Abstract

The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.

Lugano 2010: Background to the ESMO Consensus Conference

In 2009, European Society for Medical Oncology (ESMO) decided to update the ESMO clinical recommendations in lung cancer through a consensus process addressing five specific areas:

  • 1-Early and locally advanced non-small-cell lung cancer (NSCLC)

  • 2-NSCLC pathology and molecular testing

  • 3-First-line metastatic NSCLC

  • 4-Second-/third-line NSCLC

  • 5-Small-cell lung cancer (SCLC)

Five working groups were appointed, each comprised six to eight participants with multidisciplinary involvement and led by a chair, and with the assistance of one expert in methodological aspects. A total of 39 experts were involved in this consensus process (see Panel members listed in the Appendix).

The 1st ESMO Consensus Conference on Lung Cancer was held in May 2010 in Lugano. Before the conference, each group identified a number of clinically relevant questions suitable for consensus discussion and provided the available literature. At the Conference, in five parallel sessions, each group discussed and reached agreement on the questions previously chosen. Decisions were made using studies published in peer review journals. If no relevant published data were identified, expert opinions were considered. The consideration of abstracts was at the discretion of the groups. All relevant scientific literature, as identified by the experts, was considered. A systematic literature search was not carried out. The recommendations from each group were then presented to all the experts and discussed, and a general consensus was reached. The ‘Infectious Diseases Society of American-United States Public Health Service Grading System’ was used (shown in Tables 1 and 2) for level of evidence and strength of recommendation for each question raised [1].

Table 1.

Level of evidence [1]

Evidence from at least one large randomised control trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity 
II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials demonstrated heterogeneity 
III Prospective cohort studies 
IV Retrospective cohort studies or case–control studies 
Studies without control group, case reports, experts opinions 
Evidence from at least one large randomised control trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity 
II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials demonstrated heterogeneity 
III Prospective cohort studies 
IV Retrospective cohort studies or case–control studies 
Studies without control group, case reports, experts opinions 
Table 2.

Strength of recommendation [1]

Strong evidence for efficacy with a substantial clinical benefit, strongly recommended 
Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended 
Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,… ), optional 
Moderate evidence against efficacy or for adverse outcome, generally not recommended 
Strong evidence against efficacy or for adverse outcome, never recommended 
Strong evidence for efficacy with a substantial clinical benefit, strongly recommended 
Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended 
Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,… ), optional 
Moderate evidence against efficacy or for adverse outcome, generally not recommended 
Strong evidence against efficacy or for adverse outcome, never recommended 

The consensus in SCLC is detailed here. SCLC remains an important focus for treatment and research. The SCLC ESMO Guidelines 2010 [2] were endorsed and should be read in conjunction with these additional comments on specific patient situations. Table 3 provides a summary of panel recommendations. The final recommendations listed here have been approved by all participants.

Table 3.

