Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆
2021; Elsevier BV; Volume: 32; Issue: 7 Linguagem: Inglês
10.1016/j.annonc.2021.03.207
ISSN1569-8041
AutoresAnne‐Marie C. Dingemans, Martin Früh, Andrea Ardizzoni, Benjamin Besse, Corinne Faivre‐Finn, Lizza Hendriks, Sylvie Lantuéjoul, Solange Peters, Noemı́ Reguart, Charles M. Rudin, Dirk De Ruysscher, Paul Van Schil, Johan Vansteenkiste, Martin Reck,
Tópico(s)Lung Cancer Treatments and Mutations
Resumo•This ESMO Clinical Practice Guideline provides key recommendations for managing small-cell lung cancer (SCLC).•It covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Treatment algorithms for limited- and extensive-stage and recurrent SCLC are provided.•All recommendations were compiled by a multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors' collective expert opinion. Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer. Although SCLC is characterised by rapid responses to chemotherapy (ChT) and sensitivity to radiotherapy (RT), due to early treatment resistance, the 5-year overall survival (OS) is 70 years of age) patients with SCLC has increased from 23% in 1975 to 44% in 2010.4Abdel-Rahman O. Changing epidemiology of elderly small cell lung cancer patients over the last 40 years; a SEER database analysis.Clin Respir J. 2018; 12: 1093-1099Crossref PubMed Scopus (18) Google Scholar Computed tomography (CT) screening does not improve survival of SCLC, as demonstrated in three trials [I, E].5Aberle D.R. DeMello S. Berg C.D. et al.Results of the two incidence screenings in the National Lung Screening Trial.N Engl J Med. 2013; 369: 920-931Crossref PubMed Scopus (337) Google Scholar,6Silva M. Galeone C. Sverzellati N. et al.Screening with low-dose computed tomography does not improve survival of small cell lung cancer.J Thorac Oncol. 2016; 11: 187-193Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar This is possibly related to the aggressiveness of SCLC, reflected both by the occurrence of SCLC as an interval cancer, i.e. diagnosed between two CT screenings, and the primarily late-stage screen-detected SCLC. As SCLC is highly related to tobacco smoking, smoking prevention or cessation are the most effective strategies to decrease the clinical impact of the disease [IV, A]. Information regarding the diagnosis and molecular pathology/biology of SCLC can be found in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.03.207. •SCLC is a high-grade neuroendocrine carcinoma with a typical morphology and should be diagnosed according to the World Health Organization criteria [IV, A].•For pathological diagnosis, histology is preferred over cytology [V, A].•Currently, no predictive biomarker is available and programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB) testing are not recommended in routine clinical practice [I, D]. The TNM (tumour–node–metastasis) staging classification 7th edition was adopted for SCLC, harbouring a higher prognostic value compared with the previously used subdivision in limited and extensive disease [IV, A].7Shepherd F.A. Crowley J. Van Houtte P. et al.The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.J Thorac Oncol. 2007; 2: 1067-1077Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar The description of disease stages according to the 8th edition TNM, and the median, 1-year and 2-year OS data are depicted in Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.annonc.2021.03.207.8Nicholson A.G. Chansky K. Crowley J. et al.The International Association for the Study of Lung Cancer lung cancer staging project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer.J Thorac Oncol. 2016; 11: 300-311Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar However, in clinical trials, the terms ‘limited disease’, defined as the tumour being confined to one hemithorax and regional lymph nodes, and ‘extensive disease’ are used to define eligibility. For this reason, limited and extensive disease are used throughout this guideline. The staging work-up for patients diagnosed with SCLC is shown in Table 1. A medical history, physical examination and laboratory tests should be carried out [V, A]. Attention should be drawn towards potential autoimmune-mediated paraneoplastic neurological symptoms,9Gozzard P. Woodhall M. Chapman C. et al.Paraneoplastic neurologic disorders in small cell lung carcinoma: a prospective study.Neurology. 