RESUMEN
BACKGROUND: In recent years, a number of molecular markers have been tested for their potential to predict the outcome after radiotherapy or radiochemotherapy in patients with advanced head and neck squamous cell carcinomas (HNSCC). These studies have produced controversial results. PATIENTS AND METHODS: The expression patterns of the proteins p53, pRb, cyclinD1, cdk4, p21(CIP1/WAF1), p16(INK4a), bcl-2, and mib-1/ki-67 were analyzed in pretreatment tumor biopsies of 53 patients with advanced nonresectable head and neck squamous cell carcinomas (mainly UICC IV). The patterns obtained were compared with clinical outcome after accelerated radiochemotherapy with carboplatin and 5-fluorouracil or accelerated fractionated radiotherapy alone, respectively. RESULTS: The expression patterns of the proteins examined did not correlate with response to therapy or with further clinical course. CONCLUSION: In patients with advanced head and neck squamous cell carcinomas, the prognostic relevance of pretreatment expression patterns of the proteins investigated in this study, particularly p53, cyclinD1, and cdk4, has to be questioned.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Proteínas de Ciclo Celular/genética , Neoplasias de Oído, Nariz y Garganta/patología , Adulto , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Oído, Nariz y Garganta/genética , Neoplasias de Oído, Nariz y Garganta/terapia , Pronóstico , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Regarding the promising results of international trials we conducted the first German prospective multicentre phase II trial for organ preservation with primary simultaneous chemoradiation in advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: 28 of 30 recruited patients suffering from stage II and III (UICC) laryngeal and hypopharyngeal cancer were treated with primary simultaneous chemoradiation within an organ preservation program and monitored in follow-up of one year. Exclusion criteria included tumor infiltration of the laryngeal cartilage, bilateral neck nodes (N2c) and need for flap reconstruction in case of laryngectomy. The protocol included an accelerated concomitant boost chemoradiation (66 Gy) with Carboplatinum (70 mg/m2 1st and 5th week) and a restaging procedure one month after therapy. In case of residual disease, salvage laryngectomy and/or neck dissection were performed. RESULTS: After follow-up of one year 20 of 28 patients (71%) were presented with stable complete remission and functionally preserved larynx. Of these 20 patients 3 developed pulmonary metastases, 1 secondary primary carcinoma of the lung and 3 neck metastases which needed neck dissections. The other patients showed in 4 cases relapsing tumor which was indicated for laryngectomy. One patient needed tracheotomy because of persisting edema and 2 patients died due to tumor progress. One patient died after complications due to salvage surgery. CONCLUSION: The organ preservation protocol was feasible with well tolerated early toxicity. Problems of screening for recurrent disease, salvage surgery and late toxicity should be noted and pronounced in patient information. Further studies should focus on the improvement of patient selection which could be realized by induction Chemotherapy (using new components like taxan) and/or use of prediction factors such as tumor volume and hemoglobin levels.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Laríngeas/radioterapia , Laringectomía , Terapia Neoadyuvante , Adulto , Anciano , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hipofaríngeas/tratamiento farmacológico , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/cirugía , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
We report the clinical course and diagnostic findings in two patients with life-threatening Mycoplasma pneumoniae (MP) pneumonia who were treated in the same hospital in the course of only 4 months. The patients were previously healthy adults, aged 31 and 37 years, respectively. In both of them severe complications occurred which coincided with the acute MP respiratory infection.
Asunto(s)
Neumonía Bacteriana/microbiología , Neumonía por Mycoplasma , Adulto , Anticuerpos Antibacterianos/sangre , Pruebas de Fijación del Complemento , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Immunoblotting , Recién Nacido , Masculino , Neumonía Bacteriana/sangre , Neumonía Bacteriana/complicaciones , Síndrome de Dificultad Respiratoria/etiologíaRESUMEN
BACKGROUND: Primary radiochemotherapy is gaining increasing importance for the treatment of advanced head and neck squamous cell carcinomas. However, there is a lack of clinical factors concerning prognostic information in relation to treatment. In this pilot study, we examined whether molecular factors can provide such information. PATIENTS AND METHODS: The expression patterns and their possible prognostic relevance of the cell cycle regulatory proteins p53, p21(WAF/CIP1), Rb, p16(INK4A), CDK4 and Cyclin D1, MIB1 (Ki-67) and BCL-2 were analysed in pretreatment tumor biopsies from 43 patients with advanced carcinomas of the oropharynx (n = 26), hypopharynx (n = 10) and larynx (n = 7) by applying immunohistochemistry to paraffin sections of tumor specimens. All patients were treated by the same method of an accelerated "concomitant boost" radiochemotherapy with carboplatin in a phase II study. Median followup time was 56 months. RESULTS: No correlation was found between any of the markers and the remission rate, T-stage, N-stage, rate of loco-regional recurrences and distant metastases. However, independent of the tumor stage, patients with CDK4/cyclin-D1 overexpressing tumors had a significantly shortened overall survival (P = 0.014 and 0.026, respectively). CONCLUSION: The results of this pilot study indicate that CDK4 and cyclin D1 over-expression provide useful prognostic information about clinical outcome after primary radiochemotherapy of head and neck cancer patients.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Neoplasias de Oído, Nariz y Garganta/genética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Oído, Nariz y Garganta/tratamiento farmacológico , Neoplasias de Oído, Nariz y Garganta/patología , Neoplasias de Oído, Nariz y Garganta/radioterapia , Proyectos Piloto , Pronóstico , Dosificación RadioterapéuticaRESUMEN
