NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of microwave ablation for the treatment of liver metastases Treating liver metastases with microwave ablation Microwave ablation is a procedure that uses heat from microwave energy to destroy cancer cells. It can be used to treat cancer that has spread (metastasised) to the liver from other parts of the body, usually from the colon or rectum The procedure can be performed during open abdominal surgery, by using keyhole surgery (where specialised instruments are inserted through small cuts in the abdomen) or by needle puncture through the skin. Whichever method is used, special needles are inserted into the tumour(s) and microwave energy is used to heat the tumour and destroy the cancer cells. Introduction The National Institute for Health and Clinical Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in February Procedure name Microwave ablation for the treatment of liver metastases Specialty societies British Society of Interventional Radiology British Society of Gastrointestinal and Abdominal Radiology Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland Page 1 of 25

2 Description Indications and current treatment Liver metastases are a common manifestation of many primary cancers but the liver is usually the dominant site for metastases originating from colorectal or other gastrointestinal tract cancers. The number, location and size of the metastases are the key determinants of treatment intent as well as of treatment choice. For a minority of patients, surgical resection with curative intent may be possible. For most patients, however, treatment intent is palliative. Options for palliative treatment include systemic chemotherapy, external beam radiotherapy, thermal ablation techniques (such as radiofrequency or cryotherapy), arterial embolisation techniques, and selective internal radiation therapy. Multiple treatment modalities may be used for individual patients. Thermal ablation techniques are usually used in patients not considered suitable for surgery or for treating post-resection recurrence. They may also be used as an adjunct to hepatic resection to ablate small-volume disease in the remnant post-resection liver. What the procedure involves Microwave ablation is a technique that aims to destroy tumours by heating cells, resulting in localised areas of necrosis and tissue destruction, with minimal morbidity. The procedure can be performed under local or general anaesthesia and either percutaneously or surgically (either with open surgery or laparoscopy). Needle electrodes are advanced into the liver tumour(s) under image guidance and the targeted tumour(s) are ablated. Multiple pulses of energy may be delivered during one session and multiple needle electrodes can be used to treat larger tumours. A number of devices are available for this procedure. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to microwave ablation for the treatment of metastases in the liver. Searches were conducted of the following databases, covering the period from their commencement to 28 October 2010 and updated to 19 April 2011: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Page 2 of 25

3 Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with liver metastases studies with mixed populations including hepatocellular carcinoma where outcomes were not reported separately are not included. Microwave ablation (all modes of delivery) Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the overview This overview is based on approximately 1659 patients from 1 randomised controlled trial (RCT) 1, 2 non-randomised controlled studies 2,3, and 5 case series 4,5,6,7,8. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 3 of 25

4 Table 2 Summary of key efficacy and safety findings on microwave ablation for the treatment of metastases in the liver Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Shibata T (2000) 1 Number of patients analysed: n = 30 (14 MW coagulation, Operative complications 16 liver resection) Randomised controlled trial Japan Recruitment period: Study population: patients with primary colorectal carcinoma and liver metastases. mean number of tumours = 5.3, mean tumour size 30 mm n = 30 (14 MW coagulation, 16 liver resection) Age: 61 years (mean) Sex: 53% male Patient selection criteria: patients with multiple (fewer than 10) metastatic liver tumours from colorectal primaries (at least 1 confirmed histologically), largest tumour < 80 mm, and no signs of cirrhosis or chronic hepatitis Technique: open microwave coagulation using a tissue coagulator for a net period between 2 and 20 minutes at between 60 W and 100 W vs hepatic resection including lobectomy, segmentectomy, subsegmentectomy, and/or wedge resection as clinically indicated. Follow-up: not reported (imaging follow-up every 3 months) Conflict of interest/source of funding: not reported. Survival The mean survival time was 27 months in the MW group and 25 months in the hepatectomy group (p = 0.83). The mean disease-free interval was 11.3 and 13.3 months respectively (p = 0.47). During the follow up period there were 9 deaths among the 14 patients treated with microwave ablation, 6 of whom died due to hepatic failure. In the hepatic resection group there were 12 deaths among 16 patients with 7 dying from hepatic failure. Surgical parameters MW Resection p Blood loss (ml) Blood transfused (ml) Patients requiring transfusion (%) Operation time (min) Length of stay (days) Biochemical markers Carcinoembryonic antigen levels decreased significantly 4 weeks after surgery in both groups. MW: ng/ml to ng/ml (p < 0.05) Hepatectomy: ng/ml to ng/ml (p < 0.01) There were no intraoperative deaths in either group Post-operative complications Internal obstruction Bile duct fistula Hepatic abscess Wound infection MW (n = 14) Resection (n = 16) p = 0 1 N/S 1 1 N/S 1 0 N/S 0 1 N/S Hepatic function (as determined by serum bilirubin and prothrombin time) recovered to normal preoperative level within 2 weeks in both groups. IP 381_2 Study was included in original overview Follow-up issues: 25% (10/40) of patients dropped out during the surgery phase, outcomes for these patients were not compared. Study design issues: Randomisation was by computer generated sequence. Patients with all liver cancer types were randomised and only those with colorectal metastases reported here. No details were provided of blinding. No clear reporting of follow-up period and completeness. Cumulative survival calculated by Kaplan Meier method. No details given of concomitant treatment. Study population issues: There were no significant differences in clinical or demographic characteristics between the groups at baseline. Other issues: MW intervention characteristics differed for treatment of superficial and deeply seated tumours. Authors issued caution in applying microwave coagulation to tumours near a large branch of a bile duct. Page 4 of 25

