologic parameters of HIV-1 positive subjects co-infected with HHV-8. A worsening of these values were generally described in these patients as compared with those HIV-1 positive, but negative for HHV-8. Now we have studied the influence of HHV-8 co-infection of HIV-1 positive subjects on the production of some cytokines to make clear the question of its role in the immuno-deregulation of the above-mentioned subjects. In particular we have analysed serum levels of IL-4 and IL-10, Th2 type T cells cytokines, IFN-gamma, an indirect marker of Th1 cells activation and IL-18, a cytokine produced by monocytic-macrophagic cells, which is able to induce IFN-gamma production and Th1 T lymphocytes activation. No significant differences were found as regards the IFN-gamma serum levels (92.1 +/- 24.3 pg ml(-1) in the case of HIV-1 positive/HHV-8 negative subjects and 96.0 +/- 17.4 pg ml(-1) in those HIV-1 positive/HHV-8 positive). In healthy subjects the mean level of this cytokine was 17.6 +/- 5.2 pg ml(-1) (significant difference with both the former values at p < 0.001). Moreover IL-4 and IL-10, which were undetectable in healthy individuals, showed the following values in HIV-1 positive/HHV-8 negative subjects: 31.9 +/- 2.7 pg ml(-1) and 119.8 +/- 85.1 pg ml(-1) respectively and in HIV-1 positive/HHV-8 positive subjects: 30.4 +/- 4.8 pg ml(-1) and 69.4 +/- 65.3 pg ml(-1) (not significant differences). In contrast IL-18 reached a mean level of 1001.2 +/- 360.5 pg ml(-1) in HIV-1 positive/HHV-8 negative subjects, but showed a significant reduction in HIV-1 positive/HHV-8 positive subjects (737.6 +/- 284.3 pg ml(-1) --> p < 0.05) and presented very low levels in healthy individuals (21.3 +/- 30.3 pg ml(-1)). Moreover a significant correlation (-0.984 --> p < 0.001) was noticed between IL-18 reduction in HIV-1 positive subjects co-infected with HHV-8 and the degree of positivity of HHV-8. These data suggest that HHV-8 co-infection has no influence on the switch Th1 --> Th2 in HIV-1 positive subjects, but is able to reduce IL-18 production, useful for Th1 subset restoration.