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Summary of recommendations Incidence/epidemiology • Screening with LDCT reduces lung cancer-related mortality [I, A]. It is notyet ready for large-scale implementation, mainly because the lung cancer mor- tality reductionrate lacks definiteproof of a second study result, and partly becauseof remaining questions regarding definition of the at-riskpopulation, timing, interval and method of CT (especially 2D versus 3D evaluation), how to handle(false-) positive findingsand especially cost-effectiveness, notably in relation to smoking cessation[I, A]. • LDCT screening can be carried out outside a clinical trial provided it is offered within a dedicated programme with quality control, in a centre with ex- perience in CT screening, a large volumeof thoracic oncologyactivity and multidisciplinary management of suspicious findings [I, B]. Candidates are cur-rentor former heavy smokers (2: 30 pack-years or ::: 15 years since smoking cessation) aged 55–74 years, who are well informed about potential benefits and risks. Individuals offered LDCT screeningshould be referredto a smoking cessation programme. • LDCT screening should not be offered on an ad hoc individual basis, but patientsrequesting screening shouldbe referred to a dedicated programme, asrecommended above [V, B]. • Other screening methods, such as chest X-ray, sputum analysis or biomarkers are not recommended for clinical use [I, C]. Diagnosis • In patients with clinical stagesI–III lesions, a pretreatment pathological diagnosisis recommended prior to anycurative treatment. • Bronchoscopy is the recommended test to obtain a pathological diagnosisofcentrally located tumours in stages I–III withbiopsy of any visible lesion[III, A]. • The pathological classification NOS should be used only in cases where it is impossible to obtain enough tissue for further classification, orwhen stepsto further classifythe tumour are inconclusive [V, A]. • An exception to the requirement for a pretreatment diagnosis can be made if an experienced multidisciplinary group decidesthat the risksof obtaining pathology may beunacceptable in a patient in whom the likelihood of malignancy is high based onclinical and imaging findings [III, B]. • A pretreatment pathological diagnosis is strongly recommended for all patientsbefore SABR, unlessa multidisciplinary tumourboard is of the opinion that the risk-benefit ratioof the procedure is unacceptable. In such a situation, the predicted likelihood of malignancy shouldpreferably be at least 85%, based upon accepted criteria [III,B] [ 25]. • The descriptive element of the recent WHO classification of adenocarcinoma subtypes should be used to describe bronchoscopic and CT-guided biop- sies whenever possible [III, A]. • The revisedadenocarcinoma classification may identify patientsubtypes for whom an anatomical sublobar resection, ratherthan lobectomy, would besufficient [III, A]. • FDG-PET may contribute for the selection of patients for anatomical sublobar resections as low SUVmaxvaluesofperipheral tumours indicate lack of me- diastinal metastases [III, A]. This diagnosis may be made intra-operatively by video-assisted thoracoscopic biopsy and frozensection analysis. • In isolatedcases a diagnostic anatomical sublobarresection may be acceptable.Solitary pulmonary nodule • The diagnostic approach to non-calcified pulmonary nodules should be based on existingstandard guidelines [III, A], althoughnew evidence on nodulemanagement is emerging. • Likelihood of malignancy based upon risk calculation methodsused in CT screening studiesshould be used only to guide the clinical assessment of pul- monarynodules detected in the wider population [V, C]. Staging and risk assessment • In non-metastatic NSCLC, detailed locoregional stagingaccording to the 8th TNM staging system and the cardiopulmonary fitness of thepatient deter- mine the choice of treatment [III, A]. Locoregional staging • For part-solid tumours, the size of the invasive component should be used to assign the T category for clinical staging [III, A] • Subsolid lesions need dedicated radiological expertise for evaluating the lung lesioncomposition [V, A]. • If two lung lesions fulfil thecriteria for two primaries these should be evaluated and treated accordingly [III, A]. • For patients with abnormal mediastinal and/or hilar lymph nodes at CT and/or PET imaging, endosonography is recommended over surgical staging [I, A]. • The preferred first technique for pathological confirmation of suspect nodes is needle aspiration under EBUS and/or EUS guidance [I, A]. • If EBUS and/orEUS does not reveal nodal involvement in a situationof high clinicalsuspicion, mediastinoscopy is indicated [I, A]. • Mediastinoscopy is the test with the highestnegative predictive value to rule out mediastinal lymph node disease[I, A]. • Screening for brain