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 selective internal radiation therapy for non-resectable colorectal metastases in the liver Treating bowel cancer that has spread to the liver using selective internal radiation therapy. Colorectal liver metastasis occurs when cancer of the bowel has spread to the liver. Selective internal radiation therapy (known as SIRT) uses radiation put into the patient s liver to kill the cancer cells. Tiny radioactive beads are injected into branches of the artery that supplies blood to the liver. The beads then become trapped (embolise) in the small blood vessels surrounding the cancer, releasing radiation directly onto it. 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 March 011. Procedure name Selective internal radiation therapy for non-resectable colorectal metastases in the liver Specialty societies Royal College of Radiologists British Society of Interventional Radiology Association for Cancer Surgery British Society of Gastroenterology IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 1 of 40

2 Association of Coloproctology British Association of Surgical Oncology British Nuclear Medicine Society Description Indications and current treatment Colorectal cancer is a common cancer. It generally occurs in people older than 50 years of age, with the risk increasing with age. Around 50% of colorectal cancer patients will also present with hepatic metastases at some point during the course of their illness. Treatment of hepatic metastases depends on their extent and location. Treatment options include surgical resection, thermal ablation techniques, chemotherapy, different types of arterial embolisation therapy and external beam radiotherapy. What the procedure involves Selective internal radiation therapy (SIRT; micro-brachytherapy or radio-embolisation ) is used for the treatment of non-resectable hepatic metastases secondary to colorectal cancer, with limited or no extrahepatic disease. It may be used alone or in combination with chemotherapy. It aims to deliver radiation directly into the metastases, minimising the risk of radiation damage to healthy surrounding tissues. Under local anaesthesia, glass or resin microspheres containing a small radioactive source (yttrium-90, a beta radiation emitter with a physical half life of approximately.5 days) designed to embolise into small vessels around the metastases, are injected into branches of the hepatic artery (usually via a percutaneous femoral approach). In this way the microspheres can be selectively injected directly into the tumour within the liver, delivering high doses of localised ionising radiation. In a few patients the spheres may pass through the liver and lodge in the lungs. A nuclear medicine liver-to-lung shunt study may be carried out before the procedure to assess the risk of radioactive microspheres causing lung damage. In addition, radiographic imaging and selective coil embolisation of arteries to the stomach and duodenum may be done to reduce the risk of radiation damage to those organs. It takes approximately 1 hour to complete the treatment procedure, and patients may remain in hospital for up to 48 hours after the procedure. Selective internal radiation therapy is sometimes delivered in two separate treatments (a few weeks apart) if both lobes of the liver require treatment. The procedure may be repeated depending on the response achieved. A number of different products are available for this procedure. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page of 40

3 Due to the radioactive nature of the treatment, patients and carers will be provided with radiation protection advice. The Administration of Radioactive Substances Advisory Committee has issued Notes for guidance on the clinical administration of radiopharmaceuticals and use of sealed radioactive sources. These should be referred to when administering a radioactive medical product. List of studies included in the overview This overview is based on 915 patients with colorectal liver metastases from 3 randomised controlled trials (RCTs) 1,, 3, 6 case series 4,5,6,7,8,9 and case reports 10,11. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table ) have been listed in appendix A. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to selective internal radiation therapy for non-resectable colorectal metastases in the liver. Searches were conducted of the following databases, covering the period from their commencement to 7 July 010 and updated to 5 February 011: 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). Relevant published studies identified during the consultation or resolution process 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. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 3 of 40

4 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, 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 specific adverse events that were not available in the published literature. Patients with non-resectable colorectal metastases in the liver. Selective internal radiation therapy (SIRT), or SIRT in combination with chemotherapy 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. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 4 of 40

