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Cited by 2,631Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

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Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. Giaj, Kerr, K., Popat, S. +5 more·2016·Annals of Oncology
DOI 10.1093/annonc/mdw326
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  • Premisecitation

    FDG-PET or PET/CT has higher sensitivity and specificity than bone scintigraphy for detecting bone metastasis.

    “Fluorodeoxyglucose (FDG)-PET or PET/CT has higher sensitivity and specificity than bone scintigraphy [34].”
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  • Premisecitation

    MRI is more sensitive than CT for imaging the central nervous system in patients with NSCLC.

    “MRI is more sensitive than CT scan [32].”
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  • Premisecitation

    PET/CT is the most sensitive modality for detecting bone metastasis.

    “PET/CT is the most sensitive modality in detecting bone metastasis [33].”
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  • Premisecitation

    The T790M mutation is the most common finding in EGFR-mutated tumours that relapse after first- or second-generation EGFR TKI therapy.

    “the most common finding in EGFR-mutated tumours relapsing after first-/secondgeneration EGFR TKI therapy [19].”
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  • Premisecitation

    The switch maintenance benefit of pemetrexed was observed only in patients with non-squamous cell carcinoma.

    “In the case of pemetrexed, this benefit was seen only in patients with NSCC [I, B].”
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    Premisecitation

    FDG-PET/CT offers the highest sensitivity for assessing mediastinal lymph nodes and distant metastasis.

    “FDG-PET/CT scan offers the highest sensitivity for mediastinal lymph nodes [35] and distant metastasis assessment.”
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    Premisecitation

    NGS testing panels provide data on HER2, BRAF, and MET mutations, which may allow access to targeted treatment in late lines of therapy, often in clinical trials, and can be associated with significant survival outcome.

    “NGS testing panels will also provide data on HER2, BRAF and MET mutations, for example, which may allow access to targeted treatment in late lines of therapy, often in the context of a clinical trial, and, in addition, with a significant survival outcome [26][27][28].”
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    Premisecitation

    Benefit was observed across all subgroups, but increased toxicity (notably febrile neutropaenia and sepsis-related deaths) was observed.

    “Benefit was observed across all subgroups, but increased toxicity (notably febrile neutropaenia and sepsis-related deaths) was observed.”
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    • cites [66]

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    Premisecitation

    One trial of gemcitabine/cisplatin with or without bevacizumab demonstrated an objective response rate and modest progression-free survival advantage, but no overall survival benefit.

    “While one trial of non-taxane, gemcitabine/cisplatin combination with or without bevacizumab demonstrated an objective RR (ORR) and modest PFS advantage, but no OS benefit [60]”
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    Premisecitation

    Treatment with EGFR TKIs (gefitinib, erlotinib, afatinib) in the first-line setting results in improved response rate, progression-free survival, tolerability, and quality of life compared with platinum-based chemotherapy.

    “Such treatments result in improved response rate (RR) and progressionfree survival (PFS), better tolerability and superior quality of life (QoL) compared with platinum-based chemotherapy in the firstline setting, as demonstrated in several randomised trials [21].”
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    Premisecitation

    The survival benefit of pemetrexed plus platinum holds true for cisplatin-containing regimens but not for carboplatin-based regimens.

    “The survival benefit of carboplatin in combination with pemetrexed has been investigated in a meta-analysis (exploratory subgroup analysis); survival benefit for pemetrexed plus platinum held true for cisplatin-containing regimens but not for carboplatin-based regimens [54]”
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    Premisecitation

    In that study, median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (HR 0.64, 95% CI 0.52-0.78; P<0.0001); 1-year survival was 44.5% and 25.4%, respectively.

    “Median OS was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (HR 0.64, 95% CI: 0.52-0.78;P < 0.0001); 1-year survival was 44.5% (95% CI: 37.9-50.9)and 25.4% (95% CI: 19.9-31.3),respectively.”
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    Premisecitation

    Patients who have smoked may feel stigmatised or guilty after diagnosis and more pessimistic about their illness and likely outcomes, which may have adverse implications for health-related quality of life.

    “patients who have smoked may feel stigmatised or guilty after diagnosis and more pessimistic about their illness and likely outcomes, all of which may have adverse implications for health-related QoL [41].”
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    Premisecitation

    In the SQUIRE trial, adding necitumumab to cisplatin/gemcitabine produced a significant overall survival improvement (11.5 vs 9.9 months, HR 0.84, 95% CI 0.74-0.96; P=0.01) and progression-free survival improvement, with 1-year survival of 48% in the experimental arm versus 43% in the control arm.

    “In the SQUIRE trial, the addition of necitumumab to cisplatin/gemcitabine produced a significant OS improvement [11.5 versus 9.9 months, hazard ratio (HR) 0.84, 95% CI: 0.74-0.96;P = 0.01] and PFS improvement, with a 1-year survival equal to 48% in the experimental arm versus 43% in the control arm [52].”
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    Premisecitation

    In that trial, median OS was 13.9 months with pemetrexed versus 11.0 months with placebo; 1- and 2-year survival rates were 58% and 32% with pemetrexed versus 45% and 21% with placebo.

    “Median OS was 13.9 months (95% CI: 12.8-16.0months) pemetrexed and 11.0 months (95% CI: 10.0-12.5 months) placebo, with 1-and 2-year survival rates significantly longer for patients given pemetrexed (58% and 32%, respectively) than for those given placebo (45% and 21%).”
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    Premisecitation

    The nab-paclitaxel/carboplatin (nab-PC) regimen has a significantly higher response rate compared with solvent-based paclitaxel/carboplatin (sb-PC) and less neurotoxicity in a large phase 3 trial.

    “The albumin-bound paclitaxel (nab-paclitaxel)/carboplatin (nab-PC) regimen has been shown in a large phase 3 trial to have a significantly higher RR compared with the solventbased paclitaxel/carboplatin (sb-PC) and less neurotoxicity [I, B] [50].”
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    Premisecitation

    Two meta-analyses reported a favourable response rate but increased toxicity (notably haematological) with doublet compared with single-agent therapy in elderly patients, while a statistically superior overall survival was observed in one of them, in which a subgroup analysis favoured platinum-based doublets.

