Non-Small Cell Lung Cancer Guidelines

Updated: Aug 17, 2017
  • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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Guidelines

Guidelines Summary

Lung Cancer Screening

Guidelines on lung cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • American College of Chest Physicians (ACCP)
  • American Association for Thoracic Surgery (AATS)
  • National Comprehensive Cancer Network (NCCN)
  • U.S. Preventive Services Task Force (USPSTF)

The guidelines are in agreement that annual screening with low-dose, computed tomography (LDCT) scanning should be offered to patients aged 55 to 74 years and who have at least a 30 pack-year smoking history and either continue to smoke or have quit within the past 15 years. [68, 48, 67, 69, 196]

The USPSTF extends the recommended age range to 80 years, while the NCCN notes the existence of uncertainty about the upper age limit for screening and advises that screening beyond age 74 years may be considered as long as the patient's functional status and comorbidity allow consideration for curative intent therapy. [69, 67]  

The American Association for Thoracic Surgery (AATS) extends the recommended age range to 79 years and also recommends annual screening starting at age 50 for patients who have a 20 pack-year smoking history and additional comorbid conditions that produce a cumulative risk for cancer of at least 5% over the next 5 years. Additionally, it recommends annual screening in long-term cancer survivors aged 55 to 79 years. [196]

The NCCN guidelines also recommend screening starting at age 50 in patients with at least a 20 pack-year smoking history and one or more of the following risk factors [67] :

  • Radon exposure (documented sustained and substantial)
  • Occupational exposure to lung carcinogens (eg, silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, soot)
  • Cancer history (lung cancer, lymphomas, cancers of the head and neck, or smoking-related cancers)
  • Family history of lung cancer in first-degree relatives 
  • Chronic obstructive pulmonary disease or pulmonary fibrosis

The groups also agree that the shared decision making is required and should include a discussion of benefits and risks.

None of the guidelines recommend screening asymptomatic patients for lung cancer with chest radiograph (CXR) or sputum cytology.

See Small Cell Lung Cancer: Beating the Spread, a Critical Images slideshow, to help identify the key clinical and biologic characteristics of small cell lung cancer, the staging criteria, and the common sites of spread.

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ACCP Diagnosis and Management Guidelines

The American College of Chest Physicians (ACCP) updated its comprehensive set of lung cancer guidelines in 2013. The guideline set of more than 275 recommendations includes an executive summary of current recommendations for diagnosis and treatment, along with additional recommendations for screening, chemoprevention and treatment of tobacco use in patients with lung cancer. [8]

Diagnosis of Pleural Abnormalities

The updated ACCP guidelines recommendations for diagnosis of pleural abnormalities include the following [8] :

  • The least invasive and safest method (bronchoscopy with transbronchial needle aspiration, endobronchial ultrasound-guided needle aspiration, endoscopic ultrasound-guided needle aspiration, transthoracic needle aspiration, or mediastinoscopy) should be used to establish a diagnosis in individuals who have extensive infiltration of the mediastinum based on radiographic studies and no evidence of extrathoracic metastatic disease (negative positron emission tomography scan)
  • For individuals who have a solitary extrathoracic site suspicious of a metastasis, tissue confirmation of the metastatic site is recommended if a fine-needle aspiration (FNA) or biopsy of the site is feasible
  • In individuals in whom biopsy of a metastatic site would be technically difficult, it is recommended that diagnosis of the primary lung lesion be obtained by the least invasive method
  • In patients suspected of having lung cancer who have an accessible pleural effusion, ultrasound-guided thoracentesis is recommended to diagnose the cause of the pleural effusion
  • If pleural fluid cytology is negative, pleural biopsy (via image-guided pleural biopsy, medical or surgical thoracoscopy) is recommended as the next step

Diagnosis of Primary Tumor

The updated ACCP guidelines recommendations for diagnosis of primary tumor include the following [8] :

