RFA Assessed with: estimate (95%CI not reported) F/U range 19 to 46 months 1 Level III-3 study 7 Level IV studies Median survival rate, pooled 1-year 86.3% (range 83–100%) 2-year 74% (range 69.8–86%) 3-year 62.8% (range 40–74%) 5-year 28% (range 14–61%) ⨁⨀⨀⨀ VERY LOW 3 Radiotherapy Assessed with: varied instruments F/U range 21 to 30.2 months 1 Level II study 1 Level III-1 study5 Videtic et al (2015) 1-year survival 34/1 GY SBRT = 48.6% (95% CI 68.9–92.8%) 48/4 GY SBRT = 91.1 (95% CI 78.0–96.6%) 2-year survival 34/1 GY SBRT = 61.3% (95% CI 44.2–74.6%) 48/4 GY SBRT = 77.7% (95% CI 62.5–87.3%) Koshy et al (2015) 3-year survival No therapy = 28% , Conventional radiotherapy = 36%, SBRT = 48% A propensity-matched cohort reported 3 year overall survival with SBRT of 48% and with conventional radiotherapy of 40% (p = 0.001). ⨁⨁⨀⨀ LOW Median survival time MTA Assessed with: estimate (95%CI) F/U range 23 to 30 months 2 Level IV studies Han et al (2015) 35.0 months (95%CI 22.3–47.7) Yang et al (2014) 33.8 months (95%CI 31.9–35.7) 2 ⨁⨀⨀⨀ VERY LOW 5 RFA Assessed with: estimate (95%CI) F/U range 19 to 37 months 6 Level IV studies Median overall survival 42.8 months (range: 33.4–67) ⨁⨀⨀⨀ VERY LOW 3 Radiotherapy Not reported 0 studies NA NA Time to local progression
MTA for patients with lung metastases in whom the primary tumour is under control. Patients included those with primary nasopharyngeal carcinoma in one study and mixed primary cancers in another. 2 (159), Level IV Retrospective study design in one, reporting of adverse events was incomplete for one study, poor reporting in relation to consecutive recruitment of patients, comprehensive eligibility criteria and follow-up. High MTA for patients with lung metastases or primary NSCLC treated with palliative intent. 3 (103), Level III-2 (2 studies), Level IV (1 study) Studies did not allocate patients to interventions based on a randomisation procedure and patient demographics were variably reported. High MTA for mixed populations, included for an extended assessment of harms. 15 (977), Level IV Reporting of adverse events was incomplete in k = 5/15. Poor reporting in relation to consecutive recruitment of patients, comprehensive eligibility criteria and follow-up was an issue. High < k = number of studies; MTA = microwave tissue ablation; NSCLC = non-small cell lung cancer >
Table Quality appraisal of included case series investigations of MTA, according to the IHE Quality Appraisal of Case Series Studies Study ID Was the objective of the study clearly stated? Was the study conducted prospectively? Were the cases collected in multiple centres? Were patients recruited consecutively? Were patient characteristics described? Were the eligibility criteria clearly stated? Did patients enter the study at a similar point in the disease? Was the intervention clearly described? Were relevant outcome measures established a priori? Were outcome assessors blinded to the intervention? Were outcomes measured using appropriate methods? Were the statistical tests appropriate? Was follow-up long enough to capture important events and outcomes? Were losses to follow-up reported? Did the study provide estimates of random variability in the data analysis? Were the adverse events reported? Were the conclusions of the study supported by results? Were competing interests and sources of support reported? POPULATION 1 Han et al (2015) ? ? ? Liu & Steinke (2015) ? • Yang et al (2014) ? • ? POPULATION 2 Qi et al (2015) ? • Vogl et al (2015) ? • POPULATION 3 Ni et al (2015) ?
Table Quality appraisal of included case series investigations of RFA, according to the Downs and Black Checklist for Randomised and Non-Randomised Comparative Trials Study ID Reporting: Hypothesis Reporting: Outcomes Reporting: Patient characteristics Reporting: Intervention Reporting: Confounders Reporting: Main findings Reporting: Random variability in results Reporting: Adverse events Reporting: Losses to follow-up Reporting: Actual probabilities Validity: Invited sample representative Validity: Participating sample representative Validity: Facilities representative Bias: Subjects blinded Bias: Measurements blinded Bias: Data dredging Bias: Length of follow-up accounted for Bias: Statistical tests appropriate Bias: Compliance with intervention Bias: Outcomes were accurate Confounding: Recruitment same population Confounding: Recruitment same time Confounding: Randomisation Confounding: Randomisation blinded Confounding: Adjustment for confounders Confounding: Losses to follow-up Power: Power reported Safi et al (2015) 1 1 1 0 1 1 1 1 1 0 NA 1 1 0 0 1 1 1 1 1 0 1 0 NA 0 0 0 1 = yes, 0 = no, NA = not applicable.
