Daily Archives: September 18, 2024
RCT: Pembrolizumab Plus Chemotherapy Improved Overall Survival in Early-Stage Triple-Negative Breast Cancer
18 Sep, 2024 | 16:08h | UTCBackground: Early-stage triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. The phase 3 KEYNOTE-522 trial previously demonstrated that adding pembrolizumab to chemotherapy improved pathological complete response rates and event-free survival in this population.
Objective: To determine whether neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab improves overall survival compared to neoadjuvant chemotherapy alone in patients with early-stage TNBC.
Methods: In this multicenter, randomized, double-blind, placebo-controlled phase 3 trial (KEYNOTE-522), 1174 patients with previously untreated stage II or III TNBC were randomized 2:1 to receive neoadjuvant pembrolizumab (200 mg every 3 weeks) plus chemotherapy (paclitaxel and carboplatin, followed by doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide) or placebo plus the same chemotherapy regimen. After surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary endpoints were pathological complete response and event-free survival; overall survival was a key secondary endpoint.
Results: After a median follow-up of 75.1 months, the estimated 5-year overall survival was 86.6% in the pembrolizumab–chemotherapy group versus 81.7% in the placebo–chemotherapy group (hazard ratio for death, 0.66; P=0.002). The 5-year event-free survival was 81.2% versus 72.2%, respectively (hazard ratio for event or death, 0.65; 95% CI, 0.51–0.83). Grade 3 or higher treatment-related adverse events occurred in 77.1% of patients receiving pembrolizumab–chemotherapy and 73.3% receiving placebo–chemotherapy. Serious treatment-related adverse events occurred in 34.1% and 20.1% of patients, respectively.
Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improved overall survival compared to chemotherapy alone in patients with early-stage TNBC.
Implications for Practice: The addition of pembrolizumab to standard neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, should be considered a new standard of care for patients with high-risk, early-stage TNBC, offering a significant survival benefit.
Study Strengths and Limitations: Strengths include the large, international, randomized design, the use of a placebo control, and long-term follow-up. Limitations include the inability to isolate the effects of neoadjuvant versus adjuvant pembrolizumab and the exclusion of adjuvant capecitabine from the treatment protocol.
Future Research: Further studies should focus on identifying biomarkers predictive of response to pembrolizumab, optimizing the sequencing and duration of immunotherapy, and evaluating the addition of other agents to improve outcomes in early-stage TNBC.
RCT: Perioperative Durvalumab Plus Neoadjuvant Chemotherapy Improved Survival in Muscle-Invasive Bladder Cancer
18 Sep, 2024 | 15:22h | UTCBackground: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). Despite this approach, approximately 50% of patients experience recurrence within 3 years. Combining immunotherapy with chemotherapy may enhance outcomes, and durvalumab, a PD-L1 inhibitor, has shown promise when added to chemotherapy in previous studies.
Objective: To evaluate whether perioperative durvalumab combined with neoadjuvant gemcitabine–cisplatin improves event-free survival (EFS) and overall survival (OS) compared to neoadjuvant chemotherapy alone in cisplatin-eligible patients with operable MIBC.
Methods: In the phase 3, open-label, randomized NIAGARA trial, 1063 cisplatin-eligible patients with MIBC (clinical stage T2-T4aN0-1M0) were randomized 1:1 to receive either perioperative durvalumab plus neoadjuvant gemcitabine–cisplatin followed by radical cystectomy and adjuvant durvalumab (durvalumab group, n=533) or neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group, n=530). The primary endpoints were EFS and pathological complete response (pCR). The key secondary endpoint was OS.
Results: At a median follow-up of 42.3 months, the estimated EFS at 24 months was 67.8% (95% CI, 63.6–71.7) in the durvalumab group versus 59.8% (95% CI, 55.4–64.0) in the comparison group (hazard ratio [HR] for progression, recurrence, not undergoing cystectomy, or death, 0.68; 95% CI, 0.56–0.82; P<0.001). The estimated OS at 24 months was 82.2% (95% CI, 78.7–85.2) in the durvalumab group versus 75.2% (95% CI, 71.3–78.8) in the comparison group (HR for death, 0.75; 95% CI, 0.59–0.93; P=0.01). Grade 3 or 4 treatment-related adverse events occurred in 40.6% of patients in the durvalumab group and 40.9% in the comparison group. Radical cystectomy was performed in 88.0% of patients in the durvalumab group and 83.2% in the comparison group.
Conclusions: Perioperative durvalumab combined with neoadjuvant chemotherapy significantly improved event-free and overall survival compared to neoadjuvant chemotherapy alone in cisplatin-eligible patients with operable MIBC.
Implications for Practice: Adding perioperative durvalumab to neoadjuvant chemotherapy may represent a new option for cisplatin-eligible patients with MIBC, offering improved survival outcomes without increasing significant adverse events or delaying surgery.
