Acta Oncologica最新文献

Background and purpose: Treatment of cancer with immune checkpoint inhibitors (ICIs) entails a risk of immune-related adverse events (irAEs). Data on the treatment of immune-related enterocolitis (irEC) in patients with inadequate symptom control after treatment with standard therapy including corticosteroids, infliximab, and vedolizumab are scarce. Based on limited data, recommendations include treatment with the pan-Janus kinase (JAK) inhibitor tofacitinib. Filgotinib is a more recently developed JAK inhibitor with preferential inhibition of JAK1, which might imply a more favorable safety profile. Filgotinib is approved for the treatment of ulcerative colitis and might thus be an option in refractory irEC.

Patients and methods: We present two cases of metastatic melanoma treated with ICIs who developed corticosteroid and infliximab-refractory irEC. Given non-conventional pharmaceutical management, literature review was performed regarding mechanisms of action and safety profiles of JAK inhibitors.

Results: Both patients were treated with filgotinib, which resulted in rapid remission of symptoms in both cases. One of the patients was treated with off-label high-dose filgotinib, which has not been described previously. The rationale and safety regarding the use of JAK1 inhibitors in irAEs are discussed, including the seemingly diverging existing data on potential effects of JAK inhibition on ICI-induced anti-tumoral immune-responses. In addition, the rationale for the high-dose treatment is scrutinized.

Interpretation: This report suggests that filgotinib may be considered for treating irEC refractory to standard therapy.

Background: Several studies have reported associations between statin treatment and a more favourable prognosis in prostate cancer (PC) patients. The underlying biology, however, has not been fully investigated.

Objective: To perform whole-transcriptome profiling of prostate tumour samples from PC patients to identify gene expression patterns and molecular pathways that may be associated with statin treatment. Furthermore, to investigate correlations between statin-associated gene expression changes and clinical outcomes.

Material and methods: We performed messenger Ribonucleic Acid (mRNA) sequencing on radical prostatectomy specimens from 186 patients with clinically-localised PC. The final dataset included 93 statin-users (93 PC and 43 adjacent normal [AN] samples) and 93 non-users (93 PC and 43 AN samples). We performed Differential Expression Analysis and Gene Set Enrichment Analysis (GSEA) between statin-users and non-users. Genes of interest were included in uni- and multivariate analyses exploring time to Biochemical Recurrence (BCR).

Results: Comparing statin-users and non-users, there were zero significantly differentially expressed genes (DEGs) in AN samples and 163 DEGs in PC samples. In statin-users, GSEA revealed downregulation of pathways known to drive PC aggressiveness, most significantly epithelial-mesenchymal transition. Low-density Lipoprotein Receptor (LDLR) was among the top-upregulated genes and expressed higher in atorvastatin than in simvastatin users. The LDLR upregulation was associated with prolonged BCR-free survival.

Interpretation: We identified several genes and pathways in PC tissue potentially associated with the reported beneficial effects of statin treatment in PC. Specifically, we identified an association between statin treatment and intra-tumour LDLR upregulation. This study contributes to the understanding of statin-mediated effects on PC.

Background and purpose: Clinical tools to optimally select real-world metastatic renal cell carcinoma (mRCC) patients for treatment with ipilimumab-nivolumab remain to be identified.

Patient and methods: Medical records of the first 100 mRCC patients treated with ipilimumab-nivolumab at three Swedish centers were retrospectively analyzed. Data on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, baseline levels of routine blood markers, and tumor burden were collected. Outcome variables were progression-free survival (PFS), overall survival (OS), and radiological response (RR) according to clinical routine imaging.

Results: At a median follow-up of 22 months, 65% had progressed or died with a median PFS of 7 months and an estimated median OS of 28 months. The RR rate was 45%, including 11% complete responses (CR). 29% had progressive disease as best response. IMDC poor-risk patients had shorter mPFS (4 vs 14 months; HR [hazard ratio] 1.90; P = 0.009), shorter mOS (12.5 months vs not reached; HR 4.27; P < 0.0001), and lower CR rate (3% vs 16%, P = 0.06) than IMDC intermediate/favorable patients. C-reactive protein (aHR 2.67; P = 0.040), albumin (aHR, 2.13; P = 0.039), neutrophil-lymphocyte-ratio (aHR, 2.8; P = 0.009), and > 2 metastatic sites (aHR, 2.13; P = 0.024) were associated with OS after adjusting for IMDC risk. Prior nephrectomy was not (aHR, 0.84; P = 0.62). A normal C-reactive protein was associated with an increased likelihood of CR (OR 7.2; P = 0.017).

Interpretation: Baseline blood markers and number of metastatic sites add prognostic value independently of IMDC risk in real-word mRCC patients treated with ipililmumab-nivolumab.

