RESUMEN
BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.
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Acrilamidas , Compuestos de Anilina , Anticuerpos Biespecíficos , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Morfolinas , Pirazoles , Pirimidinas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Progresión de la Enfermedad , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.
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Antineoplásicos/uso terapéutico , Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Miedo/psicología , Neoplasias Ováricas/rehabilitación , Anciano , Depresión/diagnóstico , Depresión/etiología , Depresión/psicología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/psicología , Cuestionario de Salud del Paciente/estadística & datos numéricos , Proyectos Piloto , Estudios Prospectivos , Calidad de Vida , Nivel de Atención , Resultado del TratamientoRESUMEN
OBJECTIVE: Investigate the clinical landscape of ovarian carcinoma (OC) over time. DESIGN: Register-based prospectively collected data. SETTING: South East Scotland. SAMPLE: A total of 2805 OC patients diagnosed in 1981-2015. METHODS: Survival times were visualised using the Kaplan-Meier method; median survival, 5-year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences. MAIN OUTCOME MEASURES: Disease-specific survival. RESULTS: A significant increase in disease-specific survival (DSS) from 1981-1985 to 2011-2015 was observed (median 1.73 versus 4.23 years, P < 0.0001). Corresponding increase in progression-free survival (PFS) was not statistically significant (median 1.22 versus 1.58 years, P = 0.2568). An increase in the proportion of cases with low residual disease volume (RD) (<2 cm RD) following debulking was observed (54.0% versus 87.7%, P < 0.0001). The proportion of high grade serous (HGS) cases increased (P < 0.0001), whereas endometrioid and mucinous cases decreased (P = 0.0005 and P = 0.0002). Increases in stage IV HGS OC incidence (P = 0.0009) and stage IV HGS OC DSS (P = 0.0122) were observed. Increasing median age at diagnosis correlated with increasing Eastern Cooperative Oncology Group Performance Status (ECOG PS) over time (r = 0.86). CONCLUSIONS: OC DSS has improved over the last 35 years. PFS has not significantly increased, highlighting that improvement in outcome has been limited to extending post-relapse survival. Distribution of stage at diagnosis, histological subtype and RD following debulking has changed over time, reflecting evolution in tumour classification, staging and optimal debulking definitions (from low RD to minimal or zero RD). Histology, stage, RD and ECOG PS remain reliable outcome predictors. Increasing median age at diagnosis and ECOG PS indicates demographic shifts in the clinical population. TWEETABLE ABSTRACT: Significant improvement in ovarian carcinoma survival has been seen over time. Most of this improvement is due to an extension of survival following disease relapse.
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Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Edad de Inicio , Carcinoma Epitelial de Ovario/cirugía , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Estimación de Kaplan-Meier , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Ováricas/cirugía , Supervivencia sin Progresión , Sistema de Registros , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
AIMS: Hyperglycaemia, a side-effect of acute glucocorticoid exposure, is associated with poor outcome in those undergoing chemotherapy. The incidence, risk factors and diurnal profile of glucocorticoid-induced glucose dysregulation in the context of chemotherapy treatment remain incompletely understood. METHODS: Blinded continuous interstitial glucose monitoring was performed on 16 women without diabetes for 24 h prior to and 5 days following carboplatin/paclitaxel chemotherapy combined with dexamethasone treatment for gynaecological cancer. At the end of the treatment period, glucose data were analysed and integrated with baseline metabolic and anthropomorphic variables. RESULTS: 15/16 (94%) women exhibited elevated glucose levels (> 11.1 mmol/l). Peak glucose levels were highest on the day of treatment (median 14.45 mmol/l, range 10.2-22.2 mmol/l) and total time spent with an elevated interstitial glucose level was highly variable (median 3.6 h, range 0.0-55.1 h). Peak interstitial glucose levels occurred predominantly, but not exclusively, in the afternoon (13.00-15.00) and evening (19.00-22.00); however elevated levels were noted throughout the 24-h period. Baseline HbA1c was independently associated with severity and duration of elevated glucose levels in a regression adjusted for baseline BMI. CONCLUSIONS: These data report for the first time that high glucose levels are encountered by nearly all women following this regimen, the severity and duration of which are independently associated with HbA1c . Further work is required to determine if controlling glucose levels during treatment influences outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/efectos adversos , Líquido Extracelular/química , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Glucosa/análisis , Hiperglucemia/inducido químicamente , Hiperglucemia/diagnóstico , Adulto , Anciano , Glucemia/análisis , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Automonitorización de la Glucosa Sanguínea , Quimioprevención/métodos , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Estudios de Cohortes , Dexametasona/administración & dosificación , Líquido Extracelular/metabolismo , Femenino , Neoplasias de los Genitales Femeninos/metabolismo , Glucosa/metabolismo , Humanos , Hiperglucemia/metabolismo , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Piel/química , Piel/metabolismoRESUMEN
