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BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Progresión , Piridinas/uso terapéutico , Adulto , Trifluridina/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Timina/uso terapéutico , Combinación de Medicamentos , PirrolidinasRESUMEN
BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Fluorouracilo , Leucovorina , Compuestos Organoplatinos , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Masculino , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Adulto , Metástasis de la Neoplasia , Biomarcadores de Tumor/sangreRESUMEN
A wide variety of treatments have been developed to improve respiratory function and quality of life in patients with bilateral vocal fold paresis (BVFP). One experimental method is the electrical activation of the posterior cricoarytenoid (PCA) muscle with a laryngeal pacemaker (LP) to open the vocal folds. We used an ovine (sheep) model of unilateral VFP to study the long-term effects of functional electrical stimulation on the PCA muscles. The left recurrent laryngeal nerve was cryo-damaged in all animals and an LP was implanted except for the controls. After a reinnervation phase of six months, animals were pooled into groups that received either no treatment, implantation of an LP only, or implantation of an LP and six months of stimulation with different duty cycles. Automated image analysis of fluorescently stained PCA cross-sections was performed to assess relevant muscle characteristics. We observed a fast-to-slow fibre type shift in response to nerve damage and stimulation, but no complete conversion to a slow-twitch-muscle. Fibre size, proportion of hybrid fibres, and intramuscular collagen content were not substantially altered by the stimulation. These results demonstrate that 30 Hz burst stimulation with duty cycles of 40% and 70% did not induce PCA atrophy or fibrosis. Thus, long-term stimulation with an LP is a promising approach for treating BVFP in humans without compromising muscle conditions.
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Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica , Músculos Laríngeos , Parálisis de los Pliegues Vocales , Animales , Ovinos , Parálisis de los Pliegues Vocales/terapia , Parálisis de los Pliegues Vocales/fisiopatología , Terapia por Estimulación Eléctrica/métodos , Músculos Laríngeos/fisiopatología , Humanos , Marcapaso Artificial/efectos adversos , Pliegues Vocales/fisiopatología , Pliegues Vocales/patología , FemeninoRESUMEN
Quantitative imaging in life sciences has evolved into a powerful approach combining advanced microscopy acquisition and automated analysis of image data. The focus of the present study is on the imaging-based evaluation of the posterior cricoarytenoid muscle (PCA) influenced by long-term functional electrical stimulation (FES), which may assist the inspiration of patients with bilateral vocal fold paresis. To this end, muscle cross-sections of the PCA of sheep were examined by quantitative image analysis. Previous investigations of the muscle fibers and the collagen amount have not revealed signs of atrophy and fibrosis due to FES by a laryngeal pacemaker. It was therefore hypothesized that regardless of the stimulation parameters the fat in the muscle cross-sections would not be significantly altered. We here extending our previous investigations using quantitative imaging of intramuscular fat in cross-sections. In order to perform this analysis both reliably and faster than a qualitative evaluation and time-consuming manual annotation, the selection of the automated method was of crucial importance. To this end, our recently established deep neural network IMFSegNet, which provides more accurate results compared to standard machine learning approaches, was applied to more than 300 H&E stained muscle cross-sections from 22 sheep. It was found that there were no significant differences in the amount of intramuscular fat between the PCA with and without long-term FES, nor were any significant differences found between the low and high duty cycle stimulated groups. This study on a human-like animal model not only confirms the hypothesis that FES with the selected parameters has no negative impact on the PCA, but also demonstrates that objective and automated deep learning-based quantitative imaging is a powerful tool for such a challenging analysis.
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Aprendizaje Profundo , Animales , Ovinos , Estimulación Eléctrica/métodos , Tejido Adiposo , Músculos Laríngeos/fisiopatología , Terapia por Estimulación Eléctrica/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.
