Cisplatin plus etoposide chemotherapy followed by thoracic irradiation and paclitaxel plus cisplatin consolidation therapy for patients with limited stage small cell lung carcinoma.

PURPOSE: To evaluate the efficacy and tolerance of a cisplatin plus etoposide regimen followed by thoracic radiotherapy (TRT) and paclitaxel plus cisplatin consolidation chemotherapy in patients with limited stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-nine patients with limited SCLC were enrolled onto this study. Patients received three courses of cisplatin 75 mg/m2 i.v., day 1 and etoposide 100 mg/m2 i.v., days 1-3 (EP regimen), followed by TRT (45-56 Gy administered in 15 fractions), and three courses of paclitaxel 175 mg/m2 i.v., day 1 and cisplatin, as previously, on day 2 (PP regimen); cycles were repeated every 21 days. RESULTS: All patients were evaluable for toxicity and 34 for response. The overall response rate was 67% (CR: 26%; PR: 41%; intention-to-treat analysis) (95% CI: 53.0-84.2%). After a median follow-up period of 15 months, the median survival time was 15 months, the median time to tumor progression 8.3 months and the 1-year survival rate 53.8%. Grade 3/4 neutropenia occurred in 39% and 36% of patients receiving EP and PP regimens, respectively. The incidence of febrile neutropenia was 5% and 3% for EP and PP regimens, respectively. Other hematologic and non-hematologic toxicities were mild, with the exception of esophagitis occurring in 36% of patients during and/or immediately after radiotherapy. CONCLUSION: Consolidation therapy with PP after sequential EP and thoracic radiotherapy is feasible and well-tolerated; however, the efficacy results are comparable with those previously obtained in the same patients' population using a combination of EP and TRT.

Alternate paclitaxel-gemcitabine and paclitaxel-vinorelbine biweekly administration in non-small cell lung cancer patients: a phase II study.

BACKGROUND: In the present study, 3 cytotoxic agents were combined as front-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. All 3 drugs have been used in other 2-agent combinations and have been shown to be effective as first-line therapy. PATIENTS AND METHODS: Sixty-one (53 male, 8 female, median age 65 years old) out of 67 patients were evaluable for response and toxicity. Eighty percent of the patients were stage IIIB and IV and 20% were inoperable stage IIIA. In order to obviate toxicity as much as possible, paclitaxel 135 mg/m2 was combined with gemcitabine 1000 mg/m2 for the first cycle, and 2 weeks later with vinorelbine 25 mg/m2, for the second cycle; this alternate schedule was repeated every 2 weeks for 9 cycles. RESULTS: No complete responses were observed; there was a 37.7% partial response rate and stable disease in 31.1% of the patients. The median survival was 13 months and 1-year survival, 53%. Myelotoxicity involved grade 3 neutropenia in 3.3% of the patients and grade 4 in 1.6%. CONCLUSION: Adverse reactions were few in this alternate administration of paclitaxel-gemcitabine and paclitaxel-vinorelbine in NSCLC patients; in more than half of the patients there was long median and 1-year survival.

Cisplatin-etoposide alternating with topotecan in patients with extensive stage small cell lung cancer (SCLC). A multicenter phase II study.

