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ABSTRACT: INTRODUCTION:: Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design. METHODS:: Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization. RESULTS:: There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected. CONCLUSIONS:: The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2012; 7(10):1574-1582. · 4.55 Impact Factor
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Eng-Huat Tan,
Glenwood D Goss,
Ravi Salgia,
Benjamin Besse,
David R Gandara, Nasser H Hanna,
James Chih-Hsin Yang,
Raymond Thertulien,
Michael Wertheim,
Julien Mazieres,
Thomas Hensing,
Christa Lee,
Neeraj Gupta,
Rajendra Pradhan,
Jiang Qian,
Qin Qin,
Frank A Scappaticci,
Justin L Ricker,
Dawn M Carlson,
Ross A Soo
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ABSTRACT: This study assessed activity and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, in patients with locally advanced or metastatic non-small cell lung cancer.
In this open-label trial (NCT00517790), patients who received one to two prior lines of systemic therapy were randomized to oral linifanib 0.10 mg/kg (low dose) or 0.25 mg/kg (high dose) once daily. Tumor responses were assessed by independent central imaging review every 8 weeks. The primary end point was progression-free rate at 16 weeks. Secondary end points included objective response rate, time to progression, progression-free survival, and overall survival. Safety was also assessed.
Between August 2007 and October 2008, 139 patients were enrolled; 60% had two or more prior regimens, and 88% had nonsquamous cell carcinoma. The objective response rate (low dose and high dose) was 5.0% (3.1 and 6.8%), progression-free rate at 16 weeks was 33.1% (32.3 and 33.8%), median time to progression was 3.6 months (3.6 and 3.7 months), median progression-free survival was 3.6 months (3.5 and 3.6 months), and median overall survival was 9.0 months (10.0 and 8.3 months). The most common linifanib-related adverse events were fatigue (42%), decreased appetite (38%), hypertension (37%), diarrhea (32%), nausea (27%), palmar-plantar erythrodysesthesia (24%), and proteinuria (22%). These events were more common in the high-dose group. The most common linifanib-related grade 3 or 4 adverse event was hypertension (14%).
Linifanib is active in advanced non-small cell lung cancer as second- or third-line therapy. Increased adverse event rates were observed at the high dose of linifanib.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2011; 6(8):1418-25. · 4.55 Impact Factor
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ABSTRACT: Platinum-based chemotherapy has been shown to provide survival benefits in advanced non-small cell lung cancer (NSCLC). Maintenance/consolidation chemotherapy in NSCLC has gained renewed interest with improved tolerability of chemotherapy and the addition of biologic agents. Various studies have evaluated the role of prolonged duration of chemotherapy as well as maintenance/consolidation strategies with both chemotherapy and biologic agents. The available data at this time demonstrates that maintenance or consolidation therapy can improve progression free survival; however this does not result consistently in an improved overall survival. We review the literature with regard to duration of therapy and use of maintenance/consolidation therapy in advanced NSCLC.
rapeutic Advances in Medical Oncology, The 01/2010; 2(1):17-23.
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ABSTRACT: Advanced nonsmall cell lung cancer (NSCLC) remains a therapeutic challenge. Traditional chemotherapy provides response rates of about 20-40% and median survivals of 8-10 months. The outcome of patients presenting at an advanced stage is therefore disappointing. In order to improve patients' outcomes, there has been a renewed interest in evaluating the role of maintenance or consolidation chemotherapy or both. Therefore, this review is timely and also relevant to clinical practice.
Thirteen randomized clinical trials have reported that consolidation or maintenance therapy or both improves progression free survival in patients with advanced NSCLC who have achieved disease control following their initial therapy. This does not translate into survival benefits in the same patient populations. Furthermore, prolonged therapy results in more treatment-related toxicity without improvements in quality of life as documented in 11 of these trials. We summarize the current data and perspectives of consolidation/maintenance therapy in patients with advanced NSCLC.
Completed trials evaluating consolidation or maintenance therapy or both in patients with advanced NSCLC consistently demonstrate that this strategy will improve progression free survival but not overall survival. Administering maintenance or consolidation therapy to patients with advanced NSCLC to improve progression free survival alone is not recommended.
