[Organ preservation in advanced laryngeal and hypopharyngeal carcinoma by primary radiochemotherapy. Results of a multicenter phase II study]. / Organerhalt beim fortgeschrittenen Larynx- bzw. Hypopharynxkarzinom durch primäre Radiochemotherapie. Ergebnisse einer multizentrischen Phase-II-Studie.

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.

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer.

PURPOSE: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). METHODS AND MATERIALS: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). RESULTS: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072). CONCLUSION: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results.

This study seeks to evaluate treatment modalities, mortality after surgery, survival, and local control rates for a consecutive cohort of patients with cancer of the hypopharynx treated according to a prospective protocol that favors surgery as an initial approach to the disease. The charts of 228 consecutive patients with previously untreated hypopharyngeal squamous cell carcinoma were reviewed. Outcome measures (overall survival, disease specific survival, and local control) were calculated using the Kaplan-Meier estimator. Of 228 consecutive patients, 136 (59.6%) were found suitable for initial surgical treatment. Of the remaining 92 patients, 18 (7.9%) had nonresectable lymph node metastases, 16 (7.0%) had unresectable primary tumors, 13 (5.7%) refused surgery, and 13 (5.7%) presented distant metastases during initial diagnostic evaluation. Of those who had surgery, 46 had larynx-sparing procedures, 54 had total laryngectomy, and 36 had total laryngo-pharyngectomy. None of the patients who had surgery died postoperatively. Actuarial 5-year overall survival was 27.2% for all 228 patients, 39.5% for the 136 patients with surgical treatment, and 61.1% for the 46 patients who were treated with larynx-sparing procedures.

[Incidence of salivary fistulas in relation to timing of oral nutrition after laryngectomy]. / Inzidenz von Speichelfisteln in Abhängigkeit vom Zeitpunkt einer oralen Ernährung nach Laryngektomie.

BACKGROUND AND OBJECTIVE: A pharyngocutaneous fistula is the most common complication after total laryngectomy. In Germany, a traditional recommendation is to use a nasogastric tube for feeding for 10-14 days postoperatively because many surgeons believe that oral feeding after surgery contributes to fistula development. However, there is no international agreement about when to begin oral feeding after total laryngectomy. Some authors begin oral feeding between the 1st and 4th postoperative day without any nasogastric tube, while others using a nasogastric tube delay oral feedings until 7-14 days after surgery. The aim of the present study was to investigate the relationship between the timing of oral feeding and the development of fistulas after total laryngectomy. PATIENTS/METHODS: In a prospective trial with 42 consecutive patients who underwent laryngectomy, oral feeding was started on different postoperative days between the 1st and the 10th. Most patients were selected randomly for the different postoperative days. Furthermore, other potential risk factors predisposing to fistula formation were analyzed retrospectively. RESULTS: Five fistulas occurred in the total group (12%). Early postoperative oral feeding does not increase the incidence of fistulas. The fistula rate was only 9% in patients fed orally in the 1st postoperative week. The analysis of further risk factors for fistula formation showed only a significant correlation between type of resection and fistula occurrence (extended laryngectomy with partial pharyngectomy vs standard laryngectomy; p = 0.018). CONCLUSIONS: Our results indicate that early oral feeding in the 1st postoperative week does not influence fistula formation after laryngectomy.

[Clinical manifestation of Ewing's sarcoma as a retrotonsillar pharyngeal tumor]. / Klinische Manifestation eines Ewing-Sarkoms als retrotonsillärer Pharynxtumor.

BACKGROUND: Ewing's sarcoma is a malignant tumour which usually arises from bony structures. It can be found in dia- or metaphysis of bones of the extremities but as well in 50% of cases in skeletal parts of the trunk. Clinically patients often present with various symptoms as there are pain, swelling and progredient loss of function if extremities are involved. But in many cases, Ewing's sarcoma shows a lack of specific symptoms and therefore stays inapparent for a long time. CASE REPORT: A 14-year-old patient complained about intermittent nuchal pain and was sent to hospital because of an extensive retropharyngeal swelling. The preoperative imaging showed a tumour of the soft tissue of the neck. It had reached the cervical spine and after surgical treatment it was histologically and molecular biologically diagnosed as a Ewing's sarcoma arising from the transversal processes of the atlas. CONCLUSION: Since Ewing's sarcoma may have an immense component of soft tissue it has to be included in the range of differential diagnosis of soft tissue tumours of the head and neck, e.g., as there are extracranial schwannoma, inflammatory lymph nodes or lymph node metastases and lateral and medial cysts of the neck.

[Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas]. / Prognostischer Stellenwert des Hämoglobinwertes vor primärer Radiochemotherapie von Kopf-Hals-Karzinomen.

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.

[Prognostic relevance of proliferation marker Ki-67 (MIB 1), PCNA and p53 in combined surgically and radiologically treated cancers of the oropharynx and mouth cavity]. / Zur prognostischen Relevanz der Proliferationsmarker Ki-67 (MIB 1), PCNA und p53 bei kombiniert chirurgisch und radiologisch therapierten Karzinomen des Oropharynx und der Mundhöhle.

STUDY DESIGN: A matched-pair study on the relationship between proliferation associated markers Ki-67, PCNA, and p53 and treatment failure in carcinomas of the oropharynx and oral cavity. MATERIAL AND METHOD: Fifty-six T1-T3 carcinomas of the oropharynx or oral cavity, treated uniformly with primary surgery and postoperative irradiation, were investigated. Twenty-eight patients had recurrent disease and were matched with 28 patients with nonrecurrent disease regarding stage and location of tumor as well as age and therapy. MIB1 staining was used to determine the Ki-67 labeling index. Immunohistochemical studies determined the p53 status and PCNA labeling index. RESULTS: Where treatment failed, the Ki-67 labeling index was significantly (p = 0.032) higher (mean = 59.1%) than in patients without recurrence (mean = 50.5%). Mean time to relapse was 45 months (n = 25) for carcinomas with a Ki-67 (MIB1) labeling index above the median (53.7%) of the general study population, compared to 61.7 months for those cases (n = 31) below this median (p = 0.029). The PCNA labeling index did not correlate significantly with tumor recurrence, nor with time to relapse. In 46% of all tumors, p53 overexpression was present. No significant correlation could be found between p53 overexpression and tumor recurrence or time to relapse. CONCLUSION: Examination of Ki-67 is thought to provide useful prognostic information concerning squamous cell carcinomas of the oropharynx and oral cavity. Overexpression of p53 or PCNA status is not of prognostic value, which is consistent with earlier results. We conclude that the detection of Ki-67 is an unfavorable prognostic factor for squamous cell carcinoma of the oropharynx and oral cavity, at least if treated with a combination of surgery and postoperative irradiation.

[Quality assurance in ENT tumor surgery]. / Qualitätssicherung in der HNO-Tumorchirurgie.

BACKGROUND AND OBJECTIVE: Quality control is of special importance in head and neck oncology since the quality of medical care constitutes a vital parameter for the diseased patient. In contrast to other medical specialties, no quality assurance program for head and neck cancer patients has yet been established in Germany. Therefore, a survey was conducted to assess the quality assurance instruments that are in use today in otorhinolaryngology-head and neck (ORL-HNS) centers. PATIENTS AND METHODS: In a nationwide survey, questionnaires were sent out to 146 German ORL-HNS departments (the return rate was 75%). RESULTS: 56% of all departments apply dedicated quality assurance processes, and 38% have appointed a formal quality assurance officer. Interdisciplinary oncological conferences are held in the vast majority of all departments with the participation of radiation oncologists in 86 (78%), medical oncologists in 84 (76%), diagnostic radiologists in 82 (74%), and pathologists in 73 (66%). Morbidity-mortality conferences are held in seven departments (6%). A standardized follow-up of oncological patients is carried out in 95 units (86%), and 53 departments use computer-assisted data bases to organize their follow-up data (48%). A wide variety of documentation systems is in use throughout the country: 78 units (71%) offer formal follow-up to their oncological patients. CONCLUSIONS: This survey documents a wide-spread interest in quality assurance procedures. Many individual efforts are being undertaken. However, no uniform quality assurance or auditing system is currently in use in Germany nor is a commonly accepted data base available. The ability to offer oncological follow-up within the national social security system is generally considered indispensable for the maintenance of high-quality oncological care in ORL-HNS departments.

[Results of a prospective randomized trial with induction chemotherapy for cancer of the oral cavity and tonsils]. / Primäre Chemotherapie bei Mundhöhlen- und Tonsillenkarzinomen. Ergebnisse einer prospektiv randomisierten Studie.