Summary of recommendations

 Recommendations 
Staging issues  
    Recommendation 1 The new TNM 7 staging system for NSCLC is to be adopted for SCLC 
    Recommendation 2 The use of PET is not based on randomised trials and treatment decisions should not be based on PET findings alone. PET findings which could modify treatment decisions should be pathologically confirmed 
    Recommendation 3 For a solitary extrathoracic metastasis based on initial staging examinations, pathologic proof is often not feasible and may delay treatment. Depending on the clinical situation, early response evaluation to initial chemotherapy can be more appropriate in deciding whether a solitary metastasis is likely to be metastatic or not. If bone is the sole metastatic site, magnetic resonance imaging may be preferred to more invasive procedures 
Treatment issues  
    First-line treatment  
        Recommendation 4 In patients with clinical T1-2 N0-1 stage that are potential surgical patients, mediastinal node exploration should be carried out. Surgery may be indicated in patients with no mediastinal involvement, and resection should be followed by chemotherapy. Postoperative radiotherapy should be considered for pathologic N1 and unforeseen N2 disease 
        Recommendation 5 First-line chemotherapy should be offered to patients with metastatic SCLC and PS 0–2. It may be considered in selected cases in PS 3–4 
        Recommendation 6 Limited-stage patients with good PS should be considered for concomitant chemoradiotherapy, taking into account the feasibility of radiation treatment plan and good planning target volume coverage while maintaining normal tissue dose constraints 
        Recommendation 7 Thoracic radiotherapy given either concomitantly or sequentially is currently not recommended in patients with distant metastases that have responded to chemotherapy 
        Recommendation 8 In patients with brain involvement as the only metastatic site responding to chemotherapy, concomitant chemotherapy with thoracic radiotherapy is currently not recommended 
        Recommendation 9 PCI is recommended for patients with tumour response. Response should be determined by a restaging CT scan 
        Recommendation 10 PCI in patients who are 65 years or older, requires to balance the benefit and risk of possible neurocognitive impairment to be considered 
    Follow-up issues  
        Recommendation 11 Subsequent follow-up should be at 2–3 months in non-progressing patients at the end of initial treatment and response determination. The actual timing depends on patient circumstances and availability of further treatment. Imaging with CT is preferable 
Treatment issues  
    Second-line treatment and beyond  
        Recommendation 12 Sensitive disease: retreat with the same regimen that induced their initial response, usually reinduction with platinum/etoposide 
        Recommendation 13 Resistant disease: either oral or i.v. topotecan is recommended for selected patients having resistant relapse, i.e. not amenable to reinduction with first-line treatment 
        Recommendation 14 Refractory disease and beyond second-line treatment: selected patients with good PS may benefit from further treatment with a chemotherapy agent not previously used 
        Recommendation 15 Patients, not previously treated with thoracic radiotherapy with a symptomatic recurrence in the mediastinum, such as superior cava vein obstruction or obstructed major airway, may benefit from thoracic radiotherapy 
        Recommendation 16 Local brain re-irradiation, which may include stereotactic radiotherapy, may be considered in selected patients 
 Recommendations 
Staging issues  
    Recommendation 1 The new TNM 7 staging system for NSCLC is to be adopted for SCLC 
    Recommendation 2 The use of PET is not based on randomised trials and treatment decisions should not be based on PET findings alone. PET findings which could modify treatment decisions should be pathologically confirmed 
    Recommendation 3 For a solitary extrathoracic metastasis based on initial staging examinations, pathologic proof is often not feasible and may delay treatment. Depending on the clinical situation, early response evaluation to initial chemotherapy can be more appropriate in deciding whether a solitary metastasis is likely to be metastatic or not. If bone is the sole metastatic site, magnetic resonance imaging may be preferred to more invasive procedures 
Treatment issues  
    First-line treatment  
        Recommendation 4 In patients with clinical T1-2 N0-1 stage that are potential surgical patients, mediastinal node exploration should be carried out. Surgery may be indicated in patients with no mediastinal involvement, and resection should be followed by chemotherapy. Postoperative radiotherapy should be considered for pathologic N1 and unforeseen N2 disease 
        Recommendation 5 First-line chemotherapy should be offered to patients with metastatic SCLC and PS 0–2. It may be considered in selected cases in PS 3–4 
        Recommendation 6 Limited-stage patients with good PS should be considered for concomitant chemoradiotherapy, taking into account the feasibility of radiation treatment plan and good planning target volume coverage while maintaining normal tissue dose constraints 
        Recommendation 7 Thoracic radiotherapy given either concomitantly or sequentially is currently not recommended in patients with distant metastases that have responded to chemotherapy 
        Recommendation 8 In patients with brain involvement as the only metastatic site responding to chemotherapy, concomitant chemotherapy with thoracic radiotherapy is currently not recommended 
        Recommendation 9 PCI is recommended for patients with tumour response. Response should be determined by a restaging CT scan 
        Recommendation 10 PCI in patients who are 65 years or older, requires to balance the benefit and risk of possible neurocognitive impairment to be considered 
    Follow-up issues  
        Recommendation 11 Subsequent follow-up should be at 2–3 months in non-progressing patients at the end of initial treatment and response determination. The actual timing depends on patient circumstances and availability of further treatment. Imaging with CT is preferable 
Treatment issues  
    Second-line treatment and beyond  
        Recommendation 12 Sensitive disease: retreat with the same regimen that induced their initial response, usually reinduction with platinum/etoposide 
        Recommendation 13 Resistant disease: either oral or i.v. topotecan is recommended for selected patients having resistant relapse, i.e. not amenable to reinduction with first-line treatment 
        Recommendation 14 Refractory disease and beyond second-line treatment: selected patients with good PS may benefit from further treatment with a chemotherapy agent not previously used 
        Recommendation 15 Patients, not previously treated with thoracic radiotherapy with a symptomatic recurrence in the mediastinum, such as superior cava vein obstruction or obstructed major airway, may benefit from thoracic radiotherapy 
        Recommendation 16 Local brain re-irradiation, which may include stereotactic radiotherapy, may be considered in selected patients 

STAGING ISSUES

What is limited stage?