5 Table Summary of key efficacy and safety findings on selective internal radiation therapy for unresectable colorectal metastases in the liver IP 8_ Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments van Hazel G (004) Randomised controlled trial Australia Study period: not Study population: patients with colorectal liver metastases with or without extrahepatic disease. Age: 65 years; Sex: 86% male. n = 1 (11 SIRT) Inclusion criteria: histologically proven adenocarcinoma of the colon/rectum, CT scan evidence of liver metastases unable to be treated by resection or local ablation, no prior chemotherapy or radiotherapy treatment. Technique: SIRT therapy with SIR-Spheres following hepatic angiography to plan delivery and nuclear medicine test to determine potential pass through liver into the lungs. Injected via needle and transfemoral catheter into the hepatic artery..5 GBq or dose calculated depending on size of patient plus systemic chemotherapy versus systemic chemotherapy (at 4-week intervals until unacceptable toxicity, patient request or disease progression). Follow-up: not Conflict of interest: not Survival There was a statistically significant improved median survival in the SIRT group (9.4 months) compared with the chemotherapy alone group (1.8 months), hazard ratio 0.33 (95% confidence interval 0.1 to 0.91) (p = 0.05). Disease progression A measure that treatment is no longer effective (not otherwise defined). Median time to disease progression was significantly longer in the SIRT group (18.6 months) than the chemotherapy alone group (3.6 months) (p < ). Tumour response Response based on tumour size Outcome SIRT Chemotherapy alone Complete response 0% (0/11) 0% (0/10) Partial response 73% (8/11) 0% (0/10) Stable disease 7% (3/11) 60% (6/10) Progressive disease 0% (0/11) 40% (4/10) p < between groups Quality of life Assessed using a validated 3-item questionnaire, and by the Spitzer index, a 3-point scale on each of five domains: activity; daily living; health; support; and outlook (scored from 0 to 10 points; higher scores better). There was no statistically significant difference between groups in change from baseline score using either assessment method. Complications In the SIRT group there was 1 treatment related death (9% [1/11]) from chemotherapy-induced neutropenia and associated sepsis after the 4th cycle of treatment. One patient (9% [1/11]) developed radiation induced liver cirrhosis at 1-year follow-up, which improved with conservative treatment. Also in the SIRT group liver abscess occurred in 9% (1/11) of patients which resolved with drainage, and transient abdominal pain was in 36% (4/11) of patients. Grade 3 or 4 toxicity events Outcome SIRT Chemo alone Granulocytopenia 7% (3/11) 0% (0/10) Nausea 9% (1/11) 10% (1/10) Mucosis 36% (4/11) 10% (1/10) Gastritis 9% (1/11) 10% (1/10) Diarrhoea 18% (/11) 10% (1/10) Anorexia 0% (0/11) 10% (1/10) Cirrhosis 9% (1/11) 0% (0/10) Liver abscess 9% (1/11) 0% (0/10) Total grade 3 or Measurement of significance not Randomisation by independent centre using computer generation. Patients stratified at baseline on presence of extrahepatic metastases, and percentage of liver involved with tumour. Follow-up period/strategy not described. There were no significant differences between the groups in terms of clinical or demographic characteristics at baseline. Three participating sites. Outcome assessment such as CT scans were undertaken independently and blinded. CT scanning assessment was limited to every 3 months. Patients lost to follow-up or dying before 1st follow-up were regarded as having liver progression. Once protocol treatment ceased further cancer-specific treatment including nonprotocol chemotherapy was allowed. In the chemotherapy alone group out of 10 patients died before protocol treatment was initiated. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 5 of 40

6 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Hendlisz A (010) 3 Randomised controlled trial Belgium Study period: 004 to 007 Study population: patients with adenocarcinoma of the colon or rectum with metastases to the liver only that are not amenable to curative surgery or ablation and resistant or intolerant to chemotherapy. Age: 6 years; Sex: 64% male. Median time since diagnosis = months. n = 44 (1 SIRT) Inclusion criteria: patients with adequate bone marrow function, renal function and liver function. Patients without pre-existing hepatic disease, extrahepatic disease, or >0% arteriovenous shunting. No previous hepatic arterial infusion chemotherapy, transarterial embolisation, or external beam radiation therapy. Technique: SIRT therapy with SIR-Spheres plus IV chemotherapy following nuclear medicine test to determine potential pass through liver into the lungs and coil embolisation of arteries to the stomach if judged necessary. SIRT dose calculated on body surface area and extent of tumour involvement versus IV chemotherapy alone. Follow-up: 5 months (median) Conflict of interest: one author received honoraria from manufacturer. Tumour response SIRT plus chemo Chemo alone p = Partial response 9.5% (/1) 0% (0/3) 0. Stable disease 76.% (16/1) 34.8% (8/3) N/R Progression 9.5% (/1) 60.9% (14/3) N/R Not evaluable 4.8% (1/1) 4.3% (1/3) N/R Disease control (partial response or stable disease) Survival Time to progression group median scores Time to liver progression Time to progression at any site Overall survival 85.7% (18/1) 34.8% (8/3) SIRT plus chemo Chemo alone 5.5 months.1 months 4.5 months.1 months Hazard ratio p = 0.38 (95% CI 0.0 to 0.7) 0.51 (95% CI 0.8 to 0.94) IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 6 of There was no statistically significant difference in median overall survival between the SIRT group at 10.0 months and the chemotherapy alone group at 7.3 months (p = 0.80). Complications Number of events (overall, grades 1,, or 3) SIRT (n = 1) Stomatitis Diarrhoea 0 1 Nausea 5 0 Vomiting Constipation 0 3 Anorexia 5 7 Gastrointestinal (not otherwise described) 1 0 Abdominal pain 4 3 Myalgia 1 Other pain 0 1 Fatigue 8 11 Fever 3 3 Skin (not otherwise described) 0 Hand-foot syndrome 1 Dyspnoea 0 Pulmonary 0 1 Neurosensorial (not otherwise described) 0 Cognitive disturbance 1 1 Arrhythmia 0 1 Allergy 0. 1 Other 1 Chemo alone (n = ) Overall there were grade 3 toxicity in 4.8% (1/1) of patients in the SIRT group and 7.3% (6/) of the patients in the chemotherapy alone group (p = 0.10) at 5-month follow up Two patients in the SIRT arm were excluded from analysis: 1 due to bone metastases and 1 due to technical issues with administration for SIRT. Prospective follow up Open label trial, patients in the chemotherapy-alone group were allowed to cross over to SIRT at the investigators discretion, making interpretation of outcomes difficult. 43.5% (10/3) of patients in the chemotherapy alone arm crossed over to receive SIRT. Randomisation stratified by site and type of progression prior to enrollment. There groups were well balanced for clinical criteria at baseline (measurement of significance not ).

