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First-Line Systemic Chemotherapy in the Treatment of Advanced Non-small Cell Lung Cancer: A Systematic Review

      Introduction

      Non-small cell lung cancer (NSCLC) frequently presents at an incurable stage, and a majority of patients will be considered for palliative chemotherapy at some point in their disease. This article reviews the growing evidence for first-line treatment in NSCLC.

      Methods

      Studies of first-line chemotherapy regimens including new agents (docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, erlotinib, and gefitinib) were identified through Medline, Embase, the Cochrane databases, and web sites of guideline organizations.

      Results

      Two evidence-based guidelines, 10 systematic reviews, and forty-six randomized trials were eligible for inclusion. Randomized studies suggest that platinum-based doublets (platinum plus new agent) are the standard of care for first-line systemic therapy. No one new agent is clearly superior for use in combination with a platinum agent. The survival advantage of platinum-based doublets over nonplatinum combinations or older combinations is modest. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, although multiple exclusion criteria limit the applicability of these data to a subset of patients. In patients at least 70 years of age or with Eastern Collaborative Oncology Group performance status 2, a new single agent is an alternative. Treatment beyond four to six cycles impedes quality of life without prolonging life. Emerging data suggest that the choice of chemotherapy agent may be influenced by histologic subtype.

      Conclusion

      In NSCLC, a combination of a platinum agent plus a new agent continues to be the standard of care. As differences between regimens are small, toxicity and patient preference should help guide regimen choice.

      Keywords

      Forty percent of patients with non-small cell lung cancer (NSCLC) present with metastatic disease, and the majority of the patients treated with curative intent develop recurrence.
      • Carney DN
      • Hansen HH
      Non-small-cell lung cancer—stalemate or progress?.
      Most patients will, therefore, face the option of palliative chemotherapy.
      More than 3 decades of clinical trials in patients with incurable NSCLC have led to only modest gains in survival. Nevertheless, past trials have generally supported the use of two chemotherapy agents rather than one agent in terms of response rates and survival, although toxicity is increased.
      • Delbaldo C
      • Michiels S
      • Syz N
      • et al.
      Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis.
      Overall, quality-of-life (QOL) is also improved with chemotherapy, with improvements in disease-specific symptoms at a cost of some worsening in drug-related symptoms.
      • Fallowfield LJ
      • Harper P
      Health-related quality of life in patients undergoing drug therapy for advanced non-small-cell lung cancer.
      Assessments of several regimens have also shown that chemotherapy is cost effective.
      • Dranitsaris G
      • Cottrell W
      • Evans WK
      Cost-effectiveness of chemotherapy for nonsmall-cell lung cancer.
      This review takes the pragmatic view that most clinicians are not using older regimens and therefore only discusses such regimens as they compare with newer ones. It should be noted that the patients studied in the chemotherapy trials were of good performance status, typically Eastern Collaborative Oncology Group (ECOG) 0-1, and less frequently ECOG 2. Many studies restricted eligibility to patients of less than a specified age. The organization of this document is premised on the generally accepted recommendation that eligible patients receive a combination of a platinum agent (cisplatin or carboplatin) plus one new agent.
      • Spira A
      • Ettinger DS
      Multidisciplinary management of lung cancer.

      MATERIALS AND METHODS

      Questions

      What are the most effective chemotherapy options in terms of overall survival, QOL, and response in the first-line management of advanced NSCLC? The literature was reviewed for clinical trials involving doublet chemotherapy with or without a platinum agent, studies adding a third cytotoxic or targeted agent to doublet therapy, trials assessing the use of single agents, alternate or maintenance schedules, and trials of chemotherapy in the elderly population.

      Literature Search Strategy

      MEDLINE (1966 to October 2007), EMBASE (2002 to November 2007), and the Cochrane Library (Issue 4, 2007) databases were searched (strategies available in Appendix Table A1). The American Society of Clinical Oncology (2002–2007) online conference proceedings were searched, as were web sites of practice guideline organizations. Relevant articles and abstracts were selected and reviewed by two reviewers, and reference lists were searched for additional trials.

      Study Selection Criteria

      Inclusion Criteria

      Articles were eligible for inclusion, if they met the following criteria:
      • Evaluated new agents in a phase III randomized controlled trial (RCT), systematic review, meta-analysis, or evidence-based report.
      • Included adult or elderly patients receiving chemotherapy as first-line or maintenance therapy.
      • Reported on at least one of the following outcomes: overall survival, QOL, overall response rate, or toxicity.
      • Reported phase III clinical trial results in publicly available conference abstracts or presentations.

      Exclusion Criteria

      Trials were excluded if they were:
      • Published in a language other than English, as translation capabilities were not available.
      • Included patients with other than stage IIIB/IV NSCLC.
      • Included new agents listed in Appendix Table A2, but the primary objective of the study was to evaluate a noneligible agent or therapy.

      Quality Appraisal of Evidence

      The Appraisal of Guidelines Research and Evaluation tool
      The AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      was used by four independent methodologists (C.L. and others) to evaluate the quality of identified evidence-based guidelines. Systematic reviews and meta-analyses were assessed using the Overview Quality Assessment Questionnaire.
      • Oxman AD
      • Guyatt GH
      • Singer J
      • et al.
      Agreement among reviewers of review articles.
      Quality criteria considered in the assessment of RCTs included appropriateness of eligibility criteria, a reasonable and reported method of randomization, blinding, existence of treatment or attrition bias in any arm, intention-to-treat analyses, and a priori power. Discrepancies concerning quality were resolved by consensus of the authors.

      Synthesizing the Evidence

      As hazard ratios (HRs) for survival were infrequently available or calcuable, data synthesis in this report consists of descriptive statistics only. In light of the large scope of this systematic review, attempts were made to use existing systematic reviews and meta-analyses, whenever possible, to inform the research questions. For some questions, only results from particular subgroup analyses were relevant, and the limitations of such analyses should be considered.

      Literature Search Results

      Two evidence-based guidelines
      • Scottish Intercollegiate Guidelines Network
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      and 10 systematic reviews, one in abstract form, were identified and included.
      • Ardizzoni A
      • Boni L
      • Tiseo M
      • et al.
      Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.
      • Baggstrom MQ
      • Stinchcombe TE
      • Fried DB
      • et al.
      Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis.
      • Douillard JY
      • Laporte S
      • Fossella F
      • et al.
      Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials.
      • Jiang J
      • Liang X
      • Zhou X
      • et al.
      A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer.
      • Soon YY
      • Askie L
      • Stockler M
      • et al.
      Optimal duration of chemotherapy for advanced non-small cell lung cancer: A systematic review and meta-analysis (abstract).
      • Pujol JL
      • Barlesi F
      • Daures JP
      Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials.
      • D'Addario G
      • Pintilie M
      • Leighl NB
      • et al.
      Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature.
      • Le Chevalier T
      • Scagliotti G
      • Natale R
      • et al.
      Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials.
      Trials that are included in these systematic reviews are not individually included unless they are relevant for a different question. Forty-six randomized trials were eligible for inclusion in this systematic review,
      • Alberola V
      • Camps C
      • Provencio M
      • et al.
      Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.
      • Belani CP
      • Larocca RV
      • Rinaldi DA
      • et al.
      A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel [abstract].
      • Belani CP
      • Lee JS
      • Socinski MA
      • et al.
      Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.
      • Booton R
      • Lorigan P
      • Anderson H
      • et al.
      A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      • Comella P
      • Frasci G
      • Carnicelli P
      • et al.
      Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.
      • The Elderly Lung Cancer Vinorelbine Italian Study Group
      Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer.
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      • Frasci G
      • Lorusso V
      • Panza N
      • et al.
      Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial.
      • Gatzemeier U
      • Pluzanska A
      • Szczesna A
      • et al.
      Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
      • Gebbia V
      • Galetta D
      • Caruso M
      • et al.
      Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale.
      • Giaccone G
      • Herbst R
      • Manegold C
      • et al.
      Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      • Hainsworth JD
      • Spigel DR
      • Farley C
      • et al.
      Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.
      • Helbekkmo N
      • Sundstrom SH
      • Aasebo U
      • et al.
      Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity.
      • Herbst RS
      • Giaccone G
      • Schiller JH
      • et al.
      Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2.
      • Herbst RS
      • Prager D
      • Hermann R
      • et al.
      TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
      • Ichinose Y
      • Nishiwaki Y
      • Kunitoh H
      • et al.
      A multicenter randomized phase III trial of docetaxel + cisplatin (DP) vs. vindesine + cisplatin (VP) in patients with untreated stage IV non-small cell lung cancer (NSCLC) (abstract).
      • Kawahara M
      • Ogawara M
      • Nishiwaki Y
      • et al.
      Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03) [abstract].
      • Kim JH
      • Kim SY
      • Jung KH
      • et al.
      Randomized phase 3 study of gemcitabine plus cisplatin versus etoposide plus cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience (abstract).
      • Kudoh S
      • Takeda K
      • Nakagawa K
      • et al.
      Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
      • Laack E
      • Dickgreber N
      • Muller T
      • et al.
      Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.
      • Reck M
      • von Pawel J
      • Zatloukal P
      • et al.
      Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAiL.
      • Martoni A
      • Marino A
      • Sperandi F
      • et al.
      Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer.
      • Melo M
      • Barradas P
      • Costa A
      • et al.
      Results of a randomized phase III trial comparing 4 cisplatin (P)-based regimens in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC): mitomycin/vinblastine/cisplatin (MVP) is no longer a therapeutic option (abstract).
      • Novello S
      • Bruzzi P
      • Barone C
      • et al.
      Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone.
      • Ohe Y
      • Ohashi Y
      • Kubota K
      • et al.
      Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan.
      • Park HS
      • Lee SJ
      • Kim JH
      • et al.
      Randomized trial of docetaxel plus cisplatin (DC) versus etoposide plus cisplatin (EC) in locally advanced, recurrent, or metastatic non-small cell lung cancer (NCSLC) (abstract).
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      • Rigas J
      • Dragnev K
      • Kerry M
      Survival equivalence of non-platinum-based and platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC): the results of a multicenter internet-based phase III randomized study (D0112) (abstract).
      • Rubio JE
      • Sahagun G
      A randomized phase III trial comparing docetaxel + carboplatin (DCP) vs vinorelbine + carboplatin (VCP) in non small cell lung cancer (NSCLC) stage III and IV (abstract).
      • Sandler A
      • Gray R
      • Perry MC
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      • Scagliotti GV
      • De Marinis F
      • Rinaldi M
      • et al.
      Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      • Schuette W
      • Blankenburg T
      • Guschall W
      • et al.
      Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin.
      • Sculier JP
      • Lafitte JJ
      • Lecomte J
      • et al.
      A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer.
      • Souquet PJ
      • Tan EH
      • Rodrigues Pereira J
      • et al.
      GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients.
      • Tan EH
      • Szczesna A
      • Krzakowski M
      • et al.
      Randomized study of vinorelbine–gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer.
      • Treat J
      A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC) (abstract).
      • Tsukada H
      • Yokoyama A
      • Nishiwaki Y
      • et al.
      Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207 [abstract].
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      • Westeel V
      • Quoix E
      • Moro-Sibilot D
      • et al.
      Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer.
      • Takiguchi Y
      The final results of a randomized phase III trial comparing irinotecan (CPT-11) and cisplatin (CDDP) with vindesine (VDS) and CDDP in advanced non-small cell lung cancer (NSCLC).
      with 12 reported solely in abstract form.
      • Belani CP
      • Larocca RV
      • Rinaldi DA
      • et al.
      A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel [abstract].
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Ichinose Y
      • Nishiwaki Y
      • Kunitoh H
      • et al.
      A multicenter randomized phase III trial of docetaxel + cisplatin (DP) vs. vindesine + cisplatin (VP) in patients with untreated stage IV non-small cell lung cancer (NSCLC) (abstract).
      • Kawahara M
      • Ogawara M
      • Nishiwaki Y
      • et al.
      Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03) [abstract].
      • Kim JH
      • Kim SY
      • Jung KH
      • et al.
      Randomized phase 3 study of gemcitabine plus cisplatin versus etoposide plus cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience (abstract).
      • Park HS
      • Lee SJ
      • Kim JH
      • et al.
      Randomized trial of docetaxel plus cisplatin (DC) versus etoposide plus cisplatin (EC) in locally advanced, recurrent, or metastatic non-small cell lung cancer (NCSLC) (abstract).
      • Rigas J
      • Dragnev K
      • Kerry M
      Survival equivalence of non-platinum-based and platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC): the results of a multicenter internet-based phase III randomized study (D0112) (abstract).
      • Rubio JE
      • Sahagun G
      A randomized phase III trial comparing docetaxel + carboplatin (DCP) vs vinorelbine + carboplatin (VCP) in non small cell lung cancer (NSCLC) stage III and IV (abstract).
      • Treat J
      A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC) (abstract).
      • Tsukada H
      • Yokoyama A
      • Nishiwaki Y
      • et al.
      Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207 [abstract].
      • Takiguchi Y
      The final results of a randomized phase III trial comparing irinotecan (CPT-11) and cisplatin (CDDP) with vindesine (VDS) and CDDP in advanced non-small cell lung cancer (NSCLC).
      Full publications for a further 13 references identified during the search could not be obtained. Appendix Table A3 shows a summary of the search results. In response to reviewer feedback requesting additional data, an additional simplified search of Medline and American Society of Clinical Oncology was conducted for new randomized trials (Phase II or Phase III) of cetuximab and pemetrexed, published between November 2007 and August 2009. This search identified five additional references and is not described by the diagram in Appendix Table A3. Two randomized controlled trials and two abstracts were found.
      • Pirker R
      • Pereira JR
      • Szczesna A
      • et al.
      Cetuximab plus chemotherapy in patients with advanced non-small cell lung cancer (FLEX): an open-label randomised phase III trial.
      • Hirsh FR
      • Herbst RS
      • Olsen C
      • et al.
      Increased EGFR gene copy number detected by fluorescent in site hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy.
      • Belani CP
      • Brodowicz T
      • Ciuleanu T
      • et al.
      Maintenance pemetrexed (Pem) plus best supportive case (BSC) versus placebo (Plac) plus BSC: a randomized phase III study in andanved non-small cell lung cancer (NSCLC).
      • O'Byrne KJ
      • Bondarenko I
      • Barrios C
      • et al.
      Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the Flex study (abstract).
      • Patel T
      • Dreisbach L
      • McCleod M
      • et al.
      Lung cancer symptoms with cetuximab/taxane/carboplatin in first-line advanced NSCLC: Analysis of the BMS099 trial.