Limited stage should be based on the TNM (tumour–node–metastasis) 7 classification i.e. T1-4 N0-3 M0 [3]. In the new IASLC (International Association for the Study of Lung Cancer) staging system, the largest difference in patient outcomes was observed in patients with N1 versus N2 disease (19 versus 14 months median survival, hazard ratio = 1.40, P = 0.0001) [4]. Furthermore, tumour size was of particular prognostic relevance in patients with N0/N1.

Recommendation 1: The new TNM 7 staging system for NSCLC is to be adopted for SCLC.

Strength of recommendation: A

Level of evidence: I

Use of FDG–PET

Several studies have suggested that the old distinction between limited and extensive stage can be improved with positron emission tomography (PET) and that it has a potential role in adapting target volume for radiotherapy [5–8]. However, histological confirmation of discordant PET findings is not routinely carried out and the current studies have severe limitations as regards pathologic correlation.

Recommendation 2: The use of PET is not based on randomised trials and treatment decisions should not be based on PET findings alone. PET findings, which could modify treatment decisions, should be pathologically confirmed.

Strength of recommendation: C

Level of evidence: III

Single M1b

Recommendation 3.1: For a solitary extrathoracic metastasis based on initial staging examinations, pathologic proof is often not feasible and may delay treatment. Depending on the clinical situation, early response evaluation to initial chemotherapy can be more appropriate in deciding whether a solitary metastasis is likely to be metastatic or not.

Strength of recommendation: C

Level of evidence: V

Recommendation 3.2: If bone is the sole metastatic site, magnetic resonance imaging may be preferred to more invasive procedures.

Strength of recommendation: B

Level of evidence: V

TREATMENT ISSUES: FIRST-LINE TREATMENT

The figure shows a treatment algorithm using the new TNM 7 staging classification.

Should surgery be considered for any specific subgroup?

Several retrospective reports on surgically treated early SCLC patients indicated relatively favourable outcomes of this approach if there was no mediastinal lymph node involvement [9–11]. Randomised clinical trials addressing the role of surgery and adjuvant chemotherapy versus combined chemoradiotherapy in node-negative SCLC are lacking. The panel believes that these retrospective data are consistent enough to consider surgical approach in selected and adequately staged SCLC patients.

Recommendation 4: In patients with clinical T1-2 N0-1 stage who are potential surgical patients, mediastinal node exploration should be carried out. Surgery may be indicated in patients with no mediastinal involvement; resection should be followed by chemotherapy. Postoperative radiotherapy should be considered for pathologic N1 and unforeseen N2 disease.

Strength of recommendation: C

Level of evidence: V

What is the treatment of choice for chemotherapy-naive patients with M1 disease?

Platinum/etoposide chemotherapy is a standard as outlined in the 2010 ESMO recommendations [2]. A recent meta-analysis has suggested equivalence between irinotecan/platinum and etoposide/platinum in extensive-stage patients and a further study in Caucasian population has suggested that irinotecan/cisplatin is not inferior to etoposide/cisplatin [12, 13].

Recommendation 5: First-line chemotherapy should be offered to patients with metastatic SCLC and performance status (PS) of zero to two (scenario 1). It may be considered in selected cases in PS of three to four (scenario 2).

Strength of recommendation: scenario 1: A; scenario 2: C

Level of evidence: scenario 1: I; scenario 2: V

Patient eligibility for early concurrent thoracic radiotherapy on cycle 1 or 2

Patients with good PS are eligible for early concurrent thoracic radiotherapy in cycle 1 or 2 [2, 14]. Computed tomography (CT)-based three-dimensional conformal radiotherapy is recommended. Use of FDG–PET for target volume definition is being evaluated. There is no standard dose that may vary between 45 Gy (twice daily) and 55–70 Gy (once daily). Trials exploring the optimal dose and fractionation are ongoing. There are no specific recommendations for SCLC in terms of normal tissue constraints. Based on NSCLC data, both V20 corresponding to the percentage of normal lung parenchyma receiving 20 Gy and the mean lung dose (MLD) should be recorded as they correlate with the risk of radiation pneumonitis [15]. As target volumes may be large, a V20 level of 35%–40% or an MLD of 20–23 Gy can be considered acceptable, but some patients (∼10%–15%) may develop severe radiation-induced toxicity [16]. Recent studies have explored an involved-field approach without elective irradiation [17–19]. Furthermore, in subgroup analysis of prospective trials, elderly patients with good PS seem to have similar outcomes to younger patients and age does not appear to impact on efficacy [20–22]. Toxicity, particularly haematological may be greater among the elderly.

