Journal of Clinical Oncology最新文献

Immune checkpoint blockers (ICBs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). Currently, one-dose-fits-all maximalist regimens have been considered the standard of care, with ICBs administered at flat doses regardless of patients' weight. Treatment duration with ICBs is often arbitrary across stages, ranging from a fixed time point to until disease progression or unacceptable toxicity. However, the pharmacokinetic and pharmacodynamic properties of ICBs differ significantly from those of traditional cytotoxic drugs and the approved and selected doses on the basis of the maximum tolerated dose are often overestimated as there is limited evidence supporting a direct relationship between therapeutic intensity and outcomes. This can lead to overtreatment of patients, resulting in an increased risk of toxicity without enhanced efficacy. In addition, the use of these drugs is associated with significant costs that burden the global health care system and exacerbate disparities in access to care. De-escalating treatment by reducing the dose, duration, and frequency of administration of ICBs could optimize treatment efficacy, reduce toxicities, improve patients' quality of life, and even decrease costs. Ultimately, de-escalation strategies may help to reduce treatment inequalities and to improve drug access worldwide. The aim of this review is to summarize and discuss the main issues and challenges regarding the de-escalation of ICBs in patients with NSCLC, focusing on dose-intensity reduction and treatment duration selection. Moreover, we assess the economic impact of implementing de-escalation approaches.

Purpose: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC).

Methods: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m² once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points.

Results: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively.

Conclusion: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

Purpose: The value of pelvic lymph node irradiation is debated for patients with muscle-invasive bladder cancer (MIBC) undergoing curative-intent radiation therapy (RT). We sought to compare the oncologic outcomes between bladder-only (BO)-RT and whole-pelvis (WP)-RT using a large Canadian multicenter collaborative database.

Patients and methods: The study cohort consisted of 809 patients with MIBC (cT2-4aN0-2M0) who underwent curative RT at academic centers across Canada. Patients were divided into two groups on the basis of the RT volume: WP-RT versus BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance covariates across treatment groups. Regression models were used to assess the effect of the RT volume on the rates of complete response (CR), cancer-specific survival (CSS), and overall survival (OS).

Results: After exclusion criteria, 599 patients were included, of whom 369 (61.6%) underwent WP-RT. Patients receiving WP-RT were younger (ASD, 0.41) and more likely to have an Eastern Cooperative Oncology Group performance status of 0-1 (ASD, 0.21), clinical node-positive disease (ASD, 0.40), and lymphovascular invasion (ASD, 0.25). In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (ASD, 0.29) and concurrent chemotherapy (ASD, 0.44). In the IPTW cohort, BO-RT and WP-RT groups were well balanced (all pretreatment parameters with an ASD <0.10). In multivariable analysis, WP-RT was not associated with CR rates post-RT (odds ratio, 1.14 [95 CI, 0.76 to 1.72]; P = .526) but was associated with both CSS (hazard ratio [HR], 0.66 [95% CI, 0.47 to 0.93]; P = .016) and OS (HR, 0.68 [95% CI, 0.54 to 0.87]; P = .002), independent of other prognostic factors.

Conclusion: Our study demonstrated that WP radiation was associated with better survival compared with bladder radiation alone after adjusted analysis. Additional randomized controlled trials are needed to confirm our findings.

Purpose: Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3^IDHmt/Codel) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens.

Methods: The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3^IDHmt/Codel. We included patients with histologically proven O3^IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathologic review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model.

Results: 305 newly diagnosed patients with O3^IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025).

Conclusion: In patients with newly diagnosed O3^IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Purpose: Recent studies suggested fine particulate matter (PM_2.5) exposure increases the risk of breast cancer, but evidence among racially and ethnically diverse populations remains sparse.

Materials and methods: Among 58,358 California female participants of the Multiethnic Cohort (MEC) Study followed for an average of 19.3 years (1993-2018), we used Cox proportional hazards regression to examine associations of time-varying PM with invasive breast cancer risk (n = 3,524 cases; 70% African American and Latino females), adjusting for sociodemographics and lifestyle factors. Subgroup analyses were conducted for race and ethnicity, hormone receptor status, and breast cancer risk factors.

Results: Satellite-based PM_2.5 was associated with a statistically significant increased incidence of breast cancer (hazard ratio [HR] per 10 μg/m³, 1.28 [95% CI, 1.08 to 1.51]). We found no evidence of heterogeneity in associations by race and ethnicity and hormone receptor status. Family history of breast cancer showed evidence of heterogeneity in PM_2.5-associations (P_{heterogeneity} = .046). In a meta-analysis of the MEC and 10 other prospective cohorts, breast cancer incidence increased in association with exposure to PM_2.5 (HR per 10 μg/m³ increase, 1.05 [95% CI, 1.00 to 1.10]; P = .064).

Conclusion: Findings from this large multiethnic cohort with long-term air pollutant exposure and published prospective cohort studies support PM_2.5 as a risk factor for breast cancer. As about half of breast cancer cannot be explained by established breast cancer risk factors and incidence is continuing to increase, particularly in low- and middle-income countries, our results highlight that breast cancer prevention should include not only individual-level behavior-centered approaches but also population-wide policies and regulations to curb PM_2.5 exposure.