Wilfried Budach

5540 Purpose: Inoperable loco-regional recurrences of head and neck cancer in a previously irradiated volume (RH&N) represent a therapeutic dilemma. Chemotherapy alone has no curative potential, whereas re-irradiation and concurrent chemoradiation can salvage a small fraction of patients. Mucosal toxicity of concurrent chemoradiation requires substantial dose reduction of chemotherapy. Alternating chemoradiation enables one to give full-dose chemotherapy and radiotherapy. The latter maybe especially advantages for recurrent, potentially radiation resistant tumors. The feasibility and efficacy of an full-dose docetaxel containing alternating chemoradiation schedule was tested in two sequential trials. Patients and Methods: Thirty-nine patients (Karnofsky Performance score ≥ 70%) with histologically proven recurrent squamous cell cancer that occurred ≥ 6 months in a previously irradiated area (≥ 60 Gy) were considered unresectable and unsuitable for brachytherapy. Alternating chemoradiation consisted of three cycles of docetaxel 50 mg/m² d1 and cisplatin 15 mg/m² d2–5, q d22, and involved field radiotherapy 2.0 Gy QD d8–12, d15–19, d29–33, and d36–40 (patients 1 - 27 received 40.0 Gy total dose, patients 28 - 39 received 49.6 Gy total dose with concomittant boost). Dose reduction of docetaxel to 50 mg/m² was necessary, because of hematological toxicity in the first 12 patients with docetaxel 60 mg/m². Results: Alternating chemo-re-irradiation was applied as planned in 19 of 37 patients, with re-irradiation completed per protocol in 80%. Overall, patients received 80 % of the intended dose of docetaxel and 75% of cisplatin. Mucositis CTC °III occurred in 17%, leukopenia CTC ≥°III in 32%, and four early deaths were observed. Median follow up 18 months, median time to local progression and overall survival 10 months, respectively, 2-year survival rate 20%. Conclusions: Alternating chemo-re-irradiation in RH&N resulted in 80% overall response with acceptable toxicity. A significant minority of patients had durable tumor control with a chance of long-term survival.

Purpose: Permanent growth in nude mice (PGNM) may be associated with poor clinical outcome. We tested this hypothesis in a group of soft tissue sarcoma (STS) patients. Methods: Small chunks from fresh tumor biopsies of 81 patients with STS were transplanted subcutaneously into NMRI-nu/nu nude mice. Tumor cell lines exhibiting growth in nude mice for more than three tumor passages were considered as permanently established. Clinical outcome of all patients was monitored with a median follow-up of 38 months. Results: 39/81 (48%) STSs exhibited PGNM. High grade, high S-phase proportion, and aneuploidy were significant predictors of PGNM. Overall survival (OS) at 3 years was 21% (±7% standard error of median) for STS patients with PGNM and 53% (±8%) for patients without PGNM (Pn=49), 3-year-OS was 25% (±10%) and 71% (±9%) for STS with PGNM and without PGNM, respectively (P Conclusion: Permanent growth of STS on nude mice is associated with poor clinical outcome in the univariate analysis, but is not an independent predictor of survival in the multivariate analysis due to a strong co-correlation to other known adverse prognostic factors.

Purpose : The impact of apoptosis on radiation-induced eradication of clonogenic tumour cells is uncertain. The aim was to analyse the relationship of different functional stages during the apoptotic process to cell death and clonogenic cell eradication. Materials and methods : Apoptosis in Jurkat T-cells was studied by morphology, light scatter and caspase activation. Mitochondrial integrity was determined by the mitochondrial membrane potential (ΔΨ m) . Cell death was quantified using propidium iodide exclusion. Clonogenic cell death was determined using a dilution survival assay. The influence of Bcl-2 was tested using a Bcl-2 transfected Jurkat clone. Results : Irradiation induced profound apoptosis within 48 h associated with caspase activation and breakdown of ΔΨm. Inhibition of caspases abrogated the apoptotic morphology with no influence on breakdown of ΔΨm and survival. Over-expression of Bcl-2 abrogated all hallmarks of apoptosis; delayed cell death, however, had no influence on clonogenic survival after irradiation. Conclusion : Based on Bcl-2 as a positional marker, radiation-induced apoptosis can be divided into two stages: the initiation/decision phase, characterized by a breakdown of the mitochondrial membrane potential, and the execution phase, characterized by caspase activation. The execution phase had no influence on survival, whereas the initiation/decision phase controls immediate survival. However, abrogation of both phases did not influence radiation sensitivity.