OBJECTIVE: To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN: Retrospective cohort study. SETTING: Four cancer/genetics centres in Scotland. POPULATION: Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES: Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS: Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS: Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT: BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma/genética , Pruebas Genéticas/estadística & datos numéricos , Neoplasias Ováricas/genética , Adulto , Anciano , Carcinoma/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/normas , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Prevalencia , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
BACKGROUND: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer. METHODS: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma. RESULTS: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%). CONCLUSIONS: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.
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Azacitidina/análogos & derivados , Carboplatino/administración & dosificación , Metilación de ADN/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Adaptadoras Transductoras de Señales/sangre , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Carboplatino/efectos adversos , Decitabina , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Proteínas Nucleares/sangre , Proteínas Nucleares/genética , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Platino (Metal)/administración & dosificaciónRESUMEN
INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Albúminas/uso terapéutico , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico , Inflamación/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The introduction, 30 years ago, of the co-administration of appropriate hydration and ensuring a diuresis occurs during the administration of cisplatin was important in its development, allowing clinically significant doses to be given with acceptable rates of toxicity. The clinical usage of cisplatin has increased and hydration protocols have been amended to increase patient comfort and reduce resource utilization. We suspected that this had led to unnecessary variations in practice both in clinical trials and subsequently in the clinic. Therefore, we reviewed practice in the Edinburgh Cancer Centre and discovered that 25 different hydration protocols were in use, with wide variation in dilution of cisplatin, total fluid administered, use of electrolyte (potassium and magnesium) supplementation and diuretics. These differences are a reflection of adoption of variations in hydration regimes published in pivotal clinical trials. A review of the available evidence relating to cisplatin associated hydration regimens was performed and recommendations will be made for the future design of evidence-based protocols.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Protocolos Clínicos , Fluidoterapia/métodos , Neoplasias/tratamiento farmacológico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Diuréticos/administración & dosificación , Esquema de Medicación , Humanos , EscociaRESUMEN
AIMS: To determine whether the introduction of early concomitant chemoradiotherapy for patients with limited stage small cell lung cancer (LS-SCLC) has resulted in acceptable outcomes and toxicity in a UK practice. MATERIALS AND METHODS: The case records of all patients with LS-SCLC treated with chemoradiotherapy from July 2001 to 2004 were reviewed, and subjected to descriptive statistics and proportional hazards analysis. RESULTS: Concomitant chemoradiotherapy was delivered to 30 patients and sequential chemoradiotherapy was delivered to 36 patients. The former patients tended to be younger (mean 58.9 vs 64.1 years, P=0.01); the latter patients tended to have bulkier disease. There was no difference in performance status, but cisplatin was given more often in the former group (90% vs 44%, P<0.0001). Grade 3 acute oesophagitis occurred in less than 10% of either group and there were no cases of grade 3 or greater pneumonitis. Two-year actuarial survival for the concomitant group was 53% (95% confidence interval 36-71%) and 36% (95% confidence interval 20-52%) for the sequential group (P=0.018). Proportional hazards analysis showed an increased hazard of death with increasing performance status and age, sequential therapy and the use of cisplatin with sequential therapy. CONCLUSION: Concomitant chemoradiotherapy can be safely given in a UK population with outcomes comparable with those reported in North American series.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas , Cisplatino/uso terapéutico , Neoplasias Pulmonares , Radioterapia Adyuvante , Adulto , Anciano , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Traumatismos por Radiación , Estudios Retrospectivos , EscociaRESUMEN