5 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Tanaka K (2006) 2 Number of patients analysed: n = 53 (n = 16 MW, n= 37 ablation alone) Complications There were no deaths up to 60 days in Follow-up issues: Retrospective study. Non-randomised controlled study either group. No loss to follow-up. Survival Rates of complications for first treatment Japan Recruitment period: Study population: patients with multiple, bilobar colorectal liver metastases. Mean diameter = 5.1cm. n = 53 (16 MW, 37 ablation alone) Age: 60 years (mean) Sex: 62% male Patient selection criteria: Patients with 5 or more lesions in a bilobar distribution. Technique: all procedures via laparotomy. Curative hepatectomy plus MW ablation at 70 W for 45 seconds (repeated 4 or 5 times per lesion) with US guidance vs hepatectomy alone. Follow-up: 20 months (median) Conflict of interest/source of funding: not reported Hepatic recurrence-free survival Microwave + resection 1 year 56% 55% 3 years 39% 42% 5 years 39% 35% (p=0.86) Overall survival Microwave + resection 1 year 80% 87% 3 years 51% 49% 5 years 17% 44% (p=0.43) Resection Resection Treatment procedure (combined resection plus MW ablation vs resection alone) did not influence overall survival on multivariate analysis. Disease-free survival Microwave + resection 1 year 33% 26% 3 years 17% 11% (p=0.54) overall. Operative characteristics Resection Group mean ± standard deviation first treatment Microwave + resection Resection Blood loss (ml) 386 ± ± 475 Microwave + resection Resection Infection 2.7% (1/37) 12.5% (2/16) Biliary fistula 2.7% (1/37) 6.3% (1/16) Bleeding 0% (0/37) 6.3% (1/16) Hyperbilirubinemia Intestinal obstruction 2.7% (1/37) 0% (0/16) 8.1% (3/37) 0% (0/16) (measurement of significance not reported) Study design issues: Patients were selected for combined MW plus resection where resection alone could not retain sufficient vascularised hepatic parenchyma to support hepatic function. Thirty patients received neoadjuvant chemotherapy. Some patients in each group underwent a second planned hepatectomy ± MW ablation procedure, making evaluation of outcomes difficult. Study population issues: Groups were matched at baseline in terms of demographics and most clinical characteristics, however those receiving combined ablation and resection had significantly more metastases, were more likely to have had neoadjuvant chemotherapy, but less likely to have had a major hepatectomy. Other issues: Some discrepancy between text and tables in terms of length of follow-up for survival outcomes. Page 5 of 25

6 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Length of stay (days) 23 ± ±10 Measurement of significance not reported. IP 381_2 Page 6 of 25

7 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Hompes R (2010) 3 Number of patients analysed: n = 19 (6 MW, 13 RF) Complications Follow-up issues: Non-randomised controlled study Belgium Recurrence Biopsy-proven local recurrence occurred in 1 out of 6 patients in the microwave ablation group at 6-month followup. There was no local recurrence in the RF treated group. No perioperative mortality was reported. Haemobilia (resolved with conservative treatment) was reported in 1 of 6 patients in the microwave ablation group. Patient accrual method not reported No loss to follow-up in the microwave group. Recruitment period: 2008 Study population: patients with liver metastases without underlying liver disease. n = 19 (6 MW, 13 RF) Age: 61 years (median) Sex: 47% male Patient selection criteria: tumours smaller than 3 cm Technique: US guidance MW ablation either laparoscopically or percutaneously with 40W energy delivered for 10 minutes (combined with hepatectomy in 1 patient) vs RF ablation Tumour response CT scan demonstrated that tumour destruction was complete in all patients undergoing microwave ablation at 1-week follow-up. CT scan transverse tumour/ margin diameter: median (range) (length of follow up not reported). Microwave RF p= Baseline 12 mm (6 to 18) 12 mm (7 to 24) > mm (12 to 64) 34 mm (16 to 41) (measurement of significance between groups at each time point) CT scan antero-posterior diameter: median (range) Microwave RF p= Baseline 12mm (6 to 24) 12mm (7 to 17) > mm (14 to 60) 35mm (28 to 40) (measurement of significance between groups at each time point) Study design issues: Tumours matched for size and location, no other characteristics are considered. Concomitant treatment not standardised between groups. Study population issues: No comparison of groups at baseline. Other issues: A larger ablation diameter represents better outcome. Period of follow up for CT scan evaluation was not reported although measurements were taken at 1 week and 3 months. Few clinical outcomes are reported. Follow-up: 6 months (median) Conflict of interest/source of funding: none CT scan cranio-caudal diameter: median (range) Microwave RF p= Baseline 10.5 mm (6 to 20) 11 mm (8 to 20) > Postoperative Postoperative Postoperative 20 mm (10 to 73) 32 mm (20 to 45) (measurement of significance between groups at each time point) Page 7 of 25