PURPOSE: In order to investigate the feasibility of a potentially non-cross resistant drug regimen, we alternated cycles of cisplatin-etoposide with topotecan as front-line treatment in patients with extensive stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-six previously untreated patients with extensive stage SCLC received cisplatin 75 mg/m(2) IV on day 1 and etoposide 100 mg/m(2) IV on days 1-3 on cycles one, three, five and seven and topotecan 1.5 mg/m(2) IV on days 1-5 on cycles two, four, six and eight. Cycles were repeated every 21 days. Patients' median age was 60 years and performance status (WHO) was 0 for 13, 1 for 20 and 2 for three patients. All patients were evaluable for response and toxicity. RESULTS: Five (14%) patients achieved a complete response and 18 (50%) a partial response for an overall response rate of 64% (95% confidence interval: 48.2-79.6%). After a median follow up of 10 months, the median duration of response was 5.5 months, the time to tumor progression 8 months and the probability of 1-year survival 48.9%. A total of 126 cycles of cisplatin-etoposide and 117 cycles of topotecan were administered with a median number of 4 cycles/patient for each regimen. There were no toxic deaths. Treatment delays due to toxicity occurred in 13 (10%) cycles after cisplatin-etoposide and 16 (14%) cycles after topotecan while doses were reduced in seven (6%) and five (4%) cycles, respectively. Grade 3-4 neutropenia, thrombocytopenia and febrile neutropenia complicated 13, 1 and 3% of cisplatin-etoposide cycles and 28, 6 and 1% of topotecan, respectively. Non-hematologic toxicity was mild. The delivered dose intensity was 96% for cisplatin and etoposide and 98% for topotecan. CONCLUSIONS: The alternating administration of cisplatin-etoposide and topotecan is a feasible, active and well-tolerated regimen in patients with extensive stage SCLC.

Comparison of docetaxel/cisplatin to docetaxel/gemcitabine as first-line treatment of advanced non-small cell lung cancer: early results of a randomized trial.

The study compares docetaxel plus cisplatin (DC) and docetaxel plus gemcitabine (DG) regimens for the treatment of advanced non-small cell lung cancer (NSCLC). Patients were randomized to receive either the DC or the DG combination. They were stratified according to age, performance status (PS) and stage of disease. Three hundred seventeen patients entered the study. Of them, 162 received the DC regimen and 155 the DG regimen. There were no differences in the patients' characteristics between the two study arms. Preliminary analysis included 132 evaluable patients in the DC arm and 114 in the DG arm. Three complete responses (CR) (2.3%) and 39 partial responses (PR) (30%) were documented in the DC arm (response rate (RR) 32.3%; 95% CI 23.87-39.76%), whereas 1 CR (0.9%) and 38 PR (33%) were documented in the DG arm (RR: 33.9%; 95% CI 25.5-42.92%). No differences in the RR, response duration, time to tumor progression, overall survival and 1-year survival were observed between the two groups. Regarding toxicity, there were no significant differences in grade 3-4 anaemia and thrombocytopenia between the two arms. However, grade 3-4 neutropenia occurred in 40 patients (33%) treated with the DC regimen and in 31 patients (22%) treated with the DG regimen (P=0.01). Twenty-four (16%) patients in the DC arm and 20 (14%) in the DG arm developed febrile neutropenia. There was one death due to sepsis in each arm. Non-haematological toxicity was mild and equal in the two arms, with the exception of grade 3-4 nausea and diarrhoea, which were more frequent in the DC arm. In conclusion, preliminary results showed that the DG regimen was as effective as the DC regimen. The toxicity profile of the DG combination was relatively milder. Hence, cisplatin cannot be considered longer as a mandatory component of chemotherapy against NSCLC.

Sequential administration of cisplatin-etoposide followed by topotecan in patients with extensive stage small cell lung cancer. A multicenter phase II study.

