Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX. ES1. 102 study)

INTRODUCTION: Concurrent chemotherapy and radiotherapy is recommended for the treatment of locally advanced unresectable head and neck (H&N) cancer. OBJECTIVE: The primary purpose of the Phase I part of the study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose (RD) of docetaxel with hyperfractionation radiotherapy. The primary objective of the Phase II part was to determine the response rate to the RD of treatment and, secondarily, to assess the toxicity of the schedule, time to progression, duration of response and overall survival (OS). MATERIALS AND METHODS: Patients (n=9 in Phase I; n=19 in Phase II) had unresectable H&N cancer. The starting docetaxel dose was 20 mg/m(2) plus hyperfractionated radiotherapy. Ramping of docetaxel was 5 mg/m(2) if MTD was not reached. RESULTS: MTD of docetaxel was 20 mg/m(2). Limiting toxicities were grade 4 pneumonia and grade 4 mucositis. The RD was 15 mg/m(2). Phase II initial response was 76% (CR=18%; PR=9%); updated response was 89% (CR=59%; PR=29%). The median progression-free survival was 7.8 months (95%CI: 0-22.3) and the median OS was 15.1 months (95%CI: 0-35.9). Grade 3-4 toxicities included mucositis (91%), pneumonia (27%) and fatigue (27%). There were 5 toxic deaths (2 from intestinal perforation, 3 from pneumonia). CONCLUSIONS: Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify (AU)

Treatment of patients with unresectable squamous head and neck cancer with induction chemotherapy followed by hyperfractionated radiotherapy.

PURPOSE: The contribution of induction chemotherapy (CT) followed by hyperfractionated radiotherapy (hfRT) in unresectable squamous head and neck cancer has been evaluated in a single institution as an assistencial protocol. PATIENTS AND METHODS: From March 1994 to June 2000 all consecutive patients with unresectable disease were treated with four courses of platin plus fluorouracil based CT followed by hfRT. Tumor resectability and response was assessed by a multidisciplinary committee. RESULTS: Ninety-nine patients (pts) were treated. All of them had stage IV-M0 disease: 67 T4, 88 N2-N3. Tumor location: 62 oropharynx, 22 hypopharynx, eight oral cavity and seven larynx. Tumor response at the end of treatment: 61 patients complete response, 17 partial response, two stable disease, 10 progressive disease and nine unevaluated. With a median follow-up of 70 months the 5-year loco-regional control and overall survival was 30.3% (95% CI: 21.9-38.6) and 21.6% (95% CI: 13.4-29.8), respectively. Loco-regional control and overall survival is significantly influenced by prior response to induction CT. Main grade 3-4 toxicity related to CT was stomatitis, but there were five patients with an ischemic event. Grade 3-4 acute toxicity related to hfRT: 47 stomatitis, 20 epithelitis. Chronic toxicity related to hfRT: six emergency tracheotomies due to laryngeal edema, five pneumonia and one mucous/soft-tissue necrosis. There were eight toxic related deaths. CONCLUSION: Induction CT followed by hfRT might increase the overall survival rate in unresectable disease. HfRT resulted in a high rate of acute toxicity and its use would not be warranted in those patients with no response to induction CT who had a low probability of long-term control.

[Neurotrophic action of insulin-like growth factor-I in the inner ear]. / Acciones neurotróficas del factor de crecimiento similar a la insulina de tipo I en el oído interno.

INTRODUCTION: Loss of hearing constitutes one of the most frequent disabling sensory impairments in the developed world. Different therapeutic approaches are currently being studied, including treatment with stem cells, genetic manipulation and pharmacological protection. AIM: To evaluate the role played by insulin-like growth factor-I (IGF-I) in the development, maintenance and repair of auditory functioning. DEVELOPMENT: Proper development of the inner ear is dependent on a suitable coordination of the cell processes of proliferation, differentiation, neurogenesis and programmed cell death, which are regulated by different factors, one of which is IGF-I. During the embryogenesis of the inner ear, this factor is expressed in abundance and is essential for cell survival and maintaining neuronal precursors. Studies conducted in Igf-1-/- null mice have highlighted its importance in the development and continued functioning of the inner ear. Mice with a deficit in this gene display morphological disorders that correspond to severe functional deficiencies, which are confirmed by analysing brainstem auditory evoked potentials. A deficit of IGF-I in humans is also accompanied by profound sensory hypoacusis. CONCLUSIONS: In a scenario like this, IGF-I appears as a key factor in the development of auditory functioning and a candidate for regenerative therapy of the inner ear.