Recommendation 6: Limited-stage patients with good PS should be considered for concomitant chemoradiotherapy, taking into account the feasibility of radiation treatment plan and good planning target volume coverage while maintaining normal tissue dose constraints.

Strength of recommendation: A

Level of evidence: II

Other special metastatic situations

A single-centre five-arm randomised study indicated a 5.4% 5-year improvement in a subgroup of patients with metastatic disease who had either a complete or partial response within the thorax and complete remission of distant disease after initial chemotherapy with the use concomitant thoracic radiotherapy and chemotherapy versus chemotherapy alone [23]. The hypothesis generated by this subgroup analysis is being addressed in a phase III multicentre study.

Recommendation 7: Thoracic radiotherapy given either concomitantly or sequentially is currently not recommended in patients with distant metastases that have responded to chemotherapy.

Strength of recommendation: C

Level of evidence: II

Brain metastases as the only metastatic site

When the brain is the only documented metastatic site of disease, the use of whole-brain radiotherapy and thoracic radiotherapy in addition to chemotherapy may lead to more favourable results, based on a small retrospective study of 30 patients [24]. Data from a prospective study are needed to support the observation.

Recommendation 8: In patients with brain involvement as the only metastatic site responding to chemotherapy, concomitant chemotherapy with thoracic radiotherapy is currently not recommended.

Strength of recommendation: C

Level of evidence: IV

Which patients should be considered for prophylactic cranial irradiation?

Prophylactic cranial irradiation (PCI) is recommended at the end of initial therapy for patients with a tumour response and no contraindications for this procedure. It is important to define tumour response for consideration of PCI [25–27]. Although chest X-ray was most often used in the older trials included in the meta-analysis [25], the panel believes the restaging should be done with the use of CT scan. The imaging should be carried out at 3–4 weeks after the end of initial treatment, as at this stage the determination of tumour response is not yet hampered by the radiotherapy-induced fibrosis.

Recommendation 9: PCI is recommended for patients with tumour response. Response should be determined by a restaging CT scan.

Strength of recommendation: A

Level of evidence: I

Role of PCI in older patients

The mean age in the PCI meta-analysis was 59 with 25% of patients being 65 years or older. However, age older than 60–65 is a risk factor for neurocognitive impairment [28, 29].

Recommendation 10: PCI in older patients, 65 years and older, requires to balance the benefit and risk of possible neurocognitive impairment to be considered.

Strength of recommendation: B

Level of evidence: II

FOLLOW-UP ISSUES

What is the optimal follow-up?

SCLC is likely to relapse or progress after initial treatment and second-line treatment improves survival in good PS patients [30]. Detecting a relapse or progression before deterioration of PS is therefore a reasonable approach. Long-term survivors may be at risk of second lung cancer that should be histologically confirmed.

Recommendation 11: Subsequent follow-up should be at 2–3 months in non-progressing patients at the end of initial treatment and response determination. The actual timing depends on patient circumstances and availability of further treatment. Imaging with CT is preferable.

Strength of recommendation: C

Level of evidence: V

TREATMENT ISSUES: SECOND-LINE TREATMENT AND BEYOND

The majority of patients with SCLC experience relapse after their initial treatment, with a median survival of 2–3 months without second-line therapy. Although second-line therapy may induce responses in ∼10%–40% of patients, these are usually short-lived, and the median survival rarely exceeds 6 months [31].

Three categories of disease have been described in the literature regarding the response to initial therapy and the duration of response: sensitive, resistant, and refractory. ‘Sensitive’ refers to patients who have had a tumour response lasting 90 days or longer. ‘Resistant’ refers to patients who have recurred within 90 days of completing therapy. ‘Refractory’ refers to patients with tumours that never responded to first-line therapy or to those who progressed during first-line therapy [30].

Sensitive disease

Patients having sensitive disease relapsing >90 days after first-line treatment may benefit from retreatment.

Recommendation 12: Retreat with the same regimen that induced their initial response, usually reinduction with platinum/etoposide.

Strength of recommendation: C

Level of evidence: V

Resistant disease

In patients having resistant disease, topotecan improved overall survival compared with best supportive care [31]. No statistically significant difference in median survival was found in a randomised trial comparing topotecan with combination chemotherapy although topotecan caused less toxicity [32]. There is no evidence that combination chemotherapy is superior to single-agent regimens. Both oral and i.v. topotecan had similar efficacy but with slight differences in toxicity [33, 34].