    “Two meta-analyses reported a favourable RR but showed increased toxicity (notably haematological toxicity) with doublet-compared with single-agent therapy [72,73], while a statistically superior OS was observed in one of them, in which a subgroup analysis favoured platinum-based doublets.”
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    Premisecitation

    A meta-analysis of randomised trials comparing platinum-based doublets versus single-agent regimens in first-line therapy of PS 2 patients revealed platinum-based regimens to be superior in terms of response rate and survival (74% higher probability of being alive after 1 year) despite an increase in toxicities (mainly haematological).

    “A recently published meta-analysis of randomised trials comparing the efficacy and safety of platinum-based doublets versus single-agent regimens in the first-line therapy of PS 2 patients revealed platinum-based regimens to be superior in terms of RR and survival (74% higher probability of being alive after 1 year) despite an increase in toxicities (mainly haematological) [65].”
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    Premisecitation

    In stage IV NSCLC, chemotherapy compared with best supportive care reduces the risk of death by 23%, improves 1-year survival by 9%, increases median survival by 1.5 months, and improves quality of life, irrespective of age, sex, histology, and performance status.

    “Benefits of chemotherapy versus best supportive care (BSC, namely a 23% reduction of risk of death, a 1-year survival gain of 9% and 1.5-month absolute increase in median survival and improved QoL) are observed irrespective of age, sex, histology and PS in two meta-analyses [42,43].”
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    Premisecitation

    There is no overall survival benefit of six cycles versus fewer cycles of first-line platinum-based doublets, although six cycles are associated with longer progression-free survival and significantly higher toxicity.

    “Neither a large individual trial nor a meta-analysis found an overall survival (OS) benefit of six versus fewer cycles of first-line platinum-based doublets, although a longer PFS coupled with significantly higher toxicity was reported in patients receiving six cycles [46,47].”
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    Premisecitation

    Two randomised phase III switch maintenance trials found that pemetrexed and erlotinib each improve PFS and OS compared with placebo after four cycles of platinum-based chemotherapy.

    “Two randomised phase III switch maintenance trials have reported improvements in PFS and OS with pemetrexed [57] and erlotinib [77] versus placebo following four cycles of platinum-based chemotherapy.”
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    Premisecitation

    Platinum-based combinations reduce the risk of death at 1 year by 22% compared with non-platinum combinations, without an unacceptable increase in toxicity.

    “Based on a 2006 meta-analysis, revealing a statistically significant reduction (equal to 22%) in the risk of death at 1 year for platinum over non-platinum combinations, without induction of unacceptable increase in toxicity”
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    Premisecitation

    In EGFR wild-type patients who had not progressed after four cycles of platinum-based chemotherapy, early erlotinib maintenance did not improve OS compared with erlotinib at progression, with HR 1.02, 95% CI 0.85-1.22, P=0.8183, and identical 1-year event-free rates.

    “in patients with EGFR wild-type (WT) tumours who had not progressed following four cycles of platinum-based chemotherapy, and who had received 'early erlotinib' in the first-line maintenance setting, OS was not superior to erlotinib treatment upon disease progression (HR 1.02; 95% CI: 0.85-1.22;P = 0.8183) and 1-year event-free rates were the same in both treatment groups [78].”
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    Premisecitation

    Two-agent chemotherapy regimens have a survival benefit over one-agent regimens, but three-agent regimens show no survival benefit over two-agent regimens.

    “The survival benefit of two-agent over one-agent chemotherapy regimens was reported in a metaanalysis in 2004, with no survival benefit seen for three-agent over two-agent regimens [44].”
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    Premiseown data

    In CheckMate-057, the nivolumab arm had lower rates of serious adverse events (CTC grade 3/4: 10% versus 54%) and adverse events leading to treatment discontinuation (5% versus 15%) than docetaxel.

    “In the nivolumab arm, compared with docetaxel, a lower frequency of both serious adverse events (SAEs; CTC grade 3/4 events: 10% versus 54%) and AEs leading to treatment discontinuation (5% versus 15%) were observed.”
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    Interpretationreasoning

    None of the studies comparing EGFR TKIs with platinum-based chemotherapy have shown an OS benefit for the TKI, likely because of high crossover.

    “Notably, none of the above studies have shown any benefit in OS for an EGFR TKI over platinum-based chemotherapy, likely due to the high level of crossover.”
    Quote in the paperSubstantial claim

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    Premisecitation

    An unplanned pooled OS analysis of LUX-Lung 3 and LUX-Lung 6 found an OS benefit for afatinib versus chemotherapy in EGFR del-19 mutations (median 27.3 versus 24.3 months, HR 0.81, 95% CI 0.66-0.99, P=0.0374), but not in L858R mutations.

    “However, an unplanned pooled OS analysis of patients who have been recruited to either the LUX-Lung 3 or the LUX-Lung 6 trial revealed an OS benefit for afatinib compared with chemotherapy in patients with EGFR del-19 mutations (median OS: 27.3 versus 24.3 months; HR 0.81, 95% CI: 0.66-0.99;P = 0.0374), whereas this improvement was not observed in patients with EGFR L858R mutations [II, A] [115].”
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    Premisecitation

    In KEYNOTE-010, OS was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (HR 0.71, 95% CI 0.58-0.88, P=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (HR 0.61, 95% CI 0.49-0.75, P<0.0001), with median OS of 10.4, 12.7 and 8.5 months respectively.

