RESUMEN
PURPOSE: Peptide receptor radionuclide therapy (PRRT) using [177Lu]Lu-DOTATATE has been shown to effectively prolong progression free survival in grade 1-2 gastroenteropancreatic neuroendocrine tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of [177Lu]Lu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity. METHODS: Twenty-seven patients with grade 1-2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a "second-pass" effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment [177Lu]Lu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples t-test. FINDINGS: After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/NIA = 17·4 vs. T/Ncontrol = 16·2 (p = 0·299). The mean increase in T/N was 17% (1·17; 95% CI [1·00; 1·37]). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle. CONCLUSION: Intra-arterial [177Lu]Lu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.
Asunto(s)
Neoplasias Hepáticas , Tumores Neuroendocrinos , Compuestos Organometálicos , Humanos , Octreótido/efectos adversos , Compuestos Organometálicos/uso terapéutico , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , RadioisótoposRESUMEN
Rare cancers, which collectively account for almost 25 % of all malignancies, are poorly understood in terms of their aetiology and pathogenesis and are infrequently the focus of translational and clinical research to improve their diagnosis and treatment. Consequently, those affected have comparatively few treatment options, and their prognosis is worse than that of patients with more common entities. Here we review two relevant groups of rare cancers, bone and soft-tissue sarcomas and neuroendocrine tumours (NET), to illustrate recent efforts towards individualised, biology-guided clinical management to improve long-term outcomes. Specifically, we address how comprehensive, multi-layered molecular analyses, including the assessment of predisposing hereditary factors, and innovative imaging approaches can improve the diagnosis of these diseases, allow for better prognostic assessment, and provide new targets for pharmacologic and, in the case of NET, nuclear medicine interventions, whose clinical value must be determined in controlled trials optimally tailored to the particular patient population most likely to benefit. Furthermore, we describe the importance of multidisciplinary collaboration in dedicated reference centres for rare cancers and the increasingly acknowledged potential of networking across institutions at a national and international level. Finally, we illustrate the value of a learning health system based on the systematic collection and sharing of the biological and clinical profiles of patients with rare cancers to achieve continuous cross-fertilisation of scientific and clinical efforts, making the vision of stratified precision medicine in these long-overlooked diseases a reality.
Asunto(s)
Tumores Neuroendocrinos , Sarcoma , Biología , Humanos , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/terapia , Medicina de Precisión , Pronóstico , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/terapiaRESUMEN
PURPOSE: Adequate monitoring of changes in tumor load is fundamental for the assessment of the course of disease and response to treatment. There is an ongoing debate on the utility of RECIST v1.1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: In this retrospective real-life cohort study, Choi-criteria were compared with RECIST v1.1. The agreement between both criteria and the association with survival endpoints were evaluated. RESULTS: Seventy-five patients were included with a median follow-up of 35 months (range 8-53). Median progression-free survival (mPFS) according to RECIST v1.1 was 15 months (range 2-50) compared to 14 months (range 2-50) in Choi. According to RECIST, 33 (44%) patients were classified as having stable disease (SD), 40 (53%) as progressive disease (PD) and two (3%) patients as partial response (PR), compared to 9 (12%) patients classified as SD, 50 (67%) as PD and 16 (21%) as PR according to Choi-criteria. Overall concordance between the criteria was moderate (Cohen's Kappa = 0.408, p < 0.001) and agreement varied between 57 and 69% at each consecutive scan (p < 0.001). Survival analysis showed significant differences in overall survival (OS) for RECIST v1.1 categories PD and non-PD (log-rank p = 0.02), however, in Choi no significant differences in OS were found (p = 0.27). CONCLUSION: RECIST v1.1 had a better clinical utility and prognostic value compared to Choi-criteria. Still, RECIST were also not sufficient to adequately predict OS. This outlines the need for new tools that provides accurate information on the disease course and treatment response to support precise prognostication in patients with GEP-NETs.
Asunto(s)
Tumores Neuroendocrinos , Estudios de Cohortes , Humanos , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/terapia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
RATIONALE: Salivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium-iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands. METHODS: Ten patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared. RESULTS: No significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46). CONCLUSION: Muscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies.
