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PubMed2006

Age is independent of comorbidity influencing patient selection for combined modality therapy for treatment of stage III nonsmall cell lung cancer (NSCLC).

OBJECTIVES: To determine the influence of age and comorbidity in patient selection for treatment of stage III NSCLC with combined modality therapy (CMT). METHODS: There were 102 patients with a Karnofsky Performance Score greater than or equal to 70, and clinical stage III NSCLC analyzed retrospectively for comorbidity. All patients received radiotherapy, and 57 (56%) received CMT with sequential and/or concurrent chemotherapy. Comorbidity was rated retrospectively using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). The effect of an extremely severe comorbidity score on patient selection and overall survival (OS) was evaluated. RESULTS: Presence of a grade 4 comorbidity (P = 0.02) and use of radiation only (P < 0.01) were associated with a statistically significant inferior OS on multivariate analysis, whereas age greater than or equal to 70, clinical stage IIIB, >5% weight loss, and radiation dose >63 Gy were not. Patients receiving CMT were significantly younger (P < 0.001), with less comorbidity (P < 0.001), and weight loss (P = 0.003) compared with patients receiving radiotherapy alone. A multivariate analysis revealed that age (P < 0.001), comorbidity (P = 0.007), and weight loss (P = 0.002) were independent factors influencing patient selection for CMT. CONCLUSIONS: Age effects patient selection for CMT independent of comorbidity and weight loss in patients with stage III NSCLC and good performance status. This might be related to physician's biases regarding tolerability of CMT in the elderly, and might explain under-representation of elderly in clinical trials of lung cancer. Comorbidity assessment should be included in protocols studying locally advanced stage NSCLC and may be useful for stratification.

Age Factors↗

PubMed2004

Second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).

An increasing number of patients with advanced non-small cell lung cancer (NSCLC) progressing after front-line chemotherapy are still in good performance status and willing to receive further treatment. Several drugs have been tested in this setting of treatment, but the only agent registered world-wide for second-line chemotherapy of advanced NSCLC is docetaxel. This drug, at dose of 75 mg/m2 every three weeks, has been the standard of care as second-line chemotherapy since 2000, based on two trials that reported improved survival times and quality of life when comparing with best supportive care (TAX 317) and with ifosfamide or vinorelbine (TAX 320). Docetaxel, given at this dose and schedule, resulted in significant haematological toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. In a phase III study in 571 patients pemetrexed, comparing with docetaxel in second-line chemotherapy, demonstrated clinically equivalent therapeutic outcomes, but a more favourable haematological toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Others several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer, but no comparative phase III studies with docetaxel has been carried out. The epidermal growth factor receptor-tyrosine kinase inhibitors gefitinib (ZD1839, Iressa) and erlotinib (OSI 774, Tarceva) have been evaluated in the second- and third-line setting. Both drugs have demonstrated interesting response rates and toxicity profile and, in particular, erlotinib evidenced a survival advantage of 2 months respect placebo in recent phase III trial. Future developments are likely to value poli-chemotherapy or combination chemotherapy with EGFR tyrosine kinase inhibitors in second-line treatment of advanced NSCLC.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC.

Optimal management of nonsmall cell lung cancer (NSCLC) depends on tissue diagnosis and accurate staging. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is minimally invasive and provides cytological confirmation of malignant mediastinal disease. The aim was to assess the accuracy of EUS-FNA in cases of enlarged mediastinal lymphadenopathy (LN) of unknown aetiology and in the staging of NSCLC. A total of 52 consecutive patients with stage I-IIIb NSCLC or enlarged mediastinal LN of unknown aetiology underwent EUS-FNA. Negative results were confirmed with a surgical procedure: mediastinoscopy, video-assisted thoracic surgery (VATS) or lobectomy with systematic mediastinal lymph node dissection. In total, 34 patients had EUS-FNA performed for diagnosis, whilst the remaining 18 had EUS-FNA for staging. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy (95% confidence interval) were 93% (77-99), 100% (78-100), 100% (87-100), 88% (63-99) and 95% (84-99), respectively. When EUS-FNA was used in patients with NSCLC, the sensitivity, specificity, PPV, NPV and accuracy were 92% (73-99), 100% (69-100), 100% (85-100), 83% (51-98) and 94% (80-99), respectively. For mediastinal LN of unknown aetiology, no malignant disease was missed. Endoscopic ultrasound-guided fine-needle aspiration is an accurate tool for assessing mediastinal lymph node involvement in nonsmall cell lung cancer and in the diagnosis of unexplained mediastinal lymphadenopathy. Endoscopic ultrasound-guided fine-needle aspiration is a minimally invasive procedure that can be used as an adjunct or alternative to mediastinoscopy.

