• The role of high-dose chemotherapy in the treatment of non-small cell lung cancer.

• Targeting epidermal growth factor receptor in lung cancer.

• Angiogenesis inhibitors in lung cancer.

• In regard to Rosenzweiz et al. IJROBP 2001;50:681-685.

• Lung cancer: a review.

• Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase

• [Radio-chemotherapy combinations in non operable localized non small cell lung carcinoma: updates and perspectives]

• Weekly chemotherapy with carboplatin, docetaxel and irinotecan in advanced non-small-cell-lung cancer: a phase II study.

• More power to trials for non-small-cell lung cancer.

• A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally

• Vinorelbine in elderly patients with inoperable nonsmall cell lung carcinoma: a phase II study.

• Lung cancer in the elderly: current and future chemotherapeutic options.

• Protein expression profiles indicative for drug resistance of non-small cell lung cancer.

• Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small-cell lung cancer: a prospective study. Leuven

• Docetaxel (taxotere) in the treatment of non-small cell lung cancer.

• Vinorelbine in the treatment of non-small cell lung cancer.

• Neoadjuvant chemotherapy in non-small cell lung cancer.

• Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance

• Aberrant p53 staining does not predict cisplatin resistance in locally advanced non-small cell lung cancer.

• A phase II study of continuous concurrent thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable

• Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial.

• [Phase I study of biweekly paclitaxel and carboplatin administration in patients with advanced non-small cell lung cancer]

• DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug

• A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer

• Phase II study of carbetimer in non-small cell lung cancer.

• Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study.

• Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II

• Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in

• Roles of NF-kappaB and 26 S proteasome in apoptotic cell death induced by topoisomerase I and II poisons in human nonsmall cell lung carcinoma.

• To predict chemotherapy response using technetium-99m tetrofosmin and compare with p-glycoprotein and multidrug resistance related protein-1

• Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression.

• Treatment of advanced non-small cell lung cancer.

• Clinical benefit of gemcitabine-cisplatin in advanced non-small cell lung cancer elderly patients.

• Comparison of changes in the NSE levels with clinical assessment in the therapy monitoring of patients with SCLC.

• Gemcitabine, ifosfamide and vinorelbine in advanced non-small cell lung cancer: a phase II study.

• GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells.

• Gefitinib (Iressa) for advanced non-small cell lung cancer.

• Management of advanced non-small cell lung cancer: current trends.

• Chemotherapy in advanced small lung cell cancer.

• Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer.

• The role of neoadjuvant chemotherapy in marginally resectable or unresectable stage III non-small cell lung cancer.

• [Late results of the combined treatment with the use of preoperative chemotherapy and surgery of locally advanced non-small cell lung cancer]

• [Chemotherapy of advanced non-small cell lung cancer with the combination of gemcitabine and cisplatin]

• Advanced non-small cell lung cancer: induction chemotherapy and chemoradiation before operation.

• Second-line, low-dose, weekly paclitaxel in patients with stage IIIB/IV nonsmall cell lung carcinoma who fail first-line chemotherapy with

• A Phase II trial of topotecan and gemcitabine in patients with previously treated, advanced nonsmall cell lung carcinoma.

• Prospective randomized study of four novel chemotherapy regimens in patients with advanced nonsmall cell lung carcinoma: a minnie pearl

• Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results.

• A randomized pilot study of SRL172 (Mycobacterium vaccae) in patients with small cell lung cancer (SCLC) treated with chemotherapy.

• Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer.

• The case for the introduction of new chemotherapy agents in the treatment of advanced non small cell lung cancer in the wake of the

• Identical chemotherapy schedules given on and off trial protocol in small cell lung cancer: response and survival results.

• Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why?

1
UI - 11856591
AU - Fetscher S
TI - The role of high-dose chemotherapy in the treatment of non-small cell lung cancer.
SO - Crit Rev Oncol Hematol 2002 Feb;41(2):151-6
AD - Department of Internal Medicine, Division of Hematology and Oncology, City Hospital South, City Hospital South, Kronforder Allee 71/73, D-23560, Lubeck, Germany. s.fetscher@khs-online.de
The literature on high-dose chemotherapy in non-small cell lung cancer (NSCLC) with autologous bone marrow or peripheral blood stem cell transplantation does not - as of yet - provide evidence of relevant benefits. At the same time, the significant risks of treatment-related morbidity and mortality associated with dose-intensified chemotherapy in this vulnerable patient population are increasingly recognized. Whether the advent of new cytotoxic agents such as the Taxans or newer Topoisomerase inhibitors will help to improve the hitherto unsatisfying results of high-dose chemotherapy in NSCLC, remains to be determined. The few ongoing studies in the area strive to examine such newer drug-combinations in a multimodality treatment concept combining neo-adjuvant chemotherapy or chemoradiation with surgery and adjuvant thoracic radiation therapy.

