NEJM original articles

Background. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in 1993 to assess the effect of prostate-specific antigen (PSA) testing on prostate cancer mortality. Because deaths from prostate cancer are expected to rise worldwide owing to increased life expectancy and population growth, a final analysis of the long-term outcomes of prostate cancer screening is essential to understanding the benefits and harms of PSA testing.

Methods. We updated the findings from ERSPC, a multicenter, randomized study conducted across eight European countries with a focus on a predefined core age group of 162,236 men who were 55 to 69 years of age at the time of randomization. Participants were randomly assigned to the screening group and offered repeated PSA testing or to the control group and not invited for screening. The primary outcome was prostate cancer mortality.

Results. After a median follow-up of 23 years, prostate cancer mortality was 13% lower in the screening group (rate ratio, 0.87; 95% confidence interval [CI], 0.80 to 0.95), and the absolute risk reduction was 0.22% (95% CI, 0.10 to 0.34). The cumulative incidence of prostate cancer was higher in the screening group than in the control group (rate ratio, 1.30; 95% CI, 1.26 to 1.33). At a median of 23 years of follow-up, one death from prostate cancer was prevented for every 456 men (95% CI, 306 to 943) who were invited for screening, and one death from prostate cancer was averted for every 12 men (95% CI, 8 to 26) in whom prostate cancer was diagnosed, as compared with one death from prostate cancer prevented for every 628 men (95% CI, 419 to 1481) and one death averted for every 18 men (95% CI, 12 to 45) at 16 years of follow-up.

Conclusions. Long-term follow-up confirms a sustained reduction in deaths from prostate cancer with PSA testing, alongside an improved harm-benefit ratio. Future screening strategies should adopt risk-based approaches to minimize overdiagnosis while maintaining clinical benefits. (Funded by the Dutch Cancer Society and others; ERSPC ISRCTN registry number, ISRCTN49127736.).

Background. Previous results from this phase 3 trial showed that progression-free survival among participants with previously untreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC) was significantly improved with amivantamab-lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported.

Methods. We randomly assigned, in a 2:2:1 ratio, participants with previously untreated EGFR-mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab-lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety.

Results. A total of 429 participants each were assigned to receive amivantamab-lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P = 0.005); 3-year overall survival was 60% and 51%, respectively. At the clinical cutoff date, 38% of participants in the amivantamab-lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab-lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up.

Conclusions. Amivantamab-lazertinib led to significantly longer overall survival among participants with previously untreated EGFR-mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of grade 3 or higher. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Background. Physical therapy is routinely recommended for knee pain attributed to a degenerative meniscal tear, but its efficacy has not been established.

Methods. We randomly assigned participants 45 to 85 years of age with knee pain, osteoarthritis, and meniscal tear to one of four groups: home exercise (3-month home-exercise program), home exercise plus text messages to encourage exercise adherence, home exercise plus text messages plus sham physical therapy (in-clinic sham manual therapy and sham ultrasound therapy), and home exercise plus text messages plus standard physical therapy (supervised strengthening, functional, and stretching exercises and manual therapy). The primary outcome was the change in the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscore (range, 0 to 100, with higher scores indicating more pain) between baseline and 3 months, with adjustment for trial site, baseline KOOS pain subscore, and radiographic grade.

Results. A total of 879 participants underwent randomization (mean [±SD] age, 59.2±7.8 years). The difference in the 3-month change in the KOOS pain subscore between home exercise and home exercise plus text messages was -0.1 points (98.3% confidence interval [CI], -3.8 to 3.7) and between home exercise and home exercise plus text messages plus standard physical therapy was 2.5 points (98.3% CI, -1.3 to 6.2); the difference between home exercise plus text messages and home exercise plus text messages plus standard physical therapy was 2.5 points (98.3% CI, -1.4 to 6.5). Adverse events were generally nonserious and evenly distributed overall across groups.

Conclusions. For patients with degenerative meniscal tear and knee pain, the addition of physical therapy or text messages to encourage adherence to home exercises was not superior in reducing pain to a home-exercise program alone. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; TeMPO ClinicalTrials.gov number, NCT03059004.).

Background. Salmonella enterica serovar Paratyphi A (also known as S. Paratyphi A) is responsible for more than 2 million cases of enteric fever annually. There are no licensed vaccines against S. Paratyphi A.

Methods. In a double-blind, randomized, placebo-controlled trial, we evaluated an orally administered live, attenuated S. Paratyphi A vaccine (CVD 1902) using a controlled human infection model. Healthy U.K. adults were assigned in a 1:1 ratio to receive two doses of CVD 1902 or placebo 14 days apart. Twenty-eight days after the second dose, participants were challenged orally with S. Paratyphi A. The primary end point was a diagnosis of S. Paratyphi A infection within 14 days after challenge. Secondary end points included safety and immunogenicity.

Results. A total of 72 participants underwent randomization, of whom 34 in the CVD 1902 group and 36 in the placebo group were challenged with S. Paratyphi A. The median age of the participants was 32 years (range, 20 to 54), and 46% were women. The number of adverse events was generally similar in the two groups, and no vaccine-related serious adverse events were identified. CVD 1902 induced serum IgG and IgA responses to the O antigen of S. Paratyphi A. No increases in serum IgG or IgA titers occurred in the placebo group. In the intention-to-treat population, an S. Paratyphi A infection was diagnosed within 14 days after challenge in 21% of the participants in the CVD 1902 group and in 75% of those in the placebo group (P<0.001), resulting in a vaccine efficacy of 73% (95% confidence interval [CI], 46 to 86). The vaccine efficacy was 69% (95% CI, 42 to 84) in the per-protocol analysis.

Conclusions. In healthy U.K. adults who were challenged with S. Paratyphi A in a controlled human infection model, a two-dose series of CVD 1902 led to protection against S. Paratyphi A infection without safety concerns. (Funded by the Medical Research Council; VASP ISRCTN Registry number, 15485902.).