7 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Kennedy AS (006) 4 Case series USA Study period: April 00 to April 005 Study population: patients with confirmed diagnosis of colorectal adenocarcinoma with measurable unresectable disease predominantly involving the liver failed up to 3 lines of previous chemotherapy. Age 6: years (median); Sex: 6% male. n = 08 Inclusion criteria: not candidates for radiofrequency ablation, transarterial chemo-embolisation, resection, intensity modulated radiation therapy or stereotactic radiotherapy. Technique: SIRT therapy with SIR-Spheres following hepatic angiography to plan delivery (embolisation of gastric or duodenal arteries where necessary) and nuclear medicine test to determine potential pass through liver into the lungs. Dose calculated depending on size of tumour, median dose 1.7 GBq. Single treatment sessions. Follow-up: 13 months (median) Conflict of interest: some of the authors have received honoraria from manufacturer. Tumour response Assessed with various imaging studies at 1 weeks follow-up using the following criteria. Complete response: disappearance of all baseline lesions. Partial response: >50% decrease in size or number of tumours, or necrosis of most lesions. Stable disease: <50% response of lesions or <5% growth in number or size of lesions. Progressive disease: growth of >5% in number or size of lesions. Outcome 3-month follow-up Complete response 0% (0/08) Partial response 36% (74/08) Stable disease 55% (114/08) Progressive disease 10% (1/08) Survival Median survival was significantly longer amongst responders (10.5 months) compared with non-responders (4.5 months) (p = ). Complications <1% (1/08) of patients developed a pulmonary embolus at 3-day follow-up, and died within 30 days of treatment. The resin spheres were not believed to be linked to this event. There were no occurrences of veno-occlusive disease. Grade or 3 toxicity Combined early (within 30 days) or late (up to 90 days) Rate Nausea 11% (/08) Emesis 7% (14/08) Pain 13% (7/08) Gastric ulcers 6% (1/08) Weight loss 3% (7/08) Fatigue 39% (8/08) Fever % (4/08) Bilirubin 5% (10/08) Alkaline phosphatase 1% (43/08) Alanine aminotransferase 1% (/08) Aspartate aminotransferase 1% (/08) Ammonia 1% (3/08) Retrospective study Different imaging techniques used at different participating centres. Case accrual method not. No chemotherapy given. Patient selection not standardised across participating centres. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 7 of 40

8 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Atassi B (008) 5 Case series USA Study period: 001 to 006 Study population: patients with hepatocellular cancer or colorectal liver metastases. Age: not ; Sex: not. n = 37 (137 colorectal metastases) Inclusion criteria: unresectable liver tumour, with no other liver therapy planned. Patients with metastatic disease who had failed on previous chemotherapy. Technique: SIRT therapy with Thera-Spheres following hepatic angiography to plan delivery and nuclear medicine test to determine potential pass through liver into the lungs. Target dose 10 Gy prophylactic embolisation of extrahepatic vessels. One lobe treated per treatment session. Follow-up: 9 10 months (mean) Conflict of interest: one author is a consultant to a manufacturer. None of the authors have identified a conflict of interest. Efficacy outcomes were not on Complications Biliary sequelae were defined as any image finding and/or liver function adverse event of grade 3 or 4 severity. Complication Rate Alkaline phosphatase 8% (11/137) Aspartate / alanine aminotransferase 11% (15/137) Total bilirubin 13% (18/137) Overall symptomatic or asymptomatic toxicity was seen in 3% (44/137) of patients. 19% (6/137) of patients showed imaging findings related to the biliary tree. 14 had biliary necrosis on imaging. The clinical outcome of biliary necrosis seen on imaging was not separately for patients with colorectal metastases. Two participating centres Prospective follow-up protocol well defined Loss to follow-up not Some outcomes only for the entire cohort rather than separately for patients with colorectal liver metastases. Among patients with colorectal metastases risk factors for biliary complications included 9 patients who had previously received transcatheter arterial chemo-embolisation, and 1 who had previous biliaryenteric anastomosis. 90% of patients had normal bilirubin level at baseline IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 8 of 40

9 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Sato KT (008) 8 Case series Survival 49% (5/51) of patients died during follow-up. Median survival was 457 days, and mean survival 416 days. 1- and -year survival was 53.7% and 6.7% respectively. Safety outcomes were not on separately for patients with colorectal primaries. Prospective study. Two participating centres. USA Study period: 00 to 006 Study population: patients with liver-dominant chemotherapyrefractory metastases from different primary sites. Age: 63 years (median); Sex: 65% male. There was a statistically significant difference in survival between groups with colorectal primaries (mean 416 days), those with neuroendocrine primaries (591 days) and those with non-colorectal non-neuroendocrine primaries (341 days) (p = 0.01). 4 interventional radiologists with a minimum of years experience undertook all treatments. n = 137 (51 with colorectal primaries) Inclusion criteria: non-surgical candidates, bilirubin <.0 mg/dl, limited extrahepatic disease, and no other liver therapy planned. Technique: SIRT therapy with Thera-Spheres following hepatic angiography to plan delivery and nuclear medicine test to determine potential pass through liver into the lungs. For bilobar treatment one lobe treated per treatment session 30 days apart. Follow-up: years Conflict of interest: 1 author is a consultant to a manufacturer and has disclosed a conflict of interest. No industry support for this study was provided. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 9 of 40

