Cochrane · intervention · CD001829
Interventions for treating oral leukoplakia to prevent oral cancer
Lodi, G, Franchini, R, Warnakulasuriya, S, et al. · Cochrane Database of Systematic Reviews · 2016 · Cochrane Library
Full textEvery question was extracted from the full review (methods and results), not only its Summary of Findings table.
Questions
26
current version
GRADE rated
8
No studies
4
Included studies
14
as reported
No studies 4 · 15.4%Ungraded 14 · 53.8%Very low 5 · 19.2%Low 2 · 7.7%Moderate 1 · 3.8%High 0 · 0%
Ungraded means an effect was reported without a GRADE rating; it is not a gap. No studies means the review found nothing to answer the question. The six categories are a display order, not a score.
Review question
| Element | Planned (methods) | Found (results) |
|---|---|---|
| Population | Anyone with a diagnosis of oral leukoplakia (without histopathological evidence of carcinoma) as defined, at the time of the studies, by consensus conferences held in 1978, 1983, 1994 and 2005 | People with oral leukoplakia (909 participants across 14 studies; mean 64.9, range 10 to 131); smoking 8 to 86%; drinking 9 to 71%; 2 studies only betel-quid chewers (India); dysplastic lesions 18.75 to 73.2% (7 studies) |
| Intervention | Surgical removal of the lesion (surgical excision, laser surgery, cryotherapy); topical medical treatment (anti-inflammatory agents, antimycotic agents, carotenoids and retinoids, cytotoxic agents); systemic medical treatment; removal of predisposing habits (e.g. tobacco, alcohol); other treatment (e.g. photodynamic therapy); combined treatment | Vitamin A or retinoids (n=4); beta carotene or carotenoids (n=3); NSAIDs - ketorolac and celecoxib (n=2); herbal extracts - tea components, Chinese herbal mixture, freeze-dried black raspberry gel (n=4); topical bleomycin (n=1); Bowman-Birk inhibitor (n=1) |
| Comparison | Placebo; no treatment | Placebo (n=14; one used a placebo containing vitamin C, Nagao 2015) |
| Outcomes | Oral cancer development demonstrated by histopathological examination (primary); clinical resolution (proportion of lesions not resolved, with relapse data); improvement of histological features; safety (incidence of adverse effects) | Oral cancer development (n=5 reported, 3 usable); clinical resolution (n=13-14); improvement of histological features (n=6); safety/adverse effects (n=12) |
| Study designs | Randomised controlled trials comparing surgery, medical or complementary treatment (local or systemic) or risk factor cessation versus placebo | RCT (n=14; 10 two-arm, 3 three-arm, 1 four-arm parallel design) |
| Timing | Not specified | Follow-up: most studies less than 1 year; one lasted 2 years; three used open follow-up (up to 7 years) |
Search date: 2016-05. Databases: Cochrane Oral Health's Trials Register; CENTRAL; MEDLINE Ovid; Embase Ovid; CancerLit via PubMed; metaRegister of Controlled Trials; ClinicalTrials.gov; WHO International Clinical Trials Registry Platform
Questions and results
Current version onlyVitamin A or retinoids (systemic or topical; incl. 13-cis-retinoic acid, acitretin) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Clinical resolution (oral lesion not completely resolved) 4 to 12 months | SoF 1, Clinical resolution (not completely resolved) at 4 to 12 months: 'Studies could not be combined in meta-analysis. One study evaluated topical treatment and did not find evidence of benefit; 3 studies of systemic… | 4 studies | Ungraded |
Improvement of histological features (not improved) 3 months | RR 0.43 [0.24, 0.76] 889 per 1000 vs 382 per 1000 | 1 study · 41 participants | Moderate Downgraded: imprecision |
Oral cancer development 24 months (treatment lasted 12 months) | RR 0.11 [0.01, 2.05] 93 per 1000 vs 10 per 1000 | 1 study · 85 participants | Very low Downgraded: risk of bias, imprecision |
Safety of the intervention (adverse effects) 4 to 12 months | SoF 1, Safety of the intervention at 4 to 12 months: '3 studies (1 each evaluating topical acitretin, topical 13-cis-retinoic acid, 200,000 IU per week of vitamin A) found no adverse effects. Systemic 13-cis-retinoic… | 4 studies | Ungraded |
Systemic beta carotene or carotenoids (incl. lycopene) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Improvement of histological features (not improved) 5 months (treatment lasted 3 months) | RR 0.24 [0.12, 0.46] 833 per 1000 vs 200 per 1000 | 1 study · 58 participants | Low Downgraded: risk of bias, imprecision |
Safety of the intervention (adverse effects) 5 to 12 months | SoF 2, Safety of the intervention at 5 to 12 months: 'Systemic beta carotene did not cause any adverse effects in 1 study supplementing 10 mg/d (Nagao), and caused adverse effects of varying severity in 9% of… | 3 studies | Ungraded |
Oral cancer development 24 months | RR 0.71 [0.24, 2.09] 108 per 1000 vs 79 per 1000 | 2 studies · 132 participants | Very low Downgraded: risk of bias, imprecision |
