RESUMEN
BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Medicina de Precisión , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/mortalidad , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Cetuximab , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R. METHODS: Male Apc(min/+) mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc(min/+) mice (n=15-17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150. RESULTS: Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm(3) (comb) vs 248 mm(3) (AZ12253801), P=0.0003 and 47 mm(3) (comb) vs 123 mm(3) (gefitinib), P=0.0042, Mann-Whitney (two-sided) test). CONCLUSION: Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.
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Adenoma/patología , Receptores ErbB/antagonistas & inhibidores , Genes APC , Neoplasias Intestinales/patología , Inhibidores de Proteínas Quinasas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenoma/tratamiento farmacológico , Adenoma/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Gefitinib , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/genética , Isoxazoles/administración & dosificación , Isoxazoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Quinazolinas/administración & dosificación , Quinazolinas/farmacología , Carga Tumoral/efectos de los fármacosRESUMEN
We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina , Cetuximab , Neoplasias Colorrectales/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Estudios de Seguimiento , Humanos , Leucovorina/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Oxaloacetatos , Pronóstico , Tasa de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
OBJECTIVE: The management of the asymptomatic primary in stage IV colorectal cancer presents a dilemma. There is an increased morbidity and mortality from surgical resection. Nonresectional management of the primary is associated with the risks of obstruction, perforation or haemorrhage. Our practice in patients with stage IV disease is palliative chemotherapy and symptom control. We reviewed our nonoperatively managed patients with colorectal liver metastases in order to identify the percentage of patients requiring urgent operative interventions for symptoms related to the primary. SUBJECTS/PATIENTS AND METHOD: A retrospective review of all patients treated for stage IV disease at our institution from 2003-2006 was undertaken. Patients were identified from multidisciplinary team (MDT) records. Demographic detail, treatment, and follow-up data were extracted from hospital records. These were analysed with Microsoft Excel. RESULTS: Thirty-seven patients were identified. 26 Male:11 Female. Median age 63 years (range 38-78). The median survival from diagnosis was 14 months. Three (8%) patients developed obstruction whilst having palliative chemotherapy. Two required a defunctioning stoma, and one was treated by means of a stent. There were no similarities between these three patients in terms of age, sex, site or stage of primary, volume of liver metastases, and alkaline phosphatase (ALP) or carcinoembryonic antigen (CEA) levels. CONCLUSION: Of 37 patients initially treated palliatively for stage IV colorectal cancer, 92% required no surgical treatment of their primary. Therefore it is the experience of this MDT that it is acceptable to treat such patients in an expectant manner. It is not possible to predict those patients, likely to require surgical intervention.
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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Cuidados Paliativos , Adulto , Anciano , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Análisis de SupervivenciaAsunto(s)
Ensayos Clínicos como Asunto/normas , Evaluación Preclínica de Medicamentos/normas , Drogas en Investigación/uso terapéutico , Neoplasias/radioterapia , Guías de Práctica Clínica como Asunto , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Algoritmos , Ensayos Clínicos como Asunto/métodos , Drogas en Investigación/farmacología , Humanos , Modelos Biológicos , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Over the last 5 years there has been a surge in interest in the molecular classification of colorectal cancer. The effect of molecular subtyping on current treatment decisions is limited to avoidance of adjuvant 5-fluorouracil chemotherapy in stage II microsatellite unstable-high disease and avoidance of epidermal growth factor receptor-targeted antibodies in extended RAS mutant tumours. The emergence of specific novel combination therapy for the BRAF-mutant cohort and of the microsatellite unstable-high cohort as a responsive group to immune checkpoint inhibition shows the growing importance of a clinically relevant molecular taxonomy. Clinical trials such as the Medical Research Council FOCUS4 trial using biomarkers to select patients for specific therapies are currently open and testing such approaches. The integration of mutation, gene expression and pathological analyses is refining our understanding of the biological subtypes within colorectal cancer. Sharing of data sets of parallel sequencing and gene expression of thousands of cancers among independent groups has allowed the description of disease subsets and the need for a validated consensus classification has become apparent. This biological understanding of the disease is a key step forward in developing a stratified approach to patient management. The discovery of stratifiers that predict a response to existing and emerging therapies will enable better use of these treatments. Improved scientific understanding of the biological characteristics of poorly responsive subgroups will facilitate the design of novel biologically rational combinations. Novel treatment regimens, including the combination of new drugs with radiation, and the discovery and validation of their associated predictive biomarkers will gradually lead to improved outcomes from therapy.