Study Strengths and Limitations: Strengths include the large sample size and randomized, phase 3 design. Limitations encompass the open-label design and inability to isolate the effects of neoadjuvant versus adjuvant durvalumab. Additionally, the trial was conducted before the widespread use of adjuvant nivolumab, potentially affecting the generalizability of the results.
Future Research: Further studies are needed to delineate the relative contributions of neoadjuvant and adjuvant durvalumab and to explore biomarkers such as circulating tumor DNA to guide treatment decisions.
RCT: Nivolumab Plus Ipilimumab Shows Sustained 10-Year Survival Benefit in Advanced Melanoma
18 Sep, 2024 | 15:06h | UTCBackground: Advanced melanoma historically had a poor prognosis, with median survival under 12 months before 2011. The advent of immune checkpoint inhibitors like nivolumab (anti–PD-1) and ipilimumab (anti–CTLA-4) has significantly improved outcomes. Previous results from the CheckMate 067 trial showed longer overall survival with nivolumab plus ipilimumab or nivolumab alone compared to ipilimumab alone. As patients now live beyond 7.5 years, longer-term data are needed to address new clinical questions about survival and disease progression.
Objective: To assess the final 10-year outcomes of overall survival, melanoma-specific survival, and response durability in patients with advanced melanoma treated with nivolumab plus ipilimumab, nivolumab monotherapy, or ipilimumab monotherapy.
Methods: In the phase 3 CheckMate 067 trial, 945 patients with untreated, unresectable stage III or IV melanoma were randomized 1:1:1 to receive:
- Nivolumab plus ipilimumab: Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for four doses, then nivolumab (3 mg/kg) every 2 weeks.
- Nivolumab monotherapy: Nivolumab (3 mg/kg) every 2 weeks plus placebo.
- Ipilimumab monotherapy: Ipilimumab (3 mg/kg) every 3 weeks for four doses plus placebo.
Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Randomization was stratified by BRAF mutation status, metastasis stage, and PD-L1 expression. Primary endpoints were overall survival and progression-free survival; secondary endpoints included objective response rates and subgroup analyses.
Results: After 10 years, median overall survival was:
- 71.9 months with nivolumab plus ipilimumab,
- 36.9 months with nivolumab,
- 19.9 months with ipilimumab.
Hazard ratios for death were 0.53 (95% CI, 0.44–0.65; P<0.001) for nivolumab plus ipilimumab vs. ipilimumab, and 0.63 (95% CI, 0.52–0.76; P<0.001) for nivolumab vs. ipilimumab. Ten-year overall survival rates were 43% with combination therapy, 37% with nivolumab, and 19% with ipilimumab. Median melanoma-specific survival was not reached (>120 months) with combination therapy (37% alive at study end), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with combination therapy, 97% with nivolumab, and 88% with ipilimumab. No new safety signals were observed over the extended follow-up.
Conclusions: Nivolumab plus ipilimumab demonstrated a sustained 10-year survival benefit over ipilimumab monotherapy in advanced melanoma. Nivolumab monotherapy also improved survival compared to ipilimumab, though the combination provided the greatest benefit.
Implications for Practice: These 10-year results support nivolumab plus ipilimumab as a preferred first-line treatment for advanced melanoma, offering potential for long-term survival and possible cure. Clinicians should balance improved efficacy against higher adverse event rates with combination therapy and monitor patients accordingly.
Study Strengths and Limitations: Strengths include the large, randomized, multicenter design and extended follow-up, providing robust survival data. Limitations include the trial not being powered for formal comparison between combination and monotherapy, and potential confounding from subsequent therapies on long-term outcomes.
Future Research: Further studies should aim to identify biomarkers predicting long-term response, optimize patient selection for combination therapy, and develop treatments for patients unresponsive to current immune checkpoint inhibitors.
Meta-analysis: Perioperative Colchicine Reduced Postoperative Atrial Fibrillation After CABG
18 Sep, 2024 | 13:33h | UTCBackground: Coronary artery disease (CAD) remains a leading cause of mortality worldwide. Inflammation is a key factor in the development and progression of CAD, and anti-inflammatory therapies have shown potential in improving cardiovascular outcomes. Colchicine, traditionally used to treat gout, has demonstrated efficacy in reducing cardiovascular events in patients with chronic CAD. Previous individual studies have suggested that perioperative colchicine may decrease the incidence of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass grafting (CABG), but a comprehensive analysis is needed to confirm these findings.
Objective: To evaluate the effect of perioperative colchicine administration on the incidence of POAF in patients undergoing isolated CABG surgery through a meta-analysis of randomized controlled trials (RCTs).
Methods: A systematic search was conducted across MEDLINE, Web of Science, and The Cochrane Library to identify RCTs comparing perioperative colchicine administration with standard care in patients undergoing CABG. Inclusion criteria encompassed studies involving isolated CABG patients randomized to receive colchicine or standard care without colchicine. The primary outcome was the incidence of POAF during short-term follow-up.