      Quality of Included Evidence

      The included Scottish Intercollegiate Guidelines Network (SIGN) and American College of Chest Physicians (ACCP) evidence-based guidelines
      • Scottish Intercollegiate Guidelines Network
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      were of high quality (see Appendix Table A4 for scores) and thus their relevant recommendations were considered and adopted in this systematic review.
      The 10 systematic reviews included in this report ranged in quality from quite poor to exemplary on the seven-point Overview Quality Assessment Questionnaire scale.
      • Oxman AD
      • Guyatt GH
      • Singer J
      • et al.
      Agreement among reviewers of review articles.
      Six of the meta-analyses received a quality score of very good or better (six to seven on the seven-point scale)
      • Douillard JY
      • Laporte S
      • Fossella F
      • et al.
      Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials.
      • Jiang J
      • Liang X
      • Zhou X
      • et al.
      A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer.
      • Pujol JL
      • Barlesi F
      • Daures JP
      Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials.
      • Le Chevalier T
      • Scagliotti G
      • Natale R
      • et al.
      Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials.
      (see Appendix Table A5 for the complete evaluation). Two of the systematic reviews reported pharmaceutical company sponsorship.
      • Douillard JY
      • Laporte S
      • Fossella F
      • et al.
      Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials.
      • D'Addario G
      • Pintilie M
      • Leighl NB
      • et al.
      Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature.
      All intravenous regimens of the included trials were nonblinded. Six trials (14%) had issues with power, with five stopping early
      • Comella P
      • Frasci G
      • Carnicelli P
      • et al.
      Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.
      • The Elderly Lung Cancer Vinorelbine Italian Study Group
      Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer.
      • Frasci G
      • Lorusso V
      • Panza N
      • et al.
      Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial.
      • Gebbia V
      • Galetta D
      • Caruso M
      • et al.
      Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      and one not being powered for survival.
      • Kim JH
      • Kim SY
      • Jung KH
      • et al.
      Randomized phase 3 study of gemcitabine plus cisplatin versus etoposide plus cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience (abstract).
      One trial had difficulty with greater than 10% patient attrition from toxicity.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      One trial reported differences in dose intensity,
      • Rigas J
      • Dragnev K
      • Kerry M
      Survival equivalence of non-platinum-based and platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC): the results of a multicenter internet-based phase III randomized study (D0112) (abstract).
      possibly due to drug-related toxicity. In total, 18% of the included studies had some potential quality issues, but the effect of these biases on study outcomes was expected to be modest. Pharmaceutical sponsorship or an author relationship with a pharmaceutical company was reported in 20 trials.
      • Belani CP
      • Lee JS
      • Socinski MA
      • et al.
      Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.
      • Booton R
      • Lorigan P
      • Anderson H
      • et al.
      A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      • Gatzemeier U
      • Pluzanska A
      • Szczesna A
      • et al.
      Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
      • Giaccone G
      • Herbst R
      • Manegold C
      • et al.
      Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      • Hainsworth JD
      • Spigel DR
      • Farley C
      • et al.
      Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.
      • Herbst RS
      • Giaccone G
      • Schiller JH
      • et al.
      Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2.
      • Herbst RS
      • Prager D
      • Hermann R
      • et al.
      TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
      • Laack E
      • Dickgreber N
      • Muller T
      • et al.
      Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.
      • Ohe Y
      • Ohashi Y
      • Kubota K
      • et al.
      Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      • Sandler A
      • Gray R
      • Perry MC
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      • Scagliotti GV
      • De Marinis F
      • Rinaldi M
      • et al.
      Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      • Sculier JP
      • Lafitte JJ
      • Lecomte J
      • et al.
      A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer.
      • Souquet PJ
      • Tan EH
      • Rodrigues Pereira J
      • et al.
      GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients.
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      • Takiguchi Y
      The final results of a randomized phase III trial comparing irinotecan (CPT-11) and cisplatin (CDDP) with vindesine (VDS) and CDDP in advanced non-small cell lung cancer (NSCLC).
      QOL was assessed in a minority of trials. The data suffer from the common difficulties of attrition of data over time, missing data, and multiple comparisons, including the comparison of global scores, domain scores, and individual symptom scores.

      RESULTS

      New Doublets

      (Q1) Does Doublet Chemotherapy Consisting of a Platinum Agent Plus a New Agent Improve Outcomes Compared with Doublets Using Older Agents?

      Meta-analysis by Baggstrom et al.
      • Baggstrom MQ
      • Stinchcombe TE
      • Fried DB
      • et al.
      Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis.
      considered third-generation, platinum-based regimens compared with second-generation, platinum-based regimens. In a subgroup analysis of six trials (n = 1998) examining only doublet regimens, a 1-year survival rate risk difference of 6% (95% confidence interval [CI], 2 to 10%) was found in favor of doublet chemotherapy regimens containing platinum and a new agent. Toxicity data were not examined.
      Five additional trials not included in the meta-analysis of Baggstrom et al. compared new doublet therapies with older regimens (Table 1). Only one trial, comparing docetaxel plus cisplatin with vindesine plus cisplatin,
      • Ichinose Y
      • Nishiwaki Y
      • Kunitoh H
      • et al.
      A multicenter randomized phase III trial of docetaxel + cisplatin (DP) vs. vindesine + cisplatin (VP) in patients with untreated stage IV non-small cell lung cancer (NSCLC) (abstract).
      found superior survival with a newer agent. This trial also found superior QOL in the physical domain for the docetaxel-containing arm. Despite a trend toward poorer response and survival, Belani et al
      • Belani CP
      • Lee JS
      • Socinski MA
      • et al.
      Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.
      reported better early QOL with paclitaxel and carboplatin over etoposide and cisplatin. Toxicities among these five trials differed by regimen and did not consistently favor new or older regimens.
      TABLE 1New Doublets vs. Older Doublets
      TrialComparisonSurvival (95% CI), p ValueOverall Response (95% CI), p Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Belani et al.
      • Belani CP
      • Lee JS
      • Socinski MA
      • et al.
      Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.
      369PCb1907.7 (p = 0.086)3223 (p = 0.061)
      EtC1799.03715
      Ichinose et al.
      • Ichinose Y
      • Nishiwaki Y
      • Kunitoh H
      • et al.
      A multicenter randomized phase III trial of docetaxel + cisplatin (DP) vs. vindesine + cisplatin (VP) in patients with untreated stage IV non-small cell lung cancer (NSCLC) (abstract).
      311/302DCNR/15111.4 (NR)24 (NR) [2 yr] p = 0.0137 p = 0.004
      VdCNR/1519.6 (NR)12 (NR)21 (NR)
      Kim et al.40
      “Preliminary results” noted. Not clear whether referring to preliminary report, or interim analysis. No other indication this is an interim analysis.
      75/62GC39/3318.7 (NR) p = 0.29NR63.6 (NR) p = 0.001
      EtC36/2915.7 (NR)NR20.7 (NR)
      Park et al.
      • Park HS
      • Lee SJ
      • Kim JH
      • et al.
      Randomized trial of docetaxel plus cisplatin (DC) versus etoposide plus cisplatin (EC) in locally advanced, recurrent, or metastatic non-small cell lung cancer (NCSLC) (abstract).
      78/67DC40/34NRNRNR
      EtC38/33NRNRNR
      Takiguchi64210IrC104104329 (28/98)
      VdC10611.14822 (22/101)
      C, cisplatin; Cb, carboplatin; CI, confidence interval; D, docetaxel; Et, etoposide; G, gemcitabine; Ir, Irinotecan; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; P, paclitaxel; Vd, vindesine.
      a Neval only reported when analysis was not intention-to-treat.
      b “Preliminary results” noted. Not clear whether referring to preliminary report, or interim analysis. No other indication this is an interim analysis.

