The timing and indications for surgical intervention in asymptomatic patients with severe aortic stenosis remain controversial.
In a multicenter trial, we randomly assigned 145 asymptomatic patients ...with very severe aortic stenosis (defined as an aortic-valve area of ≤0.75 cm
with either an aortic jet velocity of ≥4.5 m per second or a mean transaortic gradient of ≥50 mm Hg) to early surgery or to conservative care according to the recommendations of current guidelines. The primary end point was a composite of death during or within 30 days after surgery (often called operative mortality) or death from cardiovascular causes during the entire follow-up period. The major secondary end point was death from any cause during follow-up.
In the early-surgery group, 69 of 73 patients (95%) underwent surgery within 2 months after randomization, and there was no operative mortality. In an intention-to-treat analysis, a primary end-point event occurred in 1 patient in the early-surgery group (1%) and in 11 of 72 patients in the conservative-care group (15%) (hazard ratio, 0.09; 95% confidence interval CI, 0.01 to 0.67; P = 0.003). Death from any cause occurred in 5 patients in the early-surgery group (7%) and in 15 patients in the conservative-care group (21%) (hazard ratio, 0.33; 95% CI, 0.12 to 0.90). In the conservative-care group, the cumulative incidence of sudden death was 4% at 4 years and 14% at 8 years.
Among asymptomatic patients with very severe aortic stenosis, the incidence of the composite of operative mortality or death from cardiovascular causes during the follow-up period was significantly lower among those who underwent early aortic-valve replacement surgery than among those who received conservative care. (Funded by the Korean Institute of Medicine; RECOVERY ClinicalTrials.gov number, NCT01161732.).
The timing and indications for surgical intervention to prevent systemic embolism in infective endocarditis remain controversial. We conducted a trial to compare clinical outcomes of early surgery ...and conventional treatment in patients with infective endocarditis.
We randomly assigned patients with left-sided infective endocarditis, severe valve disease, and large vegetations to early surgery (37 patients) or conventional treatment (39). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks after randomization.
All the patients assigned to the early-surgery group underwent valve surgery within 48 hours after randomization, whereas 30 patients (77%) in the conventional-treatment group underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The primary end point occurred in 1 patient (3%) in the early-surgery group as compared with 9 (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval CI, 0.01 to 0.82; P=0.03). There was no significant difference in all-cause mortality at 6 months in the early-surgery and conventional-treatment groups (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59). The rate of the composite end point of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months was 3% in the early-surgery group and 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02).
As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism. (EASE ClinicalTrials.gov number, NCT00750373.).
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary 0.0202 on the basis of number of deaths). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group.
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).
Percutaneous coronary intervention (PCI) is increasingly used to treat unprotected left main coronary artery stenosis, although coronary-artery bypass grafting (CABG) has been considered to be the ...treatment of choice.
We randomly assigned patients with unprotected left main coronary artery stenosis to undergo CABG (300 patients) or PCI with sirolimus-eluting stents (300 patients). Using a wide margin for noninferiority, we compared the groups with respect to the primary composite end point of major adverse cardiac or cerebrovascular events (death from any cause, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization) at 1 year. Event rates at 2 years were also compared between the two groups.
The primary end point occurred in 26 patients assigned to PCI as compared with 20 patients assigned to CABG (cumulative event rate, 8.7% vs. 6.7%; absolute risk difference, 2.0 percentage points; 95% confidence interval CI, -1.6 to 5.6; P=0.01 for noninferiority). By 2 years, the primary end point had occurred in 36 patients in the PCI group as compared with 24 in the CABG group (cumulative event rate, 12.2% vs. 8.1%; hazard ratio with PCI, 1.50; 95% CI, 0.90 to 2.52; P=0.12). The composite rate of death, myocardial infarction, or stroke at 2 years occurred in 13 and 14 patients in the two groups, respectively (cumulative event rate, 4.4% and 4.7%, respectively; hazard ratio, 0.92; 95% CI, 0.43 to 1.96; P=0.83). Ischemia-driven target-vessel revascularization occurred in 26 patients in the PCI group as compared with 12 patients in the CABG group (cumulative event rate, 9.0% vs. 4.2%; hazard ratio, 2.18; 95% CI, 1.10 to 4.32; P=0.02).