Results: Five RCTs published between 2014 and 2022 met the inclusion criteria, including a total of 839 patients undergoing isolated CABG. Perioperative colchicine administration was associated with a significant reduction in POAF rates compared to standard care (relative risk [RR], 0.54; 95% confidence interval [CI], 0.40–0.73; p < 0.01). Other outcomes, such as graft patency, myocardial infarction, or long-term mortality, were not uniformly reported and, therefore, not analyzed.
Conclusions: Perioperative administration of colchicine is associated with a significant reduction in the incidence of POAF in patients undergoing CABG surgery.
Implications for Practice: Colchicine may be considered as a prophylactic strategy to reduce POAF in patients undergoing CABG, potentially improving both short- and long-term outcomes. Given the association of POAF with increased perioperative morbidity and long-term adverse events, implementing colchicine could have substantial clinical benefits in this high-risk population.
Study Strengths and Limitations: Strengths of this meta-analysis include the exclusive inclusion of randomized controlled trials and the use of rigorous statistical methods, including sensitivity analysis, which confirmed the robustness of the results. Limitations involve the small number of studies (five RCTs), potential variability in colchicine dosing regimens, and the lack of data on other clinically relevant outcomes.
Future Research: Large-scale, multicenter RCTs are warranted to further assess the effects of colchicine on other important outcomes in CABG patients, such as graft patency, myocardial infarction rates, and long-term mortality. Future studies should also evaluate the risk-benefit profile of colchicine in this patient population to establish its full role in clinical practice.
Reference: Kirov H., Caldonazo T., Runkel A., et al. (2024). Colchicine in Patients with Coronary Disease Undergoing Coronary Artery Bypass Surgery – A Meta-Analysis of Randomized Controlled Trials. The American Journal of Cardiology. DOI: http://doi.org/10.1016/j.amjcard.2024.09.003
RCT: Stereotactic Body Radiotherapy Reduced Incontinence and Sexual Dysfunction vs. Prostatectomy in Localized Prostate Cancer
18 Sep, 2024 | 10:51h | UTCBackground: Men with localized prostate cancer have several treatment options, including prostatectomy and radiotherapy. Patient-reported outcomes (PROs) are crucial in guiding treatment decisions due to potential impacts on quality of life. However, randomized data comparing stereotactic body radiotherapy (SBRT) with prostatectomy are lacking.
Objective: To compare patient-reported urinary, bowel, and sexual outcomes at 2 years following SBRT versus prostatectomy in men with low- to intermediate-risk localized prostate cancer.
Methods: In the phase 3 PACE-A randomized controlled trial conducted in the UK from 2012 to 2022, 123 men with National Comprehensive Cancer Network (NCCN) low- to intermediate-risk localized prostate cancer were randomized 1:1 to receive either SBRT (36.25 Gy in five fractions) or prostatectomy. Androgen deprivation therapy was not permitted. The co-primary outcomes were the number of absorbent urinary pads used daily and the Expanded Prostate Index Composite (EPIC-26) bowel domain score at 2 years. Secondary outcomes included clinician-reported toxicity and sexual function.
Results: Among 110 men who received treatment (median age 65.5 years; median PSA 7.9 ng/ml; 92% intermediate-risk), 50 underwent prostatectomy and 60 received SBRT. At 2 years, 50% of prostatectomy patients reported using one or more urinary pads daily compared to 6.5% of SBRT patients (p < 0.001; difference 43%, 95% CI 25%–62%). Bowel domain scores were better for prostatectomy (median 100) than for SBRT (median 87.5; p < 0.001; mean difference 8.9, 95% CI 4.2–13.7). Sexual function scores were worse for prostatectomy (median 18) compared to SBRT (median 62.5; p < 0.001). Clinician-reported genitourinary and gastrointestinal toxicities were low in both groups.
Conclusions: SBRT was associated with significantly less urinary incontinence and sexual dysfunction but slightly worse bowel function compared to prostatectomy at 2 years in men with localized prostate cancer.
Implications for Practice: These findings provide preliminary evidence to inform treatment decisions for men with low- to intermediate-risk localized prostate cancer. SBRT may offer advantages in reducing urinary incontinence and sexual dysfunction, which are significant considerations for patients. Clinicians should also discuss the potential for increased bowel symptoms with SBRT.
Study Strengths and Limitations: Strengths include the randomized design, use of contemporary treatment modalities, and comprehensive assessment of PROs. Limitations involve the small sample size due to slow recruitment, differential dropout rates, and incomplete PRO responses at the 2-year mark.
Future Research: Larger-scale randomized trials are needed to confirm these findings, assess long-term outcomes beyond 2 years, and evaluate the impact on disease control and quality of life.