      (Q2) Does Doublet Chemotherapy Consisting of a Platinum Agent Plus a New Agent Improve Outcomes Compared with a New Single Agent Alone or to a Platinum Agent Alone?

      A literature-based meta-analysis of randomized trials by Hotta et al.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials.
      compared a doublet of platinum plus a new agent with a new agent alone in previously untreated patients with ECOG performance status of 0-2. Included were eight trials involving 2374 patients. Platinum-based doublets improved survival (HR, 0.87; 95% CI, 0.80–0.94; P < 0.001) and produced a higher response rate (odds ratio [OR], 2.32; 95% CI, 1.68–3.20) compared with new single-agent therapy. Platinum-based regimens increased myelosuppression, nephrotoxicity, and nausea and vomiting but not treatment-related mortality.
      One of the trial abstracts included in the Hotta et al.
      • Lilenbaum RC
      • Herndon II, JE
      • List MA
      • et al.
      Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: The Cancer and Leukemia Group B (study 9730).
      meta-analysis was later published in full without a change in results.

      (Q3) Which Doublet Chemotherapy Regimen Consisting of a Platinum Agent Plus a New Agent is most Effective in Improving Clinical Outcomes?

      Phase III trials comparing a platinum agent combined with a new agent have rarely been able to demonstrate superior survival for one combination over another
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      (Table 2). Consequently, two meta-analyses have been undertaken to assess the value of specific new drugs.
      • Douillard JY
      • Laporte S
      • Fossella F
      • et al.
      Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials.
      • Le Chevalier T
      • Scagliotti G
      • Natale R
      • et al.
      Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.
      There was no overlap of trials between the two meta-analyses.
      TABLE 2Comparison of Doublets of New Agents in Combination with Platinum Analogues
      TrialComparisonSurvival (95% CI), p ValueResponse (95% CI), p Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Fossella et al.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      1218/—DC40811.3 (10.1–12.4) p = 0.04446 (42–51)
      The hazard ratios and 95% CI of overall survival for DC and DCb vs. VC were 97.2 (0.989–1.416) and 97.2 (0.877–1.253), respectively.
      vs. VC, 31.6 (NR) p = 0.029
      DCb4069.4 (8.7–10.6)38 (33–43)vs. VC, 23.9 (NR) p = 0.870
      VC4049.9–10.1 (9.0–11.3)
      Survival estimates were adjusted for prognostic factors, and minor differences in the distribution of those factors produced slightly different values.
      40–41 (35–46)24.5 (NR)
      Gebbia et al.
      • Gebbia V
      • Galetta D
      • Caruso M
      • et al.
      Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale.
      400/NRGC138/NR8.2 (NR) p = 0.18720 (NR) p = 0.433 (26–42) p = 0.032
      VC140/NR9.0 (NR)24 (NR)44 (36–53) p = 0.007
      Data are from an interim analysis of 243 patients. At interim, VC response was statistically superior to GI–>VC, p = 0.007, all other interim comparisons not significant at a 95% confidence level.
      GI–>VC62/NRNRNR19 (10–31)
      Data are from an interim analysis of 243 patients. At interim, VC response was statistically superior to GI–>VC, p = 0.007, all other interim comparisons not significant at a 95% confidence level.
      VC–>GI60/NRNRNR32 (20–45)
      Data are from an interim analysis of 243 patients. At interim, VC response was statistically superior to GI–>VC, p = 0.007, all other interim comparisons not significant at a 95% confidence level.
      Helbekkmo et al.
      • Helbekkmo N
      • Sundstrom SH
      • Aasebo U
      • et al.
      Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity.
      432VCb2187.3 (NR) p = 0.8928NR
      GCb2146.4 (NR)30NR
      Martoni et al.
      • Martoni A
      • Marino A
      • Sperandi F
      • et al.
      Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer.
      272/—VC13711 (9–13) p = 0.75939.7 (NR)32.1 (24.5–40.5) p = 0.32
      GC13511 (9–13)44.4 (NR)26.7 (19.5–35.1)
      Ohe et al.
      • Ohe Y
      • Ohashi Y
      • Kubota K
      • et al.
      Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan.
      602/—IrC15113.9 (NR) p = ns59.2 (NR)
      This was a noninferiority trial. The difference in 1-yr survival between arms was as follows: IrC vs. PCb −8.2% (– 19.6 −3.3%), PCb vs. GC 0.4% (– 10.9 −11.7%), GC vs. VC −10.9% (–22.3 −0.5%). Conclusions of this trial are faulty. They report they cannot reject the null hypothesis of noninferiority, but still say agents are similar. The values reported here are the difference in 1-yr survival between agents and the IrC arm.
      31 (NR)
      PCb15012.3 (NR)51.0 (NR)32.4 (NR) p = 0.80
      GC15114.0 (NR)59.6 (NR)30.1 (NR) vs. IrC, p = 0.87
      VC15011.4 (NR)48.3 (NR)33.1 (NR) vs. IrC, p = 0.71
      Rubio and Sahagun5260DCb2910.2 (NR) p = nsNR46.4 (NR)
      VCb3110.7 (NR)NR45.2 (NR)
      Scagliotti et al.
      • Scagliotti GV
      • De Marinis F
      • Rinaldi M
      • et al.
      Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
      612/—VC2039.5 (8.3–11.0)37 (NR) p = 0.48
      Hazard ratio of survival was 0.87 (0.69–1.09).
      30 (24–36) p = 0.98
      GC2059.8 (8.6–11.2)37 (NR)30 (24–37)
      PCb20410.0 (9.0–12.5)43 (NR) vs. VC, p = 0.1
      Hazard ratio of survival for VC vs. PCb was 0.84 (0.67–1.05).
      32 (25–38) vs. VC, p = 0.75
      Schiller et al.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      1207/1155PC303/2887.8 (7.0–8.9) p = ns31 (26–36)21 (NR) p = ns
      GC301/2888.1 (7.2–9.4)36 (31–42)22 (NR)
      DC304/2897.4 (6.6–8.8)31 (26–36)17 (NR)
      PCb299/2908.1 (7.0–9.5)34 (29–40)17 (NR)
      Takiguchi64210IrC104104329 (28/98)
      VdC10611.14822 (22/101)
      C, cisplatin; D, docetaxel; Cb, carboplatin; CI, confidence interval; G, gemcitabine; I, ifosfamide; Ir, irinotecan; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; ns, not significant; P, paclitaxel; V, vinorelbine; Vd, Vinblastine.
      a Neval only reported when analysis was not intention-to-treat.
      b Survival estimates were adjusted for prognostic factors, and minor differences in the distribution of those factors produced slightly different values.
      c The hazard ratios and 95% CI of overall survival for DC and DCb vs. VC were 97.2 (0.989–1.416) and 97.2 (0.877–1.253), respectively.
      d Data are from an interim analysis of 243 patients. At interim, VC response was statistically superior to GI–>VC, p = 0.007, all other interim comparisons not significant at a 95% confidence level.
      e This was a noninferiority trial. The difference in 1-yr survival between arms was as follows: IrC vs. PCb −8.2% (– 19.6 −3.3%), PCb vs. GC 0.4% (– 10.9 −11.7%), GC vs. VC −10.9% (–22.3 −0.5%). Conclusions of this trial are faulty. They report they cannot reject the null hypothesis of noninferiority, but still say agents are similar. The values reported here are the difference in 1-yr survival between agents and the IrC arm.
      f Hazard ratio of survival was 0.87 (0.69–1.09).
      g Hazard ratio of survival for VC vs. PCb was 0.84 (0.67–1.05).
      Le Chevalier et al.
      • Le Chevalier T
      • Scagliotti G
      • Natale R
      • et al.
      Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.
      tested the efficacy of gemcitabine plus platinum combinations versus any other platinum-based regimen on survival outcomes. A subgroup analysis of six trials (n = 2481) with a platinum-based third-generation comparator arm found a trend toward superior survival with gemcitabine-based regimens and improved progression-free survival (HR, 0.89; 95% CI, 0.82–0.96; P value not reported). However, the gemcitabine arms of two studies
      • Scagliotti GV
      • De Marinis F
      • Rinaldi M
      • et al.
      Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      were counted more than once in the meta-analysis to allow comparison with more than one nongemcitabine arm, and without weighting. Toxicity was not compared.
      The second meta-analysis, by Douillard et al.,
      • Douillard JY
      • Laporte S
      • Fossella F
      • et al.
      Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials.
      included seven trials (n = 3271) that compared docetaxel-containing regimens with vinca-alkaloid regimens. The comparison for overall survival favored docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = 0.004), as did the subgroup analysis of three trials (n = 1762) comparing platinum-based docetaxel doublets (HR, 0.87; 95% CI, 0.79–0.96; P value not reported). However, this subgroup included a positive trial favoring docetaxel over vindesine
      • Kubota K
      • Watanabe K
      • Kunitoh H
      • et al.
      Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group.
      and double counting of the nondocetaxel arm from another trial to allow comparison with two docetaxel-containing arms.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      Neutropenia and serious adverse event rates occurred significantly less with docetaxel regimens.
      Additional studies, including two multiarmed studies reported in the earlier meta-analyses,
      • Scagliotti GV
      • De Marinis F
      • Rinaldi M
      • et al.
      Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      are shown in Table 2. Median survival in the nine trials ranged from 6.4 to 14.0 months. Consistent differences between arms were not evident.
      While five of the nine trials reported QOL outcomes, only the trial by Fossella et al.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      found statistical differences in global scores between arms; both docetaxel arms reported improvements in overall QOL compared with the vinorelbine-containing arm. In all nine trials, toxicities were particular to the drug combination used; a clear advantage to one regimen was not evident.

      (Q4) Does Doublet Chemotherapy Consisting of a Platinum Agent Plus a New Agent Improve Outcomes Compared with Nonplatinum Combination Chemotherapy Including a New Agent?