RESUMEN
BACKGROUND: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited. METHODS: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses. DISCUSSION: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Dosis Máxima Tolerada , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Radioterapia AdyuvanteRESUMEN
BACKGROUND: Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis. AIM: We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs. METHOD: A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019. RESULTS: The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44-100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs. CONCLUSION: SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.
RESUMEN
INTRODUCTION: Somatostatin receptor imaging with PET is the standard of care for patients with a neuroendocrine tumour (NET). Since therapy and imaging with somatostatin analogues utilize the same receptor, current guidelines recommend withdrawing long-acting somatostatin analogues for 3-4 weeks prior to somatostatin receptor PET imaging. The aim of this study is to prospectively assess the effect of lanreotide use on the uptake of 68Ga-DOTATATE intra-individually 1 day prior to and 1 day post injection of lanreotide. METHODS: Thirty-four patients with metastatic and/or unresectable NET and currently on lanreotide therapy for at least 4 months were included in the study. A 68Ga-DOTATATE PET/CT scan was performed on the day before and the day after lanreotide injection. In each patient 68Ga-DOTATATE uptake (SUVmax, mean, peak) was assessed in both tumour lesions and normal tissue. All scans were assessed by two blinded nuclear medicine physicians for visual analysis. Paired T-tests were performed to determine the differences between the scans. RESULTS: Of the 34 patients included, 31 were available for analyses in which 190 tumour lesions were measured. Uptake of 68Ga-DOTATATE in tumour lesions was increased significantly after lanreotide, but decreased significantly in the liver, spleen, and thyroid gland resulting in a higher tumour-to-liver ratio. CONCLUSION: Lanreotide injection prior to 68Ga-DOTATATE PET/CT does not result in decreased tumour uptake. In contrast, tumour uptake was increased, whereas the uptake in normal organs is decreased, leading to an increased tumour-to-liver ratio. However, these differences were small and not deemed clinically relevant. These results strongly suggest that discontinuation of lanreotide injections in the weeks prior to 68Ga-DOTATATE PET examinations is unnecessary and does not compromise nuclear medicine imaging results.
Asunto(s)
Tumores Neuroendocrinos/metabolismo , Compuestos Organometálicos/metabolismo , Péptidos Cíclicos/farmacología , Somatostatina/análogos & derivados , Anciano , Transporte Biológico/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Receptores de Somatostatina/metabolismo , Somatostatina/farmacologíaRESUMEN
Background: Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks. Methods: The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed. Results: The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F. Conclusion: The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.
Asunto(s)
Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Bases de Datos Factuales , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is a rare and potentially aggressive neuroendocrine tumor of the skin, with a propensity for locoregional metastases. In two expert referral centers, isolated limb perfusion (ILP) is used to obtain locoregional control in selected locoregionally advanced MCC patients. This study describes our experience. METHOD: Patients who underwent ILP for MCC were analyzed. ILP was performed with melphalan and tumor necrosis factor (TNF) combination therapy. Depending on the institution, either a normothermic or a hyperthermic temperature regimen was used. Baseline characteristics, toxicity data, locoregional progression-free survival (LPFS) and overall survival (OS) were assessed. RESULTS: Four males and 6 females with a median age of 78 years (IQR 61-84 years) were included. Four patients underwent ILP for upper extremity disease and 6 for lower extremity disease. All patients received combination therapy with Melphalan and TNF, one patient with the addition of interferon-gamma. No signs of systemic toxicity were present post-ILP. Severe locoregional toxicity (compartment syndrome) occurred in 1 patient and 1 elderly patient with extensive atherosclerosis had to undergo transfemoral amputation due to critical ischemia. Eight patients could be included for response evaluation. The overall response rate (ORR) was 87.5% with a complete response (CR) rate of 62.5%. Two long-term responses of 53 months and 71 months were observed. Median LPFS was 5 months and median OS was 54 months. CONCLUSION: ILP shows a high CR rate that can be durable. Therefore, ILP should be considered an effective treatment modality for locally advanced MCC.