2
UI - 12044241
AU - Baselga J; Albanell J
TI - Targeting epidermal growth factor receptor in lung cancer.
SO - Curr Oncol Rep 2002 Jul;4(4):317-24
AD - Medical Oncology Service, Hospital General Universitari Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain. baselga@hg.vhebron.es
Among the most promising agents in clinical development to treat non-small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) targeting agents. A series of recent studies have demonstrated the activity of anti-EGFR targeted therapies for NSCLC. In advanced NSCLC that is refractory to chemotherapy, antitumor responses have been reported with EGFR tyrosine kinase inhibitors (ZD1839 and OSI-774). The role of ZD1839 and OSI-774 as possible additions to standard chemotherapy in the first-line setting has also been evaluated, and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit. Other areas of research involve looking at the role of EGFR tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies. These exciting results and plans are further complemented by an emerging number of compounds in clinical development, including both monoclonal antibodies (ie, IMC-C225) and other tyrosine kinase inhibitors, directed at the EGFR.

3
UI - 12044242
AU - Kim ES; Herbst RS
TI - Angiogenesis inhibitors in lung cancer.
SO - Curr Oncol Rep 2002 Jul;4(4):325-33
AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston 77030, USA. edkim@mdanderson.org
Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.

4
UI - 11849815
AU - Jenkins P
TI - In regard to Rosenzweiz et al. IJROBP 2001;50:681-685.
SO - Int J Radiat Oncol Biol Phys 2002 Mar 1;52(3):878

5
UI - 11944603
AU - Cersosimo RJ
TI - Lung cancer: a review.
SO - Am J Health Syst Pharm 2002 Apr 1;59(7):611-42
AD - Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
The frequency, risk factors, pathophysiology, diagnosis, and management of lung cancer are reviewed. An estimated 157,400 Americans died of lung cancer in 2001. Lung cancer is the second most frequent cancer in both men and women. The major risk factor for lung cancer is smoking, which accounts for 75-80% of lung cancer-related deaths. Lung cancers can be broadly classified into two forms, small-cell carcinomas and non-small-cell carcinomas. Non-small-cell lung cancer is more common, accounting for up to 75% of lung cancers. Lung cancer is diagnosed by chest radiography, sputum cytology, bronchoscopy, needle biopsy, and other techniques. Surgery plays a major role in managing stage I and stage II non-small-cell lung cancer and may be used for stage III disease. Patients with stage IIIa disease may be surgical candidates, but involvement of mediastinal lymph nodes reduces the probability of survival. Adjuvant irradiation may reduce the rate of local recurrence but does not increase survival time. Adjuvant chemotherapy may confer a small survival-time advantage if the regimen includes cisplatin. Chemotherapy combined with radiation therapy may produce a survival advantage over irradiation alone. Patients with advanced non-small-cell lung cancer should receive combination chemotherapy. Several regimens have shown a survival advantage over best supportive care. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan have activity both as single agents and in combination. Surgery has only a limited role in the management of small-cell lung cancer. Patients with limited disease should receive a platinum-based chemotherapy regimen plus radiation therapy. Combination chemotherapy should be offered to patients with extensive disease. The most active regimens contain cisplatin or carboplatin. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan combinations have shown some promise. Lung cancer, although highly preventable, is usually diagnosed at an incurable stage. Chemotherapy is playing an increasingly important role alongside surgery and radiation therapy in the management of this disease.

