Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy

Al-Halabi, H.; Sayegh, Karl; Digamurthy, Subba R.; Niemierko, Andrzej; Piotrowska, Zofia; Willers, Henning; Sequist, Lecia V.

doi:10.1097/jto.0000000000000648

Cited by 100 publications

(83 citation statements)

References 40 publications

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“…al., we find the predominant pattern of failure in our patients is within existing sites of disease, and that at two years, the cumulative incidence of such failure is over 50%, compared to a much smaller incidence of new- or combined-site failure. 17 Younger age and lack of initial CNS involvement are both associated with ISF. Greater intrathoracic primary disease burden is associated with progression, and intrathoracic progression is the sole site of initial failure in nearly a third of patients that experience ISF.…”

Section: Discussionmentioning

confidence: 99%

“…Though several small reports of oligometastatic progression of oncogene-addicted NSCLC treated with local therapy have shown promising results, 13–15 only two studies to our knowledge have evaluated the pattern of failure in metastatic patients treated with TKIs—one from a group of molecularly unselected patients and one from a relatively small set of EGFRmt patients treated with TKI. 16, 17 In both, half or more of the patients had progression limited to their initial sites of disease. Using a larger cohort of molecularly-selected EGFRmt patients treated with erlotinib, we sought to further characterize the frequency with which such patients progress in their initial sites of disease, and identify potential subsets of patients most likely to exhibit this pattern and therefore, potentially benefit from early local therapy.…”

Section: Introductionmentioning

confidence: 99%

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Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

et al. 2017

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Objectives Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and Methods We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. Results Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. Conclusion The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

et al. 2017

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“…On the other hand, it has been postulated that approximately 14-17% of patients with EGFR mutant NSCLC present with isolated CNS progression after front line treatment with EGFR TKIs (34)(35)(36)(37). However, others have demonstrated a lower incidence of BM in the same population (38). In a retrospective report by Heon et al, patients with EGFR mutant NSCLC treated with front line erlotinib and gefitinib had a lower rate of CNS progression compared with patients treated with chemotherapy [21% vs. 32% at 1 year, HR =0.56; 95% confidence interval (CI), 0.34-0.94] (39).…”

Section: Egfr Tkismentioning

confidence: 98%

Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

Economopoulou¹,

Mountzios²

2016

Transl. Lung Cancer Res.

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Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis. Meanwhile, introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively. Based on their clinical activity in systemic disease, such molecular agents could offer the promise of improved BM control without substantial toxicity; however, their role in combination with radiotherapy is controversial. In this review, we discuss the controversy regarding the use of TKIs in combination with radiotherapy and illustrate future perspectives in the treatment of BM in NSCLC.

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“…Oligoprogression can include regrowth in metastatic sites and/or the lung primary. Perhaps surprisingly, a paucity of data is available on the patterns of regrowth when acquired drug resistance develops in oncogene-driven NSCLC [43]. We studied a cohort of EGFR-mutant patients and found that about half of recurrences after EGFR-targeted therapy occur first in the primary or pre-existing metastatic sites [43].…”

Section: The Concept Of Oligoprogressionmentioning

confidence: 99%

Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer

et al. 2016

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Genotype-based selection of patients for targeted therapies has had a substantial impact on the treatment of non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs) directed at cancers driven by oncogenes, such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, often achieve dramatic responses and result in prolonged survival compared with chemotherapy. However, TKI resistance invariably develops. Disease progression can be limited to only one or a few sites and might not be symptomatic, raising the important question of whether this type of oligoprogression warrants a change in systemic therapy or consideration of local treatment. Recent clinical observations suggest a growing role for stereotactic body radiation therapy (SBRT) in the treatment of oligoprogressive and perhaps even oligopersistent disease (primary and/or metastases) in oncogene-driven NSCLC. SBRTmight allow patients to continue with existing TKI treatments longer and delay the need to switch to other systemic options. We review the current data with regard to the use of SBRT for metastatic NSCLC and particularly oncogene-driven disease. Although there is great promise in the marriage of targeted therapies with SBRT, prospective data are urgently needed. In the meantime, such strategies are being used in carefully selected patients, with risk-adapted SBRT dose-fractionation regimens used to optimize the therapeutic index. The Oncologist 2016; 21:964-973 Implications for Practice: Stereotactic body radiation therapy (SBRT) or SBRT-like treatments are increasingly being used for oligoprogression in patients with oncogene-driven non-small cell lung cancer.This approach allows patients to extend the duration of tyrosine kinase inhibitor therapy and has the potential to prolong survival times. Careful patient selection and risk-adapted radiation dosing is of critical importance to minimize toxicity and preserve patient quality of life.

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Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy

Cited by 100 publications

References 40 publications

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer

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