Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer.

PURPOSE: The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit. RESULTS: The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p=0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p=0.18). Median survival was significantly longer (p=0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively. CONCLUSION: VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative.

[Survival and pattern of failure in palliative endobronchial HDR -- brachytherapy using iridium 192 in recurring bronchial carcinoma]. / Uberleben und Todesursachen nach palliativer endobronchialer Brachytherapie mit Iridium 192-High dose bei rezidivierendem Bronchialkarzinom -- Eine Matched Pair Studie.

To evaluate the impact of palliative high dose rate brachytherapy on survival and a pattern of failure, we performed a matched pair study. 94 patients with tumor recurrence after external beam radiation received endobronchial brachytherapy. They were followed prospectively and matched retrospectively with 94 comparable patients who had not received brachytherapy. Matched parameters were age, gender, smoking behaviour, histology, tumor stage, EBRT-dose and fractionation. The leading cause of death in both groups was generalized tumor growth. In the combined therapy group, fatal hemorrage was 27.7 %, two and a half times higher than in the EBRT group with 10.6 %, whereas respiratory insufficiency in the brachytherapy group was 6.4 % and 11.7 % in the EBRT group. A complete remission after brachytherapy yielded a 10.5 months longer mean survival. Patients dying from fatal hemorrhage after endobronchial brachytherapy lived on average 10.2 months longer than matched EBRT patients dying from the same cause. Analyzing the time-course of fatal hemorrage in the brachytherapy group we conclude that - because of its early onset in the first 10 months after induction of therapy roughly 20 % of the deaths can be attributed to a radiation damage. In those patients who died after 10 months the major cause of fatal hemorrhage was the natural course of sqamous cell carcinoma with prolonged survival.

Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic carcinoma.

BACKGROUND: Bulky endobronchial tumours in patients with lung cancer are difficult to treat. Brachytherapy and photodynamic therapy (PDT) are variably effective, and the combination of these treatments is not often recommended. However, cell culture studies and animal studies indicate a possible synergistic effect of combining PDT with ionising radiation. We assessed the safety and effectiveness of combined brachytherapy and PDT in patients with bulky endobronchial lung cancer. METHODS: Patients with histologically proven non-small cell bronchogenic carcinoma and bulky endobronchial tumours were treated using a combination of PDT (Photofrin, 2 mg/kg) and brachytherapy. Six weeks after PDT, brachytherapy was applied with five fractions of 4 Gy at weekly intervals. Follow up was performed with standard and autofluorescence bronchoscopy and tissue biopsies every 3 months. RESULTS: Thirty two patients were treated. Tumours were extensive with lengths ranging from 10 to 60 mm along the bronchus and estimated volumes ranging from 40 to 3500 mm3. At a mean follow up of 24 months, 26 patients were free of residual tumour and local recurrence. The remaining patients received a second treatment with PDT, brachytherapy, Nd:YAG laser coagulation, or external beam radiation. Distant metastases (lung, lymph node) developed in two of the six patients. Currently, all 32 patients are well. There is no evidence of residual or local recurrent endobronchial cancer in 28 patients and none had severe complications. CONCLUSION: The combination of PDT and brachytherapy for treating patients with lung cancer and extensive endobronchial tumour is safe and, in this study, had excellent therapeutic efficacy.

[Hemoptysis]. / Hämoptysen.

Hemoptysis is a potentially life-threatening complication of various diseases. The most common causes are infectious and inflammatory processes, followed by neoplasms, pulmonary embolisms, mitral stenoses, coagulopathies, and multiple systemic disorders. Primary examinations include a chest x-ray, an angio CT and a bronchoscopy. Sometimes, a bronchial artery angiogram is required. The patient is at risk of suffocation because blood and clots can severely obstruct his airways. Thus, the most important measures are: supplemental oxygen, positioning the patient with the bleeding side down, bronchoscopical suctioning and removal of blood and clots. Coagulopathies have to be corrected. Application of vasoactive drugs may help temporarily. In cases of bleeding from central lesions, coagulation with laser or argon-plasma-coagulator is feasible. Heavy bleeding from the periphery requires a balloon or tube tamponade. Depending on the cause and the severity of the bleeding either anti-inflammatory medical treatment, hemostyptic radiation therapy, bronchial artery embolisation or a surgical procedure must follow.

[Bronchial carcinoma. Epidemiology, diagnosis and therapy]. / Bronchialkarzinom. Epidemiologie, Diagnostik und Therapie.

