Lung cancer nice evidence update november 2012

Evidence Update 24 – Lung cancer (November 2012) 1

Lung cancer: Evidence Update November 2012 A summary of selected new evidence relevant to NICE clinical guideline 121 ‘The diagnosis and treatment of lung cancer’ (2011)

Evidence Update 24

Evidence Update 24 – Lung cancer (November 2012) 2

Evidence Updates provide a summary of selected new evidence published since the literature search was last conducted for the accredited guidance they relate to. They reduce the need for individuals, managers and commissioners to search for new evidence. Evidence Updates highlight key points from the new evidence and provide a commentary describing its strengths and weaknesses. They also indicate whether the new evidence may have a potential impact on current guidance. For contextual information, this Evidence Update should be read in conjunction with the relevant clinical guideline, available from the NHS Evidence topic page for lung cancer.

Evidence Updates do not replace current accredited guidance and do not provide formal practice recommendations.

NHS Evidence is a service provided by NICE to improve use of, and access to, evidence-based information about health and social care.

National Institute for Health and Clinical Excellence

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© National Institute for Health and Clinical Excellence, 2012. All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.

Evidence Update 24 – Lung cancer (November 2012) 3

Contents Introduction ................................................................................................................................ 4

Key points .................................................................................................................................. 5

1 Commentary on new evidence .......................................................................................... 7

1.1 Access to services and referral ................................................................................. 7

1.2 Communication .......................................................................................................... 7

1.3 Diagnosis and staging ............................................................................................... 7

1.4 Treatment ................................................................................................................ 12

1.5 Palliative interventions and supportive and palliative care ...................................... 20

1.6 Follow-up and patient perspectives ......................................................................... 20

2 New evidence uncertainties ............................................................................................. 21

Appendix A: Methodology ........................................................................................................ 22

Appendix B: The Evidence Update Advisory Group and Evidence Update project team ....... 24

Evidence Update 24 – Lung cancer (November 2012) 4

Introduction This Evidence Update identifies new evidence that is relevant to, and may have a potential impact on, the following reference guidance:

Lung cancer. NICE clinical guideline 121 (2011).

A search was conducted for new systematic reviews from 1 August 2010 to 28 May 2012. A total of 1418 pieces of evidence were identified and assessed, of which 22 were selected for the Evidence Update (see Appendix A for details of the evidence search and selection process). An Evidence Update Advisory Group, comprised of topic experts, reviewed the prioritised evidence and provided a commentary.

Although the process of updating NICE guidance is distinct from the process of an Evidence Update, the relevant NICE guidance development centres have been made aware of the new evidence, which will be considered when guidance is reviewed.

Other relevant NICE guidance The focus of the Evidence Update is on the guidance stated above. However, overlap with other accredited guidance has been outlined as part of the Evidence Update process. Where relevant, this Evidence Update therefore makes reference to the following guidance:

Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer

. NICE technology appraisal 258 (2012).

Topotecan for the treatment of relapsed small-cell lung cancer. NICE technology appraisal 184 (2009).

Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal 181 (2009).

Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 175 (2009).

Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal 162 (2008).

• 2Cryotherapy for malignant endobronchial obstruction. NICE interventional procedure guidance 142 (2005).

Quality standards • Lung cancer for adults

Feedback

. NICE quality standard.

If you have any comments you would like to make on this Evidence Update, please email [email protected]

1 NICE-accredited guidance is denoted by the Accreditation Mark 2 Guidance published prior to NICE accreditation

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Evidence Update 24 – Lung cancer (November 2012) 5

Key points The following table summarises what the Evidence Update Advisory Group (EUAG) decided were the key points for this Evidence Update. It also indicates the EUAG’s opinion on whether the new evidence may have a potential impact on the current guidance listed in the introduction. For further details of the evidence behind these key points, please see the full commentaries.

The section headings used in the table below are taken from the guidance.

Potential impact on guidance

Key point Yes No Diagnosis and staging

• Autofluorescence bronchoscopy seems to have higher sensitivity but lower specificity than white-light bronchoscopy

• Insufficient evidence exists to guide the choice between fine-needle aspiration and core-needle biopsy for diagnosing lung cancer.

• Positron emission tomography-computed tomography (PET-CT)

seems to be sensitive, specific and cost-effective when used for staging of lung cancer.

• Evidence suggests that PET-CT may have a role in radiotherapy

planning. Treatment

• Risk of death after neo-adjuvant treatment and thoracic surgery seems to be higher for right-sided pneumonectomy than for left-sided pneumonectomy.

• A medium dose of radiation in stereotactic ablative radiotherapy

(SABR; previously known as stereotactic body irradiation [SBRT]) may be associated with better 2-year survival than low or high doses.

* • Modified fractionation radiotherapy seems to be associated with

better survival in non-small cell lung cancer (NSCLC) than conventional fractionation radiotherapy.

• For patients who cannot tolerate combination chemotherapy, a

weekly dosing schedule may be associated with less neutropenia, febrile neutropenia and peripheral neuropathy than standard 3-weekly dosing.

• Combination chemotherapy with gemcitabine plus paclitaxel may

have a similar efficacy to platinum-based combination chemotherapy with less neutropenia, anaemia and thrombocytopenia in treating NSCLC.

* • Chemotherapy plus supportive care seems to be associated with

survival benefit compared with supportive care alone in treating NSCLC.

* Evidence Updates are intended to increase awareness of new evidence and do not change the recommended practice as set out in current guidance. Decisions on how the new evidence may impact guidance will not be possible until the guidance is reviewed by NICE following its published processes and methods. For further details of this evidence in the context of current guidance, please see the full commentary.

Evidence Update 24 – Lung cancer (November 2012) 6

Potential impact on guidance

Key point Yes No • Pemetrexed plus platinum-based chemotherapy seems to be

associated with longer survival than combination chemotherapy with a third-generation drug and a platinum-based drug for treating NSCLC.

• Bevacizumab plus chemotherapy seems to be associated with

slightly increased progression-free survival compared with chemotherapy alone, but does not seem to significantly affect overall survival in people with NSCLC. However adverse events and treatment-related deaths were significantly higher in people receiving bevacizumab.

• Topotecan3 plus platinum-based chemotherapy does not seem to increase overall survival as first-line treatment in small-cell lung cancer (SCLC) compared with etoposide plus platinum-based chemotherapy. However irinotecan4 plus platinum may be associated with greater overall survival than etoposide plus platinum.

• NICE technology appraisals of the epidermal growth factor-targeted therapies erlotinib and gefitinib (as second-line treatment) and cetuximab are underway and a technology appraisal of erlotinib (as first-line treatment) has recently been published.

Palliative interventions and supportive and palliative care • Cryotherapy seems to be an effective intervention to treat airway

obstruction in lung cancer.

3 Topotecan is not recommended by current guidance for first-line treatment of SCLC and, at the time of publication of this Evidence Update, did not have UK marketing authorisation for this indication. 4 Irinotecan is not recommended by current guidance for SCLC and, at the time of publication of this Evidence Update, did not have UK marketing authorisation for this indication.