Table Quality appraisal of included case series investigations of RFA, according to the IHE Quality Appraisal of Case Series Studies () Study ID Was the objective of the study clearly stated? Was the study conducted prospectively? Were the cases collected in multiple centres? Were patients recruited consecutively? Were patient characteristics described? Were the eligibility criteria clearly stated? Did patients enter the study at a similar point in the disease? Was the intervention clearly described? Were relevant outcome measures established a priori? Were outcome assessors blinded to the intervention? Were outcomes measured using appropriate methods? Were the statistical tests appropriate? Was follow-up long enough to capture important events and outcomes? Were losses to follow-up reported? Did the study provide estimates of random variability in the data analysis? Were the adverse events reported? Were the conclusions of the study supported by results? Were competing interests and sources of support reported? POPULATION 1 Ambrogi et al (2011) ? ? ? • • Dupuy et al (2015) ? • Hiraki et al (2011) • Lanuti et al (2012) • • • Liu et al (2015) ? • Ridge et al (2014) ? • • Viti et al (2014) • POPULATION 2 de Baere et al (2015) • • ? •
Yu (2014) 1 1 0 1 1 1 0 0 0 0 NA ? 1 0 0 0 1 1 1 1 1 1 0 NA 0 0 0 CA = cannot answer; 1 = yes, 0 = no, NA = not applicable. Table Quality appraisal of included case series investigations of radiotherapy, according to the IHE Quality Appraisal of Case Series Studies () Study ID Was the objective of the study clearly stated? Was the study conducted prospectively? Were the cases collected in multiple centres? Were patients recruited consecutively? Were patient characteristics described? Were the eligibility criteria clearly stated? Did patients enter the study at a similar point in the disease? Was the intervention clearly described? Were relevant outcome measures established a priori? Were outcome assessors blinded to the intervention? Were outcomes measured using appropriate methods? Were the statistical tests appropriate? Was follow-up long enough to capture important events and outcomes? Were losses to follow-up reported? Did the study provide estimates of random variability in the data analysis? Were the adverse events reported? Were the conclusions of the study supported by results? Were competing interests and sources of support reported? Agolli (2015) ?  • • • Baschnagel (2013) • ? • ? • Garcia-Cabezas (2015) • ? • •  • • • Filippi (2015) •  • • Gamsiz (2014) ? • ?  • • Kim (2009) ? • ?  • •
Table Quality appraisal of included case series investigations of surgical resection, according to the IHE Quality Appraisal of Case Series Studies Study ID Was the objective of the study clearly stated? Was the study conducted prospectively? Were the cases collected in multiple centres? Were patients recruited consecutively? Were patient characteristics described? Were the eligibility criteria clearly stated? Did patients enter the study at a similar point in the disease? Was the intervention clearly described? Were relevant outcome measures established a priori? Were outcome assessors blinded to the intervention? Were outcomes measured using appropriate methods? Were the statistical tests appropriate? Was follow-up long enough to capture important events and outcomes? Were losses to follow-up reported? Did the study provide estimates of random variability in the data analysis? Were the adverse events reported? Were the conclusions of the study supported by results? Were competing interests and sources of support reported? Kitano et al (2012) • • Renauld et al (2014) ? • Roudriguez-Fuster et al (2014) ? • Reza et al (2009) ? • • Younes et al (2009) ? • •  = yes,  = no, • = partial, ? = unclear. Note: The IHE quality appraisal tool was modified to remove two questions that are not applicable to this review. These include: Were additional interventions (co-interventions) clearly described? And, were the relevant outcome measures made before and after the intervention?
Egashira et al 2016 44 (87) Retrospective CS Median 15 (6.2–29.5) months High Pulmonary tumours of primary or secondary origind Adverse events Not used He et al (2006) 12 (16) Retrospective CS Mean: 20 months High Primary cancer not suitable for resection and patients with oligometastatic lung lesions Adverse events Not used Little et al (2013) 23 (29) Retrospective CS Median 6 months High Primary cancer not suitable for resection and oligometastatic lung lesions Adverse events Not used Lu et al (2012) 69 (93) Retrospective CS NR High Stage IIIB NSCLC or pulmonary metastases, inoperable Adverse events Not used Nour-eldin et al (2011) 164e (NR) Retrospective CS NR High Primary NSCLC or secondary lung tumours, inoperable Adverse events Not used Sun et al (2014) 29 (39) Retrospective CS Median 25 months High Primary or metastatic lung cancer Adverse events Not used Splatt & Steinke (2015) 51 (70) Retrospective CS NR High Primary pulmonary malignancies or secondary metastases Adverse events Not used Vogl et al (2012) 57 (91) Retrospective CS mean (range): 10.2 (6.0–29.2) months High Primary or oligometastatic secondary lung cancer Adverse events Not used Wolf et al (2008) 82 (NR) Retrospective CS mean (SD): 10 (6.8) months High Primary or secondary lung cancer, medically inoperable or refusing surgery Adverse events Not used