      Nonplatinum doublet regimens have been proposed as a potentially less toxic alternative to platinum-based doublets for the treatment of NSCLC. A meta-analysis of 11 phase III RCTs by Pujol et al
      • Pujol JL
      • Barlesi F
      • Daures JP
      Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials.
      assessed 4602 patients treated with a platinum-based new doublet or a combination of new nonplatinum agents. Platinum-based regimens had a 2.9% absolute reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = 0.044). Although the data were statistically heterogeneous, response rates appeared higher with platinum combinations. Toxicity was also more severe with platinum combinations, with significantly worse myelosuppression and gastrointestinal toxicity and trends to worse rates of febrile neutropenia and toxic death.
      The meta-analysis of D'Addario et al.,
      • D'Addario G
      • Pintilie M
      • Leighl NB
      • et al.
      Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature.
      which included 14 trials (n = 3307), did not find a survival benefit with platinum-based agents over nonplatinum chemotherapy regimens (OR, 1.11; 95% CI, 0.0.96–1.28; P = 0.17). Compared with the meta-analysis by Pujol et al., the meta-analysis by D'Addario et al. included trials conducted as early as 1983 (whereas Pujol et al. included trials published in 2002 and onward), included phase II studies, and included platinum combinations using three drugs. There is little trial overlap between the meta-analyses (ie, four trials). The meta-analysis by Pujol et al. is more representative of new agents.
      Four additional relevant RCTs, not assessed in the meta-analysis by Pujol et al, are shown in Table 3. Median survival in these four trials ranged from 7.6 to 13.8 months. Tan et al.,
      • Tan EH
      • Szczesna A
      • Krzakowski M
      • et al.
      Randomized study of vinorelbine–gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer.
      in a secondary end point, detected a better median survival in patients receiving gemcitabine-vinorelbine (11.5 months) versus those receiving vinorelbine-carboplatin (8.6 months) (P = 0.01). The trial by Kawahara et al.
      • Kawahara M
      • Ogawara M
      • Nishiwaki Y
      • et al.
      Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03) [abstract].
      found worse neutropenia and neuropathy in the platinum arm, but more pneumonitis, including two deaths, on the nonplatinum arm. None of the other three trials reported statistical differences in symptom or toxicity scores.
      TABLE 3New Platinum-Based Doublets vs. New Nonplatinum-Based Doublets
      StudyComparisonSurvival (95% CI), P ValueOverall Response (95% CI), p Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Kawahara et al.
      • Kawahara M
      • Ogawara M
      • Nishiwaki Y
      • et al.
      Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03) [abstract].
      401/393VG–>DNR13.1 (NR) p = 0.2855.6 (NR)23 (NR) p = 0.008
      PCbNR13.8 (NR)55.5 (NR)36 (NR)
      Rigas et al.
      • Rigas J
      • Dragnev K
      • Kerry M
      Survival equivalence of non-platinum-based and platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC): the results of a multicenter internet-based phase III randomized study (D0112) (abstract).
      928DCb4668.135NR
      GD4638.334NR
      Tan et al.
      • Tan EH
      • Szczesna A
      • Krzakowski M
      • et al.
      Randomized study of vinorelbine–gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer.
      316/—VCb1598.6 (NR) p = 0.0134.4 (NR)20.8 (NR) p = 0.15
      VG15711.5 (NR)48.9 (NR)28.0 (NR)
      Treat60929/788GCb309/2657.6 (6.83–8.96)32.1 (NR)31.7 (26–38)
      GP312/2628.2 (7.09–9.46)33.0 (NR)38.4 (32–44)
      PCb308/2617.9 (6.86–8.86)33.0 (NR)36.8 (31–43)
      Cb, carboplatin; CI, confidence interval; D, docetaxel; G, gemcitabine; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; P, paclitaxel; V, vinorelbine.
      a Neval only reported when analysis was not intention-to-treat.

      (Q5) Are New Doublets Containing Cisplatin more Effective than Doublets Containing Carboplatin?

      Three recent meta-analyses have looked at new doublet regimens containing cisplatin in comparison to those containing the cisplatin analog, carboplatin.
      The meta-analysis by Jiang et al.
      • Jiang J
      • Liang X
      • Zhou X
      • et al.
      A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer.
      showed higher overall response rates with cisplatin-based regimens in two subgroup analyses; platinum plus new drugs (eight trials) and platinum plus the same drug (nine trials) (relative risk [RR], 0.87; 95% CI, 0.78–0.97; P = 0.01 and RR, 0.79; 95% CI, 0.70–0.89; P = 0.0001, respectively). However, these findings did not translate into significant improvements in 1-year survival among the regimens containing any new agent (n = 4364, seven trials) (RR, 0.98; 95% CI, 0.90–1.07; P = 0.66) or the same agent (n = 3752, six trials) (RR, 0.91; 95% CI, 0.82–1.01; P = 0.07).
      Two other meta-analyses limited inclusion to trials that combined the same nonplatinum agent in the cisplatin and carboplatin arms but used different analytic methods. In a subgroup analysis of five trials (n = 2251), Hotta et al.
      • Hotta K
      • Matsuo K
      • Ueoka H
      • et al.
      Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer.
      showed that new platinum-based combination regimens containing cisplatin offered superior survival compared with carboplatin plus the same new agent **(HR, 1.106;1 95% CI, 1.005–1.218; P = 0.039). The objective response rate to cisplatin-based regimens was significantly higher than that of carboplatin-based chemotherapy (OR, 1.38; 95% CI, 1.14–1.67; P = 0.001). In the same subgroup of trials but using individual patient data, Ardizzoni et al.
      • Ardizzoni A
      • Boni L
      • Tiseo M
      • et al.
      Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.
      reported a greater risk for mortality in patients treated with carboplatin relative to cisplatin (HR, 1.11;1 95% CI, 1.01–1.21).
      In terms of toxicity, the three meta-analyses were consistent in finding worse nausea and vomiting and nephropathy with cisplatin and worse thrombocytopenia with carboplatin. Toxic deaths were not significantly different between the two platinum agents.
      A limited number of primary trials reported on QOL, and only the meta-analysis by Jiang et al. assessed this end point, but in a qualitative format. On balance, among the seven trials that assessed QOL, carboplatin-based regimens had an advantage in role and emotional functioning, global health status, nausea and vomiting, appetite loss, constipation, fatigue, and dyspenia. Cisplatin-based regimens had an advantage in terms of pain, central peripheral neuropathy, hemoptysis, and cough.

      Triplets

      (Q6) Does Triplet Chemotherapy Consisting of a Platinum Agent Plus a New Agent Improve Clinical Outcomes Compared with Doublet Chemotherapy Consisting of a Platinum Agent Plus a New Agent?

      In 2007, the ACCP published an updated guideline
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      that considered whether the addition of a third chemotherapeutic agent offered an advantage over two agents in patients with advanced NSCLC. The ACCP recommended the two-drug combination, noting that the addition of a third drug offers no survival benefit and may convey some degree of harm. The ACCP considered evidence from a meta-analysis of 28 trials and 12 additional RCTs. Triplets consistently failed to show superiority over conventional doublets with respect to survival. In general, response rates did improve. However, toxicity was substantially increased with the triplets.
      Six additional trials not considered in the ACCP guideline have investigated triplet regimens (Table 4). None of these trials detected a difference in median survival, which ranged from 5.5 to 10 months, or in 1-year survival.
      TABLE 4Triplet Platinum-Based Chemotherapy Involving a New Agent vs. Doublet Platinum-Based Chemotherapy Involving a New Agent
      StudyComparisonSurvival (95% CI), p ValueResponse (95% CI), p Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Alberola et al.
      • Alberola V
      • Camps C
      • Provencio M
      • et al.
      Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.
      557/NRGC182/NR9.3 (8.1–10.5)38 (NR)42 (NR) p = 0.40
      GVC188/NR8.2 (7.0–9.4)33 (NR)41 (NR) p = 0.001
      GV–>VI187/NR8.1 (6.9–9.2)34 (NR)27 (NR)
      Booton et al.
      • Booton R
      • Lorigan P
      • Anderson H
      • et al.
      A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).
      433/422DCb2179.5 (7.9–11.1) p = 0.29539 (NR)32 (NR) p = 0.790
      MIC/MVbC2168.7 (7.7–9.7)35 (NR)31 (NR)
      Laack et al.
      • Laack E
      • Dickgreber N
      • Muller T
      • et al.
      Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.
      287/214GV143/NR8.3 (NR)33.6 (NR) p = 0.7313 (NR) p = 0.004
      GVC144/NR7.5 (NR)27.5 (NR)28.3 (NR)
      Melo et al.
      • Melo M
      • Barradas P
      • Costa A
      • et al.
      Results of a randomized phase III trial comparing 4 cisplatin (P)-based regimens in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC): mitomycin/vinblastine/cisplatin (MVP) is no longer a therapeutic option (abstract).
      248MVbC62NRNR27 p = 0.016 for MVbC vs. CG GC
      VC62NRNR37.1
      CG62NRNR48.4
      GC62NRNR48.4
      Sculier et al.
      • Sculier JP
      • Lafitte JJ
      • Lecomte J
      • et al.
      A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer.
      284
      Neval only reported when analysis was not intention-to-treat.
      /—ITT
      ICCb945.5 (4.4–6.7) p = 0.20
      Of 284 patients randomized, 280 were assessable for survival (n = 94, 92, and 94); numbers randomized by arm not reported.
      23 (NR)25 (16–34) p = 0.68
      GCCb927.8 (6.4–9.0)33 (NR)31 (21–40)
      GI946.9 (6.2–7.4)35 (NR)26 (17–35)
      Souquet et al.
      • Souquet PJ
      • Tan EH
      • Rodrigues Pereira J
      • et al.
      GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients.
      259/—VC13310.0 (NR) p = 0.2438.4 (NR)34.6 (27–43)
      VIC1268.2 (NR)33.7 (NR)35.7 (27–44) p = 0.85
      C, cisplatin; Cb, carboplatin; Cl, confidence interval; E, erlotinib; G, gemcitabine; Ge, gefitinib; I, ifosfamide; ITT, intention-to-treat; M, mitomycin C; mos, months; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; ns, not significant; p, paclitaxel; V, vinorelbine; Vb, vinblastine.
      a Neval only reported when analysis was not intention-to-treat.
      b Of 284 patients randomized, 280 were assessable for survival (n = 94, 92, and 94); numbers randomized by arm not reported.
      Toxicity was generally more frequent with the triplet regimens, with one exception.
      • Booton R
      • Lorigan P
      • Anderson H
      • et al.
      A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).

      (Q7) Does the Addition of Targeted Therapy to Doublet Chemotherapy Consisting of a Platinum Agent Plus a New Agent Improve Outcomes Compared with Doublet Chemotherapy Consisting of a Platinum Agent and a New Agent?