6
UI - 12177106
AU - Albain KS; Crowley JJ; Turrisi AT 3rd; Gandara DR; Farrar WB; Clark JI;
TI - Beasley KR; Livingston RB Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019.
SO - J Clin Oncol 2002 Aug 15;20(16):3454-60
AD - Loyola University Stritch School of Medicine, Maywood, IL, USA.
PURPOSE: There are no published survival data after chemoradiotherapy (chemoRT) in pathologically documented stage IIIB non-small-cell lung cancer. Studies of radiotherapy (RT) alone or chemotherapy followed by RT yield 5-year survivals less than 10%. The Southwest Oncology Group (SWOG) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy, safety, and long-term outcome of replacing postinduction surgery with additional chemoRT. PATIENTS AND METHODS: Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1, T4N2, or N3 stage IIIB non-small-cell lung cancer. They had pulmonary function adequate to withstand combined-modality therapy, identical to the requirements of the previous trial with postchemoRT surgery. Induction therapy was two cycles of cisplatin plus etoposide (PE) concurrent with once-daily thoracic RT (45 Gy). In the absence of progressive disease, RT was completed to 61 Gy, with two additional cycles of cisplatin plus etoposide. RESULTS: Fifty eligible patients were accrued with tumor-node (TN) substage confirmed on central review: 18, T4N0/1; 12, T4N2; and 20, N3. Grade 4 neutropenia was the most common toxicity (32%). Grade 3/4 esophagitis occurred in 12% and 8%. Median follow-up was 52 months, and overall median survival was 15 months (10 to 22, 95% confidence interval). Three- and 5-year survivals were 17% and 15% (5-year T4N0/1, 17%; T4N2, 13%; and N3, 15%). CONCLUSION: Feasibility and long-term survival support the application of these results as a standard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared. These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials.

7
UI - 12135861
AU - Hasbini A; Ozanne F; Ammarguellat H; Crequit J; Dolige T; Bouchaert E;
TI - Dutel JL; Durdux C [Radio-chemotherapy combinations in non operable localized non small cell lung carcinoma: updates and perspectives]
SO - Bull Cancer 2002 Jun;89(6):599-611
AD - Service de radiotherapie-oncologie, Centre hospitalier, avenue Leon-Blum, 60021 Beauvais Cedex, France.
Optimal treatment of non operable localized non small cell lung carcinoma (NSCLC) continues to evolve. Increasing overall survival must evolute through improving local tumoral control and eradication of probable occult metastasis. Historically, median survival varies between 7 and 10 months with a standard conventional fractionated radiotherapy (RT). Induction chemotherapy (CT) followed by RT has demonstrated its superiority over RT alone, modality which is widely utilised. Other studies revealed best results with decreasing metastatic relapses. Three independent meta-analysis confirmed benefit obtained with cisplatin based CT followed by RT that allowed to consider this association as a gold standard. Other authors demonstrated an improvement of local control and survival with concomitant RT-CT or hyperfractionated accelerated RT. Results of all of these new therapeutic modalities still poor. Implication of new CT drugs has conducted for an emergence of new studies finding to demonstrate more encouraging results. Randomized trials are conducted in this way.

8
UI - 12044505
AU - Pectasides D; Visvikis A; Kouloubinis A; Glotsos J; Bountouroglou N;
TI - Karvounis N; Ziras N; Athanassiou A Weekly chemotherapy with carboplatin, docetaxel and irinotecan in advanced non-small-cell-lung cancer: a phase II study.
SO - Eur J Cancer 2002 Jun;38(9):1194-200
AD - 1st Department of Medical Oncology, Metaxas Memorial Cancer Hospital, 51 Botassi, Str. 18537, Piraeus, Greece. pectasid@otenet.gr
The aim of this study was to evaluate the efficacy and tolerability of carboplatin, docetaxel plus irinotecan given weekly to patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 50 patients with previously untreated NSCLC (stage IIIB 10; stage IV 40; 44% squamous cell carcinoma; median Eastern Cooperative Oncology Group (ECOG) status 1) received intravenous (i.v.) carboplatin area under the curve (AUC) 2, docetaxel 20 mg/m(2) and irinotecan 60 mg/m(2) on days 1, 8 and 15, repeated every 5 weeks. Prophylactic granulocyte colony-stimulating factor (G-CSF) 150 ug/m(2) was given from days 3 to 6 and 10 to 13. Response was evaluated every two cycles. Four complete responses (8%) and 24 (48%) partial responses were observed, giving an overall intent-to-treat response rate of 56%. 8 patients (16%) achieved stable disease and 14 (28%) progressed. The median time to progression (TTP) was 9.6 months (range 2.5-21.8 months), median survival was 14.8 months (range 0.3-27+ months) and actuarial 1-year survival time was 55%. Grade 3/4 anaemia and thrombocytopenia occurred in 18 and 22% of patients, respectively; 13 patients (26%) developed grade 3/4 neutropenia and 7 (14%) had neutropenic fever that required hospitalisation, but was successfully treated with antibiotics and G-CSF support. One patient developed a severe allergy during docetaxel administration and was withdrawn. Other grade 3/4 adverse events included diarrhoea (n=14; 3 required hospitalisation), nausea/vomiting (n=9), neurotoxicity (n=5) and fatigue (n=5). 6 patients required a dose reduction. This combination of i.v. carboplatin AUC 2, docetaxel 20 mg/m(2) and irinotecan 60 mg/m(2) given weekly is highly effective in the treatment of chemotherapy-naive advanced NSCLC. Toxicity was moderate, but manageable.

