January 2019

Synopsis: Among patients with metastatic pancreatic cancer, the combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has resulted in longer overall survival than gemcitabine when administered as first-line treatment in patients with metastatic pancreatic cancer. On the basis of these results, this multicenter, randomized, open-label, phase 3 trial of 493 adult patients explored the efficacy of a modified FOLFIRINOX (without bolus fluorouracil), as compared with gemcitabine, as adjuvant therapy after R0 or R1 resection of pancreatic cancer. The primary end point was disease-free survival and secondary end points included overall survival and safety. At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% CI0.46 to 0.73; P<0.001). Furthermore, the disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including those with adverse prognostic factors such as T3 or T4 tumor status, positive lymph nodes, or R1 resection. The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. In conclusion, adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with R0 or R1 resected pancreatic cancer, at the expense of a higher incidence of toxic effects. However, the data remain immature, with 61% of all the patients being alive at the time of analysis. The trial is ongoing, with 3 years of follow-up currently. 

Synopsis: With the emergence of antibiotic-resistant bacteria, there is a growing emphasis on antibiotic stewardship to limit unnecessary antibiotic use and thereby avoid selecting for resistant organisms. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers in patients with ceftriaxone-resistant E. coli or K. pneumoniae bacteremia. In this noninferiority RCT, 378 adult patients were enrolled within 72 hours of initial blood culture positive for ceftriaxone-resistant E. coli or Klebsiella spp. susceptible to piperacillin-tazobactam and meropenem. The primary outcome assessed was all-cause mortality at 30 days from randomization and secondary outcomes included time to negative cultures, clinical resolution of infection, relapsed bloodstream infection, and secondary infection with C. difficile or meropenem or piperacillin-tazobactam-resistant organism. All-cause mortality at 30 days occurred in 23 of 187 (12.3%) of patients treated with piperacillin-tazobactam as compared to 7 of 191 (3.7%) in the meropenem group (P=0.90 for noninferiority). There were no significant differences in the secondary outcomes assessed. Given delays inherent to processing of blood cultures, investigators did not control empiric antibiotic therapy before patients were randomized into treatment groups. Some patients randomized to the piperacillin-tazobactam group thus received a carbapenem as empiric therapy, and vice-versa. However, this would bias toward noninferiority. In summary, this randomized clinical trial indicates that carbapenem-sparing therapy is not appropriate for patients with ceftriaxone-resistant E. coli or K. pneumoniae bacteremia. 

Synopsis:Waiting time for a deceased-donor kidney transplant exceeds 5 years in many areas and 5-8% of patients die each year on the waitlist. Concurrently, there has been a rise in hepatitis C virus (HCV) among deceased donors, partly attributed to the opioid epidemic. Organs from HCV-infected deceased donors are often discarded. The Transplanting Hepatitis C Kidneys Into Negative KidnEy Recipients (THINKER) trial, based out of the University of Pennsylvania, demonstrated a sustained virologic response at 12 weeks (consider a virologic cure) when transplanting HCV positive kidneys into HCV negative recipients, yet long-term data are not known. In this one-year follow-up study of the 20 HCV-negative transplant candidates who received a deceased donor kidney infected with genotype 1 HCV and were treated with elbasvir-grazoprevir starting on posttranplant day 3 and continued therapy for 12-16 weeks, all patients had a sustained HCV cure. Renal function was similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months and 12 months. It is notable that a single round of antiviral treatment could be susccessful despite concomitant use of intense immunosuppression, and that HCV positivity did not impact of graft function. Kidneys from HCV-infected donors may present an important opportunity to expand the donor pool, although these data will need to be confirmed in larger patient samples and potentially in other HCV genotypes. Important logistical barriers (coverage of direct-acting antiviral agents, routine HCV genotyping of donors) still need to be considered. 

Synopsis: Acute respiratory distress syndrome (ARDS) is a subtype of respiratory failure characterized by widespread pulmonary parenchymal inflammation and fluid sequestration. Severe ARDS is defined by certain pathophysiologic parameters including PaO2:FiO2 < 50 mmHg for more than 3 hours, a PaO2:FiO2 < 80 mmHg for more than 6 hours or a pH < 7.25 with PaCO2 ≥ 60 for more than 6 hours and RR increased to 35 breath/minute with plateau pressures maintained at ≤ 32 cm of water. Mortality associated with severed ARDS approaches 60% and thus, many centers will used venovenous (VV) ECMO to “offload” the lungs. This approach prevents overdistention of ventilated lung units and subsequent lung injury intrinsic to mechanical ventilation. Research on the impact of VV in patient with severe ARDS is unknown. The objective of the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial was to determine the effect of early initiation of ECMO in patient with severe ARDS. In this international clinical trial, 249 patients were randomized to either early ECMO (intervention) or control (standardized mechanical ventilation, frequent prone positioning, neuromuscular blocking agents). Participants were only eligible if they had undergone endotracheal intubation, been receiving mechanical ventilation for at most 7 days and met criteria for severe ARDS (as outlined above). Investigators found no difference in 60-day mortality between those participants who were placed on VV ECMO versus those that were randomized to control (continued mechanical ventilation) (RR: 0.76; 95% CI: 0.55, 1.04). Of note, the trial was stopped for futility after 249 of the 331 (estimated) participants were enrolled. In addition, 35 patients crossed over from control to VV ECMO at a mean of 6.5 days (SD: 9.7 days) after randomization; 57% (20/35) of the crossover group died. Given that the crossover cohort were comparably sicker than those randomized to the control group and did not crossover to VV ECMO, the question of how this groups mortality compared to that of matched participants originally assigned to VV ECMO (for more information, see Hardin et al, 2018).

Clinical Takeaway: Early initiation of VV ECMO was not associated with reduced 60-day mortality among patients with severe ARDS. However, there may be benefit in the subgroup of patients with the most severe ARDS, who are failing open-lung strategy due to high Pplat, ongoing poor oxygenation, worsening acidosis or those who develop cardiovascular failure from open-lung strategy.