Acciones neurotróficas del factor de crecimiento similar a la insulina de tipo I en el oído interno / Neurotrophic action of insulin-like growth factor-i in the inner ear

Introducción. La pérdida de audición constituye una de las deficiencias sensoriales invalidantes más frecuentes en el mundo desarrollado. En la actualidad se estudian diferentes abordajes terapéuticos, entre los que se incluyen el tratamiento con células madre, la manipulación genética y la protección farmacológica. Objetivo. Evaluar el papel del factor de crecimientosimilar a la insulina de tipo I (IGF-I) en el desarrollo, el mantenimiento y la reparación de la función auditiva. Desarrollo. El desarrollo del oído interno depende de la adecuada coordinación de los procesos celulares de proliferación, diferenciación, neurogénesis y muerte celular programada, que se encuentran regulados por distintos factores entre los que se encuentra el IGF-I. Durante la embriogénesis del oído interno, este factor se expresa abundantemente y es fundamental para la supervivencia celular y el mantenimiento de los precursores neuronales. El estudio del ratón nulo Igf-1–/– ha puesto de manifiesto su importancia en el desarrollo y mantenimiento funcional del oído interno. Los ratones deficientes en este gen presentan alteraciones morfológicas que se corresponden con graves deficiencias funcionales, confirmadas mediante el análisis de los potenciales evocados auditivos de tronco cerebral. El déficit de IGF-I en humanos también se acompaña de hipoacusia sensorial profunda. Conclusión. En este escenario, se perfila el IGF-I como un factor clave para el desarrollo de la función auditiva y un candidato para la terapia regenerativa del oído interno

Introduction. Loss of hearing constitutes one of the most frequent disabling sensory impairments in the developed world. Different therapeutic approaches are currently being studied, including treatment with stem cells, genetic manipulation and pharmacological protection. Aim. To evaluate the role played by insulin-like growth factor-I (IGF-I) in the development, maintenance and repair of auditory functioning. Development. Proper development of the inner ear is dependent on a suitable coordination of the cell processes of proliferation, differentiation, neurogenesis and programmed cell death, which are regulated by different factors, one of which is IGF-I. During the embryogenesis of the inner ear, this factor is expressed in abundance and is essential for cell survival and maintaining neuronal precursors. Studies conducted in Igf-1–/– null mice have highlighted its importance in the development and continued functioning of the inner ear. Mice with a deficit in this gene display morphological disorders that correspond to severe functional deficiencies, which are confirmed by analysing brainstem auditory evoked potentials. A deficit of IGF-I in humans is also accompanied by profound sensory hypoacusis. Conclusions. In a scenario like this, IGF-I appears as a key factor in the development of auditory functioning and a candidate for regenerative therapy of the inner ear

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Survival evaluation of treatment modality in squamous cell carcinoma of the oral cavity and oropharynx.

The treatment of squamous cell carcinoma of the mouth and oropharynx continues to change. In this primary report, we compared the results obtained by combined surgery and radiation therapy, or either modality alone. Other methods such as brachytherapy, or hyperfractionated radiotherapy, were not included in our protocols. A statistical analysis of the 3- and 5-year survival rates in relation to location and size of the primary tumour, stage at initial presentation, treatment modality and recurrence, was carried out in 88 patients with squamous cell carcinoma of the oral cavity or oropharynx. The overall survival rate was 73.8% at 3 years and 66.3% at 5 years. Size of tumour and stage at presentation were significant when P value was adjusted by site. Survival was significantly associated with type of treatment (combined approach obtained superior results), location of primary tumour, and recurrence. The type of neck dissection did not show any effect. Therapeutic modality used, stage, and location of primary tumour significantly influenced survival. A more selective combined initial treatment according to site and stage (distribution) is recommended.

Induction chemotherapy with cisplatin, bleomycin and methotrexate in advanced head and neck cancer--lack of therapeutic gain.

Seventy patients with stage IV head and neck cancer were treated by two courses of induction chemotherapy followed by surgery plus postoperative irradiation (7) or radical radiotherapy (62). One patient renounced to further treatment after chemotherapy. Each chemotherapy course consisted of methotrexate (40 mg/m2 days 1 and 14), bleomycin (10 mg/m2 days 1, 7 and 14), and cisplatin (50 mg/m2 day 4). Three patients did not complete the two courses of chemotherapy planned due to bad tolerance whereas the rest of the patients tolerated chemotherapy well. 2 CR (3%) and 35 PR (50%) were achieved for an overall response rate to chemotherapy of 53%. 35 (50%) CR were achieved with the whole treatment schedule. The 5-year disease-free survival is 26% for the whole group of patients. The prior response to chemotherapy neither influenced the complete responses to treatment nor the relapse-free survival. The addition of this chemotherapy to conventional treatment was of no value.

[Action of radiation on the lung. Classic concepts and current interpretations]. / Acción de las radiaciones sobre el pulmón. Conceptos clásicos e interpretaciones actuales.

The effects of irradiation on the pulmonary system are analyzed according to the classical radiobiological theories and the new ones. Special emphasis is put on the lineal-quadratic model which predicts the possibility of a greater tumor control without increasing the damage to the normal lung tissue, based on the differences between the survival curves for acute and late effects of irradiation. The clinical applications of the new radiobiological concepts can be carried out in the treatment of lung cancer and other neoplasms, especially those using total body irradiation.