Current opinion in oncology 04/2009; 21(2):110-5. · 4.09 Impact Factor
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Thomas J Lynch,
George R Blumenschein,
Jeffrey A Engelman,
Igor Espinoza-Delgado,
Ramaswamy Govindan,
Jeff Hanke, Nasser H Hanna,
John V Heymach,
Fred R Hirsch,
Pasi A Janne, [......],
Ronald B Natale,
Gregory J Riely,
Lecia V Sequist,
Geoffrey I Shapiro,
Alice Shaw,
Frances A Shepherd,
Mark Socinski,
A Gregory Sorensen,
Heather A Wakelee,
Aaron Weitzman
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ABSTRACT: The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2008; 3(6 Suppl 2):S107-12. · 4.55 Impact Factor
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ABSTRACT: The purpose of this study is to determine the control of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC) with the combined use of palonosetron and olanzapine, and dexamethasone with the dexamethasone given on day 1 only.
Forty chemotherapy-naive patients received on the day of chemotherapy, day 1, an anti-emetic regimen consisting of dexamethasone, palonosetron, and olanzapine. Patients continued olanzapine for days 2-4 after chemotherapy administration. Patients recorded daily episodes of emesis, daily symptoms utilizing the M.D. Anderson Symptom Inventory, and the utilization of rescue therapy.
For the first cycle of chemotherapy, the complete response (no emesis, no rescue) for the acute period (24 h post-chemotherapy) was 100%, the delayed period (days 2-5 post-chemotherapy) 75%, and the overall period (0 120 h post-chemotherapy) 75% in 8 patients receiving HEC and was 97, 75, and 72% in 32 patients receiving MEC. Patients with no nausea for the acute period was 100%, the delayed period 50%, and the overall period 50% in 8 patients receiving HEC and was 100, 78, and 78% in 32 patients receiving MEC.
The complete response and control of nausea in subsequent cycles of chemotherapy were not significantly different from cycle one.
Olanzapine combined with a single dose of dexamethasone and a single dose of palonosetron was very effective in controlling acute and delayed CINV in patients receiving both HEC and MEC.
Supportive Care Cancer 12/2007; 15(11):1285-91. · 2.60 Impact Factor
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ABSTRACT: The aim of this study is to present an analysis investigating the association of patient characteristics with overall survival (OS) in individuals with stage III non-small-cell lung cancer (NSCLC).
Ten prognostic factors were analyzed in 203 patients with NSCLC who were enrolled in a phase III trial conducted by the Hoosier Oncology Group and US Oncology between 2002 and 2006. Eligible patients had untreated stage III NSCLC, forced expiratory volume in one second (FEV(1)) > or = 1 liter, baseline performance status of 0/1, and weight loss < 5% in 3 months preceding the trial. Univariate analysis, Cox proportional hazards regression, and parametric accelerated failure time models were performed to identify the factors that affected survival duration. Variables analyzed included age (< 70 years vs. > or = 70 years), sex, ethnicity, body mass index, performance status (0 vs. 1), FEV(1) (> 2 L vs. 1-2 L), smoking status (current vs. never/former), hemoglobin (Hb) level, use of positron emission tomography scan in staging, and stage (IIIA vs. IIIB).
Median follow-up was 25.6 months and the median OS was 21.2 months. The univariate analysis showed that Hb levels > or = 12 were associated with an improved survival (P = .033). The multivariable parametric accelerated failure time model demonstrated the association of FEV(1) > 2 L (P = .014), and higher pretreatment Hb values (P = .007) as independent prognostic factors for OS. Similarly in the Cox regression, survival was influenced by Hb and FEV(1) > 2 L.
This analysis suggests that FEV(1) > 2 L and higher pretreatment Hb values are associated with improved OS in patients with stage III NSCLC. These factors can be useful in predicting for more favorable outcomes in patients with stage III NSCLC and provide additional information when designing future studies.