PURPOSE: To evaluate the activity of the sequential administration of cisplatin-etoposide (PE) followed by topotecan (TOP) in patients with extensive stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Previously untreated patients with extensive stage SCLC received 4 cycles of cisplatin 75 mg/m(2) IV on day 1 and etoposide 100 mg/m(2) IV on days 1-3 every 21 days followed by 4 cycles of TOP 1.5 mg/m(2) IV on days 1-5 every 21 days. RESULTS: Thirty-eight patients were entered in the study. Their median age was 63 years and the performance status (WHO) was 0 for 5, 1 for 25 and 2 for 8 patients. All patients were evaluable for toxicity and 32 for response to PE and 25 to TOP. Of the 38 patients receiving PE, 1 (3%) patient achieved complete response (CR) and 17 (45%) partial responses (PR) for an overall response rate to PE of 47% (95% confidence interval: 36.7-68.5%). Four (23.5%) of the 17 patients with PR after PE, achieved CR with TOP. None of the patients with stable or progressive disease after PE responded to TOP. The response rate of the 27 patients receiving TOP following PE was 15% (95% confidence interval: 1.4-28.2%). After a median follow up of 9 months, the median duration of response was 6.5 months, the time to tumor progression 6.5 months, the median survival 8.5 months and the 1-year survival 34%. A total of 136 cycles of PE and 89 cycles of TOP have been administered with a median of 4 cycles/patient for each regimen. There were 2 toxic deaths after PE associated with grade IV febrile neutropenia. Treatment delays due to toxicity occurred in 17 (12%) cycles of PE and 20 (22%) cycles of TOP while doses were reduced in 7 (5%) and 4 (4%) cycles, respectively. Grade 3-4 neutropenia, thrombocytopenia and febrile neutropenia occurred in 24, 2 and 3% of PE cycles and 21, 12 and 1% of TOP. Non-hematologic toxicity was mild. The delivered dose intensity was 100% for PE and 93% for TOP. CONCLUSIONS: The sequential administration of TOP after PE is associated with manageable toxicity and may increase the number of CRs in patients with chemosensitive extensive stage SCLC. However, based on this data and the lack of survival benefit in a previous phase III study, the sequential regimen should not be used outside of a clinical trial.

C-erbB-2 oncoprotein expression in operable non-small cell lung cancer.

Although c-erbB-2 oncoprotein immunohistochemical expression has been thoroughly studied in a variety of human tumors, its prognostic significance remains unclear. Moreover, differences in assessment criteria further complicate the evaluation of c-erbB-2 as a prognostic marker. In the present study we examined the expression of c-erbB-2 protein in 107 patients suffering from operable (T 1,2-N0, 1 staged) non-small cell lung cancer (30 adenocarcinomas and 69 squamous cell carcinomas) treated with surgery alone. A 3-7 year of follow up (median 45 months) was available for all patients. Paraffin embedded sections were stained with the NCL-CB11 monoclonal antibody using the immunoperoxidase technique. Analysis was based on cytoplasmic reactivity as membrane staining was impossible to assess against this background. Strong positive cytoplasmic staining was identified in 20/107 (19%) of cases, weak in 30/107 (20%) and negative in 57/107 (53%). Results were correlated with patient variables (age,sex) and tumor parameters (T,N-stage, grade, histology, Ki67 proliferation index, p53 and EGFR expression). C-erbB-2 expression was not related to any of these factors. Although c-erbB-2 defined a worse prognosis, univariate analysis of survival did not confirm any statistically significant difference between the c-erbB-2 staining groups (p=0.5). T,N-stage were the only statistically significant prognostic variables. Any contribution of c-erbB-2 to the development of tumour aggressive behaviour in non-small cell lung cancer requires assessment in the specific subgroups of patients.

Expression of EGF, TGF-alpha and EGFR in squamous cell lung carcinomas.

Immunohistochemical study of epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and transforming growth factor-alpha (TGF-alpha) expression was performed on paraffin-embedded tissue specimens of 70 squamous cell lung carcinomas. The carcinomas were placed to one of the following eight groups, according to the results of EGF, TGF-alpha and EGFR expression: group 1: none, group 2: only EGFR, group 3: EGFR and TGF-alpha, group 4: EGFR and EGF, group 5: TGF-alpha and EGF, group 6: all three, group 7: only TGF-alpha and finally group 8: only EGF. Statistical analysis of the results revealed that the ratio of squamous cell lung carcinomas with lymph node metastasis was significantly higher in groups 4, 5 and 6 (P less than 0.01). We also examined whether EGF receptors were truncated with the use of two monoclonal antibodies directed against different portions of the receptor (EGFR1 and F4). No truncated EGF receptors were detected. These results suggest that lung carcinomas expressing the molecules EGF/EGFR, TFG-alpha/EGFR or TGF/alpha/EGF/EGFR display pathologic features of more aggressive disease.

Molecular and immunohistochemical study of class I growth factor receptors in squamous cell lung carcinomas.