Evidence Update 24 – Lung cancer (November 2012) 7

1 Commentary on new evidence These commentaries analyse the key references identified specifically for the Evidence Update. The commentaries focus on the ‘key references’ (those identified through the search process and prioritised by the EUAG for inclusion in the Evidence Update), which are identified in bold text. Supporting references provide context or additional information to the commentary. Section headings are taken from the guidance.

1.1 Access to services and referral No new key evidence was found for this section.

1.2 No new key evidence was found for this section.

Communication

1.3 Diagnosis and staging

Autofluorescence versus white light bronchoscopy NICE clinical guideline 121 (CG121) does not specify the type of light source to use in fibreoptic bronchoscopy.

Chen et al. (2011a) did a meta-analysis of autofluorescence bronchoscopy (AFB) compared with white light bronchoscopy (WLB) for detection of cancerous or dysplastic lesions in people with suspected lung cancer. Included studies needed to use histology for final diagnosis of lung cancer or preneoplastic lesions and provide enough data to allow assessment of the diagnostic yield. 14 prospective studies with 15 comparisons were included (1 study assessed 2 types of AFB system) with a total of 1358 patients examined by AFB.

The meta-analysis used a bivariate model to obtain pooled sensitivity and specificity. A random-effects model was used because of substantial variability in the reported sensitivity (range: AFB=0.67–1.00, WLB=0.28–0.76) and specificity (range: AFB=0.25–0.84, WLB=0.33–0.94).

The pooled sensitivity for AFB was 0.90 (95% confidence interval [CI] 0.84 to 0.93) and for WLB it was 0.66 (95% CI 0.58 to 0.73). The pooled specificity for AFB was 0.56 (95% CI 0.45 to 0.66) and for WLB it was 0.69 (95% CI 0.57 to 0.79). In the summary receiver operating characteristic curve, the area under the curve (AUC) was 0.84 (range 0.80–0.87) for AFB and 0.72 (range 0.68–0.75) for WLB, which the authors concluded was due to a slightly better diagnostic performance of AFB.

Covariate analyses for AFB showed that use of laser light source, use of control biopsy, and whether positive results were defined as ‘moderate dysplasia or worse’ or ‘mild dysplasia or worse’ did not significantly affect the pooled results.

The authors’ quality assessment of the included studies noted that only 25% detailed the standard of AFB and 65% had appreciable histopathological descriptions. The reporting of whether patients were enrolled consecutively or randomly was poor in most studies. A potential source of bias was that most studies used WLB first, then AFB, which may have favoured AFB because the bronchoscopist may have been influenced by the knowledge of lesions seen on WLB when identifying lesions with AFB.

Another meta-analysis by Sun et al. (2011) included 21 studies with 3266 patients looking at WLB plus AFB versus WLB alone for the diagnosis of intraepithelial neoplasia and invasive lung cancer, with histopathology as the reference standard.

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A random-effects model was used because of heterogeneity in both sensitivity and specificity to detect intraepithelial neoplasia. The relative risk (RR) of sensitivity and specificity was calculated on a per-lesion basis, whereby a RR of more than 1 reflected more sensitivity or specificity in the AFB plus WLB group.

The pooled per-lesion sensitivity was 84.63% for AFB plus WLB and 42.54% for WLB alone to detect intraepithelial neoplasia, and was 94.71% for AFB plus WLB and 88.53% for WLB alone to detect invasive cancer. The pooled per-lesion specificity was 60.94% for AFB plus WLB and 79.70% for WLB alone.

The pooled relative sensitivity of AFB plus WLB versus WLB alone was 2.04 (95% CI 1.72 to 2.42, p<0.00001) for detecting intraepithelial neoplasia and 1.15 (95% CI 1.05 to 1.26, p=0.003) for detecting invasive cancer. The pooled relative specificity was 0.65 (95% CI 0.59 to 0.73, p<0.00001).

The authors postulated that only WLB may be needed for detecting invasive cancer because the RR for sensitivity gained with both AFB and WLB was much smaller than the RR for sensitivity gained when detecting intraepithelial neoplasia. The lower specificity of AFB was noted as problematic because more biopsies would be needed. A funnel plot identified publication bias in studies reporting positive results for AFB plus WLB versus WLB alone.

The evidence from both Chen et al (2011a) and Sun et al. (2011) suggests that AFB may have better sensitivity than WLB especially for detecting dysplastic lesions. The specificity of AFB seems to be lower than that of WLB, so the benefits of higher detection rates might be limited by the need to do additional biopsies. These data are not likely to impact NICE CG121, which does not specify the type of light to use in fibreoptic bronchoscopy.

A critical abstract of the study by Chen et al. (2011a) was produced for the Centre for Reviews and Dissemination’s Database of Abstracts of Reviews of Effects.

Key references Chen W, Gao X, Tian Q et al. (2011) A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: a meta-analysis. Lung cancer 73: 183–8

Sun J, Garfield DH, Lam B et al. (2011) The value of autofluorescence bronchoscopy combined with white light bronchoscopy compared with white light alone in the diagnosis of intraepithelial neoplasia and invasive lung cancer. A meta-analysis. Journal of Thoracic Oncology 6: 1336–44

Supporting reference Centre for Reviews and Dissemination (2012) A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: a meta-analysis. Database of Abstracts of Reviews of Effects.

Fine-needle aspiration versus core-needle biopsy NICE CG121 recommends a range of biopsy procedures depending on the site; in most recommendations a choice of endobronchial ultrasound-guided transbronchial needle aspiration or endoscopic ultrasound-guided fine-needle aspiration (FNA) should be offered. However, additional recommendations note that the need to take adequate samples should be balanced with reducing the risk to the patient, and require local audits of different biopsy techniques.

A systematic review by Yao et al. (2012) assessed FNA versus core-needle biopsy (CNB) in people with undiagnosed lung nodule or mass seen on imaging for 3 outcomes: diagnosis, complication rates, and obtaining sufficient samples. The reference standard was histological confirmation of lung cancer from wedge biopsy, surgical resection, metastases or autopsy, or from clinical follow-up. 11 studies of 1664 people were included.

Evidence Update 24 – Lung cancer (November 2012) 9

Studies were excluded if they: included people with confirmed or recurrent lung cancer; used the results from FNA or CNB as part of the reference standard; or used different techniques in depending on the population.

The systematic review did not pool or meta-analyse the data, but instead presented ranges. Diagnostic characteristics were presented as overall (differentiating malignant and benign lesions) and specific (defining the histological subtype).

For overall diagnostic characteristics: the sensitivity was 81.3–90.8% for FNA and 85.7–97.4% for CNB; the specificity was 75.4–100.0% for FNA and 88.6–100.0% for CNB; accuracy was 79.7–91.8% for FNA and 89.0–96.9% for CNB; positive likelihood ratio was 3.67–45.46 for FNA and 7.79–75.94 for CNB; and negative likelihood ratio was 0.10–0.18 for FNA and 0.03–0.12 for CNB.