10 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Cosimelli M (010) 7 Case series Italy Study period: 005 to 007 Study population: patients with unresectable chemotherapyrefractory colorectal cancer liver metastases as the sole or dominant site of disease. Age = 64 years (mean), Sex = 74% male. Time from diagnosis to treatment = 19 months mean. n = 50 Inclusion criteria: liver disease progession following standard systemic chemotherapy, adequate renal function, haemopoietic function, performance status, suitable hepatic arterial anatomy, lung shunt <0%, patent main portal vein. Without local recurrence of primary disease, inflammatory gastrointestinal disease, or previous hepatic arterial chemotherapy or external beam radiotherapy. Technique: SIRT therapy as a single whole liver procedure under fluoroscopic guidance following hepatic angiography to plan delivery and nuclear medicine test to determine potential pass through liver into the lungs. Dose defined using body surface area and tumour involvement. Follow-up: 11 months (median) Conflict of interest: Materials supplied by manufacturer. Tumour response Response was evaluated using the response evaluation criteria in solid tumours (RECIST), n = 46 patients had follow-up scans available. Overall response rate (partial or complete response) was 4.0% (1/50). Median time between the procedure and the maximum treatment response was 6 weeks. Response type Complete response.0% (1/50) Partial response.0% (11/50) Stable disease 4.0% (1/50) Disease progression 44.0% (/50) Proportion of patients (n=50) Treatment response was not significantly associated with baseline factors of performance status (p = 0.19), number of metastases (p = 0.69), metastases size (p = 0.69), liver involvement (p = 0.74), previous anti-angiogenic agents (p = 0.5), or previous resection (p = 0.87). Downstaging-enabling resection Reduction in volume of liver metastases that enabled potentially curative resection of 3 segments was in 4.0% (/50) of patients. Survival Median progression-free survival was 3.7 months (95% CI.6 to 4.9),and median overall survival was 1.6 months (95% CI 7.0 to 18.3). Quality of life Mean anxiety levels were significantly reduced at 6-week follow-up (p < 0.01) (absolute figures not ). This outcome relates to 14 patients. Complications IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 10 of 40 Death was in 4% (/50) of patients during followup. One from acute renal failure at 40-day follow-up, and 1 after liver failure at 60-day follow-up. Early adverse events at -day follow-up Complication Rate Fever 8% (4/50) Pain 6% (3/50) Leucocytosis % (1/50) Adverse events 3- to 30-day follow-up Complication Rate Fever 6% (3/50) Chronic pain 10% (5/50) Jaundice / nausea / fatigue % (1/50) Late adverse events - to 3-month follow-up Complication Rate Gastrointestinal ulcers 4% (/50) Multicentre study, prospective follow-up. Two patients lost to follow up. No analysis of difference in baseline characteristics of these patients. Concomitant chemotherapy treatment (if any) not described Power calculation to determine sample size for response rate of 15% from baseline Efficacy and safety outcomes evaluated on an intention to treat principle Two out of 5 patients initially enrolled were excluded due to excessive hepatic disease. 76% of patients had received 4 lines of previous chemotherapy.

11 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Ogawa F (008) 10 Case report USA Study period: not Study population: patients with colorectal liver metastases with previous chemotherapy treatment. Age: 53 years (median); Sex: 33% male. Gastrointestinal symptoms and complications were described in 3 patients. Patient 1 Patient with multiple synchronous liver metastases, largest 13 cm in length. Surgical resection undertaken. 6 months later SIRT was given to palliate persistent metastatic liver deposits. SIRT with SIR-Spheres via a hepatic artery catheter after the left gastric artery was embolised with a coil to prevent extrahepatic deposition of spheres. CT scan demonstrated heterogeneous distribution throughout the liver with greatest concentration in the right lobe inferiorly. Subsequently the patient belching, heartburn and nausea, symptoms persisted sporadically for 5 months of follow-up. Upper endoscopy demonstrated a diffusely erythematous and friable duodenal bulb, and gastric antral mucosa. Gastrointestinal symptoms were controlled after discontinuation of capecitabine. Patient developed lung and bone metastases and had died at 40-month follow-up. Patient selection not. Number of patients treated at participating centres (denominator) not. Difficult to disaggregate the contribution of SIRT or chemotherapy to the adverse events described. n = 3 Inclusion criteria: not Technique: SIRT with SIR- Spheres Follow-up: 10 days to 5 months Conflict of interest: none Patient Patient with hepatic metastasis of a colonic adenocarcinoma treated with combination chemotherapy with excellent clinical results. 8 months later residual liver disease was treated with SIRT. Soon after the procedure persistent emesis and nausea developed, decreased calorific intake led to 16 lb weight loss. A few weeks later upper endoscopy showed a large gastric ulceration. Outpatient treatment with proton pump inhibitor and fluids. Patient readmitted at 4-month follow-up with persistent nausea, abdominal pain, dehydration and weight loss. A repeat gastric endoscopy showed persistent erythema, friability and granularity of the entire mucosa, and several large ulcers. Patient 3 Patient with multiple synchronous liver metastasis of a colonic adenocarcinoma treated with combination chemotherapy. 6 months later CT scan showed a persistent lesion in the right lobe of the liver. SIRT with prophylactic coil embolisation of the gastroduodenal and right gastric artery performed, with concurrent proton pump inhibitor therapy and ferrous sulphate. At 10-day follow-up nausea, diarrhoea and upper abdominal pain developed. Upper gastrointestinal endoscopy demonstrated an erythematous gastric mucosa with superficial ulceration of the antrum. Patient discharged with proton pump inhibitor; no further follow-up was described. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 11 of 40

