RESUMEN
The pretherapeutic hemoglobin level (Hb) has been postulated to constitute a prognostic marker for outcome after primary chemoradiation of patients with advanced cancer of the head and neck. However, this hypothesis has not been tested systematically in large study samples. In the years 1992-1997, 125 patients with advanced head and neck cancer (stages III/IV UICC) were treated with primary chemoradiation in two different prospective multicentric trials, 62 patients in trial A (phase II, 1992-1995), and 63 in trial B (phase III, 1995-1997). Beside initial Hb, other pretherapeutic parameters with potential prognostic relevance were assessed and correlated with clinical outcome after 43-months follow-up: total tumor volume (TTV; calculated in initial CT scans), tumor oxygenation (polarographic measurements with Eppendorf histography), TNM, tumor localization, age, and performance status. The evaluation of the clinical end points (progression-free and overall survival and local tumor control) revealed that Hb and TTV were independent parameters with strong predictive character of outcome after primary chemoradiation in both trials (n = 125). Bivariate analysis showed < median (13.5 g/dl) a hazard ratio of 2.1 (P = 0.002) for Hb; and > median (98 ml) a Hazard ratio of 2.0 (P = 0.006) for TTV. Severe anemia (Hb < 10 g/dl) was an adverse factor in three patients. Hypoxia was associated with poorer initial therapeutical response but was not predictive of clinical outcome. Furthermore, tumor oxygenation showed no correlation with Hb. The other parameters examined failed to show prognostic significance. Our results indicate a high prognostic value of initial Hb for outcome after primary chemoradiation in advanced head and neck cancer and imply a therapeutic benefit of Hb substitution or erythropoietin administration. We propose to test this in randomized clinical trials.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Hemoglobinometría , Neoplasias Laríngeas/radioterapia , Neoplasias Orofaríngeas/radioterapia , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: The purpose of this study was to evaluate the repeatability and the predictive relevance of the pretreatment pO(2) histography on the survival of patients with advanced head and neck cancer. PATIENTS AND METHODS: From July 1995 to August 1998, polarographic pO(2) measurements of lymph node metastases before therapy were performed in altogether 60 patients with histologically proven squamous cell carcinoma of the head and neck using the Eppendorf histograph. Forty-one of 60 patients were treated with an accelerated-hyperfractionated radiotherapy regimen with or without simultaneous chemotherapy as part of a multicenter phase III study. In 23 of 60 patients, two repeated independent measurements of the same tumor were performed with a time interval of approximately 24 h between the two measurements. RESULTS: The multivariate analysis revealed the fraction of pO(2) values
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/mortalidad , Oxígeno/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Femenino , Neoplasias de Cabeza y Cuello/terapia , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Dosificación Radioterapéutica , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
Recent clinical studies suggest that the degree of tumor oxygenation may be predictive of the response of radiation therapy for cancer. In an exploratory investigation of cervical lymph node metastases in 27 patients with advanced squamous cell carcinoma of the oropharynx and hypopharynx, this relationship was investigated by means of oxygen measurements with an Eppendorf PO (2) histograph. The measurements were made before the start of radiation therapy and after the first week of therapy. Clinical response was evaluated 6 weeks after the completion of therapy. Before therapy, marked hypoxia was observed in the lymph node metastases, with a mean PO (2) value of 16.1 +/- 8.2 mm Hg and a hypoxic fraction (PO (2) < 10 mm Hg) of 56.4% +/- 20.0%. After the first week of radiation (9 Gy) there was a general reoxygenation (DeltaPO (2) = 5.0 +/- 10.1 mm Hg, P < 0.05; Deltahypoxic fraction = -11.3% +/- 31.3%, P = 0.11). A relationship between the degree of reoxygenation and tumor response was not observed. Patients without at least partial lymph node response (n = 8) showed poorer pretherapeutic oxygenation (PO (2) mean = 11.1 +/- 2.9 mm Hg) than those who responded to the therapy (n = 19, PO (2) mean = 18.2 +/- 8.8 mm Hg). In this investigation of a defined set of patients with advanced carcinoma of the oropharynx and hypopharynx, we found that pretherapeutic oxygenation data are predictive for the therapeutic response to radiation therapy or radiochemotherapy.