Clinical Experience of Axillary Radiotherapy for Node-positive Breast Cancer.

AIMS: Patients with breast cancer who have positive lymph nodes are currently recommended axillary node clearance (ANC) or regional nodal irradiation (RNI). ANC is associated with complications such as lymphoedema, brachial plexopathy and shoulder stiffness. The AMAROS Group showed RNI to be non-inferior to ANC with regards to survival and recurrence, and with a better quality of life. We conducted a large real-world population study to show our centre's experience with the use of RNI and to contribute to the current discussion around the management of node-positive breast cancer. MATERIALS AND METHODS: We evaluated patients who received RNI as opposed to ANC between 2006 and 2009 (n = 190). Patients had a range of cancer subtypes/grades. All had positive axillary disease, identified by axillary node sampling or sentinel lymph node biopsy. Systemic therapy was given as per standard protocol. Our data were compared with those of patients who had RNI (n = 681) in AMAROS. Patients were followed up retrospectively and overall survival, breast cancer-specific survival, distant metastasis-free survival, locoregional recurrence and toxicity were recorded, including lymphoedema, brachial plexopathy and shoulder stiffness. Survival analysis was performed on R via the Kaplan-Meier method. Univariate and multivariate analyses were also performed. Toxicity data were reported as percentages. Patients meeting POSNOC trial criteria (one to two positive sentinel lymph nodes, macrometastasis, receiving adjuvant chemotherapy) including if oestrogen receptor-positive (stratified POSNOC) were identified for subgroup analysis in the regression model. RESULTS: Locoregional recurrence was 3.16% versus AMAROS RNI of 1.82%. Overall survival was slightly lower in our population, but cancer-specific survival was higher than AMAROS. Lymphoedema rates were 5.8% versus AMAROS 11% in RNI and 23% in ANC arms, respectively. Brachial plexopathy was 1.6% and arm/shoulder stiffness 7.4%. AMAROS conducted a quality of life survey pertaining to arm/shoulder stiffness, mobility and function, which seemed to affect about 18% in the RNI arm. Univariate analysis revealed POSNOC status, especially if also oestrogen receptor-positive, to be a low risk group with hazard ratio 0.42 (0.20-0.83, P = 0.015). Extracapsular extension of lymph node metastasis was a poor prognostic factor; hazard ratio 4.39 (1.45-14.0, P = 0.009). CONCLUSION: We support the conclusion of the AMAROS trial with survival and recurrence following RNI being non-inferior to ANC, and with similarly favourable toxicity data. We support the continuing use of RNI as a treatment option for patients with node-positive breast cancer. Further research is required to answer the key questions regarding personalised management for node-positive breast cancer, with regards to de-escalation and also intensification for the patients exhibiting adverse tumour biology.

Clinical commissioning of online seed matching protocol for prostate radiotherapy.

OBJECTIVES: Our aim was to clinically commission an online seed matching image-guided radiotherapy (IGRT) protocol using modern hardware/software for patients undergoing prostate radiotherapy. An essential constraint was to achieve this within a busy centre without reducing patient throughput, which had been reported with other techniques. METHODS: 45 patients had 3 fiducial markers inserted into the prostate and were imaged daily using kilovoltage orthogonal images with online correction applied before treatment. A total of 1612 image pairs were acquired and analysed to identify interfractional motion, seed migration and interobserver variability, and assess ease of use. RESULTS: This method of IGRT was implemented successfully in our centre with no impact on treatment times and patient throughput. Systematic (Σ) interfractional set-up errors were 2.2, 2.7 and 3.9 mm in right-left (RL), superoinferior (SI) and anteroposterior (AP) directions, respectively. Random (σ) interfractional set-up errors were 3.2 (RL), 3.7 (SI) and 5.7 mm (AP). There were significant differences between patients. Seed migration and interobserver variability were not significant issues. CONCLUSIONS: The described technique is facilitated by the advanced imaging system, allowing a fast and effective method of correcting set-up errors before treatment. Extended implementation of this technique has improved treatment delivery to the majority of our prostate radiotherapy patients. The measurement of interfractional motion in this study is potentially valuable for margin reduction in intensity-modulated radiotherapy/volumetric arc therapy. ADVANCES IN KNOWLEDGE: This technique can be used within treatment time constraints, benefiting large numbers of patients by helping to avoid geographical miss and potentially reducing toxicity to organs at risk.

Anticholinergic drugs versus non-drug active therapies for overactive bladder syndrome in adults.