Asunto(s)
Carcinoma de Células de Merkel/tratamiento farmacológico , Quimioterapia del Cáncer por Perfusión Regional , Extremidades , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Despite the wide use of cisplatin-based concomitant chemoradiotherapy (CCRT) for head and neck squamous cell carcinoma (HNSCC), data on the optimal regimen and cumulative dose are scarce and frequently conflicting. We aimed to evaluate the compliance and the impact of the cumulative dose of cisplatin on overall survival (OS), disease-free survival (DFS), loco-regional control (LRC), and distant-metastasis-free survival (DMFS) in a retrospective study. Between 2008 and 2015, 279 patients with HNSCC scheduled for CCRT (three courses of 3-week 100 mg/m2 cisplatin) were identified. Of the whole group, 14% did not receive any cisplatin and 26% received daily cisplatin. In patients planned for three courses (n = 167), 56% received 3, 20% received 2, and 24% received one course. After median follow-up of 31.6 months, the actuarial OS, DFS, LRC, and DMFS rates at 3 years for patients received cumulative dose of ≥200 mg/m2 were significantly better compared to those received <200 mg/m2; 74 vs. 51% for OS, 73 vs. 49% for DFS, 80 vs. 58% for LRC (p < 0.001), and 85 vs. 76% for DMFS (p = 0.034). At multivariate analysis, the cumulative cisplatin dose (≥200 vs. <200 mg/m2) was significantly predictive for OS (HR 2.05; 95% CI 1.35-3.13, p = <0.001). Borderline GFR (60-70 mL/min) at baseline predicts compliance for ≥two courses (p = 0.003). In conclusion, considerable proportion of patients did not receive all pre-planned courses of cisplatin. Patients receiving cumulative cisplatin dose ≥200 mg/m2 had significantly better outcome than those receiving <200 mg/m2 and cumulative dose <200 mg/m2 might even be detrimental. These findings increased the bulk of slowly growing evidence on the optimal cumulative dose of cisplatin. Baseline GFR might predict compliance.
Asunto(s)
Carcinoma de Células Escamosas , Quimioradioterapia/métodos , Cisplatino , Neoplasias de Cabeza y Cuello , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Monitoreo de Drogas/métodos , Femenino , Tasa de Filtración Glomerular , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Evaluación de Procesos y Resultados en Atención de Salud , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de SupervivenciaRESUMEN
The cardiac manifestations of a neuroendocrine tumour are referred to as carcinoid heart disease (CaHD) and are associated with a poor prognosis. Surgical intervention is the only proven therapeutic option and may prolong survival and quality of life. No consensus has been reached internationally with regard to screening for CaHD and the optimal timing for surgery. Although limited evidence is available on this matter, a trend towards early surgery and subsequent reduced mortality has been observed. In this review we provide an overview of the current understanding and propose a protocol to guide cardiologists in the screening for CaHD and the timing of referral to a specialised surgical centre.
RESUMEN
The objectives is to thoroughly analyze the pattern of failure and oncologic outcome in recurrent oropharyngeal cancer (OPC) after (chemo)radiotherapy and correlate the site of failure to the planned radiation dose. Between January 2010 and April 2014, 57 patients with recurrent OPC after (chemo)radiotherapy were analyzed. Endpoints were pattern of failure and overall survival (OS). Local (LF) and regional failure (RF) were classified as in-field [>50% within gross tumor volume (GTV)], marginal [<50% within GTV but >50% within clinical target volume (CTV)], or out-of-field (>50% outside CTV) recurrences. In the whole group, 70 recurrences were reported. Of the 31 LF, 29 (93.5%) were in-field and 2 (6.5%) were marginal. No out-field LF was reported. Of the 21 RF, 13 RF (62%) were in-field, 6 (28.5%) marginal, and 2 (9.5%) out-of-field recurrences. Forty-three percent of RF was developed in an electively treated neck level, and 2 of them were contralateral. OS at 2 years in recurrent HPV positive, compared to HPV-negative OPC, were 66 and 18%, respectively (p = 0.011). OS was also significantly better in patients that were salvage treatment which was possible (70 vs. 6%, p < 0.001). Median survival after distant failure was 3.6 months. The great majority of LFs were located within the GTV and 43% of RFs developed in an electively treated neck level. The currently used margins and dose recipe and the indication for bilateral nodal irradiation need to be reevaluated. OS was significantly better in recurrent HPV-positive OPC and in patients, where salvage treatment was possible.
