RESUMEN
Background and purpose: Biomarkers for prediction of outcome in patients with pancreatic cancer are wanted in order to personalize the treatment. This study investigated the value of longitudinal diffusion-weighted magnetic resonance imaging (DWI) for prediction of overall survival (OS) in patients with locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiotherapy (SBRT). Materials and methods: The study included 45 patients with LAPC who received 5 fractions of 10 Gy on a 1.5T MRI-Linac. DWI was acquired prior to irradiation at each fraction. The analysis included baseline values and time-trends of the apparent diffusion coefficient (ADC) and DWI parameters obtained using a decomposition method. A multivariable Cox proportional hazards model for OS was made using best-subset selection, using cross-validation based on Bootstrap. Results: The median OS from the first day of SBRT was 15.5 months (95% CI: 13.2-20.6), and the median potential follow-up time was 19.8 months. The best-performing multivariable model for OS included two decomposition-based DWI parameters: one baseline and one time-trend parameter. The C-Harrell index describing the model's discriminating power was 0.754. High baseline ADC values were associated with reduced OS, whereas no association between the ADC time-trend and OS was observed. Conclusion: Decomposition-based DWI parameters indicated value in the prediction of OS in LAPC. A DWI time-trend parameter was included in the best-performing model, indicating a potential benefit of acquiring longitudinal DWI during the SBRT course. These findings support both baseline and longitudinal DWI as candidate prognostic biomarkers, which may become tools for personalization of the treatment of patients with LAPC.
RESUMEN
Objectives: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Methods: Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Results: Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). Conclusions: In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.
RESUMEN
INTRODUCTION: Frailty constitutes a risk for unplanned hospitalizations in older adults with cancer. This study examines whether comprehensive geriatric assessment (CGA) as an add-on to standard oncologic care can prevent unplanned hospitalizations in older adults with frailty and cancer who initiate curative oncological treatment. MATERIALS AND METHODS: This randomized controlled trial included older adults aged ≥70 with frailty (Geriatric 8 [G8] ≤14), and solid cancers who initiated curative oncological treatment. Participants were randomized 1:1 to either standard oncologic care (control) or standard oncologic care supplemented with CGA-guided interventions (intervention). Baseline characteristics were retrieved prior to randomization. The primary endpoint, the between-group rate ratio of unplanned hospitalizations within six months of treatment initiation, was analyzed using negative binominal regression. Analyses were performed using an intention-to-treat approach, followed by per-protocol analysis, including participants receiving CGA within 30 days of randomization, and preplanned subgroup analyses based on treatment modality and Geriatric 8 screening. Secondary endpoints included acute hospital contacts, treatment adherence, and toxicity. RESULTS: From November 1, 2020 to May 31, 2023, 173 participants were enrolled. Median age was 75 (interquartile range 72-79), 51.5% were female, 58% had a G8 score > 12, and 84% had Eastern Cooperative Oncology Group performance status 0-1. The most common cancer sites were lung (23%), upper gastrointestinal (15%), and breast (13%). The rate (per person-years) of unplanned hospitalization was 1.32 in the intervention group and 1.81 in the control group, with a between-group rate ratio of 0.74 (95% confidence interval [CI] 0.45-1.23, P = 0.25) favoring the intervention. The between-group rate ratio increased in the per-protocol analysis (0.64 [95% CI 0.37-1.10, P = 0.10]). Similarly, no significant between group differences were found in treatment adherence, rate of acute hospital contacts, or toxicity. DISCUSSION: In this study, CGA did not significantly reduce the rate of unplanned hospitalizations. Furthermore, no between-group differences were found in treatment adherence, toxicity lead hospitalizations, or treatment completion in older adults with cancer and frailty. However, per-protocol analysis suggests that increasing adherence to CGA may improve the outcome. Larger studies ensuring higher CGA adherence are warranted to confirm our findings.
RESUMEN
BACKGROUND/OBJECTIVES: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. METHODS: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. RESULTS: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from -3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. CONCLUSIONS: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.