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Hipoxia de la Célula , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Orofaríngeas/radioterapia , Oxígeno/metabolismo , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Terapia Combinada , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Neoplasias Hipofaríngeas/tratamiento farmacológico , Neoplasias Hipofaríngeas/metabolismo , Neoplasias Hipofaríngeas/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patología , Pronóstico , Estudios Prospectivos , Dosificación RadioterapéuticaRESUMEN
It has been hypothesized that during radiation treatment a reoxygenation of hypoxic tumor tissue takes place. To test this hypothesis, we have investigated whether reoxygenation in lymph node metastases could be determined by invasive PO (2) measurements. Through a hypodermic needle inserted transcutaneously into tumor-positive lymph nodes, polarographic oxygen determinations were made in 18 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx. These measurements were performed before therapy and a week after the onset of radiotherapy or radiochemotherapy, respectively. Low PO (2) values before treatment (mean value of the patient's median was 12.6 mm Hg PO (2)) and a mean hypoxic fraction (PO (2) < 5 mm Hg) of 39.6% indicated manifest tumor hypoxia. After 1 week of treatment, a significant increase in the median PO (2) (mean value of shift: 7.3 mm Hg) and a reduction in the hypoxic fraction (mean value of shift: 13.4% PO (2) < 5 mm Hg, P < 0.03) were observed after both radiotherapy and radiochemotherapy. Thus invasive PO (2) histography fulfills the requirements for a method to confirm tumor hypoxia in head and neck tumors. The results obtained indicate that reoxygenation occurs during the initial phases of radiotherapy and radiochemotherapy, and they will form the basis for future comparative investigations on the possible influence of hypoxic parameters on tumor responsiveness toward radiation and radiochemotherapy.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias Hipofaríngeas/metabolismo , Neoplasias Hipofaríngeas/patología , Metástasis Linfática , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patología , Oxígeno/metabolismo , Adulto , Anciano , Humanos , Persona de Mediana EdadRESUMEN
The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Carcinoma de Células Escamosas/metabolismo , Fluorouracilo/farmacocinética , Neoplasias de Cabeza y Cuello/metabolismo , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biotransformación , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Esquema de Medicación , Femenino , Flúor , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Fluorouracilo/análisis , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Isótopos , Metástasis Linfática , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , beta-Alanina/análogos & derivados , beta-Alanina/análisisRESUMEN
The therapeutic effect of radiotherapy depends amongst other things on the degree of oxygenation of tumour tissue. Epithelial carcinomas of the head-neck region exhibit considerable hypoxic areas which vary markedly between individuals and not encompassed by current staging and grading. It is assumed that during radiation treatment a reoxygenation of hypoxic tumour cells takes place. It was investigated wether the occurrence of reoxygenation could be determined by invasive oxygen partial pressure measurements in lymph node metastases. Using a needle probe inserted transcutaneously into a lymph node polarographic oxygen determinations (Eppendorf pO2-Histiograph) were made on 13 patients with advanced oro- and hypopharyngeal carcinomas before therapy and after a week of accelerated radio- or radiochemotherapy. Low pO2 values before treatment (median 13.5 mmHg, average 20.3 mmHg) and a hypoxic fraction (pO2 < 10 mmHg) of 45.2% indicated manifest tumour hypoxia. After the first week of treatment a significant increase in the median- (24.1 mmHg) and the average pO2 (28.2 mmHg) as well as a reduction in the hypoxic fraction (27%) were observed. Invasive pO2 histiography fulfils the requirements for a method to confirm tumour hypoxia in head-neck tumours. The results obtained indicate that reoxygenation occurs during the initial phases of radio- and radio-chemotherapy.