Asunto(s)
Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Recurrencia Local de Neoplasia/etiología , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/terapia , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Orofaríngeas/mortalidad , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada , Terapia Recuperativa , Insuficiencia del TratamientoRESUMEN
PURPOSE: To study the feasibility of induction chemotherapy added to concomitant cisplatin-based chemoradiotherapy (CRT) in patients with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS: LAHNC patients were treated with 4 courses of docetaxel/cisplatin/5-fluorouracil (TPF) followed by randomization to either cisplatin 100 mg/m(2) with conventional radiotherapy (cis100 + RT) or cisplatin 40 mg/m(2) weekly with accelerated radiotherapy (cis40 + ART). Primary endpoint was feasibility, defined as receiving ≥ 90% of the scheduled total radiation dose. Based on power analysis 70 patients were needed. RESULTS: 65 patients were enrolled. The data safety monitoring board advised to prematurely terminate the study, because only 22% and 41% (32% in total) of the patients treated with cis100 + RT (n = 27) and cis40 + ART (n = 29) could receive the planned dose cisplatin during CRT, respectively, even though the primary endpoint was reached. Most common grade 3-4 toxicity was febrile neutropenia (18%) during TPF and dehydration (26% vs 14%), dysphagia (26% vs 24%) and mucositis (22% vs 57%) during cis100 + RT and cis40 + ART, respectively. For the patients treated with cis100 + RT and cis40 + ART, two years progression free survival and overall survival were 70% and 78% versus 72% and 79%, respectively. CONCLUSION: After TPF induction chemotherapy, cisplatin-containing CRT is not feasible in LAHNC patients, because the total planned cisplatin dose could only be administered in 32% of the patients due to toxicity. However, all but 2 patients received more than 90% of the planned radiotherapy. Clinical Trials Information: NCT00774319.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Neoplasias de Cabeza y Cuello/terapia , Taxoides/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/mortalidad , Cisplatino/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Docetaxel , Terminación Anticipada de los Ensayos Clínicos , Estudios de Factibilidad , Femenino , Fluorouracilo/efectos adversos , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Países Bajos , Dosificación Radioterapéutica , Factores de Riesgo , Taxoides/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Microparticles (MPs) carrying active tissue factor (TF) have been detected in the plasma of cancer patients in particular in those presenting with acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Experimental studies in mice have revealed that circulating MPs carrying TF contribute to thrombus formation. AIM: To study whether unselected patients with an acute confirmed PE have elevated TF activity in the MP fraction (MP-TF activity). MATERIALS AND METHODS: Plasma MP-TF activity was measured in 159 non-selected patients with clinically suspected PE and in 48 healthy controls as previously described. Blood was collected at time of inclusion. The diagnosis of acute PE was confirmed in 54 patients and excluded in 105 patients. RESULTS: Median MP-TF activity in 159 patients with clinically suspected PE was 72 fM Xa/min [range 32-6657] fM Xa/min and higher than in healthy controls (66 [range 28-183] fM Xa/min; P<0.05). There was no significant difference (P=0.169) in MP-TF activity between patients with confirmed PE (median 84.5 fM Xa/min [range 36-2149]) and patients without PE (72 fM Xa/min [range 32-6657]) fM Xa/min). In the 159 patients with clinically suspected PE we observed in an exploratory analysis higher MP-TF activity levels in patients with active cancer (median 137 fM Xa/min [range 36-6657]) and cardiovascular disease (median 131.5 fM Xa/min [range 45-2149]) than in patients without these disorders (P=0.0004 and P=0.014, respectively). CONCLUSION: In patients presenting with clinically suspected PE plasma MP-TF activity was not associated with confirmed PE.
Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Embolia Pulmonar/sangre , Tromboplastina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis. PATIENT/METHODS: We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects. RESULTS: Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TF-activity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19- 0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model. CONCLUSIONS: Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.
