Adverse Drug Reactions and Drug Interactions as Causes of Hospital Admission in Oncology

Context. Although several studies have evaluated the frequency of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) in general medicine, few studies have looked at the epidemiology of adverse drug events (ADEs) in oncology. Objectives. We sought to investigate how many hospital admissions in oncology are related to a DDI or an ADR. Methods. All cancer patients admitted to an oncology ward during an eight-month period had their charts retrospectively evaluated for reasons of hospitalization, using a 4-point scale (definitely, probably, possibly, or unlikely associated) to classify admissions by their probability of being associated with either a DDI or an ADR. Results. From September 2007 to May 2008, there were 550 hospital admissions and 458 were eligible. Among unplanned admissions (n = 298), 39 (13.0%, 95% confidence interval [CI] 9.4%-17.4%) were considered to be associated with an ADE, 33 (11.0%, 95% CI 7.7%-15.2%) with an ADR, and six (2.0%, 95% CI 0.7%-4.3%) with a DDI. The most common DDIs involved warfarin, captopril, and anti-inflammatory agents, and the most frequent ADR was neutropenic fever post-chemotherapy. Most patients were discharged completely recovered, but two patients died. Conclusion. Approximately one in 10 unplanned hospitalizations of cancer patients is associated with an ADE. Prospective and population-based studies are warranted to evaluate their magnitude in oncology. J Pain Symptom Manage 2011;42:342-353. (C) 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Cisplatin and Etoposide in Childhood Germ Cell Tumor: Brazilian Pediatric Oncology Society Protocol GCT-91

Purpose In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol. Patients and Methods From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor. Results Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P = .032), and abnormal lactate dehydrogenase value at diagnosis (P = .001). Conclusion The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.

Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

Polyunsaturated fatty acids (PUFAs) are known to inhibit cell proliferation of many tumour types both in vitro and in vivo. Their capacity to interfere with cell proliferation has been linked to their induction of reactive oxygen species (ROS) production in tumour tissues leading to cell death through apoptosis. However, the exact mechanisms of action of PUFAs are far from clear, particularly in brain tumours. The loss of bound hexokinase from the mitochondrial voltage-dependent anion channel has been directly related to loss of protection from apoptosis, and PUFAs can induce this loss of bound hexokinase in tumour cells. Tumour cells overexpressing Akt activity, including gliomas, are sensitised to ROS damage by the Akt protein and may be good targets for chemotherapeutic agents, which produce ROS, such as PUFAs. Cardiolipin peroxidation may be an initial event in the release of cytochrome c from the mitochondria, and enriching cardiolipin with PUFA acyl chains may lead to increased peroxidation and therefore an increase in apoptosis. A better understanding of the metabolism of fatty acids and eicosanoids in primary brain tumours such as gliomas and their influence on energy balance will be fundamental to the possible targeting of mitochondria in tumour treatment.

A for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study

Purpose: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. Patients and methods: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Results: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P = 0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P = 0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P = 0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P < 0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P < 0.05), except for the mucous membrane where late effects were similar in both arms. Conclusions: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Early toxicity from preoperative radiotherapy with continuous infusion 5-fluorouracil for resectable adenocarcinoma of the rectum: A phase II trial for the Trans-Tasman Radiation Oncology Group

Purpose: To assess the toxicity and the efficacy of preoperative radiotherapy with continuous infusion 5-fluorouracil (5-FU) for locally advanced adenocarcinoma of the rectum. Methods and Materials: Eligible patients had newly diagnosed localized adenocarcinoma of the rectum within 12 cm of the anal verge, Stage T3-4, and were suitable for curative resection. Eighty-two patients were treated with radiotherapy-50.4 Gy in 28 fractions in 5.6 weeks, given concurrently with continuous infusion 5-FU, using either 96-h/week infusion at 300 mg/m(2)/day or 7-days/week infusion at 225 mg/m(2)/day. Results: The median age was 59 years (range, 27-87), and 67% of patients were male. Pretreatment stages of the rectal cancer were T3, 89% and resectable T4, 11%, with endorectal ultrasound confirmation in 67% of patients. Grade 3 acute toxicity occurred in 5 of 82 patients (6%; 95% confidence interval [CI], 2-14%). Types of surgical resection were anterior resection, 61%; abdominoperineal resection, 35%; and other procedures, 4%. There was no operative mortality. Anastomotic leakage after low anterior resection occurred in 3 of 50 patients (6%; 95% CI, 1-17%). The pathologic complete response rate was 16% (95% CI, 9-26%). Pathologic Stages T2 or less occurred in 51%. Conclusion: Preoperative radiotherapy with continuous infusion 5-FU for locally advanced rectal cancer is a safe regimen, with a significant downstaging effect. It does not seem to lead to a significant increase in serious surgical complications. (C) 2001 Elsevier Science Inc.