For specific diagnostic characteristics: the sensitivity was 56.3–86.5% for FNA and 56.5–88.7% for CNB; the specificity was 6.7–57.1% for FNA and 52.4–100.0% for CNB; accuracy was 40.4–81.2% for FNA and 66.7–93.2% for CNB; positive likelihood ratio was 0.60–1.93 for FNA and 1.55–15.07 for CNB; and negative likelihood ratio was 0.30–6.56 for FNA and 0.12–0.50 for CNB.

The main complications of both FNA and CNB were pneumothorax and pulmonary haemorrhage. In 2 prospective studies using 20–22 gauge needles for FNA and 18–21.5 gauge needles for CNB, no differences were seen in rates of pneumothorax. Pulmonary haemorrhage was increased in the CNB group in one study but not in the other.

In another 7 non-prospective studies that used 20–25 gauge needles for FNA and 18–20 gauge needles for CNB, the rates of pneumothorax were 0.0–35.1% for FNA and 0.0–28.6% for CNB. None of these studies showed significant differences in rates of pulmonary haemorrhage of haemoptysis between biopsy types.

The authors noted that the design and reporting of most of the included studies was poor. Potential sources of bias included the recruitment of people with thoracic lesions (which may not be diagnosed by FNA as well as lung cancer), differences in study type (fully paired, randomised, or indirect comparison), and lack of blinding.

The authors concluded that the evidence is insufficient to guide choice of FNA, CNB or both, in practice, and that the best technique is influenced by the local expertise in biopsy technique and sample interpretation. This conclusion is consistent with the recommendations in NICE CG121 around choice of biopsy technique and the need for local audits of test performance.

Key reference Yao X, Gomes MM, Tsao MS et al. (2012) Fine-needle aspiration biopsy versus core needle biopsy in diagnosing lung cancer: a systematic review. Current Oncology 19: e16–27

Positron-emission tomography (PET) in staging In NICE CG121, PET-computed tomography (CT) is recommended for mediastinal lymph node staging in patients whose disease is potentially suitable for treatment with curative intent, such as those with low probability of mediastinal malignancy (lymph nodes up to 10 mm maximum short axis on CT). It is also an option for staging in people with intermediate probability of mediastinal metastases and for confirming distant metastases.

Lv et al. (2011) did a meta-analysis of 14 studies of PET-CT for mediastinal lymph node staging in people (n=2550) with non-small-cell lung cancer (NSCLC). Studies with histological diagnosis of lymph nodes, clear diagnostic criteria and sufficient data to calculate pooled sensitivity and specificity were included. The quality of included studies was assessed by a

Evidence Update 24 – Lung cancer (November 2012) 10

quality assessment tool for diagnostic accuracy studies (QUADAS) and reported as a percentage of the maximum score (range 54–85%, median 69%).

The patient was the unit of analysis in 11 studies; 6 studies used a standardised uptake value (SUV) cut-off point (4 used 2.5, 1 used 3.0 and 1 used 5.2); and 5 studies considered the mediastinal lymph node (MLN) malignant if the SUV was higher than normal background activity determined by qualitative analysis. The MLN was the unit of analysis in 9 studies (6 of which also did analysis by number of patients); 4 used an SUV cut-off of 2.5, 1 used a cut-off of 5.2, and 4 used qualitative analysis. Significant heterogeneity between studies was noted and publication bias was present for patient-based analysis but not for MLN analysis.

The pooled weighted sensitivity of PET-CT in studies with patient-based analysis was 0.76 (95% CI 0.65 to 0.84) and pooled specificity was 0.88 (95% CI 0.82 to 0.92). In the summary receiver operating characteristic curve, the AUC was 0.90 (95% CI 0.87 to 0.92), indicating good diagnostic performance of PET-CT. The pooled weighted sensitivity of PET-CT in studies with MLN analysis was 0.65 (95% CI 0.62 to 0.68) and specificity was 0.95 (95% CI 0.94 to 0.95). In the summary receiver operating characteristic curve, the AUC was 0.92 (95% CI 0.89 to 0.94).

The authors noted that MLN analysis may overestimate the diagnostic accuracy of PET-CT, and use of patient-based analysis is more useful clinically. Author-reported limitations included possible selection and verification biases.

The results of this meta-analysis are consistent with NICE CG121, which recommends PET-CT for mediastinal lymph node staging in people with disease suitable for potentially curative treatment.

Cao et al. (2012) undertook a systematic review of 18 studies analysing the cost effectiveness of PET-CT versus conventional imaging in people with NSCLC or solitary pulmonary nodules, one of which was the full version of the 2005 NICE clinical guideline on lung cancer. 13 studies focusing on staging in NSCLC were included with a median assumption of mediastinal disease prevalence of 31%, and assumptions of PET-CT having a median sensitivity of 91% and median specificity of 91%. Costs were converted to 2010 US dollars.

Studies reported incremental cost-effectiveness ratios (ICERs) in life-years saved or quality-adjusted life years (QALYs) gained. In the studies on NSCLC, the range of ICERs was $9687 to $14,961 per QALY and −$774 to $34,414 per life-year saved. No pooling or meta-analysis of the results was done. For solitary pulmonary nodules, the range of ICERs was −$9280 to $4445 per life-year saved.

The authors reported on conflicting results of PE-CT on the number of thoracotomies avoided and reductions in other diagnostic procedures needed. They additionally noted that most of the included cost-effectiveness assessments did not consider a long-term horizon or account for treatments such as radiotherapy or chemotherapy.

The overall conclusion of the systematic review was that most studies found that the additional information gained from PET-CT staging of newly diagnosed lung cancer and diagnosis of indeterminate solitary pulmonary nodules is cost effective, which is consistent with NICE CG121.

Ruben and Ball (2012) systematically reviewed 22 studies (n=1663) on the use of PET-CT in the staging of small cell lung cancer (SCLC). None of the included studies were randomised. Adequate clinical or pathological correlation of imaging findings was reported in 11 studies.

The authors reported that PET-CT could change the management of disease compared with conventional staging in 28% of people if including radiotherapy portal changes. If studies without data on radiotherapy portal changes were included, PET-CT changed management in

Evidence Update 24 – Lung cancer (November 2012) 11

38% of people. PET-CT may have resulted in radiotherapy to potentially prolong life in 6% of people and may have averted radiotherapy in 9%. In a cost-effectiveness calculation, use of PET-CT was associated with a cost saving of AU$2752 per life-year gained.

In conclusion, the authors recognised the limitations of the available data, but that most available studies reported adequate correlation of PET-CT findings with clinical or pathological results. A successful randomised trial was thought to be unlikely because of the large number of patients needed. NICE CG121 does not specify whether the use of PET-CT in staging applies to NSCLC or SCLC, so this evidence is consistent with current guidance.

Key references Cao JQ, Rodrigues GB, Louie AV et al. (2012) Systematic review of the cost-effectiveness of positron-emission tomography in staging of non-small-cell lung cancer and management of solitary pulmonary nodules. Clinical Lung Cancer 13:161–70

Lv Y-L, Yuan D-M, Wang K et al. (2011) Diagnostic performance of integrated positron emission tomography/computed tomography for mediastinal lymph node staging. Journal of Thoracic Oncology 6: 1350–8

Ruben JD, Ball DL (2012) The efficacy of PET staging for small-cell lung cancer: a systematic review and cost analysis in the Australian setting. Journal of Thoracic Oncology 7: 1015–20

PET for radiotherapy treatment planning NICE CG121 recommends PET-CT in staging lung cancer, but does not provide specific recommendations about how radiotherapy should be planned.

