Anti‐angiogenic therapy for lung cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the benefits and harms of angiogenesis inhibitors in the treatment of lung cancer when given alone, following or in combination with chemotherapy or chemo‐radiotherapy (in the case of locally advanced non‐metastatic NSCLC or limited stage SCLC).
Background
Description of the condition
Despite global attempts at smoking cessation strategies, lung cancer incidence and mortality continues to increase world‐wide. Unfortunately overall cure rates remain low as many patients present with advanced or metastatic disease. There has been a declining trend in incidence in small cell lung cancer (SCLC) ‐ now accounting for ˜ 15% of all lung cancers, with non‐small cell lung cancer (NSCLC) making up the majority of new cases (85%) (Pfister 2004).
Combination platinum‐based chemotherapy has been shown to improve survival and quality of life in patients with advanced lung cancer (BMJ 1995, Simon 2003, Pfister 2004). Since 1995 the main focus of clinical trial research in lung cancer has been on trying to identify better chemotherapy regimens. In NSCLC no two drug protocol has demonstrated definite superiority over another in unselected patients in the first line setting where median survival with first line chemotherapy is still only around 9 ‐10 months (Schiller 2002). Standard chemotherapy in fit patients with metastatic NSCLC would be a platinum‐containing regimen or non‐platinum doublet, and the elderly or poor performance status patients may be considered for single agent chemotherapy (Pfister 2004). Second‐line docetaxel chemotherapy has been shown to confer a survival and quality of life benefit (Bonfill 2008) with pemetrexed showing clinically comparable efficacy but less toxicity (Hanna 2004). Recently however, pemetrexed‐based chemotherapy has been shown to be more effective in patients with non‐squamous histology, perhaps spelling the end to empirical treatment decision making (Scagliotti 2007, Peterson 2007).
Description of the intervention
The term angiogenesis refers to new blood vessel formation, usually occurring in cancers as a result of sprouting from existing vessels. In 1971, it was proposed that for tumours to grow beyond 1‐2 mm3 they required the development of angiogenesis. This required an “angiogenic switch” induced by a tumour angiogenic factor (TAF). The strategy of blocking this TAF before angiogenesis is established was hypothesized to restrict tumour growth (Folkman 1971). Since then a large body of knowledge has accrued about the process of angiogenesis following the search for both pro‐ and anti‐ angiogenic molecules and consequent angiogenesis inhibitors.
Pro‐angiogenic factors identified include but are not limited to: the fibroblast growth factor family (FGFs), the vascular endothelial growth factor family (VEGFs), platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor ‐b (TGF‐b), hepatocyte growth factor (HGF), insulin like growth factor 1 (IGF‐1), angiopoietin‐1 (Ang1), nitric oxide synthase (NOS), cyclo‐oxygenase ‐2 (COX2), plasminogen activators, matrix metalloproteinases (MMPs, including heparanase) and some chemokines such as tumour necrosis factor‐a (TNF‐a ), and interleukin‐8 (IL‐8)(Carmeliet 2000, Ferrara 1999).
VEGF is a key angiogenic factor with a number of crucial roles in tumour angiogenesis. The key VEGF molecule, known as VEGF‐A belongs to a family of genes that includes placental growth factor (PLGF) and the VEGFs ‐B, ‐C and ‐ D, ‐E (Dvorak 2002, Ferrara 2003). VEGF mediates its effects through binding with its tyrosine kinase transmembrane cell surface receptors (TKR). VEGF‐A binds to VEGFR‐1(Flt‐1) and VEGFR‐2 (Flk‐1/KDR) and mediates its angiogenic effects largely through its receptor VEGFR‐2 (Dvorak 2002, Ferrara 2003).
Angiogenesis inhibitors (AIs) have been explored as a cancer treatment since the 1990s (Gasparini 2005). Angiogenesis inhibitors can be classified as direct (eg anti‐VEGF) or indirect (eg anti‐EGF) depending on their mode of action (Kerbel 2002). Strategies to block angiogenesis have focused on inhibiting known pro‐angiogenic factors as described above, or evaluating known naturally occurring anti‐angiogenesis compounds such as endostatin (Kerbel 2002).