The class I growth factor receptor family includes epidermal growth factor receptor, i.e. c-erbB-1, c-erbB-2 and c-erbB-3 molecules. These receptors have a significant sequence homology and play an important role in cell growth and differentiation. To further investigate their implication in squamous cell lung carcinomas (SqCLCs), we studied the protein expression by immunohistochemistry and examined for possible gene amplification by a novel semi-quantitative differential polymerase chain reaction (DPCR) technique. Expression of c-erbB-1, c-erbB-2 and c-erbB-3 was present in 65%, 28% and 10% respectively, of 40 SqCLCs cases. Seven of the 11 cases that expressed c-erbB-2, as well as all 4 c-erbB-3 expressing cases, also stained with the anti-c-erbB-1 mAb. Expression of c-erbB-1, but not of c-erbB-2 or c-erbB-3, correlated with the grade of tumor differentiation (100%, 64% and 36% positive cases of well, moderately and poorly differentiated cases respectively, p < 0.003). In addition, c-erbB-1 expression correlated with the presence of regional lymph node metastases within the moderately differentiated group. The c-erbB-1 gene was amplified in 11/40 (28%) cases, all of which overexpressed c-erbB-1 protein, while c-erbB-2 gene amplification was detected in only one case. There was no c-erbB-3 gene amplification in any of the 40 SqCLCs cases. These findings suggest that c-erbB-1, c-erbB-2 and c-erbB-3 receptors do not have a common role and are of different physiological importance, at least at the stage of clinically overt tumor in human SqCLCs.

Outcome of patients with brain metastases after combined modality therapy in small cell lung cancer (SCLC): a retrospective study.

The authors evaluated the role of whole brain radiotherapy (WBRT) on the outcome of brain metastasis and survival in 41 patients with small cell lung cancer (SCLC) treated in their department. In addition to chemotherapy, radiotherapy was given to the primary site in all responder patients. Six patients presented brain metastasis initially and 10 patients after the fourth course of chemotherapy. Brain metastases were symptomatic in 12 of 16 patients with a median time of 5 months (1-14) until symptoms developed. All patients but 2 with brain metastasis received WBRT (30 Gy in 10 fractions) in addition to chemotherapy. The median survival time of patients with brain metastasis was 8.3 months (3.5 to 16) compared to 12 months (4 to 34+) for patients without brain metastasis. In addition, the median survival time for patients with brain metastasis who responded to systemic chemotherapy was better than that of nonresponders. The authors found no improvement in survival in patients who received concomitant WBRT after chemotherapy compared to patients who received WBRT after completion of chemotherapy. In conclusion, the role of consolidating cranial irradiation in addition to chemotherapy in SCLC patients is unclear and warrants prospective randomized studies.

Chemotherapy of non small cell lung cancer. A prospectively randomized study of cisplatin-etoposide versus cisplatin-mitomycin-vinblastine.

Based on preclinical studies showing synergism between cisplatin and etoposide, we randomized patients with non small cell lung cancer (NSCLC) to receive either the above combination (cisplatin 100 mg/m2 day 1, etoposide 130 mg/m2 days 1-3) or the combination of cisplatin-mitomycin-c and vinca drugs (MVP) (cisplatin 100 mg/m2, vinblastine 6 mg/m2, mitomycin 10 mg/m2 day 1), a regimen with a steady response rate. Partial responses were achieved in 12/44 (27%) of the cisplatin-etoposide group and in 11/43 (26%) of the MVR group. No difference in median survival could be demonstrated between the two groups (36 weeks versus 38 weeks). Myelotoxicity and alopecia were more severe in the cisplatin-etoposide group. Compared to international experience both regimens exhibited a relatively low response rate. It seems that for NSCLC new agents are required.

Second-line chemotherapy with cisplatin-ifosfamide in patients with ovarian cancer previously treated with carboplatin-cyclophosphamide.