    “In the entire population, OS was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (HR 0.71, 95% CI: 0.58-0.88;P = 0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (HR 0.61, 95% CI: 0.49-0.75;P < 0.0001), with median OS of 10.4, 12.7 and 8.5 months in the three arms, respectively.”
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    Premisecitation

    In a phase III second-line study, pemetrexed was non-inferior to docetaxel for OS (8.3 versus 7.9 months, HR 0.99, 95% CI 0.8-1.2) and had a better toxicity profile with lower neutropaenia, alopecia and gastrointestinal adverse events.

    “A phase III second-line study demonstrated non-inferiority for OS between pemetrexed and docetaxel (8.3 versus 7.9 months, HR 0.99, 95% CI: 0.8-1.2).However, pemetrexed showed a better toxicity profile with a significantly lower rate of neutropaenia and alopaecia as well as lower rates of gastrointestinal AEs [86].”
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    Premisecitation

    Three studies using bevacizumab or anti-EGFR monoclonal antibodies given with chemotherapy and continued as monotherapy until progression showed survival benefits, but the specific contribution of the maintenance phase cannot be determined.

    “three studies, one employing bevacizumab and the other two using monoclonal antibodies against EGFR (cetuximab or necitumumab) administered concomitantly to chemotherapy and further continued as monotherapy until disease progression, have demonstrated survival benefits, but the specific role of the maintenance phase cannot be appreciated in this context [52,58,84].”
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    Premisecitation

    Nivolumab was better tolerated than docetaxel, with 85% versus 69% receiving at least 90% of planned dose intensity and treatment discontinuation rates of 10% versus 3%.

    “In the phase III trial, nivolumab was better tolerated than docetaxel, with 85% of nivolumab patients receiving at least 90% of their planned dose intensity, compared with 69% of docetaxel patients, together with a treatment discontinuation rate of 10% versus 3% of the patients treated with nivolumab and docetaxel, respectively.”
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    Premiseown data

    An exploratory retrospective analysis in CheckMate-057 found an association between nivolumab efficacy and tumour membrane PD-L1 expression, but the analysis was limited by its retrospective and unplanned nature.

    “An exploratory retrospective analysis revealed an association of efficacy by nivolumab and the level of tumour membrane expression of PD-L1.However, this analysis is limited by the retrospective and unplanned nature of this biomarker assessment.”
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    Premisecitation

    In 795 advanced SCC patients, afatinib improved PFS versus erlotinib (median 2.4 versus 1.9 months, HR 0.82, 95% CI 0.68-1.00, P=0.0427) and OS (median 7.9 versus 6.8 months, HR 0.81, 95% CI 0.69-0.95, P=0.0077).

    “Afatinib versus erlotinib was tested in a phase III trial on 795 advanced SCC patients.PFS at the primary analysis was significantly longer with afatinib than with erlotinib, with a median of 2.4 months (95% CI: 1.9-2.9)versus 1.9 months (95% CI: 1.9-2.2);HR 0.82, 95% CI: 0.68-1.00,P = 0.0427.OS was a median of 7.9 months (95% CI: 7.2-8.7)versus 6.8 months (95% CI: 5.9-7.8);HR 0.81, 95% CI: 0.69-0”
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    Premisecitation

    Updated follow-up of CheckMate 017 reported 18-month OS of 28% versus 13% and 18-month PFS of 17% versus 2.7% for nivolumab versus docetaxel.

    “An updated follow-up reported an 18-month OS of 28% and 13% in the nivolumab and docetaxel arms, respectively, and an 18-month PFS equal to 17% for nivolumab and to 2.7% for docetaxel [99].”
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    Premiseown data

    In CheckMate-057, response rate (19% versus 12%, P=0.021) and duration of response (17.2 versus 5.6 months) favoured nivolumab, while PFS did not differ significantly (median 2.3 versus 4.2 months, HR 0.92, 95% CI 0.77-1.1).

    “In addition, RR (19% versus 12%, P = 0.021) and duration of response (17.2 versus 5.6 months) were in favour of nivolumab, while no significant difference has been reported for PFS (median PFS 2.3 versus 4.2 months, HR 0.92, 95% CI: 0.77-1.1).”
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    Premisecitation

    In stage IV NSCLC after platinum-based chemotherapy, docetaxel plus ramucirumab improved median OS (10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98, P=0.023) and median PFS compared with docetaxel plus placebo.

    “The study compared docetaxel with ramucirumab or placebo in patients who had progressed after platinum-based chemotherapy.Median OS was longer (10.5 versus 9.1 months, HR 0.86, 95% CI: 0.75-0.98,P = 0.023) in the ramucirumab arm compared with the placebo arm.Median PFS was also superior in the ramucirumab arm”
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    Premisecitation

    In 222 EGFR wild-type NSCLC patients, second-line docetaxel was superior to erlotinib for PFS and OS, but only using an unplanned adjusted HR for the primary end-point analysis.

    “In a randomised trial including 222 EGFR WT NSCLC patients, initially designed to assess selected biomarkers, second-line therapy with docetaxel was shown to be superior to erlotinib with respect to PFS, as well as to OS, but only using an unplanned adjusted HR for primary end-point analysis [91].”
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    Premisecitation

    Several studies have consistently shown that EGFR TKIs (gefitinib, erlotinib, afatinib) produce higher response rates, longer PFS and improved quality of life compared with platinum-based doublet chemotherapy in PS 0-2 patients whose tumours have an activating EGFR mutation.

    “Several studies have consistently demonstrated that the EGFR TKIs (gefitinib, erlotinib and afatinib) produce higher RRs, longer PFS and improve QoL compared with standard platinum-based doublet chemotherapy in patients with good PS (PS 0-2), whose tumour harbours an activating (sensitising) EGFR mutation [105-112].”
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    • cites [105] source

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    Premisecitation

    A meta-analysis of six randomised controlled trials with 990 EGFR wild-type patients found PFS significantly inferior in the EGFR TKI group versus chemotherapy (HR 1.37, 95% CI 1.20-1.56, P<0.00001), with no OS difference (HR 1.02, 95% CI 0.87-1.20, P=0.81).