Aged↗

PubMed2004

Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. METHODS: In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m2, on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years), younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m2 or 90 mg/m2), and older patients were allocated to lower cisplatin doses (60 mg/m2 or 70 mg/m2). We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status >or= 70%, normal serum creatinine, peripheral neuropathy <or= grade 1, and no prior cancer therapy. RESULTS: Analysis was by intention to treat. Main toxicities (grade 3-4) was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3-4 emesis or renal toxicity occurred. Global median time to progression (TTP) and overall survival (OS) were 27.0 (95% CI: 10.1 to 43.7) weeks and 30.1 (95% CI: 24.4 to 35.8) weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%), with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. CONCLUSION: Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions.

Aged↗

PubMed2006

Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways.

BACKGROUND: Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC) inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB) and the nucleoside analogue gemcitabine (GEM) was evaluated and the mechanisms underlying increased cell death were analyzed. METHODS: Dose escalation studies evaluating the cytotoxicity of PB (0.01-100 mM), GEM (0.01-100 microg/ml) and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62). Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. RESULTS: Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50-80% (p = 0.012) more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2-2.7 fold) compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093) and topoisomerase IIalpha (KNS62: p = 0.008; Ben: p = 0.064) proliferation indices were clearly reduced in tumors treated by combination therapy, whereas the apoptotic index was comparably low in all groups. CONCLUSION: Therapy combining GEM and the HDAC inhibitor PB initiates a spectrum of apoptosis-inducing mitochondrial and further JNK-dependent events, thereby overcoming the therapeutic resistance of NSCLC tumor cells. In vivo, the combination therapy substantially reduced tumor cell proliferation, suggesting that the well tolerated PB is a useful supplemental therapeutic agent in NSCLC.

Journal Article↗

PubMed2005

Optimizing first-line treatment options for patients with advanced NSCLC.

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.

Antineoplastic Agents↗

PubMed2006

Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC.

The first generation of clinical trials of targeted agents in non-small cell lung cancer (NSCLC) treatment has concluded. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors, represent a further chance for tumor control and symptom palliation. In chemotherapy-naive, advanced, nonsquamous NSCLC patients, the combination of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab with chemotherapy was demonstrated to produce better survival outcomes than with chemotherapy alone. The relative failure of first-generation targeted therapies in lung cancer may be a result of multilevel cross-stimulation among the targets of the new biological agents. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of the synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. In a recent phase I/II trial, the combination of erlotinib and bevacizumab demonstrated very promising activity in the treatment of advanced NSCLC pretreated with chemotherapy. Whether the multitargeted approach is best performed using combinations of selective agents or agents that intrinsically target various targets is a matter of debate.

Animals↗

PubMed2004

Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax).

Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.

Antineoplastic Agents↗

PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗

PubMed1999

Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial.