Ung et al. (2011) did a systematic review of PET-CT used in the planning of radiotherapy in 28 studies (n=1054), mostly prospective observational studies. Only one randomised controlled trial was identified. All studies assessed NSCLC, with some additionally including people with SCLC or unspecified lung cancer.

Changes in gross tumour volume and planning target volume as a result of including PET imaging in radiotherapy planning were not reported consistently. In 11 studies reporting change in gross tumour volume, PET-CT was associated with a mean decrease of 14–71% (median 40.5%). In 10 studies reporting changes in planning target volume, PET-CT was associated with a mix of increases and decreases in planning target volume. PET-CT resulted in the detection of distant metastases in 8–25% of patients (median 17.5%) across 6 studies. The intent of radiotherapy changed from curative to palliative in 8–41% of patients across 11 studies. The reasons were not fully reported but included the detection of distant metastases or more extensive disease.

The authors noted several potential sources of bias including that the study methods may not relate completely to real-world practice: in all studies, radiotherapy plans were first developed using only CT data then with PET-CT included, but in practice clinicians would view all relevant imaging simultaneously. Retrospective case reviews may be biased because investigators may have been less conservative in their planning definitions knowing that they would not be used in real patients.

This review suggests that PET-CT has benefits over CT in planning radiotherapy for people with lung cancer. PET-CT is recommended in NICE CG121 for staging in people with lung cancer, but no specific recommendations are made for radiotherapy planning. However, the fact that PET-CT imaging in Ung et al. (2011) detected metastasis or identified that the cancer was at a more advanced stage in some people provides some limited evidence in support of using this imaging in staging. How PET-CT imaging should be used for radiation planning in UK clinical practice, where PET-CT for staging is already established, is not clear.

Evidence Update 24 – Lung cancer (November 2012) 12

Key reference Ung YC, Bezjak A, Coakley N et al. (2011) Positron emission tomography with 18Fluorodeoxyglucose in radiation treatment planning for non-small cell lung cancer: a systematic review. Journal of Thoracic Oncology 6: 86–97

1.4 Treatment

Surgery NICE CG121 recommends lobectomy as first choice surgical treatment for NSCLC, and that more extensive surgery, including pneumonectomy, should be offered only when needed to obtain clear margins. However, the guidance also states ‘do not offer neo-adjuvant chemotherapy outside a clinical trial’.

Kim et al. (2012) did a meta-analysis of 27 studies (n=2126) of perioperative mortality after pneumonectomy following neo-adjuvant chemotherapy or chemoradiation therapy for NSCLC. The overall 30-day mortality was 7%: right pneumonectomy mortality was 11% and left pneumonectomy mortality was 5% (odds ratio [OR]=1.97, 95% CI 1.11 to 3.49, p=0.02). At 90 days the overall mortality was 12%: right pneumonectomy mortality was 20% and left pneumonectomy mortality was 9% (OR=2.01, 95% CI 1.09 to 3.72, p=0.03). The most common cause of death was pulmonary complications (50% at 30 days and 40% at 90 days).

The authors concluded that left pneumonectomy after neo-adjuvant treatment is justifiable in terms of 30-day and 90-day mortality, but the risk–benefit profile of right pneumonectomy is less clear. Additionally it was not clear whether the increase in mortality between 30 and 90 days was due to the neo-adjuvant treatment, changes in cardiopulmonary function after pneumonectomy, or complications taking longer to lead to death.

Limitations recognised by the authors included use of a diverse range of chemotherapy regimens, which were not able to be analysed and no distinctions could be made between simple and complicated pneumonectomies.

The evidence suggests that risk of death is higher in right-side than in left-side pneumonectomy after neo-adjuvant treatment. Because NICE CG121 recommends lobectomy unless pneumonectomy is needed for clear margins, this evidence is unlikely to have an impact on current recommendations. The evidence does not address the efficacy of neo-adjuvant chemotherapy, so is unlikely to affect this aspect of the guidance.

Key reference Kim AW, Boffa DJ, Wang Z et al. (2012) An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non-small cell lung cancer. General Thoracic Surgery 143: 55–63

Radiotherapy NICE CG121 recommends continuous hyperfractionated accelerated radiotherapy (CHART) for medically inoperable stage I and II NSCLC suitable for radical radiotherapy. Conventionally fractionated radiotherapy is recommended if CHART is not available. However, the recommendations for radiotherapy were based on data assessed for the 2005 NICE guideline on lung cancer. In the 2011 review of the guideline these recommendations were not formally re-assessed, however a footnote was added recognising the advances in radiotherapy techniques since 2005 and that centres would reasonably wish to offer these techniques (such as stereotactic ablative radiotherapy [SABR]; previously known as stereotactic body irradiation [SBRT]) to patients.

Evidence Update 24 – Lung cancer (November 2012) 13

Zhang et al. (2011) did a meta-analysis of 34 observational studies (n=2587) investigating stereotactic body radiation therapy for treating stage I NSCLC. Patients’ outcomes were compared by the biologically effective dose, which was categorised, according to quartiles of the included studies, as low (<83.2 Gy), medium (83.2–106 Gy), medium to high (106–146 Gy) or high (>146 Gy).

In a meta-regression model, the proportion of people with tumours smaller than 3 cm significantly affected the results, so the pooled estimates were corrected to apply to a study population with the mean proportion of tumours less than 3 cm (64.2%) across all studies.

At 1 year, overall survival, cancer specific survival, and local control rate were not significantly different for any comparison of biologically effective dose, in either the uncorrected or corrected analyses. At 2 years, in corrected analyses, overall survival in the medium biologically effective dose group (0.76, 95% CI 0.62 to 0.92) was significantly higher than that of the low dose group (0.62, 95% CI 0.54 to 0.71, p=0.004) and the high dose group (0.56, 95% CI 0.50 to 0.63, p<0.001); the medium to high dose group (0.68, 95% CI 0.61 to 0.76) had significantly higher overall survival compared with the high dose group (0.56, 95% CI 0.50 to 0.63, p<0.001).

The proportion of grade 3–5 adverse events were significantly different only in the comparison of low dose (0.05, 95% CI 0.03 to 0.09) and high dose groups (0.09, 95% CI 0.07 to 0.12, p=0.043).

Although this study does not compare SABR with CHART or conventional radiotherapy, the authors noted that a previous meta-analysis of SABR showed 5-year overall survival of 42% compared with 20% for conventional radiotherapy. The evidence by Zhang et al. (2011) may help to establish optimum dosing regimens for SABR, and may have a potential impact on NICE CG121, although the details of any impact are outside the scope of the Evidence Update. Decisions on how the new evidence may impact guidance will not be possible until the guidance is reviewed by NICE following its published processes and methods.