metastases by MRI might be useful in patients considered for curative therapy [III, B]. Pretreatment risk assessment • In non-metastatic NSCLC, the cardiopulmonary fitness of the patient will determine the choice of treatment [III, A]. • The risk of postoperative morbidity and mortality can be estimated using risk-specific models, although none have been validated in a cancer population [III, B]. • Before considering surgical resection, precise assessment of cardiac and pulmonary function is necessary to estimate risk of operative morbidity [III, A]. • For cardiac assessment, use of recalibrated RCRI is recommended [III, A]. • Formal lung function testing should be undertaken to estimate postoperative lung function. For patients with FEV1 and DLCO values > 80% of their pre- dicted pulmonary function tests and no other major comorbidities, no further investigations are advised before surgical resection [III, A]. For others, exer- cisetesting and split lung functionare recommended. In these patients, VO2max can be used to measure exercisecapacity and predictpostoperative complications [III, A]. • Comorbidities should be evaluated and optimised before surgery [III, A]. • In patientswith limited pulmonary function due to emphysema, a lung volumereduction effect may be observedby resection of the lung cancer within emphysematous lung tissue [III, B]. Treatment of early stages (stages I and II) Surgery • Surgery should be offered toall patientswith stage I andII NSCLC asthe preferred treatmentto allwhoare willing toaccept procedure-related risks[III, A]. • For patients with a non-centrallylocated resectable tumour and absence of nodal metastasis on both CT and PET images, surgical resection is recom- mended [I, A]. • Anatomical resectionis preferred overwedge resection [I,A]. • Anatomicalsegmentectomy is generally considered acceptable for pure GGOlesions oradenocarcinomas insitu orwith minimal invasion [III,B]. • Lobectomy isstill considered thestandard surgical treatmentof tumours 2: 2 cmin size thathave a solidappearance onCT [II, B]. • Lymph nodedissection shouldconform to IASLCspecifications forstaging [III, A]. • Either open thoracotomy or VATSaccess can be carried out asappropriate to the expertiseof the surgeon [III, A]. • VATS shouldbe the approachof choice instage I tumours[V, C]. • Forpatients with multifocal lung cancer, completeresection is recommended whenever possible. All patients with multifocal lung cancer should be dis- cussed in a multidisciplinary tumourboard [III, B]. Systemic therapy • Adjuvant ChT should be offered to patients with resected stage II and III NSCLC[I, A] and can be considered in patients with resected stageIB disease and a primary tumour > 4 cm [II, B]. Pre-existing comorbidity, time from surgery and postoperative recovery need to be taken into account in this deci- sion taken in a multidisciplinarytumour board [V, A]. • For adjuvant ChT,a two-drug combination with cisplatin is preferable [I, A]. Inrandomised studies, the attempted cumulative cisplatin dose was up to 300mg/m2, delivered inthree to four cycles. The most frequentlystudied regimen is cisplatin–vinorelbine. • At the present time,the choice of adjuvant therapyshould not be guided by molecular analyses, e.g. ERCC1 mutation testing[IV, B]. • In the current state of knowledge, targeted agents shouldnot be used in the adjuvant setting[II, A]. • In viewof the equivalence of neoadjuvant and adjuvantChT for OS,the consistent resultsand broad evidencebase support adjuvantChT as thetiming of choice[II, C]. • (Neo)adjuvant anti-PD(L)-1 checkpoint inhibitors are currently being evaluated in addition to current standard of care. Primary radiotherapy • The non-surgical treatment of choice for stage I NSCLC is SABR. The dose should be to a biologically equivalent tumour dose of 2: 100 Gy, prescribed to the encompassing isodose [III, A]. • SABR forearly-stage peripherallung tumours isassociated withlow toxicity inpatients with COPDand the elderly[III, A]. • Salvagesurgery, if feasible,may be offered to patientshaving complications post-SABR [V,B]. • Salvage surgery, if feasible, may be offered,using the same indications as for primarysurgery in progressive disease after SABR,but surgery may be more difficult with higheroperative risk [V, B]. • For medicallyinoperable patientswith tumours witha size > 5 cm and/ormoderately centrallocation, radical RTusing moreconventional or accelerated schedules is recommended [III, A]. Radiofrequency ablation • Stage I NSCLCpatients with strong contraindications for surgery and/or SABR may be treatedwith RFA [V, C]. Postoperative radiotherapy • PORT incompletely resected early-stage NSCLC is notrecommended [I,A]. • In caseofR1 resection (positive resection margin, chestwall), PORT should be considered [IV,B]. • Even if such patients were not included in RCTs, adjuvant ChT should be