Cited by 850Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

The DOI matches its Crossref record; 87 of the 176 references it cites were found in a registry or an index, and 88 are not checked yet; none of the 194 sources its claims cite is checked for support yet.

Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update

Open access

Abstract

Purpose: To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC). Methods: An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014. Results: This guideline update reflects changes in evidence since the previous guideline. Recommendations: There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki .

Checked 2026-10-06 · 88 references not checked yet

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This ASCO guideline update provides evidence-based recommendations for systemic therapy in stage IV NSCLC, based on a systematic review of 87 publications covering 73 phase III randomized controlled trials. It stratifies treatment by histology, molecular subtype (EGFR, ALK, ROS1), and performance status, and emphasizes concurrent palliative care and that age alone should not determine therapy.

Key findings

  • There is no cure for stage IV NSCLC; for patients with PS 0–1 (and appropriate PS 2) without EGFR-sensitizing mutation or ALK rearrangement, platinum-based combination cytotoxic chemotherapy guided by histology plus early concurrent palliative care is recommended (evidence quality high; strength strong).
  • For sensitizing EGFR mutations, afatinib, erlotinib, or gefitinib are recommended (each evidence quality high; strength strong); for ALK rearrangement, first-line crizotinib is recommended (evidence quality high; strength strong); for ROS1 rearrangement, crizotinib is recommended by informal consensus (evidence quality low; strength weak).
  • Maintenance: pemetrexed continuation is recommended for stable disease or response after four cycles of a pemetrexed-containing regimen (PARAMOUNT: PFS 4.4 v 2.8 months; OS 13.9 v 11 months, unadjusted HR P = .019).
  • Second-line options: docetaxel, erlotinib, gefitinib, or pemetrexed for nonsquamous; docetaxel, erlotinib, or gefitinib for squamous; chemotherapy or ceritinib after progression on crizotinib for ALK rearrangement. Third-line erlotinib may be recommended for patients who have not received erlotinib or gefitinib; data are insufficient for routine third-line cytotoxic therapy.
  • Decisions on chemotherapy should not be made based on age alone (evidence quality high; strength strong); the IFCT-0501 trial in elderly patients showed median OS 10.3 v 6.2 months favoring carboplatin plus paclitaxel over monotherapy (HR, 0.64; P < .001).

Methods

  • An ASCO Update Committee developed recommendations based on a systematic review of phase III RCTs; PubMed was searched from January 2007 to February 2014 for non–switch maintenance questions and June 2009 to February 2014 for switch maintenance questions.
  • Inclusion criteria: population with stage IV NSCLC (many trials also included stage IIIB) and fully published English-language phase III RCTs; exclusions included meeting abstracts not subsequently published, editorials/commentaries/case reports/narrative reviews, and non-English publications.
  • A total of 87 publications concerning 73 phase III RCTs formed the evidence base (51 trials in first-line/maintenance settings, 22 in second-/third-line); recommendations were crafted using GLIDES methodology and BRIDGE-Wiz software, with ratings for type, strength, evidence quality, and potential bias; informal consensus was used where evidence was lacking but committee agreement was high.

Limitations

  • Stated: insufficient objective tools to determine which patients benefit from and tolerate combined versus single-agent chemotherapy; insufficient data for patients with PS 2; not enough data on large-cell neuroendocrine carcinoma, on ROS1 and crizotinib, on second-line treatment after first-line EGFR TKI progression or after initial response, and immature data on adding pemetrexed to bevacizumab plus carboplatin (only one phase III trial).
  • Stated: quality assessment indicated intermediate to high potential risk of bias for most identified evidence, with some factors varying between studies and lowering comparability of results.
  • Evident from the text: several recommendations rest on informal consensus or low-quality evidence (ROS1 rearrangement, large-cell neuroendocrine carcinoma, second-line after EGFR TKI progression), and some cited evidence (e.g., ceritinib, nivolumab, PROFILE 1014) was published after the systematic review's data cutoff or fell outside its date parameters.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1200/jco.2015.62.1342

Cites

87 of 175 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 194 cited sources checked · 0 supported · 0 flagged

Show all 120 claims

  • It may state two separate claims as one. 85
  • Probably not a substantial claim. 35
  • The quote only partly states this claim. 3
110 of 110
  • The paper relies on this without support.

    There is no cure for patients with stage IV NSCLC.