Recommendation 13: Either oral or i.v. topotecan is recommended for selected patients having resistant relapse, i.e. not amenable to reinduction with first-line treatment.

Strength of recommendation: B

Level of evidence: II

Refractory disease and beyond second-line treatment

A poor PS, early relapse (within 6 weeks) following first-line treatment [30], and refractory disease are adverse prognostic factors for response and for survival. There is currently no standard second-line chemotherapy regimen for patients who fail to respond to initial treatment (refractory disease) or who relapse shortly after completion of first-line treatment (resistant disease with early relapse) in contrast to resistant disease having late relapse. Active agents from phase II trials include amrubicin, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, ifosfamide, and oral etoposide (if etoposide not included in first-line treatment). No drugs have so far been approved by the Food and Drug Administration or the European Medicines Agency for this indication.

Recommendation 14: Selected patients with good PS may benefit from further treatment with a chemotherapy agent not previously used.

Strength of recommendation: B

Level of evidence: III

Symptomatic local recurrence in mediastinum

Recommendation 15: Patients, not previously treated with thoracic radiotherapy with a symptomatic recurrence in the mediastinum, such as superior caval vein obstruction or obstructed major airway, may benefit from thoracic radiotherapy [35–37].

Strength of recommendation: C

Level of evidence: IV

Repeat cranial radiotherapy

For recurrence in the brain after PCI or whole-brain radiotherapy, repeat radiotherapy may be useful in carefully selected patients if no systemic treatment options are available [38–42].

Recommendation 16: Local brain re-irradiation, which may include stereotactic radiotherapy, may be considered in selected patients.

Strength of recommendation: C

Level of evidence: V

FUTURE

Several trials could influence treatment options in the near future. These include:

  • The CONVERT and CALGB 30610 trials addressing the dose and fractionation issues of concurrent thoracic chemoradiotherapy in limited-stage SCLC.

  • The ongoing individual data meta-analysis of early versus late concurrent thoracic radiotherapy and chemotherapy.

  • The CREST Dutch trial addressing the role of thoracic radiotherapy in patients with restricted metastatic disease.

  • Studies addressing the efficacy of novel systemic treatments, including amrubicin and targeted agents.

disclosure

Rafal Dziadziuszko (speakers’ bureau and advisory board role—Roche, GSK, AstraZeneca); Wilfried Eberhardt (speakers’ bureau and advisory board role—AstraZeneca, GSK, Merck Serono, Roche, Novartis, sanofi-aventis, ImClone, Bristol-Myers Squibb, Eli Lilly, Merck USA, Bayer Schering, OSI, Pfizer); Enriqueta Felip (speakers’ bureau and advisory board role—Eli Lilly, AstraZeneca, GSK, Merck Serono, Roche, Boehringer Ingelheim); David Gandara (consulting—Amgen, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, ImClone, GSK, Genentech, Lilly, Merck, Novartis, Pfizer, Sanofi-aventis); Cesare Gridelli (speakers’ bureau and advisory board role—Roche, AstraZeneca, Eli Lilly, Merck Serono); Glenwood D Goss (research funding—Roche Canada); Pasi Jänne (consulting—Pfizer, AstraZeneca, Roche, Genentech, Boehringer Ingelheim; stock ownership—Gatekeeper Pharmaceuticals; other—royalties from patent in EGFR mutation); Tony Mok (honoraria & consulting—AstraZeneca, Roche, Pfizer; honoraria—Eli Lilly, Merck; consulting—Bristol-Myers Squibb, Eisai); Kenneth O’Byrne (advisory board role and research funding—Merck Serono, Roche, AstraZeneca); Robert Pirker (speakers’ bureau and advisory board role—AstraZeneca, Eli Lilly, Merck Serono, Roche, Pierre Fabre; advisory board role—Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer); Martin Reck (speakers’ bureau & consulting—Hoffmann-La Roche, Lilly, Merck, AstraZeneca; Consulting—Bristol-Myers Squibb); Suresh Senan (research funding—Eli Lilly); Nicholas Thatcher (speakers’ bureau and advisory board role—AstraZeneca, Roche, Lilly, Boehringer, Bristol-Myers Squibb); Johan Vansteenkiste (research funding—Eli Lilly, Amgen, AstraZeneca)

The following panel members have declared no conflicts of interest: Paul Baas, Benjamin Besse, Fiona Blackhall, Federico Cappuzzo, Fortunato Ciardiello, Filippo de Marinis, Corinne Faivre-Finn, Martin Früh, Keith M Kerr, Siow Ming Lee, Cecile Le Pechoux, Christian Manegold, Keith McGregor, Luis Paz-Ares, Pieter E. Postmus, Rafael Rosell, Egbert F. Smit, Jens B. Sorensen, Rolf Stahel, Miguel Taron, Jan P. van Meerbeeck, Paul Van Schil, Alain Vergnenegre, Walter Weder.