  • If lung cancer is suspected and sputum cytology is negative for carcinoma, further testing should be performed
  • In patients who have a central lesion, bronchoscopy should be used to confirm the diagnosis; further testing should be performed if bronchoscopy results are non-diagnostic and suspicion of lung cancer remains
  • As an adjunct imaging modality when a tissue sample is required due to diagnostic uncertainty or poor surgical candidacy, radial endobronchial ultrasonography can confirm in real time the ideal location of bronchoscopic sampling and increase the diagnostic yield over conventional bronchoscopy for peripheral nodules
  • With peripheral lung lesions difficult to reach with conventional bronchoscopy, electromagnetic navigation guidance can be used if the equipment and the expertise are available; if electromagnetic navigation is not available, transthoracic needle aspiration (TTNA) is recommended
  • In patients who have a peripheral lesion, and who require tissue diagnosis before further management can be planned, TTNA is diagnostic option; however, further testing should be performed if TTNA results are non-diagnostic and suspicion of lung cancer remains
  • The diagnosis of non–small cell lung cancer (NSCLC) made on cytology (sputum, TTNA, bronchoscopic specimens, or pleural fluid) is reliable. However, adequate tissue must be obtained to accurately define the histologic type and to perform molecular analysis when applicable.

Treatment of Clinical Stage I and II NSCLC

The updated ACCP guidelines recommendations for treatment of clinical stage I and II NSCLC include [8] :

  • Surgical resection is the primary and preferred treatment approach for patients with no medical contraindications and a lobectomy rather than sub-lobar resection is preferred; however, in patients with major increased risk of perioperative mortality or competing causes of death (due to age-related or other co-morbidities), an anatomic sub-lobar resection (segmentectomy) over a lobectomy is suggested
  • Patients should be evaluated by a thoracic surgical oncologist even if they are considered for nonsurgical therapies such as percutaneous ablation or stereotactic body radiation therapy
  • For clinical stage I patients, a minimally invasive approach such as video-assisted thoracoscopy surgery (VATS) is preferred over a thoracotomy for anatomic pulmonary resection
  • For patients with in whom a complete resection can be achieved, a sleeve or bronchoplastic resection is suggested over a pneumonectomy
  • For patients with clinical stage I NSCLC who cannot tolerate a lobectomy or segmentectomy, stereotactic body radiation therapy (SBRT) and surgical wedge resection are suggested over no therapy
  • The use of adjuvant chemotherapy for stage II NSCLC is recommended and has shown benefit
  • The use of adjuvant radiation or chemotherapy for stage I NSCLC is of unproven benefit

Treatment of Clinical Stage III NSCLC

The updated ACCP guidelines recommendations for treatment of clinical Stage III NSCLC include the following [8] :

  • Combined chemoradiotherapy is preferred over radiotherapy alone in most subsets of patients and concurrent chemoradiotherapy is recommended over sequential chemoradiotherapy
  • Consolidation chemotherapy or targeted therapy following definitive chemoradiation is not recommended
  • Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation
  • Postoperative radiotherapy improves local control without improving survival

Treatment of Clinical Stage IV NSCL

The updated ACCP guidelines recommendations for treatment of clinical stage IV NSCLC include the following [8] :

  • The treatment of stage IV NSCLC should be specific for particular histologic subtypes and clinical patient characteristics and according to the presence of specific genetic mutations.
  • Both erlotinib and gefitinib as first-line therapy in patients with stage IV NSCLC and documented  EGFR mutations based on superior response rates, progression-free survival and toxicity profiles compared with platinum-based doublets
  • Pemetrexed should be restricted to patients with nonsquamous histology (adenocarcinoma)
  • Bevacizumab in combination with chemotherapy (and as continuation maintenance) should be restricted to patients with nonsquamous histology and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
  • The use of maintenance therapy with either pemetrexed or erlotinib should be considered after four cycles of first-line therapy in those patients without evidence of disease progression
  • The use of second- and third-line therapy is recommended in those patients retaining a good PS (1-2)
  • In the elderly and in patients with a poor PS, the use of two-drug, platinum-based regimens is preferred.
  • Palliative care should be initiated early in the course of therapy for stage IV NSCLC

Palliative Care

The updated ACCP guidelines recommendations for palliative and end-of-life care include the following [8] :

  • For patients with stage IV lung cancer and/or a high symptom burden, palliative care combined with standard oncology care should be introduced early in the treatment course
  • Begin conversations about the patient's prognosis and goals of care at the time of the diagnosis, and continue these throughout the course of the illness
  • All physicians caring for patients with advanced lung cancer should initiate conversations about the goals of care, the pros and cons of life-sustaining treatment and end-of-life care options
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EGFR and ALK Molecular Testing

International evidence-based guidelines jointly published by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) in 2013 recommend all lung cancer patients with adenocarcinomas should be tested for the genetic abnormalities that indicate suitability for treatment with targeted agents, irrespective of clinical variables such as sex, ethnicity, or smoking status. [60]  These guidelines were endorsed by the American Society for Clinical Oncology (ASCO) in 2014  [197]

