Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Outcomes from the use of computerized neurocognitive testing in a recurrent glioblastoma clinical trial.

Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Meta-analysis of radical resection rates and margin assessment in pancreatic cancer.

BACKGROUND: R0 resection rates (complete tumour removal with negative resection margins) in pancreatic cancer are 70-80 per cent when a 0-mm margin is used, declining to 15-24 per cent with a 1-mm margin. This review evaluated the R0 resection rates according to different margin definitions and techniques. METHODS: Three databases (MEDLINE from 1946, PubMed from 1946 and Embase from 1949) were searched to mid-October 2014. The search terms included 'pancreatectomy OR pancreaticoduodenectomy' and 'margin'. A meta-analysis was performed with studies in three groups: group 1, axial slicing technique (minimum 1-mm margin); group 2, other slicing techniques (minimum 1-mm margin); and group 3, studies with minimum 0-mm margin. RESULTS: The R0 rates were 29 (95 per cent c.i. 26 to 32) per cent in group 1 (8 studies; 882 patients) and 49 (47 to 52) per cent in group 2 (6 studies; 1568 patients). The combined R0 rate (groups 1 and 2) was 41 (40 to 43) per cent. The R0 rate in group 3 (7 studies; 1926 patients) with a 0-mm margin was 72 (70 to 74) per cent The survival hazard ratios (R1 resection/R0 resection) revealed a reduction in the risk of death of at least 22 per cent in group 1, 12 per cent in group 2 and 23 per cent in group 3 with an R0 compared with an R1 resection. Local recurrence occurred more frequently with an R1 resection in most studies. CONCLUSION: Margin clearance definitions affect R0 resection rates in pancreatic cancer surgery. This review collates individual studies providing an estimate of achievable R0 rates, creating a benchmark for future trials.

Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer.

BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1þ) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBþCBM), 0.21; 95% CI, 0.08­0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13­0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2þ PFS HR, 0.67; 95% CI, 0.45­1.00; OS HR, 0.82; 95% CI, 0.52­1.30; VEGF-D 3þ PFS HR, 0.77; 95% CI, 0.50­1.17; OS HR, 1.28; 95% CI, 0.79­2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.

Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer.

BACKGROUND: Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study. METHODS: DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM. RESULTS: Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71-1.17)) or OS (HR 0.95 (0.71-1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37-0.85) for RAS MT and HR 0.69 (0.5-0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic. CONCLUSION: Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.

Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17.

BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.

BACKGROUND: Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain. METHODS: This meta-analysis included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39,612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated. FINDINGS: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47-0·81], 0·69 [99% CI 0·60-0·79], 0·79 [99% CI 0·74-0·85], 0·81 [99% CI 0·77-0·86], and 0·79 [99% CI 0·74-0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36-0·89, p=0·0012, and 0·61, 99% CI 0·50-0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35-0·75, and 0·63, 99% CI 0·51-0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61-0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77-0·95) and all-cause mortality (RR 0·91, 95% CI 0·85-0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96-1·04), cancer mortality (RR 0·99, 95% CI 0·93-1·06), or other non-vascular mortality. INTERPRETATION: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. FUNDING: British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

Effectiveness and cost-effectiveness of sentinel lymph node biopsy compared with axillary node dissection in patients with early-stage breast cancer: a decision model analysis.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is less invasive than axillary lymph node dissection (ALND) for staging early breast cancer, and has a lower risk of arm lymphoedema and similar rates of locoregional recurrence up to 8 years. This study estimates the longer-term effectiveness and cost-effectiveness of SLNB. METHODS: A Markov decision model was developed to estimate the incremental quality-adjusted life years (QALYs) and costs of an SLNB-based staging and management strategy compared with ALND over 20 years' follow-up. The probability and quality-of-life weighting (utility) of outcomes were estimated from published data and population statistics. Costs were estimated from the perspective of the Australian health care system. The model was used to identify key factors affecting treatment decisions. RESULTS: The SLNB was more effective and less costly than the ALND over 20 years, with 8 QALYs gained and $883,000 saved per 1000 patients. The SLNB was less effective when: SLNB false negative (FN) rate >13%; 5-year incidence of axillary recurrence after an SLNB FN>19%; risk of an SLNB-positive result >48%; lymphoedema prevalence after ALND <14%; or lymphoedema utility decrement <0.012. CONCLUSION: The long-term advantage of SLNB over ALND was modest and sensitive to variations in key assumptions, indicating a need for reliable information on lymphoedema incidence and disutility following SLNB. In addition to awaiting longer-term trial data, risk models to better identify patients at high risk of axillary metastasis will be valuable to inform decision-making.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

BACKGROUND: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. METHODS: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. FINDINGS: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. INTERPRETATION: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. FUNDING: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Photobiomodulation of pain and inflammation in microcrystalline arthropathies: experimental and clinical results.

