Clinical phase I study of paclitaxel followed by cisplatin in advanced head and neck squamous cell carcinoma.

We performed a clinical phase I trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment with this combination was repeated every 21 days. Patients who had received prior treatment with platinum-containing regimens were excluded. However, patients who had received two or fewer courses of radiochemotherapy not including platinum compounds were eligible. At present, 21 patients have been entered into this ongoing study. Doses ranged from paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2 to paclitaxel 250 mg/m2 plus cisplatin 100 mg/m2. The maximum tolerated dose was reached at paclitaxel 250 mg/m2 and cisplatin 100 mg/m2. The dose-limiting toxicity of this regimen was myelosuppression (leukopenia, granulocytopenia). Clinically, neurosensory toxicity was moderate. However, preliminary analyses of threshold electrotonus studies indicate the presence of subclinical neurotoxicity in most patients. One patient receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 developed grade 3 motor neurotoxicity. Profound orthostatic hypotension was observed in five patients receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 or higher. Neurotoxicity was of delayed onset and slowly reversible, and its severity appeared to be dose related. Twelve patients are currently evaluable for response. Of these, three partial remissions were observed (6, 6+, and 3+ months). Five additional patients had stable disease. We conclude that the combination of paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer. In addition to myelosuppression, orthostatic hypotension may be a potentially significant clinical toxicity. Clinical phase II studies have been initiated, using a dose of paclitaxel 200 mg/m2 and cisplatin 100 mg/m2.

Comparison of fluorine-18-fluorodeoxyglucose PET, MRI and endoscopy for staging head and neck squamous-cell carcinomas.

UNLABELLED: Accurate, preoperative assessment of tumor extent and lymph node involvement is mandatory for individualized therapy in patients with squamous-cell carcinomas (SCCs) of the head and neck region. Metabolic imaging, [18F]fluorodeoxyglucose (FDG) PET and MRI were compared with postoperative, histologic tissue characterization. METHODS: Dynamic and static PET with 370 MBq [18F]FDG up to 60 min postinjection and MRI were compared prospectively in 22 patients with head and neck SCCs. PET results with and without attenuation correction were compared with postoperative T and N stages based on pathologic findings. RESULTS: Kinetic characteristics and tracer uptake intensity were similar in primary tumors and lymph node metastases. In both, FDG uptake did not reach a plateau phase 60 min postinjection. There was no statistically significant correlation of FDG uptake with plasma glucose level or histologic grading. All primary tumors were clearly demonstrated by PET, which tended to overestimate tumor size. The sensitivity and specificity for detecting individual lymph node involvement were 90% and 96%, respectively, for PET and, thus, significantly higher for MRI (78% and 71%, respectively; p < 0.05). N stages were correctly identified by MRI in only 4 patients; PET correctly staged lymph nodes in 15 of 17 patients. Based on "neck sides", the sensitivity and specificity were higher for PET, 89% and 100%, respectively, compared with MRI values of 72% and 56%, respectively. CONCLUSION: FDG-PET may be helpful in detecting occult primary tumors with positive lymph nodes.

Changes in tumor oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer.

PURPOSE: To evaluate the changes in tumor oxygenation during definitive split-course radiochemotherapy in locally advanced head and neck cancer (lymph nodes and primaries). MATERIALS AND METHODS: Twenty-four patients with locally advanced head and neck cancer were investigated pretherapeutically and during a defined course of radiochemotherapy (RCTh) with a total dose of 70 Gy given in 35 fractions over 9 weeks (2-week break after 30 Gy). In weeks 1 and 6, the patients received chemotherapy (5 FU and mitomycin C) concomitant with irradiation. The oxygen partial pressure measurements were carried out using polarographic needle probes in combination with a microprocessor-controlled device (pO2 histograph/KIMOC). Times of measurements were before therapy, at the end of week 3 (30 Gy), after a 2-week break (30 Gy) and at the end of therapy if measurable lesion was found (70 Gy). RESULTS: There was a significant reduction in the median pO2 (P < 0.005, n = 18) and an increase in the hypoxic fraction (defined as the percentage of pO2 values of <5 mm Hg) after application of 30 Gy (P < 0.05, n = 18). This effect was partially reversed at the end of the 2-week break. During the break an increase in the median PO2 (P = 0.05, n = 12) and a decrease in the hypoxic fraction could be observed. Towards the end of therapy (70 Gy) a significant decrease (P = 0.02, n = 13) in the median pO2 occurred. Corresponding to this, the hypoxic fraction increased during the last 4 weeks of therapy (P = 0.06, n = 13). CONCLUSION: Statistically significant changes in oxygenation in locally advanced head and neck cancer were found during a split-course radiochemotherapy. This information was obtained in a homogenous group of patients under well-defined therapeutic conditions. The decrease in the tumor oxygenation status at doses of 30 and 70 Gy are important findings because they are in contrast to the concept of continuous improvement of the oxygenation status during fractionated radiotherapy.