      Seven large recent trials have investigated the benefit of adding targeted agents to conventional chemotherapy (Table 5). Aprinocarsen, an antisense oligonucleotide to protein kinase C-alpha, did not improve outcomes in patients with advanced disease.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      TABLE 5Targeted Agents
      StudyComparisonSurvival (95% CI), p ValueResponse (95% CI), P Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Gatzemeier et al.
      • Gatzemeier U
      • Pluzanska A
      • Szczesna A
      • et al.
      Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
      1172/1159EGC5809.9 (NR)41 (NR)31.5
      GC57910.1 (NR)42 (NR)29.9
      Giaccone et al.
      • Giaccone G
      • Herbst R
      • Manegold C
      • et al.
      Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1.
      1093/—GCGe500 mg/d3659.9 (NR) p = 0.4560
      Logrank comparison of three arms.
      43 (NR)50.3 (NR) ps = ns
      GCGe250 mg/d3659.9 (NR)41 (NR)51.2 (NR)
      GC36310.9 (NR)44 (NR)47.2 (NR)
      Herbst et al.
      • Herbst RS
      • Prager D
      • Hermann R
      • et al.
      TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
      1079/—PECb53910.6 (NR)46.9 (NR)
      Hazard ratio of overall survival for PECb vs. PCb was 0.995 (0.86–1.16), p = 0.95.
      21.5 (NR)p = 0.36
      PCb54010.5 (NR)43.8 (NR)19.3 (NR)
      Herbst et al.
      • Herbst RS
      • Giaccone G
      • Schiller JH
      • et al.
      Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2.
      1037/—PGe500 mg/d Cb3478.7 (NR)37 (NR) p = 0.64
      Neval only reported when analysis was not intention-to-treat.
      30.0 (NR) ps = ns
      PGe250 mg/d Cb3459.8 (NR)41 (NR)30.4 (NR)
      PCb3459.9 (NR)42 (NR)28.7 (NR)
      Sandler et al.
      • Sandler A
      • Gray R
      • Perry MC
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      878/850PCb444/43310.3 (NR)
      HR for death = 0.79 (0.67–0.92), p = 0.003.
      44 (NR)15 (NR) p < 0.001
      PCb + bevacizumab434/41712.3 (NR)51 (NR)35 (NR)
      Reck et al.
      • Reck M
      • von Pawel J
      • Zatloukal P
      • et al.
      Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAiL.
      1043/—GC3476.1 NRNR20 (NR)
      GC + 7.5 mg/kg bevacizumab3456.7 NRNR34 (NR)
      GC + 15 mg/kg bevacizumab3516.5 NRNR30 (NR)
      Paz-Ares et al.
      • Paz-Ares L
      • Douillard JY
      • Koralewski P
      • et al.
      Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase c-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.
      670/—GC32810.4 (8.6–12.2)44.9 (NR)
      Hazard ratio of overall survival for GC vs. GC + Ap was 1.05 (0.88–1.25), p = 0.61.
      35.0 (NR)p = 0.12
      GC + Ap34210.0 (8.4–10.8)41.8 (NR)28.9 (NR)
      Pirker et al.
      • Pirker R
      • Pereira JR
      • Szczesna A
      • et al.
      Cetuximab plus chemotherapy in patients with advanced non-small cell lung cancer (FLEX): an open-label randomised phase III trial.
      1125/—C + V + Ce55711.3 (0.762) p = 0.04447 (NR)36 p = 0.010
      C + V56810.1 (0.996)42 (NR)29 (NR)
      Ap, aprinocarsen; C, cisplatin; Cb, carboplatin; Ce, cetuximab; CI, confidence interval; E, erlotinib; G, gemcitabine; Ge, gefitinib; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; P, paclitaxel; V, Vinorelbine.
      a Neval only reported when analysis was not intention-to-treat.
      b Logrank comparison of three arms.
      c Hazard ratio of overall survival for PECb vs. PCb was 0.995 (0.86–1.16), p = 0.95.
      d HR for death = 0.79 (0.67–0.92), p = 0.003.
      e Hazard ratio of overall survival for GC vs. GC + Ap was 1.05 (0.88–1.25), p = 0.61.
      Four trials adding oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) to conventional doublets have failed to show an improvement in survival or response.
      • Gatzemeier U
      • Pluzanska A
      • Szczesna A
      • et al.
      Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
      • Giaccone G
      • Herbst R
      • Manegold C
      • et al.
      Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1.
      • Herbst RS
      • Giaccone G
      • Schiller JH
      • et al.
      Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2.
      • Herbst RS
      • Prager D
      • Hermann R
      • et al.
      TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
      The data suggest that EGFR TKIs may be more effective in specific populations, although this is not always consistent.
      • Bareschino MA
      • Schettino C
      • Troiani T
      • Martinelli E
      • Morgillo F
      • Ciardiello F
      Erlotinib in cancer treatment.
      Both the Tarceva responses in conjunction with paclitaxel and carboplatin and Tarceva Lung Cancer Investigation trials found survival was significantly increased among a subgroup of patients receiving the EGFR TKI erlotinib who never smoked. In the Tarceva responses in conjunction with paclitaxel and carboplatin trial,
      • Herbst RS
      • Prager D
      • Hermann R
      • et al.
      TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
      median survival of this subgroup (n = 116) was 22.5 months compared with 10.1 months for placebo patients (P = 0.01). In the Tarceva Lung Cancer Investigation trial (n = 18),
      • Gatzemeier U
      • Pluzanska A
      • Szczesna A
      • et al.
      Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
      median survival of this subgroup was not reached compared with 11.4 months with placebo patients; and progression-free survival was significantly longer with erlotinib (7.9 months versus 5.4 months, P = 0.02).
      Sandler et al.
      • Sandler A
      • Gray R
      • Perry MC
      • et al.
      Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
      assessed the addition of bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, to paclitaxel and carboplatin. In this trial of 878 patients, median survival was improved 2 months with the addition of bevacizumab (12.3 months versus 10.3 months; HR, 0.79; 95% CI, 0.67–0.92; P = 0.003). The response rate was also improved (35% versus 15%, P < 0.001). The population under study was restricted to patients who had good performance status (ECOG 0-1), did not have brain metastases, or dominant squamous cell histology or hemoptysis, and who had no history of bleeding diathesis or coagulopathy.
      On considering the results of the trial by Sandler et al., the ACCP came to the conclusion that bevacizumab improves survival combined with carboplatin and paclitaxel in a clinically selected subgroup of patients with advanced NSCLC and good performance status.
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      Such patients have nonsquamous histology, no evidence of brain metastases, and no hemoptysis. Based on this evidence, the ACCP recommended that, in these patients, the addition of bevacizumab to carboplatin and paclitaxel should be considered a therapeutic option. Results of a second trial have also suggested an improvement in response and a very modest improvement in progression-free survival when bevacizumab was added to cisplatin and gemcitabine.
      • Reck M
      • von Pawel J
      • Zatloukal P
      • et al.
      Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAiL.
      In the additional search conducted in response to reviewer feedback, Pirker et al.
      • Pirker R
      • Pereira JR
      • Szczesna A
      • et al.
      Cetuximab plus chemotherapy in patients with advanced non-small cell lung cancer (FLEX): an open-label randomised phase III trial.
      added cetuximab to cisplatin and vinorelbine in 1125 patients with tumors immunohistochemically positive for EGFR expression. Survival was improved with cetuximab (HR, 0.871; 95% CI, 0.762–0.996; median 11.3 versus 10.1 months) with higher rates of rash (10 versus <1% grades 3–4) and febrile neutropenia (22 versus 15% grade 3–4) and slight worsening of diarrhea, hypokalemia, and infusion reactions. Response rates were improved with cetuximab (36 versus 29%, P = 0.01). QOL did not differ between the two arms. In exploratory analyses, the development of rash was associated with an increased survival, whereas data from 379 archived tumor specimens did not demonstrate any detrimental effect to KRAS mutations.
      • O'Byrne KJ
      • Bondarenko I
      • Barrios C
      • et al.
      Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the Flex study (abstract).
      Limited data from a phase II study suggest that increased gene copy number as measured by fluorescent in situ hybridization may predict for tumor progression and survival.
      • Hirsh FR
      • Herbst RS
      • Olsen C
      • et al.
      Increased EGFR gene copy number detected by fluorescent in site hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy.
      A second trial, which added cetuximab to carboplatin plus a taxane, showed no improvement in survival, progression-free survival, or QOL.
      • Patel T
      • Dreisbach L
      • McCleod M
      • et al.
      Lung cancer symptoms with cetuximab/taxane/carboplatin in first-line advanced NSCLC: Analysis of the BMS099 trial.

      New Single Agents

      (Q8) Is a Single New Agent Superior to Best Supportive Case?

      A 2005 SIGN guideline assessed new single agents in comparison to best supportive case (BSC).
      • Scottish Intercollegiate Guidelines Network
      Three of the four RCTs (including paclitaxel, docetaxel, and vinorelbine but not gemcitabine) demonstrated increased survival over BSC. The trials also showed a trend toward improvement in QOL.
      A meta-analysis by Baggstrom et al.
      • Baggstrom MQ
      • Stinchcombe TE
      • Fried DB
      • et al.
      Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis.
      considered the same four studies plus an additional study comparing vinorelbine to 5-fluorouracil and leucovorin. More than1000 patients were included, with single-agent response rates ranging from 12 to 20% and one-year survival ranging from 14 to 32%. For 1-year survival, an absolute risk difference of 7% (95% CI, 2–12%) favored new monotherapy over BSC.

      (Q9) Is a Single New Agent Superior to Single-Agent or Doublet Therapy Including Older Agents?

      The 2007 meta-analysis by Baggstrom et al.
      • Baggstrom MQ
      • Stinchcombe TE
      • Fried DB
      • et al.
      Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis.
      considered four trials (n = 871) that compared new monotherapy with a second-generation, platinum-based combination regimen. The single agents used were vinorelbine, gemcitabine, and irinotecan, whereas the control arms consisted of cisplatin plus either vindesine or etoposide. Despite an apparent decrease in response rates with new single agents (absolute risk difference estimate for response −6%, 95% CI −11 to 0%), 1-year survival did not differ (risk difference 3%, 95% CI −3 to 10%).
      Two of the earlier four trials included in the meta-analysis attempted to assess QOL. Comparing gemcitabine with cisplatin and etoposide, ten Bokkel Huinink et al.
      • ten Bokkel Huinink WW
      • Bergman B
      • Chemaissani A
      • et al.
      Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer.
      found no difference in QOL but worse hair loss, nausea and vomiting, and appetite loss with the platinum doublet. Negoro et al.
      • Negoro S
      • Masuda N
      • Takada Y
      • et al.
      Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer.
      reported insufficient compliance to evaluate QOL.

      (Q10) Which Single New Agent is Most Effective?