Asunto(s)
Carcinoma Ductal Pancreático , Perfilación de la Expresión Génica , Neoplasias Pancreáticas , ARN Circular , Humanos , ARN Circular/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Pronóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico , Femenino , Masculino , Biomarcadores de Tumor/genética , Anciano , Persona de Mediana Edad , Regulación Neoplásica de la Expresión GénicaRESUMEN
PURPOSE: Stereotactic body radiotherapy (SBRT) has emerged as a promising new modality for locally advanced pancreatic cancer (LAPC). The current study evaluated the efficacy and toxicity of SBRT in patients with LAPC (NCT03648632). METHODS: This prospective single institution phase II study recruited patients with histologically or cytologically proven adenocarcinoma of the pancreas after more than two months of combination chemotherapy with no sign of progressive disease. Patients were prescribed 50-60 Gy in 5-8 fractions. Patients were initially treated on a standard linac (n = 4). Since 2019, patients were treated using online magnetic resonance (MR) image-guidance on a 1.5 T MRI-linac, where the treatment plan was adapted to the anatomy of the day. The primary endpoint was resection rate. RESULTS: Twenty-eight patients were enrolled between August 2018 and March 2022. All patients had non-resectable disease at time of diagnosis. Median follow-up from inclusion was 28.3 months (95 % CI 24.0-NR). Median progression-free and overall survival from inclusion were 7.8 months (95 % CI 5.0-14.8) and 16.5 months (95 % CI 10.7-22.6), respectively. Six patients experienced grade III treatment-related adverse events (jaundice, nausea, vomiting and/or constipation). One of the initial four patients receiving treatment on a standard linac experienced a grade IV perforation of the duodenum. Six patients (21 %) underwent resection. A further one patient was offered resection but declined. CONCLUSION: This study demonstrates that SBRT in patients with LAPC was associated with promising overall survival and resection rates. Furthermore, SBRT was safe and well tolerated, with limited severe toxicities.
Asunto(s)
Neoplasias Pancreáticas , Radiocirugia , Humanos , Radiocirugia/métodos , Radiocirugia/efectos adversos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Anciano de 80 o más Años , Radioterapia Guiada por Imagen/métodos , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Adenocarcinoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.
Asunto(s)
Capecitabina , Cardiotoxicidad , Neoplasias Colorrectales , Combinación de Medicamentos , Fluorouracilo , Ácido Oxónico , Tegafur , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Tegafur/efectos adversos , Tegafur/administración & dosificación , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Ácido Oxónico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Cardiotoxicidad/etiología , Capecitabina/efectos adversos , Capecitabina/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Adulto , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.
Asunto(s)
Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patología , Neoplasias Gástricas/diagnóstico , Europa (Continente) , Consenso , Metástasis de la Neoplasia , Técnica DelphiRESUMEN
Background: Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. Methods: This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. Findings: From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. Interpretation: In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Funding: Servier, Roche.
RESUMEN
Frailty in older patients with cancer increases the risk of treatment related toxicity, mortality, physical decline, and quality of life. This review summarises various screening tools. Screening tools identifying frailty serve multiple purposes, providing awareness of health issues impacting oncologic treatment and prognosis and facilitating the delivery of a Comprehensive Geriatric Assessment (CGA). CGA is an overall health assessment and treatment targeting frailty. Providing CGA to older patients with cancer reduces the risk of toxicity and functional decline, increases treatment completion, and prevents loss of quality of life.
Asunto(s)
Fragilidad , Neoplasias , Humanos , Anciano , Fragilidad/diagnóstico , Fragilidad/terapia , Evaluación Geriátrica , Calidad de Vida , Detección Precoz del Cáncer , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMEN
Due to demographic changes the incidence of older patients with cancer will increase. The complexity of systemic treatment of cancer is also evolving. Older patients with cancer are underrepresented in clinical trials and do often not represent the older population treated in real-world setting. Knowledge on how to treat older patients with cancer is sparse and mostly based on pooled analyses from larger trials including older fit patients. Only few randomised trials include older patients with frailty. Clinical trials dedicated to older or frail patients with cancer are still an unmet need, as argued in this review.
Asunto(s)
Fragilidad , Neoplasias , Humanos , Anciano , Anciano Frágil , Neoplasias/complicaciones , Neoplasias/terapia , Cuidados PaliativosRESUMEN
BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.
Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Irinotecán/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Oxaliplatino/uso terapéutico , Leucovorina/efectos adversos , Terapia Neoadyuvante/efectos adversos , Capecitabina , Gemcitabina , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Fluorouracilo/efectos adversos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/cirugíaRESUMEN
BACKGROUND: The prognostic role of resection margin status following total (TP) and distal (DP) pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) is insufficiently evaluated. In Denmark, pancreatic surgery, including the postoperative pathological examination of the resection specimens, is confined to four centres, all reporting to the Danish Pancreatic Cancer Database (DPCD). In this Danish population-based nationwide study on TP and DP for PDAC from 2015-2019, based on data from DPCD, we evaluated whether there is a prognostically relevant minimum margin clearance definition and whether certain margins hold independent prognostic information. METHODS: Clinical and pathological data were retrieved from DPCD and supplemented by review of pathology reports and re-microscopy, if needed. One of the study pathologists performed all re-microscopy. The prognostic significance of margin status was evaluated by dichotomisation of the TP cohort (n = 101) and the DP cohort (n = 90) into involved and uninvolved groups, using different clearance definitions (0.5 - ≥3.0 mm). RESULTS: Following TP, direct involvement of the superior mesenteric artery (SMA) margin had independent prognostic value. When using a clearance definition of ≥ 0.5 or ≥ 1.5 mm for SMA, median survival for R0 versus R1 was 19 (95% CI 14-26) versus 10 (95% CI 5-20) months (p = 0.010), and 21 (95% CI 15-30) versus 10 (95% CI 8-19) months (p = 0.011), respectively. Overall margin status was not of significant prognostic importance following neither DP nor TP. CONCLUSION: In this Danish population-based nationwide study, SMA margin involvement was a significant isolated prognostic factor following TP, whereas combined assessment of all circumferential margins did not hold statistically significant prognostic information. Following DP, resection margin status did not affect survival.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Pronóstico , Pancreatectomía , Márgenes de Escisión , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Dinamarca/epidemiología , PancreaticoduodenectomíaRESUMEN
INTRODUCTION: Older patients with frailty starting oncological treatment are at higher risk of experiencing declining physical performance, loss of independence, and quality of life (QoL). This study examines whether comprehensive geriatric assessment (CGA)-guided interventions added to standard oncological care can prevent declining physical performance and QoL in older patients with frailty initiating palliative treatment. MATERIALS AND METHODS: Patients aged ≥70 years, with a Geriatric-8 score of ≤14, initiating palliative oncological treatment were enrolled in an open label randomized controlled trial and randomized 1:1 to receive either CGA-guided interventions in addition to oncological standard care or oncological care alone. Baseline characteristics, physical performance measures, and QoL questionnaires were retrieved before group allocation. CGA was performed using a fixed set of domains and validated tests by a geriatrician-led team. The primary endpoint, physical performance, was measured by the 30-s chair stand test (30s-CST) at three months. Additional outcomes included 30s-CST at six months, handgrip strength test, and QoL. Outcomes were analyzed using linear mixed regression models. The trial was registered at clinicaltrials.org (NCT04686851). RESULTS: From November 1, 2020 to May 31, 2022, 181 patients were included; 88 in the interventional arm and 93 in the control arm. Median age was 77 (interquartile range [IQR] 73-81) years, 69% were male, median Geriatric-8 score was 12 (IQR 10-13), 69% had a Performance Status of 0-1, and the median 30s-CST was 9 (IQR 5-11) repetitions. The between-group difference in 30s-CST at three months was 0.67 (95%CI: -0.94 - 2.29) and 1.57 (95%CI: -0.20 - 3.34) at six months, which were not statistically significant. Subgroup analysis including participants with a baseline Geriatric-8 of 12-14 found borderline significant between-group differences in 30s-CST scores at three and six months of 2.04 (95% confidence interval [CI]: -0.07 - 4.2, P = 0.06) and 2.25 (95%CI: 0.01-4.5, P = 0.05), respectively. No within-group or between-group differences in the summary score or the Elderly Functional Index score (measuring QoL) were found. DISCUSSION: This study did not find significant between-group differences in the 30s-CST in older patients receiving palliative care. However, a tendency towards improved physical performance was seen in the least frail. These patients may represent a target group wherein CGA interventions provide particular benefit.
Asunto(s)
Fragilidad , Neoplasias , Anciano , Humanos , Masculino , Anciano de 80 o más Años , Femenino , Calidad de Vida , Evaluación Geriátrica , Fuerza de la Mano , Neoplasias/terapia , Pronóstico , Rendimiento Físico FuncionalRESUMEN
Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.
Cetuximab is a drug for patients with colorectal cancer or cancer of the head and neck. It is usually administered once a week. However, studies have shown that cetuximab given once every 2 weeks instead has similar clinical benefits and side effects. Based on this evidence, the every 2 weeks dosing schedule has been approved for use in USA and Japan. The every 2 weeks dosing schedule is a convenient alternative to the weekly schedule. It may result in fewer hospital visits, improved patient quality of life, reduced healthcare costs and more flexibility for medical staff. This review summarizes the current evidence and benefits for the every 2 weeks dosing schedule.