Mauguen et al. (2012) did a meta-analysis of individual patient data comparing hyperfractionated or accelerated radiotherapy (modified radiotherapy) with conventional radiotherapy. A total of 10 studies were included (2 in SCLC and 8 in NSCLC), with 12 comparisons (n=2685). In both SCLC trials, patients received cisplatin and etoposide concomitantly with radiotherapy (in one trial, induction and consolidation chemotherapy were also used). In the 10 NSCLC comparisons, concomitant chemotherapy was used in 2, and induction chemotherapy was used in another 2, with a range of regimens.

People with NSCLC were mostly men (75%) younger than 70 years (71%) with a performance status of 0 or 1 (>99%) and stage III cancer (>80%). People with SCLC had limited disease, were mostly younger than 70 years (83%), and 58% were men.

For NSCLC, overall results were based on 2000 patients with a median follow-up of 6.9 years and 1849 deaths. Modified radiotherapy was associated with an absolute increase in survival of 3.8% (from 15.9% to 19.7%) at 3 years and 2.5% (8.3% to 10.8%) at 5 years. Across trials, the risk of death was significantly reduced (hazard ratio [HR]=0.88, 95% CI 0.80 to 0.97, p=0.009). This increase in survival was not significantly different for groups receiving chemotherapy compared with those who did not. No subgroup of patients, stratified by age, sex, histology or stage, had significantly better response to radiotherapy.

For SCLC, overall results were based on 685 people with a median follow-up of 12.1 years and 622 deaths. Modified radiotherapy was not associated with a significant increase in survival (HR=0.87, 95% CI 0.74 to 1.02, p=0.8). People with poor performance status benefitted significantly less from modified radiotherapy than those with good performance status (performance status 2: HR=2.22 versus performance status 1 HR=0.86 and performance status 0 HR=0.81, p=0.03).

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Modified radiotherapy for NSCLC significantly increased the likelihood of acute severe oesophageal toxicity (OR=2.44, 95% CI 1.90 to 3.14, p>0.001), which was highest for ‘very accelerated radiotherapy’ (OR=3.21, 95% CI 2.41 to 4.28, p value not reported). Platelet toxicity was significantly reduced with modified radiotherapy (OR=0.55, 95% CI 0.32 to 0.96, p=0.03); however, no severe platelet toxicity was seen in people who did not have chemotherapy. In people with SCLC, modified radiotherapy was associated with increased acute oesophageal toxicity (OR=2.41, 95% CI 1.62 to 3.59, p<0.001) and reduced platelet toxicity (OR=0.70, 95% CI 0.50 to 0.98, p=0.04).

NICE CG121 recommends CHART (which is both hyperfractionated and accelerated) for medically inoperable stage I and II NSCLC suitable for radical radiotherapy. Although this evidence does not directly affect use of CHART, it suggests that modified fractionation is generally better than conventional fractionation.

Key references Mauguen A, Le Péchoux C, Saunders MI et al. (2012) Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. Journal of Clinical Oncology 30: 2788–97

Zhang J, Yang F, Li B et al. (2011) Which is the optimal biologically effective dose of stereotactic body radiotherapy for stage I non-small cell lung cancer? A meta-analysis. International Journal of Radiation Oncology Biology Physics 81: e305–16

Chemotherapy in NSCLC

Combination chemotherapy NICE CG121 recommends combination chemotherapy for advanced non-small cell lung cancer using a third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) plus a platinum drug (cisplatin or carboplatin). Dosing regimens are not specified. A single third-generation drug may be used for people unable to tolerate combination chemotherapy.

Gao et al. (2012) did a meta-analysis of 5 randomised trials (n=940) of paclitaxel-based chemotherapy regimens given once weekly compared with standard 3-weekly dosing in NSCLC. Studied regimens were paclitaxel in combination with carboplatin, or gemcitabine or carboplatin plus cetuximab.

The median overall survival was 9.8 months for weekly paclitaxel regimens compared with 10.7 months for 3-weekly paclitaxel (HR=1.00, 95% CI 0.86 to 1.17, p=0.99). The median progression-free survival was 5.2 months compared with 4.7 months respectively (HR=0.90, 95% CI 0.79 to 1.03, p=0.13).

Adverse events were not reported uniformly, but the most commonly reported were haematological toxicities, fever and peripheral neuropathy. Weekly treatment was associated with lower rates of neutropenia (OR=0.47, 95% CI 0.27 to 0.83, p=0.0009), febrile neutropenia (OR=0.46, 95% CI 0.21 to 0.98, p=0.04) and peripheral neuropathy (grade 2 and 4, OR=0.50, 95% CI 0.33 to 0.76, p=0.001). Anaemia was more common with weekly treatment (OR=2.08, 95% CI 0.20 to 3.58, p=0.009). No significant difference in treatment-related deaths was seen.

The authors noted that weekly chemotherapy may be useful for older patients with comorbidities and functional status for whom standard 3-weekly chemotherapy would not be suitable. Current guidance does not include dosing schedules, so this evidence is not likely to impact NICE CG121.

Li et al. (2010) did a meta-analysis of 4 trials (n=2186) of gemcitabine plus paclitaxel compared with carboplatin plus gemcitabine or carboplatin plus paclitaxel. Gemcitabine plus paclitaxel did not significantly affect 1-year survival (OR 1.04, 95% CI 0.89 to 1.22, p=0.62). Grade 3–4 neutropenia (OR=0.61, 95% CI 0.49 to 0.76), anaemia (OR=0.32, 95% CI 0.23 to

Evidence Update 24 – Lung cancer (November 2012) 15

0.45) and thrombocytopenia (OR=0.12, 95% CI 0.08 to 0.16) were lower with gemcitabine plus paclitaxel.

This evidence suggests that gemcitabine plus paclitaxel may have similar efficacy to and lower toxicity than combination chemotherapy including a platinum-based drug. This may have a potential impact on NICE CG121 for patients who are unable to tolerate platinum-based combination chemotherapy, although the details of any impact are outside the scope of the Evidence Update. Decisions on how the new evidence may impact guidance will not be possible until the guidance is reviewed by NICE following its published processes and methods.

A critical abstract of the study by Li et al. (2010), was produced for the Centre for Reviews and Dissemination’s NHS Database of Abstracts of Reviews of Effects.

Key references Gao G, Chu H, Zhao L et al. (2012) A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer. Lung Cancer 76: 380–6

Li C, Sun Y, Pan Y et al. (2010) Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small cell lung cancer: a literature-based meta-analysis. Lung 188 359–64

Supporting reference Centre for Reviews and Dissemination (2011) Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small cell lung cancer: a literature-based meta-analysis. Database of Abstracts of Reviews of Effects.

Chemotherapy for advanced NSCLC NICE CG121 recommends chemotherapy for stage III and IV NSCLC in people with good performance status to improve survival, disease control and quality of life.

In a Cochrane review, the Non-Small Cell Lung Cancer Collaborative Group (2010) assessed the effect of supportive care or supportive care plus chemotherapy on survival in people with advanced NSCLC whose disease was not suitable for surgery or radical radiotherapy and who had not previously received chemotherapy. Data from 16 trials were included (n=2714). The definition of supportive care included palliative radiotherapy, antibiotics, corticosteroids, analgesics, antiemetics, transfusions and psychological support.