Experimental evidence from several sources has identified a link between mismatch repair deficiency and cytotoxic drug resistance. Selection for cisplatin resistance in the human ovarian cancer cell line A2780, results in loss of expression of the mismatch repair protein hMLH1 in most (90%) of the resultant cisplatin-resistant cell lines. Here we demonstrate that the cisplatin sensitive parental cell line displays methylation of the promoter of only one hMLH1 allele, but that the resistant cell lines all exhibit hyper-methylation of the promoters of both hMLH1 alleles. Full methylation of all sites tested was found to be invariably associated with loss of hMLH1 expression, whereas a partial increase in methylation appears compatible with either loss or maintenance of expression. In addition treatment of two of the resistant cell lines with 5-azacytidine, a known inhibitor of methylation, results in re-expression of hMLH1. Clonogenic assays demonstrate that the 5-azacytidine treated cells show increased sensitivity to cisplatin. Furthermore, 12.5% (3/ 24) of ovarian tumours show hypermethylation of the hMLH1 promoter. Expression of hMLH1 is absent in the tumours that are hypermethylated, while all the unmethylated tumours still express the protein. This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.
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Metilación de ADN , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Regiones Promotoras Genéticas , Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos/farmacología , Azacitidina/farmacología , Disparidad de Par Base , Proteínas Portadoras , Cisplatino/farmacología , Reactivos de Enlaces Cruzados/farmacología , Metilación de ADN/efectos de los fármacos , Reparación del ADN/genética , Femenino , Humanos , Homólogo 1 de la Proteína MutL , Proteínas Nucleares , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patologíaRESUMEN
PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival. PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively. RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P =.010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P =.0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors. CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.
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Disparidad de Par Base , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Antineoplásicos/farmacología , Proteínas Portadoras , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Funciones de Verosimilitud , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteínas de Neoplasias/efectos de los fármacos , Proteínas Nucleares , Pronóstico , Análisis de Regresión , Estudios Retrospectivos , Estadísticas no Paramétricas , Proteína p53 Supresora de Tumor/efectos de los fármacosRESUMEN
PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.
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Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The loss of the function in any one of four human DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, is thought to lead to deficient mismatch repair (MMR) of DNA in the somatic cells leading to increased mutations and thereby cancer development. Microsatellite instability (MI) detected by PCR analysis has, to date, been the hallmark of loss of the function of these genes. Western and Northern blotting has confirmed the loss of MMR protein expression with MI. However, this technique relies on fresh samples for DNA extraction and requires a normal tissue sample (see Chapter 41). Expression of MMR proteins can now be examined in both fresh and archival paraffin-embedded tissue samples by immunohistochemistry. This was first described for polyclonal hMSH2 antibody, in paraffin-embedded tissue, by Wilson et al. (1) and confirmed by Leach et al. (2), who showed that hMSH2 is highly expressed in the nuclei cells of the gastrointestinal epithelium that undergo rapid renewal in both the ileum, colon, and esophagus. Thibodeau et al. (3) examined paraffin-embedded tissue from colorectal tumors for both hMLH1 and hMSH2 genes and function by DNA sequence analysis, MI analysis by PCR, and immunohistochemistry. They showed that loss of immunohistochemical staining for these MMR proteins corresponded very closely with loss of function of these genes detected by microsatellite analysis. Of 19 tumors showing MI, 14 had loss of either or both hMLH1 and hMSH2 immunostaining. Of eight tumors showing a germline mutation in either hMLH1 or hMSH2, seven had a corresponding loss of immunostaining for the protein. Of 14 tumors showing a negative immunostain for one or both of hMLH1 and hMSH2, all had MI on PCR analysis and seven had a germline mutation in the DNA sequence of at least one of the MMR genes. Fink et al. (4) have performed immunohistochemistry for hMLH1 and hPMS2 on fresh frozen tissue sections. They confirmed a high nuclear expression in the epithelium of the digestive tract and in the testis and ovary. We describe here a method for immunohistochemistry for hMSH2, hMLH1, and hPMS2 in both fresh and paraffin-embedded material.