Asunto(s)
Adenocarcinoma Mucinoso/sangre , Neoplasias de la Mama/sangre , Vesículas Citoplasmáticas/metabolismo , Neoplasias Pancreáticas/sangre , Tromboembolia/etiología , Tromboplastina/metabolismo , Trombosis de la Vena/etiología , Adenocarcinoma Mucinoso/complicaciones , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Antígenos de Neoplasias/sangre , Coagulación Sanguínea , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Diferenciación Celular , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Mucina-1 , Mucinas/sangre , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Tromboembolia/sangre , Tromboembolia/mortalidad , Factores de Tiempo , Trombosis de la Vena/sangre , Trombosis de la Vena/mortalidadAsunto(s)
Anticoagulantes/uso terapéutico , Cateterismo Venoso Central/efectos adversos , Premedicación , Trombosis de la Vena/etiología , Trombosis de la Vena/prevención & control , Anticoagulantes/administración & dosificación , Humanos , Incidencia , Infecciones/etiología , MEDLINE , Flebografía , Síndrome Posflebítico/etiología , Embolia Pulmonar/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Ultrasonografía Doppler en Color , Trombosis de la Vena/complicaciones , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/epidemiologíaRESUMEN
Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaive patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m(-2) on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m(-2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Quinazolinas/administración & dosificación , Tiofenos/administración & dosificación , Adulto , Anciano , Desoxicitidina/efectos adversos , Diarrea/inducido químicamente , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Quinazolinas/efectos adversos , Tasa de Supervivencia , Tiofenos/efectos adversos , GemcitabinaRESUMEN
We investigated the risk factors for venous thrombosis in cancer patients with implantable ports undergoing chemotherapy. One hundred and seventy one ports were placed in a central ("chest ports") and 84 in a peripheral vein ("arm ports"), 181 received prophylactic nadroparin and 10 coumarin. Clinically overt thrombosis was confirmed by ultrasound or angiography. Catheter-related thrombosis incidence without anticoagulants was 28% in arm and 33% in chest ports, but with anticoagulants this was 32% in arm and only 1% in chest ports (odds ratio (OR) 34.8 95% confidence interval (CI) 7.3-165). Left-sided placement compared with right-sided and catheter tip position in the superior vena cava compared with right atrium were associated with a 3.5 respectively 2.6-fold increased risk. Thrombosis was associated with elevated homocysteine levels (OR=3.8, 95% CI 1.3-11.3), but not with factor V Leiden or prothrombin 20210A gene mutations, or high concentration of factor VIII, IX or XI. Prophylaxis with anticoagulants is recommended for chest, but not for arm ports. Determination of plasma homocysteine levels may identify patients at an increased risk for thrombosis.
Asunto(s)
Catéteres de Permanencia/efectos adversos , Neoplasias/tratamiento farmacológico , Trombosis de la Vena/etiología , Adolescente , Adulto , Anciano , Anticoagulantes/uso terapéutico , Factores de Coagulación Sanguínea/antagonistas & inhibidores , Falla de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trombosis de la Vena/prevención & controlRESUMEN
AIMS: Gastric cancer in Western countries is often diagnosed in an advanced stage and prognosis is poor. We performed a randomised trial with pre-operative FAMTX vs. surgery alone in order to evaluate the effect of pre-operative chemotherapy on resectability and survival. METHODS: Patients with proven adenocarcinoma of the stomach were randomised to receive four courses of chemotherapy using 5-Fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery alone. RESULTS: Fifty-nine patients were randomised; 29 patients were allocated to the FAMTX regimen prior to surgery and 30 patients had surgery alone. Resectability rates were equal for both groups. Complete or partial response was registered in 32% of the FAMTX group. With a median follow-up of 83 months the median survival since randomisation is 18 months in the FAMTX group vs. 30 months in the surgery alone group (p=0.17). CONCLUSIONS: This trial could not show a beneficial effect of pre-operative FAMTX. Until large randomised studies prove otherwise, adequate surgery without delay is the best treatment for operable gastric cancer.