Background and purpose: The Danish Patient Association of Late Effects has received numerous inquiries from breast cancer (BC) survivors suspecting that adjuvant radiotherapy (RT) was the reason for respiratory symptoms. This study investigated patient-reported respiratory symptoms after locoregional RT and their association with ipsilateral lung radiation dose. Patient/material and methods: Patient-reported outcomes (PROs) and RT plans from BC patients treated at a single institution over 2008-2016 were collected. PROs included dyspnoea (EORTC QLQ-C30), cough (PRO-CTCAE), smoking and comorbidities. RT dose-volume metrics were registered including ipsilateral mean lung dose (MLD), and volumes receiving 5 Gy (V5) and 20 Gy (V20). Patients were stratified into MLD tertiles ('low', 'intermediate', 'high') and compared. Additionally, responders were dichotomised by dyspnoea and cough scores ('low' vs 'high'), and dose metrics were compared between symptom groups.

Results: Of 1,011 questionnaire distributed, 490 (49%) were completed and analysed. Median age was 65.8 years (interquartile range [IQR] 58.8;73.4), median time from RT to questionnaire was 11.1 years (IQR 8.9;13.2). Overall MLD was 12.9Gy (standard deviation [SD] 2.8). Any degree of dyspnoea was reported by 203 (41%) and any degree cough was reported by 175 (37%). No differences in dyspnoea/cough scores between MLD groups were found. MLD was 13.0Gy (SD 2.7) in the low dyspnoea group and 12.0Gy (SD 3.0) in the high dyspnoea group, (p = 0.04). MLD was 13.0 Gy (SD 2.7) in the low cough group and 12.5Gy (SD 3.1) in the high cough group (p = 0.23). The same pattern was found for V5lung and V20lung.

Interpretation: No associations between lung dose and patient-reported respiratory symptoms were found for node-positive BC patients 11 years after RT.

Background and purpose: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype where the prognostic implications of primary systemic therapy followed by surgery, compared to up-front surgery and subsequent adjuvant chemotherapy (ACT), are yet to be outlined. This retrospective registry-based study aimed to compare survival outcomes between patients treated with neoadjuvant chemotherapy (NACT) versus ACT for operable TNBC in a real-world setting. Patient/material and methods: We included all patients treated with chemotherapy for operable TNBC in Sweden between 2008 and 2019 using the Swedish national research database BCBaSe 3.0. To reduce confounding by indication, we implemented propensity score matching (PSM) and main study outcomes were defined as distant disease-free survival (DDFS), breast cancer-specific survival (BCSS) and overall survival (OS).

Results: A total of 4,704 patients were included in the study, of which 1,183 received NACT. Following 1:1 PSM, 837 patients in each treatment setting were available for analyses. We found no statistically significant differences in terms of DDFS (adjusted hazard ratio [aHR] 1.18; 95% confidence interval [CI] 0.93 - 1.50), BCSS (aHR 1.10; 95% CI 0.83 - 1.45) or OS (aHR 1.07; 95% CI 0.82 - 1.39) between patients treated with NACT versus ACT. However, subgroup analysis of patients with clinically node-positive disease (cN+) demonstrated a significant DDFS benefit of NACT (aHR 0.65; 95% CI 0.47 - 0.90).

Interpretation: Overall, we found comparable survival among patients with TNBC treated with NACT or ACT. Considering the anticipated survival improvements when response-guided post-neoadjuvant strategies are implemented in clinical practice, our findings may support the use of NACT in operable TNBC.

Background and purpose: Boron neutron capture therapy (BNCT) is targeted radiation therapy enabling cellular-level cancer treatment. With epithermal neutrons, the dose maximum typically occurs ~2 cm deep in tissue, challenging superficial tumor control. As in external beam radiation therapy, surface dose can be increased using a bolus. However, in BNCT, tissue equivalency is complex and strongly dependent on elemental composition. This study examined a paraffin wax bolus's effect on the epithermal neutron beam in accelerator-based BNCT (AB-BNCT) and evaluated agreement between treatment planning system (TPS) calculations and measurements.

Materials and methods: Beam characterization used the neutron activation method with gold and manganese foils. Due to its high cross-section for thermal neutrons, manganese activation serves as a surrogate for boron dose estimation. Irradiations were conducted in a 3D water tank and in a head-shaped phantom with 5 and 10 mm boluses. Dose calculation utilized the newly commissioned RayStation TPS with a Monte Carlo-based engine built on the GEANT4 toolkit.

Results: Calculated and measured results agree within 5% accuracy in significant dose region (>50% dose). Near the surface and at greater depths, agreement remains within 10%. The bolus shifts the activation depth curve toward the surface by 4-13 mm depending on its thickness. Manganese surface activation increases from 30% without a bolus to ~70% and ~ 90% with 5 and 10 mm boluses, respectively.