Navarria et al (2014) 76 (118) Prospective CS 18 (6–45) months High 1–5 lung metastases, controlled primary tumour, no progressive disease longer than 6 months, medically inoperable Overall, PF survival, adverse events Not used Navarria et al (2015) 28 (51) Prospective CS 21 (8–20) months High 1–4 lung metastases, disease, controlled primary tumour, progressive disease after chemo ± surgery Overall survival, adverse events Not used Norihasa et al (2008) 34 (43) Retrospective CS 27 (10–80) months High 1–2 pulmonary metastases, ≤ 40 mm, locally controlled primary tumour, no other metastatic sites Overall, survival, adverse events Not used Nuyttens et al (2015) 30 (57) Prospective CS 36 (4–60) months High 1–5 lung metastases, inoperable or refused surgery, primary under control Overall, survival, adverse events Not used Oh et al (2012) 57 (67) Retrospective CS 21 (3–107) months High 1–4 lung metastases, < 50 mm, with a controlled primary tumour Overall survival, adverse events Not used Osti et al (2013) 66 (103) Prospective CS 15 (3–45) months High 1–2 lung metastases, < 50 mm, controlled extra thoracic disease Overall, PF survival, adverse events Not used Ricardi et al (2011) 61 (77) Retrospective CS 20 (3–77) months High Patients with 1–3 lung metastases, <50mm, absent or controlled extra thoracic disease Overall, PF survival, adverse events Not used Takahashi et al (2014) 34 (44) Retrospective CS 24 (6–167) months High Colorectal lung metastases, resected primary, inoperable, no other metastases Overall survival, adverse events Not used Meta-analysis/ pooling 808 17 studies Where possible n/N (%) for adverse events has been calculated across all studies. Measures of central tendency and associated measures of variance have been reported if applicable Not used < CS = case series; IQR = interquartile range; mm = millimetres; n/N (%) = number with event/ total (percentage); NR = not reported; PF = progression-free >
Table Symptom improvement in lung cancer patients treated palliatively with RFA () Symptom № of lesions treated № of lesions with symptom improvement № of lesions with symptom recurrence (%) Pain 20 19 7 (37) Haemoptysis 3 3 2 (67) Cough 4 4 1 (25) Effectiveness of radiotherapy for palliation of advanced-stage lung cancer The effectiveness of radiotherapy for palliative treatment of advanced stage lung cancer was recently reported in a Cochrane review by Stevens et al (). The review included 13 RCTs that compared the effects of radiotherapy fractionation schedules on symptom improvement and overall survival. The authors noted that all of the included studies reported a benefit of radiotherapy on symptom improvement, but concluded that no strong evidence for higher doses were associated with better or longer lasting palliation. Quality of life The overall survival in patients who have good or poor performance status, with quality of evidence ratings for the reported relative effect, are presented in Table 57. Table Effectiveness and quality of evidence for palliative radiotherapy regimens () Illustrative risks comparative (95% CI) Relative effect No of patients Quality of the evidence Outcomes Less fractions More fractions (95% CI) (studies) (GRADE) Comments 1-year overall survival in patients of good performance status Mean 25.6% (9.4–45.7%) Mean 33.3% (11.4–46.2%) 1,081 (8 studies) ⨁⨁⨀⨀ LOW NO summary statistic due to heterogeneity, incomplete data – unable to source missing data from authors 1-year overall survival in patients of poor performance status Mean 14.6% (1.3–29.5%) Mean 17.5% (9.1–28.6%) RR 0.96 (0.91 to 1.02) 911 (7 studies) ⨁⨁⨁⨀ MODERATE Incomplete data - unable to source missing data from authors < CI = confidence interval; NR = not reported; RR = relative risk > GRADE Working Group grades of evidence (Guyatt et al., 2013)
Table Summary of published economic evaluation of MTA, RFA, surgery and RT to treat lung cancer Reference Time Horizon Country and Population Intervention Cost Comparator Costs Type of analysis Perspective Results Sher et al. () A lifetime horizon 65-year-old men with medically inoperable NSCLC in USA RFA treatment for eradiation of pulmonary tumour and guidance cost of $5,879.62 SBRT cost of $14,741.13 includes simulation, planning and treatment Markov model comparing RFA, SBRT and 3DCRT Payer SBRT had an ICER of $6,000/QALY compared to 3DCRT and $14,100/QALY for SBRT relative to RFA. Alexander et al () 9 years 84 patients older than 65 years of age with stage IA or IB lung cancer in the USA Median cost per month lived was $620.74 for RFA Median cost of $1,195.92 per month for a patient treated surgically Patient health histories and billing charges converted to 2009 Medicare reimbursement fees. Payer RFA patients were calculated to have a cost per month of life of $620.74, compared to $1,195.92 for surgery Kwan et al () 2 years Matched cohort of 128 patients of at least 65 years of age with stage IA/IB NSCLC in USA Ablation had a mean cost of $50,682 over 24 months Surgery had a mean cost of $57,994 over 24 months Compared medical costs for a cohort of Medicare patients. Payer Thermal ablation had lower treatment and medical costs at 1 month, 3 months, and 12 months relative to sub-lobar resection Grutters et al () 5-year Inoperable and operable stage I NSCLC. Model based on clinical data from Japan for operable and Dutch for inoperable patients. Carbon-ion and proton therapy CRT and SBRT Decision-analytic Markov model Health system Carbon-ion therapy costed €67.257 per gained compared to SBRT for inoperable stage I NSCLC.
exceeding 45 minutes inpatient 17645, 17650, 17655 Initiation of management of anaesthesia, for computerised axial tomography scanning, magnetic resonance scanning, digital subtraction angiography scanning Anaesthesiologist, delivered to inpatient 138.60 1 MBS item 21922 Administration of anaesthesia, 56 MINUTES TO 1:00 HOUR Anaesthesiologist, delivered to inpatient 79.20 1 MBS Item 22025 Anaesthesia modifier for patients over 70 Anaesthesiologist, delivered to inpatient 19.80 1 MBS Item 25015 Blood pressure monitoring Anaesthesiologist, delivered to inpatient 59.40 1 MBS Item 22012 CHEST (lung fields) by direct radiography (NR) Radiologist, delivered to inpatient 35.35 2 MBS Item 58500 Medical services – post intervention follow-up Medical oncologist consultation Outpatient 75.50 1 MBS Item 116 COMPUTED TOMOGRAPHY - scan of chest, including lungs, mediastinum, chest wall and pleura, with or without scans of the upper abdomen, with intravenous contrast medium Radiologist, as outpatient 202.00 1 MBS Item 56347 Hospital services Nurse assistant – Year 2, $847.00 per week (July 2016). Hourly rate of $22.30 based on ordinary hours of work for each full time employee being 228 hours balanced over a six-week period. Cost: $22.3 based on average 1-hour input Assist with theatre, analgesia 22.30 1 NSW Public Health System Awards and Determinations, July 2016 Registered nurse (RN) – Year 5, $1,399.30 per week $36.80 based on ordinary hours of work for each full time employee being 228 hours balanced over a period. Cost: $36.8 based on average 1-hour input Assist with theatre, analgesia 36.80 1 NSW Public Health System Awards and Determinations, July 2016