      Three RCTs, all focused on patients 70 years or older, compared new single-agent chemotherapies
      • Comella P
      • Frasci G
      • Carnicelli P
      • et al.
      Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      • Kudoh S
      • Takeda K
      • Nakagawa K
      • et al.
      Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
      (Table 6). The agents investigated included gemcitabine, vinorelbine, paclitaxel, and docetaxel. No study found a significant survival benefit. Kudoh et al.
      • Kudoh S
      • Takeda K
      • Nakagawa K
      • et al.
      Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
      reported improved response rate with docetaxel over vinorelbine (22.7 versus 9.9, P = 0.019) and an improvement in the overall symptom score (but not global QOL score) in favor of docetaxel. Gridelli et al
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      found no differences in QOL scores. In general, toxicity was similar between study arms, apart from alopecia.
      TABLE 6New Agents in the Elderly Population
      StudyComparisonSurvival (95% CI), p ValueOverall Response (95% CI), p Value
      ReferenceNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Comella et al.25
      Trial of elderly and poor performance status (PS) patients. PS 2 patients comprised 24% of the population in Frasci, 4% in Kudoh, 29% in Commella, and 35% in Hainsworth. Hainsworth included patients >65 yr of age.
      264/—GV689.7 (7.9–11.5) vs. G, p = ns32 (NR)
      Pooled comparisons of doublets vs. singles: median survival and 1-yr survival were 5.7 (95% CI, 3.9–7 5) mo and 28% for single-agent treatments, and 9.2 (95% CI, 7.6–10.8) mo and 39% for the combinations (p = 0.028).
      23 (13–35) p = ns
      GP659.2 (4.8–13.6) vs. P, p = 0.05144 (NR)32 (20–45) vs. P, p = 0.013
      G685.1 (2.2–8.0)29 (17–41)18 (9–30)
      P636.4 (4.4–8.4)25 (13–37)13 (6–24)
      ELVIS26191/154V80/766.4 (5.3–8.0) p = 0.0332 (NR)19.7 (11.5–30.5)
      BSC81/784.8 (3.7–6.2)14 (NR)NR
      Frasci et al.29
      Trial of elderly and poor performance status (PS) patients. PS 2 patients comprised 24% of the population in Frasci, 4% in Kudoh, 29% in Commella, and 35% in Hainsworth. Hainsworth included patients >65 yr of age.
      120/—V604.1 (NR)13 (NR) p = 0.0115 (7–27)
      GV606.7 (NR)30 (NR)22 (12–34)
      Gridelli et al.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      698G233/2326.4 (5.7–7.8)2816 (12–21)
      V2338.3 (6.9–10.3)3818 (13–23)
      GV2326.9 (6.2–8.3)3021 (16–26)
      Hainsworth et al.34
      Trial of elderly and poor performance status (PS) patients. PS 2 patients comprised 24% of the population in Frasci, 4% in Kudoh, 29% in Commella, and 35% in Hainsworth. Hainsworth included patients >65 yr of age.
      350/345DG1745.5 (NR)26 (NR)25 (18–34)
      D1715.1 (NR)24 (NR)17 (11–24)
      Kudoh et al.41
      Trial of elderly and poor performance status (PS) patients. PS 2 patients comprised 24% of the population in Frasci, 4% in Kudoh, 29% in Commella, and 35% in Hainsworth. Hainsworth included patients >65 yr of age.
      182/180D90/8914.3 (NR)58.622.7 (13.9–31.5)
      V92/919.9 (NR)36.79.9 (3.8–16) p = 0.019
      BSC, best supportive care; CI, confidence interval; D, docetaxel; G, gemcitabine; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not reported; P, paclitaxel; V, vinorelbine.
      a Neval only reported when analysis was not intention-to-treat.
      b Trial of elderly and poor performance status (PS) patients. PS 2 patients comprised 24% of the population in Frasci, 4% in Kudoh, 29% in Commella, and 35% in Hainsworth. Hainsworth included patients >65 yr of age.
      c Pooled comparisons of doublets vs. singles: median survival and 1-yr survival were 5.7 (95% CI, 3.9–7 5) mo and 28% for single-agent treatments, and 9.2 (95% CI, 7.6–10.8) mo and 39% for the combinations (p = 0.028).

      Maintenance Therapy and Administration of Altered Schedules of New Regimens

      (Q11) What is the Optimal Administration, Duration, and Timing of Chemotherapy for Advanced NSCLC?

      Maintenance Therapy.

      Several phase III studies have investigated the concept of extended duration or maintenance therapy in advanced NSCLC. The SIGN guideline
      • Scottish Intercollegiate Guidelines Network
      reviewed evidence from three trials that compared outcomes of prolonging chemotherapy beyond three to four cycles
      • Smith IE
      • O'Brien ME
      • Talbot DC
      • et al.
      Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin.
      • Socinski MA
      • Schell MJ
      • Peterman A
      • et al.
      Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer.
      • Vansteenkiste J
      • Vandebroek J
      • Nackaerts K
      • et al.
      Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine.
      and that concluded prolonging chemotherapy beyond four cycles improved progression-free survival but also increased the frequency of adverse events and did not improve overall survival or QOL. A meta-analysis by Soon et al.
      • Soon YY
      • Askie L
      • Stockler M
      • et al.
      Optimal duration of chemotherapy for advanced non-small cell lung cancer: A systematic review and meta-analysis (abstract).
      that included 10 trials (n = 1575) comparing a long versus a short duration of chemotherapy found longer durations of chemotherapy improved progression-free survival (HR, 0.83; 95% CI, 0.75–0.93; P = 0.0007) but not overall survival and added toxicity. QOL was assessed in five of the included trials and showed variable results.
      Trials involving new drugs beyond those assessed in the SIGN guideline are listed in Table 7; five of these are maintenance trials. In three trials, progression-free survival improved with extended therapy
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      but statistically significant improvements in overall survival were not seen. The trial by Park et al.
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      found four cycles of combination chemotherapy was noninferior to six cycles; the other fully published trials in Table 7 failed to detect superior survival with prolonged therapy.
      TABLE 7Administration or Maintenance Trials
      StudyComparisonSurvival (95% CI), p ValueOverall Response (95% CI), p Value
      AuthorNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      AgentsNrand/Neval
      Neval only reported when analysis was not intention-to-treat.
      Median (mo)1-yr %
      Maintenance trials
      Brodowicz et al.
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      215/206GCinduction→maintenance G142/13810.2 (8.0–13.4) p = 0.17NR50.7 (42.4–59.3 p = 0.55
      There was a greater increase in the number of responders in the GC arm, 18.1% (p
      GCinduction→BSC73/688.1 (6.6–11.1)NR45.6 (33.8–58.1)
      Fidias et al.
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      307GCbinduction→immediate D15311.948.542.5
      HR for death on experimental arm 1.21 (90% CI, 0.97–0.151).
      GCbinduction→delayed D1549.1 p = 0.07138.39.9″
      Park et al.
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      314C + P or D or G ×615814.9 (13.0–16.8)59.0 (NR)NR
      C + P or D or G ×415615.9 (12.4–19.4) p = 0.46162.4 (NR)NR
      von Plessen et al.
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      300/—VCb (×3)1506.4 (NR) p = 0.75
      Hazard ratio for survival for VCb x6 vs. x3 = 1.04 (0.82–1.31).
      25 (NR)NA
      VCb (×6)1507.4 (NR)25 (NR)NA
      Westeel et al.
      • Westeel V
      • Quoix E
      • Moro-Sibilot D
      • et al.
      Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer.
      181/—M-ICinduction→maintenance V9112.3 (NR)
      Hazard ratio of survival for V vs. Obs = 1.08 (0.79–1.46), p =.65.
      42 (NR) p = 0.4857.8 (NR)
      MICinduction→Obs9012.3 (NR)51 (NR)NA
      Belani et al.
      • Belani CP
      • Brodowicz T
      • Ciuleanu T
      • et al.
      Maintenance pemetrexed (Pem) plus best supportive case (BSC) versus placebo (Plac) plus BSC: a randomized phase III study in andanved non-small cell lung cancer (NSCLC).
      663/—Pem + BSC44113.4 (0.65–0.95) p = 0.012NRNR
      BSC22210.6 (NR)NRNR
      Administration trials
      Belani et al.
      • Belani CP
      • Larocca RV
      • Rinaldi DA
      • et al.
      A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel [abstract].
      444/431P(100 mg)qw (3/4w) + Cb(AUC =223/2178.9 (NR) p = 0.3939.5 (33.0–46.0)20.3 (14.9–25.6) p = 0.59
      6)q4w (× 4) P (225 mg)q3w + Cb(AUC = 6)q3w (× 4)221/21410.2 (NR)43.0 (36.4–49.6)18.2 (13.1–23.4)
      Novello et al.
      • Novello S
      • Bruzzi P
      • Barone C
      • et al.
      Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone.
      250/—GCinduction→maintenanceGC125NR52 (NR) p = ns27 (NR)
      Response rate (accumulated after initial GC chemotherapy) was 29% before randomization
      GCinduction→maintenanceG125NR42 (NR)14.5 (NR)
      Schuette et al.
      • Schuette W
      • Blankenburg T
      • Guschall W
      • et al.
      Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin.
      921/—PCbqw4578.9 (7.9–9.9) p = 0.32NR38 (NR) p = ns
      PCbq3w4649.5 (8.6–10.4)NR33 (NR)
      Abbreviations: AUC – area under curve; BSC=best supportive care; C=cisplatin; Cb=carboplatin; Cl-confidence interval; D=docetaxel; G=gemcitabine; I=ifosfamide; P=paclitaxel; mg=milligrams; mos=months; M=mitomycin-C; NA=not applicable; Neval=number of patients evaluable; Nrand=number of patients randomized; NR=not reported; ns=not significant; Obs=observation; Pem= Pemetrexed; q=every; V=vinorelbine; w=week; x=times.
      a Neval only reported when analysis was not intention-to-treat.
      b There was a greater increase in the number of responders in the GC arm, 18.1% (p
      c HR for death on experimental arm 1.21 (90% CI, 0.97–0.151).
      d Hazard ratio for survival for VCb x6 vs. x3 = 1.04 (0.82–1.31).
      e Hazard ratio of survival for V vs. Obs = 1.08 (0.79–1.46), p =.65.
      f Response rate (accumulated after initial GC chemotherapy) was 29% before randomization
      Three of the trials found no difference in toxicity with prolonged treatment.
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      • Westeel V
      • Quoix E
      • Moro-Sibilot D
      • et al.
      Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer.
      Brodowicz et al.,
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      giving maintenance gemcitabine, and von Plessen et al.,
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      giving six versus three courses of carboplatin-vinorelbine, found that prolonged therapy significantly increased transfusion requirements, by 14 and 19%, respectively. Socinski et al.
      • Socinski MA
      • Schell MJ
      • Peterman A
      • et al.
      Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer.
      detected greater peripheral neuropathy in patients receiving more than four cycles of carboplatin and paclitaxel (P = 0.02).
      Three trials examined QOL
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      and found no improvements in QOL with prolonged therapy. Park et al.
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      found that patients administered four cycles showed significant improvement in role-functioning (P < 0.05) and experienced less nausea/vomiting, sore mouth, and dyspnea (P < 0.05) than patients receiving six cycles of treatment. von Plessen et al.
      • von Plessen C
      • Bergman B
      • Andresen O
      • et al.
      Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.
      found a greater deterioration in role-functioning score (P < 0.05) and increased nausea and vomiting (P < 0.05) in patients receiving six cycles than in those receiving three cycles but no significant difference in global QOL, pain, or fatigue up to 26 weeks of the study.
      It should be noted that several trials
      • Brodowicz T
      • Krzakowski M
      • Zwitter M
      • et al.
      Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial.
      • Fidias P
      • Dakhil S
      • Lyss A
      • et al.
      Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival [abstract].
      • Park JO
      • Kim SW
      • Ahn JS
      • et al.
      Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.
      • Westeel V
      • Quoix E
      • Moro-Sibilot D
      • et al.
      Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer.
      randomized patients after initial assessments demonstrated at least stable disease, indicating that these were patients who tolerated therapy and would most be expected to benefit from prolonged drug treatment.
      In the additional search conducted in response to reviewer feedback A relevant study of maintenance pemetrexed was published in abstract form after the search period.
      • Belani CP
      • Brodowicz T
      • Ciuleanu T
      • et al.
      Maintenance pemetrexed (Pem) plus best supportive case (BSC) versus placebo (Plac) plus BSC: a randomized phase III study in andanved non-small cell lung cancer (NSCLC).
      In this trial, 663 patients with stable disease after four cycles of a platinum agent plus one of docetaxel, gemcitabine, or paclitaxel were randomized to placebo or pemetrexed until progression. The primary end point of progression-free survival was met (median 4.3 versus 2.6 months, P < 00001), as was the secondary end point of overall survival (HR, 0.79; 95% CI, 0.65–0.95; median 13.4 versus 10.6 months). Benefit seemed to be limited to the nonsquamous cell carcinoma population. Only 19% of patients randomized to placebo subsequently received pemetrexed, raising the question of whether any exposure to pemetrexed might be sufficient or whether early exposure is important.