12 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Gray B (001) 1 Randomised controlled trial Australia Study period: not Study population: patients with non-resectable liver metastases from primary adenocarcinoma of the large bowel but without distant metastases other than hepatic ones. Previous chemotherapy = 14%. Age: 61 years; Sex: 77% male. n = 70 (36 SIRT) Inclusion criteria: patients who had previous chemotherapy treatment were included in the trial; however those with previous radiotherapy were excluded. Patients in whom the liver metastases could be treated by any form of local ablation were excluded. Technique: all patients underwent laparotomy, cholecystectomy and insertion of permanent hepatic artery catheter. SIRT therapy with SIR-Spheres following nuclear medicine test to determine potential pass through liver into the lungs. Injected via needle in pulsed manner into the hepatic artery.,.5 or 3 GBq depending on size of tumour plus HAC versus HAC alone (18 cycles). Follow-up: minimum 3.5 years Conflict of interest: not Tumour response Assessed as partial response (>50% decrease in size and volume on consecutive CT scans), complete response (disappearance of all tumour on successive CAT scans not less than 3 months apart ), CEA partial response (decrease in CEA level >50% but not into normal range on any occasion), CEA complete response (decrease to normal levels), no change, progressive disease, or not assessable. Tumour area (number in each category) Outcome SIRT HAC alone Complete response 6% (/36) 0% (0/34) Partial response 39% (14/36) 18% (6/34) No change 36% (13/36) 38% (13/34) Progressive disease 8% (3/36) 4% (8/34) Not assessable 11% (4/36) 1% (7/34) p = 0.01 between groups CEA level (number in each category) Outcome SIRT HAC alone Complete response 4% (15/36) 6% (9/34) Partial response 31% (11/36) 1% (7/34) No change 6% (/36) 9% (10/34) Progressive disease 3% (1/36) 18% (6/34) Not assessable 19% (7/36) 6% (/34) p = between groups Complications Outcome SIRT HAC alone Mild pancreatitis 3% (1/36) 0% (0/34) Resolved within 3 days but exacerbated diabetes Measurement of significance not There were no other major complications in the SIRT group. Grade 3 or 4 toxicity events Outcome SIRT HAC alone Haemoglobin 0% (0/36) 3% (1/34) Bilirubin 3% (1/36) 0% (0/34) Alkaline phosphate 39% (14/36) 15% (5/34) Nausea 3% (1/36) 6% (/34) Diarrhoea 0% (0/36) 3% (1/34) Total grade 3 or No statistically significant difference between groups in total event rate Randomisation by independent investigator. Patients stratified at baseline in 3 groups depending on percentage of liver involved with tumour. Treatment allocation concealment by opaque envelopes. Outcome assessment such as CT scans were undertaken independently and blinded. 5 patients in each group had previously received chemotherapy. Many patients received non-protocol chemotherapy following end of protocol treatment. Not clear how many in each group, but was higher in the HAC alone group. Exact period of follow-up for all outcome assessments is not explicit, but minimum follow-up was 3.5 years from randomisation for survivors. However, the majority of patients may have died during follow-up IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 1 of 40

13 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Gray B (001) continued Survival Outcome SIRT HAC alone 1 year 7% 68% years 39% 9% 3 years 17% 6% 5 years 3.5% 0% Kaplan-Meier survival analysis demonstrated no statistically significant difference between groups. Mean survival SIRT 3.5 months, HAC 18.4 months, hazard ratio 1.41 (95% confidence interval 0.86 to.34) (p = 0.18). Quality of life Assessed using a validated 11-item linear analogue scale questionnaire. Of the items evaluated, only one, sexual interest/ability, deteriorated over 18 months (not clear whether in both groups). For all the other measures the trend was towards improvement up to 18 months follow-up in both groups. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 13 of 40