How the intervention might work
The most clinically developed of the angiogenesis inhibitors include the anti‐VEGF monoclonal antibody bevacizumab and the new generation small molecule VEGFR TK inhibitors. Other agents include the matrix metalloproteinase inhibitors (MMPIs) and thalidomide (Kumar 2004), whose precise mechanism of action is still not fully known (Kerbel 2002). It is hypothesised that AIs may enhance the effectiveness of chemotherapy on established tumours through a number of mechanisms and inhibit new tumour growth by inhibiting the vital process of angiogenesis (Kerbel 2006).
Why it is important to do this review
In lung cancer, tumour angiogenesis, identified by microvessel density and/or angiogenic marker expression eg VEGF, in numerous clinico‐pathologic correlative studies, has been shown to be associated with a poor prognosis (Herbst 2005). Improvements in survival of lung cancer patients treated with chemotherapy remain modest and there exists an ongoing need for better therapies. A large number of studies exploring the addition of AIs to standard chemotherapy in lung cancer have been recently published or are in progress (Coussens 2002, Herbst 2005). The use of selected AIs in lung cancer therefore has the potential to become standard of care if there is enough evidence to translate to clinical practice. Further, the type, mode, and duration of administration of AIs; the predictive effect of tumour histology; and the predictive value of angiogenic biomarkers should also be explored, in order to identify the patient and disease characteristics most likely to predict for benefit and/or toxicity.The purpose of this review is to find, organise and summarise randomized controlled trial evidence for the use of angiogenesis inhibitors (AIs) in the treatment of lung cancer.
Objectives
To determine the benefits and harms of angiogenesis inhibitors in the treatment of lung cancer when given alone, following or in combination with chemotherapy or chemo‐radiotherapy (in the case of locally advanced non‐metastatic NSCLC or limited stage SCLC).
Methods
Criteria for considering studies for this review
Types of studies
We will only include randomized controlled trials.
Types of participants
Patients with a histologic or cytologic diagnosis of NSCLC or SCLC.
Types of interventions
Studies will only be included when the agent evaluated is mechanistically described as falling into the class of angiogenesis inhibitor, (i.e. it is classified as an AI), administered intravenously or orally, alone or in combination with chemotherapy or other biologic agents (or a combination of these treatment modalities).
Therefore agents targeting multiple molecular pathways will be included only when at least one of these is clearly identified as an important angiogenesis pathway, eg. VEGF pathway inhibitor, PDGF pathway inhibitor. Studies evaluating the selective EGFR pathway inhibitors alone or with chemotherapy, such as gefitinib and erlotinib, will be excluded as these are the subject of two separate Cochrane reviews.
Trials with placebo groups and trials with open control groups (no treatment or best supportive care controls) will be included in the following clinical settings, where the only difference between treatment arms is the addition of an AI. Note that comparisons will be evaluated and reported separately for SCLC and NSCLC, and within each of these diseases according to the clinical setting stated. Unless otherwise stated, for NSCLC, the stage refers to the TNM stage (Rami‐Porta 2009).
1. Angiogenesis inhibitors (AI) in combination with chemotherapy
a. Adjuvant or neo‐adjuvant chemotherapy +/‐ AI or placebo in patients with operable or operated NSCLC, ie patients having surgery for NSCLC.
b. In patients with SIIIB (and effusion ie "wet" IIIB) or IV NSCLC or patients with limited or extensive stage SCLC:
b(i). First line treatment with chemotherapy and an AI compared to chemotherapy +/‐ placebo or no AI.
b(ii). Second line treatment with chemotherapy and an AI compared to chemotherapy +/‐ placebo or no AI.
2. Angiogenesis inhibitors as monotherapy
AI alone compared to placebo or best supportive care in third line or refractory NSCLC or any stage chemotherapy refractory SCLC.
3. Angiogenesis inhibitors as maintenance therapy
Maintenance AI after chemotherapy in any line of therapy (compared with placebo or no AI) in patients with SIIIB/IV NSCLC or any stage SCLC.
Maintenance AI after primary radical chemo‐radiotherapy compared with no AI or placebo in Stage III (inoperable but non‐metastatic) NSCLC.
4. Angiogenesis inhibitors combined with radical chemo‐radiotherapy in stage III (inoperable but non‐metastatic) NSCLC
Primary radical chemo‐radiotherapy +/‐ AI or placebo
5. Angiogenesis inhibitors combined with other biologic therapy (but not EGFR inhibitors) in any line of therapy in patients with NSCLC or SCLC:
Chemotherapy + other biologic therapy +/‐ AI
Types of outcome measures
Studies including at least one of the following outcomes will be considered for evaluation:
Primary outcomes
Overall Survival.