Clinical Lung Cancer 09/2007; 8(8):478-82. · 2.94 Impact Factor
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Journal of Clinical Oncology 01/2007; 24(35):5611-2; author reply 5612-3. · 18.37 Impact Factor
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ABSTRACT: Patients with advanced non-small cell lung cancer continue to have a poor prognosis; most die from the disease within 1 year. Chemotherapy is beneficial for some patients in the first-line metastatic setting. Three agents, namely docetaxel, pemetrexed, and erlotinib, are approved by the United States Food and Drug Administration as treatment in the second-line setting. In this article, we examine the data supporting the use of these agents in the second-line setting and review data from other completed trials. Lastly, we propose strategies to advance the treatment of patients with non-small cell lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2006; 1(6):582-7. · 4.55 Impact Factor
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ABSTRACT: Surgical resection remains the cornerstone of therapy for early-stage disease and offers the best chance for cure. Local and distant failure rates, however, remain unacceptably high with surgery alone. Radiation and systemic chemotherapy have been used to reduce recurrences in early-stage disease. Neoadjuvant and adjuvant strategies both offer sound theoretical benefit, but evidence supporting this has been lacking. The publication of a meta-analysis in 1995 triggered a reevaluation of adjuvant chemotherapy. Four randomized trials reported in the last 2 years support the use of adjuvant platinum-based chemotherapy.
This article reviews the history of clinical trials evaluating neoadjuvant and adjuvant therapy in non-small-cell lung cancer.
Adjuvant chemotherapy improves 5-year survival rates by approximately 5%-15% compared with surgery alone.
Surgical resection followed by adjuvant chemotherapy is the standard of care treatment for patients with completely resected stage I, II, and IIIA non-small-cell lung cancer.
Annals of Surgical Oncology 04/2006; 13(3):291-301. · 4.17 Impact Factor
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Toru Mukohara,
Jeffrey A Engelman, Nasser H Hanna,
Beow Y Yeap,
Susumu Kobayashi,
Neal Lindeman,
Balázs Halmos,
Joseph Pearlberg,
Zenta Tsuchihashi,
Lewis C Cantley,
Daniel G Tenen,
Bruce E Johnson,
Pasi A Jänne
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ABSTRACT: Many patients with non-small-cell lung cancer (NSCLC) who achieve radiographic responses to treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib have somatic mutations in the EGFR tyrosine kinase domain. However, little is known about the efficacy of cetuximab, an antibody against the EGFR extracellular domain, in EGFR mutant NSCLC.
NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) were treated with various dilutions of gefitinib or cetuximab relative to maximal achievable serum concentration. Cell growth was analyzed by the MTS assay, with differences between dose-response curves analyzed nonparametrically. Apoptosis was analyzed by propidium iodide staining and immunoblotting for PARP. Phosphorylation of EGFR and the downstream signaling components ERK1/2 and Akt were analyzed by immunoblotting. Statistical tests were two-sided.
Growth of NSCLC lines with wild-type EGFR was slightly (A549 and H441) or moderately (H1666) inhibited by gefitinib and cetuximab, and the effects of the two agents were similar. Both agents also induced no (H441) or moderate (H1666) apoptosis in NSCLC cells with wild-type EGFR. By contrast, gefitinib was statistically significantly more effective than cetuximab at inhibiting growth of EGFR mutant cells (H3255: P = .003, DFCILU-011: P = .011, and PC-9: P = .003), and gefitinib-treated EGFR mutant cells had higher levels of apoptosis than cetuximab-treated cells (mean fold increase in apoptosis by 1 microM of gefitinib and 10 microg/mL of cetuximab relative to control, H3255: 8.3 [95% confidence interval {CI} = 4.8 to 11.8] and 2.1 [95% CI = 2.0 to 2.2], respectively, P = .025; DFCILU-011: 5.7 [95% CI = 5.1 to 6.3] and. 0.9 [95% CI = 0.3 to 1.5], respectively, P < .001). Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect. Both gefitinib and cetuximab inhibited the growth of HCC827 cells, but gefitinib inhibited growth to a greater extent (P = .003).
EGFR mutations in NSCLC cells are associated with sensitivity to gefitinib but not to cetuximab.
CancerSpectrum Knowledge Environment 09/2005; 97(16):1185-94. · 14.07 Impact Factor
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ABSTRACT: Patients with bone metastases related to non-small-cell lung cancer (NSCLC) have a poor prognosis. In the rare situation in which a patient has a solitary bone metastasis, aggressive treatment may be warranted, as illustrated by the case reported here.