Acute symptoms, not rectally administered sucralfate, predict for late radiation proctitis: Longer term follow-up of a phase III trial - trans-Tasman radiation oncology group

Image : To assess the potential for sucralfate administered rectally to reduce the risk of late rectal morbidity in patients undergoing nonconformal radiotherapy (RT) for carcinoma of the prostate and to study the variables potentially contributing to late rectal morbidity and particularly to explore the relationship between acute and late toxicity. Image : Eighty-six patients with localized prostate carcinoma were randomized in a double-blind, placebo-controlled study to a daily enema of 3 g of sucralfate in a 15-mL suspension or the same suspension without sucralfate. The enema began the first day of RT and was continued for 2 weeks after treatment completion. The primary end point of the study was acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) toxicity; however, the patients were followed for an additional 5 years on a 6-month basis. The evaluation included late RTOG/EORTC toxicity and a patient self-assessment questionnaire. Image : With a median follow-up of 5 years, the Kaplan-Meier probability of late Grade 2 RTOG/EORTC toxicity was 12% (95% confidence interval [CI] 2–22%) for placebo and 5% (95% CI 0–12%) for sucralfate (p = 0.26). The probability of late rectal bleeding was 59% (95% CI 45–73%) for placebo and 54% (95% CI 40–68%) for sucralfate. No statistically significant difference was found between the treatment arms for the peak incidence of any of the other patient self-assessment variables. Cox proportional hazards modeling indicated acute RTOG/EORTC toxicity of Grade 2 or greater was associated with a hazard ratio of 2.74 (95% CI 1.31–5.73) for the development of late toxicity of Grade 1 or greater. Substituting the patient self-assessment variables for acute RTOG/EORTC toxicity revealed that rectal pain of a moderate or severe grade during RT was the best predictor of the subsequent development of late toxicity, with a hazard ratio of 3.44 (95% CI 1.68–7). Image : The results of this study do not support the use of sucralfate administered rectally as a method for reducing the late toxicity of nonconformal RT for prostate cancer. There appears to be an association between the development of acute and subsequent late toxicity, although the nature of this association remains to be determined

Keratinocyte Growth factor (KGF) in hematology and oncology

Keratinocyte Growth factor (KGF) is an epithelial cell growth factor of the fibroblast growth factor family and is produced by fibroblasts and microvascular endothelium in response to proinflammatory cytokines and steroid hormones. KGF is a heparin binding growth factor that exerts effects on epithelial cells in a paracrine fashion through interaction with KGF receptors. Preclinical data has demonstrated that KGF can prevent lung and gastrointestinal toxicity following chemotherapy and radiation and preliminary clinical data in the later setting supports these findings. In the experimental allogeneic bone marrow transplant scenario KGF has shown significant ability to prevent graft-versus-host disease by maintaining gastrointestinal tract integrity and acting as a cytokine shield to prevent subsequent proinflammatory cytokine generation. Within this setting KGF has also shown an ability to prevent experimental idiopathic pneumonia syndrome by stimulating production of surfactant protein A, promoting alveolar epithelialization and attenuating immune-mediated injury. Perhaps most unexpectantly, KGF appears able to maintain thymic function during allogeneic stern cell transplantation and so promote T cell engraftment and reconstitution. These data suggest that KGF will find a therapeutic role in the prevention of epithelial toxicity following intensive chemotherapy and radiotherapy protocols and in allogeneic stem cell transplantation.