2015; 85: 235-239Crossref PubMed Scopus (60) Google Scholar with their detection becoming increasingly important with the introduction of immunotherapy [V, C]. In non-metastatic disease, pulmonary function tests are also advised.10Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (699) Google Scholar Imaging consists of a chest and abdomen CT [IV, A]. In case of no metastases on CT scan, imaging should be complemented with a bone scintigraphy, or [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG–PET)–CT if available [V, B], and a magnetic resonance imaging (MRI) or a less sensitive brain CT scan if MRI is not available/possible [III, A].11Seute T. Leffers P. ten Velde G.P. et al.Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI).Cancer. 2008; 112: 1827-1834Crossref PubMed Scopus (108) Google Scholar In patients with stage IV disease who are eligible but do not wish to undergo prophylactic cranial irradiation (PCI), a baseline MRI after ChT is recommended and serial MRIs are then advised as part of the follow-up [III, B].12Takahashi T. Yamanaka T. Seto T. et al.Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 663-671Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar In case of an abnormal blood count or signs of blood–bone marrow infiltration, a bone marrow aspiration and biopsy are recommended in patients without known additional metastases in order to confirm bone marrow involvement [V, C]. The use of FDG–PET is still debated in SCLC; a review of small prospective series showed that 9% of patients were upstaged with FDG–PET and 4% were downstaged.13Martucci F. Pascale M. Valli M.C. et al.Impact of (18)F-FDG PET/CT in staging patients with small cell lung cancer: a systematic review and meta-analysis.Front Med (Lausanne). 2019; 6: 336Crossref PubMed Scopus (9) Google Scholar In the majority of these series, pathological confirmation of metastatic sites was not obtained. As false-positive results have been reported using FDG–PET, the presence of a metastasis should be pathologically confirmed if it alters the treatment plan [II, C]. Of note, in the randomised CONVERT trial exploring different RT schedules in limited-stage SCLC, the outcomes of 57% of patients who were staged by PET–CT were not different to those who underwent staging by conventional CT scan.14Manoharan P. Salem A. Mistry H. et al.(18)F-Fludeoxyglucose PET/CT in SCLC: analysis of the CONVERT randomized controlled trial.J Thorac Oncol. 2019; 14: 1296-1305Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Given the limited evidence for PET–CT in SCLC, its role in the selection of patients for curative treatment remains controversial among those without metastases on CT. However, FDG–PET is recommended to assist in RT volume delineation [III, A]. In case a suspected solitary metastasis cannot be adequately diagnosed, or diagnosis significantly delays the start of treatment, the lesion can be re-evaluated after two cycles of ChT to confirm the diagnosis of metastatic disease. If pleural fluid/pericardial fluid is negative for metastasis, and if it is the only possible site of metastasis, treatment should be according to M0 status.Table 1Diagnostic and staging work-up of SCLCHistory and clinical examination Medical history (including smoking history and comorbidities) PS Physical examination Assessment of paraneoplastic syndromes (especially when initiating immunotherapy)Laboratory analysis CBC, liver enzymes, sodium, potassium, calcium, glucose, LDH and renal functions tests should be carried outImaging CT of the thorax and abdomen should be carried out in all patients; an FDG–PET–CT is optional In case of a suspicion of bone metastasis and no other metastasis, a bone scintigraphy should be carried out unless FDG–PET is available Imaging of the brain (preferably MRI) is mandated in patients with stage I-III disease MRI of the brain is recommended for patients with stage IV disease who are eligible for PCI but who choose not to undergo PCITumour biopsy A diagnosis of SCLC is preferably assessed based on histological examination of a biopsy In case of planned surgery, invasive mediastinal staging is requiredFunctional assessment Pulmonary function testing (FEV1, VC, DLCO) is required for patients with stage I-III SCLC who are candidates for surgery or RT VO2 max assessment by cycle ergometry should be carried out if surgery is planned when pulmonary function tests are limitedCBC, complete blood count; CT, computed