9
UI - 8777165
AU - Sorensen JB; Hansen HH
TI - More power to trials for non-small-cell lung cancer.
SO - Ann Oncol 1996 Feb;7(2):119-20

10
UI - 8777169
AU - Planting A; Helle P; Drings P; Dalesio O; Kirkpatrick A; McVie G;
TI - Giaccone G A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small-cell lung cancer. An EORTC Lung Cancer Cooperative Group trial.
SO - Ann Oncol 1996 Feb;7(2):139-44
AD - Department of Medical Oncology, Rotterdam Cancer Institute/Daniel den Hoed Kliniek, The Netherlands.
BACKGROUND: The treatment results of radiotherapy in stage III non-small-cell lung cancer are very poor. Several phase II studies showed that neoadjuvant chemotherapy followed by radiotherapy was feasible in this patient group and suggested that treatment outcome might improve. A randomized phase II study was performed addressing the response rate and morbidity of high-dose split course radiotherapy (RT) versus the same radiotherapy preceded by high-dose chemotherapy (CT) in patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: Seventy eligible patients were randomized in this study. CT consisted of cisplatin 100 mg/m2 days 1 and 22, and vindesine 3 mg/m2 on days 1, 8, 22 and 29. Radiotherapy started on day 43 in the combined arm and immediately in the RT-only arm. The primary tumour and the regional nodes were treated by 30 Gy/10 fractions/2 weeks and after the split by a second course of 25 Gy/10 fractions/2 weeks. In the combined arm a third CT cycle was planned during the split between RT courses. RESULTS: In the CT + RT arm 34 patients were evaluable for response and toxicity and 30 patients in the RT only arm. After completion of treatment 7 patients had a complete response (2 in the CT plus RT arm, 5 in the RT alone arm) and 26 patients a partial response (13 in the CT plus RT arm, 13 in the RT alone arm) for an overall response rate of 52% (95% CI 39%-65%). Acute toxicity was worse in the combined treatment arm with grade 4 leucocytopenia in 8 patients and thrombocytopenia grade 4 in one patient. Three patients had reversible renal toxicity grade 2. There was one toxic death in the RT plus CT arm. There was no enhancement of acute or late radiation pulmonary or oesophageal toxicity. Time to progressive disease (median 30 vs. 35 weeks) and overall survival time (median 12 months) were equal in both treatment arms. CONCLUSION: High-dose radiotherapy preceded by high-dose chemotherapy was more toxic than radiotherapy alone and did not result in this study in any benefit in terms of response rate, time to progressive disease and overall survival.

11
UI - 10870049
AU - Buccheri G; Ferrigno D
TI - Vinorelbine in elderly patients with inoperable nonsmall cell lung carcinoma: a phase II study.
SO - Cancer 2000 Jun 15;88(12):2677-85
AD - Divisione di Pneumologia, Ospedale S. Croce e Carle, Cuneo, Italy.
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.

12
UI - 12093323
AU - Hinton S; Sandler A
TI - Lung cancer in the elderly: current and future chemotherapeutic options.
SO - Drugs Aging 2002;19(5):365-75
AD - Indiana University School of Medicine, Indianapolis, Indiana, USA.
Lung cancer is a prevalent malignancy disproportionately affecting the elderly, and in our aging societies will only increase in magnitude. Physicians typically assume that elderly lung cancer patients will have poorer prognoses. This belief is in part based on certain physiological changes of aging affecting the kidneys, liver, and bone marrow. However, there are no data to clearly support or refute increased toxicity from chemotherapy or a lessened therapeutic effect in the elderly based on these changes, although it is a field worthy of further study. Retrospective studies of treatment of elderly non-small cell and small cell lung cancer patients do not suggest a worse prognosis based on advanced age alone. Clinicians are hampered by the lack of clinical trials focusing on or even including the elderly, despite the increased incidence of lung cancer in the elderly. Phase II studies in elderly non-small cell lung cancer patients concentrate on newer agents (vinorelbine and gemcitabine) alone or combined with platinum compounds in hopes of more favourable toxicity profiles. Phase III trials have demonstrated survival benefits, quality of life improvements, and acceptable toxicity profiles for vinorelbine compared to best supportive care alone and the combination of vinorelbine and gemcitabine compared to vinorelbine alone. Data are also sparse for elderly small cell lung cancer patients. Phase II studies focused on single agent oral etoposide also in hopes of lessening toxicity. However, phase III trials have shown improvement in survival and quality of life for multiagent intravenous chemotherapy compared to oral etoposide. Given the existing data, altering therapy for lung cancer patients based on age alone would not be warranted. Given the prevalence of the disease, future studies need to include an appropriate number of elderly patients with continued emphasis on quality of life in addition to survival.