Whole body FDG PET study, performed for evaluation of a solitary pulmonary nodule where the lesion is considered unsuitable for transthoracic fine needle aspiration biopsy, or for which an attempt at pathological characterisation has failed As outpatient 953.00 1 MBS Item 61523 Respiratory function test As outpatient 138.65 1 MBS Item 11503 Medical oncologist consultation As outpatient 263.90 1 MBS Item 132 Medical services – intervention LUNG, wedge resection of Surgeon to inpatient 1,147.20 1 MBS Item 38440 THORACOTOMY, exploratory, with or without biopsy Surgeon to inpatient 958.40 1 MBS Item 38418 INTERCOSTAL DRAIN, insertion of, not involving resection of rib Surgeon to inpatient 133.55 1 MBS Item 388–6 Intra-arterial cannulation when performed in association with the administration of anaesthesia Anaesthesiologist, delivered to inpatient 79.20 1 MBS Item 22025 Pre-anaesthesia consultation. Consultations comprise 4 time-based items utilising 15 minute increments up to and exceeding 45 minutes Anaesthesiologist, delivered to inpatient 99.49 1 Mean for MBS items 17610, 17615, 17620, 17625 Referred consultation. Consultations comprise 4 time-based items utilising 15 minute increments up to and exceeding 45 minutes Anaesthesiologist, delivered to inpatient 99.49 1 Mean of MBS items 17640, 17645, 17650, 17655 Initiation of management of anaesthesia, for computerised axial tomography scanning, magnetic resonance scanning, digital subtraction angiography scanning Anaesthesiologist, delivered to inpatient 138.60 1 MBS item 21922 Administration of anaesthesia, 56 MINUTES TO 1:00 HOUR Anaesthesiologist, delivered to inpatient 79.20 1 MBS Item 23043 Anaesthesia modifier for patients over 70 Anaesthesiologist, delivered to inpatient 19.80 1 MBS Item 25015 Blood pressure monitoring Anaesthesiologist, delivered to inpatient 59.40 1 MBS Item 22012
five lesions, by MTA with curative or palliative intent, including any associated imaging services NONRESECTABLE PRIMARY LUNG CANCER OR PULMONARY METASTATIC DISEASE, destruction of >5 lesions, by percutaneous MTA with curative or palliative intent, including any associated imaging services Radiologist, delivered to inpatient 2,000.00 2,000.00 75% 1 Applicant Pre-anaesthesia consultation. Consultations comprise 4 items utilising 15 minute increments up to and exceeding 45 minutes delivered to inpatient 99.49 99.49 75% 1 Mean for MBS items 17610, 17615, 17620, 17625 Referred consultation. Consultations comprise 4 items utilising 15 minute increments up to and exceeding 45 minutes delivered to inpatient 99.49 99.49 75% 1 Mean of MBS items 17640, 17645, 17650, 17655 Initiation of management of anaesthesia, for computerised axial tomography scanning, magnetic resonance scanning, digital subtraction angiography scanning delivered to inpatient 138.60 138.60 75% 1 MBS item 21922 Administration of anaesthesia, 56 MINUTES TO 1:00 HOUR delivered to inpatient 79.20 79.20 75% 1 MBS Item 23043 Anaesthesia modifier for patients over 70 delivered to inpatient 19.80 19.80 75% 1 MBS Item 25015 Blood pressure monitoring, (central venous, pulmonary arterial, systemic arterial or cardiac intracavity), by indwelling catheter delivered to inpatient 59.40 59.40 75% 1 MBS Item 22012
RADIATION ONCOLOGY TREATMENT, using a dual photon energy linear accelerator with a minimum higher energy of at least 10MV photons, with electron facilities - each attendance at which treatment is given - to a maximum of 5 additional fields treatment delivered to primary site (lung) As outpatient 37.95 37.95 85% 20 MBS Item 15260 5F (Secondary Field) RADIATION ONCOLOGY TREATMENT VERIFICATION - volumetric acquisition, when prescribed and reviewed by a radiation oncologist and not associated with item 15700 or 15705 - each attendance at which treatment involving three fields or more is verified (ie maximum one per attendance). As outpatient 76.60 76.60 85% 4 MBS Item 15710 RPG - Linac 15254 Primary treatment field As outpatient 36.12 0.00 0.00 4 RPG 15550 Simulation As outpatient 65.2 0.00 0.00 1 RPG 15562-Level 6-Plan As outpatient 83.82 0.00 0.00 1 RPG Medical services – post intervention follow-up Medical consultation (1-month toxicity, 3 month CT) As outpatient 75.50 75.50 85% 2 MBS Item 116 COMPUTED TOMOGRAPHY - scan of chest, including lungs, mediastinum, chest wall and pleura, with or without scans of the upper abdomen, with intravenous contrast medium Radiologist, as outpatient 202.00 202.00 85% 1 MBS Item 56347
Number of MTA procedures per year 149 307 472 645 828 Total cost associated to MBS Services -220,293 -451,916 -695,440 -951,464 -1,220,621 Total costs to private and hospitals 618,952 1,269,736 1,953,956 2,673,300 3,429,543 Populations 1 and 2 equivalent Number of MTA procedures per year 367 752 1,157 1,583 2,031 Total cost associated to MBS Services -540,402 -1,108,597 -1,705,985 -2,334,039 -2,994,309 Total costs to private and hospitals 1,518,353 3,114,792 4,793,254 6,557,878 8,413,021 75% uptake Number of MTA procedures per year 302 620 955 1,306 1,676 Total cost associated to MBS Services -445,832 -914,593 -1,407,437 -1,925,582 -2,470,305 Total costs to private and hospitals 1,252,641 2,569,703 3,954,434 5,410,250 6,940,742 Adverse events Number of MTA procedures per year 202 414 636 871 1,117 Total cost associated to MBS Services -251,969 -516,897 -795,436 -1,088,274 -1,396,133 Total costs to private and hospitals 940,682 1,929,743 2,969,619 4,062,878 5,212,215 < MBS= Medicare benefits schedule; MTA= microwave tissue ablation; NSCLC = non=small cell lung cancer >
