AR Jazieh on Behalf of Saudi Lung Cancer Guidelines Association - Saudi Lung Cancer Guidelines Members¹, Abdul Rahman Jazieh², Khaled Al Kattan³, Ahmed Bamousa⁴, Ashwaq Al Olayan², Ahmed Abdelwarith⁵, Jawaher Ansari⁶, Abdullah Al Twairqi⁷, Turki Al Fayea⁸, Khalid Al Saleh⁵, Hamed Al Husaini⁹, Nafisa Abdelhafiez², Mervat Mahrous¹⁰, Medhat Faris¹¹, Ameen Al Omair¹², Adnan Hebshi¹³, Salem Al Shehri¹⁴, Foad Al Dayel¹⁵, Hanaa Bamefleh¹⁶, Walid Khalbuss¹⁶, Sarah Al Ghanem¹⁷, Shukri Loutfi¹⁷, Azzam Khankan¹⁸, Meshael Al Rujaib¹⁹, Majed Al Ghamdi²⁰, Nagwa Ibrahim²¹, Abdulmonem Swied²², Mohammad Al Kayait²³, Marie Datario^23
1 ,
² Department of Medical Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
³ Department of Surgery, Al Faisal University, Riyadh, Saudi Arabia
⁴ Department of Surgery, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
⁵ Department of Medical Oncology, King Khalid University Hospital, Riyadh, Saudi Arabia
⁶ Department of Medical Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
⁷ Department of Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
⁸ Department of Medical Oncology, Princess Noorah Oncology Center, Riyadh, Saudi Arabia
⁹ Department of Medical Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
¹⁰ Department of Medical Oncology, King Fahad Hospital, Madinah, Saudi Arabia
¹¹ Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
¹² Department of Radiation Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
¹³ Department of Radiation Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
¹⁴ Department of Radiation Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
¹⁵ Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
¹⁶ Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
¹⁷ Department of Radiology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
¹⁸ Department of Interventional Radiology, King Abdulaziz Medical City, Jeddah, Saudi Arabia
¹⁹ Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
²⁰ Department of Pulmonary, King Abdulaziz Medical City, Riyadh, Saudi Arabia
²¹ Department of Pharmacy, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
²² Department of Gastroenterology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
²³ Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Correspondence Address:
Abdul Rahman Jazieh
Department of Medical Oncology, King Abdulaziz Medical City, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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9

DOI: 10.4103/atm.ATM_92_17

Abstract

Background: Lung cancer management is getting more complex due to the rapid advances in all aspects of diagnostic and therapeutic options. Developing guidelines is critical to help practitioners provide standard of care.
Methods: The Saudi Lung Cancer Guidelines Committee (SLCGC) multidisciplinary members from different specialties and from various regions and healthcare sectors of the country reviewed and updated all lung cancer guidelines with appropriate labeling of level of evidence. Supporting documents to help healthcare professionals were developed.
Results: Detailed lung cancer management guidelines were finalized with appropriate resources for systemic therapy and short reviews highlighting important issues. Stage based disease management recommendation were included. A summary explanation for complex topics were included in addition to tables of approved systemic therapy.
Conclusion: A multidisciplinary lung cancer guidelines was developed and will be disseminated across the country.

Keywords: Lung cancer guidelines, Saudi lung cancer, Saudi lung cancer management guidelines

Methodology

1. High level (evidence levels 1 [EL-1]): Well-conducted Phase III randomized studies or metaanalysis
2. Intermediate level (EL-2): Good Phase II data or Phase III trials with limitations
3. Low level (EL-3): Observational/retrospective study/expert opinion.

Lung Cancer Management Guidelines

• High level (EL-1): Well-conducted Phase III randomized studies or well done meta-analyses
• Intermediate level (EL-2): Good Phase II data or Phase III trials with limitations
• Low level (EL-3): Observational or retrospectives studies or expert opinions.

1. All lung cancer patients
   
   1.1. Initial patient assessment
   
   1.1.1. Perform history and physical examination. Document smoking history, performance status, weight loss, and comorbidities
   
   1.1.2. Perform the following laboratory tests: Complete blood count, differential, liver function test, renal function, electrolytes, calcium, serum albumin, magnesium, and phosphorus
   
   1.1.3. Two-view chest X-ray.
   
   1.2. Diagnosis
   
   1.2.1. Obtain adequate tissue specimen for diagnostic and predictive markers
   
   1.2.2. Confirm histopathological diagnosis of lung cancer and determine the histological subtypes using most recent pathological classification of lung cancer. Utilization of proper immunohistochemistry (IHC) staining (minimal panel to include thyroid transcription factor-1 most important), cytokeratin 7 (CK7), and CK20 for adenocarcinoma and P40 (preferred) or P63 to minimize the diagnosis of “not otherwise specified”
   
   1.2.3. Obtain EGFR mutation testing by polymerase chain reaction in certified laboratory for all histology except pure squamous cell (squamous cell carcinoma with small sample or never smokers, EGFR should be done)
   
   1.2.4. In EGFR wild-type (WT) tumors, obtain EML4-ALK fusion test by fluorescence in situ hybridization (FISH) in certified laboratory. IHC can be done to screen for positive tumors to be tested by FISH
   