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Neoplasias del Colon , Consenso , Humanos , Neoplasias del Colon/terapia , Neoplasias del Colon/patología , Quimioterapia Adyuvante/normas , Recolección de Datos/normas , Ensayos Clínicos como Asunto/normasRESUMEN
PURPOSE: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). However, optimising the timing of TARE in relation to systemic therapies and patient selection remains challenging. We report here on the effectiveness, safety, and prognostic factors associated with TARE for ICC in a combined analysis of the prospective observational CIRT studies (NCT02305459 and NCT03256994). METHODS: A combined analysis of 174 unresectable ICC patients enrolled between 2015 and 2020 was performed. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every follow-up visit. Log-rank tests and a multivariable Cox proportional hazard model were used to identify prognostic factors. RESULTS: Patients receiving a first-line strategy of TARE in addition to any systemic treatment had a median OS and PFS of 32.5 months and 11.3 months. Patients selected for first-line TARE alone showed a median OS and PFS of 16.2 months and 7.4 months, whereas TARE as 2nd or further treatment-line resulted in a median OS and PFS of 12 and 9.3 months (p = 0.0028), and 5.1 and 3.5 months (p = 0.0012), respectively. Partition model dosimetry was an independent predictor for better OS (HR 0.59 [95% CI 0.37-0.94], p = 0.0259). No extrahepatic disease, no ascites, and < 6.1 months from diagnosis to treatment were independent predictors for longer PFS. CONCLUSION: This combined analysis indicates that in unresectable ICC, TARE in combination with any systemic treatment is a promising treatment option. LEVEL OF EVIDENCE: level 3, Prospective observational.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Embolización Terapéutica , Neoplasias Hepáticas , Humanos , Neoplasias de los Conductos Biliares/radioterapia , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/radioterapia , Embolización Terapéutica/métodos , Neoplasias Hepáticas/radioterapia , Estudios Prospectivos , Estudios Retrospectivos , Radioisótopos de Itrio/uso terapéutico , Estudios Observacionales como AsuntoRESUMEN
The updated edition of the German, Austrian and Swiss Guidelines for Systemic Treatment of Gastric Cancer was completed in August 2023, incorporating new evidence that emerged after publication of the previous edition. It consists of a text-based "Diagnosis" part and a "Therapy" part including recommendations and treatment algorithms. The treatment part includes a comprehensive description regarding perioperative and palliative systemic therapy for gastric cancer and summarizes recommended standard of care for surgery and endoscopic resection. The guidelines are based on a literature search and evaluation by a multidisciplinary panel of experts nominated by the hematology and oncology scientific societies of the three involved countries.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Austria , Oncología MédicaRESUMEN
Introduction: Although many different treatments were developed for facial palsy, only a few therapeutic options are available for facial synkinesis. Electrical stimulation of specific muscles via implants could be useful in restoring facial symmetry in synkinetic patients. A challenge in developing stimulation devices is finding the right stimulation location, type, and amplitude. This work assesses the ability to selectively stimulate the zygomaticus muscle (ZYG) in patients with oral-ocular synkinesis to elicit a visually detectable response of the ipsilateral corner of the mouth (COM), without causing a reaction of the orbicularis oculi muscle (OOM). We aimed to assess how close to the COM the stimulation should be delivered in order to be selective. Methods: A total of 10 patients (eight females, two males) were enrolled. Facial function was graded according to the Sunnybrook facial grading system. Needle EMG was used to test the activities of the muscles, during volitional and "unintended" movements, and the degree of synkinesis of the ZYG and OOM. Two ball electrodes connected to an external stimulator were placed on the paretic ZYG, as close as possible to the COM. Results: Independent of the waveform with which the stimulation was presented, a selective ZYG response was observed within 4.5â cm of the horizontal plane and 3â cm of the vertical plane of the COM. When the distance between the electrodes was kept to ≤2â cm, the amplitude necessary to trigger a response ranged between 3 and 6â mA when the stimulation was delivered with triangular pulses and between 2.5 and 3.5â mA for rectangular pulses. The required amplitude did not seem to be dependent on the applied phase duration (PD), as long as the PD was ≥5â ms. Conclusion: Our results show that selective stimulation of the ZYG presenting synkinetic ZYG-OOM reinnervation can be achieved using a broad PD range (25-1,000â ms) and an average amplitude ≤6â mA, which may be further decreased to 3.5â mA if the stimulation is delivered via rectangular rather than triangular waves. The most comfortable and effective results were observed with PDs between 50 and 250â ms, suggesting that this range should be selected in future studies. Clinical Trial Registration: [https://drks.de/search/de/trial/DRKS00019992], identifier (DRKS00019992).
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The assessment of muscle condition is of great importance in various research areas. In particular, evaluating the degree of intramuscular fat (IMF) in tissue sections is a challenging task, which today is still mostly performed qualitatively or quantitatively by a highly subjective and error-prone manual analysis. We here realize the mission to make automated IMF analysis possible that (i) minimizes subjectivity, (ii) provides accurate and quantitative results quickly, and (iii) is cost-effective using standard hematoxylin and eosin (H&E) stained tissue sections. To address all these needs in a deep learning approach, we utilized the convolutional encoder-decoder network SegNet to train the specialized network IMFSegNet allowing to accurately quantify the spatial distribution of IMF in histological sections. Our fully automated analysis was validated on 17 H&E-stained muscle sections from individual sheep and compared to various state-of-the-art approaches. Not only does IMFSegNet outperform all other approaches, but this neural network also provides fully automated and highly accurate results utilizing the most cost-effective procedures of sample preparation and imaging. Furthermore, we shed light on the opacity of black-box approaches such as neural networks by applying an explainable artificial intelligence technique to clarify that the success of IMFSegNet actually lies in identifying the hard-to-detect IMF structures. Embedded in our open-source visual programming language JIPipe that does not require programming skills, it can be expected that IMFSegNet advances muscle condition assessment in basic research across multiple areas as well as in research fields focusing on translational clinical applications.
