Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m2. Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

Effect of chemotherapy for advanced non-small cell lung cancer on patients' quality of life. A randomized controlled trial.

BACKGROUND: Patients with advanced non-small cell lung cancer (NSCLC) do not have curative treatment options; therefore, treatments should prolong survival and improve quality of life (QoL). We compared the effect on QoL of two docetaxel-platinum regimens with vinorelbine-cisplatin. METHODS: QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and the general EuroQol five-dimensional questionnaire (EQ-5D) in 926 chemotherapy-naïve patients with stages IIIB to IV NSCLC. Patients were randomly assigned to receive: docetaxel 75 mg/m2 plus cisplatin 75 mg/m2, every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin 6 mg/ml min, every 3 weeks (DCb); or vinorelbine 25 mg/m2/week plus cisplatin 100 mg/m2, every 4 weeks (VC). RESULTS: Overall, patients treated with either docetaxel-containing regimen had better QoL than VC-treated patients (LCSS global item "QoL today": P=0.064 for DC and P=0.016 for DCb versus VC; EQ-5D global item "health state today": P=0.016 for DC and P<0.001 for DCb versus VC). DC-treated patients experienced improved pain relief compared with VC (P=0.033), whereas pain relief with DCb and VC was similar. Patients treated with either docetaxel regimen had more favorable changes in performance status (P=0.065 for DC and P<0.001 for DCb versus VC) and mean weight loss (0.06 kg, gain of 0.08 kg, and 2.27 kg for DC, DCb, and VC, respectively; P<0.001 for both DC versus VC and DCb versus VC). CONCLUSION: The TAX 326 study shows that docetaxel-platinum regimens relieve symptoms and improve QoL in patients with advanced NSCLC. DCb and DC were superior to VC in all QoL outcomes assessed except for the difference between DC and VC in LCSS "QoL today", which was not significant.

A randomised phase II study of the efficacy and safety of intravenous topotecan in combination with either cisplatin or etoposide in patients with untreated extensive disease small-cell lung cancer.

PURPOSE: Topotecan (Hycamtin is active in small-cell lung cancer (SCLC). This phase II study investigated the efficacy and safety of topotecan in combination with either cisplatin or etoposide in untreated extensive disease SCLC (ED SCLC). PATIENTS AND METHODS: Patients with untreated ED SCLC were randomised to treatment with T/C (topotecan 1.25mg/(m(2)day) IV days 1-5, cisplatin 50mg/m(2) IV day 5; 41 patients) or T/E (topotecan 0.75 mg/(m(2)day) IV days 1-- 5, etoposide 60 mg/(m(2)day) IV days 1-5; 41 patients) every 21 days. Response was evaluated by strict radiological criteria. RESULTS: Response rates were similar for T/C (63.4%, 95% CI: 48.7-78.2%) and T/E (61.0%, 95% CI: 46-76%) with one patient in each arm who underwent complete response. Median survival was 41.6 weeks (9.6 months) for the T/C group and 43.7 weeks (10.1 months) for the T/E group. Toxicity was primarily haematological in both groups. The proportion of patients with grades 3-4 anaemia was significantly higher in the T/C arm (46.4%) versus 20% with the T/E arm (p=0.018). The proportion of patients with grade 4 neutropenia was not significantly lower with T/C (56.1%) than with T/E (65.0%, p=0.41), as was the incidence of associated events such as sepsis (T/C: 0%; T/E: 9.8%, p=0.11). The overall deliverability of either regimen was similar. The most frequent non-haematological adverse experiences of all grades per patient were nausea (T/C: 43.9%; T/E: 36.6%), and alopecia (T/C: 39.0%; T/E: 56.1%). Topotecan did not appear to increase the frequency of adverse events specifically associated with cisplatin. CONCLUSION: This study showed T/C and T/E to be effective and well tolerated in patients with ED SCLC and further evaluation of topotecan in first line SCLC is warranted.

Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer.