Chemotherapy was associated with a significant survival benefit (HR=0.77, 95% CI 0.71 to 0.83, p<0.0001) with an absolute median survival benefit of 1.5 months. Median survival increased from 4.5 months for those on supportive care to 6 months for those receiving supportive care and chemotherapy.

No significant differences were seen for type of chemotherapy drugs used, or in single drug versus combination regimens, or in subgroups of patients defined by age, sex, stage, histology or performance status.

The authors noted that their previous Cochrane review in this topic had led to discussion about whether the side-effects of chemotherapy were worthwhile for the small increase in survival. Although the authors highlighted some data to suggest that quality of life was the same or increased in people who received chemotherapy, the data for quality of life were not sufficient to assess this outcome.

The results of this study are consistent with the recommendation in NICE CG121 to offer chemotherapy in advanced NSCLC to improve survival, disease control and quality of life.

Key reference Non-Small Cell Lung Cancer Collaborative Group (2010) Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database of Systematic Reviews issue 5: CD007309

Evidence Update 24 – Lung cancer (November 2012) 16

Pemetrexed Pemetrexed plus cisplatin is recommended by NICE technology appraisal (TA) 181 for first-line treatment of locally advanced or metastatic NSCLC that has been histologically confirmed as adenocarcinoma or large-cell carcinoma. NICE CG121 includes a cross-reference directing the reader to the technology appraisal.

Li et al. (2012) did a meta-analysis of 4 randomised controlled trials (n=2518) of first-line pemetrexed plus cisplatin or carboplatin compared with third-generation drugs plus cisplatin (1 trial) or carboplatin (4 trials) in stage III or IV NSCLC. The third-generation drugs used in comparisons were gemcitabine or docetaxel.

The overall survival was greater with pemetrexed plus platinum (HR=0.91, 95% CI 0.83 to 1.00, p=0.04), and no significant heterogeneity between studies was noted. In patients with non-squamous disease (defined as adenocarcinoma or large-cell carcinoma, n=1792) the overall survival benefit of pemetrexed plus platinum (HR=0.87, 95% CI 0.77 to 0.98, p=0.02) was greater than for all NSCLC cancers. The survival benefit was marginally greater when only the pemetrexed plus cisplatin data were analysed (HR=0.85, 95% CI 0.72 to 0.99, p=0.04). No significant increase in progression-free survival was seen.

Pemetrexed plus platinum was associated with less grade 3 and 4 neutropenia (OR=0.50, 95% CI 0.34 to 0.74, p=0.0005) and leukopenia (OR=0.41, 95% CI 0.25 to 0.65, p=0.0002), but more nausea (OR=1.63, 95% CI 1.11 to 2.39, p=0.01) compared with other platinum-based chemotherapy.

The authors noted that data for squamous NSCLC such as HRs for overall survival were not mentioned in most studies; therefore no analysis was done for squamous disease. The authors recognised that their results should be interpreted with caution because of the small number of trials and patients included in the meta-analysis. The finding that overall survival is greater in people with non-squamous NSCLC is consistent with NICE TA181.

Key reference Li M, Zhang Q, Fu P et al. Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. PLoS one 7: e37229

Epidermal growth factor-targeted therapies ‘Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer’ (NICE TA258) recently recommended erlotinib as an option for the first-line treatment of people with locally advanced or metastatic NSCLC if: they test positive for the epidermal growth factor receptor tyrosine kinase mutation and the manufacturer provides erlotinib at the discounted price agreed under the patient access scheme (as revised in 2012). Although the Evidence Update found new evidence in this area (see Chen et al. 2011b in the key references below), commentary is not provided because the technology appraisal was recently issued5

A NICE multiple technology appraisal of

and should be referred to as the latest guidance.

erlotinib and gefitinib in second-line treatment of lung cancer is currently underway. Although the Evidence Update found new evidence in this area (see Chen et al. 2011b and Jiang et al. 2011 in the key references below), commentary is not provided because a technology appraisal is in progress, which should be referred to as the latest guidance once it is published. This technology appraisal combines reviews of two existing technology appraisals: ‘Erlotinib for the treatment of non-small-cell lung cancer’ (NICE TA162), which should be referred to as the latest guidance until the new guidance is issued; and ‘

5 Evidence Updates do not provide commentaries on drugs and indications covered by NICE technology appraisals issued in the 12 months before publication of the Evidence Update. The new evidence will be taken into account when

Gefitinib for the second-line treatment of locally advanced or metastatic non-

NICE TA258 is considered for review in April 2013.

Evidence Update 24 – Lung cancer (November 2012) 17

small-cell lung cancer

Although the Evidence Update found new evidence on cetuximab in advanced lung cancer (see Lin et al. 2010 in the key references below), commentary is not provided because a NICE single technology appraisal of

’ (NICE TA175), which was terminated because no evidence submission was received from the manufacturer or sponsor of the technology.

cetuximab in advanced lung cancer was recently suspended.6

Critical abstracts of the studies by Chen et al. (2011b) and Jiang et al. (2010) were produced for the Centre for Reviews and Dissemination’s Database of Abstracts of Reviews of Effects.

Key references Chen P, Wang L, Liu B et al. (2011b) EGFR-targeted therapies combined with chemotherapy for treating advanced non-small-cell lung cancer. European Journal of Clinical Pharmacology 67 235–43

Jiang J, Huang L, Liang X et al. (2011) Gefitinib versus docetaxel in previously untreated advanced non-small-cell lung cancer: a meta-analysis of randomised controlled trials. Acta Oncologica 50: 582–8

Lin H, Jiang J, Liang X et al. (2010) Chemotherapy with cetuximab of chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer 70: 57–62

Supporting references Centre for Reviews and Dissemination (2012) Gefitinib versus docetaxel in previously untreated advanced non-small-cell lung cancer: a meta-analysis of randomised controlled trials. Database of Abstracts of Reviews of Effects.

Centre for Reviews and Dissemination (2011) EGFR-targeted therapies combined with chemotherapy for treating advanced non-small-cell lung cancer. Database of Abstracts of Reviews of Effects.

Bevacizumab Bevacizumab was not evaluated for NICE CG121. A NICE technology appraisal of bevacizumab for first-line treatment of locally advanced or metastatic lung cancer was terminated because the manufacturer decided not to launch or promote bevacizumab in this indication; however, bevacizumab has marketing authorisation for this indication in the UK.

Botrel et al. (2011) did a systematic review and meta-analysis of data comparing bevacizumab plus chemotherapy with chemotherapy alone as first-line treatment for locally advanced or metastatic non-small cell lung cancer. 4 studies (n=2200) of bevacizumab 7.5 mg/kg or 15 mg/kg plus chemotherapy with carboplatin and paclitaxel or cisplatin and gemcitabine were included.