   1.2.5. For patients with WT EGFR and ALK, obtain the ROS1 test
   
   1.2.6. If tissue not adequate to do molecular testing, perform circulating tumor cell DNA (ctDNA) (plasma) testing
   
   1.2.7. Obtain programmed death-ligand 1 (PD-L1) testing by IHC 22C3 pharmDx on all nonsmall cell lung cancer (NSCLC) WT
   
   1.2.8. Next generation sequencing should be performed, if available.
   
   1.3. Staging
   
   1.3.1. NSCLC
   
   1.3.1.1 Obtain contrast-enhanced computed tomography (CT) scan of the chest and upper abdomen
   
   1.3.1.2 Obtain magnetic resonance imaging (MRI) of brain for Stages IB-IV (preferred over contrast-enhanced CT scan)
   
   1.3.1.3 Obtain total body positron emission tomography (PET)/CT scan when available if the patient is considered for radical therapy (such as surgery or chemoradiotherapy)
   
   1.3.1.4 Obtain bone scan for Stages IB-IV if PET/CT is not done
   
   1.3.1.5 Perform mediastinal lymph node (LN) evaluation in selected cases, i.e. clinical Stages (IB-III). Especially negative with central tumor and T2 to T4
   
   1.3.1.6 Determine precise tumor, node, and metastasis (TNM) staging using 7th edition (2009).
   
   1.3.2. Small cell lung cancer
   
   1.3.2.1. Obtain contrast-enhanced CT scan of chest and upper abdomen
   
   1.3.2.2. Obtain MRI of brain for Stages IB-IV (preferred over contrast-enhanced CT scan which can be if MRI is not available)
   
   1.3.2.3. Obtain PET/CT scan if the disease in Stages I-III
   
   1.3.2.4. Obtain bone scan if PET/CT is not done or it was negative with suspected bone involvement
   
   1.3.2.5. Determine precise TNM staging using 7th edition (2009).
   
   1.4. Pre-treatment assessment
   
   1.4.1. Discuss all new cases in a multidisciplinary conference (tumor board)
   
   1.4.2. Obtain cardiopulmonary assessment (pulmonary function test [PFT], 6-min walk, electrocardiogram and echocardiogram) if surgery considered and PFT for curative radiotherapy is considered.
   
   1.5. General
   
   1.5.1. Counsel about smoking cessation and pulmonary rehabilitation
   
   1.5.2. Offer available clinical research studies.



2. NSCLC
   
   2.1. Clinical Stage IA
   
   2.1.1. Anatomical surgical resection and mediastinal LN sampling
   
   2.1.2. Adjuvant chemotherapy is not recommended.
   
   2.1.3. If optimal surgery cannot be performed, consider limited surgery (wedge resection or segmentectomy) or stereotactic body radiation therapy (SBRT)
   
   2.1.4. Patients with positive surgical margins should be offered re-resection or radical postoperative radiotherapy.
   
   Definitive radical radiotherapy is an alternative for patients who are not candidates for surgery due to comorbidities, poor performance status, or refusal of surgery.
   
   2.1.5. If surgical resection is not possible, (inoperable or refusal of surgery) offer SBRT with curative intent. Poor PFT is not contraindication for SBRT (section 2.3.8)
   
   2.1.6. Follow-up and surveillance per se ction 2.8. (follow-up of NSCLC).
   
   2.2. Clinical Stage IB
   
   2.2.1. Anatomical surgical resection mediastinal LN sampling or dissection
   
   2.2.2. For lesions ≥4 cm or high-risk features (poorly differentiated, wedge resection, minimal margins, vascular invasion), consider adjuvant chemotherapy ^[22],[23]
   
   2.2.3. Chemotherapy of choice: 4–6 cycles of platinum combination cisplatin (carboplatin only if cisplatin is contraindicated) (EL-1)^{[22],[23],[24],[25]}
   
   2.2.4. If optimal surgery cannot be performed, consider limited surgery (wedge resection or segmentectomy)
   
   2.2.5. Definitive SBRT with curative intent is an alternative option for patients who are not candidates for surgery due to comorbidities or refusal of surgery. Section 2.3.8. hypofractionated radiotherapy is the second option
   
   2.2.6. Patients with positive surgical margins should be offered re-resection radical postoperative radiotherapy
   
   2.2.7. Follow-up and surveillance per se ction 2.8. (follow-up of NSCLC)
   
   2.3. Clinical Stage IIA
   
   2.3.1. Anatomical surgical resection with lobectomy or pneumonectomy and mediastinal LN sampling (EL-1)^[26],[27] or dissection is the treatment of choice
   
   2.3.2. Offer adjuvant chemotherapy as per se ction 2.2.3 (EL-1)^{[22],[23],[24],[25]}
   
   2.3.3. If optimal surgery cannot be performed, consider SBRT limited surgery (wedge resection or segmentectomy)
   
   2.3.4. Patients with positive surgical margins should be offered re-resection or radical postoperative radiotherapy
   
   2.3.5. Definitive radical radiotherapy is an alternative option that should be considered for patients with T2bN0 for patients who are not candidates for surgery due to comorbidities or who refuse surgery
   
   2.3.6. If surgical resection is not possible, offer curative radical radiotherapy for T2bN0 (section 2.3.8.)
   
   2.3.7. Follow-up and surveillance as per se ction 2.8. (follow-up of NSCLC)
   
   2.3.8. Radiotherapy with curative intent in patients with early stage, medically inoperable, NSCLC:
   
   2.3.8.1. SBRT with curative intent is an option that should be considered for patients with early-stage, node-negative, medically inoperable NSCLC
   
   2.3.8.2. Most established SBRT criteria include NO patients with:
   
   
   • <5 cm, peripherally located tumors, but tumor maybe more cautiously treated with expanded criteria of larger size (<7 cm)
   • Central location
   • Multiple synchronous lesions
   • Chest wall invasion (T3N0).
   
