Search

Background: This phase II study was designed to assess the activity and toxicity of administration of the cisplatin/paclitaxel combination in advanced non-small cell lung cancer (NSCLC)., Methods: Eligibility criteria included: age up to 70 years, pathological diagnosis of NSCLC, inoperable disease or post-operative tumour recurrence, performance status < or =2, no severe co-morbidity, no previous chemotherapy, and informed consent. Treatment consisted of intravenous infusion of cisplatin, 25 mg/m2, and paclitaxel, 80 mg/m2, every week. Chemotherapy was continued until completion of a 22-week treatment plan, disease progression, persistent toxicity, or patient refusal., Results: Forty-nine patients entered the study. They received a median of 14 cycles (range 0-22). For both drugs, the median dose-intensity was 75% of projected. Toxicity was generally acceptable, and never life threatening. Alopecia was the most common side effect, followed by anemia, leukopenia, and nausea/vomiting. Twenty patients responded (40.8% response rate), with three complete, pathologically documented responses. The estimated median time to progression was 35 weeks (95% CI: 29-41); the median survival time was 56 weeks (95% CI: not calculable), with a 2-year survival rate of 46.1%., Conclusions: When given on a weekly basis, the cisplatin/paclitaxel combination is well tolerated, active, and associated to remarkably long survivals.

Background: A phase II study of a cisplatin/paclitaxel combination given on a weekly schedule in the front-line treatment of non-small cell lung cancer (NSCLC) is reported., Patients and Methods: Treatment consisted of an intravenous infusion of cisplatin, 25 mg/m2, and paclitaxel, 80 mg/m2, every week. Chemotherapy was continued until completion of a 22-week treatment plan, disease progression, persistent toxicity, or patient refusal., Results: Seventy-nine patients entered the study. The median number of infusions per patient was 14 (range 0-22). The median dose-intensity was 75% of that projected. Toxicity was generally acceptable, and never life-threatening. Seven complete responses (pathologically documented in 4 patients) and 27partial responses were observed for an overall response rate of 43%. The estimated median survival and median time to progression was 55 (95% CI: 38-71) and 37 weeks (95% CI: 31-44), respectively., Conclusion: In our experience, the weekly combination of cisplatin and paclitaxel is well tolerated, active and associated with remarkably long survivals.

Background: This study was designed to confirm the activity of the cisplatin/vinorelbine (C/V) combination in non-small cell lung carcinoma (NSCLC)., Patients and Methods: Treatment consisted of vinorelbine, i.v. slow infusion of 30 mg/m2 every week, and cisplatin, 120 mg/m2 on days 1 and 29 and then every 6 weeks. Treatment was continued until completion of the 22-week treatment plan, disease progression, persistent toxicity, or patient refusal., Results: Seventy-five patients entered the study. The median age was 62 years; major cell types were adeno- (38), squamous (26) and large cell carcinomas (7). Nineteen patients received a suboptimal treatment with less than 6 courses of vinorelbine. The median courses of C/V were 3 (range 0-4) and 15 (range 0-22), respectively. For both drugs, the median dose-intensity was 75% of projected. Toxicity was generally acceptable, mainly hematological and never life-threatening. Thirty-five patients responded, with 8 complete responses, for an overall response rate of 46.7%. The estimated median time to progression was 28 weeks (quartile range: 13-46); the median survival 60 weeks (quartile rage: 17-108)., Conclusion: The C/V combination is fairly well tolerated, decidedly active and associated with prolonged survivals.

Chemotherapy (CT) for elderly patients is becoming a standard, since the first demonstration by Gridelli and co-workers that chemotherapy (in their case Vinorelbine (VNB), single agent) is capable to produce significant survival benefits. Much less is known concerning the use of CT for unfit patients. The purpose of this phase II trial was to perform a comprehensive evaluation of activity, toxicity, and tolerability of single-agent Gemcitabine (GEM) (Gemzar) as a first-line chemotherapy for unfit patients with inoperable or recurrent non-small cell lung cancer. Patients were eligible if they had a pathological diagnosis and no previous chemotherapy; they should be younger than 76, with a performance status (ECOG-PS) equal to three; informed consent was also required. Gemcitabine was given by intravenous infusion at a weekly dose of 1250 mg/m2, 3 weeks per month, every 28 days. Treatment was given until progression, persistent toxicity, or refusal. Forty-five patients (39 males) entered the study; median age was 73 years (range 45-75); cell types were: adenocarcinoma (21), squamous (18), large cell (6). Previous surgical treatments included three lobectomies and one pneumectomy. Because of rapid clinical deterioration or consent withdrawal, six patients, registered for study, never started their treatment; other six had early chemotherapy suspension. These patients were included in the analysis, on an "intent-to-treatment" basis. The median number of chemotherapy cycles was nine (range 0-15); median dose-intensity was 75% of projected. Toxicity was mild, mainly hematological and never life threatening (only 1 grade 4 toxicity out of 325 pre-chemotherapy evaluations). Four patients obtained a partial response (9%, C.I. 1-17%) and other six patients had some tumor regression (13%, C.I. 3-23%). The estimated median time to progression was 17 weeks (quartile range: 9-24), with a median survival of 35 weeks (quartile rage: 20-51). We have found that single-agent gemcitabine represent a sufficiently safe therapeutic option in unfit patients with inoperable non-small cell carcinoma (NSCLC).