Clinical Lung Cancer 06/2005; 6(6):367-8. · 2.94 Impact Factor
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ABSTRACT: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Although chemotherapy has been shown to increase survival for patients with advanced-stage disease, survival benefits have been modest and come at the cost of significant toxicity. Treatment options in the second-line setting have been limited. Pemetrexed, a multitargeted antifolate, has activity as a single agent and as part of combination chemotherapy against NSCLC. As reported in a recent phase III clinical trial, survival outcomes in the second-line setting for patients treated with pemetrexed or docetaxel are similar. More importantly, major toxicity with the use of pemetrexed with vitamin B(12) and folate supplementation is far less than with docetaxel. Based on its single agent activity, ease of administration, and favorable toxicity profile, pemetrexed has the potential to be incorporated in various settings against NSCLC, including metastatic disease, as adjuvant therapy, and for locally advanced disease.
Current Treatment Options in Oncology 02/2005; 6(1):83-93. · 2.68 Impact Factor
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ABSTRACT: The incidence of small cell lung cancer (SCLC) is declining in the United States (US). SCLC is nearly universally smoking-related and is very sensitive to both chemotherapy and radiation therapy. In contrast to non-small cell lung cancer (NSCLC), SCLC is staged as either limited-stage disease (LD) or extensive-stage disease (ED). Chemotherapy remains the essential component for treatment of all patients with SCLC, regardless of stage or performance status. In LD, the addition of radiation therapy improves survival over chemotherapy alone. However, the dose, timing and schedule of radiation are not well defined. Prophylactic cranial irradiation (PCI) reduces brain relapse rates, and modestly improves survival in patients in a clinical remission. Many chemotherapy agents and combinations result in high response rates in ED SCLC; however, median survival time remains 8-10 months. Cisplatin (or carboplatin) and etoposide is the standard doublet used in the United States. One study has shown cisplatin plus irinotecan to have a survival benefit over cisplatin plus etoposide, but confirmatory studies are needed. Patients with ED frequently relapse, and relapsed/refractory SCLC has a poor prognosis. The challenge remains to identify novel therapies and molecular targets to improve survival in SCLC.
Critical Reviews in Oncology/Hematology 12/2004; 52(2):117-26. · 4.41 Impact Factor
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ABSTRACT: During the past four decades, chemotherapy has failed to demonstrate a consistent clinical benefit for patients with unresectable or recurrent malignant pleural mesothelioma (MPM). Consequently, there has been no standard chemotherapy nor US Food and Drug Administration (FDA)-approved drug for patients with this disease. The introduction of pemetrexed (Alimta, Eli Lilly), a multitargeted antifolate agent, has improved the outlook for patients with mesothelioma by demonstrating a positive impact on quality of life and by prolonging survival. Pemetrexed is the first FDA-approved drug for the treatment of MPM. The combination of cisplatin plus pemetrexed is now the standard of care for the treatment of the disease. Furthermore, supplementation with vitamin B12 and folate has vastly improved the toxicity profile of pemetrexed. This article summarizes historical chemotherapy trials in MPM; discusses key features of clinical trial design for MPM; summarizes the results of a landmark Phase III trial of pemetrexed and cisplatin in MPM; discusses the relative contributions of pemetrexed and cisplatin to the regimen; explains the importance of vitamin supplementation of pemetrexed; and provides direction for future clinical trials in this disease.
Expert Review of Anti-infective Therapy 07/2004; 4(3):361-8. · 2.65 Impact Factor
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Nasser H Hanna
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ABSTRACT: Platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Based on 2 landmark studies that reported improved survival times and quality of life when comparing docetaxel with ifosfamide, vinorelbine, or BSC alone, docetaxel at 75 mg/m(2) given once every 3 weeks has been the standard of care as second-line chemotherapy since 2000. Docetaxel given at this dose and schedule resulted in significant hematologic 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. A phase III study in 571 patients comparing pemetrexed with docetaxel demonstrated clinically equivalent therapeutic outcomes in second-line treatment of patients with recurrent NSCLC; however, patients on the pemetrexed arm had a more favorable hematologic toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Based on these data, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC.