8 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Liang P (2009) 4 Number of patients analysed: n = 257 with metastases Complications Follow-up issues: (516 tumours) Case series China Recruitment period: Study population: Patients with primary or metastatic liver tumours. Of patients with metastases primary locations were colorectal = 86, breast = 49, gastrointestinal = 47, lung = 30, other = 45. n = 1136 (257 with metastases) Age: 54 years Sex: 79% male Patient selection criteria: patients with tumours <8 cm, and 7 or fewer lesions in total. Technique: General anaesthetic and ultrasound guidance. Percutaneous MW ablation with single probe used for lesions < 1.7cm. Ablation at 60 W for 300 seconds. Efficacy outcomes were not reported. Major complications were classified as those leading to substantial morbidity and disability, increasing the level of care required, or that resulted in admission or prolonged hospital stay. Major complications Outcome Skin burn requiring resection Rate < 1% (1/257) Pleural effusion 1.6% (4/257) Liver abscess < 1% (2/257) Biloma 1.6% (4/257) Patients selected for treatment with MW ablation rather than other treatment option by an MDT panel. 21 of 1157 patients lost to follow up. Prospective follow up at 1 and 3 months and then 3 6 monthly. Study design issues: Two different MW ablation systems were used during the data collection period; a cooled shaft version was introduced in Study population issues: Patient demographics and clinical characteristics relate to the study population as a whole and not specifically patients with metastases. Other issues: Only outcomes relating to patients with liver metastases (not hepatocellular or other primary liver tumours) are extracted here. Follow-up: Not reported Conflict of interest/source of funding: Page 8 of 25

9 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Case series China Recruitment period: Study population: patients with liver metastases. Mean largest tumour size 31 mm. Primary cancer colorectal = 28, gastric/cardiac = 12, lung = 11, breast = 11, other = 11. All patients had undergone resection of primary tumours 5 to 74 months prior to MW ablation. Well differentiated = 9, moderately differentiated = 33, poorly differentiated = 32. n = 74 Age: (range) Sex: 59% male Patient selection criteria: patients with liver metastases confirmed histologically. Patients were not treated surgically due to multiple lesions in multiple segments or refused surgery. Technique: Percutaneous microwave coagulation using an electrode though a 14-gauge needle under sonographic guidance. Power range W. 77% (57/74) of patients had concomitant chemotherapy. Survival The mean survival time was 22.1 months ( 13.8 months). The disease-free survival throughout the follow up period was achieved in 35.1% (26/74) of patients. Cumulative survival was 91% at 1 year falling to 29% at 5 years (absolute figures not stated). Prognostic factors for survival Multivariate analysis (encompassing sex age, location of primary, tumour differentiation grade, number of tumours, size of tumours, change in tumour size at 3 months follow up, and local recurrence or new metastases occurring) showed that three of these factors were independent predictors of survival: the number of tumours (p = 0.03) HR 1.94 (95% CI 1.06 to 3.53), tumour differentiation grade (p = 0.02) HR 0.46 (95%CI 0.23 to 0.91), and recurrence or new tumour development (p = 0.04) HR 3.58 (95% CI 1.02 to 12.64). IP 381_2 Study details Key efficacy findings Key safety findings Comments Liang (2003) 5 Number of patients analysed: n = 74 Complications Study was included in original No severe complications were reported. overview Follow-up issues: Outcome Rate (n=74) Local pain 90.5% (67/74) Minor to moderate pleural 9.5% (7/74) effusion Slight subcapsular bleeding 2.7% (2/74) (assessed by ultrasound) resolved without transfusion Skin burns, where lesion protruded beyond liver capsule 4.1% (3/74) Consecutive patients treated at one institution Good description of the proportion of patients available at each follow up point. Study design issues: Cox multivariate analysis used to determine factors predictive of survival. No details provided of sequence of adding univariate factors into the model. Study population issues: None Other issues: Difficult to assess the specific efficacy of MW ablation when combined with chemotherapy management. Authors advocate the use of a 10 mm margin around the tumour during ablation. Follow-up: 25 months (mean) Conflict of interest/source of funding: supported by a grant from a national foundation Page 9 of 25

