Systematic review of randomised clinical trials and observational studies for patients with RAS wild-type or BRAFV600E-mutant metastatic and/or unresectable colorectal cancer.

Approximately 8-10% of metastatic colorectal cancer (mCRC) tumours harbour BRAFV600E mutations. Eleven randomised controlled trials (RCTs) and 24 non-RCTs were identified. Seven studies evaluated BRAF inhibitors. Single-agent BRAF inhibitors had minimal efficacy, whereas BRAF inhibitor plus anti-EGFR therapy improved outcomes. In BEACON CRC, overall survival (OS) was significantly longer for patients receiving encorafenib plus cetuximab ± binimetinib when compared with irinotecan/FOLFIRI plus cetuximab as second- and third-line therapy. Seven prospective non-RCTs reported worse OS and progression-free survival (PFS) for patients with BRAFV600E-mutant vs BRAF wild-type mCRC. Eight RCTs reported that PFS and OS were generally shorter for patients with BRAFV600E-mutant mCRC vs those with KRAS or RAS wild-type mCRC. Patients with BRAFV600E-mutant mCRC have worse outcomes with conventional therapy vs patients with BRAF wild-type tumours. BRAF inhibitors in conjunction with anti-EGFR therapy improves outcomes for patients with BRAFV600E-mutant mCRC vs conventional therapy or a BRAF inhibitor alone.

The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis.

OBJECTIVES: Dasatinib 100 mg daily and nilotinib 600/800 mg daily have been compared to imatinib as first line treatments for CML in two recent randomised studies. However, no head to head evidence exists of the relative efficacy of dasatinib and nilotinib. METHODS: We conducted a systematic literature review and used the data extracted to perform an indirect comparison meta-analysis of the three interventions. RESULTS: Data from eight clinical studies (3,520 individuals) were included, all of which were of good quality (low risk of bias). At six months, the odds of complete cytogenetic response (CCyR) for dasatinib and nilotinib were approximately three times those for imatinib (range 2.77 to 3.06, all values not significant). At twelve months datatinib and nilotinib were significantly better than imatinib for both CCyR and major molecular response (MMR) (CCyR odds range 2.06 to 2.41, MMR odds range 2.09 to 2.87). At eighteen months dasatinib and nilotinib were again significantly better in terms of CCyR than imatinib (response odds 1.55 to 2.01). When dasatinib and nilotinib were compared to each other, for both clinical endpoints at all time points the response odds were not significantly different. CONCLUSIONS: On the basis of a systematic review of the current literature base, dasatinib 100 mg, nilotinib 600 mg and nilotinib 800 mg should be viewed as equivalent in terms of complete cytogenetic and major molecular response.

Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review.

BACKGROUND: Mycophenolate mofetil (MMF) has increasingly replaced azathioprine (AZA) as the antimetabolite of choice in immunosuppressive protocols. Initial trials comparing MMF with AZA in patients receiving cyclosporine A sandimmune showed a clinical benefit in reducing the incidence of acute rejections. It has been questioned whether this benefit remains significant when using newer formulations of cyclosporine A (neoral) and tacrolimus. METHODS: Literature searches were performed using the Transplant Library, Cochrane library, Medline, and Embase for all randomized controlled trials directly comparing MMF with AZA in renal transplant recipients. Trials were assessed for quality using the Jadad scoring system. Trials were pooled using meta-analysis software. Confidence intervals were set at 95%. RESULTS: Nineteen relevant studies were identified, including a total of 3143 patients. MMF significantly reduces the risk of acute rejection when used in combination with any calcineurin inhibitor (relative risk 0.62, 0.55-0.87, P<0.00001). The hazard for graft loss, including death with a functioning graft, is also significantly reduced in patients treated with MMF (hazard ratio 0.76, 0.59-0.98, P=0.037). There is no significant difference in patient survival or renal transplant function between groups. Risk of adverse events, including cytomegalovirus infection, anemia, leukopenia or rates of malignancy, does not differ significantly. A greater risk of diarrhea is seen in MMF-treated patients. CONCLUSIONS: We have shown that MMF used with a calcineurin inhibitor does indeed confer a clinical benefit over AZA by reducing the risk of acute rejection and also possibly reducing graft loss. This effect is independent of whether MMF is used in combination with sandimmune, neoral or tacrolimus.

The quality of reporting of randomized controlled trials in solid organ transplantation.

Randomized controlled trials (RCTs) of interventions provide the highest level of evidence about efficacy but their value either alone or within a meta-analysis is dependent on its methodological quality. For this reason recent RCTs in organ transplantation were assessed for quality. RCTs published between 2004 and 2006 (n = 332) were assessed, after excluding duplicate and nonEnglish reports. Quality was evaluated using the Jadad score plus allocation concealment and intention to treat analysis. We noted journal type, journal author instructions, funding source, sample size and number and location of study centres. Around one-third of RCTs had a Jadad score of 3 or greater (indication of a methodologically good quality trial) and the other two parameters were satisfied in just over one third. Although the majority of trials were published in speciality journals the quality of those published in general journals was superior. Commercially sponsored trials were of better quality as were multicentre trials in contrast to single centre trials. Overall quality of reporting of RCTs in organ transplantation is poor and as RCTs provide the highest level of evidence in evaluations of interventions there needs to be a concerted effort within the transplant community to improve the standards of RCTs.