Interpretation: Paraffin wax effectively moderates neutron energy, making it a suitable bolus material for AB-BNCT treatments requiring increased surface dose.

Background and purpose: We have previously shown that proton therapy results in considerable reduced doses to abdominal organs at risk (OAR) which likely reduces the patient's risk of a second malignant tumor, which is vital for this young population with favourable prognosis. Here, we present dosimetric results after implementing intensity modulated proton therapy (IMPT) as a national standard for seminoma. Patient/material and methods: Thirty patients with stage IIA and IIB (< 3 cm) seminoma were treated with five-field robustly multi-field optimised (MFO) proton therapy to 20-24 Gy (relative biological effectiveness [RBE]) to the dog-leg retroperitoneal volume followed by a boost of 10-16 Gy (RBE) to the nodal metastasis. Control CTs were performed routinely, and target coverage evaluated. A standard two cone-beam CT (CBCT) set-up strategy with four match structures was developed, enabling implementation of a standard adaptive scheme.

Results: The median clinical target volume (CTV-E) length in the craniocaudal direction was 26.9 cm, with a median volume of 551.4 cm3. Target coverage V95% = 100% for the nominal plan and V95% ≥ 98% for worst-case scenarios were fulfilled for all treatment plans and the 46 recalculated plans on control CTs. Kidney V17Gy was 0-6% and mean kidney dose 0-6 Gy across all plans. Bowel bag V15Gy was 194-698 cm3. All other OAR showed low doses. Four patients had replans (1-2 per patient). The median time for our image guidance (IG) strategy was 14:07 min across all patients with two CBCTs.

Interpretation: We have established a robust setup for treatment planning, IG strategy, treatment delivery and adequate response to replanning. Therefore, we suggest considering IMPT for testicular seminoma whenever available.

Background and purpose: Radiotherapy (RT) of head and neck cancer can cause severe toxicities. Early identification of individuals at risk could enable personalized treatment. This study evaluated whether convolutional neural networks (CNNs) applied to Magnetic Resonance (MR) images acquired early after irradiation can predict radiation-induced tissue changes associated with toxicity in mice. Patient/material and methods: Twenty-nine C57BL/6JRj mice were included (irradiated: n = 14; control: n = 15). Irradiated mice received 65 Gy of fractionated RT to the oral cavity, swallowing muscles and salivary glands. T2-weighted MR images were acquired 3-5 days post-irradiation. CNN models (VGG, MobileNet, ResNet, EfficientNet) were trained to classify sagittal slices as irradiated or control (n = 586 slices). Predicted class probabilities were correlated with five toxicity endpoints assessed 8-105 days post-irradiation. Model explainability was assessed with VarGrad heatmaps, to verify that predictions relied on clinically relevant image regions.

Results: The best-performing model (EfficientNet B3) achieved 83% slice-level accuracy (ACC) and correctly classified 28 of 29 mice. Higher predicted probabilities of the irradiated class were strongly associated with oral mucositis, dermatitis, reduced saliva production, late submandibular gland fibrosis and atrophy of salivary gland acinar cells. Explainability heatmaps confirmed that CNNs focused on irradiated regions.

Interpretation: The high CNN classification ACC, the regions highlighted by the explainability analysis and the strong correlations between model predictions and toxicity suggest that CNNs, together with post-irradiation magnetic resonance imaging, may identify individuals at risk of developing toxicity.

Background and purpose: Cancer is among the leading causes of premature death worldwide, and, in Finland, it is the most common cause of death among women aged 15-64 years who may be parenting minor children. We aim to estimate how many children are affected by maternal cancer or cancer death and if this has changed in Finland. Patient/material and methods: We used female cancers (Finnish Cancer Registry), cancer deaths, fertility rates in women and mortality rates in children (Statistics Finland) to calculate the model-based annual trend estimates of new and prevalent children under 18 years whose mother was diagnosed with cancer and new and prevalent orphans by maternal cancer type in Finland between 1968 and 2022.

Results: The estimated rate of children whose mother was diagnosed with cancer increased 1.3% annually since 1996. In 2022, the rates of new and prevalent children with maternal cancer were 218.4 and 1522.4 per 100,000, corresponding to 2,334 and 16,803 children. On the contrary, the estimated rate of new orphans due to maternal cancer mortality decreased 1.2% annually since 1998. In 2022, the age- standardised rates of new and prevalent orphans were 26.4 and 166.7 per 100,000 children, corresponding to 285 and 1,850 orphans due to maternal cancer mortality.

Interpretation: We estimated that the rate of new orphans due to maternal cancer mortality has declined over the past decades, which has benefited children. However, the increase in cancer incidence among mothers with minor children showed an opposite trend, indicating more intergenerational consequences due to cancer.