13
UI - 12177790
AU - Volm M; Koomagi R; Mattern J; Efferth T
TI - Protein expression profiles indicative for drug resistance of non-small cell lung cancer.
SO - Br J Cancer 2002 Jul 29;87(3):251-7
AD - German Cancer Research Centre, Heidelberg, Germany.
Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro. The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-pi, metallothionein, O6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). Copyright 2002 Cancer Research UK

14
UI - 9602259
AU - Vansteenkiste JF; De Leyn PR; Deneffe GJ; Lievens YN; Nackaerts KL; Van
TI - Raemdonck DE; van der Schueren E; Lerut TE; Demedts MG Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small-cell lung cancer: a prospective study. Leuven Lung Cancer Group.
SO - Ann Oncol 1998 Mar;9(3):261-7
AD - Department of Pulmonology, University Hospital Gasthuisberg, Belgium. johan.vansteenkiste@uz.kuleuven.ac.be
PURPOSE: In the pioneer data from the Memorial-Sloan-Kettering group, preoperative mitomycin-C-vindesine-platinum (MVP) induction chemotherapy in N2-NSCLC was accompanied with substantial pulmonary toxicity. In this study, the efficacy and toxicity of three-drug VIP induction chemotherapy, the pathologic response in resection specimens, the early survival and relapse patterns are examined. PATIENTS AND METHODS: proven N2-NSCLC were treated with three cycles of VIP induction, followed by definitive locoregional treatment (resection and mediastinal dissection or radical radiotherapy). Several patients had unfavorable prognostic characteristics with respect to clinical and biological findings, tumor location and bulk of disease. RESULTS: The response rate to chemotherapy was 59% (95% Confidence Interval 34-75). Twenty-three responding patients had radical locoregional treatment: radical radiotherapy in four, resection in 19. Downstaging was present in nine of the 19 resection specimens, with two pathologic complete responses. The median survival time (MST) of all patients is 19 months, with a projected two-year survival of 49%. In patients responsive to chemotherapy who received definitive local treatment, the MST is not yet reached, and the projected two-year survival is 57%. Relapses were mainly distant, with isolated brain relapse as a disturbing finding. The main toxicity's were leukopenia and vomiting, but they were manageable. In contrast with MVP, no severe pulmonary toxicity occurred. CONCLUSIONS: VIP is a suitable induction regimen for N2-NSCLC, demonstrating a good activity and very acceptable toxicity.

15
UI - 11966449
AU - Georgoulias V
TI - Docetaxel (taxotere) in the treatment of non-small cell lung cancer.
SO - Curr Med Chem 2002 Apr;9(8):869-77
AD - Medical Oncology, School of Medicine, University of Crete, Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, Crete, 711.10 Heraklion, Greece. georgsec@med.uoc.gr
Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.

16
UI - 11966450
AU - Gridelli C; De Vivo R
TI - Vinorelbine in the treatment of non-small cell lung cancer.
SO - Curr Med Chem 2002 Apr;9(8):879-91
AD - Divisione di Oncologia Medica, Azienda Ospedaliera S.G.Moscati, Avellino, Italy. cgridelli@sirio-oncology.it
Non-small cell lung cancer (NSCLC) remains a fatal disease: the majority of patients are diagnosed as having metastases or advanced inoperable tumors. The activity of chemotherapy in NSCLC patients is low with objective response rarely complete and sustained. Cisplatin-based combinations are considered as the standard chemotherapy treatment. Recently., the introduction of new and less toxic chemotherapeutic agents., such as vinorelbine., has led investigators to research for active non-cisplatin-containing combinations to treat patients with advanced disease having as primary needs symptom relief and an acceptable quality of life. This review will focus on the pharmacological properties of vinorelbine and its role in adjuvant chemotherapy., in combined chemo-radiotherapy., in advanced disease and in the particular setting of the elderly. The oral use of vinorelbine will be among the future developments of this drug.