    “Similar results have been reported in a meta-analysis carried out on six randomised, controlled trials with a total of 990 patients with WT EGFR.Results indicated that, in the secondline treatment of EGFR WT-advanced NSCLC, PFS was significantly inferior in the EGFR TKI group versus the chemotherapy group (HR 1.37, 95% CI: 1.20-1.56,P < 0.00001).However, this did not translate into an OS differenc”
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    Premisecitation

    In CheckMate 017, median OS was 9.2 months with nivolumab versus 6.0 months with docetaxel, with a 41% reduction in risk of death (HR 0.59, 95% CI 0.44-0.49, P<0.001).

    “At the data cut-off, median OS was 9.2 months (95% CI: 7.3-13.3months) on nivolumab compared with 6.0 months (95% CI: 5.1-7.3months) on docetaxel, with a 41% reduction in the risk of death in the nivolumab arm (HR 0.59, 95% CI: 0.44-0.49;P < 0.001).”
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    Premisecitation

    A phase III study of maintenance bevacizumab with or without pemetrexed after first-line bevacizumab, cisplatin and pemetrexed showed a PFS benefit for the pemetrexed-bevacizumab combination but no OS improvement.

    “Another phase III study comparing maintenance bevacizumab, with or without pemetrexed, after first-line induction with bevacizumab, cisplatin and pemetrexed showed a benefit in PFS for the pemetrexed-bevacizumab combination but no improvement in OS [82]”
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    Premisecitation

    The nivolumab arm showed a positive impact on quality of life and a longer time to symptom deterioration compared with docetaxel.

    “The experimental arm also showed a positive impact on QoL and a longer time to symptom deterioration compared with the standard arm [100].”
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    Premisecitation

    In that trial, erlotinib plus bevacizumab produced no new safety signals; any-grade adverse events and serious adverse events were similar between arms, but grade 3 or worse adverse events were more frequent with the combination and 41% discontinued bevacizumab due to adverse events, mostly non-serious and reversible.

    “No new safety signals were identified with the combination treatment, and the incidence of AEs (any grade) and SAEs were similar between the treatment arms.There was a higher frequency of grade 3 or worse AEs with the combination and a relatively high incidence of bevacizumab discontinuation due to AEs (41%); however, most of these AEs were non-serious and reversible.”
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    Premisecitation

    In CheckMate-057, nivolumab significantly prolonged OS versus docetaxel in 582 pretreated NSCC patients (median 12.2 versus 9.4 months, HR 0.73, 95% CI 0.59-0.89, P=0.002), with a small excess of early progression or death events.

    “Nivolumab led to a significant prolongation of OS compared with docetaxel in 582 pretreated patients with NSCC, who were recruited to the Checkmate-057 trial (median OS 12.2 versus 9.4 months, HR 0.73, 95% CI: 0.59-0.89;P = 0.002), although a small excess of early progression and/or death events were observed for nivolumab, compared with docetaxel.”
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    Premisecitation

    In NSCC second- or third-line treatment, paclitaxel-bevacizumab improved median PFS versus docetaxel (5.4 versus 3.9 months, HR 0.62, 95% CI 0.44-0.86, P=0.005) but showed no median OS difference (9.9 versus 10.8 months, HR 1.15, P=0.49).

    “The study compared the association of paclitaxel-bevacizumab versus docetaxel in second-third line of treatment; median PFS was longer (5.4 versus 3.9 months, HR 0.62, 95% CI: 0.44-0-86, P = 0.005) in the paclitaxel-bevacizumab arm compared with docetaxel.No difference in median OS was observed (9.9 versus 10.8 months, HR 1.15, P = 0.49) [95].”
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    Premisecitation

    Comparable second-line options include pemetrexed for non-squamous cell carcinoma only, or docetaxel.

    “Comparable options in the second line consist of pemetrexed (for NSCC only) [86] or docetaxel [I, B] [87].”
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    • cites [87]

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  • May combine two claims.

    Premisecitation

    In LUX-LUNG 7, afatinib produced a modestly higher response rate and longer PFS than gefitinib as first-line treatment of advanced NSCLC with common activating EGFR mutations (del19 or L858R): 11 versus 10.9 months, HR 0.73, 95% CI 0.57-0.95, P=0.0165.

    “The recently presented phase IIb study LUX-LUNG 7 showed that afatinib achieves a modestly higher RR and a longer PFS [11 versus 10.9 months, HR (95% CI): 0.73 (0.57-0.95);P = 0.0165] than gefitinib as first-line treatment of patients with advanced NSCLC with common activating mutations (del19 or L858R) [II, B].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] source

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  • May combine two claims.

    Premisecitation

    ALK-positive patients often have brain progression while on crizotinib because the cerebrospinal fluid concentration of crizotinib is very low.

    “ALK-positive patients often have brain progression while on crizotinib, as the CSF concentration of the latter is very low [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138]

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  • May combine two claims.

    Premisecitation

    In a phase II trial, alectinib at crizotinib resistance showed activity against brain metastases, with ORR 57% in measurable lesions, complete response in 20%, and CNS disease control rate 83% in all 84 patients with baseline CNS metastases.

    “In a phase II trial, alectinib at crizotinib resistance has demonstrated activity for brain metastases, with an ORR of 57% in patients with measurable lesions and complete response observed in 20% of patients [140].A CNS DCR of 83% was reported in all 84 patients with baseline CNS metastases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140]

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  • May combine two claims.

    Premisecitation

    When rebiopsy is not feasible or T790M is not detected, platinum-based chemotherapy alone is standard, and no data support continuing the EGFR TKI with platinum-based chemotherapy.

    “At the present time, when rebiopsy is not feasible or when the EGFR T790M mutation is not detected as a resistance mechanism, the standard of care is represented by platinum-based chemotherapy alone.There is no data to support continuation of the EGFR TKI with platinum-based chemotherapy [I, A] [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rebiopsy after EGFR TKI progression can influence the next therapeutic step or reveal alternative resistance mechanisms such as SCLC transformation or bypass tracks.

