A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice.

BACKGROUND: Adult guidelines recommend BEP (bleomycin, etoposide, cisplatin) for all ovarian germ cell tumours, causing debilitating toxicities in young patients who will survive long term. Paediatricians successfully reduce toxicities by using lower bleomycin doses and substituting carboplatin for cisplatin, while testicular and paediatric immature teratomas (ITs) are safely managed with surgery alone. AIM: The aim was to determine whether reduced-toxicity treatment could rationally be extended to patients older than 18 years. METHODS: Multicentre cohort study was carried out in four large UK cancer centres over 12 years. RESULTS: One hundred thirty-eight patients were enrolled. Overall survival was 93%, and event-free survival (EFS) was 72%. Neoadjuvant/adjuvant chemotherapy (82% BEP) caused 27 potentially chronic toxicities, and one patient subsequently died from acute lymphoblastic leukaemia. There was no difference in histology, stage or grade in patients ≤/>18 years, and EFS was not different in these age groups (≤18:28% and >18:28%; log-rank P = 0.96). Histological subtype powerfully predicted EFS (log-rank P = 4.9 × 10-7). Neoadjuvant/adjuvant chemotherapy reduced future relapse/progression in dysgerminoma (n = 37, chemo:0% vs. no chemo:20%), yolk sac tumour (n = 23, 26.3% vs.75%) and mixed germ cell tumour (n = 32, 40%vs.70%) but not in IT (n = 42, 33% vs.15%). Additionally, we observed no radiological responses to chemotherapy in ITs, pathological IT grade did not predict EFS (univariate hazard ratio 0.82, 95% confidence interval: 0.57-1.19, P = 0.94) and there were no deaths in this subtype. CONCLUSION: Survival was excellent but chemotherapy toxicities were severe, implying significant overtreatment. Our data support the extension of reduced-toxicity, paediatric regimens to adults. Our practice-changing findings that IT was chemotherapy resistant and pathological grade uninformative strongly endorse exclusive surgical management of ovarian ITs at all ages.

A randomized phase III study of 72 h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3).

BACKGROUND: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary toxicity often necessitates drug cessation and death occurs in 1%-2% of patients. A continuous infusion of bleomycin might reduce lung toxicity when compared with the conventional weekly boluses given as part of standard BEP chemotherapy. PATIENTS AND METHODS: A phase 3 trial was conducted based on 212 men with IGCCCG good prognosis metastatic germ cell tumours with 1 : 1 randomization. They were stratified for age, smoking history and renal function. Patients received either conventional BEP with weekly bleomycin (30 000 units/week i.v. bolus) or as a 90 000 unit infusion on day 1 over 72 h. The primary endpoint was CT assessed lung toxicity, secondary endpoints included progression-free survival (PFS), changes in lung function testing and quality of life. Repeated measures mixed effects model was used to analyse the data. RESULTS: CT assessed lung toxicity for the infusional and conventional arm patients were respectively 80% versus 62% at the end of treatment and 54% versus 51% at 1-year post-treatment. There was no significant difference between the two arms for CT assessed lung toxicity (estimated regression coefficient = 1.4, 95% CI: -0.36, 3.16). Older patients had higher toxicity (coefficient = 4.81, 95% CI: 3.04, 6.58). Lung toxicity increased after 1 cycle and peaked at end of treatment (P ≤ 0.002) and then declined. Lung function testing did not predict for subsequent lung damage. The median follow-up was 2.5 years. Two-year PFS rate (infusional: 93%, conventional: 94%; hazard ratio =0.91, 95% CI: 0.33, 2.52) was similar. Cough (P = 0.002) but not shortness of breath (P ≥ 0.09) was associated with bleomycin toxicity. CONCLUSIONS: Infusional bleomycin has no advantage over standard administration. It supports abandoning routine pulmonary function testing, instead the presence of cough should be sought and the early use of CT scanning of the chest to evaluate potential lung toxicity is preferred.

Proximal Resection Margin in Ivor-Lewis Oesophagectomy for Cancer.

OBJECTIVE: The purpose of this study was to investigate whether a long proximal oesophageal resection margin (PRM) is associated with improved survival after oesophagectomy for cancer and to identify the optimal margin to aim for in this patient group. METHODS: A prospectively maintained database identified 174 patients who underwent Ivor-Lewis oesophagectomy for cancer. Demographic, clinical, and pathological data were collected. X-tile software was used to identify the optimal resection point. Two models were analysed: single point resection with comparison of two groups (short and long), and two resection points with three groups (short, medium, and long) to provide a range. RESULTS: The median PRM was 4.0 cm (interquartile range: 2.5-6.0 cm). After adjustment for significant confounders, multivariable Cox PH analysis demonstrated that the optimal resection margin was 1.7 cm, and in the three-group analysis the optimum PRM was between 1.7 and 3 cm. In the two-group analysis, the long margin had no effect on DFS (p = 0.37), but carried a significantly improved overall survival (hazard ratio [HR] = 0.46, 95 % confidence interval [CI] 0.25-0.87, p = 0.02). In the three-group analysis, the medium and long groups had improved OS compared with the short group (on average 54 %, HR ≥ 0.45, p ≤ 0.04). The 5-year disease-free and overall survival rates were highest in the medium PRM group (48 and 57 % respectively). CONCLUSIONS: Optimal survival following oesophagectomy for cancer is achieved with a PRM > 1.7 cm, but a PRM > 3 cm does not yield a further survival advantage. Thus, the optimal PRM is likely to be between 1.7 and 3 cm.