17
UI - 11966451
AU - Felip E; Rosell R
TI - Neoadjuvant chemotherapy in non-small cell lung cancer.
SO - Curr Med Chem 2002 Apr;9(8):893-8
AD - Hospital Vall d'Hebron, Barcelona, Spain.
Non-small cell lung cancer (NSCLC) is a systemic illness. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. In resectable stage IIIA NSCLC the findings of three randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in locally advanced NSCLC continues to evolve and is a subject of ongoing research. One focus for present research is to integrate new active agents into the neoadjuvant setting. Another challenge is to find better treatment approaches in earlier stages of disease. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse.

18
UI - 12177774
AU - Koukourakis MI; Romanidis K; Froudarakis M; Kyrgias G; Koukourakis GV;
TI - Retalis G; Bahlitzanakis N Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection.
SO - Br J Cancer 2002 Aug 12;87(4):385-92
AD - Tumour and Angiogenesis Research Group, PO Box 12, Democritus University of Thrace, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
The substantial augmentation of the radiation sequelae during chemo-radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo-radiotherapy scheme with Stealth liposomal doxorubicin (Caelyx and Docetaxel (Taxotere in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere was 20 mg m(-2) week and of Caelyx was 15 mg m(-2) every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere/Caelyx was, thereafter, increased to 20/25 (five patients) and 30/25 mg m(-2) (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.

19
UI - 12197224
AU - Johnson EA; Klimstra DS; Herndon JE 2nd; Catalano E; Canellos GP;
TI - Graziano SL; Kern JA; Green MR Aberrant p53 staining does not predict cisplatin resistance in locally advanced non-small cell lung cancer.
SO - Cancer Invest 2002;20(5-6):686-92
AD - Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. johnson.elizabeth2@mayo.edu
Cisplatin based chemotherapies have increased the survival in nonsmall cell lung cancer. A mechanism for identifying tumors resistant to cisplatin would be useful in avoiding unnecessary toxicity of platinum regimens. Mutation of p53 has been shown to induce chemotherapy resistance in vitro. We hypothesized that tumors staining for p53 would be resistant to cisplatin. In Cancer and Leukemia Group B protocol 8935, patients with stage IIIA (N2 node positive) nonsmall cell lung cancer received chemotherapy followed by surgery, then post-operative chemotherapy and/or radiation. All patients underwent pre-treatment staging mediastinoscopy. Twenty-five out of forty-nine pre-treatment mediastinal lymph node specimens stained positively for p53. Positive staining did not correlate with response to chemotherapy or survival. It did predict a slightly higher complete or partial resection rate compared to negative staining (76 vs. 45%) (p = 0.042). A trend toward longer median survivals was seen in patients with positive p53 staining. This study does not support the ability of p53 staining to predict chemotherapy resistance.

20
UI - 11891041
AU - Atagi S; Kawahara M; Hosoe S; Ogawara M; Kawaguchi T; Okishio K; Naka N;
TI - Sunami T; Mitsuoka S; Akira M A phase II study of continuous concurrent thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small cell lung cancer.
SO - Lung Cancer 2002 Apr;36(1):105-11
AD - Department of Internal Medicine, National Kinki Central Hospital for Chest Diseases, 1180 Nagasone, Sakai, Osaka 591-8555, Japan. s-atagi@kch.hosp.go.jp
The split-course concurrent thoracic radiation therapy (TRT) and full-dose chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC) has produced promising results by comparison with the sequential approach. Instead of split-course radiation, we conducted a phase II study to investigate the feasibility of continuous concurrent TRT and chemotherapy. Twenty-two patients with unresectable NSCLC were enrolled onto a phase II study of continuous concurrent radiotherapy and chemotherapy. Treatment consisted of two courses of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29 and 36), and mitomycin (8 mg/m(2) on days 1 and 29). TRT began on day 2 at a dose of 60 Gy (2 Gy per fraction and 5 fractions per week for a total of 30 fractions). Of 22 patients assessable for response, none achieved a CR and 17 (77.3%) achieved a PR with an overall response rate of 77.3% (95% confidence interval, 54.6-92.2%). Grade 3 or 4 leukopenia was observed in 5/13 (81.8%) patients. Six patients (27.3%) experienced > or = grade 3 thrombocytopenia. Non-hematological toxicity was relatively mild. The overall median survival time was 19.0 months and the 1- and 2-year survival rates were 84.8 and 34.5%, respectively. It was possible to administer two courses of chemotherapy in 18 patients (81.8%) as planned. Nineteen (86.4%) of the 22 patients received the planned 60 Gy radiation. It seems to be difficult to administer the planned treatment without any interruption for the majority of patients. However, in the selected patients who completed the 60 Gy TRT, nearly half of the patients completed TRT without interruption. This combination regimen is considered to be feasible on condition that the stopping rule of the treatment is followed. We recommend administering radiotherapy continuously as far as possible.

