JNCI Journal of the National Cancer Institute最新文献

Background: Advance care planning and serious illness conversations can help clinicians understand patients' values and preferences. Data are limited on how to increase the number of these conversations and what their effects are on care patterns. We hypothesized that using a machine learning survival model to select patients for serious illness conversations, along with trained care coaches to conduct the conversations, would increase uptake in patients with cancer at high risk of short-term mortality.

Methods: We conducted a cluster-randomized, stepped-wedge study on the physician level. Oncologists entered the intervention condition in a random order over 6 months. Adult patients with metastatic cancer were included. Patients with a less than 2-year computer-predicted survival and no prognosis documentation were classified as high priority for serious illness conversations. In the intervention condition, clinicians received automated weekly emails highlighting high-priority patients and were asked to document prognoses for them. Care coaches contacted these patients to conduct the remainder of the conversation. The primary endpoint was the proportion of visits with prognosis documentation within 14 days.

Results: We included 6372 visits with 1825 patients in the primary analysis. The proportion of visits with prognosis documentation within 14 days was higher in the intervention condition than in the control condition: 2.9% vs 1.1% (adjusted odds ratio = 4.3, P < .001). The proportion of visits with advance care planning documentation was also higher in the intervention condition: 7.7% vs 1.8% (adjusted odds ratio = 14.2, P < .001). For high-priority visits, the advance care planning documentation rate in intervention visits was 24.2% and in control visits was 4.0%.

Conclusion: The intervention increased documented conversations, with contributions by both clinicians and care coaches.

Background: The chronic lymphocytic leukemia treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemotherapy-free regimens. Frequentist network meta-analysis allows for direct and indirect comparisons between different treatments.

Methods: Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease, objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities.

Results: A total of 30 eligible trials involved 12 818 patients, and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax in patients aged older than 65 years or with unmutated IGHV. In younger patients with comorbidities, acalabrutinib-obinutuzumab had superior PFS compared with ibrutinib-obinutuzumab, ibrutinib-venetoclax, and obinutuzumab-venetoclax. For older patients with comorbidities, acalabrutinib and acalabrutinib-obinutuzumab outperformed obinutuzumab-venetoclax without statistically difference between them. Minimal residual disease-guided ibrutinib-venetoclax surpassed obinutuzumab-venetoclax in patients without comorbidities. Ibrutinib-obinutuzumab exhibited extended PFS benefits compared with obinutuzumab-venetoclax in patients with mutated IGHV or with del(17p) and/or TP53 mutations. Ibrutinib-venetoclax and ibrutinib-obinutuzumab had lower neutropenia rates than obinutuzumab-venetoclax. Ibrutinib-venetoclax had fewer infections than acalabrutinib and acalabrutinib-obinutuzumab. Acalabrutinib-obinutuzumab caused less diarrhea than ibrutinib-venetoclax but more headaches than ibrutinib-obinutuzumab and obinutuzumab-venetoclax. Obinutuzumab-venetoclax had lower hypertension rates than ibrutinib-obinutuzumab. Ibrutinib-venetoclax had fewer arthralgia than acalabrutinib-obinutuzumab. For any grade secondary primary neoplasms, ibrutinib-venetoclax and obinutuzumab-venetoclax was less than acalabrutinib-obinutuzumab.

Conclusion: Tailored chemotherapy-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different adverse events spectra.

For many anatomic cancer sites, it is unclear to what extent differences in health insurance coverage contribute to racial and ethnic disparities in the diagnosis of stage III and IV disease. Using the National Cancer Database (1 893 026 patients aged 18-64 years, diagnosed between 2013 and 2019), we investigated a potential mediating role of health insurance (privately insured vs uninsured) in explaining racial and ethnic disparities in stage at diagnosis of 10 cancers-breast (female), prostate, colorectum, lung, cervix, uterus, stomach, urinary bladder, head and neck, and skin melanoma- detectable early through screening, physical examination, or clinical symptoms. The analyses provided evidence of mediation of disparities among non-Hispanic Black vs White individuals in 8 cancers (range of proportions mediated: 4.5%-29.1%), in Hispanic vs non-Hispanic White individuals in 6 cancers (13.2%-68.8%), and in non-Hispanic Asian or Pacific Islander vs White individuals in 3 cancers (5.8%-11.3%). To summarize, health insurance accounts for a statistically significant proportion of the racial and ethnic disparities in diagnosis of stage III and IV disease across a range of cancer types.

Background: Determining whether screening with multicancer detection (MCD) tests saves lives requires randomized controlled trials (RCTs). To inform RCT design, we estimated cancer-mortality outcomes from hypothetical MCD RCTs.

Methods: We used the Hu-Zelen model, previously used to plan the National Lung Screening Trial (NLST), to estimate mortality reductions, sample size, and power for 9 cancers for different RCT design parameters and MCD test parameters.

Results: Our base-case RCT with 5 yearly screens and 100 000 people ages 60-74 in each arm, who also undergo standard-of-care screens, has 87%-89% power to detect a 9%-10% mortality reduction (Number Needed to Screen [NNS] = 578-724) over 7-9 years. The majority of prevented deaths were from lung cancers (base-case [64%-66%] and all sensitivity analyses), 8%-10% from colorectal cancer, and 26% from the other 7 cancers, mostly from stomach or ovary or esophagus (due to excellent stage 1 survival) and less from liver or pancreas (poor stage 1 survival) or head and neck or lymphoma (excellent stage 4 survival). There was limited power for mortality reductions at most individual cancer sites. Base-case findings were sensitive to test sensitivity, stage shifts, and mean sojourn times in the preclinical state (especially for lung cancer), but 90% power could be recovered by recruiting a substantially higher risk population.