The activation of mitogenic cascades via Ras, c-Raf-1, MEK-1, Erk1/2 is a hall- mark of oncogenic transformation. The cascade is also anti-apoptotic by modulation of Bcl-2, Bcl-xL and BAD function. The impact of MEK-1 on radiation resistance and the role of drugs targeting MEK-1 for the modulation of resistance is unclear. Activation of MEK-1 in four carcinoma cell lines was analyzed using Erk1/2 phosphospecific antibodies. MEK-1 was blocked by PD98059 (2-amino-3methoxyflavin) and influence on radiation responses was determined by apoptotic morphology, caspase-3 activation and colony formation assays. MEK-1 kinase was constitutively active and inhibitable by PD98059. The low radiation induced apoptosis rate was not increased by MEK inhibition. PD98059 did not influence cell growth and radiation induced clonogenic cell death. Since PD98059 did not alter radiation responses despite blocking MEK-1 kinase, MEK-1 and Erk1/2 are not involved in radiation resistance. Thus PD98059 has no potential in the modulation of radiation responses.

This paper reports on a woman with a rapidly growing recurrent cystosarcoma phyllodes malignum after two major attempts of surgery. In this situation, neoadjuvant hyperfractionated radiotherapy, superficial hyperthermia and ifosfamide were administered. Toxicity was mild. Resection of the tumour bed revealed a pathologically complete response with an actual disease free follow-up of 48 months.

Clinically reliable predictive assays for normal tissue radiation sensitivity would help to avoid severe radiation induced morbidity and result in individualized dose prescriptions. Profound differences of individual fibroblast and lymphocyte radiation sensitivity in vitro have been documented in patients with certain genetic syndromes but also in patients without known genetic disorders. The following review evaluates whether fibroblast or lymphocyte radiation sensitivity measured in vitro correlates with the degree of acute and late radiation induced morbidity. Acute radiation side effects and lymphocyte sensitivity has been investigated in 2 studies. One of them reported an insecure correlation, the other no correlation at all. Fibroblast radiation sensitivity and the extent of acute radiation induced side effects on skin and mucosal sites has been compared in a total of 5 studies. None of these studies found a consistent significant correlation. Lymphocyte radiation sensitivity and late effects have been studied by 2 institutions. Late radiation induced skin and mucosal changes did not correlate with lymphocyte sensitivity in head and neck cancer patients, whereas in breast cancer patients a weak (R2 = 0.06) correlation between the degree of late skin reactions and lymphocyte sensitivity was observed. Late skin or mucosal radiation reactions and fibroblast sensitivity were examined by 5 research groups. Data analysis revealed significant correlations or at least a trend towards a significant correlation in all studies. The quality of the reported correlations expressed as R2 ranged from 0.13 to 0.60, indicating a low predictive value. Lymphocyte radiation sensitivity as measured by currently available assays does not or only poorly correlate with acute and late effects of radiation in patients, precluding predictive tests based on lymphocyte sensitivity. Fibroblast radiation sensitivity does not correlate with acute but generally correlates with late radiation morbidity. The quality of the later correlation is insufficient for a reliable predictive test with currently available methods to determine cellular radiation sensitivity.

Gastrointestinal toxicity is frequently observed during radiotherapy of malignancies in the abdomen and pelvis. The proposed pathophysiology of radiation enteritis is complex and a variety of different treatment strategies have been suggested for the management of acute radiation-induced diarrhea. Data are presented from an extensive review of the current literature. Radiation-induced diarrhea results from a variety of different pathophysiological mechanisms including malabsorption of bile salts and lactose, imbalances in local bacterial flora and changes in the intestinal patterns of motility. Up to date acute radiation diarrhea is predominantly treated symptomatically using opioide derivates (loperamide) or adsorbants of bile salts such as smectite. Clinical trials have been performed using L. acidophilus, smectite or sucralfate for diarrhea prophylaxis with moderate reduction of acute symptoms. Further evaluation of strategies for diarrhea prophylaxis is warranted. Due to the complex nature of radiation enteritis a multimodal approach taking into account alterations in intestinal motility patterns, malabsorption of bile salts and an imbalance of mucosal bacterial flora may offer new perspectives.