Particle therapy versus conventional radiotherapy for lung cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the clinical effectiveness of particle therapy, that is protons and C‐ions, as opposed to conventional radiotherapy in the treatment of lung cancer with curative intent.
Background
Description of the condition
Lung cancer is a frequently occurring, mostly lethal disease in all countries world wide (Ferlay 2007; Jemal 2007). Lung cancers fall into two main categories: 15% to 20% are small cell lung cancers (SCLC) and the remainder are non‐small cell lung cancers (NSCLC). Depending on tumour size, location and histology, several treatment options are available, including surgery and radiotherapy (RT), both often combined with chemotherapy (Jassem 2007). Concurrent chemoradiotherapy is the main treatment for limited stage SCLC, whereas for stage I‐II non‐small cell lung cancer (NSCLC), surgery and in some subgroups followed by chemotherapy, is the first choice treatment. For stage III, chemo‐radiation (CRT) is standard, which is in some cases combined with surgery (Rubins 2007). A major problem remains local tumour control (Farray 2005; Kim 2005). Therefore, new ways to deliver radiotherapy beyond photons have been sought for. Basically, from a theoretical point of view, a therapeutic gain can be achieved with charged particles, either protons or 12Carbon ions (C‐ions). Although the term particle therapy includes a wide range of different kind of particles such as neutrons, electrons, ions, pions etc., in this protocol the term particles refers only to protons and C‐ions.
Description of the intervention
Because of their better dose‐distribution, and, for carbon ions, also their biological characteristics, a therapeutic gain can be expected with these charged particles (Krengli 2005; St Clair 2004; Weber 2004; Baumert 2001; Miralbell 1992; Miralbell 1997; Zurlo 2000; Cozzi 2001; Lee 1999; Fogliata 2002; Isacsson 1996; Isacsson 1997). Accordingly, particle therapy should help to minimize the extent and severity of pulmonary and oesophageal injuries. This could benefit patients with localized lung cancer with or without underlying pulmonary disease, while simultaneously permitting an increased dose to the primary tumour, improving local tumour control.
How the intervention might work
It has been reported (Chang 2006) that proton treatment significantly reduces the dose to the oesophagus, spinal cord, and heart, even with dose escalation, as compared with the best available photon therapy. Recently a number of studies systematically reviewed the effectiveness of radiotherapy with protons and carbon ions for a wide range of indications (Brada 2007; Greco 2007; Lodge 2007; Olsen 2007).
Why it is important to do this review
However, the present role of particle therapy in the treatment lung cancer is still unclear. This article therefore specifically aims to systematically review the currently available clinical evidence on particle therapy in lung cancer.
Objectives
To determine the clinical effectiveness of particle therapy, that is protons and C‐ions, as opposed to conventional radiotherapy in the treatment of lung cancer with curative intent.
Methods
Criteria for considering studies for this review
Types of studies
Since it is known from recently published reviews (Brada 2007; Lodge 2007; Olsen 2007; Pijls‐Johannesma 2008) that no randomised trial (RCT) has been performed yet for lung cancer comparing particles with photons, we will extend this review to non‐randomised studies evaluating treatment outcome with respect to tumour control, normal tissue toxicity and treatment parameters. Since it can sometimes be difficult to tell from publications whether studies were actually prospective or retrospective, both types of studies will be included. However, as soon as an RCT is published it will replace the non‐randomised studies. Survival rates of at least 2 years have to be available. We will only include studies with at least 20 patients and with a follow‐up period ≥ 2 years.
Types of participants
Since we expect mainly an advantage of particle therapy in patients that are treated with curative intent, we will only include patients with histological and cytological proven stage I‐III NSCLC or limited disease (stage I‐III) SCLC, of any age and with performance status 0‐2. ”Limited disease” will be defined as: cancer confirmed to one hemi‐thorax including contralateral mediastinal and hilar lymph nodes as well as ipsilateral and / or bilateral supraclavicular involvement, but excluding malignant pleural effusion. Because of different prognoses, we will stratify the NSCLC group in stage I/II and stage III.
Types of interventions
Any regimen of particle therapy (protons or carbon‐ions) given concurrently or not with any chemotherapy regimen will be included in this review. We will undertake stratified analyses according to fractionation of radiotherapy and by different chemotherapy regimens will be undertaken. Prophylactic cranial irradiation may or may not have been given and if so we will analyse them separately.
Types of outcome measures
Clinically relevant outcomes will be studied: 1‐year progression free survival (PFS), 1, 2, 3 and 5‐year overall and disease‐specific survival, incidence of severe haematological, lung‐ and oesophageal toxicity (grade 3‐4), compliance assessed by the percentage of intended total dose completed and local control assessed by one year progression free survival. If reported, we will also take quality of life into account.