Clinical Lung Cancer 05/2004; 5 Suppl 2:S75-9. · 2.94 Impact Factor
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ABSTRACT: Thirty years ago, there was a pervasive atmosphere of pessimism concerning the management of small-cell lung cancer (SCLC). Surgery or radiation therapy alone resulted in few cures since these techniques utilize a local therapy for a disseminated disease. Chemotherapy remains the backbone of treatment for all patients with SCLC, regardless of stage. For patients with limited-stage disease (LD), the addition of thoracic radiation to chemotherapy is standard. The optimal timing, dose, and schedule of radiation remains undefined. The majority of studies demonstrate equivalent or superior survival for early radiation when compared to delayed radiation. Approximately 50% of patients with LD will achieve a complete remission with chemoradiation and will be candidates for prophylactic cranial irradiation (PCI). While phase III trials have failed to demonstrate a statistically significant survival for PCI, brain relapse is clearly reduced, and a metaanalysis reports a small long-term survival advantage favoring patients receiving PCI. Unfortunately, unlike LD SCLC, advances in extensive-stage disease have been elusive, despite the testing of numerous strategies. Four courses of cisplatin (or carboplatin) plus etoposide remain standard first-line therapy. Promising results have been seen with irinotecan/cisplatin, but confirmatory trials are still needed. A plateau has been reached with chemotherapy regimens, and novel strategies are greatly needed to improve survival for patients with SCLC.
Clinical Lung Cancer 10/2002; 4(2):87-94. · 2.94 Impact Factor
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ABSTRACT: The purpose of this study was to determine the maximum tolerated dose (MTD) of topotecan plus vinorelbine with and without filgrastim (granulocyte colony-stimulating factor) in refractory solid tumors. Cohorts of three patients with recurrent solid tumors previously treated with no more than one chemotherapy regimen were entered. All patients had a performance status of 0 to 1 with adequate hepatic, renal, and bone marrow function and were treated with topotecan 1.5 mg/m2 intravenously on days 1 to 3 followed by vinorelbine 25 mg/m2 intravenously on days 1 and 8 without filgrastim every 3 weeks. Dose escalation was based on standard criteria for phase I escalation with a maximum of five patients in a cohort until an MTD was defined (first without then with filgrastim). Three patients were treated at dose level 1 (topotecan 1.5 mg/m2 days 1-3 and vinorelbine 25 mg/m2 days 1 and 8) without filgrastim. All three experienced hematologic dose-limiting toxicity (DLT) including grade IV neutropenia in two patients and grade III thrombocytopenia in one patient. An additional two patients, supported with filgrastim, treated at dose level 1 experienced DLT. One patient had dose-limiting neutropenia and the other had significant nonhematologic toxicity. No objective responses were seen, and all patients died within 6 months of entering the trial. The combination of topotecan and vinorelbine was poorly tolerated in the dose and schedule tested in this phase I trial. Subsequent combinations of these drugs, if warranted, should focus on alternate doses, schedules, or routes of administration.
American Journal of Clinical Oncology 09/2002; 25(4):337-9. · 2.01 Impact Factor
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ABSTRACT: The value of platinum compounds has come into question with the advent of newer chemotherapy agents in the management of patients with advanced non-small-cell lung cancer. These newer agents, which include the taxanes, topoisomerase I inhibitors, gemcitabine, and vinorelbine, appear to have higher single-agent response rates and more favorable toxicity profiles when compared to the platinum compounds. However, the toxicity of the platinum compounds is now minimized with the advent of more effective antiemetics. In addition, phase III clinical trials have demonstrated that the strategy of cisplatin dose intensity and prolonged duration of therapy with platinum compounds does not improve overall survival; therefore, moderate doses of cisplatin and a shorter duration of therapy can be given to further decrease toxicity. Furthermore, while phase II trials utilizing nonplatinum-based combination chemotherapy appear to demonstrate superior response rates and survival in comparison to platinum-based doublets, results of phase III trials have demonstrated no improvement in survival. Platinum combination chemotherapy remains the standard approach for stage IV non-small-cell lung cancer. More substantial advances will likely be made with novel molecular targeted therapy, such as the epidermal growth factor receptor inhibitors, which demonstrate synergy with the platinum compounds.
Clinical Lung Cancer 06/2002; 3(4):249-53. · 2.94 Impact Factor
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The Journal of Urology 05/2002; 167(4):1781. · 3.75 Impact Factor