    “There is no cure for patients with stage IV NSCLC.”
    “There is no cure for patients with stage IV NSCLC.”
  • The paper relies on this without support.

    Understanding of the histologic and molecular subtypes of NSCLC has increased since the 2009 guideline.

    “Since the 2009 guideline, the understanding of histologic and molecular subtypes of NSCLC has increased, and as a result, the clinical questions have been reformulated for presentation in terms of histology and molecular subtype.”
  • The paper relies on this without support.

    There are no FDA-approved nonplatinum regimens.

    “There are no FDA-approved nonplatinum regimens.”
  • The paper relies on this without support.

    Platinum-based combinations are generally considered to be more effective than non-platinum-based doublets.

    “Platinum-based combinations are generally considered to be more effective than non–platinum-based doublets.”
  • The paper relies on this without support.

    Toxicity concerns, particularly major bleeding complications, are relative contraindications to the use of bevacizumab in patients with SCC.

    “Toxicity concerns, particularly major bleeding complications, are relative contraindications to the use of bevacizumab in patients with SCC.”
  • The paper relies on this without support.

    There are not yet sufficient objective tools available to clinicians to determine which patients would benefit and tolerate combined therapy in comparison with single-agent chemotherapy.

    “There are not yet sufficient objective tools available to clinicians to determine which patients would benefit and tolerate combined therapy in comparison with single-agent chemotherapy.”
  • The paper relies on this without support.

    Large-cell neuroendocrine carcinoma is clinically similar to NSCC.

    “As a result of the clinical similarity of large-cell neuroendocrine carcinoma to NSCC, the Update Committee believes a platinum plus etoposide combination may provide optimal efficacy to patients whose tumors have this histology.90”
  • The paper relies on this without support.

    Both PS 2 and elderly populations are heterogeneous, and diminished PS can be a consequence of cancer-related symptoms or MCC.

    “Because both PS 2 and elderly populations are heterogeneous, and diminished PS can be a consequence of cancer-related symptoms or MCC, chemotherapy decisions in these subgroups must be individualized, with patient and caregiver input, to optimize outcomes fully with regard to efficacy and treatment-related toxicities.”
  • The authors state this as an assumption.

    For recommendations B3.a and B3.b, clinical experience, training, and judgment are sufficient to formulate recommendations when no data meet inclusion criteria.

    “Given that there were no data meeting the inclusion criteria to inform this question, the Update Committee relied on clinical experience, training, and judgment to formulate this recommendation.”
  • The paper relies on this without support.

    FDA approval is a sufficient basis for including a therapy in a clinical practice guideline recommendation.

    “Support for including ceritinib in this recommendation is based on FDA approval.”
  • The paper relies on this without support.

    Patients with unknown EGFR/ALK status and clinical demographics (young, female, Asian, nonsmoking) are more likely to have gene mutations and benefit from targeted drugs.

    “Patients with unknown EGFR/ALK status who have clinical demographics seen commonly in patients with gene mutations (young, female, Asian, and nonsmoking) may be better served with targeted drugs such as erlotinib or gefitinib.”
  • The paper relies on this without support.

    Many other patients may lack access to care because of geographic location and distance from appropriate treatment facilities.

    “Many other patients may lack access to care because of geographic location and distance from appropriate treatment facilities.”
  • The paper relies on this without support.

    Almost one third of older patients have diabetes, heart failure, and chronic kidney disease.

    “In addition, almost one third of older patients have diabetes, heart failure, and chronic kidney disease, which have significant repercussions on treatment planning, administration, and tolerance.”
  • The paper relies on this without support.

    MCCs are most relevant for treatment of older adults and those with PS ≥ 2.

    “MCCs are most relevant for treatment of older adults and those with PS ≥ 2.”
  • The paper relies on this without support.

    MCCs are associated with greater risk of hematologic toxicity and infectious complications in patients with advanced NSCLC treated with platinum-based chemotherapy.

    “MCCs are associated with greater risk of hematologic toxicity and infectious complications in patients with advanced NSCLC treated with platinum-based chemotherapy.”
  • The paper relies on this without support.

    MCCs are also associated with early treatment discontinuation.

    “MCCs are also associated with early treatment discontinuation.”
  • The paper relies on this without support.

    The best available evidence for treating index conditions often comes from clinical trials whose study selection criteria may exclude patients with MCCs to avoid potential interaction effects or confounding of results.