The expression patterns of cancer-related genes in 13 cases of squamous cell lung cancer (SCC) were characterized and compared with those in normal lung tissue and 13 adenocarcinomas (AC), the other major type of nonsmall cell lung cancer (NSCLC). cDNA array was used to screen the gene expression levels and the array results were verified using a real-time reverse-transcriptase-polymerase chain reaction (RT-PCR). Thirty-nine percent of the 25 most upregulated and the 25 most downregulated genes were common to SCC and AC. Of these genes, DSP, HMGA1 (alias HMGIY), TIMP1, MIF, CCNB1, TN, MMP11, and MMP12 were upregulated and COPEB (alias CPBP), TYROBP, BENE, BMPR2, SOCS3, TIMP3, CAV1, and CAV2 were downregulated. The expression levels of several genes from distinct protein families (cytokeratins and hemidesmosomal proteins) were markedly increased in SCC compared with AC and normal lung. In addition, several genes, overexpressed in SCC, such as HMGA1, CDK4, IGFBP3, MMP9, MMP11, MMP12, and MMP14, fell into distinct chromosomal loci, which we have detected as gained regions on the basis of comparative genomic hybridization data. Our study revealed new candidate genes involved in NSCLC.

Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.

PURPOSE: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy. PATIENTS AND METHODS: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC). RESULTS: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL. CONCLUSION: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.

Pretreatment serum syndecan-1 levels and outcome in small cell lung cancer patients treated with platinum-based chemotherapy.

Syndecan-1 is a multifunctional transmembrane heparan sulphate proteoglycan (HSPG) that is present on a variety of cell types. The extracellular syndecan domains can be shed from the cell surface in a highly regulated process called ectodomain shedding. We studied the influence of soluble syndecan-1 on outcome in 88 small cell lung cancer (SCLC) patients treated within the context of two randomised clinical trials with platinum-based therapy. Serum syndecan-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) from sera taken prior to initiation of chemotherapy. Patients with the serum syndecan-1 level within the highest tertile (>212 microg/l) had only 38% 1-year and 3% 2-year survival, whereas 58% of those with a lower serum level survived for 1 year and 25% for 2 years following the diagnosis (P=0.0034). A high serum syndecan-1 level (>212 microg/l) was associated with a high pretreatment lactate dehydrogenase (LDH) level (P=0.0024) and a poor Karnofsky's performance status (P=0.021), but not with the clinical stage or the presence of distant metastases at diagnosis. A high serum syndecan-1 level had independent influence on survival also in a multivariate analysis (the relative risk, RR, 1.68; 95% CI, 1.02-2.77; P=0.044) together with the clinical stage (RR, 1.72; 95% CI, 1.05-2.82; P=0.032). We conclude that high pretreatment serum syndecan-1 level is associated with poor prognosis in SCLC treated with platinum-based chemotherapy.

Adjuvant and neoadjuvant treatments for NSCLC.

In stage III non-small cell lung cancer (NSCLC), the use of induction chemotherapy prior to radiotherapy produces a significant increase in median survival of three to four months (from 11 to 14 months), a benefit which appears to be achieved through improved systemic control of the disease. Hyperfractionated radiotherapy, although it enhances local control, seems not to improve survival. Concurrent chemoradiotherapy has emerged as the most successful strategy. It led to increased locoregional control and to a 3-4 month improvement of median survival when compared with induction chemotherapy prior to radiotherapy. Docetaxel is a radiosensitizing agent and has been extensively investigated in phase I/II settings of concurrent chemoradiotherapy. Use of the other cytotoxics such as paclitaxel, or irinotecan in concurrent chemoradiotherapy strategies is also feasible. Of particular interest are the results of SWOG 9504, a phase II study in which cisplatin/etoposide concurrent chemoradiotherapy was followed by three cycles of docetaxel consolidation. Median survival is 26 months, 1-year survival 76% and 3-year survival 40%. These survival data, achieved in pathologically staged IIIB patients, are highly encouraging and support further evaluation of this approach. Among stage III patients eligible for radical treatment with surgery or radiotherapy, the addition of neoadjuvant docetaxel at 100 mg/m(2) for three cycles is tolerable and appears to be associated with a trend towards increased survival.