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Carcinogénesis/clasificación , Carcinogénesis/genética , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/genética , HumanosRESUMEN
BACKGROUND: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. METHODS: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m(2) po, twice daily, days 1-14) and oxaliplatin (130 mg/m(2) i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. RESULTS: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8% (95% CI 12.05-39.5%). Stable disease was observed in a further 13 patients (31%) and progressive disease observed in 12 (28.6%) of patients. The median progression-free survival was 4.6 months (95% CI 2.8-6.4 months; Fig. 1) and the median overall survival 7.9 months (95% CI 5.3-10.4 months; Fig. 2). Fig. 1 Progression-free survival Fig. 2 Overall survival CONCLUSION: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. However, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Capecitabina/uso terapéutico , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/cirugía , Capecitabina/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Resultado del TratamientoRESUMEN
Involved field (IF) radiation was compared with extended field (EF) radiation in Hodgkin lymphoma (HL) to ascertain whether reduced radiation fields would reduce the late sequelae of radiation without compromising disease control and survival. A total of 603 patients with stage I or II HL were entered into this trial; laparotomy was carried out in 380 (63%) patients. Stage I or IIA disease patients were randomised to receive IF or EF comprising a mantle or inverted Y fields alone. Stage I and IIB patients were randomised between mantle or inverted Y fields and total nodal irradiation (TNI). The dose was 35 Gy to uninvolved sites and 40 Gy to involved sites. The median followup of surviving patients was 25.2 years with only 3.3% lost to follow-up. The treatment failure rate at 25 years in stage IA and IIA was 44% after EF and 54% after IF (P = 0.01); in stage I and IIB this was 80% (EF) and 82% (TNI) at 25 years. No difference in overall survival between the randomised groups was seen. The incidence of second malignancies was 21% after IF and 20% after EF with a slight excess of lung cancer in the EF group. No significant differences in the causes of death between the randomised arms have emerged. In conclusion, IF radiotherapy for stage I and IIA HL results in a 11% greater risk of relapse compared with EF but has no effect on overall survival, risk of second malignancy or cause of death at 25 years.
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Enfermedad de Hodgkin/radioterapia , Traumatismos por Radiación/prevención & control , Adolescente , Adulto , Anciano , Fraccionamiento de la Dosis de Radiación , Femenino , Enfermedad de Hodgkin/patología , Humanos , Laparotomía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Inducidas por Radiación , Recurrencia , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Raltitrexed (Tomudex), a thymidylate synthase inhibitor, is an alternative to 5-fluorouracil (5-FU)/leucovorin (LV) for the first-line treatment of advanced colorectal cancer. Following the completion of four phase III studies with raltitrexed at the recommended dose of 3.0 mg/m(2), it is opportune to review the efficacy and tolerability data of raltitrexed and suggest guidelines for appropriate patient management. Data are analysed from four phase III and five phase II studies including over 1300 patients with advanced colorectal cancer, some of whom were elderly or received higher doses of raltitrexed. Median survival with raltitrexed was comparable to that of bolus or infusional 5-FU/LV in three of the four randomised studies and objective response rates in the four trials were similar for the two agents. Response rates were at least comparable in elderly patients in phase II studies. For the majority of patients, treatment with raltitrexed was well tolerated even at doses higher than that recommended or in the elderly. As with other cytotoxic agents, serious and potentially life-threatening side-effects can occur; nevertheless, adherence to simple patient guidelines should minimise the incidence of serious side-effects with raltitrexed; these include the assessment of renal function before each and every treatment, dosage adjustment in the presence of renal impairment and close monitoring with prompt treatment of toxicities, particularly diarrhoea and neutropenia.