We examined the safety and efficacy of the docetaxel/cisplatin combination in patients with advanced, previously untreated NSCLC and evaluated changes in quality of life over time. Docetaxel was administered before cisplatin (both 75 mg/m2, 1-hour infusions) every 3 weeks to 47 patients with stage IIIB or stage IV NSCLC. Patients also received premedication of oral dexamethasone. The median age (range) of patients was 62 (45-78) years and 26 patients (55.3%) had adenocarcinoma. Of the 40 patients evaluable for response, one achieved a complete response and 14 had partial responses; the response rate was 37.5% (95% confidence intervals; 22.5, 52.5). In the intent-to-treat population the overall response rate was 31.9%. Time to response ranged from 3 to 20 weeks, and the median duration of response was 34.6 weeks. Median survival and median time to progression were 11.3 months and 18.9 weeks, respectively. One-year survival was 40%. Grade 3 or 4 neutropenia and febrile neutropenia were observed in 74.4% and 12.8% of patients, respectively. Severe asthenia was seen in 14.9% of patients. Other grade 3 or 4 toxicities included nausea (eight patients), vomiting (five), neurosensory effects (six), neuromotor effects (five), diarrhea (four), and infection (three). There was an improvement in emotional well-being; however, the overall quality of life score did not change with treatment. Docetaxel administered in combination with cisplatin is an active regimen in patients with NSCLC. This regimen of docetaxel (75 mg/m2) and cisplatin (75 mg/m2) repeated at 3-week intervals is being evaluated in an ongoing Eastern Cooperative Oncology Group (ECOG) randomized study in patients with advanced and metastatic NSCLC.

Journal Article↗

PubMed2005

Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations.

Celecoxib exhibits cancer preventive and therapeutic effects in animal models and clinical trials. It presumably acts through selective inhibition of cyclooxygenase-2 (COX-2) and subsequent reduction of prostaglandin (PG) synthesis. However, the concentrations of celecoxib required for growth inhibition and apoptosis induction in vitro are higher than those needed for suppression of PGs. Moreover, those concentrations are not achievable in humans raising a controversy regarding the clinical relevance of in vitro data. We investigated the activity of celecoxib alone and in combination with the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) on growth and apoptosis of human nonsmall cell lung cancer (NSCLC) cell lines. Celecoxib inhibited growth of thirteen NSCLC cell lines with IC50 values ranging from 19 to 33 microM regardless of their COX-2 expression. Apoptosis was induced in cells with high (A549) as well as low (H1792) COX-2 levels but only at a concentration of 75 microM celecoxib. However, treatment with pharmacologically feasible concentrations of celecoxib (< or = 10 microM) in combination with 4HPR (< or = 2 microM) resulted in a marked suppression of NSCLC cell growth and colony formation. Apoptosis mediated by activation of caspase-3, cleavage of PARP and lamin A was suppressed by addition of antioxidants, suggesting that the generation of reactive oxygen species was partially involved. This study indicates, that celecoxib combined with 4HPR is more effective than treatment with either agent alone in inhibition of growth and induction of apoptosis in NSCLC cells. It suggests further investigations of this combination for lung cancer treatment.

Antineoplastic Agents↗

PubMed1999

Is there any impact of new drugs on the outcome of advanced NSCLC? An overview of the Southern Italy Cooperative Oncology Group trials.

Lung cancer represents the major cause of cancer-related death in Europe and North America, accounting for 28% of all cancer deaths. Seventy to 80% of all lung cancers are non-small cell lung cancers (NSCLCs), and approximately 75 % of these patients present with locally advanced or disseminated disease. Even though chemotherapy is now recommended in the majority of cases of unresectable NSCLC, it still fails to substantially modify the fate of these patients. In recent years, several active cytotoxic drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan) have been developed, showing an overall response rate (ORR) <20% in NSCLC. Phase II/III trials testing these new agents in combination with cisplatin have been carried out in recent years with inconsistent results. Large randomized trials testing cisplatin-paclitaxel, carboplatin-paclitaxel, and cisplatin-gemcitabine regimens have been reported showing no substantial superiority of these combinations over standard treatments. The ORR remained well below 50%, and the median survival times were quite far from one year. These data could suggest that the addition of a single new agent to a platinum compound could be insufficient to substantially improve the prognosis of advanced NSCLC patients. In view of these disappointing data, the Southern Italy Cooperative Oncology Group has tried to improve the fate of patients with advanced NSCLC by testing new triplet combinations, which combined cisplatin with two rather than one of the newest chemotherapy agents. To avoid an unacceptable increase in toxicity and/or a marked decrease in dose intensity, the standard schedules of administration of the three agents used in these studies were changed, and the schedule changes were evaluated in phase I trials aimed at determining the maximum tolerated dosages of the drugs. Subsequently, phase II and III trials were conducted. The present paper summarizes the results of the clinical trials either completed or under way and aims to evaluate whether this strategy will result in a substantial prognostic improvement.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial.