      Administration.

      Other studies have tried diminishing toxicity by altering the schedule of treatment. Two trials assessed the administration of paclitaxel in a weekly versus three-weekly format combined with carboplatin.
      • Belani CP
      • Larocca RV
      • Rinaldi DA
      • et al.
      A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel [abstract].
      • Schuette W
      • Blankenburg T
      • Guschall W
      • et al.
      Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin.
      Both found that weekly treatment decreased the incidence of neuropathy, whereas Schuette et al
      • Schuette W
      • Blankenburg T
      • Guschall W
      • et al.
      Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin.
      also found a minimal increase in grade 3/4 diarrhea with weekly treatment (4.2 versus 1.1%, P = 0.005). Overall survival could not be proved superior for the weekly arm by Belani et al.,
      • Belani CP
      • Larocca RV
      • Rinaldi DA
      • et al.
      A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel [abstract].
      and Schuette et al. considered this as a secondary end point.
      After two initial cycles of cisplatin and gemcitabine, Novello et al.
      • Novello S
      • Bruzzi P
      • Barone C
      • et al.
      Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone.
      compared three more cycles of the same with gemcitabine alone. Their findings could not reject the possibility that single-agent gemcitabine was inferior in terms of survival, and QOL did not differ.

      Therapy for Elderly Patients

      (Q12) Which Single or Doublet Regimen Including a New Agent is Superior for the Elderly Population?

      The ACCP guideline
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      reviewed published retrospective comparisons of patients aged 70 years or older from randomized trials that were not designed to address the age issue. Compared with the proportion of patients in the lung cancer population (40–50%), patients aged 70 years or older are underrepresented in clinical trials (15–29%), and elderly patients entering these trials are likely to be among the fit elderly population.
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      In the trials that involved platinum combinations, survival was not worse among the elderly population, whereas leucopenia was increased. Very few patients aged 80 years or older have been included.
      • Socinski MA
      • Crowell R
      • Hensing TE
      • et al.
      Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition).
      No trial dedicated to assessing platinum agents in the elderly population has been completed.
      • Tsukada H
      • Yokoyama A
      • Nishiwaki Y
      • et al.
      Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207 [abstract].
      Six phase III trials have specifically assessed treatment in the elderly, typically defined as 70 years or older (Table 7). Four of these trials
      • Comella P
      • Frasci G
      • Carnicelli P
      • et al.
      Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.
      • Frasci G
      • Lorusso V
      • Panza N
      • et al.
      Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial.
      • Hainsworth JD
      • Spigel DR
      • Farley C
      • et al.
      Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.
      • Kudoh S
      • Takeda K
      • Nakagawa K
      • et al.
      Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
      have also included nonelderly ECOG performance status two patients, with 4 to 35% of patients of any age in those trials having a performance status of 2. The earliest trial
      • The Elderly Lung Cancer Vinorelbine Italian Study Group
      Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer.
      demonstrated a survival improvement using single agent vinorelbine over BSC. Cancer-related QOL was also improved (including dyspnea and pain), but treatment-related QOL was worse (including nausea and vomiting, alopecia, and peripheral neuropathy). A specified comparison of single agents showed no survival improvement with docetaxel over vinorelbine.
      • Kudoh S
      • Takeda K
      • Nakagawa K
      • et al.
      Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
      Other trials have compared nonplatinum doublets with single agents. Two such trials, which both closed early,
      • Comella P
      • Frasci G
      • Carnicelli P
      • et al.
      Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.
      • Frasci G
      • Lorusso V
      • Panza N
      • et al.
      Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial.
      suggested survival improvements using doublet therapy, with no apparent difference in QOL.
      • Frasci G
      • Lorusso V
      • Panza N
      • et al.
      Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial.
      Two other larger trials
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      • Hainsworth JD
      • Spigel DR
      • Farley C
      • et al.
      Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.
      have not shown survival or QOL improvements with doublets. A minority of the earlier patients were older than 80 years, with only the trial of Gridelli et al.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      providing the specific percentage (3–4%).

      Toxicity of First-Line Systemic Chemotherapy Regimens

      Table 8 compares the rates of grades 3 and 4 toxicity for several regimens combining platinum agents and new agents or using new agents alone. The rates were derived from seven large RCTs that encompassed the main treatment options with new chemotherapy agents.
      • Alberola V
      • Camps C
      • Provencio M
      • et al.
      Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      • Gridelli C
      • Perrone F
      • Gallo C
      • et al.
      Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      • Comella P
      • Filippelli G
      • De Cataldis G
      • et al.
      Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101).
      • Georgoulias V
      • Ardavanis A
      • Tsiafaki X
      • et al.
      Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial.
      • Kosmidis P
      • Mylonakis N
      • Nicolaides C
      • et al.
      Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial.
      Comparisons between trials should be avoided, and numbers are provided only to give a general sense of the toxicity of the regimens.
      TABLE 8Summary of Grade 3 or 4 Chemotherapy Toxicity (% Patients) from Large, Selected Trials in NSCLC
      Regimen Dose (mg/m2) and Administration Schedule [Reference]Febrile NeutropeniaAnemiaNausea/VomitingPeripheral NeuropathyPlateletsRenal
      Paclitaxel 100 over 1 hr days 1, 8, 15 every 4 weeks [Comella 2004 (25)]3%2%NR/0000
      Gemcitabine 1200 over 30 mins days 1, 8, 15 every 4 weeks [Comella 2004 (25)]3%10%NR/3%2%10%2%
      Vinorelbine 30 days 1, 8 every 3 weeks [Gridelli 2003 (33)]NR<4%<1%1%<1%0
      Docetaxel 60 over 1hr, day 1 every 3 weeks [Kudoh 2006 (41)]12.5%3.4%10.2%00NR
      Cisplatin/Vinorelbine 100 day 1/25 days 1, 8, 15, 22 every 4 weeks [Fossella 2003 (28)]5%24%16%/16%4% Sensory4%NR
      Cisplatin/Vinorelbine 80 day 8/30 days 1 and 8 [Georgoulias 2005 (79)]NR6%15%NR6%3%
      Cisplatin/Paclitaxel 75 day 2/135 (24 hour) day 1 every 3 weeks [Schiller 2002 (55)]16%13%25%/24%5%6%3%
      Grades 3, 4 and 5 renal toxicity.
      Cisplatin/Docetaxel 75 day 1/75 day 1 every 3 weeks [Fossella 2003 (28)]5%7%#10%/8%#4% Sensory3%NR
      Cisplatin/Docetaxel 75 day 1/75 day 1 every 3 weeks [Schiller 2002 (55)]11%15%24%/21%5%3%3%
      Grades 3, 4 and 5 renal toxicity.
      Cisplatin/Gemcitabine 100 day 1/1000 days 1, 8, 15 every 4 weeks [Schiller 2002 (55)]4%
      Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      28%
      Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      • 37%/35%
      • 9%
        Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
        /8%
        Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      9%50%t9%
      Grades 3, 4 and 5 renal toxicity.
      Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      Carboplatin/Paclitaxel AUC 6 day 1/225 (3 hour) day 1 every 3 weeks [Schiller 2002 (55)4%
      Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      10%10%10%1%
      Toxicity was significantly different between the two regimens, gemcitabine-docetaxel and cisplatin-vinorelbine (p<0.001)79.
      Carboplatin/Paclitaxel AUC 6 day 1/200 (3 hour) day 1 every 3 weeks [Kosmidis 2002 (80)]1%5%4%8%2%0%
      Carboplatin/Docetaxel AUC 6 day 1/75 day 1 every 3 weeks [Fossella 2003 (28)4%10%#6%/4%#1%Sensory7%NR
      Gemcitabine/Docetaxel 1000 days 1 and 8/100 day 8 [Georgoulias 2005 (79)]NR2%2%
      Grades 3, 4 and 5 renal toxicity.
      NR4%0%
      Gemcitabine/Paclitaxel 1000 day 1, 8/200 (3 hour) day 1 every 3 weeks [Kosmidis 2002 (80)]2%2%7%6%1%1%
      # Toxicity was significantly different than for the trial comparator regimen, cisplatin-vinorelbine (p<0.01)28.
      Abbreviations: AUC – area under curve; hr=hour; mg = milligrams; m2=metres squared; min=minutes; NR – not reported; NSCLC – non-small cell lung cancer.
      * Grades 3, 4 and 5 renal toxicity.
      Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p<0.05)55.
      * Toxicity was significantly different between the two regimens, gemcitabine-docetaxel and cisplatin-vinorelbine (p<0.001)
      • Georgoulias V
      • Ardavanis A
      • Tsiafaki X
      • et al.
      Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial.
      .
      Cisplatin-paclitaxel (135 mg/m2 over 24 hours) produced grade 3 or 4 febrile neutropenia in 16% of patients. Rates with the other regimens are all less than or equal to 5% with the exception of docetaxel combined with cisplatin (11%) in one trial.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      Anemia seems to be worse when gemcitabine or vinorelbine is given on a weekly basis without breaks.
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      Nausea and vomiting is more common with the use of cisplatin compared with carboplatin
      • Fossella F
      • Pereira JR
      • von Pawel J
      • et al.
      Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.
      or nonplatinum regimens
      • Kosmidis P
      • Mylonakis N
      • Nicolaides C
      • et al.
      Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial.
      (see also text on meta-analyses in questions 7 and 8). Thrombocytopenia has been associated more commonly with gemcitabine and carboplatin use.
      • Schiller JH
      • Harrington D
      • Belani CP
      • et al.
      Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
      Rates of alopecia are not reliably reported.

