Reference |
Design |
Other type of trial: define in words |
Date of publication |
Number of patients |
Type of intervention (define in words) |
Results description according to the endpoint |
Attrition bias? |
Reporting bias? |
Overall |
(9) |
4 |
Phase I clinical study |
2015 |
36 |
(NA chemotherapy) + lung sparing surgery + IMRT or NA chemotherapy + IMRT |
Acceptable toxicity |
No |
No |
Better survival in + IMRT group as opposed to IMRT alone |
(10) |
4 |
ERS-ESTS Guidelines |
2010 |
– |
– |
– |
– |
– |
See Table 2. To be updated in 2018 |
(11) |
4 |
ESMO clinical Guidelines |
2015 |
– |
– |
– |
– |
– |
See Table 2 |
(12) |
4 |
ASCO Guidelines |
2018 |
– |
– |
– |
– |
– |
See Table 2. Conservative position regarding role of surgery and radiotherapy, based on low quality evidence |
(13) |
4 |
BTS Guidelines |
2018 |
– |
– |
– |
– |
– |
See Table 2. Strong recommendation to avoid monotherapy with surgery, based on intermediate quality evidence |
(15) |
1 |
Not applicable |
2017 |
19,134 |
– |
Best survival outcomes in patients treated with combined modality approach |
– |
– |
Large database analysis supporting implementation of combined modality treatment. 40% of patients did not receive any MPM specific treatment |
(16) |
1 |
Not applicable |
2017 |
20,561 |
– |
2.6% of patients received trimodality therapy. Patients treated at an academic centre or who travel >26 miles for treatment were more likely to undergo trimodality therapy. Younger age, satisfactory overall condition and presence of private insurance also increased likelihood of multimodality treatment |
– |
– |
Large database analysis reporting low numbers of patients treated with surgery-based multimodality therapy. Use of combined modality treatment is stable over time |
(18) |
1 |
Not applicable |
2016 |
229 |
True adjuvant therapy vs. neo-adjuvant therapy vs. therapy reserved until disease progression vs. conservative in those unfit for chemotherapy |
True adjuvant chemotherapy may be beneficial in those with a poorer prognosis based on cell type and nodal stage |
No |
Yes |
Overall survival similar in all chemotherapy groups, even when calculated from time of diagnosis |
(19) |
3 |
Not applicable |
2011 |
112 |
Chemotherapy followed by EPP and radiotherapy or no EPP |
Hazard ratio for overall survival after factor adjustments was 2.75, P=0.016) |
No |
No |
Good quality clinical trial showed high mortality on EPP group |
(20) |
2 |
Not applicable |
2012 |
25 |
EPP, neoadjuvant chemotherapy and adjuvant radiotherapy |
18.2 treatment mortality, 81% completed trimodality treatment, median survival of 12.8 months |
Yes |
No |
Moderate case series report with shows similar survival with chemotherapy only |
(21) |
4 |
Systematic review |
2017 |
– |
Radical surgery and debulking surgery |
More RCTs required |
– |
Yes |
Author was co-investigator on the MARS1 trial and is part of ongoing MARS2 trial |
(22) |
3 |
Not applicable |
2015 |
151 |
Neoadjuvant chemotherapy followed by EPP and control/treatment group of radiotherapy |
Median locoregional relapse free survival was 7.6 months in the no radiotherapy group and 9.4 months in the radiotherapy group showing no support use of radiotherapy after chemotherapy + EPP |
No |
No |
Study terminated earlier than expected due to slow accrual. Good quality study showing no clinical benefit of post-surgery radiotherapy and an overall survival of 20 months - less than other retrospective studies |
(23) |
2 |
– |
2015 |
42 |
Induction chemotherapy, EPP and adjuvant radiation |
Macroscopic complete resection of 71% and mortality of 9.5% |
No |
No |
Prospective cohort that shows trimodality treatment is feasible in Japan |
(24) |
4 |
Systematic review |
2018 |
– |
Radical surgery ± radical RT ± photodynamic therapy ± systemic therapy vs. each other or vs. palliative care |
Not enough evidence supporting routine implementation of multimodality treatment |
No |
No |
Systematic review based on two multimodality treatment trials, including the already heavily cited MARS1trial. Limited added benefit |
(25) |
2 |
– |
2010 |
36 |
Neoadjuvant chemotherapy |
Significant improvement in FEV1 (0.13±0.30 L; P=0.01), in VO2 peak (1.76±2.91 mL kg−1 min−1; P=0.005), in PaO2 at rest (4.76±9.84 mmHg; P=0.03) and in PaO2 at peak exercise (6.26±12.72 mmHg; P=0.04) was detected. Diffusion capacity was increased but non-significantly |
No |
No |
Most significant lung function improvement in patients who showed response to chemotherapy, effect of overall better condition or true chemotherapy effect? |
(26) |
3 |
Phase II clinical study- no control group |
2010 |
59 |
Induction chemotherapy followed by EPP followed by radiotherapy |