considered in patients with R1 resection of stage IB disease and a primary tu- mour> 4 cm,stage II and III [V, A]. • Incase both ChT and RTare administered post-surgery, RTshould be administered after ChT[V, C]. Treatment of locally advanced stage (stage III) • Allpatients planned for definitive stageIII NSCLC treatment should undergo a diagnostic contrast-enhanced CT scan of the chest and upperabdomen followed by a PET or a combined PET-CT with a CT technique with adequately high resolution for initial staging purposes [I, A] in order to rule out detect-able extrathoracic, extracranial metastasis, and to assess potential mediastinal lymph node involvement, ideallywithin 4 weeks before the start of treat-ment [III, B]. Single PET-positive distant lesions need pathological confirmation [V, B]. • For patientswith operable N2 disease, pathological staging of the mediastinum is advised [III,C]. • All patients planned for curative stage III NSCLC treatment shouldreceive brain imaging for initial staging [III, B]. Contrast-enhanced brain MRI is the preferred method for staging of the brain in stage III disease [III, A]. If it is not possible to perform MRI, dedicated contrast-enhanced brain CT scan is advised [III, B]. Resectable LA-NSCLC • If, despiteadequate mediastinal staging procedures, N2 disease is only documentedintra-operatively, surgery should be followed by adjuvant ChT [I, A]. Incase of completeresection, addition of PORT is not routinelyrecommended, but may be an option following individual risk assessment [V, C]. • If single stationN2 disease can be demonstrated by preoperative pathological nodal analysis, resectionfollowed by adjuvantChT, induction ChT fol-lowed by surgery or induction CRT followed by surgery are options. If induction ChT alone is given preoperatively, PORT is not standard treatment, but may be an optionbased on criticalevaluation of locoregional relapse risks [IV, C]. • In multistation N2 orN3, concurrent definitive CRT is preferred[I, A]. Anexperienced multidisciplinary team is ofparamount importance in any complex multimodality treatment strategy decision, includingthe role of surgery in thesecases [IV, C]. • In potentially resectable superior sulcus tumours, concurrent CRT induction followed by definitive surgery is the treatment of choice [III, A]. The same strategy may be applied for potentially resectable T3 or T4 central tumours in highly selected cases and experienced centres [III, B]. In both situations, surgery should be carried out within 4 weeks after the end of RT [III, B]. Systemic therapy • For curative-intent management, patients should be abletoundergo platinum-based ChT (preferably cisplatin) [I, A]. • (Neo)adjuvant antiPD(L)-1 checkpoint inhibitorsare currently beingevaluated inaddition to currentstandard of care. • Checkpoints are also being evaluated after CRT as consolidation therapy. Unresectable LA-NSCLC • Concurrent CRT is the treatment of choice in patients evaluated as unresectable in stage IIIA and IIIB [I, A]. If concurrent CRT is not possible—for any reason—sequential ChT followedby definitive RT represents a valid and effective alternative [I, A]. • There isno role forprophylactic cranialirradiation in stageIII NSCLC [II,A]. • In the absence of contraindications, the optimal ChT to be combined with radiation in stage III NSCLC should be based on cisplatin. There are no firm conclusions supporting single-agent carboplatin as a radiationsensitiser [I, A]. • Most comparative studies of concurrent CRT versus sequentialadministration were using cisplatin þ etoposide or cisplatin þ vinca alkaloid(typically: cis- platin þ vinorelbine), or cisplatin þ pemetrexed if non-squamous histology. Thereare no comparative phase III trials using the paclitaxel/carboplatin regi- men.When delivered perioperatively cisplatin-based combinations are considered the treatment of choice, in the absenceof contraindications [I, A]. • In the stage III disease CRT strategy, two to four cycles of concomitant ChT should be delivered [I, A]. There is no evidence for further induction or con- solidation ChT. In the perioperative setting,three to four cycles of cisplatin-based ChT are recommended [I, A], aimingat a total cumulative dose of at least 300 mg/m2 of cisplatin [II, B]. • 60–66 Gyin30–33 daily fractions is recommended for concurrent CRT [I, A]. Maximum overall treatment time should not exceed 7 weeks [III, B]. ‘Biological intensification’, suchas treatment acceleration, is notstandard practice inconcurrent CRTschedules [III,B]. • In sequentialapproaches, RTdelivered ina short overalltreatment timeis recommended [I,A]. Personalised medicine • There iscurrently no rolefor targeted agentsin stage III NSCLC outsideclinical trials [I, A]. • Immunotherapy isbeing studied in early NSCLC as (neo)adjuvant therapy and as consolidationafter CRT; data shouldbeawaited before any