      DISCUSSION

      Improving the treatment of incurable NSCLC has been challenging, and the findings to the questions set out in this review indicate that, although statistical differences are often apparent, clinical differences between treatments are modest at best. When making treatment decisions with an individual patient, it is appropriate to consider the patient's own values, their performance status, and issues of toxicity and convenience. Cost considerations may also play a role, but a cost-benefit analysis is not undertaken here.
      Despite the plethora of new drug combinations studied, data continue to support the use of a platinum agent plus a new agent as the reference standard. This combination seems to have a slight survival advantage over pairs of new agents, although at a cost of additional toxicity. Among new platinum doublets, no particular combination seems to have demonstrated satisfactory or consistent superiority, and any may be chosen. There does seem to be a slight response and survival advantage to cisplatin combinations over carboplatin combinations, although the toxicity profile favors the latter.
      Both conventional cytotoxic agents and EGFR TKI's have been added to doublet chemotherapy, but neither has improved survival. Conversely, in a population carefully chosen to optimize safety, the addition of bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, may improve survival. Although it is reasonable to use bevacizumab in combination with paclitaxel and carboplatin in the trial specified population (ie, good performance status [ECOG 0-1], no brain metastasis, no dominant squamous cell histology or hemoptysis, and no history of bleeding diathesis or coagulopathy), data are presently insufficient to recommend that bevacizumab be used in the general treatment of incurable NSCLC, based on the lack of a confirmatory trial, the toxicity of the treatment, and its cost. Similarly, cetuximab produced a modest 1-month survival improvement in one of two studies, at the cost of some toxicity, and may not warrant general use.
      The evidence demonstrates that a new single agent improves survival compared with BSC, although not by more than a median of 2 months. When the use of a platinum agent plus a new agent is considered standard, the use of a single agent may be considered for some patients, including patients aged 70 years or older, patients who have a performance status of two, or patients for whom platinum therapy might be contraindicated. Single new agents also seem comparable in terms of survival with older combinations of a platinum and nonplatinum agent, although they also offer better outcomes when they are combined with a platinum agent. Combinations of new agents are not consistently superior to single agents, although these trials are relatively few and limited to the elderly and poor performance status population.
      A few additional comments can be made. The trials addressing the question of treatment duration are relatively small and underpowered, and although progression-free survival may be increased by continuing first-line chemotherapy beyond four cycles, it is at the expense of worse toxicity and QOL. For this reason, it is recommended that first-line therapy stop after four to six cycles. Although the use of maintenance pemetrexed may be reasonable in some patients, it is unknown whether delayed exposure to pemetrexed may produce the same result. The use of weekly paclitaxel should only be considered when paclitaxel must be used and there are compelling reasons to minimize neuropathy, as equivalent survival has not been demonstrated. In the population ≥70 years of age who are fit, there are good data to support the use of a new single agent but conflicting data about combining new agents. Subgroup analyses of some trials suggest that platinum-based doublet therapy may be appropriate for some older patients.

      Additional Review and Discussion

      Emerging data published outside the search parameters of this review suggest that histology may be predictive for outcomes when using pemetrexed. The original literature search (ending November 2008) was updated and restricted to pemetrexed. The updated search identified three randomized trials, one published as a full article
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      and the other two published in abstract form.
      • Peterson P
      • Park K
      • Fossella F
      • et al.
      Is pemetrexed more effective in patients with non-squamous histology? A retrospective analysis of a phase III trial of pemetrexed vs. docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) (abstract).
      • Ciuleanu TE
      • Brodowicz T
      • Belani CP
      • et al.
      Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study (abstract).
      Scagliotti et al.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      compared first-line cisplatin and pemetrexed to cisplatin and gemcitabine in 1725 patients and found pemetrexed was not inferior for overall survival (median survival 10.3 months in both arms; pemetrexed HR, 0.94; 95% CI, 0.84–1.05). However, in a subgroup analysis, patients treated with pemetrexed had an improved survival when the histology of their malignancy was adenocarcinoma (n = 847, median 12.6 versus 10.9 months; HR, 0.84; 95% CI, 0.71–0.99) or large cell carcinoma (n = 153, median 10.4 versus 6.7 months; HR, 0.67; 95% CI, 0.48–0.96) but not squamous cell carcinoma (n = 473, median 9.4 versus 10.8 months; HR, 1.23; 95% CI, 1.00–1.51). Peterson et al.
      • Peterson P
      • Park K
      • Fossella F
      • et al.
      Is pemetrexed more effective in patients with non-squamous histology? A retrospective analysis of a phase III trial of pemetrexed vs. docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) (abstract).
      have made a similar observation in a retrospective analysis of a second-line phase III study comparing pemetrexed with docetaxel. Patients with nonsquamous cell cancers had a better survival with pemetrexed (n = 399, median 9.3 versus 8.0 months; HR, 0.778; 95% CI, 0.607–0.997), whereas those with squamous carcinomas had an inferior survival with pemetrexed (n = 172, median 6.2 versus 7.4 months; HR, 1.56; 95% CI, 1.079–2.264). Such differences may be related to increased expression of thymidylate synthase in squamous carcinoma.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      An initial report from a third trial assessing pemetrexed as maintenance therapy is compatible with these findings.
      • Ciuleanu TE
      • Brodowicz T
      • Belani CP
      • et al.
      Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study (abstract).
      These data are sufficiently compelling to recommend that pemetrexed should not be used in the treatment of squamous cell carcinomas for first-line treatment. On the other hand, these data are not sufficiently compelling to recommend that pemetrexed be used preferentially over all other new agents in doublet therapy to treat adenocarcinoma in the first-line setting.

      APPENDIX

      Appendix A1Combined Search Strategy Applied to Cochrane Central Register of Control Trials (CENTRAL), MEDLINE and EMBASE
      • 1.
        Practice Guidelines/
      • 2.
        practice guideline.pt.
      • 3.
        practice guideline?.tw.
      • 4.
        systematic review?.tw.
      • 5.
        systematic overview?.tw.
      • 6.
        Meta-Analysis/
      • 7.
        meta analysis.pt.
      • 8.
        metaanalys$.tw.
      • 9.
        meta analys$.tw.
      • 10.
        meta-analys$.tw.
      • 11.
        Randomized Controlled Trials/
      • 12.
        randomized controlled trial.pt.
      • 13.
        Controlled Clinical Trials/
      • 14.
        controlled clinical trial.pt.
      • 15.
        Random Allocation/
      • 16.
        Clinical Trials/
      • 17.
        (random$ and (trial$ or stud$)).ti,ab.
      • 18.
        or/1–17
      • 19.
        Carcinoma, Non-Small-Cell Lung/
      • 20.
        NSCLC.ti,ab.
      • 21.
        (lung and (cancer$ or neoplasm$ or carcinom$ or malignan$ or tumo?r$)).ti,ab.
      • 22.
        non.ti,ab.
      • 23.
        and/21–22
      • 24.
        or/19–20,23
      • 25.
        (advanced or metastatic).ti.
      • 26.
        (stage and (III or IIIb or IIIB or IV)).ti.
      • 27.
        or/25–26
      • 28.
        and/24,27
      • 29.
        (paclitaxel or taxol or docetaxel or taxotere or gemcitabine or gemzar or vinorelbine or navelbine or irinotecan or campto or camptosar or CPT-11 or pemetrexed or ALIMTA or erlotinib or tarceva or gefitinib or iressa or bevacizumab or avastin).ti,ab.
      • 30.
        Paclitaxel/
      • 31.
        or/29–30
      • 32.
        and/18,28,31
      • 33.
        case reports.pt.
      • 34.
        letter.pt.
      • 35.
        editorial.pt.
      • 36.
        comment.pt.
      • 37.
        review.pt.
      • 38.
        or/33–37
      • 39.
        32 not 38
      • 40.
        limit 39 to english language
      • 41.
        limit 40 to humans
      • 42.
        limit 41 to yr=“1966 – 2007”
      • 43.
        phase II.ti.
      • 44.
        42 not 43
      Appendix A2Agents Considered in this Evidence-Based Series
      Drug ClassAgents
      Platinum agentscisplatin, carboplatin
      Taxanesdocetaxel, paclitaxel
      Vinca alkaloidsvindesine, vinorelbine, vinblastine
      Antimetabolitesgemcitabine, pemetrexed
      Alkylating agentsifosfamide, mitomycin C
      Topoisomerase inhibitorsirinotecan, etoposide
      EGFR TKI inhibitorserlotinib, gefitinib
      VEGF antibodyBevacizumab
      Antisense oligonucleotideAprinocarsen
      Figure thumbnail fx1
      Appendix A4Results of AGREE Tool Quality Rating of Evidence-Based Guidelines
      AGREE Domain Scores
      GuidelineScope and Purpose (%)Stakeholder Involvement (%)Rigour of Development (%)Clarity and Presentation (%)Applicability (%)Editorial Independence (%)Overall Rating
      ACCP97.270.876.283.333.375.0Strongly recommended for adoption or discussion
      SIGN77.875.084.587.569.425.0Strongly recommended for adoption or discussion
      Abbreviations: ACCP, American College of Chest Physicians; SIGN, Scottish Intercollegiate Guidelines Network.
      Appendix A5Results of Quality Assessment of Systematic Reviews and Meta-Analyses Using the Overview Quality Assessment Questionnaire (OQAQ)
      Criteria for Assessing Quality of Research Overviews*Systematic Review/Meta-analysis
      Ardizzoni 2007Baggstrom 2007Douillard 2007Jiang 2007Soon 2007Pujol 2006D’Addario 2005LeChevalier 2005Hotta 2004Hotta 2004
      Search methods reported?YesYesYesYesYesYesYesNoYesYes
      Search comprehensive?YesYesYesYesYesYesYesYesNoYes
      Inclusion criteria reported?YesYesYesYesYesYesYesYesYesYes
      Selection bias avoided?UnclearYesYesYesYesYesYesYesYesYes
      Validity criteria reported?NoYesYesYesNoYesNoYesYesYes
      Validity assessed appropriately?NoNoYesYesNoUnclearNoYesYesYes
      Methods used to combine studies reported?YesYesYesYesYesYesYesYesYesYes
      Findings combined appropriately?YesYesYesYesYesYesYesYesYesYes
      Conclusions supported by reported data?YesYesYesYesYesYesYesYesYesYes
      Overall quality of overview2477363667
      *Based on 7-point likert scale. 1=Extensive flaws (very poor), 2, 3=Major flaws (poor), 4, 5=Minor flaws (good), 6, and 7=Minimal flaws (exemplary).

      ACKNOWLEDGMENTS

      The Lung Disease Site Group would like to thank Dr G Goss, N Coakley, J MacKay, N Lloyd, C Smith, J Vanderveen and T Waldron, for taking the lead in drafting this systematic review. Please see the Program in Evidence-based Care section of Cancer Care Ontario's Web site for a list of current Disease Site Group members http://www.cancercare.on.ca/.
      Supported by Bristol Myers Sqibb, Glaxo Smith Kline and Eli Lilly (to P.E.).

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