NEJM original articles

Background. Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes.

Methods. In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response.

Results. A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 onward, 0.67 [95% CI, 0.50 to 0.90]; P = 0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant treatment was 2.3% and 4.6%.

Conclusions. Perioperative durvalumab plus FLOT led to significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or gastroesophageal junction adenocarcinoma. (Funded by AstraZeneca; MATTERHORN ClinicalTrials.gov number, NCT04592913.).

Background. Prednisone is currently recommended as the first-line treatment for pulmonary sarcoidosis but is associated with many side effects. Methotrexate, which is recommended as a second-line treatment, appears to have fewer side effects than prednisone but a slower onset of action. Data are needed on the efficacy and side-effect profile of methotrexate as compared with prednisone as first-line treatment for pulmonary sarcoidosis.

Methods. In this multicenter, open-label, noninferiority trial involving patients with pulmonary sarcoidosis who had not previously received treatment, we randomly assigned patients, in a 1:1 ratio, to receive prednisone or methotrexate according to a prespecified treatment schedule. The primary end point was the mean change from baseline to week 24 in the percentage of the predicted forced vital capacity (FVC), as estimated with the use of mixed models for repeated measures. The noninferiority margin for the primary end point was 5 percentage points.

Results. Of the 138 patients who underwent randomization, 70 were assigned to receive prednisone and 68 to receive methotrexate. The unadjusted mean change from baseline to week 24 in the percentage of the predicted FVC was 6.75 percentage points (95% confidence interval [CI], 4.50 to 8.99) in the prednisone group and 6.11 percentage points (95% CI, 3.72 to 8.50) in the methotrexate group. Methotrexate was noninferior to prednisone with regard to the primary end point, with an adjusted between-group difference of -1.17 percentage points (95% CI, -4.27 to 1.93). Adverse events occurred in a similar percentage of patients in the two trial groups. Weight gain, insomnia, and increased appetite were the most common adverse events with prednisone, and nausea, fatigue, and any abnormal liver-function test were among the most common adverse events with methotrexate.

Conclusions. In patients with pulmonary sarcoidosis, initial treatment with methotrexate was noninferior to that with prednisone with regard to the change from baseline to week 24 in the percentage of the predicted FVC. Differences in the side-effect profile between methotrexate and prednisone may inform shared decision making by providers and patients about the appropriate treatment approach. (Funded by the Dutch Lung Foundation; PREDMETH ClinicalTrials.gov number, NCT04314193.).

Background. Allogeneic peripheral-blood stem-cell transplantation (SCT) from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers. The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease (GVHD) prophylaxis in these patients. Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite. However, the effects of post-transplantation cyclophosphamide specifically after SCT from a matched related donor remain uncertain, and effects in the context of myeloablative conditioning are unclear.

Methods. We randomly assigned adults who were undergoing SCT from a matched related donor after myeloablative or reduced-intensity conditioning to receive either post-transplantation cyclophosphamide-cyclosporin (experimental prophylaxis) or cyclosporin-methotrexate (standard prophylaxis). The primary end point was GVHD-free, relapse-free survival.

Results. Among 134 patients who underwent randomization, 66 were assigned to receive experimental prophylaxis and 68 to receive standard prophylaxis. GVHD-free, relapse-free survival was significantly longer with experimental prophylaxis (median, 26.2 months; 95% confidence interval [CI], 9.1 to not reached) than with standard prophylaxis (median, 6.4 months; 95% CI, 5.6 to 8.3; P<0.001 by a log-rank test). GVHD-free, relapse-free survival at 3 years was 49% (95% CI, 36 to 61) with experimental prophylaxis and 14% (95% CI, 6 to 25) with standard prophylaxis (hazard ratio for GVHD, relapse, or death, 0.42; 95% CI, 0.27 to 0.66). The cumulative incidence of grade III to IV acute GVHD at 3 months was 3% (95% CI, 1 to 10) in the experimental-prophylaxis group and 10% (95% CI, 4 to 19) in the standard-prophylaxis group. At 2 years, overall survival was 83% and 71%, respectively (hazard ratio for death, 0.59; 95% CI, 0.29 to 1.19). The incidence of serious adverse events was similar in the two groups in the first 100 days after SCT.