The National Comprehensive Cancer Network (NCCN) guidelines recommend using erlotinib, gefitinib, or afatinib as first-line therapy in patients with documented EGFR mutations.For ALK positive patients, crizotinib receives a Category 1 recommendation as first-line therapy. [87]

 

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Video-Assisted thoracoscopy surgery (VATS)

NCCN practice guidelines recommend that VATS or minimally invasive surgery (including robotic-assisted approaches) be strongly considered for patients who have no anatomic or surgical contraindications, provided that standard oncologic and dissection principles of thoracic surgery are not compromised. The guideline notes that in high-volume centers with significant VATS experience, VATS lobectomy in selected patients results in improved early outcomes (ie, decreased pain, reduced hospital length of stay, more rapid return to function, fewer complications) without compromise of cancer outcomes. [87]

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Chemotherapy for Stage IV Disease

The American Society of Clinical Oncology (ASCO) issued guidelines on chemotherapy for stage IV NSCLC in 2015 [192] and updated them in 2017. [198] For patients with performance status (PS) 0 to 1 who receive chemotherapy (and for selected well-informed patients with PS 2 who desire aggressive treatment), ASCO recommends therapy with a combination of two cytotoxic drugs. Platinum combinations, unless contraindicated, are recommended over nonplatinum therapy. In addition, ASCO recommends early palliative care assistance for all patients with stage IV NSCLC, because it improves survival and well-being in patients with this incurable condition. [192]

First-line therapy

First-line therapy recommendations for patients with negative or unknown tumor EGFR-sensitizing mutation, ALK or ROS1 gene rearrangement status, and PS 0-1 (or possibly PS 2) include the following [198] :

  • For patients with high programmed death ligand–1 (PDL-1) expression (tumor proportion score [TPS] ≥50%), single-agent pembrolizumab should be used, if the patient has no contraindications to immune checkpoint therapy
  • Patients with low PDL-1 expression (TPS <50%) should be offered standard chemotherapy with a cisplatin- or carboplatin-based two-drug combination, unless they are not considered candidates for platinum-based therapy

Cisplatin-based two-drug combinations include the following as the second drug:

  • Docetaxel
  • Paclitaxel
  • Pemetrexed
  • Vinorelbine

Carboplatin-based two-drug combinations include the following as the second drug:

  • Nanoparticle albumin-bound (nab) paclitaxel
  • Paclitaxel
  • Pemetrexed
  • Docetaxel

For patients receiving carboplatin plus paclitaxel, the guidelines recommend adding bevacizumab, 15 mg/kg once every 3 weeks, and continuing it as tolerated until disease progression, Exceptions include patients with any of the following:

  • Squamous cell carcinoma (SCC) histologic type
  • Clinically significant hemoptysis
  • Inadequate organ function
  • ECOG PS >1
  • Clinically significant cardiovascular disease
  • Medically uncontrolled hypertension

For patients with PS 2, non-SCC, and negative or unknown tumor EGFR-sensitizing mutation and ALK or ROS1 gene rearrangement status, the guidelines recommend combination therapy, single-agent therapy, or palliative therapy alone, selected on the basis of shared decision making.

For patients SCC, negative or unknown tumor EGFR-sensitizing mutation, ALK or ROS1 gene rearrangement status, and PS 0-1 (or possibly PS 2), the guidelines recommend the following:

  • If PDL-1 expression is high (TPS ≥50%), single-agent pembrolizumab should be used, if the patient has no contraindications to immune checkpoint therapy
  • Patients with low (TPS <50%) or unknown PDL-1 expression should be offered standard chemotherapy with a cisplatin- or carboplatin-based two-drug combination, unless they are not considered candidates for platinum-based therapy

Cisplatin-based two-drug combinations include the following as the second drug:

  • Docetaxel
  • Gemcitabine
  • Paclitaxel
  • Vinorelbine

Carboplatin-based two-drug combinations include the following as the second drug:

  • Gemcitabine
  • Paclitaxel
  • Nab paclitaxel
  • Docetaxel

For patients with a sensitizing EGFR mutation, first-line options are as follows:

  • Afatinib
  • Erlotinib
  • Gefinitib

Second-line therapy

Recommendations for patients with SCC and non-SCC diseZs and negative or unknown EGFR mutation, ALK gene rearrangement status or ROS1 gene rearrangement status are as follows