Secondary outcomes
Progression free survival
Time to tumour progression
Tumour response rates
Surgical resection rates and morbidity
Quality of life
Adverse events
Cost‐effectiveness
Search methods for identification of studies
No language restriction will be applied in all searches.
Electronic searches
Randomized controlled trials will be identified by searching the following databases: MEDLINE (1966 to present; access via Pubmed), the Cochrane Controlled Trials Register (CENTRAL, The Cochrane Library 2009, last issue), and EMBASE (1980 to present; access via Ovid). The following strategy will be used to search the different databases with appropriate changes made to adapt terms to the different databases. The Cochrane validated filter will be used to retrieve trials (Robinson 2002)
1 "Angiogenesis Inhibitors"[Mesh]
2 "Angiogenesis Inducing Agents"[Mesh]
3 "Endothelial Growth Factors"[Mesh]
4 "Vascular Endothelial Growth Factors"[Mesh]
5 endothelial growth factor*[tw]
6 endothelial AND growth AND factor*[ti]
7 anti VEGF$[tw]
8 antiVEGF$[tw]
9 anti[ti] AND VEGF$[ti]
10 (macugen*[tw] OR pegaptanib*[tw] OR lucentis*[tw] OR rhufab*[tw] OR ranibizumab*[tw] OR bevacizumab*[tw])
11 OR/1‐10
12 “Lung neoplasms”[Mesh]
13 NSCLC[tiab] OR SCLC[tiab]
14 (lung[tiab] OR lungs[tiab] OR pulmonary[tiab] OR bronchus[tiab] OR brochogenic[tiab] OR bronchial[tiab] OR bronchoalveolar[tiab] OR alveolar[tiab])
15 (cancer*[tiab] OR carcinoma*[tiab] OR adenocarcinoma*[tiab] OR malignan*[tiab] OR tumor*[tiab] OR tumour*[tiab] OR neoplasm*[tiab])
16 14 AND 15
17 12 OR 13 OR 16
18 11 AND 17
The search strategy will be further applied to PREMEDLINE.
Searching other resources
The following additional sources for references and/or study results updates or updates of ongoing studies will be pursued:
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Search of relevant conference proceedings : ASCO, ESMO, ECCO, IASLC World Lung Cancer Conference
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Recognised experts in lung cancer and manufacturers of relevant drugs will be asked to provide details of outstanding or ongoing clinical trials and any relevant unpublished material.
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Search of references lists of included studies.
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Search for ongoing studies: Clinical Trials Registries and ongoing studies databases will be searched. Drug manufacturers will be also contacted.
Data collection and analysis
Selection of studies
Two primary reviewers (MK, NP) will independently assess the titles and abstracts retrieved by the search strategy. Full text articles of potentially eligible studies will be retrieved (see criteria in section: Types of Interventions). These will be assessed for quality independently and in a blinded fashion (to authors, journal, drug company, institutions and results) by two of the reviewers (MK, NP), with disagreement resolved by consensus with a third reviewer (GM).
Abstracts or unpublished data will be included only if sufficient information on the study design, characteristics of participants, interventions and outcomes is available. Further information or final study results will be sought from the primary author.
Data extraction and management
Data extraction will be performed independently by two reviewers, (NP and either MK, CL, SW or GM according to section allocation), with disagreements resolved by a third reviewer. Data will be extracted for the outcome measures indicated above. Data will be entered into RevMan5 for analysis. The following will be recorded for each eligible trial: study design, participants,setting, interventions, quality components, duration of follow‐up, efficacy outcomes, biomarker analyses and side‐effects. For studies with more than one publication, data on all outcomes will be extracted from the most recent publication.
Assessment of risk of bias in included studies
All studies that meet the inclusion criteria will be assessed for quality (based on high or low levels of risk of bias) independently by two reviewers (MK, NP), with disagreement resolved by a third reviewer (GM). The risk of bias for every included study will be assessed using the Cochrane risk of bias tool, Chapter 8.5 Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (Higgins 2008).
Each study will be assessed independently by two review authors [NP, MK] for the use of random allocation to the comparison groups.
The following criteria will be considered:
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Randomisation sequence generation. Was the allocation sequence adequately generated?
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Allocation concealment. Was allocation adequately concealed?
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Blinding of participants, personnel and outcome assessors. Was knowledge of the allocated intervention adequately prevented during the study?
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Incomplete outcome data. Were incomplete outcome data adequately addressed?