10 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Zhang X (2008) 6 Number of patients analysed: n = 88 patients followed up Complications Follow-up issues: for a minimum of 1 year Case series China Recruitment period: not reported Study population: patients with unresectable hepatic primary or metastatic tumours. Mean tumour length 5.3 cm. n = 160 (63 with metastases) Age: 62 years (mean) Sex: 78% male Patient selection criteria: not reported Technique: with direct observation or real-time ultrasound guidance, microwave ablation at W for 20 to 30 minutes. For tumours with abundant blood supply transarterial chemoembolisation was performed, and for those with tumours close to bile ducts, stomach, intestine or large vessels, percutaneous ethanol injection was undertaken prior to treatment. Survival Over all 1-year survival (in 88 patients with a minimum of 1 year follow up) was significantly higher in patients with primary liver cancer (96.6% [56/58]), than in patients with liver metastases (82.1% [23/28]) (p=0.022). There were no operative deaths, and complications were easily treated Outcome rate Fever up to 7 days 76.3% (122/160) Pleural effusions (one required drainage) Jaundice secondary to infection 8.8% (14/160) 1.3% (2/160) Retrospective study No efficacy outcomes reported for patients with less than 1-year follow-up. Study design issues: Safety outcomes were not reported separately for patients with liver metastases. Study population issues: Not clear how patients were selected as having unresectable tumours. Patients with metastases also received systemic chemotherapy Other issues: Ten patients received repeat MW ablation treatment. Follow-up: not reported Conflict of interest/source of funding: not reported. Page 10 of 25

11 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Martin R C G (2010) 7 Number of patients analysed: n = 100 (83 with Complications metastases) Case series USA Recruitment period: Study population: patients with liver metastases or primary disease amenable to complete ablation or resection plus ablation. Tumour size = 3cm, median number of tumours = 2. n = 100 (83 with metastases) Age: 60 years (median) Sex: 55% male Patient selection criteria: patients with metastases amenable to resection alone were excluded. No metastases > 5cm (although primary tumours > 6cm were allowed). Technique: MW ablation with US guidance with up to 3 probes (depending on tumour size) either laparascopically or open following segmental or wedge resection. Follow-up: 3 years (median) Conflict of interest/source of funding: not reported. Tumour response Complete ablation was defined as CT scan in which all viable tumour was ablated and without vascular perfusion. Cancer type Colorectal mets 98% Hepatocellular cancer Ablation success 100% Carcinoid mets 90% Other mets 100% (absolute numbers not reported) Group rate of recurrence at site of ablation Colorectal HCC Carcinoid Other p= 6.0% (3/50) 5.9% (1/17) 0% (0/11) 9.1% (2/22) 0.6 Survival Group median disease-free survival (months) Colorectal HCC Carcinoid Other p= Group median overall survival (months) Colorectal HCC Carcinoid Other p= Operative characteristics Overall for all patients treated, the mean MW ablation time was 13 minutes, and median operating room time 131 minutes. Mean estimated blood loss was 200ml. Median length of stay was 5 days. There were no perioperative deaths. Patients with 1 or more complication Cancer type Rate Highest grade Colorectal mets Hepatocellular cancer Carcinoid mets 30.0% (15/50) % (4/17) 2 2.7% (3/11) 1 Other mets 31.8% (7/22) 2 Compilation grade based on a 5 point scale (no further details reported) Probably some of the same patients as reported in Iannitti (2007) Follow-up issues: Prospective follow-up. Single centre study. No loss to follow-up. CT scans at 2-week follow-up and then 3 to 6 monthly thereafter. Study design issues: Not all outcomes reported separately for patients with liver metastases particularly safety outcomes. It is not clear for what comparison the p values presented represent. Study population issues: Origin of primary in patients with carcinoid metastases is not reported. Patients with hepatocellular cancer had significantly larger tumours (p < 0.001) bur fewer tumours (p = 0.003). Other issues: Additional analysis on resource use of MW compared to RF is reported but not extracted here. Authors note that it is the bias at the participating centre to use ablation as an adjunct to resection and not to replace resection as the optimal technique. Page 11 of 25