   
   2.3.8.3. Poor PFT is not contraindication to SBRT. The only practical known contraindication to SBRT that if the patient can not lie flat on the machine table during treatment delivery time
   
   2.3.8.4. Recommended fractionation schemes for SBRT should have a BED10 (LQ) of >100.
   
   2.4. Clinical staage IIB
   
   2.4.1. Anatomical surgical resection and mediastinal LN sampling. (EL-1)^[26],[27] or dissection is the treatment of choice
   
   2.4.2. Offer adjuvant chemotherapy as per se ction 2.2.3 (EL-1)^{[22],[23],[24],[25]}
   
   2.4.3. Superior sulcus tumors patients should be induced by cisplatin/etoposide with concurrent radiation therapy followed by surgical resection (EL-2)^[28],[29] and 2 cycles of adjuvant chemotherapy. Assess disease extent using MRI at baseline and preoperative (EL-2)^{[28],[30],[31],[32]}
   
   2.4.4. For T3 N0 M0 perform en bloc resection
   
   2.4.5. If optimal surgery cannot be performed, consider limited surgery (wedge resection or segmentectomy)
   
   2.4.6. Patients with positive surgical margins should be re-resection or radical postoperative radiotherapy
   
   2.4.7. Definitive radical radiotherapy SBRT for T3N0, chest wall invasion or concurrent chemoradiotherapy for T2BN1 is an alternative for patients who are not candidates for surgery due to comorbidities or refusal of surgery
   
   2.4.8. Follow-up and surveillance per se ction 2.8. (follow-up of NSCLC).
   
   2.5. Clinical Stage IIIA
   
   2.5.1. For T3 N1 M0, perform en bloc resection
   
   2.5.2. For superior sulcus tumor, offer treatment similar to section 2.4.3.^[28]
   
   2.5.3. For N2 disease, the standard of care is concurrent chemoradiotherapy. For selected cases of N2 that elected to be surgically resectable after discussion in tumor board, neoadjuvant chemoradiotherapy can be considered followed by assessment of response. For inoperable tumors, continue with the appropriate treatment based on disease status
   
   2.5.4. If N2 disease discovered during surgery by frozen section abort surgery if pneumonectomy is required (EL-2)^[33]
   
   2.5.5. For patients with incidental pathological N2 disease, adjuvant chemotherapy is recommended (EL-1)^{[22],[23],[24],[25]} and in addition radiotherapy can be considered (EL-3)^[34]
   
   2.5.6. For T4 disease T4N0 (2 nodules in ipsilateral separate lobes), offer pneumonectomy followed by adjuvant chemotherapy. SBRT with curative intent is an option that can be considered
   
   2.5.7. For T4 with (mediastinal or main airway involvement), offer surgery if potentially curative; if not possible, offer definitive concurrent chemoradiotherapy (2.5.1.)
   
   2.5.8. For non N2 Stage IIIA, not specified above, offer surgical resection with adjuvant chemotherapy
   
   2.5.9. Follow-up and surveillance per se ction 2.8 (follow-up of NSCLC).
   
   2.6. Clinical Stage IIIB and unresectable IIIA
   
   2.6.1. Offer concurrent chemoradiotherapy (EL-1)^[35],[36] followed by chemotherapy. Surgical resection for selected cases could be offered
   
   2.6.2. Follow-up and surveillance per se ction 2.8 (follow-up of NSCLC).
   
   2.7. Stage IV (Obtain palliative care consultation/evaluation on all patients [EL-1])^[37]
   
   2.7.1. Systemic therapy [Table 1]

   Table 1: Systemic therapy for metastatic non-small cell lung cancer Click here to view

   
   
   2.7.1.1. Stage M1a (with pleural effusion) assess the need for thoracentesis and pleurodesis. Offer systemic therapy as below
   
   2.7.1.2. With brain metastases [Table 2] and [Table 3]

   Table 2: Radiation Therapy Oncology Group recursive partitioning analysis for brain metastases (Gasper et al. 1997) Click here to view

   Table 3: Radiosurgery treatment indications for brain metastases Click here to view

   
   
   2.7.1.3. Isolated adrenal metastasis; consider adrenal mass biopsy followed by surgical resection or SBRT consideration after multidisciplinary team discussion
   
   2.7.1.4. No brain metastases/treated brain disease, no prior systemic treatment for metastatic disease [Table 4].

   Table 4: Systematic therapy regimens in nonsmall cell lung cancer Click here to view

   
   
   2.7.1.4.1. Adenocarcinoma/nonsquamous with sensitizing EGFR mutation.
   
   Guiding principle:
   
   Patient with driver mutation should receive tyrosine kinase inhibitor (TKI) as first line if possible. If not done, patient should receive TKI as soon as possible as switched maintenance (completing planned treatment) or any time they are available (interrupt treatment)
   
   
   1. First line:
      1. Performance Status 0–2:
         • TKIs (erlotinib, afatinib, or gefitinib) are the preferred option (EL-1)^{[38],[39],[40]}
         • Systemic chemotherapy with a platinum doublet ± bevacizumab can be considered if the EGFR status is unknown or awaited. Platinum doublet (pemetrexed combination is preferred over a gemcitabine based combination)
      2. Performance Status 3:
         • Use TKIs (erlotinib, afatinib, or gefitinib)
         • Single-agent chemotherapy if TKI not available, can be considered in selected cases.
      3. Performance Status 4:
         • Use TKIs (erlotinib, afatinib or gefitinib).
   2. Maintenance:
      1. Performance Status 0–2:
         • Continuation or switch maintenance with TKIs (EL-1).^{[41],[42],[43]} If the patient was not commenced on TKIs, then switch to TKIs as soon as possible.
      2. Performance Status 3 and 4:
         • Continuation or switch maintenance with TKIs.
   3. Second line:
      
      Assess for resistant mutations with either ctDNA (plasma) testing or rebiopsy of metastatic site.
      