Unlabelled: This phase II study was designed to assess single-agent paclitaxel (Taxol), as second-line chemotherapy., Eligibility Criteria: pathological diagnosis of inoperable non-small cell lung cancer (NSCLC) relapsing or refractory to standard front-line platinum (P)-based chemotherapy, performance status < or = 3, normal lab tests, informed consent. Ineligibility criteria: history of second or third cancer (unless surgically cured), mental instability or impairment, pre-existing moderate/severe peripheral neuropathy, previous chemotherapy non-including cisplatin, and previous second-line chemotherapy. Paclitaxel was given by intravenous infusion at a dose of 100 mg/m2 every week, until completion of the treatment plan of 21 weeks, disease progression, persistent toxicity, or patient refusal. Thirty-eight patients (32 males) entered the study; median age was 63 years (range 44-74); cell types were: adenocarcinoma (20), squamous (14), large cell (4). Previous chemotherapies: P and vinorelbine (31 patients) and P, mitomycin C and vinblastine (7 subjects), followed by 21 objective responses. Two patients had one course of paclitaxel; six other patients had early treatment suspensions. The median number of weekly infusions was 12 (range 1-21); median dose-intensity was 75% of projected. Toxicity was generally mild, mainly neurological and never life threatening (only 2 grade 4 toxicity out of 468 pre-chemotherapy evaluations). Six patients obtained a partial response; 7 others showed some tumor regression, 3 had tumor stabilization, and 13 disease progression. From the start of paclitaxel, the estimated median time to progression was 20 weeks, the median survival 58 weeks. Second-line treatment with single-agent paclitaxel is well-tolerated, active, and associated to long survivals.

The purpose of this study was to determine the prognostic significance of a high pretreatment serum CYFRA 21-1 level (a cytokeratin 19 fragment) adjusted for the effects of well-known co-variables in non-small-cell lung cancer (NSCLC). This meta-analysis based on individual updated data gathered comprehensive databases from published or unpublished controlled studies dealing with the prognostic effect of serum CYFRA 21-1 level at presentation in NSCLC of any stage (nine institutions, 2063 patients). Multivariate regression was carried out with the Cox model. The proportional hazard assumption for each of the selected variables retained in the final model was originally checked by log minus log plots baseline hazard ratio. The follow-up ranged from 25 to 78 months. A total of 1616 events were recorded. In the multivariate analysis performed at the 1-year end point, a high pretreatment CYFRA 21-1 level was an unfavourable prognostic determinant in all centres except one (Hazard ratio (95% confidence interval): 1.88 (1.64-2.15), P<10(-4)). Other significant variables were stage of the disease, age and performance status. Within the first 18 months, the procedure disclosed a nearly similar hazard ratio for patients having a high pretreatment serum CYFRA 21-1 level (1.62 (1.42-1.86), P<10(-4)). For patients who did not undergo surgery, the hazard ratio during the first year of follow-up was 1.78 (1.54-2.07), P<10(-4). Finally, in the surgically treated population, at the 2-year end point, a high pretreatment CYFRA 21-1 and a locally advanced stage remained unfavourable prognostic determinants. In conclusion CYFRA 21-1 might be regarded as a putative co-variable in analysing NSCLC outcome inasmuch as a high serum level is a significant determinant of poor prognosis whatever the planned treatment.

Background: Neuron-specific enolase (NSE) is a well known marker of small cell lung cancer. The present study was designed to assess the clinical value of NSE in non-small cell lung cancer (NSCLC), as compared to that of carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA)., Methods: The study comprised 448 new consecutive NSCLC patients seen from 1996 to 2001. A set of 30 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed-up, and their subsequent clinical course recorded., Results: Increased values of NSE were present in 32% of the patients. Bivariate analyses showed that NSE, TPA and CEA were significantly correlated with each other, lactate dehydrogenase, tumour diameter, and disease extent. Univariate analyses showed that patients with elevated concentration of both NSE and TPA had significantly shorter survivals than patients with low values (30 [95% CI: 25-35] vs. 61 weeks [46-76], and 30 [CI: 24-36] vs. 59 weeks [40-79], respectively, P=0.0000). The Cox proportional hazards model including all the 22 variables significant in univariate analysis selected, in decreasing order of significance, the following variables: (1) N factor; (2) main treatment; (3) ECOG PS; (4) CNS metastasis; (5) age; (6) tumour cavitation; (7) NSE; (8) T factor; and (9) adrenal gland metastasis., Conclusions: This data indicates that serum assay of NSE is a useful marker also in NSCLC and a significant predictor of survival, independently of the other prognostic factors.

Study Objectives: We have longstanding experience with tissue polypeptide antigen (TPA), a tumor marker of the cytokeratin (CK) family. In the mid-1990s, a new CK marker, CK 19 fragments (CYFRA 21-1), became popular and widely accepted. This is the first study specifically designed to compare the two markers., Design: Analysis of a single institution database over a 3-year period (ie, 1998 to 2000)., Setting: Community-based hospital and second referral level institution for a province of 500,000 people., Patients: The study included 180 new consecutive patients (143 men) with pathologically documented non-small cell lung cancer (NSCLC), who were observed during and after treatment, and eventually were assessed for status., Interventions: Anthropometric, clinical, and laboratory data, including TPA and CYFRA 21-1 serum levels, were recorded prospectively. Standard nonparametric tests, Kaplan-Meyer survival analyses, Cox proportional hazards models, receiver-operating characteristic (ROC) curves, and estimates were used for statistical analysis., Measurements and Results: A total of 1,299 twin TPA and CYFRA 21-1 serum assays (180 performed at diagnosis and 1,119 performed during or after treatment) were obtained. Intermarker correlation tests revealed incredibly high Spearman rho indexes, ranging from 0.935 at diagnosis to 0.813 to 0.921 at the different follow-up times. The substantial equivalence of the two tests explained all the other results, as follows: their similar profile of correlation with the other variables (objective treatment response: TPA rho, 0.456; CYFRA 21-1 rho, 0.463; follow-up performance status: rho range, 0.424 to 0.435); their superimposable capability to predict important clinical situations (eg, recognizing a metastatic disease at diagnosis with areas under the ROC curve of 0.742 and 0.706, respectively); their nearly identical prognostic significance (the D statistic of the goodness-of-fit of a multivariate survival model: TPA, 851.0; CYFRA 21-1, 851.6)., Conclusions: In most of their traditional clinical applications the two serum tests are equivalent because of their virtual identity. We strongly recommend using a CK test in the evaluation of each NSCLC patient. The choice between TPA and CYFRA 21-1 can be based on nonclinical factors, such as the laboratory experience or preference, and the cost of the two kits.