Bronchial carcinoma still has a dark prognosis and therapeutic progress remains painfully slow: the 5-year survival rate raised in the last 20 years from 11 to 15%. There are no early symptoms by the tumor and detection by screening is not effective. Worldwide incidence is raising, the falling rates in men in the western world have been compensated by a steep increase in eastern Europe an Asia. Cigarette smoking is in 85% the main cause of this epidemic. Better understanding of genetic predisposition may identify patients at higher risk. Tumor in stage IA-IIB of non small cell carcinoma could gain by neoadjuvant chemotherapy, what is more probable for stage IIA and IIIB. Radiation therapy in combination with chemotherapy improves survival in inoperable stage IIIB. In stage IV disease palliative chemotherapy is superior to best supportive care.

Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial.

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m(2) (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m(2), all repeated every 3 weeks. Survival, toxicity and quality of life were also compared. PATIENTS AND METHODS: Patients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients. RESULTS: A total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m(2). The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms. CONCLUSIONS: This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.

[Argon plasma coagulation in bronchology: a new method--alternative or complementary?]. / Die Argon-Plasma-Koagulation in der Bronchologie: Eine neue Methode--alternativ oder komplementär?

Argon plasma coagulation (APC) is a thermal coagulation technique that uses ionized argon to transmit high-frequency electrical current, contact free, to tissue. APC has been used in surgery for more than 20 years, particularly for the hemostasis of superficial bleeding. Although APC has become well established in gastrointestinal endoscopy since its introduction in 1991, very few reports of its use in bronchoscopy exist to date. From June 1994 to June 1998, 364 patients (80 women, 284 men), 88% with a confirmed malignant tumor, were treated prospectively in a total of 482 sessions. The single most common indication was recanalization of malignant airway stenoses (186 patients). The defined therapy objective was achieved with good results in 67% of patients. More than 90% of interventions were performed with rigid bronchoscopy. Despite less penetration compared with Nd:YAG laser, extensive bronchial tumors were treatable, in which coagulated tumor fractions were removed either with forceps or bronchoscope tip. The second indication was bleeding in the central airways (119 patients). Acute hemostasis was achieved in 118 patients, 20% in whom the flexible technique under local anesthesia was used. In 34 patients, APC was successfully used to recanalize occluded stents. Rare indications included benign endobronchial tumor, fistula conditioning before fibrin adhesion, and the treatment of scar tissue stenosis. Summarizing all complications, a rate of 3.7% "per treatment" was recorded. Two patients died within 24 hours; their deaths were not directly related to APC. APC is an effective and safe technique for the treatment of bronchologic tumor ablation and hemostasis and can be used with local anaesthetic with flexible bronchoscopy or rigid bronchoscopy with general anesthesia. Compared with Nd:YAG laser, APC is an economic alternative technique offering more effective hemostasis. Furthermore, APC is of particular value as a compliment to well-known techniques, increasing the options in interventional bronchoscopy.

Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

Trimodality therapy in stage III non-small cell lung cancer: prediction of recurrence by assessment of p185neu.

In a trimodality treatment approach for stage III non-small cell lung cancer the prognostic impact of pretherapeutic p185neu assessment was evaluated. Fifty-four patients were admitted to chemotherapy followed by twice-daily radiation with concomittant low-dose chemotherapy and subsequent surgery. Immunohistochemical assessment of p185neu expression was performed in paraffin-embedded mediastinal lymph node metastases, by mediastinoscopy biopsy prior to therapy. Paraffin-embedded biopsies of mediastinal lymph node metastases were available in 33 cases. Seven out of eight patients with positive p185neu staining developed distant metastases, in contrast to seven out of 25 negative cases. Expression of p185neu in mediastinal lymph node metastases was a significant predictor for progression-free survival (p=0.047) and resulted mainly from significant differences in metastases-free survival (p185neu-positive versus p185neu-negative: median, 11 versus 19 months; 2- and 3-yr rates, 13% and 0% versus 40% and 32%; p=0.04). On the basis of these preliminary results it was concluded that further evaluation of p185neu expression in trials on neoadjuvant and adjuvant therapy is warranted. When the prognostic impact of p185neu in such trials with larger patient numbers is confirmed, this may contribute to the identification of stratification variables for future treatment approaches of non-small cell lung cancer.

[Experiences with fluorescence diagnosis and photodynamic therapy in a multimodality therapy concept of operated, recurrent bronchial carcinoma]. / Erfahrungen mit Fluoreszenzdiagnostik und photodynamischer Therapie im multimodalen Therapiekonzept des operierten, rezidivierenden Bronchialkarzinoms.