In the fixed effects meta-analysis, the progression-free survival was higher in those receiving bevacizumab 7.5 mg/kg (RR=0.58, 95% CI 0.46 to 0.74, p<0.00001), and 15 mg/kg (RR=0.53, 95% CI 0.45 to 0.63) compared with chemotherapy alone. Overall survival was also significantly greater in the group receiving the higher dose of bevacizumab but not the lower dose (7.5 mg/kg HR=0.92 95% CI 0.77 to 1.09, p=0.33; 15 mg/kg HR=0.89 95% CI 0.80 to 1.00, p=0.04).

A random effects model was used because of moderate heterogeneity between studies. The progression-free survival was higher in those receiving bevacizumab 7.5 mg/kg (HR=0.80, 95% CI 0.66 to 0.97, p=0.02), and 15 mg/kg (HR=0.70, 95% CI 0.58 to 0.85, p=0.0003) compared with chemotherapy alone. Overall survival was not significantly different (HR=0.90, 95% CI 0.76 to 1.07, p=0.23). No absolute data were reported for any outcome.

Bevacizumab was associated with greater toxicity than chemotherapy alone including: neutropenia (7.5 mg/kg fixed effect RR=0.79 95% CI 0.65 to 0.96; 15 mg/kg fixed effect

6 Evidence Updates do not do not provide commentaries on drugs and indications covered by suspended NICE technology appraisals until they are formally un-referred from NICE’s technology appraisals programme.

Evidence Update 24 – Lung cancer (November 2012) 18

RR=0.77 95% CI 0.65 to 0.91); hypertension (7.5 mg/kg fixed effect RR=0.30, 95% CI 0.13 to 0.73; 15 mg/kg fixed effect RR=0.14, 95% CI 0.07 to 0.28). Additionally, bevacizumab 15 mg/kg was associated with more haemoptysis, proteinuria, vomiting, rash or desquamation and bleeding events.

Another systematic review and meta-analysis by Lima et al. (2011) looked at the same trials as Botrel et al. (2011) with the addition of a small study (n=81) of second-line treatment. The drug combinations were therefore as reported above for Botrel et al. (2011) for the overlapping studies, and for second-line chemotherapy docetaxel or pemetrexed were used alone or in combination with bevacizumab.

Overall survival was significantly higher in the bevacizumab group (HR=0.89, 95% CI 0.79 to 0.99, p=0.04). When first-line treatment only was analysed, the results were not significant (HR=0.90, 95% CI 0.79 to 1.01, p=0.08), similar to the results of the random effects model reported by Botrel et al. (2011). However, Lima et al. (2011) also estimated the absolute survival benefit as a median of 26 days.

The progression-free survival was significantly greater for people treated with bevacizumab (HR=0.73, 95% CI 0.66 to 0.82, p<0.00001). The absolute benefit of bevacizumab was 1.4 months of progression-free survival, assuming 4 months of progression-free survival for chemotherapy alone.

The toxicities identified by Lima et al. (2011) as higher in the bevacizumab group included hypertension (OR=5.51, 95% CI 3.17 to 9.55, p<0.00001), bleeding events (OR=3.16, 95% CI 1.82 to 5.48, p<0.0001) and febrile neutropenia (OR=2.12, 95% CI 1.19 to 3.81, p=0.01). Bevacizumab was also associated with an increase in deaths related to treatment (OR 1.82, 95% CI 1.04 to 3.18, p=0.04), with most deaths in this group attributable to bleeding events, complications of neutropenia, and thromboembolic events.

A further meta-analysis of bevacizumab looked specifically at its risk profile (Cao et al. 2012), and included the same studies as the meta-analysis by Lima et al. (2011). The relative risk of treatment-related deaths was higher for the bevacizumab 15 mg/kg group (RR=2.04, 95% CI 1.18 to 3.52, p=0.01) but not for the 7.5 mg/kg group (RR=1.20, 95% CI 0.60 to 2.41, p=0.60) compared with control. The authors noted that fatal pulmonary haemorrhage was an important cause of treatment-related death with bevacizumab, but did not provide data to support this statement.

Hypertension, bleeding events and neutropenia were again noted to be significantly higher with bevacizumab than with controls, although Cao et al. (2011) presented the results by dose of bevacizumab. They noted that only 362 of more than 2000 patients received bevacizumab 7.5 mg/kg, so the results for this dose should be viewed with caution.

These three studies show broad agreement in their conclusions that bevacizumab is associated with a slight increase in progression-free survival and little to no increase in overall survival, but that the adverse effects of treatment are significant. This evidence is unlikely to have any impact on NICE CG121, which did not evaluate bevacizumab in lung cancer.

A critical abstract of the study by Botrel et al. (2011), was produced for the Centre for Reviews and Dissemination’s NHS Database of Abstracts of Reviews of Effects.

Key references Botrel TE, Clark O, Clark L et al. (2011) Efficacy of bevacizumab (bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis. Lung cancer 74: 89–97

Cao C, Wang J, Bunjhoo H et al. (2012) Risk profile of bevacizumab in patients with non-small cell lung cancer: a meta-analysis of randomized controlled trials. Acta Oncologica 51: 151–6.

Evidence Update 24 – Lung cancer (November 2012) 19

Lima AB, Macedo LT, Sasse AD (2011) Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS one 6: e22681

Supporting reference Centre for Reviews and Dissemination (2012) Efficacy of bevacizumab (bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis. Database of Abstracts of Reviews of Effects.

Chemotherapy in SCLC

Topotecan NICE TA184 recommends oral topotecan as an option in people with relapsed SCLC for whom re-treatment with the first-line regimen is not appropriate and for whom the combination of cyclophosphamide, doxorubicin and vincristine is contraindicated. Intravenous topotecan is not recommended. Irinotecan is not mentioned for SCLC in NICE CG121, which recommends platinum-based combination chemotherapy for extensive-stage SCLC, but does not specify the particular drugs to use. At the time of publication of this Evidence Update irinotecan did not have marketing authorisation in the UK for the treatment of lung cancer, and topotecan did not have marketing authorisation in the UK for first-line treatment of SCLC.

Lima et al. (2010) did a systematic review and meta-analysis of camptothecins (topotecan and irinotecan) plus platinum drugs compared with etoposide plus platinum drugs as first-line treatment of extensive disease SCLC. 8 studies (n=3086) were identified: 6 used irinotecan and two used topotecan; 6 used cisplatin as the platinum drug (15–25 mg/m²/week) and 2 used carboplatin (1.25–1.70 AUC/week). Etoposide was administered intravenously in 7 trials at doses of 100–140 mg/m²/week. Tests for interaction showed significant differences between the efficacy of topotecan and irinotecan, so these regimens were analysed separately.

Studies of irinotecan had moderate heterogeneity, which the authors attributed to one trial that included exclusively Japanese patients and was terminated early due to positive results in an interim analysis. Excluding this trial, irinotecan was associated with significantly greater overall survival than etoposide (HR=0.87, 95% CI 0.78 to 0.97, p=0.02). This relates to an absolute overall survival benefit of 1–2 months, based on expected overall survival of 8–10 months for etoposide-based regimens. Topotecan did not show a significant increase in overall survival compared with etoposide (HR=0.99, 95% CI 0.88 to 1.11, p=0.87).