      For isolated or oligoprogression, consider local therapy. For multiprogression, switch to second line.
      
      
      1. If T790M positive, use osimertinib.^[44]
      2. Performance Status 0–2:
         • Use TKIs, if not used in first line
         • Systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).
      3. Performance Status 3:
         • Use TKIs, if not used in first line
         • If TKI used, consider single-agent chemotherapy (pemetrexed preferred over gemcitabine).
      4. Performance Status 4:
         • Use TKIs, if not used in first line
         • If TKIs were used, consider single-agent chemotherapy or referral to palliative care.
   4. Third line and beyond
      • Obtain T790M testing if it was not done earlier, consider doing ctDNA (plasma) testing.
      
      
      
      1. Performance Status 0–2:
         • Use TKIs, if not used before
         • Consider immunotherapy (nivolumab or pembrolizumab, or atezolizumab)
         • Systemic chemotherapy (single-agent chemotherapy, pemetrexed if not used, docetaxel, etc.)
         • Ramucirumab/docetaxel.
      2. If T790M positive, use osimertinib
      3. Performance Status 3 and 4:
         • Use TKIs, if not used in first line
         • If TKIs were used, refer to palliative care.
   
   
   2.7.1.4.2. ALK-positive adenocarcinoma/non-squamous
   
   
   1. First line:
      1. Performance Status 0–2:
         • Crizotinib is the recommended treatment option (EL-1)^{[45],[46],[47]}
         • Systemic chemotherapy with a platinum doublet (± bevacizumab) can be considered (platinum-pemetrexed combination is preferred over a gemcitabine-based combination)
         • Crizotinib is also very effective in patients with ROS1 rearrangements.
      2. Performance Status 3:
         • Use crizotinib
         • Single-agent chemotherapy can be considered.
      3. Performance Status 4:
         • Use crizotinib
         • Palliative care.
   2. Maintenance:
      1. Performance Status 0–2:
         • Continuation or switch maintenance with crizotinib. If was not started on crizotinib, patient should be switched to crizotinib as soon as possible.
      2. Performance Status 3 and 4:
         • Continuation or switch maintenance with crizotinib. If was not started on crizotinib, patient should be switched to crizotinib as soon as possible.
   3. Second line
      • For isolated or oligoprogression, consider local therapy
      • For multiple site progression, consider rebiopsy to assess the cause of resistance if TKI is used in first line.
      
      
      
      1. Performance Status 0–2:
         • Ceritinib or alectinib are the recommended treatment options for patients with disease progression or intolerance to crizotinib ^{[48],[49],[50]}
         • Use crizotinib, if not used in first line
         • Systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).
      2. Performance Status 3 and 4:
         • Use ceritinib, If crizotinib used before
         • Use crizotinib, if not used before.
   4. Third line and beyond
      1. Performance Status 0–2:
         • Use crizotinib or ceritinib or alectinib, if not used before
         • Systemic chemotherapy (single-agent chemotherapy, pemetrexed, if not used, docetaxel)
         • Consider immunotherapy (pembrolizumab, nivolumab or atezolizumab).
      2. Performance Status 3 and 4:
         • Use crizotinib or ceritinib or alectinib, if not used in first line
         • If both agents where used, palliative care.
   
   
   2.7.1.4.3. EGFR/ALK WT adenocarcinoma/non-squamous (including EGFR Exon 20 mutation or primary resistance mutation)
   
   
   1. First line:
      1. Performance Status 0–2:
         • If PD-L > 50%
         • Use pembrolizumab (preferred EL-1),^{[51],[52],[53]} if it is not available use systemic chemotherapy (platinum doublet+/-bevacizumab) (pemetrexed is preferred over gemcitabine).
         • If PD-L < 50%
         • Systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).
      2. Performance Status 3:
         • Single-agent chemotherapy can be considered
         • Palliative care.
      3. Performance Status 4:
         • Palliative care.
   2. Maintenance:
      1. Performance Status 0–2:
         • Continue pembrolizumab if commenced in first line
         • Continue or switch maintenance with pemetrexed for PD-L1 < 50%.
         • Continue bevacizumab, if started in first line.
      2. Performance Status 3:
         • Continue or switch maintenance with pemetrexed.
      3. Performance Status 4:
         • Palliative care.
   3. Second line
      1. Performance Status 0-2:
         • Give nivolumab, atezolizumab, or pembrolizumab (PD-L1 positive), if received chemotherapy as first line ^{[51],[52],[53],[54],[55]}
         • Platinum doublet if pembrolizumab used as first line
         • Single-agent systemic chemotherapy (pemetrexed if not used, docetaxel). If chemotherapy doublet is used as first line.
      2. Performance Status 3:
         • Single-agent systemic chemotherapy (pemetrexed if not used, docetaxel).
      3. Performance Status 4:
         • Palliative care.
   4. Third line and beyond
      1. Performance Status 0–1:
         • Consider ramucirumab + docetaxel or nintedanib + docetaxel
      2. Performance Status 0–1
         • Single-agent systemic therapy.
      3. Performance Status 3 and 4:
         • Palliative care.
   
   
   2.7.1.4.4. Adenocarcinoma/nonsquamous with (EGFR and ALK unknown status)
   
   
   • Consider doing ctDNA (plasma) testing of rebiopsy is not possible. All efforts should be made to test for a driver mutation.
   