12 Abbreviations used: CT, computed tomography; HCC, hepatocellular carcinoma; HR, hazard ratio; MW, microwave; RF, radiofrequency; US, ultrasound; W, Watts Study details Key efficacy findings Key safety findings Comments Iannitti D A (2007) 8 Number of patients analysed: n = 87 (64 with metastases) Complications Case series USA Recruitment period: Study population: Patients with unresectable primary or metastatic liver cancer. Colorectal metastases = 33, HCC = 23, Breast metastases = 11, carcinoid metastases = 8. Mean tumour diameter = 2.6 cm. n = 87 (64 with metastases) 224 tumours Age: 67 years (mean) Sex: 47% male Patient selection criteria: not reported Technique: MW ablation via percutaneous, laparascopic or open approach. 45 W delivered for 10 minutes. Tumour response Local recurrence at ablation sites occurred in 2.7% (6/224) of tumours treated, and regional recurrence was reported in 42.5% (37/87) of patients. Survial Overall 47.1% (41/87) of patients were alive with no evidence of disease at 16-month follow-up. Outcome by cancer type at 19-month follow-up. Cancer type Alive with no disease Alive with disease Died of disease HCC 60.8% (14/23) 13.0% (3/23) 26.1% (6/23) Colorectal mets. 57.6% (19/33) 24.2% (8/33) 18.2% (6/33) Breast mets. 36.4% (4/11) 9.1% (1/11) 54.5% (6/11) Carcinoid mets. 25.0% (2/8) 75.0% (6/8) 0% (0/8) Renal mets. 0% (0/3) 0% (0/3) 100% (3/3) Lung mets. 0% (0/3) 33.3% (1/3) 66.7% (2/3) Adrenal mets. 100% (1/1) 0% (0/1) 0% (0/1) Oesophageal mets 0% (0/1) 0% (0/1) 100% (1/1) Gallbladder mets. 0% (0/1) 0% (0/1) 100% (1/1) Gastric mets. 0% (0/1) 0% (0/1) 100% (1/1) Melanoma mets. 100% (1/1) 0% (0/1) 0% (0/1) Ovarian mets. 0% (0/1) 100% (1/1) 0% (0/1) There were no procedure-related deaths. Procedure-related complications (for all cancer types) per person Outcome Rate Skin wound 3.4% (3/87) Wound breakdown 2.3% (2/87) Readmission (nausea / sedation) Pain requiring termination of procedure 1.1% (1/87) 1.1% (1/87) Fluid collection 2.3% (2/87) Persistent postoperative ileus (not otherwise described) 2.3% (2/87) Haematoma 1.1% (1/87) Fever/infection 1.1% (1/87) (time of events not reported). Probably some of the same patients as reported in Martin (2010) Follow-up issues: Loss to follow-up not reported. Patients underwent imaging at 1 month, then every 4 months for 2 years. Study design issues: A variety of approaches for MW ablation delivery were used, outcomes for each were not reported separately. Study population issues: A mixed study population with both primary liver cancer and liver metastases. Not all outcomes are reported separately for each. Origin of primary in patients with carcinoid metastases is not reported Other issues: None. Follow-up: 19 months (mean) Conflict of interest/source of funding: not reported Page 12 of 25

13 Efficacy Survival An RCT of 30 patients with multiple colorectal liver metastases reported that the mean overall survival was 27 months in patients treated by MW ablation alone, and 25 months in patients treated by hepatectomy (p = 0.83) 1. In the same study, the mean disease-free survival period was 11.3 and 13.3 months respectively (p = 0.47). A non-randomised controlled study of 53 patients with liver metastases reported that there was no statistically significant difference in overall survival between patients treated by resection plus MW ablation (17%) or by resection alone (44%) at 5-year follow-up (p = 0.43) 2. Similarly, there was no statistically significant difference in hepatic recurrence-free survival (39% and 35% respectively) at 5- year follow-up (p = 0.86). Disease-free survival at 3 years was 17% and 11% among patients treated by resection plus MW ablation and resection alone, respectively (p=0.54).a case series of 74 patients with liver metastases reported that mean overall survival time was 22.1 months following MW ablation and that disease-free survival was achieved in 35% (26/74) of patients at 25-month followup 5. Tumour response A non-randomised controlled study of 19 patients with liver metastases reported that the mean ablation diameter on post-operative computed tomography (CT) scan (transverse) was significantly smaller following MW ablation (18.5 mm) than following radiofrequency ablation (RFA) (18.5 mm vs 34 mm, p = 0.003) 3. A case series of 100 patients (83 with liver metastases) reported that complete ablation on post-operative CT scan was achieved in 98% of patients with colorectal liver metastases, 90% of patients with carcinoid metastases (origin of primary not reported), and 100% of patients with other metastases (absolute figures not reported) 7. Safety Mortality There were no procedure-related deaths following MW ablation in the RCT of 30 patients 1, two non-randomised controlled studies of 53 2 and 19 3 patients, or three case series of 160 6, and 87 8 patients. Fistulae The non-randomised controlled study of 53 patients reported that biliary fistula (not otherwise described) occurred in 1 out of 37 patients undergoing combined Page 13 of 25