The authors thank Marianne Paesmans of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium for her great support in methodological aspects during the consensus process. The authors also thank Claire Bramley and all ESMO staff for their support throughout the whole consensus process.

appendix

Members of the panel

Prof. L. Crino, D. Gandara, and M. Reck, were unable to attend the conference, but had a major impact on the preparatory work for the conference and on the final manuscript.

Paul Baas, Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Benjamin Villejuif, Department de Medicine, Institut Gustave Roussy, Villejuif, France; Fiona Blackhall, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Federico Cappuzzo, Department of Medical Oncology, Ospedale Civile di Livorno, Livorno, Italy; Fortunato Ciardiello, Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery F. Magrassi and A. Lanzara, Second University of Naples, Naples, Italy; Lucio Crinò, Department of Oncology, Hospital Santa Maria della Misericordia, Sant Andrea delle Fratte, Perugia, Italy; Filippo de Marinis, Thoracic Oncology Unit I, San Camillo Forlanini Hospitals, Rome, Italy; Rafal Dziadziuszko, Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; Wilfried Eberhardt, Department of Medicine, West German Tumor Centre, University Hospital of University Duisburg-Essen, Essen, Germany; Corinne Faivre-Finn, Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Enriqueta Felip, Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain; Martin Früh, Department of Oncology/Hematology, Cantonal Hospital St Gallen, Switzerland; David Gandara, Division of Hematology/Oncology, University of California Davis Cancer Center, Sacramento, CA, USA; Cesare Gridelli, Division of Medical Oncology, San Giuseppe Moscati Hospital, Avellino, Italy; Glenwood Goss, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; Pasi A. Jänne, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Keith Kerr, Department of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK; Siow Ming Lee, University College London Hospital and UCL Cancer Institute, London, Department of Oncology, University College Hospital, London, UK; Cecile Le Péchoux, Radiotherapy Department, Institut Gustave Roussy, Villejuif, France; Christian Manegold, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Germany; Keith McGregor, The European Society for Medical Oncology, Lugano, Switzerland; Tony Mok, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; Kenneth O’Byrne, St James’s Hospital, Dublin, Ireland; Luis Paz-Ares, University Hospital—Virgen del Rocio, Seville, Spain; Robert Pirker, Medical University of Vienna, Vienna, Austria; Pieter E. Postmus, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Martin Reck, Hospital Grosshansdorf, Department of Thoracic Oncology, Grosshansdorf, Germany; Rafael Rosell, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; Suresh Senan, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands; Egbert F. Smit, Department of Pulmonary Diseases, Vrije Unversiteit Medical Centre, Amsterdam, The Netherlands; Jens B. Sorensen, Department of Oncology, Finsen Centre, National University Hospital, Copenhagen, Denmark; Rolf A. Stahel, University Hospital Zurich, Zurich, Switzerland; Miquel Taron, Medical Oncology Service, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; Nicholas Thatcher, Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK; Jan P. van Meerbeeck, Thoracic Oncology, Ghent University Hospital, Gent, Belgium; Paul Van Schil, Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Belgium; Johan Vansteenkiste, Respiratory Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium; Alain Vergnenegre, Service de Pathologie Respiratoire, CHU, Limoges, France; Walter Weder, Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

References

1.
Dykewicz
CA
Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients
Clin Infect Dis
 , 
2001
, vol. 
33
 (pg. 
139
-
144
)
2.
Sorensen
M
Pijls-Johannasma
M
Felip
E
On behalf of the ESMO Guidelines Working Group
Small-cell-lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up
Ann Oncol
 , 
2010
, vol. 
21
 