   
   
   1. First line:
      1. Performance Status 0–2:
         • If PDL >50%:
         • Use pembrolizumab, if it is not available use systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).^{[51],[52],[53]}
         • If PD-L <50%:
         • Systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).
      2. Performance Status 3:
         • Single-agent chemotherapy (pemetrexed is preferred over gemcitabine)
         • Use TKIs (erlotinib).
      3. Performance Status 4:
         • Palliative care.
   2. Maintenance:
      1. Performance Status 0–2:
         • Continue or switch maintenance with pemetrexed
         • Continue bevacizumab, if started in first line.
      2. Performance Status 3:
         • Continue or switch maintenance with pemetrexed.
      3. Performance Status 4:
         • Palliative care.
   3. Second line
      1. Performance Status 0–2:
         • Immune systemic chemotherapy (platinum doublet ± bevacizumab) (pemetrexed is preferred over gemcitabine).
         • If immune therapy not used, use (nivolumab or pembrolizumab or atezolizumab)^{[51],[52],[53],[54],[55]}
         • Consider using ramucirumab.
      2. Performance Status 3:
         • Single-agent chemotherapy (pemetrexed if not used).
      3. Performance Status 4:
         • Palliative care.
   4. Third line and beyond
      1. Performance Status 0–2:
         • Systemic chemotherapy (single-agent chemotherapy, pemetrexed if not used or docetaxel)
         • Erlotinib, if immunotherapy and pemetrexed used.
      2. Performance Status 3 and 4:
         • Palliative care.
   
   
   2.7.1.4.5. Squamous cell carcinoma:
   
   
   1. First line:
      1. Performance Status 0–2:
         • If PD-L1 <50%^{[51],[52],[53]}
         • Systemic chemotherapy (platinum doublet) (no bevacizumab or pemetrexed).
         • If PD-L1 >50% use pembrolizumab (EL-1).^{[51],[52],[53]}
      2. Performance Status 3:
         • Single-agent chemotherapy (no pemetrexed).
      3. Performance Status 4:
         • Palliative care.
   2. Maintenance:
      1. Performance Status 0–2:
         • Continue pembrolizumab for 2 years
         • Continuation or switch maintenance with docetaxel.
      2. Performance Status 3 and 4:
         • Palliative care.
   3. Second line
      1. Performance Status 0–2:
         • Immune therapy (nivolumab, pembrolizumab or atezolizumab), if pembrolizumab not used. (EL-1)^{[51],[52],[53],[54],[55]}
           
           Systemic chemotherapy doublet if immune therapy used as first line (no pemetrexed)
         • Consider using ramucirumab/docetaxel
         • Afatinib.
      2. Performance Status 3:
         • Single-agent systemic therapy.
      3. Performance Status 4:
         • Palliative care.
   4. Third line and beyond
      1. Performance Status 0–2:
         • Single-agent systemic therapy.
      2. Performance Status 3 and 4:
         • Palliative care.
   
   
   2.8. Follow-up of NSCLC Evaluation includes: History and physical examination, laboratory and chest X-ray.
   
   2.8.1. For tumor Stage I-III: Evaluation every 3 months for 2 years then every 6 months for 3 years then annually. CT scan of the chest every 6 months for 2 years then annually for additional 3 years. Consider annual screening CT scan after 5 years
   
   2.8.2. Stage IV: Evaluation every 2–3 months as clinically indicated.



3. Small cell lung cancer
   
   3.1. Stage I-III (Previously called limited stage):
   
   3.1.1. Offer cisplatin/etoposide with radiation therapy then consolidate with two cycles of cisplatin/etoposide (EL-1).^[56] May substitute cisplatin with carboplatin in patients with neuropathy, renal dysfunction or hearing problem
   
   3.1.2. After definitive therapy with any response offer prophylactic cranial irradiation (PCI) (EL-1)^{[57],[58],[59]}
   
   3.1.3. For stage (T1-2 N0 confirmed by mediastinoscopy), offer surgical resection followed by chemotherapy and prophylactic brain radiotherapy
   
   3.1.4. Follow-up and surveillance as per se ction 3.3.
   
   3.2. Stage IV (previously extensive stage)
   
   3.2.1. Offer cisplatin/etoposide or cisplatin/irinotecan × 6 cycles (EL-1). Use of carboplatin cisplatin is not indicated ^{[60],[61],[62]}
   
   3.2.2. After definitive chemotherapy with evidence of response and good performance status offer. Thoracic irradiation and PCI
   
   3.2.3. For previously treated patients who relapsed in <6 months from initial treatment, offer topotecan or cyclophosphamide, adriamycin and vincristine, or irinotecan
   
   3.2.4. For relapse after 6 months from initial treatment, may use original regimen
   
   3.2.5. Follow-up and surveillance as per se ction 3.3.
   
   3.3. Follow-up and surveillance
   
   3.3.1. Evaluation includes: History and physical examination, laboratory data, and chest X-ray
   
   3.3.2. Stage I-III: Evaluation every 3 months for 2 years then every 6 months for 3 years then annually. CT scan of the chest every 6 months for 2 years then annually for additional 3 years. Consider annual screening CT scan after 5 years
   
   3.3.3. Stage IV: evaluation every 2–3 months as clinical indicated.

Image-Guided Percutaneous Transthoracic Biopsy in Lung Cancer

• Fine-needle aspiration (FNA) biopsy
• Core biopsy.

• Confirm the diagnosis of indeterminate pulmonary nodule or mass
• Characterize the tumor histopathology.