Allergic reactions after systemic administration of glucocorticosteroid therapy.

OBJECTIVE: To describe patients who developed allergic reactions (ie, erythema on their face and body, itching, flushing, drop in blood pressure, respiratory distress, and cold sweats) immediately after intravenous injection of prednisolone hemisuccinate (SoluDecortin H, E Merck, Darmstadt, Germany). SETTING: Academic medical center. RESULTS: Three of 4 patients had a positive reaction to an intracutaneous test with prednisolone hemisuccinate (SoluDecortin H) but no reaction to the additive sodium succinate. The results of the prick test were negative for all patients. Although no specific IgE antibodies were detected in the serum of these patients, allergic reaction was noted in 3 cases, since standardized techniques to detect antibodies in the serum for hydrocortisone acetate (ie, prednisolone) are lacking. One female patient had a cross-reaction to prednisolone and dexamethasone (Fortecortin, E Merck, Darmstadt, Germany). A renewed application of prednisolone hemisuccinate was well tolerated by all patients when histamine1 and histamine2 receptors were blocked with the use of cimetidine hydrochloride, 200 mg twice per day (1-0-1 ampules, Tagamet, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa) and dimethindene maleate, 4 mg twice per day (1-0-1 ampules, Fenistil, Novartis, Munich, Germany); calcium was given for membrane stabilization. CONCLUSIONS: Allergic reactions to glucocorticoid therapy are only occasionally mentioned in the literature. These reactions appear more often when glucocorticoids are applied topically and may lead to dangerous complications in patients if administered systemically. Therefore, when allergic reactions result from glucocorticoid therapy, (immediate-type reactions should be suspect), consider corticosteroid allergy as a differential diagnosis.

Lymph node detection of head and neck squamous cell carcinomas by positron emission tomography with fluorodeoxyglucose F 18 in a routine clinical setting.

BACKGROUND: Accurate determination of lymph node involvement is a prerequisite for individualized therapy in patients with squamous cell carcinoma of the head and neck region. In a previous study, we showed that positron emission tomography (PET) with fluorodeoxyglucose F 18 with and without attenuation correction is superior to magnetic resonance imaging for this purpose in a scientific setting. OBJECTIVE: To evaluate the diagnostic accuracy of a shortened PET protocol (acquisition time, 20 minutes) in a routine clinical setting. DESIGN: The results of static, nonattenuation-corrected PET performed on patients in 2 bed positions starting 40 minutes after the intravenous injection of 370 MBq of fluorodeoxyglucose F 18 and the results of morphologic procedures (computed tomography and magnetic resonance imaging) were compared prospectively in 70 patients for lymph node staging. Postoperative pathologic findings served as a criterion standard. SETTING: An academic medical center. RESULTS: The diagnostic accuracy of PET for detecting "neck sides" with malignant involvement was superior to morphologic procedures, with a sensitivity and specificity of 87% and 94%, respectively, compared with computed tomographic values of 65% and 47% and magnetic resonance imaging values of 88% and 41%, respectively. CONCLUSION: A short PET protocol that is suitable for routine clinical use is superior to morphologic procedures (computed tomography and magnetic resonance imaging) for the detection of lymph node involvement in head and neck squamous cell carcinomas.

Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck.

