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NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.

Background: Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program., Patients and Methods: To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks., Results: Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild., Conclusion: Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.

Background: The cisplatin and gemcitabine (GC) regimen is usually administered as a 4- or 3-week schedule; however, the best schedule to use is still unclear. We therefore started a randomized phase II trial to compare toxicity and dose intensity (DI) between these two GC schedules., Patients and Methods: Ninety-six patients with non-small-cell lung cancer (NSCLC) and an additional 11 patients with an advanced epithelial neoplasm [bladder (n = 5), head and neck (n = 3), cervix (n = 1), esophageal (n = 1) or unknown primary carcinoma (n = 1)] were randomized to receive cisplatin 70 mg/m(2) intravenously on day 2 plus either gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle or gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21-day cycle. Planned DI (PDI) for the 4-week schedule was 750 mg/m(2)/week for gemcitabine and 17.5 mg/m(2)/week for cisplatin; for the 3-week regimen PDI was 666 mg/m(2)/week and 23 mg/m(2)/week for gemcitabine and cisplatin, respectively., Results: From July 1998 to March 2000, 107 patients were randomized. Grade 3/4 neutropenia was observed in 27.8% of patients in the 3-week versus 22.5% in the 4-week arm (P = 0.69), while grade 3/4 thrombocytopenia was higher in the 4-week arm (29.5% versus 5.5% of patients; P = 0.14). A total of 398 cycles of therapy were delivered. Overall, 51% of cycles were modified in dose, timing or both in the 4-week arm, and 19% in the 3-week arm. The 21-day schedule of GC leads to a similar received DI of gemcitabine and higher cisplatin DI. Both regimens had activity in NSCLC, with a response rate of 39% (38% for the 4-week arm, and 42% for the 3-week arm)., Conclusions: The 3-week schedule has similar DI to the 4-week schedule. However the 3-week regimen has a better compliance profile and a comparable response rate in NSCLC, supporting the use of such a schedule.

The bcl-2 proto-oncogene functions as a cell death suppressor, and its expression prolongs cell survival by blocking apoptosis. Data available on the clinical relevance of bcl-2 protein expression in patients with non-small-cell lung cancer (NSCLC) are controversial. We analysed the role of bcl-2 protein expression on 6-year relapse-free survival in 229 patients with stage I-IIIa NSCLC (101 squamous cell carcinomas and 128 adenocarcinomas) subjected to surgery, with curative intent. Immunohistochemical analysis was performed on archival material by using a monoclonal antibody anti-bcl-2 (clone 124). Bcl-2 protein expression, which was detected in 22% of the cases, was significantly related to stage, histology and grading, and was an indicator of clinical outcome. The probability of relapse-free survival at 6 years was longer for patients with bcl-2-positive tumours (74%) than for those with bcl-2-negative tumours (57%) (P=0.02). This finding was mainly evident for the subgroups of patients with stage IIIa tumours (P=0.05), squamous cell carcinoma (P=0.03) or moderately/poorly differentiated tumours (P=0.02). However, multivariate analysis by Weibull's regression model indicated that bcl-2 protein expression was not an independent prognostic risk factor in patients with curable NSCLC when the information provided by stage was available.

The identification of biomarkers to complement pathological stage for a more accurate prognosis and help clinicians decide on treatment is still an open problem for patients with lung cancer. Expression of P53 protein was detected by an immunohistochemical approach using the monoclonal antibody PAb1801 on paraffin-embedded sections of tumours obtained surgically from 102 stage II - IIIa patients with non-small-cell lung cancer (52 squamous cell carcinomas, 50 adenocarcinomas). [3H]Thymidine labelling index, an indicator of the S-phase cell fraction, was evaluated on histological sections of [3H]thymidine-labelled tumour samples. DNA ploidy was defined by flow cytometric analysis on frozen tumour tissue. The biomarkers, histology and pathological stage were analysed in relation to relapse-free survival in univariate and multivariate analyses. Stage and interaction between [3H]thymidine labelling index and histology provided significant prognostic information for the overall series. [3H]thymidine labelling index was an independent prognostic indicator of 3 year relapse-free survival in patients with adenocarcinoma. The results indicate the importance of cell proliferation to complement prognostic information provided by pathological stage in patients with stage II-IIIa adenocarcinomas.