Primary outcomes
‐ 1,2, 3 and 5‐year overall and disease‐specific survival
‐ Local control (1‐year PFS)
‐ Incidence of severe haematological, lung‐ and oesophagus toxicity (grade 3‐4)
Secondary outcomes
‐ Compliance of intended total dose completed (chemo‐ and radiotherapy)
‐ Quality of life
Search methods for identification of studies
A search for identification of studies on the review topic will be undertaken using the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL, 2009 Issue 1), MEDLINE (1966 to present), EMBASE (1974 to present), CINAHL (1982 to present). Further, we will search the Cochrane Lung Cancer Review Group specialised register.
We will perform searches without restricting the language of studies retrieved.
Electronic searches
The following search strategy will be used (MEDLINE, assessed through Ovid ):
1. exp lung neoplasms/
2. carcinoma, non small‐cell lung/
3. (lung$ adj2 cancer$).tw.
4. (lung$ adj2 carcinoma$).tw.
5. (lung$ adj2 neoplasm$).tw.
6. (pulmonary$ adj2 neoplasms$).tw.
7. (lung$ adj2 metast$).tw.
8. exp carcinoma,bronchogenic/
9. exp bronchial neoplasms/
10. (bronch$ adj2 cancer$).ti,ab,rw,sh.
11. (bronch$ adj2 carcinoma).ti,ab,rw,sh.
12. exp pleural neoplasms/
13. or/1‐12
14. (lung$ or bronch$ or pulmonary).tw.
15. carcinoma, non small cell/
16. exp carcinoma, non small cell/
17. ((non small adj cell) and (carcinoma$ or cancer$)).tw.
18. ((reserve adj cell) and (carcinoma$ or cancer$)).tw.
19. ((oat adj cell) and (carcinoma$ or cancer$)).tw.
20. or/15‐19
21. 14 and 20
22. 13 or 21
23. (hadron* therap* or hadrontherap*) in ti,ab
24. (proton therap* or protontherap*) in ti,ab
25.(ion therap* or iontherap*) in ti,ab
26. ((hadron* or proton) adj beam therap*) in ti,ab
27. ((hadron* or proton) adj beam irradiation) in ti,ab
28.((hadron* or proton) adj radiation) in ti,ab
29.((hadron* or proton) adj beam radiation) in ti,ab
30.((hadron* or proton) adj radiotherap*) in ti,ab
31.Ions/therapeutic‐use
32.Protons/therapeutic‐use
33.((light ion*) near2 (treatment or therap*)) in ti,ab
34.((heavy ion*) near2 (treatment or therap*)) in ti,ab
35. exp particle therapy/
36. or/23‐35 and 22
37. exp radiotherapy, computer‐assisted/
38. exp radiation dosage/
39. exp radiotherapy dosage/
40. exp radiotherapy,high‐energy/
41. exp radiotherapy, adjuvant/
42. exp dose fractionation/
43. exp brachytherapy/
44. exp radiation oncology/
45. radiotherap$.tw.
46. (thorac$ adj2 radiotherap$).ti,ab,rw,sh.
47. (radiat$ adj2 therap$).ti,ab,rw,sh.
48. (thorac$ adj2 radiat$).ti,ab,rw,sh.
49. irradiation.tw.
50. or/ 37‐49 and 36
Searching other resources
The electronic searches for clinical studies will be complemented with manual searches of the following Oncology journals (2005 to present): International Journal of Radiation, Oncology, Biology and Physics; Radiotherapy and Oncology; Journal of Clinical Oncology; Clinical Oncology; Lung Cancer; Journal of Thoracic Oncology ; Radiological Sciences and Thorax. In addition, abstract books of the following conferences will be searched: ASCO, ESTRO, IASLC and PTCOG. Reference lists from identified studies will be scrutinized for any other additional studies.
Data collection and analysis
Non‐randomised studies identified by the search will be assessed to determine if they meet the inclusion criteria. They will be assessed by three independent reviewers (MPJ, JG, DDR) both for the quality of the methods against pre‐determined criteria (see below) and for the results of key outcomes, which will be identified and tabulated.
Selection of studies
Two reviewers (MPJ, JG) will extract the data independently to ensure validity and discrepancies will be resolved by a third referee (DDR). We will collect patient data for all patients randomised, including those who had been excluded from the investigator’s own analysis according to the intention‐to treat principle.
