Acta Oncologica最新文献

Background and purpose: Molecular profiling guides cancer treatment, by identifying actionable genomic alterations. The IMPRESS-Norway trial (NCT04817956) is a nation-wide precision medicine trial evaluating the efficacy of approved cancer drugs on a novel indication in patients with advanced cancers harbouring potentially actionable alterations. Trametinib, a selective MEK1/2 inhibitor targeting the Mitogen-Activated Protein Kinase (MAPK) signalling pathway, is approved for BRAF V600 mutant melanoma but may also show activity in tumours with other alterations. This sub-study aimed to assess the efficacy of trametinib monotherapy across tumour types with alterations activating the MAPK signalling pathway. Patient/material and methods: In the IMPRESS-Norway trial patients are screened with the TruSight Oncology 500 panel or circulating tumour DNA profiling. Eligible patients are offered biomarker matched targeted therapies. In this subgroup analysis, we identified patients treated with trametinib monotherapy. Primary endpoints were disease control rate (DCR) after 16 weeks and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).

Results: DCR after 16 weeks of treatment was 39% in 52 response evaluable patients, with four patients (8%) experiencing partial response, and 16 (31%) stable disease. Responses were seen in tumours harbouring BRAF fusions, GNA11, GNAQ, KRAS, NF1, and NRAS alterations, most frequently in low-grade serous ovarian cancer, central nervous system tumours, and uveal melanoma. Forty-eight percent of patients experienced treatment-related adverse events, including two treatment related deaths. Median PFS and OS were 4 and 9 months, respectively.

Interpretation: Trametinib monotherapy achieved a 39% DCR in patients lacking standard options, supporting further studies to confirm efficacy and identify predictive biomarkers for treatment response.

Background and purpose: Antibiotic treatment (ABT) has been associated with worse outcomes of cancer immunotherapy. However, this association might be confounded by other poor prognostic factors. We aimed to evaluate the use of ABT and outcomes of immune checkpoint inhibitors (ICI) in metastatic kidney cancer (mRCC). Patient/material and methods: We identified retrospectively 192 patients treated with ICI for mRCC between 2015 and 2021 at three academic hospitals in Finland. Information on patient characteristics, ABT, and immunotherapy was collected from electronic medical records. Cox regression and Kaplan-Meier methods were used for survival analyses.

Results: A total of 61 (32%) patients had received early ABT (3 months before and 1 month after the first dose of ICI), of whom 31 (51%) had ABT > 7 days. Patients with early ABT had shorter median overall survival (mOS) than patients without early ABT (20.4 vs 27.9 months, p = 0.046). Patients with ABT > 7 days had shorter mOS than patients with ABT 0-7 days (17.2 vs 27.5 months, p = 0.015). After adjustment for International Metastatic Renal Cell Carcinoma Database Consortium risk groups, histological renal cell carcinoma subtype, baseline levels of C-reactive protein, and tumor burden, the risk of death was higher in patients with ABT > 7 days (hazard ratio 1.83 (95% confidence interval 1.06-3.17). No significant differences in progression-free survival times (PFS) were observed.

Interpretation: Early ABT and prolonged ABT duration were associated with shorter OS, but not with PFS, in patients treated with ICI for mRCC. Prolonged ABT indicated poor prognosis regardless of other risk factors.

Background and purpose: Advanced breast cancer (ABC) involves substantial end-of-life (EOL) healthcare use and costs. Understanding cost drivers can inform care delivery and resource allocation. Patient/material and methods: We conducted a retrospective, population-based study of individuals (n = 1,437) who died with breast cancer in the Stockholm Region (2015-2023). Healthcare utilization and costs during the last 12 months of life were obtained from the Stockholm Regional Healthcare Data Repository (VAL) and estimated using the Region Stockholm cost model. Variables included age, sex, socioeconomic status (Mosaic), Charlson Comorbidity Index, Hospital Frailty Risk Score (HFRS), systemic therapy, and place of death. Descriptive statistics and generalized linear models assessed cost associations.

Results: Total costs rose toward EOL, increasing 140% in the final 3 months versus the prior quarter. Hospitalizations and specialized palliative care drove costs, while outpatient visits declined. Younger age (18-69 years), high frailty (HFRS > 15), and systemic therapy were independently associated with higher costs. Hospital death was associated with lower expenditures than dying elsewhere (rate ratio [RR]: 0.84, 95% confidence interval [CI]: 0.78-0.91). The top 5% of cost users were mainly younger, frail patients receiving systemic therapy.