In this randomized trial involving patients with unprotected left main coronary artery stenosis, PCI with sirolimus-eluting stents was shown to be noninferior to CABG with respect to major adverse cardiac or cerebrovascular events. However, the noninferiority margin was wide, and the results cannot be considered clinically directive. (Funded by the Cardiovascular Research Foundation, Seoul, Korea, and others; PRECOMBAT ClinicalTrials.gov number, NCT00422968.).
Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer.
Patients were stratified and randomly assigned to receive sunitinib 37.5 mg ...once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS).
Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio HR, 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%).
OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.
KEYNOTE-158 ( ClinicalTrials.gov identifier: NCT02628067) is a phase II basket study investigating the antitumor activity and safety of pembrolizumab in multiple cancer types. We present interim ...results from patients with previously treated advanced cervical cancer.
Patients received pembrolizumab 200 mg every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors (version 1.1) by independent central radiologic review. Safety was a secondary end point.
Ninety-eight patients were treated. Median age was 46.0 years (range, 24 to 75 years), and 65.3% of patients had Eastern Cooperative Oncology Group performance status of 1. Eighty-two patients (83.7%) had programmed death-ligand 1 (PD-L1)-positive tumors (combined positive score ≥ 1), 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. Median follow-up was 10.2 months (range, 0.6 to 22.7 months). ORR was 12.2% (95% CI, 6.5% to 20.4%), with three complete and nine partial responses. All 12 responses were in patients with PD-L1-positive tumors, for an ORR of 14.6% (95% CI, 7.8% to 24.2%); 14.3% (95% CI, 7.4% to 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Median duration of response was not reached (range, ≥ 3.7 to ≥ 18.6 months). Treatment-related adverse events occurred in 65.3% of patients, and the most common were hypothyroidism (10.2%), decreased appetite (9.2%), and fatigue (9.2%). Treatment-related grade 3 to 4 adverse events occurred in 12.2% of patients.
Pembrolizumab monotherapy demonstrated durable antitumor activity and manageable safety in patients with advanced cervical cancer. On the basis of these results, the US Food and Drug Administration granted accelerated approval of pembrolizumab for patients with advanced PD-L1-positive cervical cancer who experienced progression during or after chemotherapy.
Summary Background Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin ...chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. Methods In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m2 (on days 1–14) and intravenous cisplatin 80 mg/m2 (on day 1), with or without weekly cetuximab (400 mg/m2 initial infusion on day 1 followed by 250 mg/m2 per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. Findings Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4·4 months (95% CI 4·2–5·5) compared with 5·6 months (5·1–5·7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1·09, 95% CI 0·92–1·29; p=0·32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3–4 adverse events, including grade 3–4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3–4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3–4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. Interpretation Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. Funding Merck KGaA.
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas
. ...More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours
. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer
, there are preclinical
and clinical
rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma
( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Purpose To compare the clinical and radiologic results of partial meniscectomy with those of refixation in patients with medial meniscus posterior root tears (MMPRTs) at a minimum 5-year follow-up. ...Methods Between 2005 and 2009, patients with MMPRTs who had been followed up for at least 5 years after a partial meniscectomy (group M, n = 20) or pullout repair (group R, n = 37) were recruited. The mean follow-up duration was 67.5 months in group M and 72.0 months in group R. Clinical assessments, including the Lysholm score and International Knee Documentation Committee (IKDC) Subjective Knee Form score, and radiographic assessments, including the Kellgren-Lawrence (K-L) grade and medial joint space width, were evaluated preoperatively and at final follow-up. We compared the preoperative results with the final results in each group, and we compared the final results of groups M and R. Five-year survival rates were also evaluated. Results The mean Lysholm score ( P = .039) and IKDC score ( P = .037) improved significantly. However, the width of the medial joint space ( P < .001) and K-L grade ( P < .001) worsened significantly in both groups. When we compared the final results, group R had significantly better Lysholm scores ( P = .002) and IKDC scores ( P < .001) than group M. Group R showed less K-L grade progression ( P = .005) and less medial joint space narrowing ( P < .001) than group M. The rate of conversion to total knee arthroplasty was 35% in group M, whereas there was no conversion to total knee arthroplasty in group R. The 5-year survival rates in groups M and R were 75% and 100%, respectively ( P < .001). Conclusions For MMPRTs, refixation was more effective than partial meniscectomy in terms of the clinical and radiologic outcomes and survival for at least 5 years' follow-up. Refixation slowed the progression of arthritic changes compared with partial meniscectomy, although it did not prevent the progression of arthrosis completely. Level of Evidence Level III, retrospective comparative study.
The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III ...study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer.
Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world ROW). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety.
Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW.
Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.
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