Clinical resolution (oral lesion not completely resolved) 5 to 12 months | SoF 2, Clinical resolution (not completely resolved) at 5 to 12 months: 'The 3 studies could not be combined in meta-analysis. 2 found benefit for systemic beta carotene, and 1 did not.' No GRADE rating. Effects text… | 3 studies | Ungraded |
Topical bleomycin vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Clinical resolution (oral lesion not completely resolved) 3 months | RR 0.55 [0.29, 1.04] 917 per 1000 vs 504 per 1000 | 1 study · 22 participants | Very low Downgraded: risk of bias, imprecision |
Safety of the intervention (adverse effects) up to 3 months | SoF 5, Safety of the intervention up to 3 months: 'All patients in the bleomycin group developed erythema with erosion by the end of the applications, whereas erythema developed in the placebo group. Discomfort was… | 1 study | Ungraded |
Oral cancer development up to 7 years | RR 3.00 [0.32, 27.83] 83 per 1000 vs 250 per 1000 | 1 study · 20 participants | Very low Downgraded: risk of bias, imprecision |
Improvement of histological features (not improved) 3 months | RR 0.49 [0.22, 1.10] 818 per 1000 vs 401 per 1000 | 1 study · 21 participants | Very low Downgraded: risk of bias, imprecision |
Herbal extracts (tea components; Chinese herbal mixture; freeze-dried black raspberry gel) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Oral cancer development | SoF 4 (Herbal extracts vs placebo), Cancer development: SoF cell 'Not measured'. Effects text: cancer development was among the outcomes in Tsao 2009 (green tea extract) but it was not possible to analyse the data… | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) 3 to 6 months | SoF 4, Clinical resolution (not completely resolved) at 3 to 6 months: '3 studies (freeze-dried black raspberry gel, green tea extract capsules, mixed tea) did not find evidence of benefit.' No GRADE. Effects text:… | 4 studies | Ungraded |
Improvement of histological features (not improved) 3 months | SoF 4, Histological changes (not improved) at 3 months: '2 studies (green tea extract capsules and freeze-dried raspberry gel) did not find evidence of benefit.' No GRADE. Effects text: Mallery raspberry RR 0.97… | 2 studies | Ungraded |
Safety of the intervention (adverse effects) up to 3 months | SoF 4, Safety of the intervention up to 3 months: '3 studies measured adverse effects: green tea extract capsules caused high frequency (93%) of adverse effects of varying severity in 1 study; the mixed tea study did… | 3 studies | Ungraded |
Surgical removal of the lesion (surgical excision, laser surgery, cryotherapy) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | 'We did not identify any RCTs that compared surgical treatments with placebo or no treatment.' Three surgical RCTs were found (Chee 2013, Lopez-Jornet 2013, Schwarz 2005) but all excluded because they did not include a… | NR | No studies |
Removal of predisposing habits (e.g. tobacco/alcohol cessation) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | '...nor did we identify any RCTs of risk factor cessation.' Removal of predisposing habits (e.g. smoking cessation) was a planned intervention; no eligible RCT found. | NR | No studies |
NSAIDs (ketorolac oral rinse; systemic celecoxib) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Improvement of histological features (not improved) | SoF 3, Histological changes: 'Not measured'. Effects text: 'Histological changes were not among the outcomes in the studies testing NSAIDs.' | 0 studies | No studies |
Oral cancer development | SoF 3 (NSAIDs vs placebo), Cancer development: SoF cell 'Not measured'. Effects text: cancer development was among outcomes in Papadimitrakopoulou 2008 (celecoxib) but did not occur in either arm, probably because of… | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) 3 months | SoF 3, Clinical resolution (not completely resolved) at 3 months: '1 study evaluated systemic treatment and 1 evaluated topical treatment. Neither found benefit for NSAIDs.' No GRADE. Effects text: celecoxib… | 2 studies | Ungraded |
Safety of the intervention (adverse effects) over 3 months | SoF 3, Safety of the intervention over 3 months: systemic celecoxib (1 study) - 32 intervention participants reported 56 adverse effects, 20 placebo participants reported 20; 4 grade 3 events; 2 discontinued. Ketorolac… | 2 studies | Ungraded |
Bowman-Birk inhibitor vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Improvement of histological features (not improved) | SoF 6, Histological changes: 'Not measured'. Effects text: data on histological changes from Armstrong 2013 were not available for analysis, but study authors reported no statistically significant differences in… | 1 study | Ungraded |
Oral cancer development | SoF 6 (Bowman-Birk inhibitor vs placebo), Cancer development: 'Not measured'. Effects text: 'Cancer development was not among the outcomes of the study testing the Bowman-Birk inhibitor (Armstrong 2013).' | 0 studies | No studies |