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Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Quinazolinas/administración & dosificación , Tiofenos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Antimetabolitos Antineoplásicos/efectos adversos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Diarrea/inducido químicamente , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Dolor/inducido químicamente , Quinazolinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Tiofenos/efectos adversos , Vómitos/inducido químicamenteRESUMEN
The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.
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Nitroimidazoles/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Combinación de Medicamentos , Etanidazol , Humanos , Neoplasias/metabolismo , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Fármacos Sensibilizantes a Radiaciones/farmacocinéticaRESUMEN
The hydrophilic 2-nitroimidazole radiosensitizer etanidazole is currently undergoing clinical evaluation. Although considerably less neurotoxic than misonidazole because of its rapid renal clearance and partial exclusion from the nervous system, total dose is limited by peripheral neuropathy. Monitoring plasma etanidazole concentration in patients to determine the area under the curve (AUC0-infinity) has been proposed as a method of predicting patients at risk, and of providing a quantitative basis for dose reduction in such patients. Successful application of this policy requires accurate assessment of AUC0-infinity. We have analyzed plasma data for 18 patients receiving 2 g/m2 etanidazole to determine the errors introduced in the estimation of AUC0-infinity caused by omitting selected time points from the analysis. A 'baseline' AUC0-infinity value was calculated by integration of the rate equation for the 2-compartment model using data points at 0, 15, and 30 min and 1, 2, 4, 8, 12, and 24 hr after the end of infusion. The mean +/- SD area for AUC0-infinity was 502 +/- 152 micrograms ml-1 h (2.35 +/- 0.71 mM.h). Omitting the zero or the 24 hr time point, the average errors were quite small (2.5% in both cases), but errors of up to 16.4 and 7.3%, respectively, were seen for individual patients. Leaving out both the 8 hr and 12 hr points at the same time gave a similar low average error of 2.9%, with a highest error of 7.3%. Omitting all data points after 4 hr, the mean error was 24.7% and 15 of 18 patients had errors in excess of 10%. In addition, failure to correct for infusion time results in an underestimation of AUC0-infinity averaging 4.5% (range 1.9-8.7%). The choice of sampling times for toxicological monitoring will depend upon the accuracy with which the AUC0-infinity must be known. Including all data points between 0 and 24 hr will minimize errors. Considering the general similarity in the errors introduced by omitting the 8 hr and 12 hr points together compared to those seen with exclusion of the single 24 hr point, the choice between these truncated sampling options would be expected to lie in the relative inconvenience caused to patients and medical staff for the particular dose schedule used. The short sampling schedule (0-4 hr) should not be used.
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Nitroimidazoles/sangre , Fármacos Sensibilizantes a Radiaciones/sangre , Etanidazol , Semivida , Humanos , Monitoreo Fisiológico/métodos , Nitroimidazoles/administración & dosificación , Nitroimidazoles/efectos adversos , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/efectos adversosRESUMEN
The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.
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Nitroimidazoles/farmacocinética , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Anciano , Ensayos Clínicos como Asunto , Etanidazol , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/radioterapia , Nitroimidazoles/efectos adversos , Fármacos Sensibilizantes a Radiaciones/efectos adversosRESUMEN
The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.
