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non-small cell carcinoma of the lung (NSCLC)

Any carcinoma of the lung, except small cell carcinoma. Often grouped together, because collectively they behave & are treated differently than small cell carcinoma. Classification: 1) lung squamous carcinoma (occurs in predominantly in smokers) 2) lung adenocarcinoma (most common, occurs in never smokers) 3) lung adenosquamous carcinoma 4) lung mucoepidermoid carcinoma 5) lung large cell carcinoma 6) lung adenoid cystic carcinoma Etiology: - tobacco smoke - 15% of 15% of patients are non-smokers or have a minimal smoking history [10] - see lung carcinoma Epidemiology: - 85% of lung cancers [45] - 15% of patients with NSCLC are never-smokers [50] - incidence of NSCLC among never-smokers increased from 8% in 1990 to 15% in 2013 [50] - increased incidence largely, if not exclusively, due to increased incidence of lung adenocarcinoma in never-smokers Genetics: 1) epidermal growth factor receptor (EGFR)-activating mutations in some patients [4] (10%) - mutation (EGFR T790M) confers resistance to tyrosine kinase inhibitors [27] 2) abnormalities in the anaplastic lymphoma kinase (ALK) protein in some patients [4] - inv(2)(p21:q23) resulting in EML4-ALK fusion gene [14] 3) HER2 overexpression, amplification, & point mutations (esp exon 20) [73] 4) gene for LRP1B prefentially inactivated 5) defects in NAT6, ZMYND10 found in NSCLC cell lines 6) amplification of WHSC1L1, PRKCI 7) downregulation of INTS6 (frequent) 8) mutations in oncogenes c-myc &c-raf & in tumor suppressor genes Rb gene & p53 gene 9) other implicated genes NBPF3, TUSC1, DMTF1, INTS6, TRY6, VTCN1 Clinical manifestations: 1) see lung carcinoma 2) Horner's syndrome 3) shoulder pain & scapula pain, followed by cough & hemoptysis (case report) [27] 4) bone pain & neurologivc signs with metastases Laboratory: 1) serum chemistries a) comprehensive metabolic panel - serum sodium: elevated with SIADH - serum calcium: elevated with hypercalcemia of malignancy - serum ALT - serum ALP 2) complete blood count (see lung cancer) 3) microarray or PCR for expression of 5 gene set (DUSP6, MMD, STAT1, ERBB3, LCK) predicts relapse & survival [7] 4) EGFR gene mutation [27, NICE] - indicated for lung adenocarcinoma [10] - may not be indicated for lung squamous cell carcinoma [10] - Guardant360 CDx is a companion (to amivantamab) diagnostic test for NSCLC with EGFR exon 20 insertion mutation(s) [81] 5) ALK gene rearrangement - chromosomal inversion inv(2)(p21:q23) [14] 6) ROS1 gene rearrangement 7) RET fusion gene 8) HER2 (ERBB2) overexpression, amplification, & point mutations [73] - HER2 expression by immunohistochemistry commonly used - fluorescence in situ hybridization (FISH) used experimentally 9) VeriStrat testing offered for NSCLC without EGFR mutation 10) PDL-1 expression [10,88] 11) MET exon 14 skipping, NTRK1/2/3 fusions, RET rearrangements [8] 12) BRAF p.V600E mutations [88] 13) KRAS G12C mutation - H-ras, K-ras, & N-ras occur largely in adenocarcinoma (30%) [88] 14) sputum cytology: - centrally located endobronchial squamous cell carcinomas may exfoliate malignant cells into sputum * also see ARUP consult [69] Special laboratory: 1) lymph node biopsy if lymphadenopathy - needle aspiration rather than biopsy of lymph node diagnostic according to ref [10] 2) bronchoscopy 3) thoracentesis with indwelling pleural catheter if pleural effusion - pleurodesis as indicated 4) mediastinoscopy if indicated by imaging studies (no metastases) - endobronchial ultrasound-guided mediastinal lymph node biopsy [10,17] - needle aspiration rather than biopsy of lymph node diagnostic according to ref [10] 5) pulmonary function testing - including FEV1 & DLCO - prediction of postoperative pulmonary reserve [10] - many patients with lung cancer have COPD [10] Radiology: - see lung carcinoma - may present