Psychosocial Morbidity and its Correlates in Cancer Patients of the Mediterranean Area: Findings from the Southern European Psycho-Oncology Study

BACKGROUND: A few and partial data are available on psychosocial morbidity among cancer patients in Mediterranean countries. As a part of a more general investigation (Southern European Psycho-Oncology Study-SEPOS), the rate of psychosocial morbidity and its correlation with clinical and cultural variables were examined in cancer patients in Italy, Portugal and Spain. METHODS: A convenience sample of cancer outpatients with good performance status and no cognitive impairment were approached. The Hospital Anxiety-Depression scale (HAD-S), the Mini-Mental Adjustment to Cancer scale (Mini-MAC), and the Cancer Worries Inventory (CWI) were used to measure psychological morbidity, coping strategies and concerns about illness. RESULTS: Of 277 patients, 34% had pathological scores ("borderline cases" plus "true cases") on HAD-S Anxiety and 24.9% on HAD-S Depression. Total psychiatric "caseness" was 28.5% and 16.6%, according to different HAD cut-offs (14 and 19, respectively). Significant relationships of HAD-S Anxiety, HAD-S Depression, HAD-S Total score, with Mini-MAC Hopeless and Anxious Preoccupation, and CWI score were found. No differences emerged between countries on psychosocial morbidity, while some differences emerged between the countries on coping mechanisms. Furthermore, Fatalism, Avoidance and marginally Hopeless were higher compared to studies carried out in English-speaking countries. LIMITATIONS: The relatively small sample size and the good performance status prevent us to generalize data on patients with different cancer sites and advanced phase of illness. CONCLUSIONS: One-third of the patients presented anxiety and depressive morbidity, with significant differences in characteristics of coping in Mediterranean countries in comparison with English-speaking countries.

Do Spirituality and Faith Make a Difference? Report from the Southern European Psycho-Oncology Study Group

OBJECTIVE: In the last decade, some attention has been given to spirituality and faith and their role in cancer patients' coping. Few data are available about spirituality among cancer patients in Southern European countries, which have a big tradition of spirituality, namely, the Catholic religion. As part of a more general investigation (Southern European Psycho-Oncology Study--SEPOS), the aim of this study was to examine the effect of spirituality in molding psychosocial implications in Southern European cancer patients. METHOD: A convenience sample of 323 outpatients with a diagnosis of cancer between 6 to 18 months, a good performance status (Karnofsky Performance Status > 80), and no cognitive deficits or central nervous system (CNS) involvement by disease were approached in university and affiliated cancer centers in Italy, Spain, Portugal, and Switzerland (Italian speaking area). Each patient was evaluated for spirituality (Visual Analog Scale 0-10), psychological morbidity (Hospital Anxiety and Depression Scale--HADS), coping strategies (Mini-Mental Adjustment to Cancer--Mini-MAC) and concerns about illness (Cancer Worries Inventory--CWI). RESULTS. The majority of patients (79.3%) referred to being supported by their spirituality/faith throughout their illness. Significant differences were found between the spirituality and non-spirituality groups (p ≤ 0.01) in terms of education, coping styles, and psychological morbidity. Spirituality was significantly correlated with fighting spirit (r = -0.27), fatalism (r = 0.50), and avoidance (r = 0.23) coping styles and negatively correlated with education (r = -0.25), depression (r = -0.22) and HAD total (r = -0.17). SIGNIFICANCE OF RESULTS: Spirituality is frequent among Southern European cancer patients with lower education and seems to play some protective role towards psychological morbidity, specifically depression. Further studies should examine this trend in Southern European cancer patients.

Hopelessness and Related Variables among Cancer Patients in the Southern European Psycho-Oncology Study (SEPOS).

BACKGROUND: Although hopelessness has been studied in cancer, no data are available in non-English-speaking countries. OBJECTIVE: The authors sought to amass data from Southern European countries (Italy, Portugal, Spain, and Switzerland) in order to fill this void. METHOD: A group of 312 cancer patients completed the Mini-MAC Hopelessness subscale, the Hospital Anxiety and Depression Scale (HADS), the Cancer Worry Inventory (CWI), and a six-item Visual Analog scale (VAS) to measure intensity of physical symptoms, general well-being, difficulty in coping with cancer, intensity of social support from close relationships, leisure activity, and support from religious beliefs. RESULTS: Regression analysis indicated that HADS-Depression, VAS Maladaptive Coping and Well-Being, and the CWI explained 42% of the variance. CONCLUSION: Hopelessness in cancer patients seems not exclusively to correspond to depression, but is related to various other psychosocial factors, such as maladaptive coping, as well.