#5 #1 OR #2 14544 18647 5156 Microwave Ablation #6 #5 #4 AND #3 2 9 - Studies identified via checking references - Inappropriate study type: the article did not report the structure or results or didn’t consider MTA, RFA or Radiotherapy in an economic evaluation 2 9 - Number of included publications - - - No studies were found that investigated the cost effectiveness of MTA. Literature search strategies used to identify RFA economic studies Search terms MEDLINE Citations retrieved EMBASE Citations retrieved Global Health Citations retrieved Search terms #9 ablation.mp. or radiofrequency ablation device/ or ablation device/ or tumor ablation/ or ablation therapy/ or radiofrequency ablation/ 67205 125620 1701 #10 #9 AND #4 AND #3 63 418 - Studies identified via checking references - Inappropriate study type: the article did not report the structure or results or didn’t consider MTA, RFA or Radiotherapy in an economic evaluation 60 418 - Number of included publications 3 4 - Literature search strategies used to identify radiotherapy economic studies Search terms MEDLINE Citations retrieved EMBASE Citations retrieved Global Health Citations retrieved #11 Radiosurgery/ or Radiotherapy/ or Stereotactic.mp. 201680 400,124 143,503 #12 #11 AND #4 AND #3 2236 2047 375
Yang et al (2014) China Retrospective CS Level IV Risk of bias: High Hospital setting 30 (7–70) months Patients with stage Ia or Ib peripheral NSCLC, who were medically inoperable or declined surgery N = 47 (47) Maximum tumour sixe > 35 mm in 24, ≤ 35 mm in 23 Male/Female ratio: 29:18 Mean age 69.4 (range 56–82) years Comorbidities (n, %) were: pulmonary disease (19, 40.4%), cardiovascular disease (39, 83%), diabetes mellitus (16, 34%), renal insufficiency (2, 4.3%), refusal of surgery (1, 2.1%) Intervention: CT-guided MTA Local anaesthesia Duration: preset ablation time was 6–8 minutes Comparator: N/A 1. Overall survival and local control: Kaplan-Meier test (for all survival outcomes) 2. Local progression: defined as the contrast enhancement by CT scans in the site of ablation 3. Therapeutic outcome of MTA: measured using the modified RECIST criteria 4. Adverse events: reported according to terminology outlined by Ahmed et al (2014) and Goldberg et al (2005) POPULATION 2 Qi et al (2015) China Retrospective CS Level IV Risk of bias: High Hospital setting Mean: 14 (3–24) months Patients with lung metastases (from nasopharyngeal carcinoma) whose primary lesions were in complete remission N = 17 (29) Tumour size: range: 8–42 mm Male/Female ratio: 15:2 Mean age 45.7 (range 28–65) years Prior treatments included (n, %): radical radiotherapy (all patients), neoadjuvant/adjuvant chemotherapy (14, (82%), failed systemic chemotherapy (10, 58.8%), recurrence after surgery (2, 11.8%) Intervention: CT-guided MTA Anaesthesia: NR Duration: range of 5–10 minutes Comparator: N/A 1. Treatment response: ssessed by CTd 2. Local control: measured by number of new metastases inside the lung
Belfiore et al (2013) Italy Retrospective CS Level IV Risk of bias: High Hospital setting NR Patients with primary or secondary lung cancer who were not suitable for surgical procedures due to tumour extension or concomitant disease N = 56 (69) Maximum diameter mean (SD): 30 (9) M/F ratio: 35:21 Mean age (SD): 61.5 (9.13) years 44 patients had lung cancer (31 adenocarcinomas, 10 squamous carcinomas, 3 small cell carcinomas). 12 patients had metastatic disease (9 had primary colorectal cancer and 3 had primary breast cancer) Intervention: CT-guided MTA Conscious sedation Duration: 6–10 minutes Comparator: N/A 1. Adverse events: non-specified Carafiello et al (2014) Italy Retrospective CS Level IV Risk of bias: High Hospital setting mean (range): 9.9 months (3–26) Patients with NSCLC stages IA-IV or metastases, all patients judged to be inoperable or refusing surgery N = 24 (26) Mean index of max diameter (range): 30.96 (8–100) mm M/F ratio: 15:9 Mean age (range): 71.7 (46–83) years Primary cancers were: 6 squamous cell, 7 adenocarcinomas, 1 neuroendocrine carcinoma. There were 11 metastases and 1 microcytoma. Intervention: CT-guided MTA Conscious sedation Duration: NR Comparator: N/A 1. Safety: defined as the frequency of intra-, peri- and adverse events. All patients were evaluated for the presence of post ablation syndrome. Pain was evaluated with VAS
Carafiello et al (2012) Italy Retrospective CS Level IV Risk of bias: High Hospital setting NR Patients with primary or secondary lung tumours treated by MTA or RFA, Patients were judged to have inoperable disease or refused surgery N = 16 with MTA (17) Mean tumour size(range): 37.5 (28–47) mm M/F ratio: NR Mean age (range): 74.75 (40–84) years Reasons for inoperability: 9 based on advanced stage, 6 comorbidities, 1 with metastases from an advanced primary Intervention: CT-guided MTA Conscious sedation Duration: total ablation time of 10 minutes Comparator: N/A 1. Adverse events: Classified as side effects and major and minor adverse events in accordance with the classification proposed by the Society of Interventional Radiology (SIR). Patients were evaluated for the presence of post ablation syndrome and pain was measured with VAS. Chung et al 2014 United Kingdom Retrospective CS Level IV Risk of bias: High Hospital setting NR Patients with lung tumours treated by MTA underperformed with normal respiration under conscious sedation (NR-CS) or high-frequency jet ventilation under general anaesthesia (HFJV-GA) N = 39 (63) Mean (SD) tumour size NR-CS: 27.38 (14.73), HFJV-GA: 16.09 (9.21) M/F ratio: 24:15 Mean age HF JV-GA (range): 66.39 (12.20), NR-CS: 69.15 (15.59) years Other details NR Intervention: Percutaneous MTA with HFJV under GA with CT guidance Anaesthesiologist time mean (SD): 27.78 (17.78) Comparator: Percutaneous MTA with NR under CS with CT guidance Anaesthesiologist time mean (SD): 21.08 (8.45) 1. Adverse events: defined according tothe standardization of terminology and reporting criteria set out by the International Working Group on Image- Guided Tumour Ablation