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Selective outcome reporting. Are reports of the study free of suggestion of selective outcome reporting?
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Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
Under each criterion, studies will be given a judgement according to the following:
i. 'YES'. (i.e. low risk of bias).
ii. 'NO'. (i.e. high risk of bias).
iii. 'UNCLEAR'. (uncertain risk of bias).
A final summary assessment for risk of bias under each criterion will be provided.
This classification will be used as the basis of a sensitivity analysis.
Measures of treatment effect
The primary outcome analyses will be based on the trial reported Intention‐to‐treat analyses for these outcomes where available, or if such information has been provided by the author. That is, if the outcome measure from a particular trial is reported in an ITT analysis and separately according to "treatment received", the ITT analysis data will be used.
Statistical Analysis will include the use of risk ratios (RR), hazard ratios (HR) and odds ratios (OR). Time to event outcomes (overall survival ‐OS, progression free survival ‐PFS) will be expressed using hazard ratios where possible. If HR is not reported in a study publication it will be obtained indirectly using the methods described by Parmar et al using either other available summary statistics or from data extracted from published Kaplan‐Meier curves (Parmar 1998). If HRs can't be calculated (due to lack off appropriate data) then RRs will be used based on the number of individuals per event. OS will be based on events at 1 year for advanced disease or metastatic studies and 5 years for adjuvant studies. Response rates will be analysed as dichotomous variables (complete or partial vs stable disease or no response) and a pooled relative risk will be derived. Toxicity data will be extracted from the treated population and the total number of grade III or IV events and number at risk added up across trials and used to calculate a single odds ratio (with 95% confidence intervals) using a random effects model. Outcomes such as QoL or pain scores will be presented as percent change. If data is not presented in the same format across studies, then standardised mean differences will be used. Data will be extracted for the outcomes described independently.
Unit of analysis issues
This is not applicable to this review.
Dealing with missing data
Study authors will be contacted to request missing data where possible. Studies where data for a particular outcome cannot be identified or obtained from the author, will not be included for analysis of that outcome.
Assessment of heterogeneity
Heterogeneity will be tested with standard methods as follows: using the chi‐squared test of heterogeneity and I2 statistics. The criterion for heterogeneity will be a p‐value of less than 0.10 using the chi‐squared test and a value of I2 greater than 50%. When there is no statistical evidence for heterogeneity effect sizes, a fixed‐effects model will be used for the summary meta‐analysis statistic. When significant heterogeneity is identified, careful clinical review of the data will be conducted to explore the sources of heterogeneity. The final reported analyses will be based on fixed effects models unless there is significant heterogeneity, in which case random effects models will be used. Sensitivity analyses and funnel plots will also be performed.
Assessment of reporting biases
The possibility of publication bias will be explored using funnel plots where appropriate, ie if there are sufficient number of trials for the relevant comparisons.
Data synthesis
The numbers of participants experiencing each outcome and total number of patients randomised for each study arm will be extracted. Data analysis will be by intention‐to‐treat principle for the meta‐analysis. The Mantel‐Haenszel method will be used to calculate pooled results if there was no significant heterogeneity, or the random‐effects model where significant heterogeneity is identified. Statistical heterogeneity is considered significant when p<0.10 or I‐squared>50%.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses will be performed where the data for the outcomes according to the relevant subgroup are available from the trial report or from the study author.
Specific a priori subgroups include:
1. Histology: NSCLC (Squamous v non‐squamous) and SCLC
2. Disease stage (resected v metastatic v locally advanced inoperable NSCLC; limited v extensive stage SCLC);
3. Known patient related prognostic factors such as age, sex and performance status.
4. AIs as monotherapy, maintenance therapy or in combination with chemotherapy (or chemo‐radiotherapy) and by their position in the lung cancer treatment paradigm ‐ first line, second line or 3rd line.
5. Drug class (monoclonal antibodies v receptor tyrosine kinase inhibitors (TKIs) v MMPI v Other (Unspecified or not definitely known eg thalidomide)
6. Molecular tumour or blood based predictive factors eg Angiogenesis factor levels (e.g. VEGF, E‐Selectin, VCAM, MMP‐9, LDH); single nucleotide polymorphisms; proteomic profiles
Sensitivity analysis
Sensitivity analyses will be performed to examine the robustness of the review findings.
The following factors will be considered as possible sources of heterogeneity across studies: differing study quality (based on high or low levels of risk of bias), different dose or scheduling differences of the individual agents.