Interpretation: ABC-related costs escalate in the final year of life, driven by hospitalizations, palliative care, and systemic therapies. Younger, frailer patients incur higher costs, while those dying in hospital settings are associated with lower costs. Early palliative integration and frailty-based risk stratification were associated with distinct patterns of healthcare utilization and costs toward the EOL.

Background and purpose: Radiotherapy (RT) is a key treatment for locally advanced non-small cell lung cancer (NSCLC). Tumours near the heart may result in unintended cardiac radiation exposure, increasing the risk of cardiotoxicity, such as de novo atrial fibrillation (DNAF) and de novo heart diseases (DNHD) as ischemic heart disease, heart failure, arterial hypertension or sudden cardiac death. This study investigated associations between radiation dose to cardiac substructures and risk of DNAF and DNHD. Patient/material and methods: This retrospective cohort study included patients treated between January 1, 2010, and December 31, 2020 for NSCLC with definitive RT. The heart, right atrium (RA) and sinoatrial node (SAN) were delineated. Associations between dose-volume parameters and cardiac outcomes were analysed using multivariable models adjusted for relevant confounders. Kaplan-Meier curves estimated survival; p-values < 0.05 were significant.

Results: Among 273 included patients, 9.5% had AF pre-RT and 12.8% developed DNAF. DNAF was significantly associated with SAN Dmax (hazard ratio [HR] = 1.01), RA Dmax (HR = 1.02), RA Dmean (HR = 1.03), mean heart dose (MHD) (HR = 1.04) and heart V40Gy (HR = 1.03). One-year probabilities of DNAF and DNHD were 9.3% and 11%, increasing to 12.2% and 13.2% at 2 years. DNHD was significantly associated with SAN Dmax (HR = 1.02), RA Dmax (HR = 1.02), RA Dmean (HR = 1.04), MHD (HR = 1.06), heart V25Gy (HR = 1.03) and V40Gy (HR = 1.03).

Interpretation: The RA and SAN may be considered organs at risk in future RT planning. Minimising cardiac radiation is important to reduce DNAF and DNHD risk. Validation in an independent cohort is warranted.

Background and purpose: Implementation of low-dose computed tomography (LDCT) screening for lung cancer is recommended. The Norwegian Lung Cancer Screening pilot (TIDL) has been conducted to explore recruitment strategy, detection rate and the value of a radiology-led screening program. This publication presents baseline results from the screened participants. Patient/material and methods: All 125,095 individuals aged 60-79 years in Akershus county, Norway were invited to participate. Ever-smokers completed a risk questionnaire based on the PLCOm2012NoRace model: those with ≥35 pack-years or a ≥2.6% 6-year lung cancer risk were eligible for inclusion. Of 2,499 eligible participants, 1,006 underwent baseline LDCT between August 2022 and May 2023, and up to two more rounds later. Nodules were categorized by Lung-RADS v2022. Follow-up and staging were managed by thoracic radiologists; High-suspicion cases were referred to pulmonologists.

Results: At baseline, lung cancer was diagnosed in 23 participants (2.3%), whereof 19 (83%) in stage I and 2 (9%) in stage II. Most underwent curative treatment, primarily robot-assisted surgery. Only 2.9% of the screened individuals were referred for further diagnostic evaluation. The false positive rate was 0.6% after pulmonologist referral and 1.7% after radiological staging. A total of 13.8% required 3- or 6-month imaging follow-up. Complication rates from diagnostic procedures were low.

Interpretation: LDCT screening using combined risk-based eligibility and a radiology-led model is feasible and effective in the Norwegian context. The high detection rate and low clinical burden support its potential for national implementation. These findings may guide the development of future lung cancer screening programs in the Nordic countries and beyond.

Background and purpose: Cancer therapies place an increasing financial burden on societies. In metastatic colorectal cancer (mCRC), an optimised curative-intent treatment combines metastasectomy, local ablative therapy, and perioperative systemic anti-cancer therapy (SACT) under multidisciplinary team guidance. The resource-intensive operative treatment strategy results in better survival than a non-operative approach with SACT only. The cost-effectiveness of the strategy including operative treatment has not been investigated in the era of modern treatment options. Patient/material and methods: A Markov model was developed to estimate lifetime healthcare costs and quality-adjusted life-years (QALYs). Patients receiving operative treatment, including metastasectomy along with SACT, and those receiving non-operative treatment with SACT only, were identified from the prospective Finnish RAXO study that recruited 1,086 patients between 2012 and 2018. Cost-effectiveness analyses and sensitivity analyses were conducted from the healthcare payer's perspective using 2023 cost levels.