tomography; DLCO, diffusing capacity of the lung for carbon monoxide; FDG, [18F]2-fluoro-2-deoxy-D-glucose; FEV1, forced expiratory volume; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCI, prophylactic cranial irradiation; PET, positron emission tomography; PS, performance status; RT, radiotherapy; SCLC, small-cell lung cancer; VC, vital capacity; VO2 max, maximal oxygen uptake. Open table in a new tab CBC, complete blood count; CT, computed tomography; DLCO, diffusing capacity of the lung for carbon monoxide; FDG, [18F]2-fluoro-2-deoxy-D-glucose; FEV1, forced expiratory volume; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCI, prophylactic cranial irradiation; PET, positron emission tomography; PS, performance status; RT, radiotherapy; SCLC, small-cell lung cancer; VC, vital capacity; VO2 max, maximal oxygen uptake. Poor prognostic factors in SCLC include impaired performance status (PS), weight loss, increased age, male sex, elevated lactate dehydrogenase (LDH) and low sodium [syndrome of inappropriate antidiuretic hormone secretion (SIADH)].15Foster N.R. Mandrekar S.J. Schild S.E. et al.Prognostic factors differ by tumor stage for small cell lung cancer: a pooled analysis of North Central Cancer Treatment Group trials.Cancer. 2009; 115: 2721-2731Crossref PubMed Scopus (78) Google Scholar In addition, a higher total gross tumour volume predicts a worse outcome in patients with locally advanced SCLC treated with chemoradiotherapy (CRT).16Reymen B. Van Loon J. van Baardwijk A. et al.Total gross tumor volume is an independent prognostic factor in patients treated with selective nodal irradiation for stage I to III small cell lung cancer.Int J Radiat Oncol Biol Phys. 2013; 85: 1319-1324Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar •Staging of SCLC should be according to the TNM 8th edition [IV, A].•Initial assessment should include smoking history, physical examination, complete blood count, liver enzymes, sodium, potassium, calcium, glucose, LDH, creatinine and lung function test (if localised disease) [V, A].•Attention should be drawn towards potential autoimmune-mediated paraneoplastic neurological symptoms [V, C].•A contrast-enhanced CT of the chest and abdomen is recommended [IV, A].•Imaging of the brain, preferably MRI, is recommended in localised disease [III, A].•Brain MRI is also recommended for stage IV patients not undergoing PCI [II, B].•FDG–PET is optional for staging in limited-stage disease. FDG–PET findings that modify treatment decisions should be pathologically confirmed [II, C]. However, FDG–PET is recommended to assist in RT volume delineation [III, A].•In limited-stage disease, additional bone scintigraphy is advised when no FDG–PET–CT has been carried out [V, B].•In limited-stage disease, a bone marrow aspiration and biopsy are advised in the case of abnormal blood counts suggesting bone marrow involvement [V, C].•In patients eligible for immunotherapy, attention should be paid to the detection of paraneoplastic disorders [V, C]. A proposed treatment algorithm for patients with stage I-III SCLC eligible for treatment of curative intent (selected limited-stage disease) is shown in Figure 1. Indications and results of surgical resection for SCLC remain controversial and only a minority of patients with SCLC qualify for surgical resection. In 2017, a Cochrane systematic review concluded that currently available randomised controlled trials (RCTs) do not support a role for surgical resection in the management of stage I-III SCLC.17Barnes H. See K. Barnett S. et al.Surgery for limited-stage small-cell lung cancer.Cochrane Database Syst Rev. 2017; 4: Cd011917PubMed Google Scholar However, the conclusions were of limited value due to the lack of contemporary data and the low quality of available evidence. In a recent retrospective analysis of 205 patients with SCLC who underwent resection, for those with pathological stages I and II, 5-year survival rates were 63.8% and 65.5%, respectively.18Zhao X. Kallakury B. Chahine J.J. et al.Surgical resection of SCLC: prognostic factors and the tumor microenvironment.J Thorac Oncol. 2019; 14: 914-923Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In another analysis of the National Cancer Database, 507 patients with stage I/II SCLC undergoing lobectomy and adjuvant ChT were matched with patients receiving concurrent CRT.19Wakeam E. Acuna S.A. Leighl N.B. et al.Surgery versus chemotherapy and radiotherapy for early and locally advanced small cell lung cancer: a propensity-matched analysis of survival.Lung Cancer. 