High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer.

Basic fibroblast growth factor (bFGF) is a secreted multifunctional cytokine and a potent stimulator of angiogenesis. We measured bFGF concentrations from serum samples taken from 103 patients with small cell lung cancer at the time of diagnosis. Serum concentration of bFGF (S-bFGF) ranged from undetectable to 54 pg/ml (median, 6 pg/ml). S-bFGF was not associated with age, sex, performance status, or stage. A high pretreatment S-bFGF was associated with poor overall survival. The 1- and 2-year survival rates of the patients within the highest quartile of S-bFGF (>or=17 pg/ml) were only 26% and 11%, respectively, in contrast to the 49% and 20% 1- and 2-year survival rates of those patients with S-bFGF < 17 pg/ml (P = 0.013). The 1- and 2-year survival rates of the patients with extensive-stage disease were 33% and 10%, respectively (P = 0.0091). Interestingly, S-bFGF provided additional prognostic information to the stage because the 1- and 2-year survival rates of patients with extensive-stage disease and a high S-bFGF (>or=17 pg/ml) were as low as 16% and 5%, respectively (P = 0.0026). Similarly, in the multivariate model of survival analysis, patients with both extensive-stage disease and a high S-bFGF (>or=17 pg/ml) were found to have a particularly poor prognosis (relative risk of death, 2.1; 95% confidence interval, 1.2-3.6; P = 0.0057). We conclude that a high S-bFGF at diagnosis is associated with poor outcome in small cell lung cancer, possibly reflecting active angiogenesis and rapid tumor growth, and may complement prognostic information obtained by staging.

Concurrent LOH at multiple loci in human malignant mesothelioma with preferential loss of NF2 gene region.

Human malignant mesothelioma (MM) is a highly aggressive neoplasm related to occupational asbestos exposure and characterised by a long latency period between the exposure and onset of disease. Previous studies indicate that losses at different genomic regions are present in MM. We examined allele loss at three known tumour suppressor gene regions (22q/NF2 gene, 9p/p16 gene, and 3p/FHIT gene) and at two other frequently deleted areas (14q and 6q) in MM. Loss of heterozygosity (LOH) was investigated in cell cultures and primary tumours with several highly polymorphic markers for each site. To study if LOH of the NF2 gene is a consistent feature in MM, we performed a more detailed analysis of chromosome 22q that included a NF2 marker (NF2CA3). We observed a high frequency of LOH occurring simultaneously at multiple loci. In particular, 100% of the cultured MM cells exhibited LOH at the NF2 gene region. From the other chromosomal sites analysed, recurrent allele loss was detected at 9p (5/7; 71%), 3p (4/7; 57%), 14q (3/7; 43%), and 6q (3/7; 43%). Of the 32 tumours, even those trimmed to exclude normal tissue, few showed LOH, suggesting consielment by normal cells within MM tumours, whereas tumour cells in primary cultures showed LOH already in passages 1-2. In conclusion, our present LOH data indicate that MM cells exhibit allele losses at multiple tumour suppressor gene sites concurrently, involving NF2 gene preferentially. This supports the view that the accumulation of multiple genetic hits is characteristic to malignant transformation of MM cells.

DNA copy number changes in lung adenocarcinoma in younger patients.