    “Patients who progress after an EGFR TKI should undergo a rebiopsy to perform molecular analysis specifically looking for EGFR T790M mutation.This approach could influence the next therapeutic step or reveal alternative EGFR TKI resistance mechanisms such as transformation to SCLC or bypass tracks that could potentially be addressed in clinical trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In patients with EGFR mutation and brain metastases, afatinib produced a PFS improvement similar to that in patients without brain metastases, and PFS was significantly better with afatinib than chemotherapy (8.2 versus 5.4 months, HR 0.50, P=0.0297).

    “In patients with EGFR mutation and brain metastases, the PFS improvement with the irreversible inhibitor afatinib was similar to that observed in patients without brain metastases [159].The PFS was significantly better with afatinib versus chemotherapy (8.2 versus 5.4 months; HR 0.50; P = 0.0297).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] source

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  • May combine two claims.

    Premisecitation

    Two phase I studies, including ASCEND-1, showed significant ceritinib activity in ALK-rearranged NSCLC with crizotinib resistance, with ORR 56% and PFS 6.9 months, including intracranial responses in patients with brain metastasis.

    “Two phase I studies, including the multicentre open-label ASCEND-1 study, showed a significant activity of ceritinib, based on an ORR of 56% and 6.9 months of PFS in patients with ALK-rearranged NSCLC with crizotinib resistance [139].The benefit also included intracranial responses in patients with brain metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139]

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    A Japanese observational study of 1194 patients with 1-10 newly diagnosed brain metastases treated with SRS found median OS of 13.9 months for a single metastasis, 10.8 months for 2-4 tumours, and 10.8 months for 5-10 tumours, with similar OS for 2-4 and 5-10 tumours.

    “The observational study enrolled 1194 eligible patients with 1-10 newly diagnosed brain metastases in a 3-year period, with the largest tumour <10 ml in volume and <3 cm in longest diameter; total cumulative volume ≤15 ml, and a KPS score of 70 or higher, with all patients undergoing standard SRS [152].Median OS after SRS was 13.9 months (95% CI: 12.0-15.6)in the 455 patients with a single met”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152]

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    A phase III head-to-head trial in untreated ALK-positive advanced NSCLC showed alectinib 300 mg b.i.d. was superior to crizotinib 250 mg b.i.d. for PFS, with HR 0.34 (99.6826% CI 0.17-0.70, P<0.0001); median PFS was not reached with alectinib versus 10.2 months with crizotinib.

    “Furthermore, alectinib was tested in a phase III head-to-head trial comparing this molecule (300 mg b.i.d.) with crizotinib (250 mg b.i.d.) in untreated ALK-positive advanced NSCLC patients, demonstrating the superiority of alectinib as an initial targeted treatment [142].Two hundred and seven patients were enrolled, when an independent data monitoring committee recommended the release of study”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142]

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  • May combine two claims.

    Premisecitation

    Crizotinib improved symptoms and quality of life compared with pemetrexed and docetaxel.

    “Crizotinib also showed an advantage over both pemetrexed and docetaxel with regards to the improvement in symptoms and QoL [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136]

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  • May combine two claims.

    Premisecitation

    Crizotinib anti-tumour activity was initially shown in two multicentre single-arm studies, with significant ORR and PFS advantages and a survival advantage compared with other treatment options.

    “The anti-tumour activity of crizotinib, a dual ALK and MET TKI, was initially demonstrated in two multicentre single-arm studies, with significant ORR and PFS advantages [133] as well as a survival advantage compared with other treatment options [134].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [133]

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    • cites [134]

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  • May combine two claims.

    Premisecitation

    The QUARTZ trial found no difference between best supportive care plus whole brain radiotherapy and best supportive care alone in symptom relief, steroid use, OS, quality of life, or quality-adjusted life years, but full publication is awaited.

    “This trial (QUARTZ) demonstrated no difference between the treatment arms regarding the relief of symptoms, steroid use, OS, QoL or quality-adjusted life years, but full publication is awaited [154].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Denosumab is not inferior to zoledronic acid and shows a trend towards superiority for skeletal-related event prevention in lung cancer.

    “Denosumab is not inferior to [I, B] and shows a trend towards superiority to zoledronic acid in lung cancer in terms of SRE prevention [II,B] [161].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an individual patient data meta-analysis of three phase III trials, age significantly influenced survival (P=0.04), with SRS alone favoured in patients aged 50 or younger and no significant survival differences in those older than 50; age also significantly affected brain failure outside the radiation field (P=0.043), with similar failure rates in both arms for patients 50 or younger and riskre

    “The age of the patient significantly influenced survival (P = 0.04), with SRS alone favoured in patients aged 50 or younger, and with no significant survival differences in patients aged >50.Patient age was also a significant factor for brain failure outside of the radiation field(s) (P = 0.043), with similar failure rates in both arms for patients ≤50 years of age, while the risk was reduced with”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two phase II studies of alectinib showed response rates between 45% and 50% and PFS of 8.9 months, and alectinib was also effective for brain metastases.

    “Two phase II studies have also demonstrated RR between 45% and 50% and PFS of 8.9 months [140, 141].Alectinib was also effective for brain metastases.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140]

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    • cites [141]

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  • May combine two claims.

    Premisecitation

    A randomised trial showed that introducing specialised palliative care early after diagnosis of stage IV disease improved quality of life and mood, reduced aggressive treatment, and improved median OS.

    “A randomised trial evaluating the impact of introducing specialised palliative care early after diagnosis of stage IV disease on patient QoL in ambulatory patients was able to show an improvement in QoL and mood, a reduction in aggressive treatment and an improvement in median OS [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147]

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  • May combine two claims.

    Premisecitation

    The most frequent whole brain radiotherapy schedules are 20 Gy in 5 fractions or 30 Gy in 10 fractions, with no difference in outcome.