Background: In the current study, we report the carcinoembryonic antigen (CEA) capability to predict early tumor relapses after a pulmonary resection for nonsmall cell lung cancer (NSCLC)., Methods: We studied 118 consecutive NSCLC patients who were clinically judged operable and were eventually operated upon. Anthropometric, clinical, and CEA data along with the results of both preoperative and postoperative stage classifications were recorded. All patients were followed up for at least 1 year after surgery and the time to the first clinical recurrence recorded. Receiver-operating characteristic (ROC) curves and diagnostic formulas were used for data analysis., Results: In this series the CEA test was among the most accurate methods to predict an early postoperative recurrence (ROC area: 0.72, 95% confidence interval [CI]: 0.60 to 0.85, p = 0.001; accuracy rate for CEA at the threshold of 10 ng/mL: 83%, CI: 76% to 90%). Also predictive was the postoperative pathologic stage of disease (ROC area: 0.68, CI: 0.56 to 0.80, p = 0.007). In tumors pathologically classified in stage Ia to IIb, a preoperative CEA level higher than 10 ng/mL was associated with a 67% probability of tumor relapse. In the same stages of disease, a CEA level less than 10 ng/mL increased the baseline probability of no recurrence from 80% to 88%., Conclusions: In operable patients with NSCLC the frequency of abnormal serum concentrations of CEA is low (17% in our series). However, it is important to identify such a small group of high-risk patients as many of them (in our study, 55% and 70% of those with a CEA value in excess of, respectively, 5 and 10 ng/mL) will develop an early postoperative recurrence. Such patients should be investigated preoperatively by mediastinoscopy or positron emission tomography in even in the absence of suspicious symptoms and signs. Then after an apparently successful operation, they should be carefully followed up. These patients could represent a suitable target for neoadjuvant clinical trials of selected high-risk groups.

In both clinical practice and scientific reporting, various definitions of weight loss (WL) are currently in use. A comparison of their efficiency would be appropriate. In this report, we describe the first clinical evaluation of different WL definitions. New consecutive non-small-cell lung cancer (NSCLC) patients (388) were prospectively studied at the Pulmonary Unit of 'S. Croce and Carle' Hospitals from 1995 to 1999. Multiple anthropometric, clinical and pathological data, along with eight WL-related variables, were analysed. Patients' length of survival was estimated using the Kaplan-Meier function and the Cox's multivariate regression. In univariate analysis, all WL variables were prognostically significant. Among them, total WL (i.e. the percent difference between the weight at diagnosis and the last weight recorded while in good health, dichotomised by the threshold level of 11%) was the most significant factor (Log-rank: 29.65, P=0.0000). The best Cox's model for survival prediction, constructed using all the available clinical information, included, in order of importance, the following three factors: stage of disease classification, performance status and total WL. Contrary to what one might expect, WL speedy was less predictive than WL quantity. Evidence from this study suggests that, while the loss of body weight is confirmed a significant prognostic factor in NSCLC, the value of this factor is partially dependent on its definition.

Objectives: Copious literature shows that in lung cancer many serum markers, especially the cytokeratin degradation products, correlate with the extent of disease. In 1995, we suggested the possibility of predicting the resectability of non-small cell lung cancer by measuring the plasma level of the tissue polypeptide antigen, a marker of the cytokeratin family. This study was designed (1) to confirm the earlier data in a new prospective evaluation, (2) to comparatively assess another classic biomarker (ie, the carcinoembryonic antigen), and (3) to incorporate their results into the preoperative evaluation of non-small cell lung cancer., Methods: We analyzed the database of a single institution over a 5-year period (1994-1998) in a community-based hospital and second referral level institution for a province of 500,000 people. The database included 124 consecutive patients (105 men) with pathologically documented lung cancer (50% with adenocarcinoma) accurately staged, clinically judged operable or potentially operable, and eventually operated on. Anthropometric, clinical, and laboratory data (including the carcinoembryonic antigen and tissue polypeptide antigen serum levels) and the results of a complex staging workup were prospectively recorded. Receiver-operating characteristic curves and diagnostic formulas were used for data analysis., Results: Computed tomography of the thorax, upper part of the abdomen, and brain was the most accurate preoperative method to assess tumor resectability (receiver-operating characteristic area: 0.76, 95% confidence intervals: 0.67-0.86, P =.000; accuracy rate: 77%, confidence intervals: 69%-84%). Tissue polypeptide antigen was also predictive for tumor resectability (receiver-operating characteristic area: 0.62, 95% confidence intervals: 0.51-0.73, P =.035; accuracy rate at a threshold level of 110 U/L: 65%, 95% confidence intervals: 56%-73%). Carcinoembryonic antigen was diagnostic only at the extreme values of its distribution (accuracy rate at a level up to 10 ng/mL: 69%, 95% confidence intervals: 60%-77%). The probability of finding resectable disease at the time of the operation increased from 78% (baseline computed tomography-based probability) to 83% when the concentration of tissue polypeptide antigen was lower than 90 U/L and to 85% when the concentration of carcinoembryonic antigen was below 10 ng/mL. The probability of discovering an advanced disease increased from 68% (baseline computed tomography-based probability) to 89% when tissue polypeptide antigen levels were abnormal and to 100% when carcinoembryonic antigen concentrations were higher than 10 ng/mL. Conversely, the predictability of computed tomography was diminished by contrasting biomarker results, requiring further clinical investigations., Conclusions: Computed tomography remains the gold standard for the preoperative evaluation of non-small cell lung cancer, although it may significantly underestimate the real tumor extension. The addition of the easy and inexpensive tissue polypeptide antigen test (with or without carcinoembryonic antigen) is capable of correcting this underestimation and helps to decide whether to completely rely on computed tomography or order additional clinical investigations.