Conclusions: Large-scale MCD RCTs would have 89% power to detect an approximate 10% cancer mortality reduction over a relatively short 7-9 year timeframe from trial entry. The estimated NNS for MCD RCTs compares favorably with mammographic screening. Most prevented cancer deaths in a well-powered MCD RCT would likely be from lung cancer. Non-lung and non-colorectal cancer sites could be a meaningful proportion of prevented cancer deaths, but power is insufficient to isolate non-lung-cancer mortality reductions.

Background: We sought to assess the effectiveness and harms of initial treatment strategies for stage I through III anal squamous cell anal cancer.

Methods: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between January 1, 2000, and March 2024, for randomized controlled trials and nonrandomized studies of interventions comparing initial treatment strategies. Individual study risk of bias and overall strength of evidence were evaluated for a prespecified outcome list using standardized methods.

Results: We identified 33 eligible studies and extracted data. Six were deemed low to moderate risk of bias. Compared with radiation therapy alone, chemoradiation therapy (CRT) with 5-fluorouracil (5-FU) and mitomycin C probably shows a benefit in locoregional failure, disease-specific survival, and colostomy-free survival (moderate strength of evidence) yet may result in greater overall and acute hematological toxicity, with no difference in late harms (low strength of evidence). CRT with 5-FU plus mitomycin C may show a benefit in locoregional failure, disease-specific survival, and colostomy-free survival rates compared with 5-FU alone (low strength of evidence). CRT with 5-FU plus cisplatin vs 5-FU plus mitomycin C probably results in no differences in several effectiveness outcomes or overall acute or late harms and probably increases hematological toxicity with mitomycin C (moderate strength of evidence). Compared with CRT using capecitabine plus mitomycin C, CRT with capecitabine plus mitomycin C and paclitaxel may improve overall survival, disease-specific survival, and colostomy-free survival yet cause more acute harms (low strength of evidence). Evidence was insufficient for remaining comparisons.

Conclusions: CRT with 5-FU plus mitomycin C or 5-FU plus cisplatin is likely more effective yet incurs greater acute hematological toxicity than radiation therapy alone or single-agent CRT. Adding paclitaxel to capecitabine plus mitomycin C may increase treatment efficacy and toxicity. Evidence is insufficient comparing posttreatment surveillance strategies and patient-reported outcomes, highlighting research opportunities.

Background: It is increasingly recognised that frailty should be assessed and considered in treatment decision-making in patients with cancer. This review and meta-analysis synthesises existing evidence evaluating the association between baseline frailty and Systemic Anti-Cancer Treatment (SACT) outcomes in adults with cancer.

Methods: Five databases were systematically searched from database inception to January 2023 to identify prognostic factor studies (cohort/case-control design) reporting the associations between validated frailty assessments (pre-treatment) and follow-up outcomes in adults with solid-organ malignancy undergoing SACT. Risk of bias (RoB) was assessed via Quality of Prognosis Studies in Systematic Reviews tool. Where appropriate, associations between frailty and outcomes (survival, toxicity, treatment tolerance, functional decline/quality of life and hospitalisation) were synthesised in meta-analysis and presented as forest plots.

Results: 58 studies met inclusion criteria. They were undertaken in a range of tumour sites and mainly in older patients and advanced disease/palliative settings. Most had low/moderate RoB. Nine frailty assessment tools were evaluated. Four outcomes were synthesised in meta-analysis, which demonstrated the prognostic value of two tools: Geriatric-8 (G8; survival, treatment tolerance, hospitalisation) and Vulnerable Elders Survey-13 (VES13; survival, toxicity, treatment tolerance). Overall pooled estimates indicate that frailty conveys an increased risk of mortality (hazard ratio (HR) 1.68, 95% confidence interval 1.41-2.00), toxicity (odds ratio (OR) 1.83, 1.24-2.68), treatment intolerance (OR 1.68, 1.32-2.12) and hospitalisation (OR 1.94, 1.32-2.83).

Conclusion: Simple, brief frailty assessments including G8 and VES13 are prognostic for a range of important outcomes in patients undergoing SACT. Risk estimates should be used to support shared decision-making.

Background: World Health Organization Grade 2 meningiomas (G2Ms) often recur and resist therapies. G2Ms with histopathological necrosis have been associated with worse local control (LC) following radiation therapy, but the drivers and biomarkers of radiation resistance in G2Ms remain unknown.

Methods: We performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of genetic and microenvironmental factors on clonogenic survival following ionizing radiation. We performed transcriptional profiling of our in vitro model and 18 human G2M tumors by bulk RNA sequencing as well as eight G2Ms by single nuclei RNA sequencing.

Results: NF2 loss-of-function (LOF) mutations were associated with necrosis in G2Ms (p = .0127). Tumors with NF2 mutation and necrosis had worse post-radiation LC compared to NF2 wildtype tumors without necrosis (p = .035). Under hypoxic conditions, NF2 knockdown increased radiation resistance in vitro (p < .001). Bulk RNA sequencing revealed NF2- and hypoxia-specific changes and a 50-gene set signature specific to radiation resistant, NF2 knockdown and hypoxic cells, which distinguished NF2 mutant/necrotic patient G2Ms by unsupervised clustering. Enrichment analysis revealed downregulation of apoptosis pathway genes and upregulation of proliferation-associated genes and genes normally downregulated after UV radiation exposure in NF2-mutant/necrotic tumor cells, which were validated with functional assays.

Conclusions: NF2 LOF in the setting of hypoxia confers radiation resistance through transcriptional programs that reduce apoptosis and promote proliferation. These pathways may identify tumors resistant to radiation and represent therapeutic targets that in the future could improve LC in patients with radiation resistant G2Ms.