clinicaluse [I, A]. Follow-up, long-term implications and survivorship • NSCLC patients treated with radical intent should be followed for treatment-related complications, detection of treatable relapse or occurrence of se- cond primary lung cancer [III, A]. • Surveillance every 6 monthsfor 2 years with a visit including history, physical examination and—preferably contrast-enhanced—volume chest CT scan at least at 12 and 24 months is recommended, and thereafter an annual visit including history,physical examination and chest CT scan in order to detectsecond primary tumours [III, B]. • For individualpatients, follow-upwith six-monthly CTscans for 3years is recommended for patientswho are suitablefor salvage treatment(e.g. sur- gery, local ablative therapy) [III, B]. The frequency of the follow-up visits can be tailored to the individual patient for those not suitable for salvage treat- ment [V, B]. • The selectiveuse of FDG–PET isrecommended whenrecurrence afterSABR is suspected based on serialspiral chest CT[III, B]. • Due to a high number of false-positive findingson PET, patientssuitable for salvagetherapy should undergoa biopsy, wheneverpossible [III, B]. • NSCLC patientsshould be offered smoking cessation, as this leads to superior treatmentoutcomes. Combining behaviour techniques with pharmaco- therapy is the preferred approach [I, A]. 2D, 2 dimensional; 3D, 3 dimensional; ChT, chemotherapy; COPD, chronic obstructive pulmonary disease; CRT, chemoradiotherapy; CT, computed tomography; DLCO,diffusing capacity of the lungsfor carbonmonoxide; EBUS, endobronchial ultrasound; EUS, endoscopic ultrasound; FDG–PET, fluorodeoxyglucoseposi- tron emissiontomography; FEV1, forced expiratory volume in 1 second; GGO, ground glass opacity; IASLC, International Association for the Study of Lung Cancer; LA-NSCLC,locally advanced NSCLC; LDCT, low-doseCT; MRI,magnetic resonance imaging; NSCLC, non-small-celllung cancer; NOS, not otherwisespecified; OS, overall survival; PET,positron emission tomography; PORT, postoperativeradiotherapy; RCRI, revised cardiac riskindex; RCT, randomised controlled trial; RFA, radiofrequency ablation; RT, radiotherapy; SABR, stereotactic ablative radiotherapy;SUVmax, maximum standardiseduptake value; TNM, tumour, nodeand metastasis; VATS, video-assistedthoracoscopic surgery; VO2max, maximal oxygen consumption; WHO,World Health Organization.
Figure 1. Suggested algorithm for locoregional lymph node staging in patients with non-metastatic NSCLC.
CT, computed tomography; EBUS, endoscopic bronchial ultrasound; EUS, endoscopic ultrasound; FDG, fluorodeoxyglucose; LN, lymph node;
NPV, negative predictive value; NSCLC, non-small-cell lung cancer; PET, positron emission tomography; VAM, video-assisted mediastinoscopy.
Reprinted from [137] with permission.
Figure 2. Treatment recommendations for patients with locoregional NSCLC, based on imaging, invasive lymph node staging tests and multidisciplinary assessment.
*Category description according to CT imaging as in ACCP staging document [42].
**See text for factors involved in the choice between non-surgical and surgical multimodality treatment.
ACCP, American College of Chest Physicians; CT, computed tomography; LN, lymph node; NSCLC, non-small-cell lung cancer; PET, positron-emission tomography.
Figure 3. Preoperative respiratory evaluation.
DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 second; ppo, predicted postoperative;
VO2, oxygen consumption.
Reprinted from [50], with permission from the European Respiratory Society.
Figure 4. Algorithm for patients with clinical stage I lung cancer and limited pulmonary function due to emphysema.
CT, computed tomography; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume 1; FVC, forced vital capacity; ILD,
interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LVRS, lung volume reduction surgery; RFA, radiofrequency ablation; RV, reserve volume;
SBRT, stereotactic body radiotherapy; TLC, total lung capacity.
Reprinted from [45], with permission from Elsevier.
Figure 5. Preoperative cardiac evaluation.
AHA/ACC, American Heart Association/American College of Cardiology; CABG, coronary artery bypass grafting; ECG, electrocardiogram; PCI,
percutaneous coronary intervention; RCRI, revised cardiac risk index; TIA, transient ischaemic attack.
Reprinted from [50], with permission from the European Respiratory Society.
Unresectable LA-NSCLC
Unresectable in this situation refers to the situation that—even after induction therapy—a complete resection (R0) would not be possible, based on evaluation within a multidisciplinary team,
including an experienced thoracic surgeon.
Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, Escriu C, Peters S; ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv1-iv21. doi: 10.1093/annonc/mdx222. PMID: 28881918.
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