    “The WBRT most frequent schedules are 20 Gy in 5 fractions or 30 Gy in 10 fractions, with no difference in outcome [I, A] [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155]

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  • May combine two claims.

    Premisecitation

    Most patients progress after 9-12 months of EGFR TKI treatment, and multiple mechanisms of acquired resistance to first-generation EGFR TKIs have been described.

    “The majority of patients will progress after 9-12 months of treatment with an EGFR TKI, and various mechanisms of acquired resistance to first-generation EGFR TKIs have been described [118].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] source

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  • May combine two claims.

    Premisecitation

    PROFILE 1014 showed that first-line crizotinib improved PFS versus cisplatin-pemetrexed in ALK-positive advanced NSCC (10.9 versus 7.0 months, HR 0.45, 95% CI 0.35-0.60, P<0.001) and increased ORR (74% versus 45%, P<0.001), with median OS not reached in either group.

    “Subsequently, the phase III study PROFILE 1014 compared crizotinib with cisplatin-pemetrexed without maintenance pemetrexed as first-line treatment in ALK-positive advanced NSCC [137], and demonstrated a significantly longer PFS (median of 10.9 versus 7.0 months; HR for progression or death with crizotinib 0.45; 95% CI: 0.35-0.60;P < 0.001) and higher ORR with crizotinib compared with chemotherapy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] source

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  • May combine two claims.

    Premisecitation

    PROFILE 1007 confirmed that crizotinib is superior to chemotherapy (pemetrexed or docetaxel) as second-line treatment, with better ORR and PFS.

    “The phase III PROFILE 1007 study confirmed the benefit of crizotinib over chemotherapy, pemetrexed or docetaxel (investigator's choice), as second-line treatment with better ORR and PFS [135].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135]

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  • May combine two claims.

    Premisecitation

    Liquid biopsy is a validated alternative to tissue rebiopsy, provides a surrogate source of DNA, and is a new strategy for tumour genotyping mainly at progression in EGFR-mutated patients.

    “A valid alternative to tissue rebiopsy is represented by liquid biopsy, which has been validated [126], represents a surrogate source of DNA and is a new strategy for tumour genotyping, mainly at the time of progression for EGFR-mutated patients [III, A] [127-129].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [126] source

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    • cites [127]

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    • cites [128] source

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    • cites [129]

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  • May combine two claims.

    Premisecitation

    Crizotinib penetration into cerebrospinal fluid is negligible, which is relevant because ALK-rearranged NSCLC has a high propensity to metastasise to the brain.

    “Furthermore, crizotinib penetration into the cerebrospinal fluid (CSF) is negligible, and this pharmacological limitation is extremely relevant in treatment decisions, taking into account the high propensity of ALK-rearranged NSCLC to metastasise to the brain [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138]

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  • May combine two claims.

    Premisecitation

    The T790M mutation substitutes methionine for threonine at position 790, increases affinity for ATP, and causes resistance to reversible EGFR TKIs such as gefitinib and erlotinib.

    “This mutation leads to the substitution of threonine by methionine at position 790, which encodes part of the kinase domain of the receptor and results in increased affinity for ATP, causing resistance to competitive inhibition by reversible EGFR TKIs such as gefitinib and erlotinib [121,122].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] source

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    • cites [122]

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  • May combine two claims.

    Premisecitation

    The methodology of trials included in that systematic review was poor; only two randomised trials were eligible, and neither compared radionuclide treatment with placebo or best standard of care.

    “However, the methodology in the included trials was poor; only two randomised trials were eligible, and neither compared radionuclide treatments with placebo or best standard of care.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Ungraded statements were considered justified standard clinical practice by the experts and the ESMO faculty.

    “Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Denosumab is not inferior to zoledronic acid and shows a trend toward superiority to zoledronic acid for SRE prevention in lung cancer.

    “Denosumab is not inferior to [I, B] and shows a trend towards superiority to zoledronic acid in lung cancer in terms of SRE prevention [II, B].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [I, B]

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    • cites [II, B]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Pemetrexed (for non-squamous NSCLC only) and docetaxel are comparable options as second-line therapy.

    “Comparable options as second-line therapy consist of pemetrexed-for NSCC only-or docetaxel [I, B].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [I, B]

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The IASLC review concluded that few features definitively distinguish a second primary lung tumour from a metastasis in patients with more than one pulmonary cancer site; many commonly used factors are suggestive but carry substantial misclassification risk because most second primary lung tumours share the same histology.

    “This review concluded that few features are definitive, with many commonly used factors being suggestive, but carry a substantial risk of misclassification as the majority of second primary lung tumours are of the same histology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168]

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  • May combine two claims.

    Premisecitation

    In that review, overall survival was predicted by synchronous versus metachronous metastases (P<0.001), N-stage (P=0.002), and adenocarcinoma histology (P=0.036).

    “Predictive factors for OS were synchronous versus metachronous metastases (P < 0.001), N-stage (P = 0.002) and adenocarcinoma histology (P = 0.036).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167]

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  • May combine two claims.

    Premisecitation

    In that review, surgery was the most common treatment for both primary tumours (n=635, 83.9%) and metastases (n=339, 62.3%).

    “Surgery was the most common treatment modality for both primary (n = 635, 83.9%) and metastases (n = 339, 62.3%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    These clinical practice guidelines were developed according to ESMO standard operating procedures for clinical practice guideline development.

    “Theseclinicalpracticeguidelinesweredeveloped in accordance with the ESMO standard operating procedures for clinical practice guidelines development”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Levels of evidence and grades of recommendation were applied using the system shown in Table 6.

    “Levels of evidence and grades of recommendation have been applied using the system shown in Table6.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In that review, the median age at diagnosis was 61 years, 98% had good performance status, and two-thirds had early-stage intrathoracic disease staged IA-IIB after metastatic disease was excluded.

    “These patients had a median age at diagnosis of 61 years, 98% had a good PS and two-thirds of patients had early-stage intrathoracic disease staged IA-IIB (after excluding metastatic disease).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    ESMO-MCBS v1.0 was used to calculate scores for new therapies or indications approved by the EMA since 1 January 2016.