Data extraction and management
The following data will be requested: identifiers, gender, age, performance status at start treatment, initial disease stage, definition on chemotherapy regimen, induction treatment that led to a complete response, start date of induction treatment and update information on survival, brain metastasis, other metastases and local recurrence and comorbidity if available.
Assessment of risk of bias in included studies
In case of RCTs, risk of bias will be assessed using the tool described in the Cochrane Handbook for Systematic Reviews of interventions (Higgins 2008) with the following criteria:
Sequence generation
‐ Yes, if investigators describe a random component in the sequence generation process such as a computer random number generator or coin tossing etc.
‐ No, if investigators describe a non‐random component in the sequence generation process.
‐ Unclear, if insufficient information is provided about the sequence generation process to permit judgement of ‘Yes’ or ‘No’.
Allocation concealment
‐ Yes, if enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation, e.g.central allocation or sequentially numbered
‐ No, e.g. if allocation sequence could be foretold by patients, investigators or treatment provider
‐ Unclear, e.g. not reported
Incomplete outcome data
We will record the proportion of participants whose outcomes were not reported at the end of the study; we will note if loss to follow‐up was not reported. We will code a satisfactory level of loss to follow‐up for each outcome as:
‐ Yes, if fewer than 20% of patients were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms
‐ No, if more than 20% of patients were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms
‐ Unclear if loss to follow‐up was not reported
Risk of bias in non‐randomised studies will be assessed in accordance with five additional criteria:
Cohort selection
1. Does the study contain a control arm?
‐ Yes
‐ No, single arm study
‐ Unclear
2. Was the study design prospective?
‐ Yes
‐ No
‐ Unclear
3. Were relevant details of criteria for assignment of patients to treatments provided?
‐ Yes
‐ No
‐ Unclear
4. Was the group of patients who received the experimental intervention representative?
‐ Yes, if representative of patients with lung cancer
‐ No, if groups of patients were selected
‐ Unclear, if selection of group was not described
5. Was the group of patients who received the comparison intervention representative?
‐ Yes, if drawn from the same population as the exposed cohort
‐ No, if drawn from a different source
‐ Unclear, if selection of group not described
Measures of treatment effect
We will use the following measures of the effect of treatment:
‐ For time to event data, we will use the hazard ratio, if possible.
‐ For dichotomous outcomes, we will use the relative risk.
‐ For continuous outcomes, we will use the mean difference between treatment arms, if all studies measured the outcome on the same scale, otherwise standardised mean differences will be used.
Unit of analysis issues
Survival data from the included will be evaluated using Revman 5.
For studies in which outcomes are published in the form of percentages, the number of events will be calculated. Meta regression, stratified for studies, will be used to adjust the analysis for co‐variables.
Dealing with missing data
We will not impute missing outcome data.
Assessment of heterogeneity
In case of randomised trials, Chi‐square heterogeneity tests will be used to test for statistical heterogeneity among trials and will calculate weighted estimates of the typical treatment effect across studies, 'the typical odds ratio' using the standard Odds ratio. For non‐randomised studies, the meta‐analysis will be performed according to the guidelines proposed by the Meta‐analysis of Observational Studies in Epidemiology group (Stroup 2000).
Assessment of reporting biases
Funnel plots corresponding to meta‐analysis of the primary outcome will be examined to assess the potential for small study effects such as publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random‐effects model (REM), further meta‐analyses will be performed using fixed‐effects models (FEM).
Data synthesis
If sufficient clinically similar studies are available, their results will be pooled in meta‐analyses. Adjusted summary statistics will be used if available; otherwise unadjusted results will be used.
‐ For time‐to‐event data (e.g. overall survival), hazard ratios will be pooled using the generic inverse variance facility of RevMan 5.
‐ For any dichotomous outcomes (e.g. adverse events, and numbers of patients who relapse or die, if it is not possible to treat these outcomes as time‐to‐event data), relative risks will be pooled.
‐ For continuous outcomes (e.g. quality of life measures), the mean differences between the treatment arms at the end of follow‐up will be pooled using the mean difference method if all studies measured the outcome on the same scale, or using the standardised mean difference method otherwise.
Subgroup analysis and investigation of heterogeneity
If sufficient studies are available, subgroup analyses will be performed. Factors such as age, stage, type of intervention, length of follow‐up and adjusted/unadjusted analysis will be considered in interpretation of any heterogeneity.
Sensitivity analysis
Sensitivity analyses will be done for identification of heterogeneity in all categories.
The analysis will be performed on the 2‐year survival data as well as the 5‐year survival data. The analysis will be repeated using a random‐effects model. This procedure gives an indication of the robustness of the results.