There is evidence that malnutrition is an important cause of morbidity and mortality in lung cancer patients and may have an impact on the clinical course of disease. The simplest way to assess nutritional status at the patient's bedside remains recourse to anthropometric measurements. This study was carried out in order to assess the clinical and prognostic significance of triceps skinfold thickness (TST), arm circumference (AC), and wrist circumference (WC) in lung cancer. The patient population was a consecutive series of 388 patients seen for a newly diagnosed primary non-small-cell lung cancer during the last 4 years. A set of 22 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed up, and their subsequent clinical course was recorded. The median values of TST, WC and AC were 8 mm (range 2-25 mm), 18 cm (range 10-27 cm), and 25 cm (range 15-35 cm), respectively. In 107 patients (27.6% of the total) TST values were below the reference value, and 37 of these patients also had a pathologically low small circumference. In all, AC was below the normality range in 60 of the 388 subjects (15.5%). Among the three variables, the strongest relationships were those between AC and WC (r(s)=0.541), and between TST and AC (r(s)=0.521). Univariate analyses of survival showed that TST was strongly predictive of a better prognosis (P<0.001), while WC was unrelated to outcome (P=0.101). Patients with higher values of AC had significantly longer survival than patients with lower values (P<0.018). The multivariate model, in contrast, did not confirm the prognostic capability of any of the anthropometric measures. These data indicate that the anthropometric measures may be significant predictors of survival, although not independently of the other prognostic factors.

After a certain degree of nihilism, chemotherapy has become the standard treatment for advanced and metastatic non-small cell lung cancer (NSCLC). The new chemotherapeutic drugs (vinorelbine, taxanes, gemcitabine, and irinotecan) and their associations with cisplatin have shown better response rates and survival in comparison with the standard regimens. This increase of survival is the main motive of the possible consideration of a second-line therapy in NSCLC patients. To this regard, the most promising drug may be docetaxel that, in a randomized trial comprising a best supportive care arm (BSC), documented a response rate of 7.6%, a longer median survival (31 weeks versus 21 of BSC), and a statistically better quality life. Other phase II studies obtained a response rate of 20% and 1-year survival of 40% using docetaxel. Also gemcitabine has shown interesting results in this setting, with a 19% response rate and a median and 1-year survival rate of 34 weeks and 45%, respectively. The activity of paclitaxel is not well defined because of conflicting results and deserves further investigations, while the efficacy of vinorelbine and irinotecan has been dismal. Large randomized trials comparing the treatment arm with best supportive care and a careful analysis of quality of life and cost-effectiveness will be needed to clarify the role of second-line therapy in advanced NSCLC.

Background: Cancer in the elderly is becoming a complex and frequent issue. At least 30% of lung carcinomas are expected to arise each year in elderly patients, who often have significant comorbidity. The most appropriate treatment for this large portion of cancer patients remains unknown. The purpose of this Phase II trial was to make a comprehensive evaluation of the activity, toxicity, and tolerability of single-agent vinorelbine in elderly and relatively poorly performing patients with inoperable nonsmall cell lung carcinoma (NSCLC)., Methods: Patients age 70 years or older were eligible to participate in this trial if they had a pathologic diagnosis, a performance status lower than 4 (Eastern Cooperative Oncology Group [ECOG] scale), and gave informed consent. Vinorelbine was given intravenously (i.v.) at a dose of 25 mg/m(2) every week until progression, persistent toxicity, or refusal., Results: Forty-six patients entered the study; their median age was 75 years (range, 70-83 years). Five patients never started on vinorelbine; 27 others had early treatment suspensions. The median number of weekly infusions was 5 (range, 0-28); the median dose intensity was 70% of projected. Toxicity was generally mild, mainly hematologic, and never life-threatening. ECOG performance status, body weight, and almost all the scores from the quality-of-life questionnaires remained constant during the first 6 weeks of treatment. Two patients obtained partial response, 10 patients had some tumor regression, and 26 had tumor stabilization. The estimated median time to progression was 19 weeks (quartile range, 11-23 weeks), and the median survival 34 weeks (quartile range, 16-63 weeks)., Conclusions: In our group of patients who had poor prognoses, vinorelbine was well tolerated, moderately active, and capable of ensuring relatively long survival. It may represent a valuable therapeutic option for the treatment of nonresectable NSCLC in elderly patients., (Copyright 2000 American Cancer Society.)