14 resection and MW ablation, and in 1 out of 16 patients undergoing resection alone (measurement of significance and length of follow-up not reported) 2. Pleural effusion A case series of 1136 patients (257 with metastases) reported that pleural effusion occurred in 2% (4/257) of those with liver metastases treated by MW ablation (length of follow-up not reported) 4. The case series of 74 patients reported minor to moderate pleural effusion in 9% (7/74) of patients (length of follow up not reported) 5. The case series of 160 patients (63 with liver metastases) reported pleural effusions (1 requiring drainage) in 9% (14/160) of patients (length of follow-up not reported) 6. Ileus The case series of 87 patients (64 with metastases) reported persistent postoperative ileus (not otherwise described) in 2% (2/87) of patients treated by MW ablation 8. Pain The case series of 87 patients (64 with metastases) reported pain requiring termination of the MW ablation procedure in 1 out of 87 patients 8. Validity and generalisability of the studies Very little randomised controlled data or data comparing the procedure with other ablative treatment modalities. Limited long-term data with only 1 study to 5-year follow-up. Most studies also included patients with primary liver cancer and metastases, and results not always reported separately for these groups. Some studies report outcomes per patient and some per tumour, making comparison between studies difficult. Patient selection not always clearly defined in studies, particularly with regard to whether patients had tumours that were resectable or not. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. Page 14 of 25

15 Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Selective internal radiation therapy for non-resectable colorectal metastases in the liver. NICE interventional procedures guidance 93 (2004). Available from This guidance is currently under review and is expected to be updated in Laparoscopic liver resection. NICE interventional procedures guidance 135 (2005). Available from Radiofrequency ablation for colorectal liver metastases. NICE interventional procedures guidance 327 (2009). Available from Cryotherapy for the treatment of liver metastases. NICE interventional procedures guidance 369 (2010). Available from Specialist Advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society. Dr F Miller (British Society of Interventional Radiology), Mr G Poston (British Association of Surgical Oncology), Mr G Toogood (Great Britain and Ireland Hepato-Pancreato-Biliary Association), Dr R Uberoi (British Society of Interventional Radiology). Two Specialist Advisers classified the procedure as a minor variation on an existing procedure that is unlikely to alter that procedure s safety and efficacy. One Adviser said that it is novel and of uncertain safety and efficacy, and one considered it to be the first in a new class of procedures. Page 15 of 25

16 The main comparator for this procedure is RFA. Other interventions used include trans-arterial chemoembolisation, percutaneous ethanol injection, and other forms of percutaneous tumour ablation. Adverse events reported or known from experience include abscess, bleeding, infection, pneumothorax, colonic perforation, fever, pain, tumour seeding, pleural effusion, and (rarely) bile duct injury. Additional, theoretical complications might include deterioration in liver function, and adjacent organ damage to kidney, lung or heart. The key efficacy outcomes for this procedure are disease-free and long-term survival. One Specialist Adviser noted that there are relatively poor data on survival rates and minimal data comparing the procedure with radiofrequency ablation The procedure is essentially the same as RFA. Additional training may be required for medical device training to operate the microwave generator. The procedure is being taken up by most units in the UK, and with the availability of the percutaneous probe, it is likely to find increasing applications. It is currently overtaking RFA. Patient Commentators opinions NICE s Patient and Public Involvement Programme was unable to gather patient commentary for this procedure. Issues for consideration by IPAC Non-English language studies were not selected for inclusion in this overview. Data have been included for metastases from all primary sites, as in most studies the results for patients with metastases from colorectal primaries were not reported separately. Studies including microwave ablation by any approach (laparoscopic / open / percutaneous) have been included on the advice of clinical opinion, and many studies include a mixture of these approaches. Page 16 of 25

17 This is the third ablation procedure for liver metastases that IPAC has been asked to consider. Previous guidance has been produced on radiofrequency and cryotherapy ablation. Please see Appendix B. Page 17 of 25

18 References 1 Shibata T, Niinobu T, Ogata N et al. (2000) Microwave coagulation therapy for multiple hepatic metastases from colorectal carcinoma. Cancer 89: Tanaka K, Shimada H, Nagano Y et al. (2006) Outcome after hepatic resection versus combined resection and microwave ablation for multiple bilobar colorectal metastases to the liver. Surgery 139: Hompes R, Fieuws S, Aerts R et al. (2010) Results of single-probe microwave ablation of metastatic liver cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 36: Liang P, Wang Y, Yu X et al. (2009) Malignant liver tumors: treatment with percutaneous microwave ablation complications among cohort of 1136 patients. Radiology 251: Liang P, Dong B, Yu X et al. (2003) Prognostic factors for percutaneous microwave coagulation therapy of hepatic metastases. AJR Am J Roentgenol. 181: Zhang X, Chen B, Hu S et al. (2008) Microwave ablation with cooled-tip electrode for liver cancer: an analysis of 160 cases. Hepato-Gastroenterology 55: Martin RC, Scoggins CR, and McMasters KM. (2010) Safety and efficacy of microwave ablation of hepatic tumors: a prospective review of a 5-year experience. Annals of Surgical Oncology 17: Iannitti DA, Martin RC, Simon CJ et al. (2007) Hepatic tumor ablation with clustered microwave antennae: the US Phase II trial. HPB 9: Page 18 of 25