Results: The mean lifetime costs (158,309€) for patients with an operative treatment produced 6.57 life years and 5.91 QALYs according to the Markov model. The non-operative treatment group had costs of 77,182€, producing 1.99 life years and 1.74 QALYs. The incremental cost-effectiveness ratio (ICER) was 19,455€/QALY, with the caveat that more favourable characteristics were present in the operative group. In probabilistic sensitivity analyses with a willingness-to-pay threshold of 30,000€/QALY, the operative treatment group had an 81% probability of being cost-effective. The results were robust in adjusted sensitivity analyses, including propensity score matched subgroups.

Interpretation: An operative treatment strategy is cost-effective at a commonly referenced acceptability threshold.

Background and purpose: Particle therapy (PT), including proton (PRT) and carbon ion radiotherapy (CIRT), offers physical and biological advantages over photon radiotherapy (XRT), particularly for radioresistant tumours such as glioblastoma and osteosarcoma. However, systematic preclinical comparisons using physiologically relevant models remain limited.

Material and methods: T98G (glioblastoma), Saos-2 and U2-OS (osteosarcoma) cells were cultured as two-dimensional (2D) monolayers and three-dimensional (3D) spheroids and irradiated with XRT, PRT or CIRT at 2, 4 or 6 Gy. Clonogenic survival, metabolic activity (PrestoBlue), invasion and spheroid growth kinetics were quantified. Relative biological effectiveness (RBE) was derived from survival data, and spheroid sections were analysed histologically (H&E).

Results: CIRT induced the strongest cytotoxic and anti-invasive effects across all models. In 2D cultures, the surviving fraction at 2 Gy decreased from 0.62 to 0.69 after XRT to 0.16-0.28 following CIRT (RBE = 2.1-2.4 vs. 1.1 for PRT; p < 0.0001). 3D spheroids exhibited overall higher radioresistance, yet CIRT markedly reduced growth and invasion, lowering normalised indices to 0.52 ± 0.12 (T98G) and 0.58 ± 0.09 (Saos-2) at 6 Gy, while photons often promoted invasion (> 1.2; p < 0.001). RBE values in 3D reached 3.6-4.0. H&E staining confirmed dose-dependent architectural disruption, with carbon ions inducing extensive necrosis and cellular degeneration.

Interpretation: This study introduces a robust 3D preclinical platform for radiobiological assessment of particle therapy. CIRT consistently overcame intrinsic and microenvironment-mediated resistance, outperforming photons and protons in suppressing viability, invasion and spheroid integrity, thus reinforcing the translational relevance of 3D models and the therapeutic promise of carbon ion therapy for resistant malignancies.

Background and purpose: In the current landscape of tumour-agnostic oncology drugs receiving European Medicines Agency (EMA) authorisation, Health Technology Assessment (HTA) bodies face challenges in assessing these innovative drugs. Due to these products' non-randomised, single-arm nature, uncertainty exists regarding their real-world benefit. In the Netherlands, the Drug Access Protocol (DAP), a programme developed by oncologists, insurers and the healthcare public institute, aims to provide an innovative solution to address this uncertainty. This study aims to investigate the key characteristics, enablers and challenges of the programme by exploring stakeholders' perceptions. Patient/material and methods: A qualitative, semi-structured interview study was conducted. A supporting interview guide was drafted using available literature and a flowchart figure to illustrate the process. Interviews were conducted with market authorisation holders (MAHs) who participated in the programme, the insurer, the DAP study management and the DAP's governance committee. Recorded interviews were transcribed, pseudonymised and subsequently coded using NVivo software. Inductive thematic analysis was used to identify common themes, enablers and challenges for participating in the programme.

Results: In total, eight organisations were interviewed. Although MAHs indicated several enablers (e.g. providing patient access, collecting real-world data), several challenges (e.g. the lack of transparency) lead to questions regarding the feasibility of the programme. Health insurers acknowledge these outcomes and expect products that obtain regular reimbursement to serve as an example.

Interpretation: As the Drug Access Protocol may be a promising solution to mitigate uncertainties for healthcare decision-makers, implementation challenges can hamper its feasibility. Addressing these challenges could realise the potential of such programmes.