    “ESMO-MCBS v1.0[181]was used to calculate scores for new therapies/indications approved by the EMA since 1 January 2016.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] source

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  • May combine two claims.

    Premisecitation

    A systematic review of radionuclide treatment in lung cancer found pain relief in 75% of patients in eligible trials, with onset within 1-5 weeks and lasting up to 6 months.

    “A systematic review analysed the use of radionuclide treatment in lung cancer and in the eligible trials, pain relief was reported in 75% of the patients having the onset of pain relief within 1-5 weeks after treatment, lasting up to 6 months [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164]

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  • May combine two claims.

    Premisecitation

    In that review, RPA identified a low-risk group with metachronous metastases and 5-year OS of 48%, an intermediate-risk group with synchronous metastases and N0 disease and 5-year OS of 36%, and a high-risk group with synchronous metastases and intrathoracic N1/N2 disease and 5-year OS of 14%.

    “RPA for risk groups identified a good prognosis (low-risk) group presenting with metachronous metastases (5-year OS of 48%), an intermediate-risk group presenting with synchronous metastases and N0 disease (5-year OS of 36%) and, finally, a high-risk group presenting with synchronous metastases and intrathoracic N1/N2 disease (5-year OS of 14%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167]

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  • Classified as probably not a substantial claim.

    Premisecitation

    Solitary lesions in the contralateral lung should usually be considered synchronous secondary primary tumours.

    “Solitary lesions in the contralateral lung should, in most cases, be considered as synchronous secondary primary tumours and, if possible, treated with radical intent [IV, B].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [IV, B]

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  • May combine two claims.

    Premisecitation

    In PD-L1-negative tumours, nivolumab and docetaxel produced similar overall survival results, with a more favourable toxicity profile for nivolumab.

    “In PD-L1-negative tumours, nivolumab and docetaxel showed similar results, with a more favourable toxicity profile for nivolumab [II, A].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [II, A]

      Not checked in the free run.

79 of 79

  • The paper relies on this without support.

    EGFR mutations are found in approximately 10-12% of Caucasians with adenocarcinoma and are more frequent in never smokers, females, and patients of East Asian ethnicity.

    “EGFR mutations are found in ∼10%-12% of Caucasians with adenocarcinoma and are more frequent in never smokers, females and in patients of East Asian ethnicity.”

  • The paper relies on this without support.

    ALK TKIs are effective therapies for ALK-rearranged NSCLC.

    “ALK TKIs are effective therapies, and routine testing for ALK rearrangements is recommended in the same patient groups tested for EGFR mutations, principally those with NSCC [II, A].”

  • The paper relies on this without support.

    IHC has a high positive and negative predictive value for ALK fusion.

    “IHC has a high positive and negative predictive value for ALK fusion.”

  • The paper relies on this without support.

    Meta-analyses show higher response rates for cisplatin combinations compared with carboplatin combinations.

    “Meta-analyses have shown higher RRs for cisplatin combinations compared with carboplatin combinations.”

  • The paper relies on this without support.

    Cisplatin-based chemotherapy is associated with more gastrointestinal, neuro-, and nephrotoxicity, while bone marrow toxicity is more common with carboplatin.

    “Cisplatin-based chemotherapy is associated with more gastrointestinal, neuro-and nephrotoxicity, while bone marrow toxicity is more common with carboplatin.”

  • The paper relies on this without support.

    In patients with PS 2, chemotherapy compared with best supportive care prolongs survival and improves quality of life.

    “In patients with PS 2, chemotherapy compared with BSC prolongs survival and improves QoL [I, B].”

  • The paper relies on this without support.

    CGA can predict morbidity and mortality in elderly patients with cancer and can help adapt cancer management to each patient's fitness or frailty.

    “CGA can predict morbidity and mortality in elderly patients with cancer and can help to adapt cancer management to each patient's fitness or frailty [III, C].”

  • The paper relies on this without support.

    PET-CT scan may demonstrate unexpected metastases in 5%-10% of patients with presumed non-metastatic stage based on conventional imaging.

    “Moreover, PET-CT scan may demonstrate unexpected metastases in 5%-10% of the patients with presumed non-metastatic stage based on conventional imaging.”

  • The paper relies on this without support.

    Therapeutic decisions for NSCLC patients are dependent upon specific tumour histological subtype.

    “Therapeutic decisions for NSCLC patients are dependent upon specific tumour histological subtype, and this should be given whenever possible.”

  • The paper relies on this without support.

    Genetic alterations, which are key oncogenic events (driver mutations), have been identified in NSCLC, with EGFR mutations and ALK rearrangements determining approved, selective pathway-directed systemic therapy.

    “Genetic alterations, which are key oncogenic events (driver mutations), have been identified in NSCLC, with two of these-EGFR mutations and the anaplastic lymphoma kinase (ALK) rearrangements-determining approved, selective pathwaydirected systemic therapy.”

  • The paper relies on this without support.

    Single-agent chemotherapy improves disease-related symptoms and overall survival in advanced NSCLC.

    “Single agents improve disease-related symptoms and OS.”

  • The paper relies on this without support.

    Lung cancer has historically been poorly immunogenic, with no established benefit from cytokine modulation or vaccines.

    “Lung cancer has been historically considered poorly immunogenic, with no established benefit from cytokine modulation or vaccines.”

  • The paper relies on this without support.

    Between 30% and 40% of patients with NSCLC develop bone metastases.

    “Given the incidence of bone metastases in NSCLC (30%-40% of patients with NSCLC develop bone metastases), it may be reasonable to evaluate for bone disease upon disease diagnosis.”

  • The paper relies on this without support.

    Synchronous and metachronous oligometastatic disease may have different biological features and outcomes.

    “The biology and prognosis related to synchronous and metachronous oligometastases may differ.”