Irinotecan was associated with more grade 3–4 diarrhoea but less grade 3–4 haematological toxicity than etoposide. Toxicities associated with topotecan were heterogeneous so meta-analysis was not done.

NICE CG121 recommends platinum-based combination chemotherapy for extensive-stage SCLC, but does not specify the particular drugs to use, so the evidence for irinotecan is not likely to have an impact on current guidance.

NICE TA184 recommends topotecan for some patients with relapsed SCLC; the evidence suggests no benefit as first-line treatment, which is also unlikely to have an impact on guidance.

A critical abstract of the study by Lima et al. (2010), was produced for the Centre for Reviews and Dissemination’s Database of Abstracts of Reviews of Effects.

Key reference Lima JP, dos Santos LV, Sasse EC et al. (2010) Camptothecins compared with etoposide in combination with platinum analog in extensive stage small cell lung cancer: systematic review and meta-analysis. Journal of Thoracic Oncology 5: 1986–93

Evidence Update 24 – Lung cancer (November 2012) 20

Supporting reference Centre for Reviews and Dissemination (2012) Camptothecins compared with etoposide in combination with platinum analog in extensive stage small cell lung cancer: systematic review and meta-analysis. Database of Abstracts of Reviews of Effects

1.5 Palliative interventions and supportive and palliative care

Cryotherapy NICE CG121 recommends radiotherapy, endobronchial debulking, or stenting as palliative interventions in patients with impending endobronchial obstruction. NICE interventional procedures guidance (IPG) 142 recommends cryotherapy as an option for treating endobronchial obstruction, but stresses that clinicians should ensure that patients know that this intervention is one of several available treatment options.

Lee et al. (2011) did a meta-analysis of 16 studies (n=2355) of cryotherapy compared with other treatments including laser therapy, electrocauterisation, brachytherapy, stent insertion and photodynamic therapy to treat airway obstruction in lung or bronchial tumours. One study was a comparative observational study, the rest were case studies.

No pooling or meta-analysis of results was undertaken; however, the authors concluded that endoscopic cryotherapy generally showed treatment success in about 80% of cases, with variation by operation methods and target patient groups. Limitations recognised by the authors included cryotherapy not being standardised, individual studies having different research methods and frequencies, and varying patient characteristics.

This evidence supports the efficacy of cryotherapy and is not likely to have an impact on current guidance, because this intervention is currently available as a treatment option.

Key reference Lee SH, Choi WJ, Sung SW et al. (2012) Endoscopic cryotherapy of lung and bronchial tumours: a systematic review. Korean Journal of Internal Medicine 26: 137–44

1.6 Follow-up and patient perspectives No new key evidence was found for this section.

Evidence Update 24 – Lung cancer (November 2012) 21

2 New evidence uncertainties During the development of the Evidence Update, the following evidence uncertainties were identified for the NHS Evidence UK Database of Uncertainties about the Effects of Treatments (UK DUETs).

Diagnosis and staging • The role of fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) - alone or

in combination - for diagnosing lung cancer in patients with a lung lesion

• Interobserver variation in the delineation of target volumes using positron emission tomography for non-small cell lung cancer patients with atelectasis

• Optimal positron emission tomography intensity for defining the gross tumour volume of a lung tumour

• Hybrid Positron Emission Tomography/computerised Tomography vs Positron Emission Tomography in lung cancer

• The role of positron emission tomography (PET) staging for small cell lung cancer (SCLC)

Treatment • The biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell

lung cancer

• The biologically effective dose of stereotactic body radiotherapy for lung cancer

Further evidence uncertainties for lung cancer can be found in the UK DUETs database and in the NICE research recommendations database.

UK DUETs was established to publish uncertainties about the effects of treatments that cannot currently be answered by referring to reliable up-to-date systematic reviews of existing research evidence.

Evidence Update 24 – Lung cancer (November 2012) 22

Appendix A: Methodology

Scope The scope of this Evidence Update is taken from the scope of the reference guidance:

• Lung cancer. NICE clinical guideline 121 (2011).

Searches The literature was searched to identify systematic reviews relevant to the scope. Searches were conducted of the following databases, covering the dates 1 August 2010 (the end of the search period of NICE clinical guideline 121) to 28 May 2012:

• AMED (Allied and Complementary Medicine Database)

• BNI (British Nursing Index)

• CDSR (Cochrane Database of Systematic Reviews)

• CENTRAL (Cochrane Central Register of Controlled Trials)

• CINAHL (Cumulative Index to Nursing and Allied Health Literature)

• EMBASE (Excerpta Medica database)

• MEDLINE (Medical Literature Analysis and Retrieval System Online) • PsycINFO

Table 1 provides details of the MEDLINE search strategy used, which was adapted to search the other databases listed above. The search strategy was used in conjunction with validated Scottish Intercollegiate Guidelines Network search filters for systematic reviews.

1 other study (Mauguen et al. 2012) was also identified outside of the literature search.

Figure 1 provides details of the evidence selection process. The long list of evidence excluded after review by the Chair of the EUAG, and the full search strategies, are available on request from [email protected]

There is more information about how NICE Evidence Updates are developed on the NHS Evidence website.

Table 1 MEDLINE search strategy (adapted for individual databases) 1 exp Lung Neoplasms/

2

(lung adj (neoplasm$ or cancer$ or carcinoma$ or adenocarcinoma$ or angiosarcoma$ or chrondosarcoma$ or sarcoma$ or teratoma$ or lymphoma$ or blastoma$ or microcytic$ or carcinogenesis or

tumour$ or tumor$ or metast$)).ti,ab. 3 (NSCL or SCLC).ti,ab.

4 or/1-3

Evidence Update 24 – Lung cancer (November 2012) 23

Figure 1 Flow chart of the evidence selection process

EUAG – Evidence Update Advisory Group

Evidence Update 24 – Lung cancer (November 2012) 24

Appendix B: The Evidence Update Advisory Group and Evidence Update project team Evidence Update Advisory Group

The Evidence Update Advisory Group is a group of topic experts who review the prioritised evidence obtained from the literature search and provide the commentary for the Evidence Update.

Dr Chris Alcock – Chair Consultant Clinical Oncologist, Oxford University Hospitals NHS Trust and Clinical Lead, NHS Evidence

Dr David Baldwin Consultant Physician, Nottingham University Hospital NHS Trust

Mr Sion Barnard Consultant Thoracic Surgeon, Freeman Hospital, Newcastle-upon-Tyne

Dr Jeremy Braybrooke Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

Dr Paul Cane Consultant Histopathologist, Guys & St Thomas' NHS Foundation Trust, London

Dr Matthew Hatton Consultant Clinical Oncologist, Weston Park Hospital, Sheffield

Dr Ruth MacPherson Consultant Radiologist, Churchill Hospital, Oxford

Dr Andrew Wilcock Macmillan Clinical Reader in Palliative Medicine and Medical Oncology, University of Nottingham

Evidence Update project team

Marion Spring Associate Director

Sian Rees, Chris Weiner Clinical Advisers

Cath White Programme Manager

Bazian Information specialist support

Lynne Kincaid Medical Writer