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BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Adolescente , Humanos , Masculino , Femenino , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Pirazoles/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Progresión de la EnfermedadRESUMEN
BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Trifluridina/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Calidad de Vida , Neoplasias del Recto/tratamiento farmacológico , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosAsunto(s)
Países en Desarrollo , Neoplasias , Humanos , Renta , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Using data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours. METHODS: We analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS). RESULTS: All-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade ≥ 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS. CONCLUSION: Our study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.
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Carcinoma Hepatocelular , Neoplasias Colorrectales , Embolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/terapia , Microesferas , Calidad de Vida , Radioisótopos de Itrio/efectos adversos , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Europa (Continente)/epidemiología , Neoplasias Colorrectales/terapiaRESUMEN
PURPOSE: MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2â/high microsatellite instability, HER2â/microsatellite stable [MSS]/BRAFwt or HER2â/MSS/BRAFmut/RASmut). METHODS: Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). RESULTS: Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50-1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90-2.29; P = 0.128). CONCLUSIONS: Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2â/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02291289.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Bevacizumab , Cetuximab , Proteínas Proto-Oncogénicas B-raf/genética , Vemurafenib/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Fluorouracilo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , LeucovorinaRESUMEN
Metastatic colorectal cancer (mCRC) is a heterogenous disease caused by various genetic alterations. The BRAFV600E mutation occurs in approximately 8-12% of patients and is characterised by an aggressive clinical course and poor prognosis. Here we review the current knowledge on BRAFV600E-mutant mCRC and provide a series of consensus statements on its clinical management. The treatment landscape for BRAFV600E-mutant mCRC has changed greatly due to the emergence of molecular targeted therapies (including BRAF inhibitors) and immune checkpoint inhibitors. A scientific literature search identified available data on molecular testing, treatments, and clinical monitoring of patients with BRAFV600E-mutant mCRC. Consensus statements were discussed and developed by a European expert panel. This manuscript provides consensus management guidance for different clinical presentations of BRAFV600E-mutant mCRC and makes recommendations regarding treatment sequencing choices. To guide appropriate clinical management and treatment decisions for mCRC patients, tumour tissue analysis for DNA mismatch repair/microsatellite status and, at a minimum, KRAS, NRAS, and BRAF mutational status is mandatory at the time of diagnosis. Finally, we discuss the rapidly evolving treatment landscape for BRAFV600E-mutant mCRC and define priorities for the development of novel therapeutic strategies that are needed to improve patient outcomes.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , MutaciónRESUMEN
SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinical and clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.
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Biosimilares Farmacéuticos , Neoplasias del Colon , Neoplasias del Recto , Humanos , Bevacizumab/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Aprobación de DrogasRESUMEN
INTRODUCTION: SARS-CoV-2 infected patients with cancer have a worse outcome including a significant higher mortality, compared to non-cancer patients. However, limited data are available regarding in-hospital mortality during the Omicron phase of the pandemic. Therefore, the aim of the study was the comparison of mortality in patients with history of cancer and patients with active cancer disease during the different phases of the COVID-19 pandemic, focusing on the current Omicron variant of concern. METHODS: We conducted a multicenter, observational, epidemiological cohort study at 45 hospitals in Germany. Until July 20, 2022, all adult hospitalized SARS-CoV-2 positive patients were included. The primary endpoint was in-hospital mortality regarding cancer status (history of cancer and active cancer disease) and SARS-CoV-2 virus type. RESULTS: From March 11, 2020, to July 20, 2022, a total of 27,490 adult SARS-CoV-2 positive patients were included in the study. 2,578 patients (9.4%) had diagnosis of cancer, of whom 1,065 (41.3%) had history of cancer, whereas 1,513 (58.7%) had active cancer disease. Overall 3,749 out of the total of 27,490 patients (13.6%) died during the hospital stay. Patients with active cancer disease had a significantly higher mortality compared to patients without cancer diagnosis, in both phases of the pandemic (wild-type to Delta: OR 1.940 [1.646-2.285]); Omicron: 2.864 [2.354-3.486]). After adjustment to co-variables, SARS-CoV-2 infected patients with active cancer disease had the highest risk for in-hospital mortality compared to the other groups, in both phases of the pandemic. CONCLUSION: The CORONA Germany study indicates that hospitalized patients with active cancer disease are at high risk of death during a SARS-CoV-2 infection. Mortality of patients with history of cancer improved to nearly the level of non-cancer patients during Omicron phase.