Egashira et al 2016 United Kingdom Retrospective CS Level IV Risk of bias: High Hospital setting 15 (6.2–29.5) months Patients who underwent high-energy MTA of one or more pulmonary tumours of primary or secondary origin N = 44 (87) Tumour size median (range): 12 (6–45) M/F ratio: 21:23 Median age (range): 66(17–89) years Primary tumour: 23/44 (52.2%) sarcoma, 16/44 (36.4%) colorectal, 2/44 (4.5%) lung, 1/44 (2.3%) oesophagus, 1/44 (2.3%) breast, 1/44 (2.3%) bladder. Intervention: CT-guided MTA Anaesthesia: NR Duration: median (range) 2 (1–9) minutes Comparator: N/A 1. Adverse events: defined based on the Society of Interventional Radiology (SIR) classification of adverse events He et al (2006) China Retrospective CS Level IV Risk of bias: High Hospital setting Mean: 20 (6–40) months Patients with primary or secondary lung cancer who underwent MTA at a single centre N = 12 (16) Tumour size range: 20–60 mm M/F ratio: 7:5 Mean age (range): 47.5 (31–69) years Reasons for choosing MTA included refusal of surgery (5), poor cardiopulmonary reserve (3), severe side effects from prior chemotherapy and/or radiotherapy (4) Intervention: US-guided MTA Local anaesthesia Duration: NR Comparator: N/A 1. Adverse events: non-specified
Nour-eldin et al (2011) Germany Retrospective CS Level IV Risk of bias: High Hospital setting NR Patients with primary NSCLC or secondary lung tumours deemed medically inoperable or where the patient had refused surgery. Patients with metastatic lung tumours were without evidence of extrapulmonary metastases N = 164 (NR, 248 ablation sessions) Tumour size: NR M/F ratio: 92:72 Mean (SD) age: 59.7 (9.8) years 20/248 (8.1%) of ablation sessions were for primary lesions, 228/248 (91.9%) were for metastatic lesions Intervention: CT-guided MTA or RFA Conscious sedation Duration: NR Comparator: N/A 1. Pneumothorax: categorised as mild, moderate or severe Sun et al (2014) China Retrospective CS Level IV Hospital setting 25 (3–45) months Patients with primary or metastatic lung cancer, primary cancers included stage I-IV lung cancer. Distant metastases of patients with stage IV cancer and primary tumours of patients with pulmonary metastases had achieved complete response or stable disease following prior therapy N = 29 (39) Tumour size - mean (range): 37 (15–58) mm M/F ratio: 12:12 Median (range) age: 63 (39–74) years Primary NSCLC patients: 7/15 (46.7%) stage I, 2/15 (13.3%) stage II, 4/15 (26.7%) stage III, 2/15 (13.3%) stage IV. Metastases patients: 8/14 (57.1%) intestinal adenocarcinoma, 4/14 (28.6%) liver cancer, 2/14 (14.3%) breast cancer. Intervention: CT-guided MTA Conscious sedation Duration: mean (range): 8 (5–12) minutes Comparator: N/A 1. Adverse events: any associated symptoms occurring within 30 days following ablation were considered complications
Hiraki et al (2011) Japan Retrospective CS Level IV Risk of bias: High 37 (2–88) months Patients with stage IA-IB NSCLC, inoperable or refused surgery N = 50 (52 lesions) Mean size 21 (7–60) mm Males 29 (58%): Females 21 (42%) Mean age 75 (52–88) years Prior therapy: resection of extrapulmonary lesions (16/50, 32%) Intervention: CT-guided RFA Local anaesthesia + conscious sedation 52 ablation sessions Ablation duration 12–15 mins per lesion Comparator: N/A Overall survival: time from RFA to death (calculated with Kaplan-Meier method) Cancer-specific survival: time from RFA to cancer-related death (calculated with method) Disease-free survival: time from RFA to death or cancer recurrence (calculated with method) Parenchymal recurrence: recurrence in the same lobe but away from ablation zone Regional recurrence: recurrence in hilar and ipsilateral mediastinal lymph node Distant recurrence: all other recurrences Adverse events: CTCAE v 4.0 Lanuti et al (2012) USA Retrospective CS Level IV Risk of bias: High 32 (2–75) months Patients with stage IA-IB NSCLC, inoperable or refused surgery, lesion diameter < 50 mm, no disease outside involved lobe N = 45 (55 lesions) Mean size 20 (7–45) mm Males 18 (40%): Females 27 (60%) Median age 70 (51–89) years Prior therapy: resection of NSCLC (26/45, 58%) Intervention: RFA (guidance NR) Local anaesthesia + conscious sedation 55 ablation sessions Ablation duration NR Comparator: N/A Overall survival: not defined (calculated with Kaplan-Meier method) Disease-free survival: not defined (calculated with Kaplan-Meier method) Local control: no focal or diffuse enlargement of the ablated lesion on CT and no evidence of eccentric enhancement on PET at 3 or more months of follow-up. Adverse events: not defined
Liu et al (2015) China Retrospective CS Level IV Risk of bias: High 19 (2–75) months Patients with stage IA–IB NSCLC, inoperable or refused surgery, ECOG status ≤ 2 N = 29 (29 lesions) Mean size 31 (15–48) mm Males 18 (58%): Females 11 (42%) Median age 78 (56–85) years Prior therapy: NR Intervention: CT-guided RFA Local anaesthesia + conscious sedation 33 ablation sessions Mean procedure duration 39 (15–120) mins [mean ablation duration 22 (12–32) mins] Comparator: N/A Overall survival: time from RFA to death (calculated with Kaplan-Meier method) Cancer-specific survival: not defined (calculated with Kaplan-Meier method) Local progression: Focal enhancement of soft tissue compared with initial CT Adverse events: puncture-related and complications, minor complications, major complications Ridge et al (2014) USA Retrospective CS Level IV Risk of bias: High 30 (12–85) months Patients with stage IA-IIA NSCLC, no prior in-field RT