September 2016

Synopsis: The utility of prophylactic pelvic drains to reduce the incidence of anastomotic leakage and pelvic sepsis after total mesorectal excision (TME) has not been vigorously studied. This French multicenter trial of 469 patients with mid- and low-rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME (75% with diverting ileostomy) randomized patients to prophylactic drainage (n=236) or control (n=233). There was no difference in the rate of anastomotic leakage (14.8% vs. 15.1%, p=0.94), need for operation for pelvic sepsis (10.2% vs 12%, p=0.52), or time to diagnosis of pelvic sepsis (p=0.10). The authors recommend against pelvic drains given their findings of non-superiority. Major limitations of this study include: (1) the strikingly high rate of pelvic sepsis and need for reoperation, and (2) conflation of drain non-superiority with dispensability. In that regard, it remains to be determined if prophylactic drains reduce the severity or burden of anastomotic leaks when they do occur. 

Synopsis: Genomic testing of tumors can enable improved matching of individual patients with treatments, but it can also identify situations where a specific intervention is less effective. In the phase III RCT MINDACT trial, 6693 early-stage breast cancer patients were stratified into 4 subgroups according to genomic risk (using the 70-gene signature assay Mammaprint) and clinical risk (using AdjuvantOnline!): A) low clinical/low genomic risk, B) high clinical/genomic risk, C) low clinical/high genomic risk, and D) high clinical risk/low genomic risk. While groups A through C received chemotherapy, the trial examined whether the Mammaprint assay would enable a reduction in the use of chemotherapy in the discordant subgroup D (n=1,550). The investigators asked whether the no chemotherapy group would have non-inferior 5-year metastasis-free survival (MFS) rate, established as a predefined benchmark of 92%. The 5-year MFS was 94.7% in the no chemotherapy group (95% CI, 92.5-96.2). The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy - results that met the study criterion for non-inferiority - suggesting that ~46% of earlybreast cancer patients at high clinical risk might not benefit from chemotherapy based on the genomic profiles of their tumors. Major limitation of this study is that the comparison between the chemotherapy vs. observation group was statistically underpowered and in disparate clinical/genomic subgroups, i.e., there was no true randomization in the high clinical/low genomic risk subgroup, which would have required recruitment of thousands more patients. 

Synopsis: Massive transfusion protocols are standard of care for exsanguinating trauma patients, but strategies to guide utilization of such protocols vary widely from ratio-based transfusions, to conventional coagulation assays, to viscoelastic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM). This trial enrolled 111 trauma patients that met criteria for massive transfusion protocol activation at a level-1 trauma center. Given the emergency nature of care, patients were randomized by week rather than individually and assigned to have transfusion managed by TEG or conventional coagulation assays (CCA), with the option for providers to review both sets of results if clinically necessary. Notably, the TEG variables included activated clotting time (time to beginning of clot formation), angle (rate of cloth strength increase), maximum amplitude (maximal clot strength achieved) and percent clot lysis 30 minutes after reaching max amplitude. In both the intent-to-treat and as-treated analyses, the CCA group had a significantly higher risk of death (hazard ratio = 2.17, 36.4% versus 19.6%), with most deaths occurring in the first 6 hours from ED arrival. The major limitations of this study are a relatively small sample size; moreover, the study uses a rather unconventional randomization scheme, though the groups appear similar in the measured baseline characteristics. In the trauma population, further trials should be able to determine the relative efficacy of goal-directed versus ratio-based massive transfusion, and viscoelastic assays warrant further investigation for guidance of transfusion in non-trauma surgical patients with coagulopathy and massive hemorrhage. 

Synopsis: Whether carotid artery stenting (CAS) is an effective alternative to carotid endarterectomy (CEA) for asymptomatic carotid artery stenosis is unknown. The largest prior randomized study of CEA vs. CAS, CREST (2010) looked at both symptomatic and asymptomatic patients with carotid artery stenosis, and concluded that CAS was non-inferior in a composite endpoint of stroke, MI, and death, although the rate of MI was significantly higher with CEA and the rate of stroke was significantly higher with CAS. There were not enough asymptomatic patients in CREST to evaluate them alone. The ACT-1 trial aimed to examine CEA vs. CAS in just asymptomatic patients. A total of 1453 patients were recruited in a multi-institutional randomized study. The primary composite endpoint was death, stroke, or MI within 30 days or ipsilateral stroke at 1 year. CAS was found to be non-inferior to CEA for the primary endpoint (3.8% vs. 3.4%, P=0.01 for non-inferiority). At 30 days, the rates of stroke (2.8% vs. 1.4%, P= 0.23) and MI (0.5% vs. 0.9%, P= 0.41) were not significantly different. They therefore concluded that CAS is non-inferior to CEA in patients with an asymptomatic 70-99% carotid stenosis. The limitations of this study are primarily the lack of a medical management arm. In asymptomatic patients, it is not entirely clear that intervening decreases the stroke rate as the original trials establishing the benefit of intervening on carotid stenosis were conducted prior to advances in medical management (notably the widespread use of statins). This is the rationale for an ongoing RCT CREST-2, which randomizes asymptomatic patients to carotid revascularization (CEA or CAS) vs. intensive medical management alone, and is currently accruing patients.