In an effort to use antineoplastic drug combinations which are active in platinum resistant ovarian cancer or which can induce a second response after a platinum first-line treatment, we conducted a study on 30 ovarian cancer patients previously treated with carboplatin plus cyclophosphamide who were given ifosfamide 5 g/m2 i.v. divided over days 1 to 3 plus mesma combined with cisplatin 100 mg/m2 i.v. divided over days 1 to 3 every 4 weeks as second-line treatment. Eight patients had never entered remission with first-line chemotherapy while 22 patients had tumor recurrence within 6 to 18 months after the end of chemotherapy and their tumors were considered potentially platinum sensitive. Responding patients received 6 courses while palliative treatment for nonresponders was provided. Of the 22 patients with tumor recurrence, 8 patients responded with one partial response (PR) and 7 complete clinical responses (CCR). Two out of the 8 patients with platinum resistant disease demonstrated short lasting PR. Seven patients with CCR underwent second-look operation and in two a pathological CR was documented. Median time to progression was 6 mo (4-12). The median overall survival was 12 mo (4-20). Myelotoxicity despite G-CSF administration was significant with grade 4 leukopenia in 40% and grade 3 thrombocytopenia in 20% of patients. Central nervous system (CNS) toxicity was significant with 30% somnolence, 20% disorientation and an episode of grand-mal epilepsy ascribed to ifosfamide. With a 33% response rate the combination is as effective as new agents employed in relapsed ovarian cancer. Platinum-refractory disease may respond to a lesser degree. The most important determinant of response was the progression-free interval from first-line chemotherapy. Whether patients recurring after carboplatin plus cyclophosphamide have a greater chance to respond to cisplatin plus ifosfamide or vice-versa cannot be supported by the current data and therefore randomized studies should be performed to this end.

Optimal duration of chemotherapy in small cell lung cancer: a randomized study of 4 versus 6 cycles of cisplatin-etoposide.

With the purpose of investigating whether the 6-course standard dose treatment of etoposide-platinum (EP) in small cell lung cancer could be reduced to 4 courses without compromising patient's survival, 70 patients were randomized to receive either 4 or 6 cycles of etoposide 120 mg/m2 i.v. days 1-3 and cisplatin 80 mg/m2 day 1. With the intention of comparing these two durations as primary treatment policies, patients were randomized on admission and not after the fourth course. From the 69 evaluable patients 34 received EPx4 cycles and 35 EPx6 cycles. Objective response for EPx4 was achieved by 21 patients (62%, 95% CI 44%-78%) compared to 24 patients (69%, 95% CI 51%-83%) of the EPx6 group. Median times to progression were 6 mo (4-19) and 7 mo (4-40) respectively (P=0.06) in the two groups. Median survivals were 8.5 mo (4-28.5) and 9.5 mo (4-51) (p=0.04) respectively. No differences in the survival of limited-disease patients were shown with 10.5 mo (6-28.5) and 12 mo (8-51) respectively, in the two groups. Patients with extensive disease had a trend favoring prolonged chemotherapy with a median survival of 9 mo (5-16) versus 6.5 mo (4-16.5) for those in the EPx4 group (p=0.09). Toxicity was not significantly more severe in the EPx6 group. In conclusion, patients achieving complete response within 4 cycles may not need continued chemotherapy, but patients with extensive disease may benefit from 2 more cycles.

Treatment of lower respiratory tract infections with amoxycillin/clavulanic acid in adults.

Patients with lower respiratory tract infections [pneumonia (n = 16), bronchiectasis (n = 5) and acute exacerbations of chronic bronchitis (n = 44)] were treated daily with amoxycillin/clavulanic acid given either 1.2 g intravenously three times daily or 625 mg orally three times daily for 7-15 days. Symptoms, signs and sputum volume and colour were monitored daily. Chest X-ray, sputum culture and Gram-stain examinations were also carried out on days 1 and 5, and immediately after the end of the treatment. There was a clinical improvement, as indicated by the incidence of cough, dyspnoea and rales, and by sputum volume and colour in 90.8% of the patients. Microbiological improvement, as indicated by the complete elimination of sputum pathogens and pus cells, was achieved in the same proportion of patients (90.8%). In one patient, an adverse side-effect, diffuse exanthema, was noted. Amoxycillin/clavulanic acid possesses a high clinical and microbiological efficacy for lower respiratory tract infections.