Even of those few patients who are operated because of bronchial cancer up to a quarter develop a recurrence. One reason is certainly that tumor-cells already present at the time of surgery are bronchoscopically invisible. Fluorescence methods might be able to detect these malignant cells. For patients with post-surgical recurrences the therapeutical choices are limited due to the loss of parenchyma. Photodynamic therapy (PDT) with the hematoporphyrine derivative Photofrin is one laborious but promising option. Based on an argon-dye laser we have developed a combined system for the diagnostical measurement of autofluorescence and Photofrin-induced fluorescence at 488 nm and the therapeutical PDT at 630 nm. Under the excitation with blue light from the argon laser, differences in the autofluorescence of malignant and benign cells can be distinguished. Following the injection of Photofrin a spectrum peak at 628 nm clearly delineates tumor cells. In six out of twelve patients with post-surgical recurrences a single PDT course resulted in tumor eradication. With additional PDT courses and brachytherapies local tumor control could be achieved in all cases. The general photosensitivity and the necessary light protection were tolerated by all patients. In order to avoid severer complications such as asphyxia, obstruction of bronchi and pneumotharaces resulting from fibrin-plugs and necrotic tissue following PDT must be considered. Especially in patients with pneumonectomy a careful surveillance and debridement is mandatory.

The role of brachytherapy in the treatment and control of central bronchial carcinoma.

Endobronchial brachytherapy is by far the oldest interventional bronchiological treatment procedure. In the decades following its inception in 1922, it has undergone progressive modification by innovations in radiation physics and techniques, and has enjoyed a renaissance with the introduction of fibreoptic bronchoscopy, local anaesthesia, modern afterloading devices, and high dose rate (HDR) treatment with iridium-192, an isotope with very high activity. However, there is little standardization of dose-specification, fractionation and optimal dosage using this isotope, and homogeneous, objective analyses of the clinical results of treatment using iridium-192 is lacking. Very often, the exact staging of patients is lacking. For such reasons, any evaluation of the efficacy of endobronchial brachytherapy is significantly impeded. However, reliable data are available on the palliative effect of HDR-brachytherapy, which is safe, fast in onset and apparently superior to external beam radiotherapy (EBRT) alone. In addition, some studies document the curative effects, or complications, offers not only an insight into the working principles of radiation treatment but also into the biological behaviour of bronchial tumours. Endobronchial HDR-brachytherapy should be compared to the other interventional procedures focusing on the same aim, namely that of restoring patency of a previously occluded bronchus. This is the overall challenge to pneumologists working in this field.

[Lung surgery in elderly patients, a retrospective study (1985-1994)]. / Lungenchirurgie im Senium, eine retrospektive Studie (1985-1994).

From 1985 to 1994, we performed 4568 thoracic operations, 234 of these patients (176 males, 58 females) were older than 70 years of age; the oldest patient was 82 years. Of these 234 patients, 144 suffered from bronchial carcinornas, 25 from lung metastases, 21 from recurrent pneumothoraces, 12 from thymomas, 21 from tuberculomas, hamartomas, an intrathoracic goiter or mesothelioma; in 11 patients, diagnostic thoracotomias or biopsies had been done. We did 146 anatomical resections, 59 atypical wedge resections, 14 decortications, pleurectomies, thymectomies or exstirpations of mediastinal tumors; in addition, three resections of an intrathoracic goiter were done. The hospital lethality was 3.8%, the total rate of complications 56%, mostly cardiac arrhythmias. The survival rate of the patients suffering from a bronchial carcinoma was the same as in younger patients.

[Pleuro-mediastinitis in pulmonary actinomycosis as a rare differential bronchial carcinoma diagnosis]. / Pleuro-Mediastinitis bei pulmonaler Aktinomykose als seltene Differentialdiagnose des Bronchialkarzinoms.

A 48-year old patient complaining of immitigable coughing with purulent and sanguineous sputum and a loss of weight of 8 kg within the last three months was admitted to our hospital. Due to anamnesis and radiological findings (tumor of the right side upper lung field with infiltration of the chest wall and the mediastinum) we suspected a bronchogenic carcinoma. As bronchoscopy and histological examinations of biopsies revealed no hints to the underlying disease, we submitted the patient to a right side explorative thoracotomy. It showed a tumorous involvement of the right side upper lung field with infiltration and partial destruction of the chest wall and infiltration of the apical segment of the lower lobe of the lung and a phlegmonous infiltration of the paratracheal tissue. Histological examination confirmed chronical course of actinomycosis. Therapy consisted in resection of the affected tissue and long-term administration of antibiotics. Response to therapy was excellent concerning both radiological findings and subjective complaints.

Endobronchial radiation therapy for obstructing malignancies: ten years' experience with iridium-192 high-dose radiation brachytherapy afterloading technique in 365 patients.

From 1983 to 1993, 365 patients with obstructing endobronchial malignancies were treated by endobronchial high-dose radiation (HDR) iridium-192 afterloading. In 346 patients, the objective was palliation, and in 19, the objective was curative. A dose of 5 Gy at 10 mm from the source axis was administered on three (palliation) and four (cure) occasions, at intervals of 14 days. The majority of patients were treated after exhaustion of external beam radiation therapy (EBRT), often in conjunction with other interventional bronchologic modalities such as endobronchial laser resection. Of the patients, 65% had a squamous cell carcinoma. Endobronchial HDR brachytherapy results in few acute complications and can be performed with no major discomfort on an outpatient basis. In approximately 66% of patients, a palliative effect is achieved, even after the exhaustion of conventional treatment. Life may be prolonged for a few months, but the enhancement of survival is difficult to assess for several reasons. Mean survival is 9 months for limited disease and 5 months for extensive disease. Endobronchial HDR brachytherapy influences the pattern of failure: a 21% rate of fatal hemorrhages is probably the result of the selection of patients for this treatment rather than a treatment-related complication. There is sufficient evidence to suggest the rational use of HDR brachytherapy in combination with EBRT to effect a cure, or even on its own when tumor growth is strictly limited. However, the standardization of radiotherapy and endoscopic indications is an urgent priority. Prospective, controlled, and cooperative studies are mandatory. Endobronchial iridium-192 HDR brachytherapy complements endobronchial laser resection and is currently an established technique in the treatment of advanced malignant airway obstruction.

Pattern of failure and survival in endobronchial laser resection. A matched pair study.

To evaluate the influence of endobronchial laser resection on survival and the pattern of failure in patients with bronchial malignancies, we investigated 75 patients prospectively. These patients had radiation therapy (mean external dose, 53.1 Gy) and endobronchial laser resection to treat an inoperable or recurrent bronchial carcinoma occluding a major airway. Complete recanalization was achieved in 36 percent, partial recanalization was achieved in 51 percent, and no recanalization was achieved in 13 percent. These 75 patients were matched retrospectively with a group of 75 patients who received external radiation therapy because of the same indications, but because of endobronchial compression of a major airway by the tumor, received no laser resection. The patients were matched for age, sex, TNM-status, histologic features, external radiation dose and fractionation, lung resection, cytotoxic therapy, and brachytherapy; they were treated in the same period. The incidence of terminal hemorrhage was four times higher in patients who received endobronchial laser resection (34.5 percent) compared with those who did not (7.7 percent). Successful laser reopening of a major airway influenced the pattern of failure: with full recanalization the cause of death in 23.3 percent of cases was respiratory failure and in 26.7 percent, terminal hemorrhage; whereas with no recanalization these figures were 56.3 percent and 18.8 percent, respectively. Laser resection did not influence overall survival, but in patients with full reopening of a bronchus, the time interval from treatment to death was prolonged by more than 4 months compared with those patients in whom recanalization failed. Comparing our observations on the immediate cause of death with reports in the literature, we conclude that the higher percentage of terminal hemorrhage in patients receiving endobronchial laser resection is not directly related to the treatment, but reflects different patterns of tumor growth with respect to mucosal destruction not covered by the TNM system.

The role of ultrasound assisted thoracoscopy in the diagnosis of pleural disease. Clinical experience in 687 cases.

Ultrasonic examination is an established method used to differentiate between solid and liquid structures in the pleural space. It can estimate the volume of a pleural effusion and demonstrate whether the effusion is associated with loculations or adhesions. It is complementary to thoracoscopy. In the diagnosis of pleural disease ultrasonic-assisted thoracoscopy should only be used when the less invasive methods of diagnosis such as pleural aspiration for cytological, bacteriological and chemical examinations and needle biopsy of the pleura have not yielded a diagnosis. Although thoracoscopy is a relatively invasive procedure, it has the advantages of speed and accuracy in the diagnosis of pleural disease. This procedure is not widely used as it requires specialized instruments and equipment and may be time-consuming. The latter disadvantage may be minimized by the use of prior pleural sonography. The ultrasonic examination will indicate the optimal point of entry of the thoracoscopy to avoid adhesions. In order to evaluate feasibility, complications and clinical results in ultrasonic-assisted thoracoscopy, we investigated 687 patients with pleural diseases from 1987 to 1990. As prior induction of a pneumothorax under X-ray control was not necessary, the 20-30 min required for this procedure was saved in all patients. Very few complications were attributable to ultrasonic-assisted thoracoscopy as it could normally be performed under local anesthesia. A macroscopic diagnosis was made in 80% of malignant diseases and 77% of inflammatory diseases in our total of 687 thoracoscopies. The diagnosis of a malignant pleural effusion was confirmed histologically and cytologically in 95% of those 190 patients in whom it was present.(ABSTRACT TRUNCATED AT 250 WORDS)

[Conservative therapy of malignant pleural effusion]. / Die konservative Therapie des malignen Pleuraergusses.

The nonsurgical treatment of malignant pleural effusion is palliative in principle. This aim must be achieved with a minimum of side effects and risks to the patients. Before treatment, a clear histologic diagnosis must be made. Thoracoscopy offers a fast and safe result with a more than 90% reliability. Systemic cytotoxic treatment and local procedures are available. Using pleurodesis, talkum is clearly superior to tetracycline in achieving a very low recurrence rate. The median survival in 287 patients was 9 months.