or resection, no chemo 12 months prior N = 29 (29 lesions) Median size 14 (10–26) mm Males 12 (41%): Females 17 (59%) Mean age 73 (55–86) years Prior therapy: resection ± radiotherapy for pulmonary lesions (14/29, 48%) Intervention: CT-guided RFA General anaesthesia Number of sessions NR Ablation/procedure time NR Comparator: N/A Overall survival: time from RFA to death or last follow-up (Kaplan-Meier) Progression-free survival: time from RFA to disease progression or death (Kaplan-Meier) Local control: decrease in tumour diameter of at least 30%, no evidence of peripheral tumour growth, loss of lesional FDG avidity on PET/CT Local progression: interval increase in size or FDG uptake within the ablation lesion Intrapulmonary recurrence: new lesion within treated lobe or adjacent pleura with increasing FDG uptake or increase size on follow-up Distant recurrence: new metastasis at extralobar or extrathoracic site Adverse events: CTCAE
POPULATION 1 Koshy et al (2015) USA Retrospective MC cohort study with propensity-matched subgroup analysis Level III-1/III-2 Risk of bias: Moderate Median 21 (IQR 11–43) months Patients with stage I NSCLC who did not undergo surgery N = 13,036 (NR lesions) Size: NR Males 6531 (50%): Females 6505 (50%) Age 18–59 (8.5%), 60–69 (22.5%), 70–79 (40%), 85+ (29%) years Prior therapy: NR Intervention: SBRT Dose and fractions NR Comparator: Conventional radiotherapy Minimum 60 Gy in 30 fractions Comparator: No treatment Overall survival: not defined (calculated with Kaplan-Meier method) Price et al (2012) UK RCT OL MC Level II Risk of bias: Moderate Follow-up NR Patients with stage IA-IIB NSCLC, age 18+, unfit for resection, performance status ≤ 2, no prior treatment, no other malignancy in previous 5 years, not pregnant or breast feeding N = 56 (NR lesions) [intervention] N = 55 (NR lesions) [comparator] Median size 38 (3–89) mm [intervention] Median size 30 (3–55) mm [comparator] Males 38 (68%): Females 18 (32%) [intervention] Males 32 (58%): Females 23 (42%) [comparator] Median age 75 (range 49–88) years [intervention] Median age 74 (range 58–88) years [comparator] Prior therapy: NR Intervention: Radical radiotherapy “majority” had 55 Gy in 20 fractions over 4 weeks Comparator: Radical radiotherapy + chemo “majority” had 55 Gy in 20 fractions over 4 weeks plus gemcitabine Overall survival: Actuarial survival for 1-year and 2-year rates. Survival curve shown (calculated with Kaplan-Meier method) Progression- or event-free survival: patients at the end of the trial that were alive and had not progressed - "progression" was note defined (calculated with Kaplan-Meier method) Adverse events: CG-CTC v2.0 (assumed same as CTCAE from other studies
Siva et al (2015) Australia Retrospective cohort Level III-2 Risk of bias: Moderate Median 25 months Patients with 1–3 lung metastases, ≤ 50 mm, extrathoracic disease treated definitively N = 41 (49 lesions) [intervention] N = 24 (33 lesions) [comparator] Size NR Males 24 (59%): Females 17 (41%) [intervention] Males 14 (58%): Females 10 (42%) [comparator] Median age 70 (IQR 64–79) years [intervention] Median age 67 (IQR 51–76) years [comparator] Prior therapy [all patients]: 23 (40%) had prior pulmonary metastasectomy before SBRT. 13 (20%) had systemic chemotherapy for metastatic disease before SBRT. Of these, 2/13 had two lines of chemotherapy, whereas the remaining 11/13 patients had a single line of chemotherapy. Primary cancer [intervention]: colorectal 10/41 (24%), lung 16/41 (39%), bone and soft tissue 4/41 (10%), other 12/41 (29%)* Primary cancer [comparator]: colorectal 10 (43%), head and neck 7 (30%), other 6 (26%) Intervention: Single-fraction SBRT 18 GY in 1 fraction (n = 1/40, 2%) 26 GY in 1 fraction (n = 39/40, 98%) Comparator: Multi-fraction SBRT 48 GY in 4 fractions (n = 14/24, 58%) 49 GY in 7 fractions (n = 1/24, 4%) 50 GY in 5 fractions (n = 9/24, 38%) Overall survival: time from SBRT to death (calculated with Kaplan-Meier method) Local control: failure defined as the combination of a CT demonstrable serially enlarging mass as per RECIST criteria, with the absence of air bronchograms and FDG avidity on PET scanning Adverse events: CTCAE v4.0
Table Profiles of studies on Surgery included in the systematic literature review Author (Year) Location Study design Level of evidence Risk of bias A Median follow-up B Study population characteristics: N (lesions, tumour size, male/female ratio, age, prior therapy, primary cancer (P2/3 only) Description of Intervention and Comparator Relevant outcomes: measurement and methods of analysis POPULAITON 2 Renaud et al (2014) Retrospective CS Level IV Risk of bias: High 21.6 months (0–192) Lung metastases originating from a CRC who underwent resection with curative intent N = 320 (median number of resected lesions=2) Tumour size NR M/F ratio: 215:105 Median age: 63 (IQR: 13.75) years Primary cancer: colon - 164/320 patients (51%), rectum - 156/320 patients (49%) Intervention: surgical resection Comparator: NA 1. Postoperative mortality: death occurring during hospitalisation or within 30 days of surgery 2. Overall survival: Kaplan-Meier test