The aims of this study were: to assess the attitude of non-small-cell lung cancer (NSCLC) patients to being treated with chemotherapy, determining whether and how much it differs from that expressed by patients with benign diseases or by healthy people; and to investigate how the information received about the treatment may influence the patients' decisions. A three-item self-assessment questionnaire measuring willingness to be treated with chemotherapy and presented according to three different scenarios (with an optimistic, neutral, and pessimistic physician's presentation) was administered to 104 NSCLC patients, 129 other patients with respiratory diseases (RDP), 140 health care providers (HCP) and 120 students (STU). Guttman's coefficient of reproducibility confirms the hierarchical structure of the three scenarios ranging from an optimistic to a pessimistic view. Relative to the other groups, cancer patients showed: (a) a consistently higher degree of uncertainty about whether to accept or reject chemotherapy; (b) the lowest acceptance rate in the optimistic and neutral scenario and, in contrast, the highest in the pessimistic scenario; (c) the highest percentage of constant answers, independently of the scenario presented, particularly as regards the answers "I don't know" (NSCLC = 25%, RDP = 9%, HCP = 2%, STU = 5%) and "Yes, I accept" (NSCLC = 29%, RDP = 31%, HCP = 19%, STU = 16%). Answer patterns differed markedly between cancer patients, the HCP, and the STU group, and in most cases the difference was statistically significant at a confidence level of 0.001. The differences between NSCLC and RDP patients were less marked, and not always statistically significant. The choice between accepting and rejecting chemotherapy is very difficult for patients with NSCLC, much more so than for healthy people, and it is often independent of the way the information is provided.

Study Objectives: The International Staging System for Lung Cancer (ISSLC) was revised in 1997. Validation studies are numerous but include only selected surgical patients. This study aims to verify the following: (1) the reliability of the ISSLC in an unselected lung cancer population; (2) the likely improvement in prognostic capability of the new classification; and (3) the possibilities for further improvements., Design: Analysis of a single institution database over a 16-year period from 1983 to 1998., Setting: Community-based hospital and second referral level institution for a province of 500,000 people., Patients: The study included 1,296 consecutive patients (1,117 men), with pathologically documented lung cancer (46% with squamous cell cancer), staged both clinically (77%) and pathologically (23%), and treated, for the most part, with chemotherapy (52%)., Interventions: Anthropometric, clinical, and laboratory data were recorded prospectively. Survival analysis was performed by the Kaplan-Meier method and Cox multivariate regression analysis., Measurement and Results: The 1997 revised ISSLC classification fit well with the cohort studied. Each stage and substage significantly differed from each other, except for stage IIA. In this stratum, there were only 13 patients. Comparing the 1986 and the 1997 classifications, no substantial differences were observed (log-rank statistics, 295 vs 293, respectively; p < 0.0001). Independent of the classification used, the Cox models were always highly predictive of the outcome. The only way to increase their efficiency was to replace the variable stage with the original TNM descriptors., Conclusions: Since grouping different TNM subsets into one stage is not really helpful, we might choose to use TNM descriptors in clinical practice and in research.

This study was carried out in order to assess the potential prognostic significance of serum copper (SCL) and zinc levels (SZL) and the copper/zinc ratio in 145 consecutive patients, seen for a new lung cancer during the last 2 yrs. SCL and SZL, along with 26 other clinical parameters (anthropometric, clinical and laboratory variables) were prospectively recorded in all the patients. Mean SCL and SZL were, respectively, 140.4 micrograms.dL-1 (134.7-146.1, 95% confidence interval (CI), and 71.4 micrograms.dL-1 (66.8-75.9, 95% CI). Patients, 28%, showed abnormally elevated SCLs, and 57% of patients had abnormally low SZLs. The mean Cu/Zn ratio was 2.28 (2.10-2.46, 95% CI). Univariate analyses of survival showed that patients with either an SCL > 138 micrograms.dL-1 or an ZSL < 66 micrograms.dL-1 survived significantly shorter times (p = 0.03, log rank test). Elevated Cu/Zn ratios (> 2.075) were associated with a median survival of 25.39 weeks, as compared to the 40.85 weeks of subjects with lower ratios (p = 0.01). A multivariate analysis of survival (Cox's proportional hazards regression analysis) selected, in decreasing order of significance, the following variables: 1) stage of disease; 2) Eastern Cooperative Oncology Group performance status; 3) sex; 4) Cu/Zn ratio; 5) lymphocyte count; 6) histology; and 7) tissue polypeptide antigen levels. It is concluded that SCL, SZL and the Cu/Zn ratio are simple and inexpensive determinations, and do have some prognostic significance in lung cancer.

Combination chemotherapy with cytotoxic agents is the regular treatment for patients with advanced non-small cell lung cancer (NSCLC), good performance status, and no major clinical contraindications. Since the early 1980s, platinum-based chemotherapy is the cornerstone of this treatment, while combinations containing long-acting alkylating agents have been nearly abandoned, and represent a sort of historical treatment. Nevertheless, the real survival benefits of cisplatin are uncertain and still debated. To attempt an answer, the Cuneo Lung Cancer Study Group (CuLCaSG) carried out a clinical trial comparing a platinum (MVP) versus a non-platinum-based combination chemotherapy (MACC). The study comprised 156 patients with advanced NSCLC randomly assigned to the two treatment arms. MACC and MVP chemotherapies were given as originally described and continued until progression of disease, unacceptable toxicity, or refusal by the patient. For a medium of four cycles of MVP and three cycles of MACC, the median dose intensity (DI) reached was, respectively, 95% and 100% of the intended (P = 0.0132). In all, 27 objective responses (1 complete and 16 partial responses in patients allocated to MVP versus 10 partial responses of the MACC group) were observed. Median progression-free and global survivals were, respectively, 21 and 34 weeks for MVP and 20 and 31 weeks for MACC (non-significant differences). The treatment plan was found non-significant also multivariate analysis of survival. Toxicity was rather similar in the two arms, except for more severe neurological toxicity, anemia, thrombocytopenia, nausea, and vomiting in patients on MVP. Alopecia was more common after MACC. Subjective tolerance to treatment, and perception of physical and psychological well-being were rated similarly by patients of both groups. In conclusion, MVP was moderately more active than MACC, and showed a foreseeable and reversible toxicity, of a low-medium grade. However, this CuLCaSG study failed to substantiate any survival benefit from the use of platinum in combination with other cytotoxic agents.