Clinical resolution (oral lesion not completely resolved) 6 months | RR 1.00 [0.91, 1.09] 957 per 1000 vs 957 per 1000 | 1 study · 21 participants | Low Downgraded: risk of bias, imprecision |
Safety of the intervention (adverse effects) up to 6 months | SoF 6, Safety of the intervention up to 6 months: 'Trial authors reported that there were no significant adverse effects. 33 participants in the intervention group reported 75 adverse effects. 25 participants in the… | 1 study | Ungraded |
Vitamin A or retinoids (systemic or topical; incl. 13-cis-retinoic acid, acitretin) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic 13-cis-retinoic acid 79%; vitamin A 300,000 IU/wk 26%; topical acitretin (Gaeta), topical 13-cis-retinoic acid (Piattelli), vitamin A 200,000 IU/wk (Stich) no adverse effects. | 5 studies | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), systemic vitamin A (Sankaranarayan 1997): not estimable; none of the treatments showed benefit vs placebo (2 studies, 172 participants). | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.69 [0.50, 0.96] | 5 studies · 245 participants | Ungraded |
Histological worsening (variation in histological features) | RR 0.51 [0.32, 0.81] | 1 study | Ungraded |
Systemic beta carotene or carotenoids (incl. lycopene) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): beta carotene 360 mg/wk 9%; lycopene 8 or 4 mg (Singh) 0/40 vs 0/18, no adverse effects. | 2 studies | Ungraded |
Histological worsening (variation in histological features) | RR 0.24 [0.12, 0.46] | 1 study · 58 participants | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), systemic beta carotene (Sankaranarayan 1997): not estimable; no benefit vs placebo. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.69 [0.54, 0.88] | 2 studies · 168 participants | Ungraded |
Topical bleomycin vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Clinical resolution (oral lesion not completely resolved) | RR 0.55 [0.29, 1.04] | 1 study · 22 participants | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), topical bleomycin (Epstein 1994): not estimable; no benefit vs placebo. | 1 study | Ungraded |
Safety of the intervention (adverse effects) | Adverse effects (Table 1): topical bleomycin 10/10 vs 0/12 (100%). | 1 study | Ungraded |
Histological worsening (variation in histological features) | Histological changes, topical bleomycin (Epstein 1994): assessed; no significant benefit; no pooled estimate reported. | 1 study | Ungraded |
Mixed tea (green tea extract, polyphenols and pigments; topical plus systemic) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic and topical tea (Li) 0/32 vs 0/32; no adverse effects. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 1.0 [0.94, 1.06] | 1 study · 64 participants | Ungraded |
Surgical removal of the lesion (surgical excision, laser surgery, cryotherapy) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Description of studies: one RCT evaluating surgical interventions was found (Schwarz 2005) but excluded because it did not include a no-treatment/placebo group; no eligible surgical RCT. | NR | No studies |
Removal of predisposing habits (e.g. tobacco/alcohol cessation) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Removal of predisposing habits (risk factor cessation) was a planned intervention; no eligible RCT found. | NR | No studies |
NSAID (ketorolac oral rinse) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): ketorolac oral rinse (Mulshine) 11/38 vs 3/19 (29%); pain, toxicity grade 1 and 2; one withdrawal after first dose due to mouth pain. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | Clinical resolution (Comparison 1, Outcome 1.2), ketorolac oral rinse (Mulshine 2004): assessed as a single study, showed no benefit vs placebo (grouped with bleomycin and tea as single-study treatments). | 1 study | Ungraded |
Vitamin A or retinoids (systemic or topical; incl. 13-cis-retinoic acid, acitretin) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic 13-cis-retinoic acid 79%; vitamin A 300,000 IU/wk 26%; topical acitretin (Gaeta) 0/14 vs 0/7 no AEs; topical 13-cis-retinoic acid (Piattelli) 0/5; vitamin A 200,000 IU/wk (Stich) 0/30. | 5 studies | Ungraded |
Histological worsening (variation in histological features) | RR 0.51 [0.32, 0.81] | 1 study | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 01, Outcome 01), systemic vitamin A (Sankaranarayan 1997): not estimable; none of the treatments showed benefit vs placebo (2 studies, 227 participants). | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.69 [0.50, 0.96] | 5 studies · 245 participants | Ungraded |
Systemic beta carotene or carotenoids (incl. lycopene) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): beta carotene 360 mg/wk 5/55 vs 1/55 (9%). | 1 study | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 01, Outcome 01), systemic beta carotene (Sankaranarayan 1997): not estimable; no benefit vs placebo. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.77 [0.65, 0.92] | 1 study · 110 participants | Ungraded |