• Previous pneumonectomy and other instances of a single lung
• Suspected hydatid cyst or vascular malformation.

• Coagulopathy or anticoagulant therapy
• Significant pulmonary arterial hypertension
• Severe lung disease (respiratory failure - mechanical ventilation, severe obstructive lung disease, and severe emphysematous disease)
• Large bullae
• Inability of the patient to cooperate (may performed under general anesthesia).

• Size and location of the lesion
• Availability of imaging systems
• Local expertise and preference.

• Advantages
  • Low cost
  • Short procedure time
  • Real-time visualization of the needle advancement.
• Disadvantages
  • Difficulty in accessing central lesions
  • Difficulty in avoidance of bullae and vascular structures in the needle pass.

• Advantages
  • Real-time visualization of the needle advancement with multiplanar capability allowing accurate placement of the needle
  • Low cost
  • Short procedure time
  • No radiation – safe.
• Disadvantages
  • Cannot access be used for accessing central lesions
  • Difficulty in avoidance of bullae and vascular structures in the needle pass.
  CTis the preferred and most common and standard used guidance imaging modality.^[81]

• Advantages
  • Revealing the anatomic structure
  • Characterizes the lesion (shape, necrosis and solid tumor)
  • Minimizing needle passage through aerated lung, bullae, fissures or vessels
  • Accurate accessing central and small lesion.
• Disadvantages
  • Radiation
  • Relative long procedure time.

• End-cut biopsy needle provides full cannula width of tissue as the entire lumen with the whole length of needle advancement within the lesion
• Side-notch biopsy needle provides shorter length of tissue than the needle advancement with less tissue volume than the entire needle lumen.

• Coaxial technique
  • Needle stability in the chest wall
  • Obtaining multiple sampling with a single pleural puncture.
• Single shaft (noncoaxial) technique
  • More flexible
  • Guiding the needle to the correct location.
• Choice between needles and techniques based on:
  • Operator's preference and expertise
  • Needle availability
  • Institutional experience.

• Obtaining the patient history and indications for the biopsy
• Obtaining an informed consent including potential risks and benefits in details
• Obtaining baseline chest CT to determine the biopsy route and technique based on the size and location of the lesion, availability of imaging systems, and local expertise
• Choosing the needle path as a straight pathway from the skin to lesion with a 90° angle between the needle and the pleura avoiding transversal of bullae, vessels and bronchi ^[84]
• Choosing the more peripheral or upper lesion or upper over a deep or lower lesion
• Avoiding necrotic portions of lesions.

• Consideration of position should be made during biopsy planning as the patient should maintain the same position throughout the entire procedure.
• Prone position is ideal due to:
  • Least amount of chest wall motion
  • More comfortable “biopsy side down” supine position during recovery, which may reduce the chance of developing a pneumothorax
  • The patient will not see the biopsy needle which may reduce both anxiety and movement.

• Sedation and intravenous analgesic medications are usually not required with the liberal use of chest wall local anesthetic
• The pain and burning sensation are usually limited and momentary and arise from administration of the local anesthetic through the needle into the partial pleura
• Sedation and analgesia are primarily used for anxious and uncooperative patients, some selected elderly people with musculoskeletal diseases who cannot maintained raised arms, lesions adherent to periosteum and chest wall or when the procedure is lengthy.

• mA and slice thickness
• Choosing low-dose axial scan with 120 kVp with 40 mA or lower per slice
• Choosing slice thickness should be less than half the diameter of the targeted lesion as the following:
  • 1 cm or 5 mm for lesions >3 cm in diameter
  • 5 mm for lesion 1–3 cm in diameter
  • 3 mm cm for lesions 5 mm–1 cm
  • 3 mm for lesions <5 mm in diameter.

• Positioning the patient on the CT table
• Placing a radiopaque marker or grid on the patient's skin over the area of interest
• Obtaining a short CT scan of the region of interest with suspended respiration
• Choosing the appropriate table position and needle
• Measuring the depth from the skin entry site to the lesion
• Prepping and draping the skin site using sterile technique
• Administrating local anesthesia into the skin, subcutaneous tissues, and intercostal muscles
• Advancing 17- or 19- gauge introducer needle with appropriate length based on the lesion depth while the patient's respiration is suspended
• Coaxial advancing an 18- or 20-guage automated cutting needle smaller than the introducer needle toward the periphery of or inside the lesion
• Obtaining a short segment CT to verify the needle angle and tip position based on the last scan (a sequential technique). The needle is then advanced in one motion through the pleura to the prescribed depth
• Confirming documenting the location of needle tip position at the periphery of or within the lesion
• Firing the needle into the lesion during suspended respiration and obtaining at least two tissue samples but more can be obtained based on the lesion characteristics.

• Obtaining a short CT scan to evaluate for immediate complications.^[85] If the scan is normal with no significant pneumothorax and the patient is asymptomatic, the patient is transported to the designated area for clinical monitoring
• The patient should remain recumbent throughout the monitoring period
• Obtaining follow-up sitting upright expiratory chest radiographs at 1–2 h after biopsy
• Discharging the patient if the chest radiograph shows no new changes
• Instructing the patient to abstain from strenuous or weight-bearing activities for 3 days
• Anticoagulants, antiplatelet and nonsteroidal anti-inflammatory drugs are not allowed.

• The overall accepted complication rate of percutaneous transthoracic lung biopsies of 10% with threshold success rate of 85% are acceptable ^[86]
• Most complications occur immediately or within the first hour of a biopsy and they can be treated conservatively, often on an outpatient basis ^{[87],[88],[89]}
• Common complications include pneumothorax and hemorrhage ^[90]
• Rare complications include air embolism, vasovagal reaction, cardiac tamponade, and seeding of the tract with tumor.