14 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Chua T C (010) 9 Case series Australia Study period: Mar 006 to May 009 Study population: patients with inoperable liver metastases. 6% (8/140) chemotherapy naïve. Age: 64 years (median); Sex: 59% Male. n = 140 Inclusion criteria: patients with radiologically proven liver metastases from colorectal cancer, able to undergo selective visceral catheterisation, adequate blood count, renal function, and heptatic function Technique: SIRT therapy with SIR-Spheres following scintigraphy scan to assess potential shunting (temporary balloon occlusion when >0% shunt) A mean of 1.8 GBq administered. Survival 73.6% (103/140) of patients had died at final follow-up. Median overall survival was 9 months (95% CI 6.4 to 11.3 months) following SIRT treatment. 1 year survival was 4%, and 3 year survival 0%. Tumour response Tumour response was classified as complete response (disappearance of all lesions) partial response ( 30% reduction in longest diameter of index lesions), stable disease (<30% decrease or <0% increase), and progressive disease ( 0% increase). Outcome Final follow up Complete response 0.7% (1/140) Partial response 30.7% (43/140) Stable diseas 31.4% (44/140) Progressive disease 36.4% (51/140) Multivariate analysis identified patients undergoing concomitant or post radioembolisation chemotherapy as the single factor predictive of a favourable tumour response, hazard ratio.9 (95% CI 1.3 to 6.1) (p=0.007). Complications Events following initial radioembolisation Outcome Rate Intestinal ulceration 0.7% (1/140) Nausea 5.0% (7/140) Vomiting 0.7% (1/140) Gastritis.1% (3/140) Abdominal pain 14.3% (0/140) Delayed events (length of follow up not ) Outcome Rate Radiation-induced liver dysfunction.1% (3/140) Intestinal ulceration.9% (4/140) Gallbladder / biliary complication 0.7% (1/140) Consecutive case accrual of patients referred for treatment Mixed cohort of patients, some chemotherapy naïve, most failed at least 1 line of chemotherapy. 34% of patients received concomitant or post radioembolisation chemotherapy. 36% had extrahepatic disease, and 90% had bilobar disease. Follow-up: 9 months (median) Conflict of interest: none IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 14 of 40

15 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Stubbs RS (006) 6 Case series New Zealand Study period: Jan 1997 to Mar 003 Study population: patients with extensive colorectal liver metastases previous chemotherapy treatment status not. Age: 61 years (median); Sex: 6% Male. Time since diagnosis 6. months (median). n = 100 Inclusion criteria: patients not considered suitable for either resection or cryoablation. Technique: SIRT therapy with SIR-Spheres via a surgically implanted hepatic artery portacath or a temporary percutaneous hepatic catheter through the femoral artery. Dose titrated depending on the extent of the disease. One treatment session. Some patients were treated by concomitant hepatic arterial chemotherapy. Follow-up: 11 months (median) Conflict of interest: not Tumour response CT imaging status 3 months n = 80 Disappeared 1 Reduced Stable Increased months n = 65 Median CEA as a percentage of baseline Baseline 3 months 6 months 1 months 100% 1% 1% 33% Survival 5% (5/100) of patients had died at 6-month follow-up. Median survival was 11 months (range 0.1 to 76.6) from SIRT treatment. Estimated survival following SIRT was 48% (±5% standard error) at 1 months, 18% (±3.8%) at 4 months and 9% (±.9%) at 30 months. Independent predictors of survival Concomitant HAC treatment: relative risk 3.83 (95% confidence interval 1.99 to 7.34) (p = 0.00) Extent of liver disease: relative risk 1.86 (95% confidence interval 1.0 to.88) (p = 0.005) Lymph node status of primary tumour: 1.70 (95% confidence interval 1.00 to.89) (p = 0.048) Complications deaths: 1 (1%) due to radiation hepatitis 9 weeks after SIRT; and 1 (1%) due to acute pancreatitis with peptic ulceration 10 weeks after SIRT (believed to be caused by misperfusion of the pancreas/stomach/duodenum with microspheres). Peptic ulceration: 8% (8/100) this group includes 1 patient who died with acute pancreatitis with peptic ulceration, as described above. One operation is in this group, as well as 4 oesophageal strictures (successfully dilated). Liver abscess requiring percutaneous drainage: 1% (1/100). Cardiac arrest: 1% (1/100), patient survived. All patients experienced lethargy and some anorexia for up to 5 or 6 weeks. Consecutive case accrual. First patients treated/initial experience at the study centre. 8 patients who had normal CEA level at baseline were excluded from analysis on CEA change. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 15 of 40