A single-blind crossover study of two different slow release theophylline preparations.

In a single-blind crossover study, two slow release theophylline preparations were evaluated in 18 patients with chronic bronchitis or asthma without cardiac, renal or liver disease. After randomization into two groups, patients were treated, in a crossover study design, with 600 mg choline theophyllinate or 300 mg anhydrous theophylline administered orally every 12 h for 7 days. A 2-day washout period separated the two periods of treatment evaluation. Blood samples in which plasma theophylline concentration was to be measured were taken at 7.30 a.m., 2.00 p.m. and 7.30 p.m. during the last 5 days of therapy with each drug. The mean fluctuation in plasma theophylline concentration was less than or equal to 40% in all 18 patients taking choline theophyllinate yet in only 15 (83%) patients administered anhydrous theophylline. Salbutamol inhaler was more frequently required for the relief of bronchospasm when taking anhydrous theophylline than when taking choline theophyllinate (total of 41 vs 25 puffs, respectively, over 7 days). Drug-related adverse reactions occurred in four patients while taking anhydrous theophylline and in one patient while taking choline theophyllinate.

Partial effective times of the forced expiratory spirogram in health and mild airways obstruction.

The partial effective times of the expiratory spirogram were calculated in 80 normal non-smoking subjects aged from 20 to 69 years and in 30 patients aged from 30 to 58 years with chronic bronchitis. Of these patients, 28 had a normal FEV1/FVC ratio, while the other two had a low ratio. Partial effective times were calculated for 10% segments of the expired FVC from total lung capacity (0% FVC) to residual volume (100% FVC) and became progressively longer after 50% of the FVC had been expired in normal subjects. The elongation to the partial effective times was more pronounced with age. In the patients with simple chronic bronchitis (normal FEV1/FVC ratio) the partial effective times were longer than normal after 50% of the FVC had been expired and after 10% of the FVC had been expired in the two patients with chronic bronchitis and low FEV1/FVC ratio. The partial effective times of the forced expiratory spirogram, especially that at the 80--90% part of the FVC, seem to be very sensitive indices for the early detection of mild airways obstruction.

The smoking-cessation promotion practices of physician smokers in Greece.

In order to investigate Greek physicians' smoking habits and how these affect their role in promoting smoking cessation, a survey of 148 hospital physicians was undertaken. According to their answers, 44% of the internists and 54% of the surgeons admitted to smoking more than 20 cigarettes per day for at least five years. Major obstacles for quitting were their personalities (70-80%) and stress in hospitals (40%). For those willing to quit, an antismoking policy in their homes (32%) and hospitals (26-29%) could have been of a great help. With respect to smoking cessation, all (100%) of the non-smoking physicians were involved in smoking-cessation counseling or stressing the health hazards of smoking, compared with only 50% of the smoking group (p < 0.001). Moreover, the smokers tended to underestimate the risks of several smoking-related health hazards and did not emphasize them when counseling patients. Major obstacles to advising smoking cessation were lack of counseling time (53-70%) and pessimism regarding the outcomes of their efforts (60%), while 8% of the internists and 14% of the surgeons believed that counseling was not part of their role. The authors conclude that physician smokers need to be encouraged in their efforts to quit by their colleagues and by members of their families. Quitting smoking might help them to develop an optimistic view of success in their cancer-prevention practices.

Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial.