BACKGROUND: Overactive Bladder Syndrome (OAB) is defined as urgency, with or without urgency incontinence, usually with frequency and nocturia. Pharmacotherapy with anticholinergic drugs is often the first line medical therapy, either alone or as an adjunct to various non-pharmacological therapies. The commonest non-pharmacologic therapies are: bladder training, pelvic floor muscle training with or without biofeedback and electric stimulation to affect detrusor muscle activity. OBJECTIVES: To compare the effects of various anticholinergic drugs with various non-pharmacologic therapies for idiopathic overactive bladder syndrome in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Register (searched 29 November 2005), The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to September 2004), PREMEDLINE, Dissertation Abstracts and the reference lists of relevant articles. SELECTION CRITERIA: All randomised, or quasi-randomised, controlled trials of treatment with anticholinergic drugs for overactive bladder syndrome or urge urinary incontinence in adults, in which at least one management arm involved a non-drug new therapy. Trials amongst patients with neuropathic bladder dysfunction were excluded. DATA COLLECTION AND ANALYSIS: Two authors evaluated the trials for appropriateness for inclusion and methodological quality. Three authors were involved in the data extraction. Data extracted was based on predetermined criteria. Data analysis was based on standard statistical approaches used in Cochrane reviews. MAIN RESULTS: Thirteen trials with 1770 participants were included; all were designed as parallel groups except for one cross-over trial. Trial groups were well matched for baseline characteristics in all trials. Treatment duration was 3 to 12 weeks, with one trial carrying out a follow-up analysis at 24 weeks after starting treatment. During treatment, symptomatic improvement was more common amongst those on anticholinergic drugs compared with bladder training (RR 0.73; 95% CI 0.59 to 0.90). Combination of anticholinergics with bladder training was also associated with more improvement than bladder training alone but with wide confidence intervals (RR 0.55; 95% 0.32 to 0.93). Similarly, the limited data favoured a combination of anticholinergics with bladder training compared with anticholinergics during treatment but the difference was not statistically significant (RR for improvement 0.81; 95% CI 0.61 to 1.06). For all comparisons, there were too few data to compare symptoms after treatment had ended. Adverse effects, such as dry mouth, were reported by around a third of those taking anticholinergics. AUTHORS' CONCLUSIONS: The use of anticholinergic drugs in the management of OAB is well established. During initial treatment there was more symptomatic improvement when (a) anticholinergics were compared with bladder training alone, and (b) anticholinergics combined with bladder training were compared with each modality alone. Anticholinergics have well recognised side effects, such as dry mouth. There were too few data to assess whether or not effects are sustained after stopping treatment.

Adrenergic drugs for urinary incontinence in adults.

BACKGROUND: Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which may limit their clinical use. OBJECTIVES: To determine the effectiveness of adrenergic agonists in the treatment of urinary incontinence in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group specialised trials register (searched 9 March 2005) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials in adults with urinary incontinence which included an adrenergic agonist drug in at least one arm of the trial. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Reviewers' Handbook. MAIN RESULTS: Twenty-two eligible randomised trials were identified, of which 11 were crossover trials. The trials included 1099 women with 673 receiving an adrenergic drug (phenylpropanolamine in 11 trials, midodrine in two, norepinephrine in three, clenbuterol in another three, terbutaline in one, eskornade in one and Ro-115-1240 in one). No trials included men. The limited evidence suggested that an adrenergic agonist drug is better than placebo in reducing the number of pad changes and incontinence episodes, as well as improving subjective symptoms. In two small trials, the drugs also appeared to be better than pelvic floor muscle training, possibly reflecting relative acceptability of the treatments to women but perhaps due to differential withdrawal of women from the trial groups. There was not enough evidence to evaluate the use of higher compared to lower doses of adrenergic agonists nor the relative merits of an adrenergic agonist drug compared with oestrogen, whether used alone or in combination. Over a quarter of women reported adverse effects. There were similar numbers of adverse effects with adrenergics, placebo or alternative drug treatment. However, when these were due to recognised adrenergic stimulation (insomnia, restlessness and vasomotor stimulation) they were only severe enough to stop treatment in 4% of women. AUTHORS' CONCLUSIONS: There was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment. There was not enough evidence to assess the effects of adrenergic agonists when compared to or combined with other treatments. Further larger trials are needed to identify when adrenergics may be useful. Patients using adrenergic agonists may suffer from minor side effects, which sometimes cause them to stop treatment. Rare but serious side effects, such as cardiac arrhythmias and hypertension, have been reported.

Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults.