• The average incidence is 20%
• Requiring chest tube varies from 5% to 18%
• Occur during or immediately after the procedure
• Risk factors include lesion contact with the pleura,^[91] the presence of emphysema, transgression of fissures, a small angle of the needle with the thoracic pleura, and multiple repositioning of the needle ^[92]
• Small pneumothorax (<20% lung volume) is asymptomatic and stable - do not require treatment except conservative management
• Symptomatic pneumothorax, size >30% of the lung volume, and/or its size continues to increase is requiring treatment (supplemental nasal oxygen and positioning biopsy side-down if possible, manual aspiration If the biopsy needle is still within the thorax, decompression with a chest tube if the biopsy needle has been removed)^{[93],[94],[95]}
• Serial expiratory upright chest radiographs should obtained to observe for the recurrence of pneumothorax with appropriate clinical monitoring.^[96]

• Second most common and most dangerous potential complication
• Every biopsy is associated with some degree of hemorrhage
• Most often self-limited and resolves spontaneously without treatment
• It may occur with or without hemoptysis
• Hemorrhage and hemoptysis occur in approximately 11% and up to 7%, respectively ^[97]
• More likely to occur with abnormal coagulation, pulmonary arterial hypertension, cutting needles larger than 18 gauge, lesion depth >2 cm, lesion size smaller than 2 cm, vascularity, cavitation, enlarged bronchial vessels in the vicinity, and central location ^[98]
• The patient should be placed in decubitus position with the biopsy side down to prevent transbronchial aspiration of blood. If the patient is hemodynamically unstable, appropriate supportive management with fluid resuscitation with or without blood transfusion is required.

• Most severe complications but it is one of the least frequent (0.07%)
• Air enters the pulmonary venous system leading to systemic air embolism. Air embolism can cause myocardial infarction, arrhythmia, stroke and death ^[99]
• The patient should be placed in the left lateral decubitus position or in trendelenburg position to prevent residual air in the left atrium from entering the cerebral circulation. Supplemental 100% oxygen should be administer and general symptomatic support should be provided.^[76]

The Role of Endoscopic Ultrasound/Gastroenterologist in Lung Cancer Diagnosis and Management

Role in Primary Tumor (T) Evaluation and Mediastinal Invasion (T4)

Combined Endoscopic Ultrasound-Fine Needle Aspiration and Endobronchial Ultrasound-Transbronchial Needle Aspiration for Mediastinal Evaluation

• In patients with high suspicion of N2, N3 involvement, either by discrete mediastinal LN enlargement or PET uptake (and no distant metastases), EBUS-FNA, EUS-FNA, or combined EBUS/EUS-FNA is recommended over surgical staging as a mostly suitable diagnostic modality (Grade 1B)
• In patients with an intermediate suspicion of N2, N3 involvement, i.e. a radiographically normal mediastinum (by CT and PET) and a central tumor or N1 LN enlargement (and no distant metastases), EBUS-TBNA, EUS-FNA, or combined EBUS/EUS-FNA is suggested over surgical staging as a mostly suitable diagnostic modality (Grade 2B).^[103]

Future Perspectives

Guiding Principles of Systemic Therapy in Metastatic Non-small Cell Lung Cancer

1. Pathology work-up:
   
   Tumor profiling is a must for all NSCLC to determine
   
   
   1. Histology subtype: especially to differentiate squamous cell from non-squamous cell for strong reasons including:
      1. Avoiding potentially harmful treatment for squamous cell lung cancer such as bevacizumab or less beneficial treatment for this disease (i.e., pemetrexed)
      2. Performing molecular profiling for non-squamous non-small cell lung carcinoma.
   2. Obtaining EGFR, ALK, and ROS1 testing in all non-squamous cell carcinoma, preferably using next generation sequencing
   3. PD-L1 testing in all NSCLC subtypes at diagnosis.
2. Management of EGFR sensitizing mutation tumors:
   • TKIs should be used upfront whenever possible. If systemic chemotherapy was initiated, a switch to TKI should be done as soon as possible
   • TKIs showed better response rate (RR), progression-free survival (PFS), and quality of life compared to chemotherapy and all efforts should be made for patients to receive TKI irrespective of performance status.
3. Management of EGFR resistant tumors:
   • Tumors with secondary resistance should be tested for T790 mutation and if positive osimertinib should be used
   • If T790 mutation is not detected, switch to platinum doublet chemotherapy. Local therapy should be considered for single or oligometastatic disease progression.
4. ALK fusion positive tumor:
   • The patient should receive crizotinib as early as possible. if progressed, ceritinib and alectinib should be used in second line. Chemotherapy should be reserved for third line.
5. ROS1 positive tumor patients should be treated with crizotinib as early as possible. Chemotherapy should be used for subsequent lines
6. Management of WT tumors (no EGFR, ALK, or ROS1 mutation)
   1. PD-L1 tumor proportion score >50%
      
      Pembrolizumab is preferred treatment option over chemotherapy.
   2. PD-L1 TPS < 50% - chemotherapy doublet is preferred option.
7. EGFR/ALK unknown NSCLC:
   