Although induction chemotherapy administered prior to local therapy produces encouraging initial response rates in head and neck cancer, randomized studies have failed to demonstrate an improvement in survival rates. All randomized studies included only patients with advanced stage III and IV disease. In our opinion, this is the main reason for the low rate of complete responses demonstrated in the randomized trials (maximum 18%). Frei et al. estimate that a 40%-50% complete response rate is necessary before improved survival rates are seen. To date, such complete response rates with induction chemotherapy have only been attainable in resectable T2-T3, N0-N2 disease. Therefore, we initiated a prospective randomized trial including only patients with the mentioned disease stages. Patients (pts) were randomized to receive either induction chemotherapy with three cycles of carboplatin/5-FU prior to surgery and radiotherapy (arm A, 70 pts) or standard treatment with surgery and radiotherapy (arm B, 74 pts). Patients were classified according to primary tumour site and neck disease. The observed remission rate after chemotherapy confirmed the primary estimated rate for this subgroup of patients with head and neck cancer (CR: 43%, PR: 37%, NR: 15%, PD: 5%). After a follow-up of 12-96 months overall survival was 58% in arm A and 45% in arm B (n.s.). Disease-free survival in arm A (61%) is statistically significantly better than in arm B (43%, P=0. 03). Therefore, we recommend further controlled trials to investigate the role of induction chemotherapy in patients with primary resectable carcinomas of the oral cavity and tonsils and stage T2-T3 and N0-N2 disease prior to surgery.

Prognostic significance of Ki-67 (MIB1), PCNA and p53 in cancer of the oropharynx and oral cavity.

Up to now results concerning the prognostic value of tumor proliferation markers in squamous cell head and neck carcinoma have been equivocal. Beside biological reasons, different treatment modalities are hypothetically responsible for contradictory findings. The aim of this study was to investigate the relationship between proliferative capacity, represented by the immunohistochemical labeling index of proliferation markers Ki-67, PCNA and p53 status, and treatment failure in a matched-pair study design of recurrent and non-recurrent carcinoma initially treated with primary surgery combined with curative post-operative radiation. From a group of 239 patients with T1-T3 carcinoma of the oropharynx or oral cavity, 28 patients with recurrent disease were selected and matched with 28 patients with non-recurrent disease regarding stage and location of tumor as well as age and therapy. All patients received primary surgery combined with post-operative radiation. Immunohistochemistry determined the p53 status and the PCNA and MIB1 (Ki-67) labeling index. The Ki-67 labeling index was significantly (p=0.032) higher in tumors from patients suffering from treatment failure (mean=59. 1%) than in non-failures (mean=50.5%). Carcinoma with a Ki-67 (MIB1) labeling index above the median (53.7%) of the general study population showed a mean time to relapse of 45 months (n=25), whereas mean time-to-relapse was 61.7 months for those cases (n=31) below the median of the general study population (p=0.029). The PCNA labeling index did not correlate significantly with tumor recurrence (mean=50.2% for treatment failures, 45% for non-failures, p=0.31), nor with time-to-relapse (p=0.26). Forty-six percent of tumors showed p53 over-expression. However, there was no significant correlation between p53 over-expression and tumor recurrence or time-to-relapse. We present the largest series of oropharyngeal and oral cavity carcinoma investigated by immunohistochemistry in a controlled study. We conclude that a high Ki-67 labeling index is an indicator for treatment failure in these patients. Like other investigations for different head and neck subsites, we found no relationship between p53 or PCNA status and tumor prognosis. Our data, obtained from a group of patients treated with a combination of surgery and post-operative irradiation, show that for squamous cell carcinoma of the oropharynx and oral cavity the detection of Ki-67 is an unfavorable prognostic factor.

[Value of monoclonal antibodies (PC 10, MIB1, p53 and LeuM 1) for assessing the prognosis of patients with squamous epithelial carcinoma of the larynx after partial laser resection]. / Wertigkeit monoklonaler Antikörper (PC 10,MIB 1,p53 und LeuM 1) für die Abschätzung der Prognose von Patienten mit Plattenepithelkarzinomen des Larynx nach Laserteilresektion.