Suppl 5
(pg. 
v120
-
v125
)
3.
Shepherd
FA
Crowley
J
Van Houtte
P
, et al.  . 
International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions
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
, vol. 
2
 (pg. 
1067
-
1077
)
4.
Detterbeck
FC
Boffa
DJ
Tanoue
LT
Wilson
LD
Details and difficulties regarding the new lung cancer staging system
Chest
 , 
2010
, vol. 
137
 (pg. 
1172
-
1180
)
5.
Bradley
JD
Dehdashti
F
Mintun
MA
, et al.  . 
Positron emission tomography in limited-stage small-cell lung cancer: a prospective study
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
3248
-
3254
)
6.
Fischer
BM
Mortensen
J
Langer
SW
, et al.  . 
A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis
Ann Oncol
 , 
2007
, vol. 
18
 (pg. 
338
-
345
)
7.
Niho
S
Fujii
H
Murakami
K
, et al.  . 
Detection of unsuspected distant metastases and/or regional nodes by FDG-PET [corrected] scan in apparent limited-disease small-cell lung cancer
Lung Cancer
 , 
2007
, vol. 
57
 (pg. 
328
-
333
)
8.
Vinjamuri
M
Craig
M
Campbell-Fontaine
A
, et al.  . 
Can positron emission tomography be used as a staging tool for small-cell lung cancer?
Clin Lung Cancer
 , 
2008
, vol. 
9
 (pg. 
30
-
34
)
9.
Badzio
A
Kurowski
K
Karnicka-Mlodkowska
H
, et al.  . 
A retrospective comparative study of surgery followed by chemotherapy vs non-surgical management in limited-disease small cell lung cancer
Eur J Cardiothorac Surg
 , 
2004
, vol. 
26
 (pg. 
183
-
188
)
10.
Yu
JB
Decker
RH
Detterbeck
FC
, et al.  . 
Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer
J Thorac Oncol
 , 
2010
, vol. 
5
 (pg. 
215
-
219
)
11.
Schreiber
D
Rineer
J
Weedon
J
, et al.  . 
Survival outcomes with the use of surgery in limited-stage small cell lung cancer: should its role be re-evaluated?
Cancer
 , 
2010
, vol. 
116
 (pg. 
1350
-
1357
)
12.
Jiang
J
Liang
X
Zhou
X
, et al.  . 
Meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small-cell lung cancer
J Thorac Oncol
 , 
2010
, vol. 
5
 (pg. 
867
-
873
)
13.
Zatloukal
P
Cardenal
F
Szczesna
A
, et al.  . 
A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease
Ann Oncol
 , 
2010
, vol. 
21
 (pg. 
1810
-
1816
)
14.
De Ruysscher
D
Pijls-Johannesma
M
Bentzen
SM
, et al.  . 
Time
between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
1057
-
1563
)
15.
Marks
LB
Bentzen
SM
Deasy
JO
, et al.  . 
Radiation dose-volume effects in the lung
Int J Radiat Oncol Biol Phys
 , 
2010
, vol. 
76
 
3 Suppl
(pg. 
S70
-
S76
)
16.
De Ruysscher
D
Faivre-Finn
C
Nestle
U
on behalf of the Lung Group and the Radiation Oncology Group of the European Organization for Research and Treatment of Cancer (EORTC)
EORTC recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer
J Clin Oncol
 , 
2010
, vol. 
28
 (pg. 
5301
-
5310
)
17.
Baas
P
Belderbos
JS
Senan
S
, et al.  . 
Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study
Br J Cancer
 , 
2006
, vol. 
94
 (pg. 
625
-
630
)
18.
De Ruysscher
D
Bremer
RH
Koppe
F
, et al.  . 
Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial
Radiother Oncol
 , 
2006
, vol. 
80
 (pg. 
307
-
312
)
19.
van Loon
J
De Ruysscher
D
Wanders
R
, et al.  . 
Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study
Int J Radiat Oncol Biol Phys
 , 
2010
, vol. 
77
 (pg. 
329
-
336
)
20.
Quon
H
Shepherd
FA
Payne
DG
, et al.  . 
The influence of age on the delivery, tolerance, and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
1999
, vol. 
43
 (pg. 
39
-
45
)
21.
Yuen
AR
Zou
G
Turrisi
AT
, et al.  . 
Similar outcome of elderly patients in intergroup trial 0096: cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma
Cancer
 , 
2000
, vol. 
89
 (pg. 
1953
-
1960
)
22.
Shimizu
T
Sekine
I
Sumi
M
, et al.  . 
Concurrent chemoradiotherapy for limited-disease small-cell lung cancer in elderly patients aged 75 years or older
Jpn J Clin Oncol
 , 
2007
, vol. 
37
 (pg. 
181
-
185
)
23.
Jeremic
B
Shibamoto
Y
Nikolic
N
, et al.  . 
Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study
J Clin Oncol
 , 
1999
, vol. 
17
 (pg. 
2092
-
2099
)
24.
Kochhar
R
Frytak
S
Shaw
EG
, et al.  . 
Survival of patients with extensive small-cell lung cancer who have only brain metastases at initial diagnosis
Am J Clin Oncol
 , 
1997
, vol. 
20
 (pg. 
125
-
127
)
25.
Auperin
A
Arriagada
R
Pignon
JP
, et al.  . 
Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group
N Engl J Med
 , 
1999
, vol. 
341
 (pg. 
476
-
484
)
26.
Slotman
B
Faivre-Finn
C
Kramer
G
, et al.  . 
Prophylactic cranial irradiation in extensive small-cell lung cancer
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
664
-
672
)
27.
Le Pechoux
C
Dunant
A
Senan
S
, et al.  . 
Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial
Lancet Oncol
 , 
2009
, vol. 
10
 (pg. 
467
-
474
)
28.
Crossen
JR
Garwood
D
Glatstein
E
Neuwelt
EA
Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy
J Clin Oncol
 , 
1994
, vol. 
12
 (pg. 
627
-
642
)
29.
Wolfson
AH
Bae
K
Komaki
R
, et al.  . 
Secondary endpoints of a phase II randomized trial (RTOG 0212): impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited disease small-cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
2009
, vol. 
75
 