2017; 109: 78-88Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Median OS was 48.6 and 28.7 months, respectively, favouring the surgical approach (P < 0.0001). After extensive work-up, surgery, in the context of a multimodal treatment approach, may be considered in patients with clinical stages I and II disease (cT1-2N0) [III, B] and in those suspected of having a mixed histology of SCLC and non-small-cell lung cancer (NSCLC).20Villaruz L. Karlovits B.J. Burns T.F. et al.Small-cell lung cancer.in: LoCicero III, J. Colson Y.L. Feins R.H. Shields' General Thoracic Surgery. Wolters Kluwer, Philadelphia, PA2019: 1308-1319Google Scholar SCLC may also be an incidental finding in patients undergoing surgery for a solitary pulmonary nodule, as seen in 4%-12% of cases.21Kreisman H. Wolkove N. Quoix E. Small cell lung cancer presenting as a solitary pulmonary nodule.Chest. 1992; 101: 225-231Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar When considering surgical treatment of SCLC, extensive pathological mediastinal staging is required [IV, A].22Ernani V. Ganti A.K. Surgery for limited-stage small cell lung cancer: ready for prime-time?.J Thorac Dis. 2017; 9: 3576-3578Crossref PubMed Scopus (3) Google Scholar,23Stinchcombe T.E. Current treatments for surgically resectable, limited-stage, and extensive-stage small cell lung cancer.Oncologist. 2017; 22: 1510-1517Crossref PubMed Scopus (21) Google Scholar As with NSCLC, the aim of surgical treatment should be a complete (R0) resection according to the International Association for the Study of Lung Cancer criteria [III, A].24Rami-Porta R. Wittekind C. Goldstraw P. Complete resection in lung cancer surgery: proposed definition.Lung Cancer. 2005; 49: 25-33Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar Intraoperatively, a systematic nodal dissection should be carried out [IV, A]. Sublobular resection is not recommended [V, E]. Due to the aggressive nature of SCLC, the risk of progression to unresectable or incurable disease while awaiting surgery should be taken into account. In an analysis of the National Cancer Database, the 5-year OS rate of 954 patients who underwent R0 resection for pT1-2N0M0 SCLC was 47%.25Yang C.F. Chan D.Y. Speicher P.J. et al.Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer.J Clin Oncol. 2016; 34: 1057-1064Crossref PubMed Scopus (108) Google Scholar A multivariate analysis showed that adjuvant ChT or ChT with PCI were associated with improved survival compared with no adjuvant therapy. Adjuvant ChT should therefore be administered after surgical resection of SCLC [IV, A]. In patients with unexpected, positive mediastinal lymph nodes (N2) or R1-R2 resection, adjuvant ChT must be combined with RT, preferably concurrently [IV, A].22Ernani V. Ganti A.K. Surgery for limited-stage small cell lung cancer: ready for prime-time?.J Thorac Dis. 2017; 9: 3576-3578Crossref PubMed Scopus (3) Google Scholar The role of induction ChT in patients with locally advanced SCLC has not been clearly established and this approach is not indicated for SCLC.20Villaruz L. Karlovits B.J. Burns T.F. et al.Small-cell lung cancer.in: LoCicero III, J. Colson Y.L. Feins R.H. Shields' General Thoracic Surgery. Wolters Kluwer, Philadelphia, PA2019: 1308-1319Google Scholar The role of PCI is not well established, as discussed later. The preferred ChT regimen for patients with limited-stage (stage I-III) SCLC is cisplatin plus etoposide [I, A].26Mascaux C. Paesmans M. Berghmans T. et al.A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis.Lung Cancer. 2000; 30: 23-36Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar When cisplatin is not feasible, carboplatin plus etoposide is a possible alternative, with similar or slightly worse outcomes seen in small comparative studies [II, A].27Karam I. Jiang S.Y. Khaira M. et al.Outcomes of small cell lung cancer patients treated with cisplatin-etoposide versus carboplatin-etoposide.Am J Clin Oncol. 