as pneumonia (case report) [27] - chest X-ray - computed tomography (CT) of the chest - MRI of brain to rule out brain metastases [45] - also surgical candidates & candidates for chemoradiation [10] - MRI of spinal cord if spinal cord compression is suspected [88] - bone scan (scintigraphy) if bone metastases suspected [88] - positron emission tomographic (PET) for staging [45] Complications: - intractable cancer pain associated with metastatic cancer [27] - radiation therapy relieves pain [10] - paraneoplastic syndromes - hypercalcemia of malignancy due to PTH-related protein - hypertrophic pulmonary osteoarthropathy - inflammatory myopathy - thoracic radiation therapy for pulmonary airway obstruction, superior vena cava syndrome, or spinal cord metastases (after surgical decompression) [10] - thoracic radiation therapy palliative in 90% of patients [41] - unsatisfactory antibody response to Omicron variant of Covid-19 after Covid-19 vaccine booster in ~25% of patients with NSCLC [94] - unclear if this is bivalent vaccine or univalent native strain booster Differential diagnosis: - pneumonia - tuberculosis - carcinoid - granuloma - abscess - hamartoma - small cell lung carcinoma - metastatic cancer - superior vena cava syndrome [88] Staging: - see staging of lung cancer Management: - palliative care referral for advanced-stage NSCLC [35,37,38] - virtual palliative care as effective as in person palliative care for improving quality of life in patients with advanced NSCLC [100] - concurrent chemotherapy & palliative care can improve quality of life & increase life expectancy 20% [10,35] - Patient selection: - neither age nor comorbidities predicts response to therapy, progression-free survival, or disease-specific survival [8] - comorbidities do predict shorter overall survival [8] - performance status should be considered while making shared palliative care treatment decisions for advanced NSCLC [77] - smoking cessation [10] - continued smoking increases risk of complications associated with treatment & reduces potential benefit of treatment - continued smoking increases risk of secondary cancers in patients with lung cancer === Stages 1, 2 & some 3a === 1) stages 1 & 2 -> surgical resection within 12 weeks [79] (lobectomy) - pre-operative pulmonary function testing to assess pulmonary reserve [10] - sublobar resection (segmentectomy) may be appropriate for some patients [87] 2) stage 1A may be treated with surgery alone - sublobar resection is standard of care for confirmed T1aN0 NSCLC [93] 3) stage 1B & 2: surgery plus adjuvant chemotherapy* 4) stage 3a with minimal N2 involvement a) surgical resection b) complete mediastinal lymph node dissection c) consideration of adjuvant chemotherapy* 5) adjuvant cispatin-based chemotherapy 4 cycles is standard [88] - neoadjuvant cispatin-based chemotherapy plus nivolumab (3 cycles) improves outcomes [86,98] - adjuvant cispatin-based chemotherapy plus nivolumab as well [98] 6) lobectomy associated with better outcomes than sublobar resection in elderly patients [26] - overall survival for sublobar resection (segmentectomy) noninferior to lobectomy [87] 7) thoracoscopic lobectomy with similar survival, shorter hospital stays, & fewer complications than open thoracotomy [25] 8) stereotactic ablative radiotherapy - may be an option for elderly patients with comorbidities [26,51] - peripherally located tumors (in 3 fractions) with less risk than centrally located tumors (in 4-5 fractions) [51] - small tumors, conventional radiation used for large tumors [10] * cispatin-based chemotherapy, 4-6 cycles without radiation for stage 2 & 3 tumors [10] * adjuvant platinum-based doublet chemotherapy 4 cycles after surgical resection improves 5 year survival for stage II NSCLC 51% vs 43% for surgery alone [45] * 1st line nivolumab + ipilimumab for patients with high tumor mutational burden, irrespective