19 Appendix A: Additional papers on microwave ablation for the treatment of liver metastases The following table outlines the studies that are considered potentially relevant to the overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies. Page 19 of 25

20 Article Abe H, Kurumi Y, Naka S et al. (2005) Openconfiguration MR-guided microwave thermocoagulation therapy for metastatic liver tumors from breast cancer. Breast Cancer 12: Ahmad F, Strickland AD, Wright GM et al. (2005) Laparoscopic microwave tissue ablation of hepatic metastasis from a parathyroid carcinoma. European Journal of Surgical Oncology 31: Idani H, Narusue M, Kin H et al. (2001) Hepatic resection for liver metastasis of sigmoid colon cancer after incomplete percutaneous microwave coagulation therapy. Hepato- Gastroenterology 48: Jagad RB, Koshariya M, Kawamoto J et al (2008) Laparoscopic microwave ablation of liver tumors: our experience. Hepato-Gastroenterology 55 (81) Jiao D, Qian L, Zhang Y et al (2010) Microwave ablation treatment of liver cancer with 2,450-MHz cooled-shaft antenna: an experimental and clinical study. Journal of Cancer Research & Clinical Oncology 136 (10) Mitsuzaki K, Yamashita Y, Nishiharu T et al. (1998) CT appearance of hepatic tumors after microwave coagulation therapy. AJR American Journal of Roentgenology 171: Number of patients/follow-up n = 8 Follow-up = 26 months n = 1 Follow-up = 15 months n = 1 Follow-up = 22 months n = 57 (46 with metastases) Follow-up = 21 months n = 60 (20 with metastases) Follow-up = 17 months n = 63 Follow-up = not reported Direction of conclusions No major complications; 5 patients alive with new metastatic foci No local or distal recurrence at final followup Incomplete necrosis required surgical resection Laparoscopic microwave ablation is a feasible and safe alternative to open microwave ablation of the liver tumors. It carries all the advantage of minimal invasive surgery. In experienced hands, microwave ablation using laparoscopic technique can be done safely and effectively Effective local tumor control was achieved during one microwave ablation session Complications included abscess n = 4, haematoma n = 2, nodular dissemination n = 3, ascites n = 5 and portal vein thrombosis n = 1 Page 20 of 25 Reasons for noninclusion in table 2 Larger series included in table 2. Larger series included in table 2. Larger series included in table 2. Follow up treatment of resection in case of failed microwave coagulation Larger series included in table 2. Larger series included in table 2. Only 9 of the 63 cases had secondary metastases the other 53 had primary tumours. Outcomes were not reported separately for each group Larger series included in table 2 Ong SL, Gravante G, n = 328 metastases MW ablation is a minimally Systematic review with

21 Metcalfe MS et al (2009) Efficacy and safety of microwave ablation for primary and secondary liver malignancies: A systematic review. European Journal of Gastroenterology and Hepatology 21 (6) Sato M, Watanabe Y, Kashu Y et al. (1998) Sequential percutaneous microwave coagulation therapy for liver tumor. American Journal of Surgery 175: Seki T, Wakabayashi M, Nakagawa et al (1999) Percutaneous microwave coagulation therapy for solitary metastatic liver tumours from colorectal cancer. A pilot clinical study. The American Journal of Gastroenterology 94: Shibata T, Yamamoto Y, Yamamoto N et al. (2003) Cholangitis and liver abscess after percutaneous ablation therapy for liver tumors: incidence and risk factors. Journal of Vascular and Interventional Radiology: JVIR 14: Tanemura H, Ohshita H, Kanno A et al. (2002) A patient with small-cell carcinoma of the stomach with long survival after percutaneous microwave coagulating therapy (PMCT) for liver metastasis. International Journal of Clinical Oncology 7: Umeda T, Abe H, Kurumi Y et al. (2005) Magnetic resonance-guided percutaneous microwave coagulation therapy for liver metastases of breast cancer in a case. Breast Cancer 12: Yamashita Y, Sakai T, Maekawa T et al. (1998) Thoracoscopic Follow-up = not reported n = 6 Follow-up = not reported n = 15 Follow-up = not reported n = 70 Follow-up = not reported n = 1 Follow-up = 33 months n = 1 Follow-up = 15 months n = 6 Follow-up = 4 23 months invasive technique that has broadened the therapeutic option for patients with conventionally unresectable liver tumours with promising survival data. Future advances in the applicator design and treatment monitoring may further improve its efficacy and widen the indications 3 patients undergoing curative MW coagulation had no recurrence Percutaneous microwave coagulation therapy is a safe and effective treatment for metachronus small liver tumours that have metastasized from colorectal cancer Cholangitis or liver abscess occurred in 10 patients (1.5% of treatments) Complete necrosis on CT scan and no recurrence to final follow-up No recurrence of metastatic tumour at final follow-up Average length of stay was 11 days, no recurrence during follow-up period Page 21 of 25 no meta-analysis. Mixed patient population with HCC and liver metastases without outcomes reported separately. All studies included with liver metastases populations are included elsewhere in this overview Larger series included in table 2. Larger series included in table 2. Outcomes of patients with hepatocellular carcinoma or secondary metastases are not distinguished. Larger series included in table 2. Larger series included in table 2. Larger series included in table 2.