BACKGROUND: To date, standard recommendations for the management of stress urinary incontinence (SUI) would be either pelvic floor muscle training (PFMT) or surgery. A new form of drug treatment with a serotonin-noradrenaline reuptake inhibitor (SNRI), duloxetine, may now have a place in treatment of this condition. OBJECTIVES: To determine whether a SNRI is better than placebo (or no treatment, other pharmacological and non-pharmacological therapies, or surgery) in the treatment of women with SUI, or mixed urinary incontinence that includes stress incontinence (MUI), or both and which doses should be used. SEARCH STRATEGY: We searched the Cochrane Incontinence Group specialised register (searched 1 December 2004), (CENTRAL) (Issue 2, 2004), MEDLINE (January 1966 to September 2004), PREMEDLINE (11 March 2004), Dissertation Abstracts and the reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of treatment for SUI or MUI, in which at least one management arm involved a SNRI. DATA COLLECTION AND ANALYSIS: Two authors evaluated the trials for appropriateness for inclusion and methodological quality. Three authors performed the data extraction using predetermined criteria. Analyses were performed using the Cochrane Review Manager software, RevMan. MAIN RESULTS: Nine randomised trials were included, involving 3327 adults with predominantly SUI, randomised to receive duloxetine or placebo. Both arms in individual trials were comparable for various baseline characteristics. Treatment duration was between three weeks and 12 weeks. Duloxetine was significantly better than placebo in terms of improving patients' quality of life (WMD 5.26, 95%CI 3.84 to 6.68. P< 0.00001) and perception of improvement. Individual studies demonstrated a significant reduction in the Incontinence Episode Frequency (IEF) by approximately 50% during treatment with duloxetine. With regard to objective cure, however, meta-analysis of stress pad test and 24 hour pad weight change failed to demonstrate a benefit for duloxetine over placebo though data were relatively few. Subjective cure favoured duloxetine, albeit with a small effect size (3%). One trial suggested that duloxetine was better than pelvic floor muscle training alone in reducing IEF (P < 0.05) based on median percentage decrease in IEF per week. Although significant side effects were commonly associated with duloxetine, they were reported as acceptable. AUTHORS' CONCLUSIONS: The available evidence suggests that duloxetine treatment can significantly improve the quality of life of patients with stress urinary incontinence, but it is unclear whether or not benefits are sustainable. Adverse effects are common but not serious. About one in three participants allocated duloxetine reported adverse effects (most commonly nausea) related to treatment, and about one in eight allocated duloxetine stopped treatment as a consequence.

Adrenergic drugs for urinary incontinence in adults.

BACKGROUND: Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which may limit their clinical use. OBJECTIVES: To determine the effectiveness of adrenergic agonists in the treatment of urinary incontinence in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group trials register (January 2002) and the reference lists of relevant articles. Date of the most recent searches: January 2002. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials which include an adrenergic agonist drug in at least one arm for adults with urinary incontinence. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Collaboration Handbook. MAIN RESULTS: Fifteen randomised trials were identified, which included 832 women, of whom 506 received an adrenergic drug (phenylpropanolamine in 11 trials, Midodrine in two and Clenbuterol in another two). Of these, six were crossover trials. No trials included men. The limited evidence suggested that an adrenergic agonist drug is better than placebo in reducing number of pad changes and incontinence episodes, as well as improvement in subjective symptoms. The drugs also appeared to be better than pelvic floor muscle training in two small trials, possibly reflecting relative acceptability of the treatments to women but perhaps due to differential withdrawal of women from the trial groups. There was not enough evidence to evaluate the use of higher compared to lower doses of adrenergic agonists nor the relative merits of an adrenergic agonist drug compared with oestrogen, whether used alone or in combination. REVIEWER'S CONCLUSIONS: There was weak evidence to suggest that use of an adrenergic agonist is better than placebo treatment. There was not enough evidence to assess the effects of adrenergic agonists when compared to or combined with other treatments. Patients using adrenergic agonists may suffer from minor side effects, only occasionally leading them to stop treatment. Rare but serious side effects such as cardiac arrhythmias and hypertension have been reported, however.

Cyclooxygenase-2: a possible target in schistosoma-associated bladder cancer.

OBJECTIVE: To analyse and compare the expression of cyclooxygenase (COX) enzymes in schistosoma-associated bladder cancer, and to determine any association with tumour grade or stage. MATERIALS AND METHODS: Sixty paired samples of tumour and adjacent nonmalignant urothelium were identified. There were 25 squamous and 28 transitional cell carcinomas, and seven adenocarcinomas. Serial sections were obtained and a standard three-layer immunohistochemistry protocol, using COX-1- and COX-2-specific mouse monoclonal antibodies, applied. RESULTS: COX-1 was expressed mostly in nonvascular smooth muscle with weak reactivity in malignant and nonmalignant urothelium. Nonmalignant urothelium expressed COX-2 weakly, notably in areas of dysplasia and squamous metaplasia whereas there was a significant increase in COX-2 (P < 0.001) with moderate to strong granular cytoplasmic expression in all three malignant histological types. The COX-2 reactivity was higher in transitional and adenocarcinomas than in squamous cell carcinoma (P < 0.001). Areas of carcinoma in situ showed COX-2 reactivity comparable with that in invasive areas and more intense than that detected in dysplastic or metaplastic urothelium (P < 0.001). There was a statistically significant positive correlation between COX-2 expression and tumour grade (P = 0.0052). CONCLUSION: COX-2 is over-expressed in schistosoma-associated bladder cancer, consistent with a potential role for COX-2 inhibitors in the prevention and management of this disease.