Background: One regimen consisting of a continuous infusion of cisplatin and fluorouracil was designed to be minimally toxic, and suitable for application with radiotherapy in non-small-cell lung carcinoma (NSCLC)., Patients and Methods: Forty-four NSCLC patients received daily 8 mg/m2 of cisplatin on days 1-2, 8-9, 15-16, 22-23, and 300 mg/m2 of fluorouracil on days 3-7, 10-14, 17-21, 24-28 (35-day courses)., Results: Two patients experienced grade 3-4 toxicities. Eleven achieved objective responses. The median progression-free and observed survival was 22 and 39.5 weeks., Conclusions: The schedule management was fully ambulatory. Toxicity was negligible. The activity was moderate, but the combination with radiotherapy is advisable due to the radioenhancing properties of both of the drugs.

Purpose: To evaluate the therapeutic effectiveness of a combined chemoradiotherapy program, followed by surgery in selected cases, in Stage III non-small cell lung cancer., Methods and Materials: Between August 1988 and February 1990, 43 patients Staged IIIa-b (UICC 1987, 58% IIIb) have been treated with concomitant chemotherapy (cisplatin 15 mg/m2 and VP16 75 mg/m2, 5 days a week on week 1 and 5) and radiotherapy (40 Gy split course, 2 Gy/day on week 1, 2, 5, and 6), followed by attempted curative thoracotomy or more cycles of full dose chemotherapy with the same two drugs., Results: Planned chemoradiotherapy has been given to 91% of patients; 13/43 patients have been operated, with 12 complete resections and three (7%) pathological complete responses. Toxicity was significant, with two postoperative deaths and two fatal radiation pneumonitis. Crude progression-free survival rate is 21% at 30 months, with nine patients (21%) alive and free from progression at follow-up times ranging from 31 to 49 months. Subset survival analysis showed a possibly greater therapeutic effect for non-squamous histology as compared to squamous carcinoma., Conclusion: These results are encouraging in a cohort of patients with quite advanced disease (58% Stage IIIb).

Thirty-eight patients with non-resectable non-small-cell Stage IIIa-b lung cancer were treated in a Phase II study with radiotherapy (50 Gy in a 25-fraction split-course) plus con-current continuous infusion of cisplatin given at a daily dose of 6 mg/m2, with the aim of investigating its radiopotentiation properties. Treatments were given on an outpatient basis by means of a central venous catheter and a portable pump. Adjuvant surgery was undertaken when feasible. Toxicity was mild to moderate. The probability of a partial or complete locoregional response at 4 weeks after treatment completion was 83% (confidence limits at 95%: 13). Eighteen patients were resected. Overall 1-, 2- and 3-year progression-free survival probabilities were 42, 24 and 21%. These figures were 63, 37 and 24% in observed survival curves. Patients with squamous-cell tumors had observed survival rates of 82, 50 and 28% at 1, 2 and 3 years, compared to 42, 19 and 19% in patients with non-squamous histology. The high response and survival rates obtained at a low price according to toxicity require further investigation.

The laboratory findings in patients receiving high-dose vitamin A as adjuvant treatment for stage I lung cancer are here reported. A group of 283 patients were randomized to either treatment with retinyl palmitate (300,000 IU daily for 12 months) or standard follow-up, and are now evaluable after a median observation period of 28 months. At regular intervals, all the patients underwent a physical examination, chest roentgenogram, blood chemistries, haematological assays, hepatic and renal function tests and determinations of serum triglycerides and cholesterol. Serum transaminase abnormalities were of similar magnitude in cases and controls, while gamma-glutamyltransferase levels were abnormally elevated in 69% of the treated patients compared to 39% of controls (mean values 149 vs 57 IU/l at 24 months, P less than 0.05). Serum triglyceride concentrations over 150 mg/dl were seen in 74% of treated patients compared to 43% of controls at 12 months, the average concentration was 283 mg/dl compared to 179 mg/dl (P less than 0.05). Cholesterol levels showed a modest, non-significant rise with time in both groups, and there was no other laboratory evidence of toxicity attributable to vitamin A. Serum retinol and retinol-binding protein, assessed on a limited sample of patients, were higher in the treatment arm (P less than 0.05) at 12 months. In our experience 300,000 IU/day of retinyl palmitate can be administered as a possible chemopreventive agent with reasonable safety for up to 2 years.