RESUMEN
Epidermal growth factor receptor (EGFR) mutation analysis is recommended for lung cancer patients prior to the prescription of first-line EGFR tyrosine kinase inhibitors in order to predict response to treatment. There are many methods available to identify mutations in the EGFR gene; a large number of clinical laboratories use the therascreen EGFR RGQ PCR kit (Qiagen). We report a case where this kit detected an exon 19 deletion, predicting sensitivity to tyrosine kinase inhibitors (TKIs), which on further analysis was found to be a 2â bp indel (c.2239_2240delinsCC, p.(Leu747Pro)). Two of four published cases with this mutation were found to be associated with resistance to EGFR TKI. The sample was also tested using two other commercial kits, one of which indicated a deletion. This is a rare mutation making the erroneous detection of a deletion unlikely; however, it is important that clinical laboratories are aware of the potential failings of two commercial kits for EGFR mutation analysis.
Asunto(s)
Adenocarcinoma/genética , Análisis Mutacional de ADN , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Antineoplásicos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
We present a review of 111 patients who were treated over an initial 3-year period with erlotinib. The median treatment time was 68 days and 59% of patients had stopped treatment within the first 3 months. However, 20 patients were on erlotinib for more than 12 months. Performance status and smoking history were the significant prognostic factors. The overall 3-year survival in patients who had never smoked was 26%.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Adenocarcinoma Bronquioloalveolar/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Escocia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Thirty-one patients with advanced renal carcinoma or malignant melanoma were treated in the first feasibility study of alpha-interferon (Roferon) and the new oral immunomodulating agent, Linomide. Linomide 5 mg or 10 mg p.o. daily was given for 2 weeks; alpha-interferon was then added at 3 MU s.c. three times weekly, escalating in each patient by 3 MU per week, if tolerable, up to 12 MJ. The combination was poorly tolerated with nausea, vomiting, somnolence and myalgia commonly reported. Adverse events accounted for treatment withdrawal in ten patients and contributed to withdrawal in four other patients. Treatment with Linomide alone in the first 2 weeks led to a significant increase in white blood cells, neutrophils and platelets. When alpha-interferon was added, the platelet count decreased significantly over the following 6 weeks. Nineteen patients had white cell phenotype and function measured. After 2 weeks of 5 mg Linomide, a transient but significant decrease in the absolute number of activated T-helper cells (CD4+DR+) was observed. No changes in natural killer (NK) cell number or activity were observed. Twenty-two patients were evaluable for response. One with metastatic renal cell carcinoma had a complete response and six had stable disease. This study does not support the use of the combination because significant toxicity was seen without the anticipated immunological benefits.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interferón-alfa/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Humanos , Hidroxiquinolinas/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.
Asunto(s)
Antídotos/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antídotos/efectos adversos , Antídotos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma/metabolismo , Estudios de Cohortes , Neoplasias del Colon/metabolismo , Quimioterapia Combinada , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias del Recto/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37-55%) with ECF, and 21% (95% CI, 13-28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8-20%) for the ECF arm, and 5% (95% CI, 2-10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting.