Neoadjuvant therapy affects tumor growth markers in early stage non-small-cell lung cancer.

INTRODUCTION: While adjuvant therapy of early-stage non-small-cell lung cancer (NSCLC) is widely accepted, literature data concerning neoadjuvant treatment provide contradictory results with both improved and unaffected survival rates. Also, data concerning potential effects of neo-adjuvant therapy on cellular level are scarce. OBJECTIVE: The aim of present study was to analyze the effect of chemotherapy followed by surgical resection on several key biological markers of tumor growth (TGF-beta, VEGF), apoptosis (sAPO-1/Fas/CD95) and invasiveness (TIMP-1) assessed in the sera of NSCLC early-stage patients (IB-IIIA). - MATERIAL AND METHODS: Measurements were performed by ELISA method in blood serum from 24 NSCLC patients (I-IIIA) collected prior therapy, one day before surgery and 3 days after. RESULTS: TGF-beta serum concentrations were significantly lower after both chemotherapy (P<0.05) and surgery (P<0.01) in comparison to the baseline. VEGF levels decreased following NEO therapy with subsequent significant up-regulation after surgery (P<0.001). Interestingly, post-surgery serum VEGF strongly correlated with TGF-beta concentration (r = 0.52, P = 0.014). No significant differences were observed for serum sAPO-1/CD95/FAS as well as TIMP-1 concentrations at any of three evaluated time-points. CONCLUSION: Neoadjuvant treatment of early-stage NSCLC affects mostly mechanisms responsible for tumor growth and vascularization. Its effect on cancer cells apoptotic activity needs further evaluation.

Neuroendocrine phenotype of non-small cell lung carcinoma: immunohistological evaluation and biochemical study.

AIMS AND METHODS: The prevalence and distribution of neuroendocrine differentiation in non-small cell lung cancer (NSCLC) was estimated by assays for synaptophysin (SYN), chromogranin A (CgA), Leu7 and neuron-specific enolase (NSE). Serum NSE and CgA were determined in parallel to find the values of these markers for distinguishing neuroendocrine differentiation in NSCLC. Fifty-eight resected NSCLC specimens and 34 sera of NSCLC patients entered the study. Neuroendocrine differentiation was graded according to the percentage of neuroendocrine tumor cells as NE0--0%, NE1-NE4--1%->76%. Serum NSE <12.5 ng/mL and serum CgA <46 U/L were taken as cutoff levels. RESULTS: 63.8% (37/58) of NSCLC were scored as NE1-NE4 according to the SYN, CgA and Leu7 levels; 34.5% as NE1; 29.3% as NE2-NE4. 56.8% of tumors were positive for SYN, 34.4% for CgA, 22.4% for Leu7, and 79.3% for NSE. A significant relationship was found between tumor SYN and tumor CgA expression, and between tumor SYN expression and tumor stage. Adenocarcinomas showed a significantly higher rate of neuroendocrine differentiation than squamous cell carcinomas. All normal serum CgA levels corresponded to a lack of CgA expression in the tumors. The increased serum NSE levels presented by 26% of NSCLC patients (mainly <16 ng/mL) did not correlate with tumor NSE expression. CONCLUSIONS: The prevalence of neuroendocrine differentiation in NSCLC varies and depends on the immunohistochemical criteria used; this warrants standardization of the immunohistochemical criteria for neuroendocrine differentiation in NSCLC. NSE expression in the tumor and a mild increase in serum NSE are poor markers for distinguishing neuroendocrine differentiation in NSCLC.

Combination chemotherapy with vincristine, epirubicin and cyclophosphamide in small cell lung carcinoma. Polish Lung Cancer Cooperative Group.

The aim of this prospective study was to assess the activity of a combination of vincristine, epirubicin and cyclosphosphamide (VEC) in previously untreated patients with limited small cell lung carcinoma (SCLC) and to delineate the feasibility of dose escalation for epirubicin in this regimen. The chemotherapy schedule included cyclophosphamide, 1000 mg/m2, vincristine, 1 mg/m2 and escalating doses of epirubicin: 50 mg/m2, 70 mg/m2 and 90 mg/m2; respectively in three consecutive groups of patients. Drug cycles were repeated every 3 weeks. 118 patients from eight institutions were enrolled in this study between February 1986 and March 1989. Objective tumour response was observed in 81 of 116 evaluable patients (70%) including 25 patients (22%) who achieved a complete remission. Responding patients received thoracic radiation after the fourth cycle of chemotherapy. The median duration of response was 30 weeks and the median duration of survival was 52 weeks. There were no significant differences in treatment results between the consecutive groups of patients. The regimen was well tolerated for all doses of epirubicin. The main toxicities included alopecia (96%), nausea and vomiting (81%) and leukopenia (44%). Grade 4 haematological toxicity was observed in 3 patients (2.6%). No significant epirubicin dose-dependent side effects, except for mucositis were observed.

The prognostic significance of bone marrow metastases in small cell lung cancer patients.

One-hundred forty-six SCLC patients were classified as localised (56) or extensive (90) using chest X-ray, bronchoscopy, brain CT, bone scintigraphy, ultrasonography of the abdomen and bilateral bone marrow trephine biopsy. Bone marrow metastases were found in 28 cases. Patients with bone marrow metastases had significantly shorter time to progression (median 20 weeks) and significantly shorter survival time (median 31 weeks) than other patients with extensive disease (medians 30 and 46 weeks). Patients with bone marrow involvement had significantly more often metastases in three or more organs than others with extensive disease. The negative prognostic significance of bone marrow involvement was however independent of the negative prognostic significance of the number of organs with metastases.

Survival of patients with limited small cell lung cancer in whom complete remission was obtained (a non-randomised retrospective study of 124 consecutive patients.

The aim of this study was to assess whether thoracic radiotherapy (TRT) is necessary for those patients (pts) with limited small cell lung cancer (SCLC) who obtained CR after induction chemotherapy (ChT). The analysis include retrospective material of 124 consecutive pts with limited SCLC. All pts had induction ChT (3-5 courses): 78 with CAVE (cyclophosphamide, doxorubicine, etoposide) and 46--with other regimens without etoposide. After induction ChT 55 pts were irradiated on tumor and mediastinum and in 69 the same ChT was continued for 6-8 courses or till progression. After induction ChT CR was obtained in 31 pts, PR in 67 and NR in 26. TRT significantly increased the number of CR among those pts who did not achieve satisfactory tumor response after induction ChT. The median survival was 24 months for those patients who obtained CR, 12 months for those who obtained PR and 9 months for those who did not respond. In the group of patients who obtain CR, survival was the same for those treated with ChT alone and for those treated with ChT and TRT. We conclude that in the treatment of individual patient with limited SCLC TRT is indicated for those who did not obtain CR after ChT. Whether patients in whom CR after chemotherapy was obtained can further gain by application of TRT is worth further randomised studies.

Fatal infection in patients treated for small cell lung cancer in the Institute of Tuberculosis and Chest Diseases in the years 1980-1994.

The study was performed to explore the frequency of infections present at death and infection as the main cause of death (fatal infection - FI) in 845 consecutive patients (pts) treated for small cell lung cancer (SCLC) at the Institute of Tuberculosis and Chest Diseases in Warsaw, in the period 1980-1994. Diagnosis of infection was based on clinical signs and symptoms, the presence of new lesions on the chest X-ray, microbiological tests and/or autopsy examination. All cases of fungal infection, Pneumocystis carinii pneumonia (PCP) and tuberculosis were proved by autopsy and microscopic examination (including special staining). FI was diagnosed if no progression of cancer was noted and no other complications occurred. Infection was present at the time of death in 116 patients (13.7%) and FI was the cause of death in 39 of them (4.6%). Nine patients died from fungal infection, eight from bacterial infection, seven from PCP and two from tuberculosis. In 13 cases the aetiology of infection found at autopsy was not determined. All FI patients received chemotherapy and corticosteroids, 16 of them also had radiotherapy on the tumour and mediastinum. Thirty-two out of 35 patients had leucopenia. The risk of death from infection was greater in patients above 60 years of age. Patients in bad performance status died of infection significantly earlier than others (P<0.05).

Combination chemotherapy with cyclophosphamide, epirubicin and etoposide in small cell lung cancer.

From March 1987 to February 1991, 136 patients with untreated small cell lung cancer (64 patients with limited disease and 72 with extensive disease), were treated as part of a prospective multi-center study, with a combination of cyclophosphamide 1000 mg/m2 i.v. on day 1, epirubicin 70 mg/m2 i.v. on day 1 and etoposide 100 mg/m2 i.v. on days 1, 3 and 5. Courses were repeated every 3 weeks. One-hundred thirty-four patients were evaluable. There were 42 (31%) complete responses and 66 (49%) partial responses for an overall response rate of 80% (95% confidence interval 71-87%). A complete response was seen in 24 patients (38%) with limited disease and in 18 patients (26%) with extensive disease, while a partial response was observed for 31 (48%) and in 35 (50%) patients, respectively. The median duration of response for all patients was 8.9 months (range, 1-60+ months). The median duration of survival for the entire group was 11.4 months (12.5 months for limited disease and 9.8 months for extensive disease). The 2-year survival rate for the whole group was 13%. The main side-effects were myelosuppression, alopecia, nausea and vomiting. Grade 4 toxicity was seen in 8.5% of patients. In conclusion, the studied regimen was found to be active and well tolerated and may be considered as an alternative to standard chemotherapy combinations in SCLC.

The clinical value of Cyfra 21-1 estimation for lung cancer patients.

Cytokeratin-19, one of the cytoskeletal proteins, is expressed both in bronchial epithelium and in lung cancer cells. The aim of our study was to establish the value of serum cytokeratin-19 soluble fragment (Cyfra 21-1) measurement in lung cancer patients. Cyfra 21-1 levels were estimated in 35 patients (pts) with benign lung diseases and in 116 lung cancer patients: 55 pts with squamous cell lung cancer, 38 pts with small cell lung cancer and 23 pts with adenocarcinoma. The cutoff level was set at 4 ng/ml with a specificity of 94% and a sensitivity of 40%. Elevated Cyfra 21-1 values were found in 44% of squamous cell lung cancer, 39% of adenocarcinoma and 34% of small cell lung cancer pts (the difference was not significant). In squamous cell lung cancer and in adenocarcinoma elevated Cyfra 21-1 values were observed more often in patients with advanced disease than in patients with limited disease. There was no significant correlation between the initial Cyfra 21-1 level and the response to chemotherapy. Cyfra 21-1 was not a prognostic indicator, although in operable squamous cell lung cancer the proportion of survivors in the second year of observation was higher among the patients with normal preoperative Cyfra 21-1 levels.

[Recurrent atypical bronchial tumor diagnosed as small cell lung cancer]. / Wznowa atypowego rakowiaka oskrzela rozpoznana jako drobnokomórkowy rak pluca.

The case of atypical carcinoid was presented. 5 years after resection of mediastinal mass, the tumor in main left bronchus developed and the diagnosis of small cell lung cancer was established. The pathological analysis of previous slides from resected tumour and bronchial biopsy showed the same atypical carcinoid. The patient was successfully treated using chemotherapy.

[Usefulness of examining levels of carcinoembryonic antigen in pleural fluid for establishing the cause of pleural effusion]. / Przydatnosc badania stezenia antygenu rakowoplodowego w plynie z jamy oplucnej dla ustalenia przyczyny wysieku.

The levels of CEA in pleural effusion fluid and serum were determined in 132 patients with pleural effusions. Malignancy was the cause of pleurisy in 92 patients, in the remaining 40 patients the cause of pleurisy were non-malignant disorders. CEA levels exceeding 15 ng/ml were found in 42/92 patients with malignancy (45.7%) and in 2 patients with non-malignant disorders (5.0%). The serum CEA levels exceeded the value of 15 ng/ml in 23/92 patients with malignancy (25.0%) and in 1 patient of the remaining group (2.5%).

[Granulomatous lung lesions after occupational exposure to glass fibers]. / Ziarniniakowe zapalenie pluc po ekspozycji zawodowej na wate szklana.

39 years old man with granulomatous lesions in both lungs caused by occupational contact with glass fibers was described. He has been working as an bricklayer-plasterer for 18 years and was in contact with lime, cement, plaster, asbestos, dust of coal and wood and with glass fibers. For the last two years before admission in 1993 he has had frequent bronchial infections. On admission he was in good general condition, his spirometric examination and blood gases were within normal limits. On chest x-ray disseminated lesions were found. Those lesions were of the round shapes on chest CT. Many sputum cultures for tubercle bacilli were negative. ANA and ANCA were not found in the serum. ACE was within normal limits. No precipitins to environmental antigens were found. Cancer metastases were suspected and lung biopsy during videothoracoscopy was done. Many foreign body type granulomas were found throughout the specimen. The character of the lesions was not typical for tuberculosis, sarcoidosis, extrinsic allergic alveolitis, silicosis or asbestosis. There are some reports concerning the possibility of development of such lesions after the exposition to glass fibers. We suspect that case is an example of such pathology. His occupational exposition was stopped in 1993 and he was observed without treatment. During the 5 years of observation (up till 1998) he was in good health with stable chest x-ray picture and results of respiratory system function.

[Alveolar hemorrhage caused by exposure to pesticides]. / Krwawienie pecherzykowe wywolane ekspozycja na pestycydy.

17 years old boy was admitted because of cough, hemoptysis and mild fever. These symptoms appeared a day after exposure to Decis-pesticide of relatively low toxicity for people. In hospital respiratory failure (pO2 48.5 mmHg) and alveolar haemorrhage (the presence of bloody fluid with hemosiderin loaded macrophages, the signs of alveolar filling in chest HRCT scan and elevation of diffuse capacity) were recognised. All symptoms completely disappeared after 5 month of corticosteroids therapy.

[The role of pleural needle biopsy and determination of Carcinoembryonic antigen in pleural fluid for diagnosing the etiology of pleural effusion]. / Znaczenie iglowej biopsji oplucnej oraz oznaczania stezenia antygenu karcinoembrionalnego w plynie oplucnowym dla rozpoznawania etiologii wysieku w jamie oplucnej.

Results of histopathological and bacteriological examinations of specimens taken in 213 patients with pleurisy by Abrams' needle biopsy of parietal pleura were presented. Malignant cells were found in histological survey of excisions from pleura in 48/128 patients with final diagnosis of cancer (37.5%). The same examination accompanied by bacteriological survey led to establish proper diagnosis in 41/60 patients with pulmonary tuberculosis (68.3%). In 31 patients with cancer pleural fluid was searched for concentration of the carcinoembryonic antigen (CEA). In this group, in 7/19 patients with negative histological results of pleural biopsy CEA concentrations were markedly increased. This finding strongly supported further searching for malignancy in those cases. Finally, the diagnosis was established due to the pleural needle biopsy in 89/213 patients (41.8%).

[Frequency of bone marrow involvement in patients with small cell lung carcinoma before treatment based on selected laboratory parameters]. / Czestosc wykrywania przerzutów do szpiku u chorych na drobnokomórkowego raka pluca przed leczeniem w zaleznosci od wyników wybranych badan laboratoryjnych.

Bone marrow bilateral biopsy was done in 106 small cell lung cancer patients before treatment. Full blood count, serum alkaline phosphatase activity, serum albumin concentration and serum Na+ concentration were compared according to presence or absence of bone marrow metastases. Decreased red cell count and elevated alkaline phosphatase activity were found significantly more often in the group of patients with bone marrow involvement. Thrombocytopenia and "blast" smear occurred only in patients with bone marrow metastases. Although bone marrow was found more often in association with low albumin level, this was not significant. It was impossible to anticipate the presence of bone marrow metastases on the base of total blood count, examination increased serum alkaline phosphatase activity or decreased serum Na+ or albumin levels. However in the presence of thrombocytopenia and "blastic" smear bone marrow metastases are very probable.

[Infection as a main or additional cause of death in patients treated for small cell lung cancer]. / Zakazenia jako glówna lub dodatkowa przyczyna zgonu u chorych leczonych z powodu drobnokomórkowego raka pluca.

The aim of this study was to analyse the frequency of infection as a cause of death in small cell lung cancer (SCLC) patients. Our material consisted of 845 unselected SCLC patients, 246 women and 599 men, aged 29-78 years, treated between 1980-1994 in the Institute of Tuberculosis in Warsaw. 479 patients had limited and 366 extensive disease. 530 were in good (0-2) and 315 in bad (3-4) performance status. 784 patients died. Autopsy was done in 211 patients. Infection was regarded as a main cause of death in 39 patients (4.6%) and as a coexistent cause in 77 (9.1%). At the time of death from and/or with infection in 16 patients complete remission and in 27 partial remission of cancer was confirmed. The risk of death from and/or with infection was not related to the age and sex or to the performance status of patients and to extension of cancer. The risk of death from and/or with infection in the first 3 months of treatment was however greater for patients in bad performance status and with extensive disease and later (after 3rd months) for patients in good performance status and with limited disease.

[Evaluation of the value of determining levels of cytokeratin-19 fragments for diagnosis of lung cancer]. / Ocena wartosci oznaczania stezenia fragmentu cytokeratyny-19 w rozpoznawaniu raka pluca.

Cytokeratins, the intermediate filaments, are expressed by many epithelial cells. Immunohistochemistry revealed the presence of cytokeratin-19 both in bronchial epithelium and in lung cancer cells. The aim of our study was to establish the value of serum cytokeratin-19 estimation by immunoenzymatic assay (Enzymun Cyfra 21-1, Boehringer Mannheim) in the patients (pts) with lung cancer (Ic). 153 pts (104 men, 49 women, median age 50 years) entered this study. The group consisted of 37 pts with benign lung diseases (control group), 56 pts with squamous cell Ic, 37 pts with small cell Ic and 23 with adenocarcinoma. Cut off value was determined at 4 ng/ml, with 96% of specificity. Elevated cytokeratin-19 values were found in 41% of pts with lung cancer (45% of squamous cell Ic, 39% of adenocarcinoma and 35% of small cell Ic). Median cytokeratin-19 values were 2.2 ng/ml in the control group, 3.4 ng/ml in squamous cell Ic, 3.3 ng/ml adenocarcinoma and 2.9 in small cell Ic. Cytokeratin-19 elevation was observed more often in non small cell Ic pts with advanced disease, stage III--46%, stage IV--50% than in early stages (I + II)--34%. In small cell Ic pts the frequency of cytokeratin-19 elevation was 20% in limited disease versus 45% in extensive disease. We conclude that cytokeratin estimation is not valuable in the recognition of histologic type of lung cancer, although elevated levels are seen more often in squamous cell Ic. Cytokeratin-19 estimation may be also helpful in lung cancer staging.

[The role of radiotherapy in combined treatment of limited small cell lung cancer in relation to results of induction chemotherapy]. / Rola radioterapii w leczeniu skojarzonym ograniczonej postaci drobnokomórkowego raka pluca w odniesieniu do wyników chemioterapii indukcyjnej.

The comparison between results of chemotherapy (ChT) and ChT plus radiotherapy (RT) was performed in the group of 124 patients with limited SCLC. After induction ChT 25% pts obtained CR, 54%-PR and 21% did not respond. In 69 pts ChT was continued and in 55 others RT was added to ChT. The number of patients in whom tumor response was observed increased significantly after addition of RT to ChT. The degree of complete response had important impact on survival time. The pts who obtained CR had significantly longer survival time than those who achieved only PR or NR. Median survival time was very similar in both groups (13 months after ChT alone and 15 months after ChT plus RT). This was also true for the groups of patients who obtained CR after completion of treatment. Achievement of complete response is the most important factor for good prognosis. RT is indicated in those patients who achieved only PR after induction ChT.

[The value of diagnostic methods used to assess the response to treatment in patients with limited small cell lung carcinoma]. / Wartosc metod oceniajacych odpowiedz na leczenie u chorych na ograniczona postac drobnokomórkowego raka pluca.

Tumor response is used as a main criterion whether or not the treatment yields an anticancer activity. The tumor response criteria are defined by WHO recommendation but little is known about the tests must be used. The aim of this paper was to compare the degree of response to the treatment of 268 patients with limited small cell lung cancer, using independently 3 methods: radiological, bronchoscopic and cytological of bronchial material. Particular categories of response (CR, PR NR and presence or absence of carcinomatous cells) were related to survival time of patients independently to method of assessment. Multivarinte Cox analysis selected 3 parameters related to 3 different methods as independent survival risk factors. We conclude that each of diagnostic method (chest x-ray, bronchoscopy, cytological examination of bronchial material yield independent information correlated with survival risk of particular patient.

[Chemotherapy versus chemoradiotherapy in patients with limited small cell lung carcinoma]. / Chemioterapia versus naprzemienna chemio-radioterapia u chorych z ograniczona postacia drobnokomórkowego raka pluca.

62 patients with a limited small cell lung cancer were randomly qualified into two groups. 32 patients of the first group were treated only with the chemotherapy regimen, consisted of three drugs (Carboplatine, Etoposide and Vincristine administered in 6 courses, on regular, 3-weeks basis). The second group of 30 patients had been treated with the identical chemotherapy schedule, but alternatively combined with a primary site irradiation in a total dose of 40Gy, applied in parts after the chemotherapy courses 2, 3, and 4. The significantly higher proportion of a complete remission results was observed in the alternate-treatment group: 14/30 (46.7%), compared with the chemotherapy-only group: 10/32 (31%). Alternate chemoradiotherapy resulted both in the increased median remission duration time, and the increased median survival time. Only in the alternate chemotherapy group, in 14/30 patients (46.7%) the pneumotoxicity symptoms appeared, whilst no differences in other organ-specific treatment-induced toxic effects were noted.

[Soft tissue sarcomas as a rare cause of pleural effusion]. / Miesaki tkanek miekkich jako rzadka przyczyna wysiekowego zapalenia oplucnej.

Malignant disease is the cause of about 24% of all pleural effusions. They are caused mainly by lung and breast cancer. Three cases of pleural effusion caused by very rare neoplasm, soft tissues sarcoma are presented. In two of them the lesion found in the leg was observed for 4-14 month and not connected with the presence of pleural effusion. Difficulties in the histologic diagnosis of pleural sarcoma and of differentiating this tumour from mesothelioma are also presented.