  • The paper relies on this without support.

    PET imaging has high sensitivity but low specificity.

    “Follow-up with PET is not routinely recommended, due to its high sensitivity and relatively low specificity.”

  • The paper relies on this without support.

    Second-line treatment provides clear benefit to patients who initially responded to first-line chemotherapy and retain good performance status.

    “Given the clear benefits of second-line therapy in patients who presented an initial response to first-line chemotherapy and maintain good PS, radiological follow-up should be considered every 6-12 weeks to allow for early initiation of second-line”
16 of 16

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?

  • Among patients with EGFR-mutant advanced NSCLC, EGFR TKIs are standard first-line therapy.

    “Among patients with advanced non–small-cell lung cancer with a mutant epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy.1–4”

    From Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer (2017) · cites this paper as [2]

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.

  • Conflicting guidance on CNS imaging at diagnosis

    Major

    The abstract restricts CNS imaging to patients with neurological symptoms or signs, but the radiology section recommends imaging at diagnosis when available, without that restriction.

  • Conflicting PD-L1 threshold for pembrolizumab benefit score

    Minor

    The figure assigns a benefit score of 3 when PD-L1 expression is below 1%, while the treatment recommendation assigns that score when expression is above 1%. These thresholds identify opposing patient groups.

  • Different recommendation grades for single-agent chemotherapy in PS 2

    Minor

    The treatment algorithm gives single-agent chemotherapy a grade of A, whereas the accompanying PS 2 discussion gives the same alternative a grade of B.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 18

  1. Chang, 2012, Meta-analysis: comparison of F-18 fluorodeoxyglucose-positron emission tomography and bone scintigraphy in the detection of bone metastasis in patients with lung cancer, Acad Radiol, 19, 349, 10.1016/j.acra.2011.10.018 · DOI
  2. Ung, 2016, Impact of the lung oncology multidisciplinary team meetings on the management of patients with cancer, Asia Pac J Clin Oncol, 12, e298, 10.1111/ajco.12192 · DOI
  3. Rowland, 2016, Quality of life, support and smoking in advanced lung cancer patients: a qualitative study, BMJ Support Palliat Care, 6, 35, 10.1136/bmjspcare-2013-000589 · DOI
  4. Cortot, 2016, Weekly paclitaxel plus bevacizumab versus docetaxel as second or third line treatment in advanced non-squamous non-small cell lung cancer (NSCLC): results from the phase III study IFCT-1103 ULTIMATE, J Clin Oncol, 34
  5. Reckamp, 2015, Phase 3, randomized trial (CheckMate 017) of nivolumab (NIVO) vs docetaxel in advanced squamous (SQ) cell non-small cell lung cancer (NSCLC), J Thorac Oncol, 10, S174
  6. Gralla, 2015, Evaluation of disease-related symptoms in patients with advanced squamous non-small cell lung cancer treated with nivolumab or docetaxel, J Thorac Oncol, 10, S233
  7. Stahel, 2015, Ann Oncol, 26
  8. Mitsudomi, 2015, AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 phase II study, J Thorac Oncol, 10, S320
  9. Shaw, 2004, Pleurodesis for malignant pleural effusions, Cochrane Database Syst Rev, 1, CD002916
  10. Patil, 2012, Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases, Cochrane Database Syst Rev, 9, CD006121
  11. Soon, 2014, Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases, Cochrane Database Syst Rev, 3, CD009454
  12. Mulvenna, 2015, Whole brain radiotherapy for brain metastases from non-small lung cancer: quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomised clinical trial (ISRCTN 3826061), J Clin Oncol, 33
  13. Tsao, 2012, Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases, Cochrane Database Syst Rev, 4, CD003869
  14. Vecht, 1994, Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day, Neurology, 44, 675, 10.1212/WNL.44.4.675 · DOI
  15. Rosen, 2004, Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial, Cancer, 100, 2613, 10.1002/cncr.20308 · DOI · Paper page
  16. Kozower, 2013, Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest, 143, e369S, 10.1378/chest.12-2362 · DOI · Paper page
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  18. Saenger, 2008, The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases, Cancer Immun, 8, 1

Cited by

Sorted by citations

Authors
Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. G., Kerr, K., Popat, S., Reck, M., Senan, S., Simo, G. V., Vansteenkiste, J., & Peters, S.
Affiliations
  • University of Turin (IT)
  • The Christie Hospital (GB)
  • Karolinska University Hospital (SE)
  • Centre Hospitalier Universitaire de Grenoble (FR)
  • University of Aberdeen (GB)
  • Royal Marsden Hospital (GB)
  • German Center for Lung Research (DE)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Universidad de Salamanca (ES)
  • Universitair Ziekenhuis Leuven (BE)
  • Centre Hospitalier Universitaire Vaudois (CH)
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2016-09
Volume
27
Issue
suppl 5
Pages
v1-v27
ISSN
0923-7534 (ISSN-L)
DOI
10.1093/annonc/mdw326
OpenAlex
W2163351155
Cited by
2,631
References
159
Citations by year
2026: 10 · 2025: 43 · 2024: 151 · 2023: 212 · 2022: 265 · 2021: 473 · 2020: 375 · 2019: 329 · 2018: 246 · 2017: 164 · 2016: 54 · 2015: 87 · 2014: 79 · 2013: 71 · 2012: 41
FWCI
236.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • IRIS (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Amgen
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Ariad Pharmaceuticals
  • Celgene
  • F. Hoffmann-La Roche
  • Varian Medical Systems
  • Les Laboratories Pierre Fabre
  • Clovis Oncology
  • Daiichi-Sankyo
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
metastatic non-small cell lung cancer, lung squamous cell carcinoma, non-small cell lung cancer, EGFR mutation testing, ALK rearrangement, molecular testing, staging, risk assessment, bone metastasis, systemic therapy, chemotherapy, targeted therapy, immunotherapy, smoking cessation, multidisciplinary tumor board, treatment follow-up

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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