Conclusions. The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis after transplantation from a matched related donor with either reduced-intensity or myeloablative conditioning in patients with blood cancers. (Funded by the Australian Government Medical Research Future Fund and others; ALLG BM12 CAST Australian-New Zealand Clinical Trials Registry number, ACTRN12618000505202.).

Background. Ondansetron improves outcomes when administered in emergency departments to children with acute gastroenteritis-associated vomiting. It is commonly prescribed at discharge to reduce symptoms, but evidence to support this practice is limited.

Methods. We conducted a double-blind, randomized superiority trial involving children 6 months to less than 18 years of age with acute gastroenteritis-associated vomiting in six pediatric emergency departments. Caregivers were provided with six doses of oral ondansetron or placebo to administer in response to ongoing vomiting during the first 48 hours after enrollment. The primary outcome was moderate-to-severe gastroenteritis, defined by a score of 9 or higher on the modified Vesikari scale (scores range from 0 to 20, with higher scores indicating greater severity), during the 7 days after enrollment. Secondary outcomes included the presence of vomiting, the duration of vomiting (defined as the time from enrollment to the last vomiting episode), the number of vomiting episodes within 48 hours after enrollment, unscheduled physician visits within 7 days after enrollment, and receipt of intravenous fluids.

Results. A total of 1030 children underwent randomization. Moderate-to-severe gastroenteritis occurred in 5.1% (23 of 452 participants for whom data were available) in the ondansetron group and 12.5% (55 of 441) in the placebo group (unadjusted risk difference, -7.4 percentage points; 95% confidence interval [CI], -11.2 to -3.7). After adjustment for site, weight, and missing data, ondansetron was associated with a lower risk of moderate-to-severe gastroenteritis than placebo (adjusted odds ratio, 0.50; 95% CI, 0.40 to 0.60). Although we did not observe any meaningful difference between the groups in the presence or median duration of vomiting, the total number of vomiting episodes within 48 hours after enrollment was lower with ondansetron than with placebo (adjusted rate ratio, 0.76; 95% CI, 0.67 to 0.87). The percentage of children who had unscheduled health care visits and the percentage who received intravenous fluids after enrollment did not differ substantially between the groups. The incidence of adverse events also did not differ meaningfully between the groups (odds ratio, 0.99; 95% CI, 0.61 to 1.61).

Conclusions. Among children with gastroenteritis-associated vomiting, the provision of ondansetron after an emergency department visit led to lower risk of moderate-to-severe gastroenteritis during the subsequent 7 days than the provision of placebo. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT03851835.).

We report a method for the recovery of hearts for transplantation from deceased donors after circulatory death that obviates the need for thoracoabdominal normothermic regional perfusion or ex situ perfusion systems. After death, the aorta is clamped and a flush circuit is established to perform a controlled, extended, ultraoxygenated flush of the donor heart at a mean aortic-root pressure of 80 mm Hg. In the first three reported cases in which this method was used, the hearts were transplanted successfully with normal biventricular function, no evidence of acute cellular or antibody-mediated rejection, and excellent early postoperative outcomes. No adverse events were reported during the perioperative period. By avoiding the limitations of ex situ perfusion platforms as well as the controversial aspects of thoracoabdominal normothermic regional perfusion, this method of heart recovery offers the possibility of broad application.

Cardiac allotransplantation is warranted in children with end-stage heart failure or irreparable congenital heart disease. A dearth of organs for transplantation has contributed to long wait-list times and resultant deaths in this population. Donation after circulatory death (DCD) with normothermic regional perfusion has the potential to increase the donor pool by up to 30%. Ethical concerns have limited adoption of this technique in the United States and abroad. Consequently, a method facilitating ex vivo resuscitation of hearts from deceased donors after circulatory death (i.e., DCD hearts) is needed. We describe an on-table reanimation of a pediatric DCD heart transplanted into a 3-month-old recipient. Adverse events are reported.