BACKGROUND: Although the use of salvage chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial, pretreated symptomatic patients often need some kind of treatment to achieve symptoms relief. Gemcitabine is one of the most active new drugs in advanced NSCLC and preliminary reports suggest that it is active also in patients previously treated with platinum compounds. AIM: to evaluate activity and toxicity and the effect on quality of life of gemcitabine in platinum-pretreated patients with advanced NSCLC. METHODS: single-stage phase 2 trial with p0 = 5%, p1 = 20%, alfa = 5%, beta = 10%; 34 patients required and 4 objective responses expected to warrant further studies. Gemcitabine was administered at dose of 1000 mg/m2, i.v., d 18-15, every 4 weeks, for a maximum of 6 cycles. Quality of life was measured by EORTC C-30 and LC-13 questionnaires. RESULTS: from September 1996 to July 1998, 30 patients have been enrolled. There were 6 (20% exact 95% CI 8-39%) partial responses (2 responses were in pts with brain metastases and 2 in patients progressed during first-line chemotherapy). All patients (but one died because myocardial infarction, progressed; median time to progression was 10 weeks (95% CI 7-12); 28 patients died; median survival was 22 weeks (95% CI 17-29). Quality of life analysis showed no significant change but for the improvement of cough after 3 cycles of chemotherapy. There was no severe toxicity. CONCLUSION: gemcitabine is active as second line for patients with advanced NSCLC who received platinum-based first line treatment. In view of such results randomized trials comparing gemcitabine versus best supportive care are warranted.

Adult↗

PubMedDate not supplied

The circulating urokinase plasminogen activator (uPA) and its soluble receptor (suPAR) are not up-regulated by the circulating P105 fraction of the HER-2/neu proto-oncogene: in vivo evidence from patients with advanced non-small cell lung cancer (NSCLC).

It has been suggested that uPA in cancer cells is up regulated by the p 185 kD form of the HER-2/neu oncogene. We elected to see if the extra cellular domain of HER-2/neu, the p 105 fraction, which is found in the circulation, has any regulatory influence on uPA or uPAR in those patients with NSCLC Levels of uPA, uPAR and p 105 HER-2/neu were determined in blood from age-matched controls and patients with advanced NSCLC. In the patients with NSCLC, samples were obtained before and following treatment. A large increase in both uPA and uPAR compared to controls was seen in the patients prior to treatment. The uPAR level post-treatment decreased from pre-treatment values, which is favorable. There was a significant increase in uPA and a decrease in HER-2/neu in the post-treatment time frame. Additionally, correlation analysis of circulating uPAR, uPA and HER-2/neu against each other in both the controls and treatment groups indicated no relationship. It appears that circulating uPA and uPAR are elevated in NSCLC patients. The up-regulation of uPA by HER-2/neu seen in lung cancer cells in vitro is apparently lost in the blood in vivo as is evidenced by the lack of correlation between them which is also true for the receptor as well.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

Gemcitabine as single agent chemotherapy in elderly patients with stages III-IV non-small cell lung cancer (NSCLC): a phase II study.

INTRODUCTION: In the past the unfavourable profile of toxicity of antineoplastic drugs employed (i.e. cisplatinum) weakened the role of chemotherapy in aged patients with non-small cell lung cancer (NSCLC). Recently, new active drugs with lesser toxicity have became widely used in this setting. In this prospective study we evaluated the efficacy and tolerability of gemcitabine in elderly patients with stages III-IV NSCLC. MATERIALS AND METHODS: From December 1996 to April 1999, we enrolled 52 previously untreated elderly patients with advanced/metastatic NSCLC. Gemcitabine was administered at 1000 mg/mq i.v. over 30 minutes weekly for three consecutive weeks every 28 days. The planned number of cycles was three while responding or stable patients received chemotherapy until disease progression or the ninth cycle. A total of 291 cycles were delivered with a median number of 6 cycles (range: 3-9). An evaluation of the quality of life was performed every three courses of gemcitabine. RESULTS: After three cycles of treatment, a complete response was seen in four patients (7.7%), partial response in 16 patients (30.8%) with an overall response rate of 38.5%. Nineteen patients (36.5%) showed stable disease, while thirteen patients (25%) progressed. Median progression-free survival was 22 weeks, median duration of response 26 weeks, median overall survival 34 weeks and 1-year overall survival 46.1%. A statistically significant improvement in the quality of life was registered only after the first three cycles of gemcitabine (p = 0.045). Toxicity was extremely mild. CONCLUSION: In elderly patients with stages III-IV NSCLC gemcitabine showed good activity with a mild toxicity and could be considered a valid therapeutic option in this setting.