OBJECTIVE: This article presents the results of laser therapy in crystal (hydroxyapatite, calcium pyrophosphate, and urates) deposition-induced arthritis in rats and the clinical applications in humans. BACKGROUND DATA: Microcrystalline arthropathies are prevalent among geriatric patients, who are more vulnerable to the side effects of drugs. The effectiveness of laser therapy for pain relief, free of side effects, has been reported in painful conditions. METHODS: Two milligrams of each of the above-mentioned crystals was injected in both joints of the back limbs in three groups of rats; these groups were then treated with laser irradiation. Three other groups received no treatment after the injections. We determined the plasmatic levels of inflammatory markers (fibrinogen, prostaglandin E2, and TNF(alpha)), tissues (prostaglandin E(2)) and conducted anatomopathological studies. Twenty-five patients with acute gout arthritis were randomized into two groups and treated over 5 days: group A, diclofenac 75 mg orally, twice a day; and group B, laser irradiation once a day. Forty-nine patients with knee chronic pyrophosphate arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Thirty patients with shoulder chronic hydroxyapatite arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. RESULTS: Fibrinogen, prostaglandin E(2), and TNF(alpha) concentrations in the rats injected with crystals and treated with laser decreased significantly as compared with the groups injected with crystals without treatment. Both laser therapy and diclofenac achieved rapid pain relief in patients with acute gouty arthritis without significant differences in efficacy. Laser therapy was more effective than diclofenac in patients with chronic pyrophosphate arthropathy and in patients with chronic apatite deposition disease. CONCLUSION: Laser therapy represents an effective treatment in the therapeutic arsenal of microcrystalline arthropathies.

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer.

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m(-2), respectively) (n=59) or the daily x 5 Mayo Clinic schedule (425 and 20 mg m(-2), respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79-1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71-1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred.

Taxane containing regimens for metastatic breast cancer.

BACKGROUND: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. OBJECTIVES: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library. SELECTION CRITERIA: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present. MAIN RESULTS: Twenty one eligible trials were identified of which 12 have published time-to-event data and 16 have reported response data. The quality of randomisation was generally not described. An estimated 2621 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.93 (95% CI=0.86-1.00, p=0.05) and no statistically significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.11). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.92, 95%CI 0.85-0.99, p=0.02) and overall response in assessable women (overall OR 1.34, 95%CI 1.18-1.52, p<0.00001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials. AUTHORS' CONCLUSIONS: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

Single agent versus combination chemotherapy for metastatic breast cancer.

BACKGROUND: It is commonly thought that combining chemotherapy agents for treating women with metastatic breast cancer will result in regimens that are more active, offer superior tumour response rates with more time before progression and improve overall survival. However, it is not known whether giving patients more intensive chemotherapy regimens (judged according to some measure eg dose, dose intensity, response rate, or toxicity) results in better health outcomes. One way to investigate the effect of more versus less-intensive chemotherapy is to compare regimens containing a single drug (and hence possibly less active treatment) with regimens containing a greater number of drugs (and hence possibly more active but more toxic), even when adjustments are made to dosages or schedules to account for toxicity. OBJECTIVES: To compare use of single chemotherapy agents with regimens containing a combination of agents for the treatment of metastatic breast cancer. SEARCH STRATEGY: The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the group to create the register, and the procedure used to code references, are described in the group's module on The Cochrane Library. SELECTION CRITERIA: Randomised trials comparing single agent chemotherapy with combination therapy in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present. MAIN RESULTS: Thirty seven eligible trials were identified of which 28 had published time-to-event data. The quality of randomisation was generally not described. Data, based on an estimated 4220 deaths in 5707 women, show a modest advantage for combination chemotherapy regimens compared with single agents with a hazard ratio (HR) for overall survival of 0.88 (95% CI=0.83-0.94, P<0.0001) and no evident heterogeneity. Results are similar if the analysis is limited to trials in women receiving first-line chemotherapy. Combination regimens are favourably associated with time to progression (overall HR of 0.78 (95% CI=0.73-0.83, P<0.00001) and tumour response rates (OR 1.28, CI=1.15-1.42, P<0.00001) although significant heterogeneity was observed (P=0.002 and P<0.00001 respectively). This probably reflects the varying efficacy of the comparator regimens used in the trials. Women receiving combination regimens experienced a higher toxicity level for leukopenia, hair loss and nausea and vomiting compared with those receiving a single agent, which was statistically significant. AUTHORS' CONCLUSIONS: Compared with single-chemotherapy agents, combination regimens show a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival and significantly worse toxicities.