16 Abbreviations used: CEA, carcino-embryonic antigen; CI, confidence interval; CT, computed tomography; GBq, gigabecquerel; Gy, gray; HAC, hepatic artery chemotherapy; IV, intravenous; SIRT, selective internal radiation therapy Study details Key efficacy findings Key safety findings Comments Leung TW (1995) 11 Case report Hong Kong Study period: not Study population: patients with colorectal liver metastases or hepatocellular carcinoma. Previous chemotherapy treatment status not. Age: 59 years; Sex: 100% male. n = 5 (1 Colorectal liver metastases) Inclusion criteria: Not. The paper describes respiratory function complications (pneumonitis) that developed following SIRT treatment. Patient 1 Patient with colorectal liver metastasis. SIRT dose 5.0 GBq, 14.8% lung shunting. Estimated radiation dose to the lungs Gy. Patient developed symptoms of dry cough and progressive exertional dyspnoea without fever between 1- and 6-month follow-up. Chest X-ray and CT scans showed extensive patch consolidation with well defined lateral margin. Spirometry testing demonstrated forced expiratory volume.4 l, and forced vital capacity of.49 l. No positive bacterial cultures of viral cultures identified suggesting a non-infective cause. Patient treated with prednisolone 0 mg/day and symptoms improved. Partial tumour response to SIRT treatment; survival 16.5 months. 6% (5/80) of patients treated at the institution developed radiation pneumonitis. Outcome for patient with colorectal liver metastases. Radiation dose was substantially more than in other trials in this overview. Some outcomes described for all patients who developed pneumonitis (including patients with hepatocellular carcinoma) rather than those with colorectal liver metastases specifically. Technique: SIRT with SIRtherapy following nuclear medicine scan to determine lung shunting. Follow-up: 16.5 months Conflict of interest: not IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 16 of 40

17 Efficacy Chemotherapy naïve patients An RCT of 1 patients with colorectal liver metastases unable to be treated by resection or local ablation, that median survival was significantly longer in the SIRT plus systemic chemotherapy group (9.4 months) than in the systemic chemotherapy alone group (1.8 months), hazard ratio 0.33 (95% confidence interval [CI] 0.1 to 0.91) (p = 0.05). An RCT of 1 patients that there was no statistically significant difference in change of quality of life score from baseline (using a validated questionnaire or the Spitzer index) to follow-up (not ) between patients treated with SIRT plus systemic chemotherapy and those treated with chemotherapy alone. Chemotherapy refractory patients An RCT of 44 patients treated by SIRT plus chemotherapy or chemotherapy alone median overall survival of 10 and 7.3 months respectively (p = 0.80) 3. An RCT of 44 patients that median time to liver progression was significantly longer following SIRT plus chemotherapy (5.5 months) than following chemotherapy alone (.1 months), hazard ratio 0.38 (95% CI 0.0 to 0.7) (p = 0.003) 3. A case series of 08 patients a partial response in 36% (74/08) of patients, stable disease in 55% (114/08) of patients, and progressive disease in 10% (1/08) of patients at mean 13-month follow-up 4. Median survival was significantly longer amongst responders (10.5 months) compared with non-responders (4.5 months) (p = ). A reduction in volume of liver metastases that enabled potentially curative resection of 3 or more segments to be carried out was achieved in 4.0% (/50) of patients treated by SIRT in a case series of 50 patients 7. In the same study, mean anxiety levels of patients treated by SIRT, were significantly reduced (compared with pre-treatment levels) in 14 patients questioned at 6 weeks after treatment, (p<0.01) 7. Both chemotherapy naïve and chemorefractory patients /prior chemotherapy treatment status not described An RCT of 70 patients with non-resectable liver metastases from primary adenocarcinoma of the large bowel that there was no statistically significant difference in survival between the SIRT plus hepatic artery chemotherapy group (mean 3.5 months) and the hepatic artery chemotherapy alone group (mean 18.4 months) (p = 0.18) 1. In this study median time to disease IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 17 of 40

18 progression was significantly longer in the SIRT plus chemotherapy group (18.6 months) than in the chemotherapy alone group (3.6 months) (p < ). A case series of 100 patients with extensive colorectal liver metastases (not otherwise defined) that 5% (5/100) had died within 6-month follow-up, and that estimated survival following SIRT was 48% at 1 months, 18% at 4 months and 9% at 30 months 6. An RCT of 70 patients that tumour response (in terms of tumour area evaluated on computed tomography scans) was significantly better following SIRT plus hepatic artery chemotherapy than following hepatic artery chemotherapy alone at a minimum follow-up of 3.5 years (p = 0.01) 1. Similarly carcino-embryonic antigen concentrations were significantly better in the SIRT plus hepatic artery chemotherapy group than in the hepatic artery chemotherapy alone group (p = 0.004) at a minimum follow-up of 3.5 years. Safety An RCT of 1 patients 1 treatment-related death (9% [1/11]) in the SIRT plus systemic chemotherapy group because of chemotherapy-induced neutropenia and associated sepsis. In the same treatment group radiation-induced liver cirrhosis occurred in 9% (1/11) of patients at 1-year follow-up, which improved with conservative treatment, and liver abscess occurred in 9% (1/11) of patients; this resolved with drainage. Overall there were 13 grade 3 or 4 toxicity adverse events in the SIRT plus systemic chemotherapy group and 5 events in the systemic chemotherapy alone group (measurement of significance and length of follow-up not ). An RCT of 44 patients that overall there were grade 3 toxicity events in 5% (1/1) of patients in the SIRT plus chemotherapy group and 7% (6/) of the patients in the chemotherapy alone group (p = 0.10) at a median follow-up of 5 months 3. An RCT of 70 patients mild pancreatitis in 3% (1/36) of patients following SIRT and hepatic artery chemotherapy and in 0% (0/34) of patients who received hepatic artery chemotherapy alone (measurement of significance not ) 1. In the same study there was no statistically significant difference between the groups in the total number of grade 3 or 4 toxicity adverse events. A case series of 140 patients treated with SIRT that radiation-induced liver dysfunction occurred in % (3/140) of patients (median follow up 9 months) 9. A case series of 37 patients (137 with colorectal liver metastases) that 19% (6/137) of patients showed abnormal imaging findings related to the biliary tree, of which 14 patients had biliary necrosis at 9 to 10 months follow-up 5. A case series of 100 patients peptic ulceration in 8% (8/100) of patients at 11 months follow-up resulting in 1 death in a patient who developed acute pancreatitis. The same study also radiation hepatitis in 1% (1/100) of patients resulting in death 6. A case report of 3 patients who became symptomatic IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 18 of 40