The optimal treatment for regionally advanced non-small cell lung cancer (NSCLC, Stage IIIa/IIIb) remains unknown. Proposed approaches include surgery, radiotherapy, chemotherapy, and combinations of these. No treatment modality, however, has ever shown other than modest or minimal beneficial effects. When differences between new and old treatments appear trivial, as in the management of the locally advanced NSCLC, controlled studies are necessary to select the best approach. This review is based on a systematic overview of data from randomized trials comparing different treatment modalities. The following six points emerged from the cited literature. (1) It is sufficiently proved that chemotherapy alone prolongs survival in patients with both locally advanced and metastatic disease. (2) Although it is probably true that radiation therapy is better than no active treatment, this idea is supported by very limited evidence. (3) Although it is probably also true that radiotherapy alone is not worse than chemotherapy alone, this is another insufficiently proved issue. (4) The possible superiority of chemo-radiotherapy to chemotherapy alone or to supportive care is also poorly documented. (5) There is abundant evidence that chemo-radiotherapy is better than radiotherapy alone (however, this information may be unhelpful if point 2, or 3 remains unclarified). (6) Although neoadjuvant treatments have improved resectability and may ensure overall better results, the surgical cure, either alone or in combination with chemotherapy or chemo-radiotherapy, is another unproved option. Based on the above six points, it was concluded that new randomized studies are urgently needed to confirm the possible superiority of chemo-radiotherapy to chemotherapy. Only after such a validation, will the many ongoing trials, designed to prove the possible superiority of local surgical control to the more traditional approaches based on thoracic irradiation, have a practical sense.

Background: Thoracic computed tomography (CT) provides most of the staging information needed before operation for lung cancer and can reduce the number of exploratory thoracotomies. In recent years a new immunoscintigraphic technique with anti-carcinoembryonic antigen (CEA) monoclonal antibodies has been shown to be effective in lung cancer staging. This study compares the yields of CT scans and immunoscintigraphy in the preoperative evaluation of the medistinal lymph nodes of patients with non-small cell lung cancer., Methods: One hundred and thirty one patients believed on clinical grounds to have a operable non-small cell lung cancer were photoscanned with the indium-111 labelled F(ab')2 fragments of the antibody FO23C5. Both planar and single photoemission computed tomography (SPECT) thoracic views were recorded. CT scan of the thorax, abdomen, and brain were obtained in all patients. Seventy of the patients eventually underwent surgery, an additional seven underwent mediastinoscopy or mediastinotomy, and a further 10 had both cervical exploration and thoracotomy. Pathological evaluation of the mediastinal nodes was available in all 87 patients, but in only 80 of them was the diagnosis of lung cancer eventually confirmed., Results: The diagnostic accuracy of planar immunoscintigraphy, SPECT immunoscintigraphy, and CT scanning for N2 disease was 76%, 74%, and 71%, respectively. The corresponding sensitivity and specificity rates were 45%, 77%, 64% and 88%, 72%, and 74%. These were not significantly different., Conclusions: This study shows that anti-CEA immunoscintigraphy has no advantage over conventional CT scanning in assessing mediastinal lymphoadenopathy in patients with lung cancer. CT scanning remains the gold standard test in these patients.

Combination chemotherapy with anti-proliferative agents is often used in patients with advanced non-small cell lung cancer (NSCLC) in good performance status. The mitomycin C, vinblastine and cisplatin (MVP) regimen has been the Eastern Cooperative Oncology Group (ECOG) standard for several years because of high response rates in spite of significant toxicity. In a phase II study, we observed 55 consecutive patients treated with MVP chemotherapy using the same dosage, schedule, and precautions as used by the ECOG group. The dose intensity reached for each drug was 85% of the projected dose. Fifty-one patients were assessable for response and toxicity, while all subjects were evaluable for survival. There was no complete remissions, 8 partial (15%), 34 stable (66%) and 9 progressive (17%) in patients. The median survival rate was 34 weeks (95% confidence interval 28-37 weeks). There were no treatment-related deaths and no grade 4 toxicity. Alopecia and emesis were the most significant adverse effects. Haematological toxicity was minimal. Other side-effects, such as neuropathy and nephrotoxicity, were also rare. Hence, response rates and toxic complications were lower than previously reported. We conclude that the MVP regimen has to be re-evaluated.

Study Objective: To estimate the quality of the studies and to compare single-agent with combination chemotherapy in advanced non-small cell lung cancer., Design: Identification of published randomized trials and extraction of essential results directly from the published reports., Measurements and Results: Survival probability at 1 year, as estimated from the published survival curves, has been considered as the end-point of interest. Quality scoring of the studies has also been performed. Arithmetical calculation, concerning the estimation of quantities necessary for the meta-analysis of the literature, has been addressed. The estimated pooled Odds Ratio of death was 0.8, with 95% confidence interval of 0.6-1.0, thus favoring combination chemotherapy., Conclusions: The results of our meta-analysis favor combination chemotherapy. They must, however, be considered in the light of their clinical relevance and of the balance between quality of life, toxicity and costs of chemotherapy.