Trimodality treatment completed in 64.9% of patients. 24/42.1% patients met success of treatment (primary end point) and median overall survival was 18.4 months |
No |
No |
Good quality clinical study showed that TMT is feasible but did not met the definition of success as per primary endpoint |
(27) |
4 |
Phase I/II clinical study |
2016 |
62 |
IMRT followed by EPP and adjuvant chemotherapy (SMART protocol) |
Ongoing phase II study—SMART protocol is feasible and 39% developed 3 + complications, 4.8% developed grade 5 complications and died |
No |
No |
Moderate quality study suggesting a protocol with high complications to a selective population |
(28) |
4 |
Phase II clinical study- no control group |
2013 |
56 |
Chemotherapy followed by EPP followed by radiotherapy |
Median event free survival (EFS) was 6.9 months, 33% achieved 1 year EFS and 24% 2 years EFS. Median PFS was 8.6 months and 1 year PFS 40.7% |
No |
No |
Good quality phase II study shows trimodality treatment is feasible in highly selective population |
(29) |
1 |
Not applicable |
2009 |
60 |
Chemotherapy followed by EPP followed by radiotherapy |
50% patients completed protocol, 5-year survival 53% of those completed the protocol-median survival of all patients included was 14 months |
No |
No |
High selective population-retrospective study with 6.7% mortality of EPP |
(32) |
4 |
Systematic review |
2012 |
16 studies, 744 patients |
Radical pleurectomy followed by chemotherapy (Cis-Pem) and radiotherapy |
Inconsistent results of long term survival from current studies |
No |
No |
Good quality systematic review shows inconsistent results between prospective/retrospective and 1 randomized trial no allowing definitive conclusions to be drawn for the surgical procedures |
(33) |
1 |
Not applicable |
2014 |
39 |
Postoperative highly conformal versus 3D conformal radiotherapy |
Better local control in treatment group, problematic distant relapsing affecting overall survival |
No |
Yes |
The more conformal, the lesser toxicity |
(35) |
4 |
Phase II clinical study- no control group |
2016 |
45 |
Chemotherapy followed by PD followed by hemithoracic intensity modulated pleural radiation therapy (IMPRINT) |
|
Less than 50% of enrolled patients did not undergo surgery |
No |
Moderate quality clinical study which showed the safety of IMPRINT but not established any clinical use |
(36) |
1 |
Not applicable |
2011 |
24 |
Helical tomotherapy radiotherapy after chemotherapy and EPP or chemotherapy only |
HT had comparable toxicity compared to IMRT |
No |
No |
Retrospective study which suggests that HT is safe based on a retrospective study |
(37) |
1 |
Not applicable |
2012 |
51 |
Induction chemotherapy (carboplatin or cisplatin) followed by EPP or PD and radiotherapy |
Response rate of 22% (carboplatin) versus 17 (cisplatin). Higher grade 3 anaemia on the carboplatin group |
No |
No |
Moderate quality retrospective study with selection bias not clear conclusions to be drawn |
(39) |
3 |
Not applicable |
2014 |
25 |
IMRT followed by EPP and adjuvant chemotherapy (SMART protocol) |
Feasibility study with 25 patients completed trial with no grade 3–5 toxicities |
No |
No |
82% of patients screened were not eligible for the study. Selective population only conclusion that can be drawn is that IMRT followed by EPP is feasible on a selective population |
(42) |
1 |
Not applicable |
2017 |
20,561 |
– |
Cancer-directed surgery, chemotherapy, and radiation therapy were associated with improved survival (hazard ratio, 0.77, 0.74, and 0.88, respectively) |
No |
Yes |
Immortal time bias |
(30) |
2 |
Not applicable |
2015 |
69 |
PD or extended P/D, chemotherapy and radiotherapy (IMRT) |
OS, PFS and locoregional control no different between groups |
No |
Not clearly demonstrated results |
Moderate quality prospective study showing a high OS post PD and no toxicities post radiotherapy |
(31) |
4 |
Phase II clinical study- no control group |
2009 |
77 |
Chemotherapy followed by EPP followed by radiotherapy |
median survival of 16.8 months, 5% of EPP pathological complete response was observed |
No |
No |
Clinical study that showed feasibility of TMT on a selective population |
(43) |
1 |
Not applicable |
2015 |
169 |
Extrapleural pneumonectomy (EPP) and chemotherapy and radiotherapy |
75% of patients developed recurrent disease with multimodality treatment |
No |
Yes |
Poor quality retrospective analysis with variabilities on chemotherapy and radiotherapy among patients |
(44) |
1 |
Not applicable |
2102 |
530 |
Extrapleural pneumonectomy and chemotherapy and radiotherapy |
Median survival of multimodality group 317 days |