Suppl 1
pg. 
S34
 
30.
Cheng
S
Evans
WK
Stys-Norman
D
Shepherd
FA
Chemotherapy for relapsed small cell lung cancer. A systematic review and practice guidelines
J Thorac Oncol
 , 
2007
, vol. 
2
 (pg. 
348
-
354
)
31.
O’Brien
M
Ciuleanu
T
Tsekov
H
, et al.  . 
Phase III trial comparing supportive care alone with oral topotecan in patients with relapsed small-cell lung cancer
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
5441
-
5447
)
32.
Von Pawel
J
Schiller
JH
Shepherd
FA
, et al.  . 
Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer
J Clin Oncol
 , 
1990
, vol. 
17
 (pg. 
658
-
667
)
33.
Eckardt
JR
von Pawel
J
Pujol
JL
, et al.  . 
Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer
J Clin Oncol
 , 
2007
, vol. 
25
 (pg. 
2086
-
2092
)
34.
Von Pawel
J
Gatzemeier
U
Pujol
JL
, et al.  . 
Phase II comparator study of oral vs. intravenous topotecan in patients with chemosensitive small-cell lung cancer
J Clin Oncol
 , 
2001
, vol. 
19
 (pg. 
1743
-
1749
)
35.
Ihde
DC
Bilek
FS
Cohen
MH
, et al.  . 
Response to thoracic radiotherapy in patients with small cell carcinoma of the lung after failure of combination chemotherapy
Radiology
 , 
1979
, vol. 
132
 (pg. 
443
-
446
)
36.
Ochs
JJ
Tester
WJ
Cohen
MH
, et al.  . 
“Salvage” radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy
Cancer Treat Rep
 , 
1983
, vol. 
67
 (pg. 
1123
-
1126
)
37.
Salazar
OM
Yee
GJ
Slawson
RG
Radiation therapy for chest recurrences following induction chemotherapy in small cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
1991
, vol. 
21
 (pg. 
645
-
650
)
38.
Sadikov
E
Bezjak
A
Yi
QL
, et al.  . 
Value of whole brain re-irradiation for brain metastases—single centre experience
Clin Oncol (R Coll Radiol)
 , 
2007
, vol. 
19
 (pg. 
532
-
538
)
39.
Hazel van
GA
Scott
M
Eagan
RT
The effect of CNS metastases on the survival of patients with small-cell cancer of the lung
Cancer
 , 
1983
, vol. 
51
 (pg. 
933
-
937
)
40.
Sheehan
J
Kondziolka
D
Flickinger
J
Lunsford
LD
Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors
J Neurosurg
 , 
2005
, vol. 
102
 
Suppl
(pg. 
247
-
254
)
41.
Ammirati
M
Cobbs
CS
Linskey
ME
, et al.  . 
The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline
J Neurooncol
 , 
2010
, vol. 
96
 (pg. 
85
-
96
)
42.
Albain
KS
Crowley
JJ
Hutchins
L
, et al.  . 
Predictors of survival following relapse or progression of small cell lung cancer Southwest Oncology Group Study 8605 report and analysis of recurrent disease data base
Cancer
 , 
1993
, vol. 
15
 (pg. 
1184
-
1191
)
See Appendix for members of the Panel.
*if no confirmation of solitary metastasis is obtained, radiotherapy may be added after first response evaluation and may be omitted in case of obvious metastatic involvement