Through the development of somatostatin scintigraphy with the labeled somatostatin analog Indium111-Octreotide, it has recently become possible to accurately diagnose primary tumors of the APUD system as well as their metastases, since these tumors usually have somatostatin receptors. Experience with this method is already available for endocrine and exocrine tumors of the gastrointestinal tract, neuroendocrine and breast tumors, small cell bronchial carcinomas and certain lymphomas. In the present study, this new diagnostic technique was used for the first time in various head and neck tumors (carcinoid of the larynx, Merkel cell tumor, glomus tumor of the carotid and glomus jugulare tumor). Concurrently, some of these tumors shown by this diagnostic method to be somatostatin receptor positive were treated using the somatostatin analog Octreotide, a therapeutic approach new for the ENT-specialty. Our initial results prove that the detection of the ENT tumors which we studied by means of receptor scintigraphy is reliable. The preliminary results of this Octreotide therapy show a growth inhibitory effect, especially for those tumors of the head and neck which are inoperable or are difficult to approach surgically.

[Drainage of the middle ear]. / Zur Drainage des Mittelohres.

Otitis media with effusion occurs very frequently in childhood and usually heals without therapy. The condition is thought to be due to a higher susceptibility to infections of the upper respiratory tract and the fact that the Eustachian tube is not yet functioning perfectly at that age. Many authors explain this astonishingly high rate of spontaneous recoveries by tube malfunction alone, never even considering a middle ear clearance system. It is known from the paranasal sinuses that the cavities are regularly and continually cleaned according to very precise rules. In in-vivo experiments with guinea pigs the author proved that there is an obvious similarity between the paranasal sinus and the middle ear as far as the clearance system is concerned. By applying tracer substances to the middle ear mucosa the usual drainage pathways out of the middle ear into the Eustachian tube, and the different rates of drainage were very precisely defined.

[Pontine deafness--a new disease picture?]. / Die pontine Taubheit--ein neues Krankheitsbild?

The clinical features of pontine deafness are demonstrated in six patients with typical findings in pure-tone audiogram and speech audiometry, in stapedial reflex recordings, in brainstem-evoked potentials and cortical evoked potentials. The results of positron emission tomography (PET), magnetic response tomography (MRT), electrocochleography and the promontory test are presented. Results of cerebral spinal fluid and antibody titres in the serum are given. Pontine deafness is characterised by an interruption of the central auditory pathway cranial to the olive. This deafness should be differentiated from other forms of sensorineural hearing loss. The pathogenesis of pontine deafness is still unknown. However we should take it into consideration in the diagnosis of sudden unilateral deafness. No medical treatment method is known to date.

[Latency of the acoustic evoked stapedius reflex and its clinical significance]. / Die Latenzzeit des akustisch ausgelösten Stapediusreflexes und ihre klinische Bedeutung.

We measured the mean latency of the stapedius reflex by normal listeners. We observed a prolongation of the latency by patients with operative and histological confirmed neurinoma of the VIII. nerve. Even if the measured stapedius reflex latency considerably varies, this method represents, any way, an important support to BERA to discover tumours of the cerebello-pontine angle.

[Thorotrastoma--late damage following thorotrast arteriography]. / Thorotrastome--Spätschäden nach Thorotrast-Arteriographie.

We report two cases of cervical thorotrastoma. Thorotrast is no longer used as a radiographic contrast agent, so that the rare thorotrastoma is often forgotten in the differential diagnosis of hypopharyngeal tumours. Surgical treatment of a thorotrastoma is not recommenced.

[Clinical aspects of the osteolytic (inflammatory) phase of cochlear otosclerosis]. / Zur Klinik der osteolytischen (entzündlichen) Phase der cochleären Otosklerose.

During the last years it has been demonstrated that the active stage of otosclerosis (French: otospongieuse) is caused by an osteolytic inflammation associated with a measles-virus infection. Under influences that are not yet well understood (e.g. estrogens), the osteolytic process is arrested and changed to osteoblast activity accompanied by new bone formation. This latter process can be understood as a scar formation. If the process takes place within the area of the oval window, it results in fixation of the stapes and conductive hearing loss. When the otosclerotic process is restricted to the cochlea, clinical signs are not well defined. We report on exemplary cases of progressive bilateral sensorineural hearing loss caused by otosclerosis, restricted to the cochlea. The characteristics of the clinical course include: 1. Bilateral asymmetric sensorineural hearing loss. 2. Roaring tinnitus. 3. Episodes of sudden hearing loss. 4. Excellent response to prednisolone therapy. 5. In the late stage of the disease a small but transitory conductive hearing loss. High resolution computed tomography in such cases reveals diffuse osteolytic foci within the cochlear walls. In severe cases of such progressive deafness we discuss an antiproliferative (immunosuppressive) therapy with cyclosporine and/or a radionuclide therapy with Sn-117 m, an isotope with a very small irradiation radius.