  • If first-line therapy did not include an immune checkpoint inhibitor, use single-agent nivolumab, pembrolizumab, or atezolizumab in patients with positive tumor PDL-1 expression (TPS ≥ 1%, 22C3 assay); in patients with negative or unknown tumor PDL-1 expression (TPS <1%) use single-agent nivolumab or atezolizumab
  • If first-line therapy included an immune checkpoint inhibitor, offer standard platinum-based chemotherapy
  • For patients with contraindications to immune checkpoint inhibitor therapy, use docetaxel
  • For patients with non-SCC whose pevious therapy did not include pemetrexed, offer pemetrexed

For patients with a sensitizing EGFR mutation who experienced disease progression with a first-line EGFR tyrosine kinase inhibitor (TKI) recommendations include the following:

  • If the T790M resistance mutation is present, recommend osimertinib
  • If the T790M mutation is not present, clinicians offer treatment with a platinum-based doublet
  • If the patient had an initial response to first-line treatment but then experienced slow or minimal disease progression at isolated sites, EGFR TKI treatment can be continued, with local therapy to the isolated sites

For patients with ROS1 rearrangement, recommendations include the following:

  • Single-agent crizotinib, if first-line therapy did not include crizotinib
  • Platinum-based therapy with or without bevacizumab, if first-line therapy included crizotinib

For patients with BRAF mutations, recommendations include the following:

  • Offer atezolizumab, nivolumab, or pembrolizumab (if PDL-1 TPS >1%), unless first-line therapy included an immune checkpoint inhibitor

Third-line therapy

Recommendations for third-line therapy include the following"

  • For patients with BRAF mutations whose second-line therapy included immunotherapy, clinicians may offer dabrafenib alone or in combination with trametinib
  • For patients with non-SCC, negative or unknown tumor EGFR-sensitizing mutation, or ALK or ROS1 gene rearrangement status and PS 0-1 (or possibly PS 2), who received chemotherapy with or without bevacizumab and immune checkpoint therapy, clinicians should offer single-agent pemetrexed or docetaxel
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Radiation Therapy for Locally Advanced Disease

In 2015, the American Society for Radiation Oncology (ASTRO) released evidence-based guidelines for definitive and adjuvant radiotherapy in locally advanced NSCLC. [199, 200]  The American Society for Clinical Oncology has endorsed these guidelines. [201]

The guidelines cover patients with stage II or III locally advanced NSCLC whose disease is unresectable, and patients with stage II or III disease who are eligible for surgery. Key recommendation include the following [199, 200] :

Curative-intent Treatment

  • Concurrent chemoradiation improve s local control and overall survival and is recommended over sequential chemotherapy followed by radiation or radiation therapy alone
  • The standard dose-fractionation of radiation with concurrent chemotherapy is 60 Gy given in fractions of 2 Gy once per day over 6 weeks
  • Dose escalation beyond 60 Gy has no demonstrated benefit.
  • There is no role for the routine use of induction chemotherapy beforechemoradiation
  • Current data fail to support routine use of consolidation chemotherapy after chemoradiotherapy, but this remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy.
  • The ideal concurrent chemotherapy regimen has not been determined. The two most common regimens are cisplatin/etoposide and carboplatin/paclitaxel.
  • For patients who cannot tolerate chemoradiation, sequential chemotherapy followed by radical radiation improves overall survival when compared to radiotherapy alone.

Adjunctive Therapy

  • Radiotherapy alone may be used for patients ineligible for combined modality treatment; it may offer better tolerability, but poorer survival.
  • Postoperative radiotherapy may be recommended for patients with complete resection of N2 disease to improve local control, but should be delivered sequentially after adjuvant chemotherapy.
  • For patients receiving postoperative radiotherapy for R0 disease, conventionally fractionated doses in the range of 50 Gy to 54 Gy (in 1.8-2.0 Gy/day) should be used.
  • Postoperative radiotherapy with conventionally fractionated doses in the range of 54 Gy to 60 Gy (in 1.8-2.0 Gy/day) to improve local control for patients with R1 disease (incomplete resection), to be given either concurrently or sequentially with chemotherapy. 
  •  Patients with R2 disease may be candidates for postoperative radiotherapy with conventionally fractionated doses of at least 60 Gy (in 1.8-2.0 Gy/day fraction size) to improve local control, to be given either concurrently or sequentially with chemotherapy.
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