22 transdiaphragmatic microwave coagulation therapy for a liver tumor. Surgical Endoscopy 12: Page 22 of 25

23 Appendix B: Related NICE guidance for microwave ablation for the treatment of liver metastases in the liver Guidance Interventional procedures Recommendations Selective internal radiation therapy for colorectal metastases in the liver. NICE interventional procedures guidance 093 (2004). 1.1 Current evidence on the safety of selective internal radiation therapy (SIRT) for colorectal metastases in the liver appears adequate. With regard to efficacy, the procedure may reduce tumour bulk, but there is a lack of evidence of symptom relief or increased survival, and combination with other treatments makes interpretation of the published literature difficult 1.2 Clinicians wishing to undertake selective internal radiation therapy for colorectal metastases in the liver should take the following actions. Ensure that patients understand the uncertainty about the procedure s safety and efficacy and provide them with clear written information. Use of the Institute s Information for the Public is recommended. Audit and review clinical outcomes of all patients having selective internal radiation therapy for colorectal metastases in the liver. 1.3 Publication of research studies with outcome measures which include survival will be useful in reducing the current uncertainty about the efficacy of the procedure. The Institute may review the procedure upon publication of further evidence. Laparoscopic liver resection. NICE interventional procedures guidance 135 (2005). 1.1 Current evidence on the safety and efficacy of laparoscopic liver resection appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance. 1.2 Patient selection for laparoscopic liver resection should be carried out by a multidisciplinary team. Surgeons undertaking laparoscopic liver resection should have specialist training and expertise both in laparoscopic techniques and in the specific issues relating to liver surgery. Radiofrequency ablation for the treatment of colorectal liver metastases. NICE interventional procedures guidance 327 (2009). 1.1 Current evidence on the safety and efficacy of radiofrequency (RF) Page 23 of 25

24 ablation for colorectal liver metastases is adequate to support the use of this procedure in patients unfit or otherwise unsuitable for hepatic resection, or in those who have previously had hepatic resection, provided that normal arrangements are in place for clinical governance, consent and audit. 1.2 Patient selection should be carried out by a hepatobiliary cancer multidisciplinary team Cryotherapy for the treatment of liver metastases. NICE interventional procedures guidance 369 (2010). 1.1 Current evidence on the safety of cryotherapy for the treatment of liver metastases appears adequate in the context of treating patients whose condition has such a poor prognosis, but the evidence on efficacy is inadequate in quality. Therefore cryotherapy for the treatment of liver metastases should only be used with special arrangements for clinical governance, consent and audit or research 1.2 Clinicians wishing to undertake cryotherapy for the treatment of liver metastases should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand that other ablative treatments are available and provide them with clear written information. In addition, the use of NICE s information for patients ( Understanding NICE guidance ) is recommended (available from Audit and review clinical outcomes of all patients having cryotherapy for liver metastases (see section 3.1). 1.3 Patient selection and treatment should be carried out by a hepatobiliary multidisciplinary team with expertise in the use of ablative techniques Page 24 of 25

25 Appendix C: Literature search for microwave ablation for the treatment of liver metastases Database Date searched Version/files Cochrane Database of 20/04/2011 Issue 4 of 12, Apr 2011 Systematic Reviews CDSR (Cochrane Library) Database of Abstracts of 20/04/ Reviews of Effects DARE (CRD website) HTA database (CRD website) 20/04/ Cochrane Central Database of 20/04/2011 Issue 4 of 12, Apr 2011 Controlled Trials CENTRAL (Cochrane Library) MEDLINE (Ovid) 20/04/ April Week MEDLINE In-Process (Ovid) 20/04/2011 April 19, 2011 EMBASE (Ovid) 20/04/ week 15 CINAHL (NLH Search 2.0) 20/04/ Present The following search strategy was used to identify papers in MEDLINE. A similar strategy was used to identify papers in other databases. 1 ((microwave* or micro-wave*) adj3 (ablat* or coagulat* or therap* or themotherap* or thermoablat*)).tw. 2 (mct or pmct or mwa or mw).tw. 3 Microwaves/tu [Therapeutic Use] 4 or/1-3 5 ((liver or hepatic*) adj3 (secondar* or neoplasm* or cancer* or carcinoma* or adenocarcinom* or tumour* or tumor* or malignan* or metastas*)).tw. 6 Liver Neoplasms/ 7 or/ and 7 9 Animals/ not Humans/ 10 8 not 9 Page 25 of 25