21
UI - 11891040
AU - Masotti A; Zannini G; Gentile A; Morandini G
TI - Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial.
SO - Lung Cancer 2002 Apr;36(1):99-103
AD - Divisione di Pneumologia, Piazzale Stefani 1, Verona, Italy.
This phase II trial was designed to investigate the efficacy and tolerability of gemcitabine combined with carboplatin in patients with advanced or metastatic NSCLC. Patients were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and carboplatin AUC 5 mg/ml/min on day 2 of each cycle. Fifty patients (Zubrod-ECOG-WHO performance status 0/1 in 70/30%, stage IV disease in 64%) entered the study and were evaluable for response and toxicity. There was 1 complete response and 24 partial responses among 50 evaluable patients, for a response rate of 50% (95% CI: 36.0-64.1%). The median survival time was 13 months (range: 6-22 months), and the 1-year survival rate was 54%. Hematologic toxicities included grades 3 and 4 neutropenia in 24 and 8% of patients, respectively, and grades 3 and 4 thrombocytopenia in 48 and 8% of patients, respectively. These were without clinical sequelae. Seven (14%) patients had grade 3 nausea and vomiting. The combination of gemcitabine and carboplatin is highly active and well tolerated in patients with advanced or metastatic NSCLC.

22
UI - 12214466
AU - Ichiki M; Rikimaru T; Gohara R; Oshita Y; Kamimura T; Hoashi S; Koga T;
TI - Aizawa H [Phase I study of biweekly paclitaxel and carboplatin administration in patients with advanced non-small cell lung cancer]
SO - Gan To Kagaku Ryoho 2002 Aug;29(8):1389-94
AD - First Dept. of Medicine, Kurume University, School of Medicine.
A phase I study of a biweekly outpatient regimen composed of carboplatin (CBDCA) and paclitaxel (TXL) was conducted for advanced non-small cell lung cancer. TXL was given in combination with a fixed dose of CBDCA (AUC 3) every 2 weeks. The starting dose of TXL was 100 mg/m2, and the dose was escalated in increments of 20 mg/m2. Three to six patients were allocated to each level. Toxicities were evaluated in the first 4 courses to determine the maximum tolerated dose (MTD). TXL 160 mg/m2 dosages proved to be MTD, and the dose limiting toxicity (DLT) was hematotoxicity (neutropenia). The patients, however, recovered from neutropenia using G-CSF immediately, when G-CSF was used. Gastrointestinal toxicity was well-tolerated. A response was found in 9 out of 20 patients who received 4 courses or more (45%). These results suggest that the recommended dose would be CBDCA (AUC 3) + TXL 140 mg/m2. The biweekly regimen has a high level clinical activity and excellent tolerability, and is suitable for outpatients. We started a phase II study because of these results.

23
UI - 12110502
AU - Monks NR; Blakey DC; East SJ; Dowell RI; Calvete JA; Curtin NJ; Arris
TI - CE; Newell DR DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug therapy ZD2767.
SO - Eur J Cancer 2002 Jul;38(11):1543-52
AD - Cancer Research Unit, University of Newcastle, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK.
Cellular determinants of sensitivity to the bifunctional alkylating agent 4-[N,N-bis(2-iodoethyl)amino]phenol (ZD2767D), the active drug produced by ZD2767 antibody-directed enzyme prodrug therapy (ADEPT), were studied. The prodrug 4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl L-glutamic acid (ZD2767P)+activating enzyme carboxypeptidase G2 (CPG2) displayed growth inhibitory activity (IC(50) 0.04-2.2 microM) in colorectal tumour and non-small cell lung cancer (NSCLC) cell lines, and was more potent than a monofunctional ZD2767D analogue (colorectal cell lines-IC(50) 18-38 microM), synthesized for the first time. ZD2767P + CPG2 rapidly formed DNA-DNA interstrand cross-links (maximal at 10 min), and semi-quantitative analyses indicate that levels were similar in 3 of 4 cell lines studied (25-75 rad equivalents) at equitoxic (10 x IC(50)/LC(50)) concentrations. In matched HCT116 TP53 functional/non-functional cell lines, there was no significant difference in the sensitivity to ZD2767P+CPG2. Together, these results suggest that cellular sensitivity to ZD2767P+CPG2 is, in part, related to the levels of interstrand crosslinks, but that TP53 status does not markedly effect chemosensitivity.