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COVID-19 , Neoplasias , Adulto , Humanos , SARS-CoV-2 , Mortalidad Hospitalaria , Pandemias , Estudios de Cohortes , Alemania/epidemiologíaRESUMEN
PURPOSE: Microsatellite instability (MSI) due to mismatch repair (MMR) defects accounts for 15-20% of colon cancers (CC). MSI testing is currently standard of care in CC with immunohistochemistry of the four MMR proteins representing the gold standard. Instead, label-free quantum cascade laser (QCL) based infrared (IR) imaging combined with artificial intelligence (AI) may classify MSI/microsatellite stability (MSS) in unstained tissue sections user-independently and tissue preserving. METHODS: Paraffin-embedded unstained tissue sections of early CC from patients participating in the multicentre AIO ColoPredict Plus (CPP) 2.0 registry were analysed after dividing into three groups (training, test, and validation). IR images of tissue sections using QCL-IR microscopes were classified by AI (convolutional neural networks [CNN]) using a two-step approach. The first CNN (modified U-Net) detected areas of cancer while the second CNN (VGG-Net) classified MSI/MSS. End-points were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). RESULTS: The cancer detection in the first step was based on 629 patients (train n = 273, test n = 138, and validation n = 218). Resulting classification AUROC was 1.0 for the validation dataset. The second step classifying MSI/MSS was performed on 547 patients (train n = 331, test n = 69, and validation n = 147) reaching AUROC and AUPRC of 0.9 and 0.74, respectively, for the validation cohort. CONCLUSION: Our novel label-free digital pathology approach accurately and rapidly classifies MSI vs. MSS. The tissue sections analysed were not processed leaving the sample unmodified for subsequent analyses. Our approach demonstrates an AI-based decision support tool potentially driving improved patient stratification and precision oncology in the future.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Inteligencia Artificial , Medicina de Precisión , Neoplasias del Colon/patología , Repeticiones de Microsatélite , Inestabilidad de Microsatélites , Neoplasias Colorrectales/patologíaRESUMEN
Background & Aims: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is an established treatment option for patients with hepatocellular carcinoma (HCC). However, optimising treatment application and patient selection remains challenging. We report here on the effectiveness, safety and prognostic factors, including dosing methods, associated with TARE for HCC in the prospective observational CIRT study. Methods: We analysed 422 patients with HCC enrolled between Jan 2015 and Dec 2017, with follow-up visits every 3 months for up to 24 months after first TARE. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every 3-month follow-up visit. We used the multivariable Cox proportional hazard model and propensity score matching to identify independent prognostic factors for effectiveness outcomes. Results: The median OS was 16.5 months, the median PFS was 6.1 months, and the median hepatic PFS was 6.7 months. Partition model dosimetry resulted in improved OS compared to body surface area calculations on multivariable analysis (hazard ratio 0.65; 95% CI 0.46-0.92; p = 0.0144), which was confirmed in the exact matching propensity score analysis (hazard ratio 0.56; 95% CI 0.35-0.89; p = 0.0136). Other independent prognostic factors for OS were ECOG-performance status >0 (p = 0.0018), presence of ascites (p = 0.0152), right-sided tumours (p = 0.0002), the presence of portal vein thrombosis (p = 0.0378) and main portal vein thrombosis (p = 0.0028), ALBI grade 2 (p = 0.0043) and 3 (p = 0.0014). Adverse events were recorded in 36.7% of patients, with 9.7% of patients experiencing grade 3 or higher adverse events. Conclusions: This large prospective observational dataset shows that TARE is an effective and safe treatment in patients with HCC. Using partition model dosimetry was associated with a significant improvement in survival outcomes. Impact and implications: Transarterial radioembolization (TARE) is a form of localised radiation therapy and is a potential treatment option for primary liver cancer. We observed how TARE was used in real-life clinical practice in various European countries and if any factors predict how well the treatment performs. We found that when a more complex but personalised method to calculate the applied radiation activity was used, the patient responded better than when a more generic method was used. Furthermore, we identified that general patient health, ascites and liver function can predict outcomes after TARE. Clinical trial number: NCT02305459.