PURPOSE: It is well known that chemotherapy and radiotherapy in other tumor sites than head and neck cause immunomodulating effects. The purpose of this trial was to assess the influence of radiochemotherapy in head and neck on cellular and subcellular immunity. PATIENTS AND METHODS: In a phase II/III-trial fifty patients with advanced squamous cell carcinoma of the head and neck were treated by simultaneously accelerated radiochemotherapy with Carboplatin (70 mg/sqm). Total radiation dose was 66 Gy/35 days. The following immunological parameters were investigated at several time points during therapy: total lymphocytes, total T-lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, monocytes, natural killer cells, interleukin-2-receptor-positive T-cells, MHC class II-positive B-cells, monocytes and T-cells, CD4/CD8-ratio; Cytokines: II-1, soluble II-1-receptor antagonist, II-2, soluble II-2-receptor, II-3, II-4, II-6, soluble II-6-receptor, II-8, interferon-alpha, granulocytes-macrophages-colony-stimulating-factor, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1. In addition, responses to the in vitro stimulation of lymphocytes by mitogens was tested. RESULTS: During therapy lymphocyte subpopulation counts decreased significantly but reversibly. Simultaneously, the function of lymphocytes was significantly but reversibly reduced. Also, II-8-concentration decreased significantly whereas concentrations of II-6 and soluble II-1-receptor antagonist significantly increased. CONCLUSIONS: The accelerated radiochemotherapy with Carboplatin induces a severe impairment of cellular immunity, followed by compensatory cytokine reaction.
Asunto(s)
Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/radioterapia , Citocinas/sangre , Inmunidad Celular/efectos de la radiación , Neoplasias de Oído, Nariz y Garganta/radioterapia , Adulto , Anciano , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Terapia Combinada , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/efectos de la radiación , Inmunidad Celular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neoplasias de Oído, Nariz y Garganta/tratamiento farmacológico , Neoplasias de Oído, Nariz y Garganta/inmunología , Dosificación RadioterapéuticaRESUMEN
BACKGROUND AND PURPOSE: The existence of hereditary factors influencing the cellular response to ionising radiation has led to the hypothesis that the inter-patient variability of clinical radiation reactions may, at least in part, be attributable to an individual, or intrinsic, radiosensitivity. Considerable effort has been spent in the development of test systems that would determine individual radiosensitivity before or early during radiotherapy to possibly predict treatment outcome, but the results are still conflicting. The present explorative study was therefore aimed at the detection of associations between acute and late radiation effects, tumour control and in vitro radiosensitivity of primary normal tissue fibroblasts. PATIENTS AND METHODS: Sixty-eight patients with squamous cell carcinoma of the head and neck (93% UICC stage IV) were treated with a simultaneous concomitant boost radiochemotherapy with Carboplatin as part of a prospective non-randomised multicenter study at the University of Heidelberg. Primary fibroblasts were obtained from skin biopsies prior to treatment from 25 unselected patients of this study and the SF2 was determined using the colony forming assay and high dose-rate irradiation. The median follow-up was 21 months (range 2.5-81 months). RESULTS: The locoregional control rate at three years was 32%. No significant association between acute (mucosa reaction grade 1 or 2 vs. grade 3 and 4), late radiation effects (subcutaneous fibrosis, osteonecrosis, larynx oedema), locoregional tumour control and SF2 of primary fibroblasts was found using Cox proportional hazards regression analysis, log-rank test and Mann-Whitney U-test. Although a steep dose-response relationship was observed for the radiation-induced severe larynx oedema, Cox proportional hazards regression analysis could not fully explain the occurrence of severe radiation-induced larynx oedema with the dose to the larynx (P = 0.09). In the subgroup of twenty-five patients, where the SF2 was determined, bivariate analysis revealed about the same non-significant influence of the dose to the larynx on the larynx oedema (P = 0.1) and no influence of the SF2 (P = 0.5). CONCLUSIONS: In our study of patients with advanced cancer of the head and neck, neither the normal fibroblast SF2 nor the severity of acute radiation effects were able to predict late radiation effects or locoregional tumour control.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Fibroblastos/efectos de la radiación , Neoplasias de Cabeza y Cuello/radioterapia , Tolerancia a Radiación , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Predicción , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Edema Laríngeo/etiología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Traumatismos por Radiación/etiología , Dosificación Radioterapéutica , Piel/citología , Resultado del TratamientoRESUMEN
In addition to mucositis and myelotoxicity as well known early reactions after radiotherapy or radiochemotherapy in advanced head and neck tumors, late toxicity following treatment is an often underestimated problem. Between 1992 and 1995, 68 patients with advanced oro- and hypopharyngeal tumors were treated primarily with accelerated concomitant boost radiochemotherapy (total dose irradiations of 66 Gy and carboplatin as chemotherapy). Ninety-three per cent of the patients had stage IV disease according to the UICC-TNM classification. Monitoring of follow-up included late toxicity with special attention given to laryngeal edema. In 37 patients (54%) edema of the larynx as a late complication of radiochemotherapy was observed by clinical investigation and CT scan. The median onset of laryngeal edema was found 121 days after completion of therapy, with a median time of observation of 250 days. Observations in these patients demonstrated the chronic character of this edema. An increase in the laryngeal edema in 5 cases resulted in tracheostomy. Laryngeal edema in 10 patients was associated with recurrence of tumor. These results show that after xerostomia laryngeal edema is the main late toxicity in the head and neck after radiochemotherapy and should lead to further investigations to exclude possible recurrent tumor.