2015; 38: 51-54Crossref PubMed Scopus (18) Google Scholar Standard dosing should be used, i.e. cisplatin 60-80 mg/m2 on day 1 and etoposide 100-120 mg/m2 on days 1, 2 and 3 of every 3-week cycle, with avoidance of dose reduction, especially during the first two cycles.28Arriagada R. Pignon J.P. Le Chevalier T. Initial chemotherapeutic doses and long-term survival in limited small-cell lung cancer.N Engl J Med. 2001; 345: 1281-1282Crossref PubMed Scopus (18) Google Scholar The dose of cisplatin can also be split over 3 days (etoposide 100 mg/m2 on days 1-3 and cisplatin 25 mg/m2 on days 1-3) as this tends to be better tolerated and reduces the need for hydration.29Faivre-Finn C. Snee M. Ashcroft L. et al.Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.Lancet Oncol. 2017; 18: 1116-1125Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF) concomitant with CRT has been discouraged based on one randomised study of GM-CSF, but more recent data from the CONVERT trial have shown that these agents can be administered safely when indicated [II, B].29Faivre-Finn C. Snee M. Ashcroft L. et al.Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.Lancet Oncol. 2017; 18: 1116-1125Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 30Gomes F. Faivre-Finn C. Mistry H. et al.Safety of G-CSF with concurrent chemo-radiotherapy in limited-stage small cell lung cancer—secondary analysis of the randomised phase 3 CONVERT trial.Lung Cancer. 2021; 153: 165-170Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 31Bunn Jr., P.A. Crowley J. Kelly K. et al.Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group.J Clin Oncol. 1995; 13: 1632-1641Crossref PubMed Scopus (160) Google Scholar The number of cycles is usually four; however, only small series have compared four with six cycles in localised SCLC.32Veslemes M. Polyzos A. Latsi P. et al.Optimal duration of chemotherapy in small cell lung cancer: a randomized study of 4 versus 6 cycles of cisplatin-etoposide.J Chemother. 1998; 10: 136-140Crossref PubMed Scopus (11) Google Scholar The success of introducing immune checkpoint inhibition with durvalumab as consolidation therapy after CRT for NSCLC has fostered interest in this approach in limited-stage SCLC.33Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1193) Google Scholar Consolidation treatment with nivolumab–ipilimumab in patients treated with CRT was investigated in the randomised phase II STIMULI trial.34Peters S. Pujol J.L. Dafni U. et al.LBA84 consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy: results from the ETOP/IFCT 4-12 STIMULI trial.Ann Oncol. 2020; 31: S1211Abstract Full Text Full Text PDF Google Scholar However, no improvement in progression-free survival (PFS) or OS was observed in patients treated with nivolumab–ipilimumab compared with the observational group. A number of trials addressing the role of immunotherapy in this setting are ongoing (NCT02046733, NCT03540420, NCT03703297, NCT03811002). With the exception of patients with very early disease, those with T1-4N0-3M0 tumours and a PS of 0-1 should be treated with concurrent ChT and thoracic RT [I, A]. The current standard of care of twice-daily (b.i.d.) RT delivered concurrently with ChT is based on an RCT which demonstrated superiority in terms of survival for RT of 45 Gy b.i.d. in 30 fractions over 3 weeks versus 45 Gy once daily (o.d.) in 25 fractions over 5 weeks, both delivered concurrently with cisplatin plus etoposide.35Turrisi 3rd, A.T. Kim K. Blum R. et al.Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.N Engl J Med. 1999; 340: 265-271Crossref PubMed Scopus (1180) Google Scholar However, there has been a lack of consensus regarding the routine use of b.i.d. RT due to concerns regarding toxicity (one-third of patients developed grade ≥3 radiation oesophagitis in an historical study), debate about the RT schedule used in the control arm and practical/logistical issues. The CONVERT trial compared b.i.d. RT (45 Gy/30 fractions over 3 weeks) to a higher dose of o.d. RT (66 Gy/33 fractions over 6.5 weeks), both given concurrently with ChT (starting on cycle two).29Faivre-Finn C. Snee M. Ashcroft L. et al.Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.Lancet Oncol. 2017; 18: 1116-1125Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar CONVERT is the first RCT providing outcomes data in patients staged with PET–CT using the TNM classification and treated with modern RT techniques (i.e. three-dimensional conformal RT or intensity-modulated RT without elective nodal irradiation).14Manoharan P. Salem A. Mistry H. et al.(18)F-Fludeoxyglucose PET/CT in SCLC: analysis of the CONVERT randomized controlled trial.J Thorac Oncol. 