Aged↗

PubMed2003

Proliferation arrest in G1 phase of a non-small cell lung cancer cell line (NSCLC-N6) treated by an original compound methyl-4-methoxy-3-(3-methyl-2-butanoyl) benzoate (VT1) independently of the p53/p21 cascade.

Non-small cell lung cancers remain difficult to treat and have a high death rate and poor 5-year survival. New therapeutic strategies are urgently needed, which should be more specific for the cancer cell and less toxic for normal cells. In this respect, induction of the terminal differentiation of tumor cells appears to be a particularly suitable approach, which can only be achieved after proliferation arrest in G1 phase. This study describes the activity of a chemical compound with an original structure, namely methyl-4-methoxy-3-(3-methyl-2-butanoyl) benzoate (VT1), which induced irreversible proliferation arrest in G1 phase of two lung cancer lines, NSCLC-N6 and NSCLC-derived A549 cells. The p53 gene is now unanimously regarded as a key gene for cell cycle arrest in G1 phase, and A549 cells possess a wild-type p53 gene. The similarity of effects obtained on both lines led us to consider whether the p53/p21 cascade was activated in NSCLC-N6 cells during VT1 treatment. The mutational status of p53 gene was first established in the NSCLC-N6 line using a PCR SSCP technique, and a reporter gene was then used to assess the functionality of P53 protein.

Alkenes↗

PubMedDate not supplied

Loss of PTEN expression is not uncommon, but lacks prognostic value in stage I NSCLC.

The PTEN gene is a tumor-suppressor gene that is inactivated in several types of human tumors. The loss of PTEN expression has been supported as a prognostic marker. Using immunohistochemical analysis, we retrospectively analyzed PTEN expression in specimens from 53 patients with completely resected stage I non-small cell lung cancer (NSCLC) for whom clinical follow-up data were available. Seven of the 53 specimens showed a total lack of staining for PTEN. No statistically significant relationship could be found between PTEN expression and clinicopathological parameters. Although genetic alterations of the PTEN gene are rare in NSCLC, loss of PTEN protein is not an uncommon event in early-stage NSCLC (13.2%). Here, we also report that the level of PTEN protein expression is not an independent prognostic marker in early-stage NSCLC.

Adult↗

PubMed2004

Carboplatin/gemcitabine combination in advanced NSCLC.

The treatment of advanced non-small-cell lung cancer (NSCLC) has evolved rapidly over the past few years. Systemic chemotherapy is associated with both quality of life and modest survival benefit for patients with advanced NSCLC. Platinum-based doublet combinations are the "standard of care." The US Food and Drug Administration (FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to be used in combination with cisplatin for the treatment of advanced NSCLC in the first-line setting. Randomized clinical trials have established comparable efficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine and other platinum doublets. Nonhematologic toxicities occur at a lower frequency with carboplatin/gemcitabine combinations compared with other "standard" platinum-based doublets, whereas dose-limiting thrombocytopenia, the most common toxicity, rarely requires therapeutic intervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the 3-week regimen is preferred. The combination of carboplatin and gemcitabine is an effective regimen with an acceptable toxicity profile for the treatment of advanced NSCLC. This regimen can also be used as a foundation for the development of innovative combinations with molecularly targeted agents.

Antineoplastic Combined Chemotherapy Protocols↗