    “In addition, the best available evidence for treating index conditions often comes from clinical trials, the study selection criteria of which may exclude these patients to avoid potential interaction effects or confounding of results associated with MCCs.”
  • The paper relies on this without support.

    Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners, survivors of cancer, and caregivers and the need to provide adequate services in the face of limited resources.

    “Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners, survivors of cancer, and caregivers and the need to provide adequate services in the face of limited resources.”
18 of 18

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Significant second-line survival result conflicts with Table 3

    Major

    The text identifies reference 41 as one of two second-line trials with a significant OS or median-survival difference. Table 3 reports its OS comparison as P = .10, which is not statistically significant.

  • Quoix adverse-event counts are reversed between tables

    Major

    For the 225-patient carboplatin-paclitaxel arm, Table 4 reports 28 cases of neutropenia, six of febrile neutropenia, and two of thrombocytopenia. Table 5 reports 108, 21, and 15, respectively, for the same arm.

  • Published phase III crizotinib result is later described as unpublished

    Minor

    The crizotinib section says that the phase III PROFILE 1014 trial was published, then says no peer-reviewed phase III results had yet been published.

  • PointBreak hypertension percentage does not match its count

    Minor

    Table 4 reports six cases among 442 patients as 2.1%; the stated count and denominator give approximately 1.36%.

    Reported 2.1 · recomputed 1.357466

  • REVEL nausea percentage does not match its count

    Minor

    Table 5 reports 27 cases among 618 patients as 1.0%; the stated count and denominator give approximately 4.37%.

    Reported 1 · recomputed 4.368932

  • Quoix diarrhea percentage does not match its count

    Minor

    Table 4 reports two cases among 223 patients as 2.9%; the stated count and denominator give approximately 0.90%.

    Reported 2.9 · recomputed 0.896861

  • AVAPERL thrombocytopenia percentage does not match its count

    Minor

    Table 4 reports one case among 120 patients as 1.8%; the stated count and denominator give approximately 0.83%.

    Reported 1.8 · recomputed 0.833333

7 of 7

Citations

Cites

Flagged first, then by citations

Show all 176 references

1 of the 176 references couldn’t be matched to a known paper.

Research works printed but not linked: 8

  1. Ridolfi L, 2011, Int J Oncol, 39, 1011
  2. Chang JW, 2008, Chang Gung Med J, 31, 559
  3. Non-Small Cell Lung Cancer Collaborative Group, 2010, Cochrane Database Syst Rev, 5, CD007309
  4. Finn JW, 2002, Proc Am Soc Clin Oncol, 21, 154s
  5. Krakauer E, Presented at the American Society of Clinical Oncology Multidisciplinary Cancer Management Course
  6. McGuire L, 1990, Pharos, 53, 6
  7. Mead H, 2008, Health Care: A Chartbook
  8. Piccirillo JF, 2003, J Registry Manage, 30, 8

Cited by

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Items 101–200 of 850

Metadata

Authors
Masters, G. A., Temin, S., Azzoli, C. G., Giaccone, G., Baker, S., Brahmer, J. R., Ellis, P. M., Gajra, A., Rackear, N., Schiller, J. H., Smith, T. J., Strawn, J. R., Trent, D., & Johnson, D. H.
Affiliations
  • Christiana Care Health System (US)
  • American Society of Clinical Oncology (US)
Venue
Journal of Clinical Oncology
Published
2015-10-20
Volume
33
Issue
30
Pages
3488-3515
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
OpenAlex
W2125665528
Cited by
850
References
176
Citations by year
2026: 5 · 2025: 8 · 2024: 40 · 2023: 42 · 2022: 83 · 2021: 107 · 2020: 120 · 2019: 115 · 2018: 135 · 2017: 116 · 2016: 75 · 2015: 4
FWCI
87.12
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
stage IV non-small cell lung cancer, systemic therapy, EGFR mutation, ALK rearrangement, ROS1 rearrangement, large cell neuroendocrine carcinoma, first-line therapy, second-line therapy, third-line therapy, maintenance therapy, pemetrexed, bevacizumab, crizotinib, ceritinib, erlotinib, gefitinib, afatinib, platinum-based chemotherapy, palliative care, performance status
MeSH terms
Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neoplasm Staging, Randomized Controlled Trials as Topic

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