Tissue polypeptide antigen (TPA) is a protein produced and released by proliferating cells that has been shown to possess several characteristics for an ideal tumor marker. Our purpose was to determine the yield of TPA in the pretreatment assessment of non-small cell lung cancer (NSCLC), in comparison with a baseline clinical evaluation and multiorgan computed tomography (CT) assumed to be the gold standard for presurgical staging. One hundred four patients with NSCLC underwent thoracotomy, mediastinoscopy, or biopsy of suspected metastatic deposits, in addition to an extensive noninvasive evaluation of their stage of disease. We restaged retrospectively (UICC 1987 classification) these patients, on the basis of the following: (1) clinical history and physical examination, routine laboratory tests, bronchoscopy, chest radiographs, and any other examination as indicated by the prior baseline evaluation (BE stage); (2) the serum level of TPA (TPA stage); (3) the reading of a CT scan of brain, thorax, and abdomen obtained with no limitation to clinical information (CT stage); and (4) pathologic findings (RE stage). The TPA stage was calculated using 20 threshold values ranging from 45 U/L to 450 U/L. On the basis of the RE stage, sensitivity, specificity, accuracy, and predictive capabilities of BE, CT, and TPA were determined for stage I and II (full operability, FO), stage IIIa (possible operability, PO), and stage IIIb and IV (full inoperability, FI). The TPA thresholds were 110 U/L for detecting FO with the highest rate of success, and 160 U/L for detecting FI. Using these thresholds BE, CT, and TPA showed a diagnostic accuracy of, respectively, 75%, 79%, and 68% for FO; 87%, 69%, and 77% for PO; 87%, 77%, and 76% for FI. The accuracy of BE, CT, and TPA for both FO and FI was, respectively, 85%, 69%, and 69%. Of 74 patients classified operable by BE, 6 had a serum concentration of TPA less than 50 U/L and all 6 were confirmed in stage I or II at the subsequent thoracotomy; 15 others, out of 26 patients judged to have inoperable conditions by BE, had a TPA test result above 135 U/L and all 15 were pathologically classified in stage IIIb or IV. Using appropriate threshold values of TPA, it should be possible to predict NSCLC resectability with a diagnostic accuracy similar to that routinely achieved by CT.

With the possible exception of chemotherapy for the small-cell type, a complete surgical excision is still the only effective treatment of lung cancer. Routine brain computed tomography (CT) for staging purposes has been both advocated and opposed. In this retrospective study, we aimed to assess the clinical yield of the technique. We saw 184 consecutive patients with a new histologically proven non-small-cell lung cancer. Using as reference criteria clinical judgment supported by a strict follow-up evaluation, we counted 1 false- and 23 true-positive brain CT results, plus 2 false- and 158 true-negative findings. These figures allow for sensitivity, specificity, and accuracy of 92 percent, 99 percent, and 98 percent. The frequency of brain metastases did not correlate with the various histologic types, even though adenocarcinoma was the most common cause of cerebral metastases. The absence of neurologic symptoms did not exclude cerebral involvement: in our experience, 16 of 25 patients with positive brain CT scans were asymptomatic (64 percent). Three of 31 subjects (10 percent) with an otherwise operable carcinoma were found to have metastases after brain CT. We conclude that routine cranial CT is useful in the staging evaluation of the patient with non-small-cell lung cancer (NSCLC) and that it should be performed in any candidate prior to surgical resection.

Combination chemotherapy with anti-proliferative agents is the usual treatment for patients with advanced non-small cell lung cancer (NSCLC), good performance status and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anti-cancer activity of conventional cytotoxic drugs, with no increase of specific toxicity. Following a pilot study of feasibility, we now report the results of a randomised trial evaluating MACC chemotherapy, as originally described, versus the same regimen+LND. 151 patients with advanced NSCLC were assigned at random to the two treatment arms. LND 150 mg was given orally three times daily. Treatment was continued until progression of disease, unacceptable toxicity or refusal by the patient (median number of cycles of MACC, three for both arms; median duration of LND administration, 8 weeks in the arm concerned). Actual dose intensities (DI) of MACC and LND were, respectively, 100 and 83% of those intended (median values). There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient, but no correlation between the duration of treatment with LND and its DI. DIs of LND and MACC were not correlated with each other. In all, 15 objective responses (one complete and four partial responses in the MACC group, 10 partial responses in patients on MACC+LND) were observed. Median progression-free survivals were 20 weeks (confidence interval, CI 14-22) for the group on LND and 17 weeks (CI 12-17) for the control group (non-significant difference). Median overall survivals were, respectively, 30 weeks (CI 23-40) and 27 weeks (CI 22-34), P = non-significant. Toxicity was as expected by the use of MACC, and similar in both arms, except for more severe anaemia and gastric toxicity in the group on MACC+LND. Other uncommon side-effects, seen only in this latter group, were mild to moderate and reversible and included myalgia, asthenia, testicle pain, headache, visual troubles, incubi and dizziness. Subjective tolerance to the treatment, and perception of physical and psychological well-being were rated similarly by patients of both groups. MACC plus LND is a moderately active regimen in advanced NSCLC, with a foreseeable and reversible toxicity of low-medium grade. Potential enhancements of anti-tumour efficacy of chemotherapy, and possible host survival benefits derived from the use of LND are not substantiated by the results of this trial.