We performed a comparative genomic hybridization study on 25 lung adenocarcinoma samples from younger patients (<41 y of age) and compared the results with a previous comparative genomic hybridization analysis of lung adenocarcinoma samples from older patients (50-81 y of age). Twenty of the 25 tumor samples from younger patients had DNA copy number changes. Gains, losses, and high-level amplifications were seen more frequently in the specimens from the younger group. The most striking difference between the two groups was the high frequency of gains and/or high-level amplifications in the long arm of chromosome 20 in the samples from the younger patients (14/25, 56%) compared with that in the samples from the older patients (2/24, 8%, P <.001). Gains in the long arm of chromosome 22 and of the chromosomal band 11q13 were also detected significantly more often in the younger group. No correlation was found between DNA copy number changes and clinical parameters. Our results suggest that amplification of genes in the long arm of chromosome 20 may be important in the tumorigenesis of lung adenocarcinoma in young adults. Several candidate genes have already been described in the long arm of chromosome 20, particularly in breast cancer.

Interferon trials in small cell lung cancer at one institution: a comparison of results obtained before and after initiation of systematic treatment trials using IFN-alpha in combination with other modalities.

Chemotherapy became the primary treatment for small cell lung cancer (SCLC) in the early 1970s. The standard drug combinations were first vincristine, adriamycin, and cyclophosphamide (VAC) and then, from the early 1980s, etoposide-platinum combinations. Despite a good initial objective response, however, patients usually suffer a rapid relapse. Treatment development has, therefore, focused on ways to overcome drug resistance, and on the addition of cytokines to the chemotherapeutic arsenal. Interferon (IFN) was one of the first cytokines found to have anticancer effects, and it was introduced into the combined modality regimens used to treat SCLC in the early 1980s in an attempt to overcome the problem of early relapse. The role of IFN was investigated with the aim of establishing how best to combine it with other treatments for SCLC. In this paper, we review the impact of IFN on the outcome for 714 SCLC patients who were treated in randomized IFN trials at one institution over a period of 20 years and IFN trials conducted at other institutions during the same period. The parameters we used at our institution to measure outcome tended to improve during the period when patients were being treated in our three randomized IFN trials, compared with the period when patients received only standard treatment in a nonclinical trial setting. However, the differences were not statistically significant. During this period, IFN was used as maintenance therapy, concomitantly with chemotherapy, and combined with other treatment modalities. Our experience is that IFN-alpha is most effective when administered as low-dose maintenance treatment. Other IFN trials published during the same period were small and heterogeneous. Results were inconsistent and added little new information, although it has been shown that high pretreatment levels of serum vascular endothelial growth factor (VEGF) predict a poor response to treatment and consequently a poor outcome. The recently confirmed antiangiogenic properties of IFN deserve to be investigated in studies of maintenance treatment, in combination with other biologic agents. Patient should be selected according to criteria based on pretreatment assessment of biologic markers, such as VEGF and basic fibroblast growth factor (bFGF). Our studies, all at one institution, pioneered the biologic treatment of solid tumors and developed a solid basis of knowledge for future studies of biologic agents in cancer treatment.

Computed tomography screening for lung cancer in asbestos-exposed workers.

We conducted a computed tomography (CT) screening for lung cancer in a high-risk population. Six hundred and two workers (38-81 years, 97% smokers) with asbestos-related occupational disease were screened using spiral CT and chest radiography. The national cancer registry was checked for possible false negative cases. The screening detected 111 patients with non-calcified nodules >0.5 cm in diameter and 66 of them were referred for further hospital examination. We found five lung cancers (106 false positive cases) with a histological spectrum similar to the national, natural occurrence of the disease (two adeno, one squamous cell, one anaplastic and one metastatic carcinoma) and one peritoneal mesothelioma. Three cases were potentially operable (stage I-II). Unfortunately there was one false negative fine-needle aspiration biopsy (FNAB) with misinterpretation of the follow-up CT scan and another patient who refused further investigations after an inadequate FNAB. In the end only one patient with adenocarcinoma underwent surgery. After 3 years of follow-up two new lung cancers were reported to the cancer registry with no evidence of tumour in the retrospective analysis of the screening CT scan. The sensitivity of CT screening was 100%. CT was capable of detecting early lung cancer in asbestos-exposed patients with a lot of confusing pulmonary and pleural pathology. Due to the high number of positive findings attention should be paid to patient compliance and the follow-up protocols and patient selection in future screening programmes.