of PD-L1 expression [62] * 1st line pembrolizumab (Keytruda) effective even with minimal PD-L1 expression [64] postoperative radiation therapy for resected localized lung cancer with positive surgical margins [10] radiation does not benefit patients with negative surgical margins [10] proton therapy as effective as conventional radiotherapy but no less toxic [34] early NSCLC located too close to vital organs for conventional treatment may be amenable to proton beam therapy [46] === Stage 3a, Stage 3b === Stage 3a & some T3 tumors 1) bulky mediastinal or hilar lymph node involvement generally considered unresectable & treated with chemoradiation [10] - unresectable tumors treated with chemoradiation + durvalumab for 1 year if chemoradiation results in a partial or complete response [88] 2) tumors with chest wall invasion (T3) a) enblock resection of the tumor with involved chest wall b) consideration of postoperative radiation therapy 3) superior sulcus (Pancoast) (T3) tumors a) preoperative radiation therapy (3000-4500 cGy) b) enblock resection of the involved lung & chest wall c) consideration of intraoperative brachytherapy d) consideration of postoperative radiation therapy 4) proximal airway involvement (< 2 cm for carina) without mediastinal nodes a) sleeve resection preserving distal normal lung b) pneumonectomy (if sleeve resection not feasible) Stage 3a, Stage 3b, & clinically evident N2 (with tolerable radiation port) 1) curative radiation therapy plus chemotherapy 2) radiation therapy alone if performance status is poor 3) stage 3a with N2 disease - combined radiation therapy & chemotherapy* without surgery 4) stage 3a with advanced N2 disease - consider neoadjuvant chemotherapy plus surgical resection Stage 3b with carinal invasion (T4), but without N2 involvement - consider pneumonectomy with tracheal sleeve resection with direct reanastomosis to contralateral mainstem bronchus Stage 3 & more advanced Stage 3b 1) radiation therapy to symptomatic local sites 2) patients with pleural effusion or pericardial effusion do not benefit from radiation [15] 3) chemotherapy for patients with good performance status 4) large malignant pleural effusions -> chest tube drainage 5) isolated brain or adrenal metastases - consider resection of primary tumor & metastasis === Metastatic disease (including malignant pleural effusion) === - palliative chemotherapy vs palliative care - carboplatin + permetrexed + pembrolizumab (Keytruda) [10] - 1st line pembrolizumab (Keytruda) effective even with minimal PD-L1 expression [64] - if PD-L1 expression 1-49%, cisplatin-based chemotherapy + pembrolizumab [88] - if PD-L1 expression > 50%, pembrolizumab alone [88] - 26 month median survival, 32% 5-year survival pembrolizumab every 3 weeks for 35 cycles (about 2 years) [83] - nivolumab (Opdivo) for metastatic disease with progression on or after platinum-based chemotherapy [28] - 1st line nivolumab + ipilimumab for patients with high tumor mutational burden, irrespective of PD-L1 expression [62] - tislelizumab monotherapy in previously treated advanced NSCLC may extend survival 6 months vs docetaxel regardless of PD-L1 expression [78] - radiation therapy with curative potential - selected patients with a single site of metastasis can be treated with surgical resection of the metastatic lesion & aggressive treatment of the primary NSCLC [10] - adding atezolizumab (Tecentriq) to platinum-based chemotherapy slows tumor progression, but does not improve survival [63] brain metastasis 1) glucocorticoids & whole brain radiation therapy for multiple brain metastases 2) surgery, sterotactic radiosurgery for single metastasis if feasible radiation therapy relieves pain from metastatic disease [10] === Chemotherapy for non small-cell lung cancer [2] === 1) regimens a) cisplatin + gemcitabine (squamous cell carcinoma) [10] b) cisplatin + pemetrexed (adenocarcinoma) [10] c) cisplatin + paclitaxel (histologic type uncertain) [10] d) cisplatin + docetaxel (histologic type uncertain) [10] e) cisplatin + etoposide f) cisplatin + irinotecan g) carboplatin + placitaxel [36] - addition of bevacizumab of no benefit [39] h) carboplatin + gemcitabine every 21 days for 4 cycles followed by docetaxel every 21 days for 6 cycles [9] i) recommended duration of adjuvant chemotherapy is 1 year [96] 2) cisplatin + irinotecan may result in best survival 3) adjuvant chemotherapy has become standard of treatment for stage 1B to stage 3 [4,5,10,19] a) cisplatin plus etoposide or vinorelbine b) cisplatin plus vinorelbine [5] c) platinum-based chemotherapy + bevacizumab [10] d) durvalumab after chemoradiotherapy [54] - extends progression-free survival (23.2 vs 14.6 months) 4) immunotherapy vs platinum-based chemotherapy [64] - 1st line nivolumab + ipilimumab or pembrolizumab (Keytruda) may be effective even with minimal PD-L1 expression [62,64] - immunotherapy (PD-L1 inhibitor) may result in hyper-progression of NSCLC in 9-14% of patients [55] - communities of intestinal bacteria influence response to checkpoint inhibitors in patients with non-small cell lung carcinoma [99] 5) advanced disease: pemetrexed (Alimta, Rolazar, Tifolar) 6) maintenance therapy with pemetrexed after induction therapy - standard of care [23] - pemetrexed 500 mg/m2 IV on day 1 of 21-day cycles - only switch-maintenance therapy with pemetrexed & erlotinib FDA-approved [45] - maintenance therapy with pemetrexed not an option for squamous cell carcinoma of lung [45] 7) patients with activating EGFR gene mutation - erlotinib or osimertinib (Tagrisso) [56] - osimertinib (Tagrisso) may be superior to erlotinib [56] - gefitinib NOT recommended (NICE) [NGC] - not recommended in early stage NSCLC (assumes complete resection) - standard chemotherapy superior to EGFR tyrosine kinase inhibitor in patients with wild-type EGFR [24] - in patients with EGFR gene mutation, stopping erlotinib can worsen disease even if cancer has progressed despite erlotinib therapy [27] - a large portion of the overall tumor burden may remain erlotinib sensitive [27] - erlotinib & osimertinib (Tagrisso) cross blood brain barrier [61] - amivantamab (Rybrevant) FDA-approved for NSCLC with EGFR exon 20 insertion mutation(s) [81] 8) ALK rene rearrangement - alectinib is MKSAP19-recommended agent [10] - alectinib superior to crizotinib with lower toxicity in untreated ALK-positive NSCLC [52] - crizotinib no longer recommended; not recommended (NICE) - crizotinib & alectinib cross blood brain barrier [61] - lorlatinib for ALK-Positive NSCLC - lorlatinib with longer progression-free survival & higher frequency of intracranial response than crizotinib [75] - ensartinib with superior efficacy to crizotinib in both systemic & intracranial disease [85] 9) ROS1 gene rearrangement - alectinib is MKSAP19-recommended agent [10] - crizotinib no longer recommended 10) RET gene fusion positive locally advanced or metastatic NSCLC - selpercatinib is FDA-approved 11) BRAF V600E mutation positive metastatic NSCLC - dabrafenib + trametinib (previously untreated) [68] 12) HER2 aberrations - unlike breast cancer, trastuzumab ineffective as a monotherapy for HER2-overexpressing NSCLC [73] - HER2 point mutations susceptible to ado-trastuzumab emtansine (Kadcyla) [73] - fam-trastuzumab deruxtecan-nxki FDA-approved for unresectable or metastatic NSCLS with activating HER2 mutation refractory to prior chemotherapy [95] 13) patients with good performance status who have failed one chemotherapy regimen: - single agent chemotherapy - docetaxel, erlotinib, or pemetrexed [10] - patients who have failed platininum-based chemotherapy, erlotinib or crizotinib - ramucirumab + docetaxel [43] - nivolumab (FDA-approved regardless of PD-L1 expression) [44] - pembrolizumab for patients