An immunohistochemical analysis with monoclonal antibodies against Ki-67 (MIB 1), PCNA (PC10), p53 and Lewis X antigen was performed on 47 squamous carcinomas of the larynx after partial laser resection. Ki-67 index and expression of Lewis X antigen correlated significantly with both tumor recurrence rate and tumor-free interval. A much weaker relationship was found for the expression of proliferating cell nuclear antigen (PCNA), and no correlation existed with p53 expression. In conclusion, examination of Ki-67 and Lewis X antigen is thought to provide useful prognostic information concerning laser-resectable squamous carcinomas of the larynx.

[Preliminary results of a prospective randomized study of primary chemotherapy in carcinoma of the oral cavity and pharynx]. / Vorläufige Ergebnisse einer prospektiv randomisierten Studie zur primären Chemotherapie bei Mundhöhlen- und Pharynxkarzinomen.

Although induction chemotherapie given prior to local therapy produces encouraging initial response rates in head and neck cancer, randomized studies have failed to demonstrate an advantage in survival. All randomized studies have included only patients with far advanced stage III and IV disease. To us this is the main reason for the low rate of complete responses demonstrated (maximum, 18%). Frei et al. estimate that 40-50% complete responders are necessary before improved survival benefit will occur. To date, such complete response rates with induction chemotherapy are only attainable in resectable T2-T3, N0-N2 disease. Therefore, we started a prospective randomized trial that included only patients with earlier disease. Patients were randomized to receive either induction chemotherapy with 3 cycles of carboplatin/5-fluorouracil prior to surgery and radiotherapy (arm A, 49 patients) or standard treatment with surgery and radiotherapy (arm B, 48 patients). Patients were stratified by primary tumor site and neck disease. After a follow-up of 12-48 months, overall survival was 72% in arm A and 53% in arm B, but this difference was not significant. Considering only the results in patients with cancer of the oral cavity and tonsils, overall survival was 87% in arm A and 45% in arm B (p < 0.04). At present, the numbers of patients with cancers of the tongue base and hypopharynx are too small for a statistically significant statement. However, preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients. Therefore, we now recommend induction chemotherapy in all patients with stage T2-T3 and N0-N2 carcinomas of the oral cavity and tonsils prior to surgery but not in patients with cancers of the hypopharynx and base of tongue.

Transoral laser resection with staged discontinuous neck dissection for oral cavity and oropharynx squamous cell carcinoma.

Transoral laser resection of oral cavity and oropharynx squamous cell carcinoma (OOSCC) is a widely accepted approach in the absence of cervical lymph node metastases. This study investigated the results of transoral laser surgery and discontinuous neck dissection (ND) for OOSCC with clinically obvious or suspected cervical node metastases. One hundred seventeen patients with infiltrating oral carcinoma were treated for cure with transoral resection of the primary and staged ND. Twenty-nine primaries were classified as T1, 50 as T2, 35 as T3, and 3 as T4. Lymph node metastases were identified in the ND specimen of 36 patients. All patients were followed for a minimum of 3 years unless they died. Estimated tumor-related survival after 5 years is 81% for stage I and II disease of the oral cavity, 86% for stage I and II disease of the oropharynx, 73% for stage III disease of the oral cavity, 65% for stage III disease of the oropharynx, and 21% for stage IV disease of the oral cavity and the oropharynx. Local and regional control of cancer was achieved in 72 (62%) of the 117 patients. Forty-five local and regional recurrences were diagnosed during the follow-up period. Two patients died of distant metastases with no evidence of local or regional recurrence. The combination of transoral laser resection and staged ND for the treatment of OOSCC seems to offer satisfactory cure rates for a selected group of patients. These two minor surgical interventions cause less morbidity than commando-type surgery and lead to low perioperative mortality and morbidity.

[Cisplatin/5-FU versus carboplatin/5-FU. 5 year follow-up]. / Cisplatin/5-FU versus carboplatin/5-FU. Fünfjahresergebnisse.

Between March 1986 and October 1987, 73 patients with advanced squamous cell carcinomas of the head and neck underwent initial chemotherapy before surgery and/or radiotherapy. Chemotherapy consisted of three courses of carboplatin/5-FU or cisplatin/5-FU. Pretreatment tumor states, remission rates and ages of the patients were comparable. Carboplatin as a modification of cisplatin showed significantly less gastrointestinal nerval and ototoxic side effects. After five years of followup, 30% of the patients treated with carboplatin and 33% of the cisplatinum group were alive and clinically free of disease. In contrast, 97% of all patients treated with sequential chemoradiotherapy have died. The data fails to support a "downstaging" of disease. These results document that the only prognostic factor for long-term survival is histologically complete resection of tumor. Further studies must compare the influence of prior chemotherapy and surgery, both followed by conventional fractionated radiotherapy in resectable tumors. Findings show that induction chemotherapy should not be used for unresectable tumors or for sequential chemo-radiotherapy. The use of carboplatin is preferred since oncological efficiency is comparable while side-effects are significantly less.