[Cytomegalovirus infection and inner ear deafness]. / Zytomegalieinfektion und Innenohrschwerhörigkeit.

Bilateral sensorineural hearing loss of patients is correlated with elevated antibody titres against cytomegaly virus in serum in children as well as in adults. Unilateral deafness correlates with mumps infection. This is shown in a German population as well as in a Mediterranean group of patients. There is no evidence between antibody titer of Coxsackie virus, adenovirus and herpes virus or toxoplasma gondii interaction and sensorineural hearing loss neither unilaterally nor bilaterally.

Experiences with the Montgomery Salivary Bypass Tube (MSBT)

Patients with hypopharyngeal and cervical esophageal strictures and fistulas caused by advanced malignancy, ingestion of caustic material, or following surgery or radiation therapy often suffer from marked dysphagia. In such cases the implantation of a Montgomery Salivary Bypass Tube (MSBT) can be an effective therapeutic option to bridge the fistulous tract or bypass a stenosis. Being able to eat and drink without the need for intravenous supplementation or nasogastric or gastrostomy tube feeding in general greatly improves the patient's quality of life. Since 1981 we have successfully inserted the MSBT in 44 cases suffering from dysphagia of different etiology. Our experiences with the indications for implantation, insertion techniques, and postoperative results are presented. Three selected cases of progressive dysphagia in which the MSBT is demonstrated to be the treatment of choice are described in more detail. In one case, a tracheoesophageal fistula and in another a stricture of the upper esophageal sphincter (UES) were bypassed so that oral intake of soft food became possible again. The third patient suffered from a disturbance of the esophageal motility after resection of a Hippel-Lindau tumor in the spinal cord and syringe drainage; even swallowing saliva was impeded. After insertion of a MSBT, uncomplicated soft food intake became possible again.

The anti-tumor effect of in vitro tumor-stimulated autologous peripheral blood lymphocytes measured by the subrenal capsule assay.

Lymphokine-activated killer cells (LAK) are able to kill natural killer (NK)-resistant fresh bioptic tumor cells. We have tried to increase the antitumor activity of peripheral blood lymphocytes by the simultaneous stimulation with interleukin-2 and autologous tumor extract (TE). The influence of LAK cells and LAK cells stimulated with TE was compared in the subrenal capsule assay in nude mice. Experiments were performed with eight head and neck tumors following their surgical extirpation. The tumors were first grown in the renal capsule space while lymphocytes were being stimulated in vitro. Following this, the lymphocytes were injected into the growing tumors. The autologous TE-stimulated LAK cells were more effective in treating tumors than were the LAK cells. Tumors regressed in some cases so treated, a finding which was never observed with LAK cells alone.

Use of the subrenal capsule assay to measure antibody-dependent, cell-mediated cytotoxicity against head and neck tumors.

Experience with antibody-dependent, cell-mediated cytotoxicity (ADCC) has shown that antibody can increase the localization and killing capacity of lymphocytes. We tested the possibility of improving the activity of lymphokine-activated killer cells (LAK) on human tumor using the subrenal capsule assay in nude mice. The tumors were first grown in the renal capsule space and the effector cells injected later. In the model experiment we used M21 melanoma and monoclonal antibody against melanoma-associated antigen GD3. This antibody increases the tumor inhibitory activity of LAK cells from healthy donors in comparison to LAK alone. We have been able to prove the clinical relevance of such an approach. Tumor bioptic material from five tumor patients was tested with various monoclonal antibodies, following which the highly reactive antibodies were selected and incubated with the patient's LAK cells. Such pretreated LAK cells have a high growth-inhibitory effect on autologous tumor growing in the renal capsule space of the test mice.

