Guideline Essentials: 2023 ESMO Recommendations on Diagnosis, Staging, and Follow Up of Metastatic Non-small Cell Lung Cancer

Introduction

In 2023, the European Society for Medical Oncology (ESMO) published guidance on the diagnosis, treatment, and follow up of patients with oncogene addicted and non-oncogene addicted metastatic non-small cell lung cancer (NSCLC).

This specialist Guidelines overview for secondary care oncologists covers the diagnosis, pathology, staging, risk assessment, and follow up of patients with metastatic NSCLC. It combines recommendations from the ESMO guideline on oncogene addicted NSCLC and the ESMO guideline on non-oncogene addicted NSCLC, highlighting the differences when relevant. 

Please refer to the full ESMO guidelines for all of the recommendations, rationale, and background information. 

Diagnosis, Pathology, and Molecular Biology 

Oncogene AND Non-oncogene Addicted NSCLC

• Obtain adequate tissue material for histological diagnosis and molecular testing to allow for individual treatment decisions
• Preferably, biopsy metastatic lesions for diagnosis and staging
  • for central lesions, bronchoscopy is ideal and can be used with bronchial washing, brushing, and bronchial and transbronchial biopsy
  • regional lymph nodes can be evaluated using endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)
  • for mid-to-peripheral lesions, use transthoracic fine-needle aspiration and/or core biopsy guided by imaging (usually computed tomography [CT])
  • for pleural effusion, use thoracentesis for diagnosis and symptomatic treatment
  • re-biopsy (if possible) may be needed if initial sampling is inadequate
  • consider more invasive, surgical techniques (such as mediastinoscopy, mediastinotomy, and thoracoscopy) when accurate diagnosis is not possible through a less invasive approach (such as EBUS, EUS, transthoracic fine-needle aspiration, and core biopsy)
  • to improve diagnostic yields, systematic collaboration and constant communication between pathologists and interventionalists is beneficial (possibly including rapid onsite sample evaluation)
• Characterise pathology according to the 2021 World Health Organization classification of lung tumours
• Carry out specific subtyping of all NSCLCs when possible, to inform therapeutic decision making
• Use immunohistochemistry (IHC) stains to reduce the rate of unspecified NSCLC to <10% of diagnosed cases.

Non-oncogene Addicted NSCLC Only

• Systematically determine programmed death ligand 1 [PD-(L)1] IHC in advanced NSCLC
• PD-(L)1 testing is required for:
  • first-line pembrolizumab, atezolizumab, or cemiplimab monotherapy
  • first-line nivolumab–ipilimumab
  • second-line pembrolizumab.

Oncogene Addicted NSCLC Only

• Use the molecular tests listed below for patients who have advanced non-squamous cell carcinoma
  • these are not recommended for patients with a confident diagnosis of squamous cell carcinoma, except in unusual cases:
    • young people (<50 years)
    • people who have never smoked (<100 cigarettes in a lifetime)
    • former light smokers (15 pack–years, all kinds of tobacco)
    • long-time ex-smokers (quit >15 years ago, all kinds of tobacco)
• Determine epidermal growth factor receptor (EGFR) mutation status:
  • the test methodology should cover mutations in exons 18–21, including those associated with resistance to some therapies
  • at a minimum, the most common activating mutations (exon 19 deletion, exon 21 L858R point mutation) should be determined
• Given the availability of tyrosine kinase inhibitors (TKIs) that are effective against T790M-mutated recurrent disease, T790M testing is mandatory in cases of relapse on first- or second-generation EGFR TKIs
• Test for anaplastic lymphoma kinase (ALK) rearrangements
  • fluorescence in situ hybridisation (FISH) is the standard method
  • IHC with high-performance ALK antibodies and validated assays is an acceptable alternative
• Test for ROS1 rearrangements
  • FISH is the standard method
  • IHC may be used for screening
• Test BRAF V600 mutation status
• Test for neurotrophic tyrosine receptor kinase (NTRK) rearrangements
  • use IHC or next generation sequencing (NGS); validate a positive result with appropriate follow up
• Test for:
  • mesenchymal epithelial transition (MET) exon 14 skipping mutations
  • MET amplifications
  • rearranged during transfection (RET) rearrangements
  • Kirsten rat sarcoma (KRAS) virus G12C mutations
  • human EGFR-2 HER2 mutations
• Multiplex platforms (NGS) for molecular testing are preferred, if they are available
• RNA-based NGS is preferred for identifying an expanding range of fusion genes
• Use cell-free DNA (cfDNA) liquid biopsy to test for oncogenic drivers and resistance mutations; however, tissue biopsy must still be performed on all patients whose cfDNA blood test is negative.

Staging and Risk Assessment 

• Record a complete history, including a precise smoking history, comorbidities, weight loss, Eastern Cooperative Oncology Group performance status, and physical examination
• Perform standard tests including routine haematology, renal and hepatic function, and bone biochemistry
  • additional tests may be needed depending on treatment
• At diagnosis, carry out:
  • central nervous system (CNS) imaging for patients with neurological symptoms or signs (consider this for all patients with metastatic disease)
  • bone imaging, if bone metastases are clinically suspected
    • bone scintigraphy, ideally coupled with CT, can be used
    • [¹⁸F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission topography (PET)–CT is the most sensitive method for detecting bone metastases
  • brain imaging and FDG–PET–CT for patients with suspected oligometastatic disease (≤five metastases)
• Stage NSCLC according to the American Joint Committee on Cancer/Union for International Cancer Control tumour node metastasis 8th edition staging manual
• If imaging shows a solitary metastatic site, attempt to obtain cytological or histological confirmation of stage IV disease
• Evaluate response using the same radiographic investigation that demonstrated tumour lesions initially:
  • after 8–12 weeks of treatment for oncogene addicted NSCLC
  • after two to three cycles of systemic therapy for non-oncogene addicted NSCLC
• Follow up with PET is not routinely recommended, due to its high sensitivity and relatively low specificity
• Follow the Response evaluation criteria in solid tumours (RECIST) version 1.1 for measurements and response assessment
  • for immune checkpoint inhibitor (ICI) therapy, RECIST should formally be used
  • immune-related RECIST, immunotherapy RECIST, and immune-modified RECIST have not been validated, but may have a role in the overall assessment of therapy
  • patients can derive benefit from continuing the same TKI after RECIST version 1.1 progression; therefore, in some cases, the clinical relevance of RECIST in evaluating response is uncertain.

Additional Recommendations for Oncogene Addicted Metastatic NSCLC 

• Consider CNS imaging with gadolinium-enhanced magnetic resonance imaging for all patients
• For oligometastatic disease, mediastinal disease should be pathology-proven if this might impact the treatment plan
• Perform an electrocardiogram if the targeted therapy can cause adverse cardiac events, including rhythmic modifications (for example, long QT).

Follow Up, Long-term Implications, and Survivorship 

• Follow up if there is an option for a next line of therapy:
  • every 8–12 weeks for oncogene addicted NSCLC
  • every 6–12 weeks for non-oncogene addicted NSCLC
• Offer psychosocial support if needed
• Encourage smoking cessation
• For patients with non-oncogene addicted NSCLC who completed ICI treatment without signs of disease progression, offer follow-up CT scans every 3–4 months; if patients remain off therapy for 5 years, this interval can be increased.

Palliative Care in Stage IV Disease 

• Early palliative care is recommended in parallel with standard oncological care.