[Results of accelerated radiotherapy and simultaneous carboplatin administration in inoperable head-neck cancers]. / Ergebnisse nach akzelerierter Radiotherapie und simultaner Carboplatinapplikation bei inoperablen Kopf-Halskarzinomen.

Until now, radical irradiation has been the treatment of choice for patients with unresectable squamous cell carcinomas of the head and neck. In spite of improved radiation techniques, conventional radiotherapy remains mainly palliative for patients with advanced and unresectable disease stages. Our own results with accelerated radiotherapy (2 x 2.1 Gy/day, day 1-4 in week 1, 2, 5 and 6, total dose of 67.2 Gy) and simultaneous chemotherapy with carboplatin (50 mg/m2/treatment day) suggest that combined radiochemotherapy might improve the poor results achieved with conventional radiotherapy or sequential chemoradiotherapy in these patients. However, further studies are necessary to clarify whether modified radiotherapy or simultaneous chemotherapy or the combination of both are the reason for the improved treatment results. Furthermore, accelerated radiotherapy and simultaneous chemotherapy should also be investigated as an adjuvant postoperative treatment modality in primary resectable patients with advanced stage of disease to improve their poor prognosis.

[Detection of 8 oncogenes in squamous epithelial cancers of the head and neck]. / Untersuchungen für 8 Onkogene in Plattenepithelkarzinomen des Kopfes und des Halses.

Squamous cell carcinomas of the head and neck from 50 untreated patients were analyzed for rearranged or amplified proto-oncogenes by Southern blot hybridization. The bcl-1 and hst genes were coamplified 8- to 32-fold in 5 of 46 patients (11%) and the c-erb A1 and c-erb B2 genes 32-fold in 1 of 46 patients (2%). Eight to 16-fold amplification of c-myc was observed in 4 of 46 tumor samples (8%), while 4-fold amplification of Ha-ras was found in 2 of 46 tumor samples (4%). There was one patient with a 64-fold c-erb B2 amplification without accompanying c-erb A1 amplification. RNA-expression analysis using Northern blot and poly-A-+RNA techniques did not reveal any changes in the RNA expression of c-erb A1 while c-erb B2, hst and bcl-1 were not expressed at all. No Ki-ras or N-myc amplification was observed, nor was any rearrangement of the above-mentioned oncogenes found. Clinical correlation existed between tumor stage and oncogene amplification: patients with stage I and II disease (IUCC,AJCC) showed no amplification at all, whereas 14 patients with stage III and IV disease showed amplified oncogenes (P = 0.015,chi 2-test). In contrast, there was no correlation between oncogene amplification and disease development (observed over a minimum period of 3 years), nor could amplification be correlated with other clinical parameters (sex, tumor site, -histology) for any of the oncogenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Accelerated split-course radiation and simultaneous chemotherapy in patients with unresectable head and neck-cancer.

Forty-nine patients with unresectable squamous cell carcinomas of the head and neck were treated with accelerated radiotherapy (2 x 2.1 Gy/day, day 1-4 in week 1,2,5 and 6, total dose of 67.2 Gy) and simultaneous carboplatin (50 Mg/M2/ treatment day). Mucositis (21% grade 3 and 4, WHO) and leukopenia (40% grade 3 and 8% grade 4, WHO) were the most important side effects but did not limit the treatment schedule. The response rate was: 46.5% CR (20 pts), 46.5% PR (20 pts), 5% NC (2 pts) and 2% PD (1 pt). After three years overall survival was 35% (median 14 month) and in complete responders disease-free survival was 52%. Our results indicate that combined accelerated radio-chemotherapy might improve the poor results achieved with conventional radiotherapy or sequential chemo-radiotherapy in this difficult patient population. Further studies are neccessary to clarify whether modified radiotherapy or simultaneous chemotherapy or the combination of both are the reason for the improved treatment results.