Complications of biliary-enteric anastomoses.

INTRODUCTION Biliary-enteric anastomoses are performed for a range of indications and may result in early and late complications. The aim of this study was to assess the risk factors and management of anastomotic leak and stricture following biliary-enteric anastomosis. METHODS A retrospective analysis of the medical records of patients who underwent biliary-enteric anastomoses in a tertiary referral centre between 2000 and 2010 was performed. RESULTS Four hundred and sixty-two biliary-enteric anastomoses were performed. Of these, 347 (75%) were performed for malignant disease. Roux-en-Y hepaticojejunostomy or choledocho-jejunostomy were performed in 440 (95%) patients. Perioperative 30-day mortality was 6.5% (n=30). Seventeen patients had early bile leaks (3.7%) and 17 had late strictures (3.7%) at a median of 12 months. On univariable logistic regression analysis, younger age was a significant risk factor for biliary anastomotic leak. However, on multivariable analysis only biliary reconstruction following biliary injury (odds ratio [OR]=6.84; p=0.002) and anastomosis above the biliary confluence (OR=4.62; p=0.03) were significant. Younger age and biliary reconstruction following injury appeared to be significant risk factors for biliary strictures but multivariable analysis showed that only younger age was significant. CONCLUSIONS Biliary-enteric anastomoses have a low incidence of early and late complications. Biliary reconstruction following injury and a high anastomosis (above the confluence) are significant risk factors for anastomotic leak. Younger patients are significantly more likely to develop an anastomotic stricture over the longer term.

The selective outpatient treatment of adults with imported falciparum malaria: a prospective cohort study.

BACKGROUND: Current UK malaria treatment guidelines recommend admission for all patients diagnosed with falciparum malaria. However, evidence suggests that certain patients are at lower risk of severe malaria and death and may be managed as outpatients. AIM: To prospectively assess the risk of post-treatment severe falciparum malaria in selected cases managed as outpatients. The readmission rate and treatment tolerability were assessed as secondary outcomes. DESIGN: Prospective cohort study. METHODS: Adults (>15 years old) diagnosed with falciparum malaria between May 2008 and July 2012 were selected for outpatient treatment using locally defined clinical and laboratory indicators based on known risk factors for severity and death. Treatment outcomes were assessed in clinic or by telephone 4-6 weeks after treatment. RESULTS: 269 adults were diagnosed with falciparum malaria on blood film between May 2008 and July 2012. Of 255 eligible participants, 106 patients were offered ambulatory treatment, of which 95 completed the study. The severe malaria rate was 0% (95% confidence interval (CI) 0-3.8%) and the readmission rate was 5.3% (95% CI 1.7-11.9) in the outpatient group. In addition, 10.6% (95% CI 5.2-18.7%) of outpatients reported drug-related side effects. CONCLUSIONS: The outpatient treatment of selected cases of falciparum malaria is effective in our high volume UK setting. We recommend adopting a similar approach to managing this infection in other non-endemic settings where immediate access to specialist advice is available.

Smaller sample sizes for phase II trials based on exact tests with actual error rates by trading-off their nominal levels of significance and power.

BACKGROUND: Sample sizes for single-stage phase II clinical trials in the literature are often based on exact (binomial) tests with levels of significance (alpha (α) <5% and power >80%). This is because there is not always a sample size where α and power are exactly equal to 5% and 80%, respectively. Consequently, the opportunity to trade-off small amounts of α and power for savings in sample sizes may be lost. METHODS: Sample-size tables are presented for single-stage phase II trials based on exact tests with actual levels of significance and power. Trade-off in small amounts of α and power allows the researcher to select from several possible designs with potentially smaller sample sizes compared with existing approaches. We provide SAS macro coding and an R function, which for a given treatment difference, allow researchers to examine all possible sample sizes for specified differences are provided. RESULTS: In a single-arm study with P(0) (standard treatment)=10% and P(1) (new treatment)=20%, and specified α=5% and power=80%, the A'Hern approach yields n=78 (exact α=4.53%, power=80.81%). However, by relaxing α to 5.67% and power to 77.7%, a sample size of 65 can be used (a saving of 13 patients). INTERPRETATION: The approach we describe is especially useful for trials in rare disorders, or for proof-of-concept studies, where it is important to minimise the trial duration and financial costs, particularly in single-arm cancer trials commonly associated with expensive treatment options.

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol.

