Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy

PURPOSE: To compare acute and late gastrointestinal (GI) and genitourinary (GU) side effects in prostate cancer patients randomized to receive 68 Gy or 78 Gy. METHODS AND MATERIALS: Between June 1997 and February 2003, 669 prostate cancer patients were randomized between radiotherapy with a dose of 68 Gy and 78 Gy, in 2 Gy per fraction and using three-dimensional conformal radiotherapy. All T stages with prostate-specific antigen (PSA) <60 ng/mL were included, except any T1a and well-differentiated T1b-c tumors with PSA < or =4 ng/mL. Stratification was done for four dose-volume groups (according to the risk of seminal vesicles [SV] involvement), age, hormonal treatment (HT), and hospital. The clinical target volume (CTV) consisted of the prostate with or without the SV, depending on the estimated risk of SV invasion. The CTV-planning target volume (PTV) margin was 1 cm for the first 68 Gy and was reduced to 0.5 cm (0 cm toward the rectum) for the last 10 Gy in the 78 Gy arm. Four Dutch hospitals participated in this Phase III trial. Evaluation of acute and late toxicity was based on 658 and 643 patients, respectively. For acute toxicity (<120 days), the Radiation Therapy Oncology Group (RTOG) scoring system was used and the maximum score was reported. Late toxicity (>120 days) was scored according to the slightly adapted RTOG/European Organization for Research and Treatment of Cancer (EORTC) criteria. RESULTS: The median follow-up time was 31 months. For acute toxicity no significant differences were seen between the two randomization arms. GI toxicity Grade 2 and 3 was reported as the maximum acute toxicity in 44% and 5% of the patients, respectively. For acute GU toxicity, these figures were 41% and 13%. No significant differences between both randomization arms were seen for late GI and GU toxicity, except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05). The 3-year cumulative risk of late RTOG/EORTC GI toxicity grade > or =2 was 23.2% for 68 Gy, and 26.5% for 78 Gy (p = 0.3). The 3-year risks of late RTOG/EORTC GU toxicity grade > or =2 were 28.5% and 30.2% for 68 Gy and 78 Gy, respectively (p = 0.3). Factors related to acute GI toxicity were HT (p < 0.001), a higher dose-volume group (p = 0.01), and pretreatment GI symptoms (p = 0.04). For acute GU toxicity, prognostic factors were: pretreatment GU symptoms (p < 0.001), HT (p = 0.003), and prior transurethral resection of the prostate (TURP) (p = 0.02). A history of abdominal surgery (p < 0.001) and pretreatment GI symptoms (p = 0.001) were associated with a higher incidence of late GI grade > or =2 toxicity, whereas HT (p < 0.001), pretreatment GU symptoms (p < 0.001), and prior TURP (p = 0.006) were prognostic factors for late GU grade > or =2. CONCLUSIONS: Raising the dose to the prostate from 68 Gy to 78 Gy resulted in higher incidences of acute and late GI and GU toxicity, but these differences were not significant, except for late rectal bleeding requiring treatment and late nocturia. Other factors than the studied dose levels appeared to be important in predicting toxicity after radiotherapy, especially previous surgical interventions (abdominal surgery or TURP), hormonal therapy, and the presence of pretreatment symptoms.     

In defense of the oral cavity: the protective role of the salivary secretions

Saliva performs important protective roles in the oral cavity. Debate in the 1970s over the "specific" or "non-specific" action of salivary components has given way to current attempts to identify the full complement of all proteins in saliva that are now considered to act in concert. At the same time, more fundamental protective qualities of saliva water and pH control are receiving less attention. These qualities may be among saliva's most important. This presentation will review recent advances in the genomics and proteomics of saliva, as well as saliva's roles in tissue coating, alimentation, and regulation of the oral flora.     

Healthcare-associated bloodstream infection: A distinct entity? Insights from a large U.S. database