Pfannschmidt et al (2007) ** To assess the published evidence for the efficacy of pulmonary metastasectomy in patients with colorectal cancer (population 2) 20 studies included (2,320 patients) Publication date range of included studies: 1999–2006 Study inclusion criteria Studies on patients who underwent surgical resection with curative intent for colorectal pulmonary metastases. Patients who underwent repeat pulmonary resection and hepatic and pulmonary metastases resection were also included. Prospective and retrospective studies reporting the outcome of surgical resection with curative intent of colorectal pulmonary metastases. Restricted to studies published between 1995 and December 2006. Other criteria included at least 40 patients in the study, at least 30 days of follow-up after the operation for postoperative morbidity and mortality and at least 24 months for inclusion of survival data. English articles included. Study exclusion criteria NR Overall 5-year survival: All studies reported overall survival of 5 years for all patients undergoing resection of pulmonary metastases (median: 48%, range: 41.1–56%) Authors concluded there is a substantial body of evidence from retrospective case series demonstrating that resection of colorectal pulmonary metastases can be performed safely with a low mortality rate. For a subset of highly selected patients the overall 5-year actuarial survival rates ranged between 38.3% and 63.7% which the authors reported as being comparable with surgical resection for colorectal liver metastases. MODERATE QUALITY 1. Was an ‘a priori’ design provided? YES 2. Duplicate study selection and data extraction? CANNOT ANSWER 3. Comprehensive literature search? YES 4. Publication status (i.e. grey literature) used as an inclusion criterion? NO 5. List of studies provided? NO 6. Characteristics of the included studies provided? YES 7. Scientific quality of the included studies assessed? NO 8. Scientific quality of the included studies used in conclusions? NO 9. Methods used to combine the findings of studies appropriate? N/A 10. Publication bias assessed? N/A 11. Conflict of interest stated? NO
Table Evidence profile table for population one Outcome (units, follow-up) No. of studies and study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Results Quality Importance MTA Median OS Follow up: range 22.5 months to 30 months; assessed with: Kaplan-Meier estimate (95%CI)1 observational studies (k = 2) serious 2 not serious not serious serious 5 none Han et al (2015): 1.9 months (95%CI 38.8–49.9), Yang et al (2014): 41.9 months (95%CI 38.8–49.9) 4 ⨁⨀⨀⨀ VERY LOW CRITICAL Median cancer-specific OS Follow up: range 22.5 months to 30.0 months; assessed with: Kaplan-Meier estimate (95%CI) observational studies (k = 2) serious 2 not serious not serious serious 5 none Han et al (2015): 1.9 months (95%CI 38.8–49.9), Yang et al (2014): 41.9 months (95%CI 38.8–49.9) 4 ⨁⨀⨀⨀ VERY LOW CRITICAL Survival rates at 1-,2-,3- and 4 or 5-years Follow up: range 22.5 months to 30 months; assessed with: Kaplan-Meier estimate (95% CI not reported) observational studies (k = 2) serious 2 not serious not serious very serious 6 none Han et al (2015): 1-year: 91.7%, 2-year: 76.5%, 3-year: 47.9% and 4-year: 47.9% Han et al (2015) cancer-specific: cancer-specific survival rate was 1-year: 94.7%, 2-year: 73.9%, 3-year: 64.7% and 4-year: 64.7%; Yang et al (2015): 1-year: 89%, 2-year 63%, 3-year 43%, and 5-year: 16% 4 ⨁⨀⨀⨀ VERY LOW CRITICAL RFA
with: Median and range) <CI = confidence interval, MTA= microwave thermal ablation, NA = not applicable, OS = overall survival, k = number of studies.> GRADE Working Group grades of evidence (Guyatt et al., 2013) ⨁⨀⨀⨀ Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect This is based on the results of one study with 22patients in one arm and 18 in the other, study reporting quality was low. Measures of variance are not available. The small sample size reduces the reliability of the outcomes. Wei et al (2015) reports on small sample sizes and inherent drawbacks in study design are problematic Measures of variance show wide confidence intervals associated with OS. The small sample size reduces the reliability of the outcomes. Due to inherent limitations in case series evidence. Table Evidence profile table for safety outcomes Outcome (units, follow-up, assessment) No. of studies and study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Results Quality Importance Procedure-related mortality MTA Follow up: range 6 – 30 mths Assessed with: n/N (%), per patient Observational studies (k=20) serious 1 not serious not serious Not serious none 2/916 (0.22%)2 ⨁⨀⨀⨀ VERY LOW CRITICAL RFA Follow up: range 10 – 46 mths Assessed with: n/N (%), per patient Observational studies (k=17) serious 1 not serious not serious Not serious none 1/1259 (<0.1%) ⨁⨀⨀⨀ VERY LOW IMPORTANT Radiotherapy Follow up: range 13 – 82 mths Assessed with: number of patients who died Observational studies (k=17) serious 3 not serious not serious not serious none There were two cases of mortality across all included 17 studies.4 ⨁⨀⨀⨀ VERY LOW IMPORTANT Surgery Follow up: NA Observational studies (k=3) serious 1 not serious not serious not serious none Pfannschmidt et al (2007): postoperative mortality was reported by ⨁⨀⨀⨀ VERY LOW IMPORTANT
Assessed with: number of patients who died 4/20 studies, range 0.0 to 2.5 % Renaud et al (2014) and Kitano et al (2012): 0/365 (0%) 30-day mortality MTA Follow up: range 6 – 30 mths Assessed with: n/N (%), per patient Observational studies (k=16) serious 1 not serious not serious not serious none 1/739 (0.14%) ⨁⨀⨀⨀ VERY LOW CRITICAL RFA Follow up: range 10 – 36 mths Assessed with: n/N (%), per patient Observational studies (k=8) serious 1 not serious not serious Not serious none 2/810 (<0.1%) ⨁⨀⨀⨀ VERY LOW IMPORTANT Radiotherapy Follow up: range 13 – 82 mths Assessed with: number of patients who died Observational studies (k=17) serious 3 not serious not serious not serious none No deaths within 30 days were reported by any study. ⨁⨀⨀⨀ VERY LOW IMPORTANT Surgery Follow up: NA Assessed with: n/N (%), per patient Observational studies (k=4) serious 1 not serious not serious not serious none 10/1,499 (0.67%) ⨁⨀⨀⨀ VERY LOW IMPORTANT Pneumothorax MTA Follow up: range 6 – 30 mths Assessed with: n/N (%), per ablations Observational studies (k=22) serious 1 not serious not serious not serious none n/N (%): 280/1025 (27.3) Median: 30.2 (8.3 – 63.8) ⨁⨀⨀⨀ VERY LOW IMPORTANT RFA Follow up: range 12 – 46 mths Assessed with: n/N (%), per ablations and per patient Observational studies (k=19) serious 1 not serious not serious not serious none Per ablation: n/N (%):674/1497 (45%) Median: 24% (9–67%) Per patient: ⨁⨀⨀⨀ VERY LOW IMPORTANT