with metastatic NSCLC on or after platinum- containing chemotherapy with PD-L1 expression on at least 50% of tumor cells [42,59] - 1st line pembrolizumab effective even with minimal PD-L1 expression [64] - atezolizumab 2-year survival is 24% vs 12% for chemotherapy [44,97] 14) durvalumab (Imfinzi) for stage 3 NSCLC without disease progression after concurrent chemoradiation (median overall survival is 47.5 months) [80] - presence of activating EGFR gene mutation is an exception [80] 15) anti-PDCD1 &/or anti-CD274 antibody may induce tumor regression & prolonged stabilization in patients with advanced non-small-cell lung cancer, cutaneous melanoma, or renal cell carcinoma [15] 16) immune checkpoint inhibitors nivolumab, pembrolizumab, or atezolizumab 1st line for NSCLC with PD-L1 expression on at least 50% of tumor cells [42,49] - pembrolizumab may be preferred agent [49,59] - EGFR/ALK/ROS1 negative [49] - improves quality of life relative to chemotherapy [47] - survival gains from immune checkpoint inhibitors may not be generalizable to the elderly [92] - communities of intestinal bacteria influence response to checkpoint inhibitors in patients with non-small cell lung carcinoma [99] 17) nivolumab or atezolizumab may be used if PD-L1 expression is negative or unknown [49] 18) atezolizumab if patient unable to tolerate platinum-based chemotherapy [89] 19) neoadjuvant chemotherapy with nivolumab 4 weeks before surgery may reduce tumor burden [60] 20) investigational agents for NSCLC - sotorasib for NSCLC with KRAS p.G12C mutation 21) metformin not indicated in the absence of diabetes mellitus [82] Avoid: epoetin-alpha Do NOT treat patients with poor performance status with chemotherapy, regardless of age [10] Treat patients with poor performance status & advanced NSCLC without a driver mutation with supportive care === Radiation therapy === 1) does not improve survival & may be harmful to patients with early stage NSCLC [16] 2) does not improve survival in locally advanced disease [3] 3) hypofractionated image-guided radiation therapy (60 Gy in 15 fractions) is not superior to conventionally fractionated radiotherapy (60 Gy in 30 fractions) for patients with stage II/III NSCLC with poor performance statys ineligible for concurrent chemoradiotherapy [84] 4) benefits symptomatic unresectable patients only [3] 5) post-operative radiation therapy improves median disease-free survival from 22 months to 31 months, but does not substantially improve overall survival [74] 6) radiation doses of 15 Gy to > 10% of left anterior descending coronary artery (LAD) increases risk for major adverse cardiac events & mortality [76] 7) treatment of choice for superior vena cava syndrome [41] 8) passive scattering proton therapy (PSPT) or intensity-modulated (photon) radiotherapy (IMRT), with concurrent chemotherapy, for inoperable NSCLC - improvements in either - no significant difference in radiation pneumonitis === Endobronchial therapy [10] === 1) photodynamic bronchoscopy 2) laser bronchoscopy 3) bronchoscopic brachytherapy 5) bronchial stent placement === Prognosis === 1) 5-year survival by stage a) operable - stage 1A: 77-92% - stage 1B: 68% - stage 2A: 60% - stage 2B: 53% - stage 3A: 36% -------------------------------- b) inoperable - stage 3B: 26% - stage 3C: 13% - stage 4: < 10% [62] 2) mean survival: 10-12 months for patients for non-resectable disease depending on chemotherapy [9]

Related

brachytherapy clinical trials, non-small-cell lung cancer Pancoast tumor (superior pulmonary sulcus tumor) staging of lung cancer

Specific

adenocarcinoma of the lung adenoid cystic carcinoma, lung adenosquamous carcinoma, lung large cell carcinoma, lung mucoepidermoid carcinoma, lung nonsquamous non-small cell lung cancer squamous cell carcinoma, lung

General

carcinoma of the lung

References

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