This paper reports our results with sublobar resections for stage I non small cell lung cancer. Sixty-one cases of wedge or segmental resection were compared with 517 standard resections (411 lobectomies and 106 pneumonectomies), performed during the years 1971-88. Operative mortality was 0% in the limited resection group and 4% (19/517) in the standard resection group; cancer recurrence was detected in 36% of both groups; actuarial survival at 5 years was 55% versus 48% overall. In 28 patients with pre-existing cardiac or pulmonary co-morbidity, limited resection yielded a similar 5-year survival than standard resection (53% vs 49%) with no perioperative deaths (0 vs 6%). Our data support the experience of other authors on conservative management of stage I lung cancer. Particularly in patients with concomitant cardio-pulmonary disease, previous cancer or small peripheral tumors, limited resection combined with adequate nodal staging may be as effective as standard lobar resection with respect to long term survival.

On the basis of epidemiologic and experimental evidence of an anticancer activity of vitamin A, a randomized clinical trial was activated in Milan with the aim of evaluating if retinol palmitate administration (per os, 300,000 I.U. daily) after complete resection of stage Ia non small-cell lung cancer could reduce the occurrence of cancer relapses (within 3 years) and/or the occurrence of new primary tumors (beyond 3 years). By September 1987, 181 patients had entered the trial: 87 in the treatment arm and 94 in the control arm. After a median follow-up of 14 months, the interim analysis was focused on the evaluation of toxicity, compliance, and early recurrences. Although the large majority of patients were affected by skin and mucous membrane desquamation and dryness during treatment, these symptoms were generally mild and well tolerated, and never induced the patient to stop the treatment. Other side effects like headache, hair loss, itching, or dyspepsia were detected at a much lower frequency. Only in 3 patients the treatment was interrupted, because of signs or symptoms potentially related to vitamin A administration. At the time of the analysis, a total of 42 (23%) patients had relapsed; 16 (18%) in the treated arm, and 26 (28%) in the control arm. The largest difference between treated patients and controls was observed for bone metastases (2 vs. 7) and brain metastases (3 vs. 6), and for squamous histology (6 vs. 11). Only 2 cases of new primary cancer were detected, both in the control arm. These results are promising both in terms of tolerance and efficacy of treatment, but given the short median follow-up they must be very cautiously interpreted. A longer follow-up is necessary to establish whether a significant proportion of early recurrences could be prevented, or only delayed, by vitamin A administration.

Based on the experience of blood-related immunosuppression in kidney transplants, some retrospective studies have reported an adverse relationship between blood transfusion and survival after curative resection for cancer. In order to confirm these findings, we have retrospectively evaluated our population of resected stage Ia non-small cell lung cancers (years 1974-79). Two hundred and eighty-three patients were included in this analysis: 65 underwent pneumonectomy (23%), 205 lobectomy (72%) and 13 sublobar resections (5%). Patients submitted to perioperative blood transfusions were 157 (55%), without major differences according to surgery or tumour extent. The cumulative survival at 8 yr was 40% for transfused patients and 41% for nontransfused, relapse-free survival was respectively 36% and 34%; no differences were detectable stratifying for the amount of blood transfused or the extent of operation. Our experience does not support the hypothesis of an adverse prognosis related to perioperative blood transfusion.

From January 1971 to June 1983, 35 lobectomies with bronchoplastic procedures for invasive non-small-cell lung carcinoma were performed. Sleeve lobectomy was carried out in 21 cases, wedge lobectomy in 11, and upper sleeve bilobectomy in 3. There were 23 stage I, 10 stage II, and 2 stage IIIa tumors. Completion pneumonectomy was required in 1 case for anastomotic fistula and in 2 for atelectasis of residual lung. One of these patients died later due to empyema. The 5-year probability of death with recurrence was 31.98%. The 5-year disease-free survival was 58.57%. Metastatic relapse was observed in 8 cases and loco-regional recurrence in 5. A new primary lung tumor occurred in 2 patients.