2019; 14: 1296-1305Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar OS did not differ significantly between the two groups. OS achieved in both arms was higher and the toxicity much lower (>50% reduction) than previously reported in the literature. The 2- and 5-year OS were 56% and 34% in the b.i.d. group and 51% and 31% in the o.d. group, respectively. There was no difference in grade 3-4 oesophagitis or grade 3-4 radiation pneumonitis between the groups (19% versus 19% and 3% versus 2% in the b.i.d. and o.d. groups, respectively). In addition, a Norwegian phase II RCT, comparing 45 Gy/30 fractions b.i.d. with 42 Gy/15 fractions o.d., showed that there was no difference in major toxicity between the schedules and a numerically higher OS for treatment with 45 Gy b.i.d.36Grønberg B.H. Halvorsen T.O. Fløtten Ø. et al.Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer.Acta Oncol. 2016; 55: 591-597Crossref PubMed Scopus (29) Google Scholar Since CONVERT was designed to show superiority of o.d. RT and was not powered to show equivalence, the implication is that b.i.d. RT (45 Gy/30 fractions over 3 weeks) should remain as the standard of care in this group of patients [I, A]. When b.i.d. RT is not possible due to logistical reasons, o.d. RT (66 Gy/33 fractions over 6 weeks) is an alternative option. It should, however, be noted that the role of concurrent CRT is not as well defined in patients >70 years of age or in those who are frail. Regarding the timing of RT and ChT, evidence from clinical trials suggest that thoracic RT should be initiated as early as possible, preferably starting on the first or second cycle of ChT. However, two recent meta-analyses investigating the timing of high-dose thoracic RT with ChT showed no difference in OS between earlier (≤30 days after starting ChT) and later (>30 days after starting ChT) RT initiation. Furthermore, a higher incidence of toxicity (haematological, oesophagitis and cardiac toxicity) was reported with early versus late thoracic RT.37De Ruysscher D. Lueza B. Le Péchoux C. et al.Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.Ann Oncol. 2016; 27: 1818-1828Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,38Lu H. Fang L. Wang X. et al.A meta-analysis of randomized controlled trials comparing early and late concurrent thoracic radiotherapy with etoposide and cisplatin/carboplatin chemotherapy for limited-disease small-cell lung cancer.Mol Clin Oncol. 2014; 2: 805-810Crossref PubMed Google Scholar However, in the individual patient data meta-analysis, the hazard ratio (HR) was significantly in favour of earlier/shorter RT in trials where patients received ChT without a dose reduction or delay [HR 0.79; 95% confidence interval (CI) 0.69-0.91] [II, A].37De Ruysscher D. Lueza B. Le Péchoux C. et al.Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.Ann Oncol. 2016; 27: 1818-1828Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar When the patient PS or dose to the organs at risk do not allow for the early administration of thoracic RT, it may be postponed until the start of the third ChT cycle [II, B]. Sequential CRT is an option for patients who are not considered candidates for concurrent CRT due to poor PS, comorbidities and/or disease volume [V, B]. In sequential CRT, the optimal target volume remains an area of debate. An historical Southwest Oncology Group (SWOG) trial without contemporary imaging or RT techniques randomised patients achieving a partial response or stable disease after ChT to either wide-volume RT (pre-ChT tumour volume plus the mediastinum) or reduced-volume RT (post-ChT tumour volume with a margin of 2 cm) followed by further ChT.39Kies M.S. Mira J.G. Crowley J.J. et al.Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study.J Clin Oncol. 1987; 5: 592-600PubMed Google Scholar The local recurrence rate was similar in both arms. Therefore, it is recommended that the post-ChT primary tumour volume should be included in the radiation field [II, B]. No prospective studies are available on the nodal target volume after ChT. Thus, similar to NSCLC, including the involved nodal stations before ChT in the target volume is recommended [V, B]. Omission of elective node irradiation based on CT scans should be used with caution as this strategy may result in nodal failures.40De Ruysscher D. Bremer R.H. Koppe F. et al.Omission of elective node irradiation on basis of CT-scans in patients wit
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