BMC Cancer 2006, 6:30 http://www.biomedcentral.com/1471-2407/6/30 oncology at the Charité. The first, sequential (SEQ) proto- col was performed between 1987 and 1992 and included neoadjuvant chemotherapy with a subsequent radiother- apy course. The second protocol was performed after 1992 and consisted of concomitant radiochemotherapy with subsequent hyperfractionation. The first protocol was approved by the ethical committee at the Virchow-Klinikum and the second by the ethical committee of the Campus Charité-Mitte of the Charité. Eligibility criteria Patients were eligible if they had primary, histologically proven, non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, assessed as unresectable in the department of head-and-neck sur- gery because of size, extension or location. Patients who had previously undergone cytostatic therapy or radiother- apy were excluded, along with those with contraindica- tions against radiotherapy or the cytostatic agents used (5- FU, FA, CDDP, MMC). Written informed consent was obtained from all patients before therapy. Evaluation of patients For every patient, clinical, laboratory and imaging exami- nations were performed to achieve an accurate TNM stage (UICC, 5th ed.) [6] and to allow follow-up. During therapy, the patients were examined for acute tox- icity every week. Acute side effects were indexed according to EORTC criteria [7]; late side effects were classified according to the LENT tables [8]. The response (primary as well as lymph nodes) was assessed by clinical examina- tion and CT according to WHO criteria [9]. After completion of therapy, each patient was followed up within 6–8 weeks by an interdisciplinary consultation involving clinical evaluation (head and neck status) com- plemented by CT. After specific symptoms or suspicious findings, diagnostic procedures were extended. Further follow-up included examinations at intervals extending from 6 weeks initially to 6 – 12 months after the third year. In cases of histologically proven local recurrence, all avail- able salvage treatment options were offered (brachyther- apy, hyperthermia, external re-irradiation, chemotherapy); most often palliative chemotherapy with MTX (methotrexate) was performed. Treatment records (fig. 1A+B) In the first sequential (SEQ) protocol, 2 three-weekly courses of neoadjuvant chemotherapy were applied, con- sisting of cisplatin (CDDP; 100 mg/m2 i.v., on day 1) fol- lowed by 50 mg/m2 folinic acid (day 1) and parallel 120 h continuous infusions of folinic acid (250 mg/m2 per day, days 1–5) and 5-fluorouracil (600 mg/m2, days 1–5). Six weeks later (day 43), the third chemotherapy course was started at a 60% reduced dose concomitantly with the definitive radiotherapy. External beam radiotherapy was applied without preference to both groups, with photon energies of 1.2 MeV (telecobalt unit) or 4–8 MV (linear accelerator). The primary tumor and regional lymph drainage areas received 60 Gy in single fractions of 1.8–2 Gy. To shield the spinal cord after achieving a dose of 40 Gy, the dorsal parts of the target volume were treated with fast electrons of 9-12MeV. Primary tumor and lymph node areas that were macroscopically involved were boosted to a total dose of 70 Gy. In the second, concomitant (CON) schedule, an RCT pro- tocol was conducted concomitantly with chemotherapy as in the study of Budach [4,10]. Here, chemotherapy was initiated with intravenous short infusions of folinic acid (50 mg/m2, day 1) and 5-FU (350 mg/m2, day 1), fol- lowed by parallel 120 h continuous infusions with both drugs (folinic acid, 100 mg/m2 daily; 5-FU, 350 mg/m2 daily). In addition, short infusions of mitomycin C (10 mg/m2) were administered on days 1 and 36. Radiother- apy began synchronously with chemotherapy, starting with single doses of 2 Gy up to a total dose of 30 Gy over the entire affected volume. Gross areas were then boosted using hyperfractionation, with two daily 1.4 Gy fractions separated by an interval of at least 6 hours, to a total dose of 70.6 Gy (10 patients) or 72 Gy (42 patients). Lymph node regions at low or intermediate risk of subclinical infiltration were irradiated to total doses of 50 Gy (nor- mofractionated) or 60 Gy (hyperfractionated after 30 Gy), respectively. The dorsal paravertebral parts of the target volume were irradiated with lateral 6–9 MeV electron fields after 36–40 Gy at the myelon, conventionally frac- tionated if not clinically involved, hyperfractionated oth- erwise. Statistical evaluation We used the distribution-free Mann-Whitney test to com- pare the two patient groups (SEQ/CON). A univariate analysis of prognostic factors was carried out through a comparison of survival times and local control rates using the log-rank test. A multivariate analysis was carried out for all parameters with significant correlations in the uni- variate analysis according to the proportional-hazard model. Time-to-progression (TTP), tumour specific and overall survival were identified from the first day of treat- ment up to the day of death or last patient contact follow- ing the Kaplan-Meier method [11]. In particular, TTP was defined as the time from day 1 of treatment until clinical progression, i.e. the timing of a more than 25% increase in post-therapeutic volume (determined 6–8 weeks after Page 3 of 9 (page number not for citation purposes)