BACKGROUND: Docetaxel in combination with cisplatin or gemcitabine are active chemotherapy reigimes against non-small-cell lung cancer. We compared the efficacy and safety of a combination of cisplatin and docetaxel (group 1) with that of gemcitabine and docetaxel (group 2) in the treatment of advanced non-small-cell lung cancer in a prospective, randomised, multicentre trial. METHODS: Patients with stage IIIB or IV lung cancer who had not had prior chemotherapy were allocated either to group 1 and treated with docetaxel (100 mg/m(2), day 1) and cisplatin (80 mg/m(2), day 2) or to group 2 and treated with gemcitabine (1100 mg/m(2), days 1 and 8) and docetaxel (100 mg/m(2), day 8). All patients received recombinant human granulocyte colony-stimulating factor (150 mg/m(2)). All patients received recombinant human granulocyte colony-stimulating factor (150 mg/m(2)) had appropriate standard premedication. Response and toxicity were assessed using WHO criteria. Analysis was by intention to treat. FINDINGS: 441 patients were randomly assigned to receive docetaxel/cisplatin (group 1, n=219) or gemcitabine/docetaxel (group 2, n=222). 14 patients in group 1 and 21 patients in group 2 were not evaluable. Objective response rates were similar in the two groups: group 1, 32.4% (95% CI 26.2-38.6%; 1.4% complete response and 31% partial response); group 2, 30.2% (24.5-36.2%; 0.9% complete response and 29.3% partial response). The two groups did not differ in median duration of response, time to tumour progression, overall survival, or 1 year or 2 year survival rates. INTERPRETATION: Both drug combinations had comparable activity in patients with advanced cancer who had not previously had chemotherapy; however, gemcitabine and docetaxel had the most favourable toxicity profile.

Epidermal growth factor receptor expression in squamous cell lung carcinomas: an immunohistochemical and gene analysis in formalin-fixed, paraffin-embedded material.

Epidermal growth factor (EGF) and its receptor (EGFr) constitute an important and well-characterized mitogenic system in various ectodermal tissues. We evaluated the expression of EGFr and examined possible EGFr gene alterations in 18 formalin-fixed, paraffin-embedded squamous cell lung carcinomas (SCLC) by an immunohistochemical assay, Southern blotting and differential polymerase chain reaction (DPCR). The immunohistochemical study employing the F4 and EGF-R1 monoclonal antibodies, directed against the intra- and extra-cellular portion of the receptor respectively, showed EGFr over-expression in 89% of the SCLC cases examined. All cases showed positive immunostaining for both antibodies, thus excluding the possibility of truncated receptors. In addition, analysis of the EGFr gene was carried out by Southern blotting and DPCR on paraffin extracted DNA from the same carcinoma cases. We found amplification of the EGFr gene in 5/18 (27%) SCLCs. All 5 positive cases showed EGFr over-expression, suggesting a possible correlation between the presence of EGFr gene amplification and over-expression of receptor protein. No correlation was observed among EGFr staining, EGFr gene amplification and differentiation of carcinomas. In addition, Southern blot analysis with HER-A2, a probe which hybridizes a sequence of the receptor's intracellular domain, revealed three novel EcoRI restriction fragment patterns. We suggest that these patterns correspond to EcoRI polymorphic sites of the receptor's tyrosine kinase domain.

Alterations of the p16-pRb pathway and the chromosome locus 9p21-22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression.

The p16-pRb and p53-MDM2 pathways represent vital cell cycle checkpoints. Recent studies provide evidence that these pathways are directly linked via MDM2-pRb interaction and p53 suppression of the RB1 gene. In the present study we investigated the alterations of this G1 phase protein network using immunohistochemical and molecular methods in a series of 68 non-small-cell lung carcinomas (NSCLCs) and correlated the findings with clinicopathological features and prognosis of the patients. Aberrant expression (Ab) of p16 and pRb was observed in 33 (49%) and 27 (40%) of the carcinomas, respectively. Analysis of the region that encodes for p16 by deletion mapping, a polymerase chain reaction (PCR)-based methylation assay and PCR single-strand conformation polymorphism (SSCP) analysis revealed that deletions and transcriptional silencing by methylation might represent the main mechanisms of CDKN2/p16ink4a inactivation in NSCLCs. The results of deletion mapping also suggest that other tumor suppressor genes may reside at the 9p21-22 region, which encodes for CDKN2/MTS1/p16ink4a, p14ARF, and MTS2/p15ink4b. In addition, microsatellite instability was observed with a frequency of 16% in the 9p21-22 chromosome area. Overexpression (P) of p53 and MDM2 proteins was found in 39 (58%) and 47 (70%) of the cases, respectively. A highly significant association was observed between p53 overexpression and p53 mutations (P = 0.006). Statistical analysis of the expression patterns of the biologically relevant molecules (p16/pRb, p53/MDM2, MDM2/pRb, and p53/pRb) showed coincident overexpression of p53 and MDM2 (P = 0.04) and that abnormal pRb was correlated with elevated levels of MDM2 (P = 0.013) and p53 (P = 0.01), respectively. We suggest that deregulated expression of these molecules may act synergistically. An important finding of the study was that multiple impairments (three and four molecules affected) of the p16/pRb/p53/MDM2 network occurred in a large proportion (43%) of the carcinomas. This finding in addition to the absence of correlation with clinical stage of the tumors suggests that multiple hits of this network may be a relatively early event in the development of a subset of NSCLCs. The relationship between the factors examined in the present study, clinicopathological features, and survival of the patients did not reveal any significant correlations with the exception of smoking, which was associated with microsatellite alterations (loss of heterozygosity and microsatellite instability) at the 9p21-22 locus (P = 0.04) and the immunophenotypes p53(P)/MDM2(P) (P = 0.04) and p16(Ab)/pRb(Ab)/p53(P)/MDM2(P) (P = 0.03), respectively. We suggest that in a subset of NSCLCs, simultaneous deregulation of the members of this network may represent one way of initiating the oncogenic procedure whereas in other NSCLC subgroups alternative pathways may play this role.

A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer.

BACKGROUND: Previous phase I-II studies have shown that the combination of paclitaxel-cisplatin-etoposide (TEP) is very active and well tolerated in patients with small-cell lung cancer (SCLC). In order to compare the TEP combination to cisplatin etoposide (EP) regimen as front-line treatment in patients with SCLC, we conducted a randomised multicenter study. PATIENTS AND METHODS: One hundred thirty-three chemotherapy-naïve patients with histologically proven limited or extensive stage SCLC were randomised to receive either paclitaxel 175 mg/m2 i.v. three-hour infusion on day 1 and cisplatin 80 mg/m2 i.v. on day 2 and etoposide 80 mg/m2 i.v. on days 2-4 with G-CSF support (5 mcg/kg s.c. days 5-15) or cisplatin 80 mg/m2 i.v. on day 1 and etoposide 120 mg/m2 i.v. on days 1-3 in cycles every twenty-eight days. RESULTS: Due to excessive toxicity and mortality observed in the TEP arm, an early interim analysis was performed and the study was closed. Sixty-two patients received two hundred sixty-one cycles of TEP and seventy-one patients three hundred twenty-three cycles of EP The two patient groups were well balanced for age, sex, performance status, stage of disease and the presence of abnormal LDH at diagnosis. In an intention-to-treat overall analysis both regimens were equally active with a complete and partial response rate of 50% (95% confidence interval (CI): 37.5%-62.4%) for TEP and 48% (95%) CI: 36.2%-59.5%) for EP (P = 0.8). The median time to disease progression was 11 months for TEP and 9 months for EP (P = 0.02). The duration of response, one-year survival and overall survival were similar in the two arms. Similarly, in an intention-to-treat subgroup analysis of patients with limited or extensive stage disease, there was no difference in the activity between the two regimens except of a longer median time to disease progression in the extensive stage in favour of the TEP regimen, eight versus six months (P = 0.04). However, there were eight toxic deaths in the TEP arm versus none in the EP arm (P = 0.001). Moreover, the TEP regimen was associated with more severe toxicity than the EP regimen in terms of grade 4 neutropenia (P = 0.04), grade 3-4 thrombocytopenia (P = 0.02), febrile neutropenia (P = 0.08), grade 3-4 diarrhea (P = 0.01), grade 3-4 asthenia (P = 0.05) and grade 3 neurotoxicity (P = 0.06). CONCLUSIONS: In this early terminated study, the TEP regimen was significantly more toxic than the EP regimen. The TEP regimen is associated with significant toxicity and mortality, and should not be used outside of a protocol setting. For future investigations, dose and schedule modifications are necessary to reduce toxicity.