Asunto(s)
Carcinoma de Células Escamosas , Humanos , Cetuximab/efectos adversos , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
INTRODUCTION: Patient perspectives on functioning are often overlooked in oncology practice. This study externally validates the ELderly Functional Index (ELFI), a patient-reported measure for assessing multidimensional functioning, in older patients with gastrointestinal cancer receiving chemotherapy. The study compares ELFI scoring methods, evaluates its diagnostic value with geriatric oncology tools, and proposes a cut-off point for clinical use. MATERIALS AND METHODS: Danish patients aged ≥70 years with gastrointestinal cancer undergoing chemotherapy from a prospective, observational study were included. Two ELFI scoring methods, item-based and domain-based, were compared. Internal consistency reliability, validity, and correlations between ELFI, its component scales, and measures of functioning/frailty (including Eastern Cooperative Oncology Group Performance Status [ECOG-PS], Geriatric-8 [G8], Vulnerable Elders Survey-13 [VES-13], Timed-Up-and-Go [TUG], and 30-s chair stand test [30CST]) were investigated. Sensitivity and specificity analyses evaluated the ability of ELFI to predict frailty outcomes and identified frailty thresholds. Receiver operating characteristic analyses assessed the diagnostic ability of ELFI, alongside other measures, for oncological outcomes and frailty differentiation. Equipercentile equating methods enabled ECOG-PS, ELFI, and G8 mapping. RESULTS: One hundred fifty-four patients (median age 73.5 years, range 70-85) undergoing curative- or palliative-intent chemotherapy (49%) were included. ELFI demonstrated good internal consistency (Cronbach's alpha = 0.82) and acceptable convergent, structural, and discriminant validity. ELFI showed moderate to very strong correlations with its component scales (r = 0.40-0.93), and weaker correlations with frailty measures (r = 0.02-0.60). ELFI score < 80 indicated frailty risk, with almost fivefold risk of ECOG-PS 2 at follow-up (odds ratio[OR] = 4.8, 95% confidence interval [CI] 1.4-15.9), and predicted G8, VES-13, TUG, and 30CST frailty at follow-up, not completing planned chemotherapy (OR = 3.1; 95%CI 1.5-6.2), mono-therapy (OR = 3.5; 95%CI 1.5-8.1), initial dose reduction (OR = 4.9; 95%CI 2.0-12.1), and shorter overall survival (hazard ratio = 2.0, 95%CI 1.4-3.0). A preliminary crosswalk between ECOG-PS, ELFI, and G8 was established. DISCUSSION: ELFI was validated as a concise patient-reported measure of functional status in older patients with cancer and its relationship to frailty. ELFI demonstrated comparable predictive ability to other tools for oncological outcomes. Both scoring methods yielded similar results, with the domain-based method (ELFI v2.0) endorsed for consistency. ELFI v2.0 score of 80 was suggested as the frailty threshold in this population, supporting its clinical utility.
Asunto(s)
Fragilidad , Neoplasias Gastrointestinales , Anciano , Humanos , Anciano de 80 o más Años , Fragilidad/diagnóstico , Anciano Frágil , Estudios Prospectivos , Reproducibilidad de los Resultados , Estado Funcional , Neoplasias Gastrointestinales/tratamiento farmacológico , Dinamarca , Evaluación Geriátrica/métodosRESUMEN
BACKGROUND: In this Danish nationwide population-based study, we evaluated the prognostically relevant minimum tumour-free margin width following pancreaticoduodenectomy (PD) for ampullary adenocarcinoma (AAC) and evaluated whether certain margins hold independent prognostic information. METHODS: We included 128 patients who underwent PD for AAC from 2015 to 2019. Clinical and pathological data including well-known prognostic factors were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. All PD specimens were examined using a standardised pathological protocol including multicolour inking, axial slicing and exact reporting of margin widths. The cohort was dichotomised into involved and uninvolved groups, using different margin clearance definitions (0.5-≥3.0 mm). RESULTS: Following PD for AAC, margin clearance of ≥1 mm was independently associated with improved chance of survival compared with <1 mm (HR: 0.30, 95 % CI: 0.14-0.64 (p = 0.002)). Posterior and anterior margin widths were narrower compared with superior mesenteric artery and vein margins. Posterior margin and anterior surface had isolated prognostic significance in multivariable analysis. CONCLUSION: Following PD for AAC, margin clearance of at least 1 mm is independently associated with improved survival. Our data further indicate that anterior surface and posterior margin hold particular prognostic value.
Asunto(s)
Adenocarcinoma , Neoplasias del Conducto Colédoco , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomía , Pronóstico , Neoplasias Pancreáticas/patología , Neoplasias del Conducto Colédoco/cirugía , DinamarcaRESUMEN
BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/patología , MutaciónRESUMEN
In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Inmunoterapia , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patologíaRESUMEN
Objectives: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Methods: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25â¯% of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline. Results: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2â¯%) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37â¯% received bidirectional treatment. More than 90â¯% of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients. Conclusions: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.