Asunto(s)
Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/radioterapia , Edema Laríngeo/etiología , Laringe/efectos de la radiación , Neoplasias Orofaríngeas/radioterapia , Traumatismos por Radiación/etiología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Terapia Combinada , Femenino , Humanos , Edema Laríngeo/inducido químicamente , Edema Laríngeo/patología , Laringe/efectos de los fármacos , Laringe/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/patología , Traumatismos por Radiación/patología , Dosificación RadioterapéuticaRESUMEN
PATIENTS: Between 1989 and 1992, 38 patients with advanced squamous cell carcinomas of the head and neck were treated by an accelerated hyperfractionated split-course radiochemotherapy (SCRC). This therapy was carried out at the ENT department and department of radiooncology of the University of Heidelberg. Within 51 days, 70.2 Gy were applied in three courses. In every course, simultaneous chemotherapy with cisplatin (60 mg/m2/week)/5 Fu (bolus: 350 mg/m2/d)/Leucovorin (bolus: 50 mg/m2 + 100 mg/m2/24 h) was carried out. Between 1992 and 1994, 50 patients suffering from advanced head and neck cancer (stage III, V) were also treated with an accelerated hyperfractionated concomitant-boost radiochemotherapy (CBRC) at the same departments. A total dose of 66 Gy, was applied within 33 days. The patients were also treated with simultaneous chemotherapy with carboplatin (70 mg/m2/24 h) in the first and fifth week. RESULTS: In about 50% of the patients treated with SCRC, the therapy was more than 10 days longer than the scheduled period. The lack of compliance due to toxicity was considered as one of the main reasons for this delay. After the first course of SCRC, eight of 38 patients showed mucositis of the upper aerodigestive tract (WHO grade > 3); after the second course, 11 of 38 patients; and after the third course, 15 of 38 patients. Fifty-two percent of the patients developed emesis, 10% leucopenia < 1 nl, 10% nephrotoxicity, 3% pancreatitis, 3% thrombosis, 3% gastritis, and 3% auditory threshold shifts of about more than 10 dB. In about 7.5% of the patients treated with CBRC, the therapy was more than 10 days longer than the scheduled period. The mucositis of the upper aerodigestive tract (50% of the patients showed WHO-grade > 3) was considered to be the main reason for this. In four patients a neutropenia < 1 nl was detected, in one patient anemia < 7 g/dl and n 33 patients thrombocytopenia < 100/nl. CONCLUSIONS: In conclusion, the concomitant boost radiochemotherapy showed a lower toxicity and higher acceptance than the split-course radiochemotherapy. This is documented in lower protocol delays and better results in the two-years survival time in case of concomitant boost radiotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Radioterapia de Alta Energía , Adulto , Anciano , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Dosificación RadioterapéuticaRESUMEN
Despite numerous treatment measures mucositis of the mouth and pharynx due to radiochemotherapy frequently remains refractory to therapy. In most cases high doses of pain medications are till required. However, mucositis as a strong early reaction may be controllable by limiting cancer therapy. Within the current framework of accelerated radiochemotherapy with carboplatin, 50 patients with inoperable squamous cell carcinomas of the head and neck were followed from 1992 to 1994. Acute toxicity was documented from the first through eighth week after starting therapy. From the fifth week on, the degree of mucositis found was > 3 (WHO scale) in 24 patients. The extent of mucositis in 5 patients required interrupting therapy for 10 days on average. In 14 cases the average stay in hospital had to be prolonged by 10.2 days because of severe inflammation. In all, the average duration of mucositis after the end of the therapy amounted to 9.6 weeks. Twenty patients required bypass feedings with transnasal stomach tubes or percutaneous gastrostomy (PEG) tubes that were later removed. In addition, the incidences of dysphagia, xerostomia, hoarseness, skin reactions, nausea or vomitus and myelotoxicity were recorded. Descriptions of the supportive care concepts used at the University of Heidelberg are given and the supportive care concepts available scientific literature is updated.