OBJECTIVE: To gain a better understanding of the epidemiology, microbiology, and outcomes of early-onset, culture-positive, community-acquired, healthcare-associated, and hospital-acquired bloodstream infections. DESIGN: We analyzed a large U.S. database (Cardinal Health, MediQual, formerly MedisGroups) to identify patients with bacterial or fungal bloodstream isolates from 2002 to 2003. SETTING: The data set included administrative and clinical variables (physiologic, laboratory, culture, and other clinical) from 59 hospitals. Bloodstream infections were identified in those hospitals collecting clinical and culture data for at least the first 5 days of admission. PATIENTS: Patients with bloodstream infection within 2 days of admission were classified as having community-acquired bloodstream infection. Those with a prior hospitalization within 30 days, transfer from another facility, ongoing chemotherapy, or long-term hemodialysis were classified as having healthcare-associated bloodstream infection. Bloodstream infections that developed after day 2 of admission were classified as hospital-acquired bloodstream infection. A total of 6,697 patients were identified as having bloodstream infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Healthcare-associated bloodstream infection accounted for more than half (55.3%) of all bloodstream infections. Nearly two thirds (62.3%) of hospitalized patients with bloodstream infection suffered from either hospital-acquired bloodstream infection or healthcare-associated bloodstream infection and had higher morbidity and mortality rates than those with community-acquired bloodstream infection. Of all bloodstream infection pathogens, fungal organisms were associated with the highest crude mortality, longest length of stay in hospital, and greatest total charges. Of all bacterial bloodstream infections, methicillin-resistant Staphylococcus aureus was associated with the highest crude mortality rate (22.5%), the longest mean length of stay (11.1 +/- 10.7 days), and the highest median total charges ($36,109). After we controlled for confounding factors, methicillin-resistant S. aureus was associated with the highest independent mortality risk (odds ratio 2.70; confidence interval 2.03-3.58). S. aureus was the most commonly encountered pathogen in all types of early-onset bacteremia. CONCLUSIONS: Healthcare-associated bloodstream infection constitutes a distinct entity of bloodstream infection with its unique epidemiology, microbiology, and outcomes. Methicillin-resistant Staphylococcus aureus carries the highest relative mortality risk among all pathogens.     

Healthy participants in phase I clinical trials: the quality of their decision to take part

Aims and objective. This study was set out to test the quality of the decision‐making process of healthy volunteers in clinical trials. Background. Researchers fear that the decision to volunteer for clinical trials is taken inadequately and that the signature on the consent forms, meant to affirm that consent was ‘informed’, is actually insubstantial. Design. The study design was quasi‐experimental, using a convenience quota sample. Methods. Over a period of a year, candidates were approached during their screening process for a proposed clinical trial, after concluding the required ‘Informed Consent’ procedure. In all, 100 participants in phase I trials filled out questionnaires based ultimately on the Janis and Mann model of vigilant information processing, during their stay in the research centre. Results. Only 35% of the participants reached a ‘quality decision’. There is a definite correlation between information processing and quality decision‐making. However, many of the healthy research volunteers (58%) do not seek out information nor check alternatives before making a decision. Conclusions. Full disclosure is essential to a valid informed consent procedure but not sufficient; emphasis must be put on having the information understood and assimilated. Research nurses play a central role in achieving this objective.     

Asystole after the first dose of ceftriaxone

The incidence of ceftriaxone-related hypersensitivity skin reactions is between 1% and 3%, whereas anaphylaxis is rare. To the best of our knowledge, the following case is the first report of asystole after the administration of single-dose ceftriaxone. A 55-year-old man was admitted to our emergency department because of high fever, abdominal pain, dysuria, and weakness. To determine the cause of his fever, blood and urine cultures were obtained. Then, an infusion of 1 g ceftriaxone was started slowly. One minute later, cardiac arrest occurred. The rhythm was asystole. Cardiopulmonary resuscitation and tracheal intubation were performed immediately, and the ceftriaxone infusion was discontinued. Within 20 minutes, circulation was restored. The time of onset was suggestive of ceftriaxone-induced anaphylaxis. The patient was discharged in good clinical condition on the 10th day of admission. Emergency physicians should be mindful of the possibility of anaphylaxis and asystole that could occur with the first dose of ceftriaxone and should also make sure to offer receiving detailed informed patient consent, too.     

Carbamazepine-induced hypogammaglobulinemia

Carbamazepine is used to control seizures. Its common side effects are sleep disorders, anorexia, nausea, vomiting, polydipsia, irritability, ataxia, and diplopia. Involvement of the immune system is rare, and few cases of decreased immunoglobulin levels have been reported. We describe a patient with low immunoglobulin levels due to carbamazepine use who presented with recurrent urinary tract infection. Intravenous immunoglobulin was administered, and immunoglobulin levels increased to safer levels after discontinuation of carbamazepine. Previous reports describe severe infection after carbamazepine-induced hypogammaglobulinemia. Therefore, in patients using antiepileptics, particularly carbamazepine, serum immunoglobulin levels should be checked in those with recurrent infections.     

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon‐based therapy: FUNDAMENTAL,a Phase II trial

Alisporivir (ALV) is an oral, investigational host‐targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double‐blind, placebo‐controlled, Phase II study explored the efficacy and safety of ALV with peginterferon‐α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four‐hundred‐and‐fifty‐nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon‐free regimens in combination with direct‐acting antiviral agents.