Topical bleomycin vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): topical bleomycin 10/10 vs 0/12 (100%). | 1 study | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 01, Outcome 01), topical bleomycin (Epstein 1994): not estimable; no benefit vs placebo. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.55 [0.29, 1.04] | 1 study · 22 participants | Ungraded |
Histological worsening (variation in histological features) | Histological changes, topical bleomycin (Epstein 1994): worsened more often with placebo but difference not significant; no pooled estimate reported. | 1 study | Ungraded |
Mixed tea (green tea extract, polyphenols and pigments; topical plus systemic) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic and topical tea (Li) 0/32 vs 0/32; no adverse effects. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 1.0 [0.94, 1.06] | 1 study · 64 participants | Ungraded |
Surgical removal of the lesion (surgical excision, laser surgery, cryotherapy) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Description of studies: 'We found no randomised controlled trials (RCTs) evaluating surgical interventions.' Surgery vs no treatment/placebo not studied in any eligible RCT. | NR | No studies |
Removal of predisposing habits (e.g. tobacco/alcohol cessation) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Removal of predisposing habits (e.g. tobacco/alcohol cessation) was a planned intervention; no eligible RCT of risk factor cessation was found. | NR | No studies |
Vitamin A or retinoids (systemic or topical; incl. 13-cis-retinoic acid, acitretin) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic 13-cis-retinoic acid (Hong) 19/24 vs 4/20 (79%); vitamin A 300,000 IU/wk (Sankaranarayan) 13/50 vs 1/55 (26%); topical 13-cis-retinoic acid (Piattelli) 0/5 vs 0/5; vitamin A 200,000… | 4 studies | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.72 [0.52, 1.01] | 4 studies · 224 participants | Ungraded |
Histological worsening (variation in histological features) | RR 0.51 [0.32, 0.81] | 1 study | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), systemic vitamin A subgroup (Sankaranarayan 1997): not estimable (RevMan RR 0.0 [0.0, 0.0], totals not selected); none of the treatments showed benefit vs placebo… | 1 study | Ungraded |
Systemic beta carotene or carotenoids (incl. lycopene) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): beta carotene 360 mg/wk (Sankaranarayan) 5/55 vs 1/55 (9%). | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.77 [0.65, 0.92] | 1 study · 110 participants | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), systemic beta carotene subgroup (Sankaranarayan 1997): not estimable (RevMan RR 0.0 [0.0, 0.0], totals not selected); no benefit vs placebo. | 1 study | Ungraded |
Topical bleomycin vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): topical bleomycin (Epstein) 10/10 vs 0/12 (100%). | 1 study | Ungraded |
Malignant transformation (oral cancer development) | Malignant transformation (Comparison 1, Outcome 1.1), topical bleomycin subgroup (Epstein 1994): not estimable (RevMan RR 0.0 [0.0, 0.0], totals not selected); no benefit vs placebo. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 0.55 [0.29, 1.04] | 1 study · 22 participants | Ungraded |
Histological worsening (variation in histological features) | Histological worsening (Comparison 1, Outcome 1.3), topical bleomycin (Epstein 1994): histological aspect worsened more often with placebo but difference not significant; no pooled estimate reported (totals not… | 1 study | Ungraded |
Mixed tea (green tea extract, polyphenols and pigments; topical plus systemic) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Safety of the intervention (adverse effects) | Adverse effects (Table 1): systemic and topical tea (Li) 0/32 vs 0/32; no adverse effects. | 1 study | Ungraded |
Clinical resolution (oral lesion not completely resolved) | RR 1.0 [0.94, 1.06] | 1 study · 64 participants | Ungraded |
Surgical removal of the lesion (surgical excision, laser surgery, cryotherapy) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Description of studies: 'We found no RCTs evaluating surgical interventions.' Surgical treatment (excision, laser, cryotherapy) versus no treatment/placebo not studied in any RCT. | NR | No studies |
Removal of predisposing habits (e.g. tobacco/alcohol cessation) vs Placebo or no treatment
Population: People with a diagnosis of oral leukoplakia
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Outcome NR | Discussion: 'Trials evaluating interventions directed against risk factors (i.e. smoking) are also missing.' Removal of predisposing habits was a planned intervention but no eligible RCT was found. | NR | No studies |