Antitumour antibiotic containing regimens for metastatic breast cancer.

BACKGROUND: Antitumour antibiotics are used in the management of metastatic breast cancer. Some of these agents have demonstrated higher tumour response rates than non-antitumour antibiotic regimens, however a survival benefit has not been established in this setting. OBJECTIVES: To identify and review the randomised evidence comparing anti-tumour antibiotic containing chemotherapy regimens with regimens not containing an anti-tumour antibiotic in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May, 2003 using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy and coding applied by the Group to create the register are described in the Group's module on The Cochrane Library. SELECTION CRITERIA: Randomised trials comparing anti-tumour antibiotic containing regimens with regimens not containing anti-tumour antibiotics in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios (HRs) were derived from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Quality of life and toxicity data were extracted where present. A primary analysis was conducted for all trials and by class of antitumour antibiotic. MAIN RESULTS: Thirty-three trials reporting on 45 treatment comparisons were identified. All trials published results for tumour response and 26 trials published time-to-event data for overall survival. The observed 4084 deaths in 5284 randomised women did not demonstrate a statistically significant difference in survival between regimens that contained antitumour antibiotics and those that did not (HR 0.97, 95% CI 0.91 to 1.03, P = 0.35) and no significant heterogeneity. Antitumour antibiotic regimens were favourably associated with time-to-progression (HR 0.84, 95% CI 0.77 to 0.91) and tumour response rates (odds ratio (OR) 1.34, 95% CI 1.21 to 1.48) although statistically significant heterogeneity was observed for these outcomes. These associations were consistent when the analysis was restricted to the 29 trials that reported on anthracyclines. Patients receiving anthracycline-containing regimens were also more likely to experience toxic events compared to patients receiving non-antitumour antibiotic regimens. No statistically significant difference was observed in any outcome between mitoxantrone-containing and non-antitumour antibiotic-containing regimens. REVIEWERS' CONCLUSIONS: Compared to regimens without antitumour antibiotics, regimens that contained these agents showed a statistically significant advantage for tumour response and time to progression in women with metastatic breast cancer but were not associated with an improvement in overall survival. The favourable effect on tumour response and time to progression observed in anthracycline-containing regimens was also associated with greater toxicity.

Uso de un compuesto a base de gel de hidróxido de bismuto coloidal con pectina en la diarrea aguda / Use of a gel compound with colloidal bismuth hydroxide and pectin in acute diarrhea

El estudio tuvo un año de duración. Se evaluó la eficacia terapéutica de un compuesto a base de un gel de hidróxido de bismuto coloidal al 3% con pectina (Crema de Bismuto Chobet) en la diarrea aguda del lactante. El estudio se realizó en 48 lactantes afectados de diarrea aguda de menos de 24 horas de evolución. La investigación utilizó metodología a doble ciego, fue randomizada y controlada con placebo. Ambos grupos de tratamiento fueron similares en cuanto a características demográficas y etiopatogénicas. El porcentaje de niños mejorados clínicamente a las 24 horas de tratamiento y la reducción del número de deposiciones fue del 45,8% en el grupo placebo y del 83,4% en el grupo tratado con la Crema de Bismuto (p

Platinum containing regimens for metastatic breast cancer.

BACKGROUND: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. OBJECTIVES: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library. SELECTION CRITERIA: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present. MAIN RESULTS: Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens. REVIEWERS' CONCLUSIONS: In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Platinum containing regimens for metastatic breast cancer.

BACKGROUND: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. OBJECTIVES: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library. SELECTION CRITERIA: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present. MAIN RESULTS: Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens. REVIEWERS' CONCLUSIONS: In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Taxane containing regimens for metastatic breast cancer.

BACKGROUND: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. OBJECTIVES: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library. SELECTION CRITERIA: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Data were collected from published trials. Studies were assessed for eligiblity and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present. MAIN RESULTS: Twenty eligible trials were identified of which 17 had published at least some results, and 12 had published time-to-event data. The quality of randomisation was generally not described. An estimated 2659 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.90 (95% CI=0.84-0.97, p=0.009) and no significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.12). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.87, 95%CI 0.81-0.93, p<0.0001) and overall response (overall OR 1.29, 95%CI 1.13-1.47, p<0.0001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials. REVIEWER'S CONCLUSIONS: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.