24
UI - 12168889
AU - Kakolyris SS; Kouroussis C; Koukourakis M; Kalbakis K; Mavroudis D;
TI - Vardakis N; Georgoulias V A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer previously treated with a cisplatin-based front line chemotherapy.
SO - Anticancer Res 2002 May-Jun;22(3):1891-6
AD - Department of Clinical Oncology, University General Hospital of Heraklion, Crete, Greece.
PURPOSE: CPT-11 and gemcitabine are both active agents against non-small cell lung cancer (NSCLC). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of their combination in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Twenty-seven patients with histologically confirmed NSCLC, who had failed cisplatin-based front-line chemotherapy, were enrolled. The patients' median age was 56 years, 24 were male and 22 had a performance status (WHO) 0-1. Gemcitabine was administered on days 1 and 8, as a 30-minute i.v. infusion, at escalated doses ranging from 900 to 1200 mg/m2. CPT-11 was given over a 60-minute i.v. infusion on day 8 at escalated doses ranging from 200 to 350 mg/m2, following gemcitabine administration. The treatment was repeated every three weeks. RESULTS: The MTD was exceeded at dose-level 7 with CPT-11 350 mg/m2 and gemcitabine 1200 mg/m2, where all three enrolled patients presented DLTs (one patient grade 4 thrombocytopenia, one grade 3 diarrhea and one grade 3 asthenia). The recommended doses for future phase II studies are CPT-11 300 mg/m2 on day 8 and gemcitabine 1200 mg/m2 on days 1 and 8. A total of 107 treatment cycles were administered. Grade 3/4 neutropenia was observed in 13 (13%) cycles, febrile neutropenia in 3 (3%) and grade 3/4 thrombocytopenia in 2 (2%). Grade 2/3 diarrhea was seen in 6 (6%) cycles, grade 2/3 nausea and vomiting in 13 (13%) and grade 2/3 asthenia in 8 (8%). Other toxicities were mild. Among 23 patients evaluable for response, PR was achieved in one (4.5%), SD in 12 (52.5%) and PD in 10 (43%). CONCLUSION: The results of this phase I study clearly demonstrate that gemcitabine and CPT-11 can be efficiently combined in a low-toxicity regimen with doses equal or near monotherapy levels. Further studies are needed to evaluate the efficacy of this combination in both chemotherapy-naive and pre-treated patients with advanced NSCLC.

25
UI - 1964676
AU - Keaton M; Brown T; Craig J; Fries G; Harmon G; Zaloznik A; Orczyk G; Von
TI - Hoff D Phase II study of carbetimer in non-small cell lung cancer.
SO - Invest New Drugs 1990 Nov;8(4):385-6
AD - Brooke Army Medical Center, Fort Sam Houston, TX.

26
UI - 11863089
AU - Monnet I; de CH; Soulie P; Saltiel-Voisin S; Bekradda M; Saltiel JC;
TI - Brain E; Rixe O; Yataghene Y; Misset JL; Cvitkovic E Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study.
SO - Ann Oncol 2002 Jan;13(1):103-7
AD - Centre Hospitalier Intercommunal, France.
BACKGROUND: Oxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study. PATIENTS AND METHODS: Twenty-eight chemotherapy-naive patients (22 men and six women: median age 58 years, range 33-70), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure. RESULTS: A total of 117 cycles were given, for a median of three per patient (range 1-8). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25 cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed. CONCLUSIONS: The oxaliplatin-vinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.

27
UI - 11863090
AU - Chen YM; Perng RP; Lee YC; Shih JF; Lee CS; Tsai CM; Whang-Peng J
TI - Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small-cell lung cancer previously untreated.
SO - Ann Oncol 2002 Jan;13(1):108-15
AD - Chest Department, Taipei Veterans General Hospital, National Yang-Ming University, National Health Research Institute, Taiwan. ymchen@vghtpe.gov.tw
BACKGROUND: Paclitaxel (Taxol) plus carboplatin (PC) has shown activity in the treatment of advanced non-small-cell lung cancer (NSCLC). Non-platinum-containing combination chemotherapy, such as paclitaxel plus gemcitabine (P

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