[Clinical significance of allergic reactions in glucocorticoid therapy]. / Klinische Bedeutung allergischer Reaktionen bei Glukokortikoidbehandlung.

BACKGROUND: Glucocorticoids are widely used in medicine. Within the last few years, however, patients have become very suspicious of corticoids. The attending physicians frequently has to use a great deal of persuasion prior to applying this very effective and often indispensable group of medication. PATIENTS: We report on four patients who developed allergic reactions (i.e. erythema in face and on body, itching, flushing, drop in blood pressure, respiratory distress, cold sweats, etc.) immediately after intravenous administration of prednisolone-21 hydrogen succinate (Solu-Decortin H, SDH). RESULTS: Three out of four patients had a positive reaction to an intracutaneous test with SDH, but no reaction to the additive sodium succinate. The prick test was negative in all patients. No specific IgE antibodies were detected in the serum of these patients. However allergic reaction to SDH must be presumed in at least three cases as it is difficult to detect glucocorticoid antibodies in serum and standardizes techniques are lacking. One female patient had a cross-reaction to prednisolon and dexamethasone. A renewed application of SDH was tolerated well by all patients when H1- and H2-receptors were blocked and calcium was administered to stabilize membranes. CONCLUSIONS: Allergic reactions after glucocorticosteroid therapy are only occasionally mentioned in literature, appear more often when the agent is applied topically, and may lead to dangerous complications in patients if administered intravenously. Therefore, when allergic reactions result from glucocorticoid therapy (immediate reactions should be suspect), corticosteroid allergy should be considered as a differential diagnosis.

Diagnostic procedures for detection of lymph node metastases in cancer of the larynx.

Squamous cell carcinoma is the most common malignant neoplasm of the larynx. One of the most important influences on prognosis is the presence of metastases to the cervical lymph nodes. Accurate determination of lymph node involvement is therefore a prerequisite for individualized therapy in patients with squamous cell carcinoma of the larynx. Clinical palpation of the neck is not very accurate and the role of imaging techniques such as ultrasound, ultrasound-guided fine needle aspiration cytology, color Doppler ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography is being applied in order to improve upon the results of clinical investigation alone. According to our investigations and review of the literature, the accuracy of computed tomography scanning (84.9%) and magnetic resonance imaging (85%) was superior to palpation (69.7%) and ultrasound (72.7%). Ultrasound-guided fine needle aspiration cytology showed an accuracy of 89% and was in the same range with positron emission tomography (90.5%).

[Initial results of immunotherapy approaches to tumor treatment in the animal model]. / Erste Ergebnisse immuntherapeutischer Ansätze zur Tumorbehandlung im Tiermodell.

The possibilities of using immunocytes in cancer therapy have been increasing during the last few years. Contrary to the promising results gained by in vitro experiments, several clinical trials have shown that, on the one hand, it is difficult to preserve a quantity of cells big enough to inhibit tumours, and they have also shown that, on the other hand, antitumour lymphocytes do not get into the tumour. That is why we concentrated on improving the tumour selectivity of the antitumour lymphocytes. We carried this out practising two sets of experiments. First we incubated patient lymphocytes with tumour extract and vaccinated them in this manner. Secondly, by binding antitumour antibodies to lymphocytes, we could improve the ability of lymphocytes to bind with tumour cells. We tested these therapy models on human tumours and on tumour cell lines. Both were implanted in the renal capsule space of nude mice.

[Sedation in ambulatory BERA (brainstem electric response audiometry) studies in childhood]. / Zur Frage der Sedierung bei ambulanten BERA-Untersuchungen im Kindesalter.

We use BERA to determine the hearing threshold of children. This examination is most of the time performed on outpatients and often combined with a minor surgery. That's the reason why a sedation has to fulfill following conditions: 1. a quick, non-traumatic induction of anaesthesia--normally--without premedication; 2. an anesthesia deep enough to enable us to carry out a minor surgery as well as to get the best reliable BERA results; 3. a short period of wake-up as the patient should leave the hospital as soon as possible. In short, we got the best results first using Halothane as inhalant for the minor surgery and continuing with Midazolam as i.v. sedative for BERA examination.