BACKGROUND: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). METHODS: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan-Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. RESULTS: At study entry, the median age was 76 years (inter-quartile range: 70-80 years), the median PSA was 79 ng ml(-1), and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ≥11 g dl(-1) decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25-0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno-thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001). CONCLUSION: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

Predictors of patient satisfaction with initial diagnosis and management of malignant melanoma.

BACKGROUND: Malignant melanoma (MM), accounts for around 10% of skin cancers. To date, there have been few data on patient satisfaction with initial management of MM. OBJECTIVE: To identify the predictors of patient satisfaction with initial diagnosis and management of MM. METHODS: Data on 214 patients were collected using a questionnaire filled in by a clinician during a face-to-face interview when the patient attended an appointment at a tertiary melanoma centre. Age, gender, ethnic origin, date of diagnosis, site of lesion, and overall stage at diagnosis and at interview were obtained from the hospital notes. Patients were asked about their satisfaction level at the end. RESULTS: In total, 64 (29.9%) patients were dissatisfied with the time they had to wait to receive a diagnosis. Patients whose initial biopsy was taken by a dermatologist were more satisfied than those whose biopsy was taken by a general practitioner (GP) (P < 0.003) and women were more dissatisfied than men (P = 0.04). Delay in diagnosis (P < 0.001) and number of visits (P < 0.001) were found to be predictors for dissatisfaction in univariate analysis, but in multivariate analysis, only the number of visits (P < 0.001) was a significant predictor of patient satisfaction. For each additional visit made by the patient, the odds of dissatisfaction increased by 3.5 times, irrespective of who did the initial biopsy, any delay in diagnosis, and the age and gender of the patient. CONCLUSIONS: Patients whose initial biopsy was taken by dermatologist were more satisfied than those with a biopsy taken by a GP. The number of visits was an important predictor of patient satisfaction.

Predictors of survival after haemorrhagic stroke in a multi-ethnic population: the South London Stroke Register (SLSR).

OBJECTIVES: To identify the predictors of long-term survival after haemorrhagic stroke. METHODS: Data were collected within the population-based South London Stroke Register covering a multiethnic source population of 271,817 inhabitants (2001) in South London. Death data were collected at post-stroke follow-up. The impact of patients' demographic and clinical characteristics, ethnic origin, pre-stroke risk factors and acute treatment on long-term survival were investigated. Survival methods included Kaplan-Meier curves and Cox's proportional hazards model. RESULTS: Between January 1995 and December 2004, a total of 566 patients with first-ever haemorrhagic stroke (395 primary intracerebral haemorrhage; 171 subarachnoid haemorrhage) were registered. Mean age was 62.3 years; 365 (64.5%) were white, 132 (23.3%) were black and 69 (12.2%) were other or unknown ethnic origin; there were 1340 person-years of follow-up. After multivariable adjustment, age (p<0.001) and having diabetes (hazard ratio (HR), 1.69; 95% CI 1.06-2.70) were associated with increased risk of death. Patients with severe stroke (Glasgow Coma Scale (GCS) <9) had an increased risk of death (HR 6.5; 95% CI 4.68 to 8.90) compared with those with mild stroke (GCS >12). Treatment on a stroke unit reduced the long-term risk of death (HR 0.70; 95% CI 0.50 to 0.98). Black patients had a reduced risk of death (HR 0.62; 95% CI 0.42 to 0.92) compared with white patients. CONCLUSIONS: Age, diabetes, stroke severity and stroke unit care influenced the long-term risk of death after haemorrhagic stroke. An independent survival advantage was observed in black patients. These factors can be utilised for clinical predictions but the cause of the observations in black patients remains unclear.

Effect of hyaluronidase on ocular motility and eyelid function in sub-Tenon's anaesthesia: randomised controlled trial.

PURPOSE: To assess the effect of hyaluronidase on eye and eyelid movements when used as an adjunct in sub-Tenon's anaesthesia. METHODS: A total of 60 patients who had sub-Tenon's anaesthesia prior to phacoemulsification surgery were divided into two equal groups in a double-masked randomised controlled fashion. Of these, Group A had 4 ml lignocaine 2%, while Group B had 4 ml lignocaine 2% with the addition of sodium hyaluronidase 75 IU/ml. Ocular motility, levator, and orbicularis oculi function were measured in all patients at 5 and 8 min. Levator function was scored from 0 (no function) to 3 (complete function) while orbicularis function was scored from 0 to 2. The score for ocular motility was the sum in four positions of gaze, each position scoring from 0 to 2. Results were compared using a nonparametric test. RESULTS: Group B achieved significantly better ocular and lid akinesia than Group A both at 5 and 8 min with P<0.01. The median scores for levator function at 5 and 8 min were 2 for Group A and 0 for Group B. For orbicularis function, the median scores at both time intervals were 2 for Group A and 1 for Group B. For ocular motility, the median score for Group A at 5 min was 3 and at 8 min was 2.5; for Group B at 5 min was 0.5 and at 8 min was 0. CONCLUSIONS: The addition of hyaluronidase in sub-Tenon's anaesthesia has a significant effect in improving ocular and lid (levator and orbicularis) akinesia.