No |
No |
Poor quality retrospective analysis, no control group for comparison, relative risk of death between multimodality treatment and untreated 0.57 and 0.61 respectively |
(45) |
1 |
Not applicable |
2015 |
53 |
Adjuvant radiotherapy following EPP |
18.7 months follow up survival |
No |
Yes |
Poor quality retrospective analysis, no control group for comparison, selection bias and no regular reporting of CT scans |
(46) |
2 |
Not applicable |
2012 |
25 |
EPP, neoadjuvant chemotherapy and adjuvant radiotherapy |
28% average increase in FVC and 23.9% increase in FEV1 |
Yes (9 patients excluded) |
No |
Moderate case series report which shows improvement of FVC/FEV1 post trimodality treatment with high mortality rates and poor design |
(47) |
2 |
Not applicable |
2011 |
102 |
Radical pleurectomy (RP) followed by chemotherapy (Cis/Pem) and radiotherapy |
Surgical morbidity and mortality were 20% and 2.9%. Trimodality mortality was 5.8% |
Yes |
Yes from the initial 102 patients only 35 included in the analysis and not clear why the rest were not included |
Moderate case series showing a lower mortality-morbidity rate with RP |
(48) |
1 |
Not applicable |
2009 |
55 |
Induction chemotherapy, EPP and adjuvant radiation |
Overall mortality after EPP 4.3% |
Yes |
No |
Poor quality case series with selection bias, most aggressive cases were excluded from the cohort |
(49) |
2 |
Not applicable |
2015 |
24 |
Intensity modulated radiation therapy after pleurectomy/decortication (PD) or EPP |
IMRT post PD produced high grade toxicity but better overall survival compared to IMRT post EPP |
No |
Yes-minimal information for the matched control group |
Poor quality study |
(50) |
4 |
Phase I clinical study |
2012 |
3 |
EPP followed by hemithoracic IMRT |
1 patient had grade 2 complication, 1 developed recurrence |
No |
No |
Phase I feasibility study |
(51) |
1 |
Not applicable |
2012 |
41 |
Chemotherapy followed by EPP followed by radiotherapy |
1 year survival was 45% (overall) and patients with trimodality therapy showed significantly better survival rates after 1, 2, 5 years |
No |
No |
Good quality retrospective study suggests that trimodality treatment should be considered in highly selected patients |
(52) |
3 |
Not applicable |
2011 |
38 |
PD and photodynamic therapy |
Median progression free survival (PFS) 9.6 months and median survival of 31.7 months |
No |
No |
Retrospective study with selection bias suggesting the safety of lung sparing surgical approach |
(53) |
1 |
Not applicable |
2009 |
36 |
EPP, adjuvant chemotherapy and radiotherapy |
Mortality of 11%, PFS was 19 months |
No |
No |
Retrospective study with selection bias, total mortality of 11% |
(54) |
1 |
Not applicable |
2015 |
17 |
Induction chemotherapy, EPP and adjuvant radiation using volumetric modulated arc therapy (VMAT) |
1 year overall survival and progression free survival of 43.1% and 55.7 respectively |
No |
No |
Retrospective study which shows suggests that VMAT is safe |
(55) |
2 |
Not applicable |
2016 |
210 |
Registry-no interventions planned |
Differences on population treated with MTM compared to chemotherapy or best supportive care |
No |
No |
Registry that shows patients who were treated with MTM were significantly younger, fitter and with better PS |
(56) |
1 |
Not applicable |
2009 |
26 |
Chemotherapy followed by EPP followed by radiotherapy (IMRT) |
1 patient died from intracranial hemorrhage, 4 patients had grade 5 toxicities |
No |
No |
Retrospective study focusing on toxicities post radiotherapy |
(57) |
2 |
Not applicable |
2015 |
186 |
Induction chemotherapy followed by EPP |
Prognostication score based on database results proposed |
No |
No |
No validation cohort to assess prognostication score-limited use at this stage |
(58) |
1 |
Not applicable |
2013 |
103 |
Hyperthermic intraoperative pleural cisplatin chemotherapy |
Patient on treatment group exhibited a significantly longer interval to recurrence (27.1 vs. 12.8) and overall survival (35.3 vs. 22.8) compared to control |
No |
No |
Poor quality retrospective study with highly heterogenous groups |
(59) |
2 |
Not applicable |
2015 |
62 |
Chemotherapy followed by EPP followed by radiotherapy |
Overall survival was 20.4 months, no grade 4 toxicities with radiotherapy |
No |
No |
Retrospective study of moderate quality |
(60) |
2 |
Not applicable |
2009 |
83 |
Chemotherapy followed by EPP (or EPP followed by chemotherapy) followed by radiotherapy |
Overall survival of 14.9 months, 4.8% mortality rates |
No |
No |
Retrospective study showed site experience on trimodality treatment |
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