19 following SIRT describes erythema and/or ulceration on subsequent gastric endoscopy 10. A case report of 5 patients (one with colorectal liver metastases) radiation pneumonitis following SIRT in this patient who had an estimated 14.8% lung shunting of radiation spheres; symptoms improved with prednisolone treatment 11. Across the studies pain following SIRT was in between 13% (7/08) 4 and 36% (4/11) of patients, and nausea in 3% (1/36) 1, 9% (1/11) and 11% (/08) 4 ; concomitant chemotherapy regimens varied between studies. A case series of 08 patients fever in % (4/08) of patients following the procedure (median follow-up 13 months) 3. Validity and generalisability of the studies Some of the non-controlled studies included patients treated with SIRT plus chemotherapy, and for those studies, it is difficult to apportion the specific effect of SIRT or chemotherapy on the outcomes. Many of the included studies stated that patients with advanced disease were included, beyond a stage at which local surgical or ablative treatment may be possible. In the uncontrolled studies, it is difficult to differentiate the side effects of concomitant local or systemic chemotherapy from the possible side effects of the internal radiation therapy. Few studies attempted to evaluate quality of life outcomes. Some randomised studies included use of non-protocol chemotherapy once initial protocol had finished. Although this may have been mandated by ethical considerations, it nevertheless makes interpretation of findings more difficult. Few studies included patients who were chemotherapy naive, some studies included patients who were refractory to chemotherapy, and some studies included a mixed group of patients with regard to chemotherapy history. This makes comparison of outcomes between studies difficult. Existing assessments of this procedure This procedure was assessed by the Australian Medical Services Advisory Committee (MSAC) for the treatment of non-resectable liver tumours (including colorectal liver metastases) in 005. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 19 of 40

20 SIR-Spheres for the treatment of non-resectable liver tumours. August 005. MSAC application The following is an excerpt from the Executive summary of the report, pertaining to patients with colorectal liver metastases: Recommendation MSAC recommends that on the strength of evidence pertaining to the treatment of patients with hepatic metastases secondary to colorectal cancer which are not suitable for resection or ablation, interim public funding should be supported for first line treatment by administration of SIR-Spheres in combination with systemic chemotherapy using 5FU and leucovorin, with the collection of survival data. This data should be to MSAC within three years. The Radioembolization Brachytherapy Oncology Consortium (REBOC) has developed recommendations for SIRT including the following. Recommendations 1) The panel believes that there is sufficient evidence to support the safety and effectiveness of yttrium-90 (Y90) microsphere therapy in selected patients. and 3) Candidates for radioembolization are patients with unresectable primary to metastatic hepatic disease with liver-dominant tumor burden and a life expectancy >3 months. From Kennedy A, Nag S, Salem R et al (007) Recommendations for Radioembolization of Hepatic Malignancies Using Yttrium-90 Microsphere Brachytherapy: A Consensus Panel Report from the Radioembolization Brachytherapy Oncology Consortium. Int. J. Radiation Oncology Biol. Phys. 68: 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. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 0 of 40

21 Interventional procedures Microwave ablation for the treatment of metastases in the liver. NICE interventional procedures guidance 0 (007). Available from Radiofrequency ablation for the treatment of colorectal metastases in the liver. NICE interventional procedures guidance 09 (004). Available from Technology appraisals NICE Technology appraisal guidance 118. Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Available from NICE Technology appraisal guidance 176. Cetuximab for the first line treatment of metastatic colorectal cancer. 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. Prof. A Adam (Royal College of Radiologists), Mr G Poston (British Association of Surgical Oncology), and Dr P Tait (British Society of Interventional Radiology). One Specialist Adviser categorised this procedure as novel and of uncertain safety and efficacy, whereas two considered it to be established and no longer new. The main comparator is chemotherapy. Adverse events or seen with this procedure include pain, vomiting, anorexia, fatigue, portal hypertension, and problems in the delivery and distribution of radioembolic material when antiangiogenic chemotherapeutic agents have previously been used. IP overview: Selective internal radiation therapy for non-resectable colorectal metastases in the liver Page 1 of 40