   All efforts should be made to get the test done including ctDNA. If not possible, it should be treated like WT. TKI, erlotinib can be considered for second or third line as third of our patients may have mutations, which is much more common than Western population.
8. Immunotherapy:
   • Checkpoint inhibitors are approved in NSCLC as follows:
     1. Pembrolizumab first line for all NSCLC subtypes with PD-L1 TPS >50% and for second line for positive PD-L1 tumors
     2. nivolumab: approved for 2^nd line treatment of all nsclc irrespective of histology or pd-l1 status
     3. Atezolizumab: approved for second line treatment of all NSCLC irrespective of histology and PD-L1 status.
   • Immune therapy should be used in patients with good PS 0-1 and monitored closely for immune therapy-related adverse events which are less common than chemotherapy and different pattern, but they can be serious and life-threatening
   • Role of immunotherapy in the EGFR and ALK sensitizing tumors is not known but should not be used before TKI and systemic chemotherapy combination at present time.
9. Selection of chemotherapy regimen:
   1. Non squamous NSCLC
      • Preferred chemotherapy regimen is platinum doublet with or without bevacizumab
      • Pemetrexed is very active and preferred agent due to its efficacy and toxicity profile.
   2. Squamous cell carcinoma
      • Bevacizumab should be avoided due to risk of fatal pulmonary hemorrhage
      • Pemetrexed also is not recommended due to being less efficient than Gemcitabine
      • Gemcitabine and texans combination are reasonable choices.
10. Managing patients with poor performance status:
    1. PS2 is the most difficult to decide about as it was not included in most studies and should be individualized. Using single agent may be reasonable
    2. PS3–4 systemic therapy is not recommended usually except for TKI for patient with sensitizing driver mutation.
11. Patient involvement in setting the goals of care:
    
    It is very critical to prioritize the goal of care clearly and involve the patients and their families
12. Finally, having multidisciplinary team is more important than ever due to the complex and multiple available treatment options that can be offered to the patients and require specific workup and close monitoring.

Immunotherapy of Non-small Cell Lung Cancer

Immunotherapy in The First-line Setting

Immunotherapy in Pretreated Patients with Advanced Non-small Cell Lung Cancer (Following Platinum-based Chemotherapy)

Role of Tumor Programmed Death-ligand 1 Expression as a Biomarker

Management of Immune-related Adverse Events (irAEs)

General Approach to Management of Immune-related Adverse Events

• For patients with Grade 2 (moderate) irAEs, treatment with the checkpoint inhibitor should be withheld and should not be resumed until symptoms resolve to Grade 1 or less. Corticosteroids (methylprednisolone 0.5–1 mg/kg/day or equivalent) should be commenced if symptoms do not resolve within a week
• For patients developing Grade 3-4 (severe or life-threatening) irAEs, treatment with the checkpoint inhibitor should be permanently discontinued. High-dose corticosteroids (methylprednisolone 1–4 mg/kg/day or equivalent) should be administered
• When corticosteroids are used, then this should be tapered gradually over 1 month upon improvement of symptoms as rapid tapering may lead to worsening or recurrence of the irAE
• For patients with irAEs that do not improve with corticosteroid use, administration of other systemic immunosuppressant should be considered.

Specific Immune-related Adverse Events and Its Management

• Grade 3 or 4 pneumonitis: checkpoint inhibitors must be permanently discontinued, and corticosteroids should be initiated at a dose of 2–4 mg/kg/day methylprednisolone equivalents
• Grade 2 pneumonitis: Checkpoint inhibitors should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, checkpoint inhibitors may be resumed after tapering of steroids. If worsening or no improvement occurs, then manage as per guidelines for Grade 3–4 pneumonitis.

• Grade 4 diarrhea or colitis: Permanently discontinue checkpoint inhibitors and initiate corticosteroids at a dose of 1–2 mg/kg/day methylprednisolone equivalents
• Grade 3 diarrhea or colitis: Withhold checkpoint inhibitors and initiate corticosteroids (1–2 mg/kg/day methylprednisolone equivalents)
• Grade 2 diarrhea or colitis: Withhold checkpoint inhibitors and initiate corticosteroids (0.5–1 mg/kg/day methylprednisolone equivalents)
• In severe cases where symptoms do not improve with oral corticosteroids, hospitalization for intravenous corticosteroids, hydration, and electrolyte management is required. If intravenous corticosteroids (up to 2 mg/kg methylprednisolone twice a day) do not lead to symptom resolution, infliximab at a dose of 5 mg/kg, once every 2 weeks should be considered.^[117]

• Hypophysitis: Administer corticosteroids for Grade 2 or higher. Withhold checkpoint inhibitors for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis
• Adrenal insufficiency: Administer corticosteroids for Grade 3 or 4. Withhold checkpoint inhibitors for Grade 2 and permanently discontinue for Grade 3 or 4
• Hypothyroidism: Hormone-replacement therapy
• Hyperthyroidism: Medical management
• Type I diabetes: Commence on insulin. Withhold checkpoint inhibitors for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

Initial Treatment of Epidermal Growth Factor Receptor Mutation Non-small Cell Lung Cancer

Treatment Beyond Progression in Driver Mutant Lung Cancer

Conclusions

Management of Tyrosine Kinase Inhibitors Side Effects

Table 5: Management of dermatological toxicities Click here to view

Table 6: Management of diarrhea Click here to view

• It is a very rare but potentially fatal toxicity. Prompt evaluation of new or worsening pulmonary symptoms is requested to detect early radiographic signs of pulmonary toxicity.
• If toxicity confirmed, TKI should be discontinued and treat the patient appropriately
• If toxicity confirmed, TKI should be discontinued and treat the patient appropriately
• Start empiric treatment with corticosteroids till the toxicity ruled out as prednisolone 1 mg/kg daily for 2–4 weeks. Then, tapper the dose to minimal.

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