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Neoplasias/radioterapia , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Adulto , Anciano , Terapia Combinada , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etanidazol , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamenteRESUMEN
The aim of the study was to assess whether endoscopic ultrasound (EUS) could accurately measure the locoregional response to chemoradiotherapy in patients with carcinoma of the esophagus. Seventeen patients with esophageal carcinoma underwent EUS examination before and on completion of chemoradiotherapy. The EUS findings were correlated with the results of histologic examination of the esophagectomy specimen. The accuracy of EUS in these patients was compared with the accuracy of EUS in a control group of 17 patients treated by surgery alone. In 16 of 17 patients EUS-determined tumor (T) stage was unchanged following treatment and in one patient there was T-stage progression. No patient demonstrated downstaging of the primary tumor according to classical EUS criteria. In 10 of 17 patients a reduction in maximum tumor depth of >/=2 mm was observed (range 2 to 18 mm). Histologic examination revealed that four patients with squamous cell carcinoma had experienced a complete pathologic response. These four patients had significantly lower posttreatment EUS tumor depths compared to patients without a complete response (5.0 vs. 9.0 mm; P <0.05). Based on the post-treatment EUS examination, the accuracy was 59% for T stage and 59&percnt for node (N) stage. The accuracy of EUS in patients treated by surgery alone was 94% for T stage and 94% for N stage, indicating a significant reduction in the accuracy of EUS in patients following chemoradiotherapy (P <0.05). The accuracy of EUS examination in patients with carcinoma of the esophagus treated by chemoradiotherapy was poor. EUS did not detect downstaging of the primary tumor, even in the presence of a complete pathologic response. EUS assessment of maximum tumor depth was a better measure of response to therapy.
Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/terapia , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/terapia , Endosonografía , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/terapia , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A novel chelating derivative of alpha melanocyte stimulating hormone, bis MSH-DTPA, has been used for the diagnostic targeting of malignant melanoma. 15 patients were investigated of whom nine were shown by other means to have active disease at the time of the scan. Tumours were imaged in all of these nine patients. Of a total of 46 lesions over 10 mm encountered, 41 (89%) were imaged. There were no false positives and in two cases bisMSH-DTPA was instrumental in reversing diagnoses made using ultrasound. Derivatives of melanocyte stimulating hormone may be of considerable value in targeting melanomas.
Asunto(s)
Quelantes , Radioisótopos de Indio , Hormonas Estimuladoras de los Melanocitos , Melanoma/diagnóstico por imagen , Ácido Pentético , Adulto , Anciano , Evaluación de Medicamentos , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Metástasis Linfática , Masculino , Melanoma/secundario , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias Palatinas/diagnóstico por imagen , Cintigrafía , Neoplasias de la Columna Vertebral/diagnóstico por imagenRESUMEN
Cysts within the oesophageal wall may represent inclusion cysts, retention cysts or developmental cysts. Foregut duplications are developmental anomalies, which occur as a result of abnormal canalization of the foregut during intrauterine life. Malignant transformation is an extremely rare event occurring within oesophageal cysts, adenocarcinoma being the most common histology. We report a case of squamous cell carcinoma arising within an oesophageal cyst affecting the upper third of the oesophagus. The malignant cyst was not amenable to primary surgical resection and hence was treated using chemo-radiotherapy. The treatment gave good disease control, at the expense of a high oesophageal stricture. Chemo-radiotherapy is an alternative treatment modality to achieve long-term disease control in squamous cell carcinoma complicating oesophageal foregut cyst when primary surgical resection is not possible.
Asunto(s)
Carcinoma de Células Escamosas/patología , Quiste Esofágico/patología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Quiste Esofágico/complicaciones , Quiste Esofágico/terapia , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/terapia , Femenino , Humanos , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
A model of undergraduate education based on a one to one relationship between a student and a patient with cancer has become a core module within the University of Wales College of Medicine undergraduate curriculum. The project combines the powerful impact of a one to one interaction with an active investigative and reflective approach to issues triggered from that patient's cancer journey. The aim is to provide each medical student with an understanding of the impact of a malignant disease and its treatment on patients and their families through the experience of one patient with cancer. The benefits of the project cover the areas of attitudes, skills and knowledge. Students are assessed on their involvement with the patient, in tutorials and on their portfolio, in which they record all aspects of the project. Student evaluations indicate high levels of appreciation of the project, despite its potentially strong emotional content.