Background: Combination chemotherapy with conventional antiproliferative drugs is becoming the treatment of choice for patients with advanced non-small cell lung cancer (NSCLC), a good performance status, and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anticancer activity, without increasing toxicity., Methods: In a Phase II study, 46 patients with advanced NSCLC were assigned to receive chemotherapy with the methotrexate, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (MACC) regimen, as originally described, plus LND, 150 mg orally, three times per day. Treatment was continued until progression of disease, occurrence of unacceptable toxic effects, or refusal by the patient (the median duration of MACC treatment was 6 weeks; 7 weeks for LND)., Results: For the whole group of patients, actual dose intensities (DI) of MACC and LND were 95% and 67% of those projected (median values), respectively. There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient. On the contrary, there was no correlation between the duration of treatment with LND and its DI. The DI of LND and MACC were not correlated with each other. In all, seven objective responses (only partial responses) were observed. The overall median survival time was 42 weeks (confidence limits [CL], 20-52). The median survival length of patients receiving the full dose of LND (450 mg daily for at least 1 week) was 46 weeks (CL, 28-67), as compared with the median survival of 19 weeks (lower CL, 9 weeks) for the remaining patients; this difference was statistically significant (P < 0.05, Breslow test). Toxic effects were as expected with the use of MACC. They were mainly gastrointestinal (any grade of toxicity occurring in 64% of the patients), hematologic (anemia, 44%; leukopenia, 36%; thrombocytopenia, 8%), oral (25%), renal (14%), and cardiac (11%). There was only one treatment-related death, from myocardial infarction and neutropenic sepsis. Uncommon side effects, which were attributed to LND, were mild to moderate and reversible; they included myalgia (26%), asthenia (15%), testicle pain (11%), visual problems (7%), and gastric intolerance (7%)., Conclusions: MACC plus LND is a moderately active regimen in advanced NSCLC, with foreseeable and reversible toxic effects of low-medium grade. Potential enhancements of antitumor activity and possible host survival benefits may be expected by the addition of LND to MACC, but a Phase III study must be performed to identify them.

Ninety-two nonsmall cell lung cancer (NSCLC) patients were treated with a combination chemotherapy containing methotrexate, adriamycin, cyclophosphamide and CCNU (MACC). The regimen was administered in the dose and schedule originally reported. Median survival for all patients was 32 weeks. Only 6 patients demonstrated an objective response with a median survival rate of 51 weeks. The remaining 70 evaluable patients were nonresponders. These latter patients had a survival probability reduced to 29 weeks. Median time to progression for the whole group was 17 weeks. Partial responses were seen in 3 squamous, 1 large cell carcinoma and 1 adenocarcinoma. One patient with bronchiolo-alveolar carcinoma had complete disease regression and is still alive 136 weeks after starting treatment. Toxicity was significant with 2 treatment-related deaths. The major toxic effects consisted of myelosuppression, nausea, vomiting, and stomatitis. Alopecia was nearly universal; a mild cardiac, renal, or hepatic toxicity was relatively infrequent. Polychemotherapy with MACC regimen may benefit a few selected patients with NSCLC, but its overall antitumor efficacy appears to be very limited.

Recommendations concerning the continuation of chemotherapy in nonresponding patients with non-small cell lung cancer (NSCLC) and stable disease after the first chemotherapy test are empirical and often conflicting. Between 1984 and 1987, 116 inoperable NSCLC patients were treated with methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC regimen). After two or three cycles of therapy, 74 patients were judged to have stable disease and assigned at random either to chemotherapy maintenance with the same regimen (38 subjects) or to chemotherapy discontinuation (36 subjects). The two study groups were comparable for all the major prognostic factors. Median time to progression was 26 weeks for the chemotherapy group compared to 24 weeks for the nonchemotherapy group (P = NS). Median survival was prolonged in the treatment arm (47 weeks) compared to nontreatment arm (30 weeks), which was statistically nonsignificant. A patient self-assessment of the quality of life revealed a significantly worse tolerance to therapy and a better physical condition in the chemotherapy group. Objective MACC toxicity was significant with two treatment-related deaths. This study failed to demonstrate sufficient therapeutic benefits to justify the increased cost and toxicity of continuing treatment in nonresponding NSCLC patients.

To evaluate the clinical significance of tumor Ga-67 uptake, we studied 89 consecutive patients with a potentially resectable non-small cell lung cancer (NSCLC) by performing a whole body Ga-67 scan. For each scintigraphy, an overall Ga-67 accumulation index (T-N) and a volume independent index (T/Nr) were calculated. Both parameters were related to disease extent, response to subsequent treatment and host survival. With the exception of the significant correlations of T-N to both stage of disease and survival-the higher the T-N, the more advanced the disease and the worse the prognosis-no other relationship was found. Based on these findings, we conclude that, in NSCLC at least, gallium uptake is mainly dependent on tumor size and, therefore, of limited practical value.

One hundred and one patients with histologically proved non-small cell lung cancer underwent whole body gallium-67 (TB Ga-67) scintigraphy as a part of their routine pretreatment evaluation. Twenty-eight of these patients were subsequently operated and pathologically staged for hilar and mediastinal disease. Two other patients underwent mediastinoscopy, but were judged unresectable at that time. All had computed tomography (CT) of the thorax, as well as radionuclide or CT scans of suspicious metastatic areas, and were carefully followed-up. When possible, a biopsy was performed of each suspected metastasis. Primary lung tumors concentrated Ga-67 in 94 patients. Sensitivity, specificity, and accuracy for hilar and mediastinal node metastases were 58%, 89%, and 77%, respectively. There were no false-negative gallium scans as regards secondary involvement of both liver and bone, whereas only 1 of the 4 brain metastases was detected by the technique. Sensitivity, specificity, and accuracy for all metastatic sites were 82%, 38%, and 56%, respectively. Fifty-five patients were classified as having a more advanced stage of disease by TB Ga-67 scintigraphy than at the initial clinical evaluation. However, 42 gallium-staged patients were ultimately re-classified differently according to all available clinical data. Using TB Ga-67 scintigraphy, 21 patients were found to have occult metastases which would not otherwise have been recognized; for the above reason, an unnecessary intervention was avoided in 6 of them.