HTA REPORT Selective Internal Radiation Therapy (SIRT) in colorectal liver metastases

HTA REPT Selective Internal Radiation Therapy (SIRT) in colorectal liver metastases May 2014 1

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This report should be cited as: Chiarolla E, Paone S, Lo Scalzo A, Cosimelli M, Jefferson T, Cerbo M. HTA report: Selective Internal Radiation Therapy (SIRT) in colorectal liver metastases, Rome, July 2013. 3

Contributions Authors Emilio Chiarolla 1, Simona Paone 1, Alessandra Lo Scalzo 1, Maurizio Cosimelli 2, Thomas Jefferson 1, Marina Cerbo 1 1 Agenzia nazionale per i servizi sanitari regionali, Sezione Innovazione Sperimentazione e Sviluppo (Roma); 2 Istituto Nazionale Tumori Regina Elena (IFO) (Roma) Corresponding author Emilio Chiarolla (chiarolla@agenas.it) External Reviewer Vincenzo Mazzaferro MD PhD Director, G.I. Surgery and Liver Transplantation Coordinator Hepato-Oncology Multidisciplinary Group Istituto Nazionale Tumori, Fondazione IRCCS Acknowledgements The authors and Agenas would like to thank Patrizia Brigoni for search strategy; Fabio Bernardini for literature search; Lucio Capurso and Tiziana Pugliese, Maria Perrone and Chiara Falcicchio (IFO Istituto Nazionale Tumori Regina Elena) for scientific support; Jane Lapon (BTG International Canada Nordion Inc.) and Karin Sennfalt (Sirtex Medical Ltd, North Sydney, Australia) for technical support; Francesca Gillespie for the editing; Mario Del Giacco for the support in the survey management and all the Centers who participated in our suvey. 4

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HTA REPT Selective Internal Radiation Therapy (SIRT) in colorectal liver metastases INDEX AUTHS... 4 CRESPONDING AUTH... 4 FEWD... 8 PREFAZIONE... 9 EXECUTIVE SUMMARY... 10 SYNTHESIS... 12 SINTESI... 17 1. BACKGROUND... 22 1.1 SELECTIVE INTERNAL RADIATION THERAPY (SIRT) IN COLECTAL LIVER METASTASES: INDICATION AND CLINICAL PROBLEMS... 22 1.2 EPIDEMIOLOGICAL DATA AND POPULATION... 22 BIBLIOGRAPHY... 23 2. DESCRIPTION OF SIRT... 24 2.1 THE TECHNOLOGY... 24 2.2 DESCRIPTION OF THERASPHERE... 25 2.3 DESCRIPTION OF SIR-SPHERES... 25 2.4 PROCEDURE... 26 2.5 ALTERNATIVES... 27 2.6 CHARACTERISTICS OF THE HOSPITAL WHERE SIRT CAN BE PERFMED... 28 BIBLIOGRAPHY... 29 3. OBJECTIVES, POLICY AND RESEARCH QUESTIONS... 30 POLICY QUESTION... 30 RESEARCH QUESTIONS... 30 4. ASSESSING THE EFFECTIVENESS FROM CLINICAL STUDIES... 31 4.1 SYSTEMATIC REVIEW... 31 4.2 OBJECTIVES OF THE SYSTEMATIC REVIEW... 31 4.3 METHODS... 31 4.4 RESULTS OF THE SYSTEMATIC REVIEW... 33 4.5 CLINICAL TRIALS REGISTERED IN CLINICAL TRIALS.GOV... 34 BIBLIOGRAPHY... 35 5. CONTEXT ANALYSIS... 36 5.1 OBJECTIVES OF THE CONTEXT ANALYSIS... 36 5.2 METHODS F CONTEXT ANALYSIS... 36 5.3 RESULTS OF CONTEXT ANALYSIS... 36 6

BIBLIOGRAPHY... 42 6. ECONOMIC ANALYSIS... 43 6.1 OBJECTIVES OF THE ECONOMIC ANALYSIS... 43 6.2 SYSTEMATIC REVIEW OF ECONOMIC EVIDENCE OF SIRT... 43 6.2.1 Methods... 43 6.2.2 Results... 44 6.3 COST ANALYSIS FROM THE CONTEXT ANALYSIS... 44 6.3.1 Methods... 44 6.3.2 Results... 44 6.4 REIMBURSEMENT OF SIRT... 48 6.5 COST OF THE SIRT PROCEDURE... 48 6.6 BUDGET IMPACT ANALYSIS (BIA) OF SIRT... 49 6.7 CONCLUSION... 49 BIBLIOGRAPHY... 51 7. PATIENTS VIEWS... 52 7.1 OBJECTIVES... 52 7.2 METHODS... 52 7.3 RESULTS... 52 7.4 CONCLUSIONS... 54 BIBLIOGRAPHY... 56 8. DISCUSSION... 57 9. RECOMMENDATIONS... 58 10. FUNDING... 59 11. COMPETING INTERESTS DECLARATION... 60 APPENDIX 1 - LITERATURE SEARCH STRATEGY ON EFFECTIVENESS AND SAFETY... 61 APPENDIX 2 - DATA EXTRACTION SHEET... 63 APPENDIX 3 - LIST OF THE BACKGROUND REFERENCES... 68 APPENDIX 4 - INCLUDED STUDY... 68 APPENDIX 5 - LIST OF EXCLUDED STUDIES AND REASONS OF EXCLUSION... 69 APPENDIX 6 - QUESTIONNAIRE F THE SURVEY... 71 APPENDIX 7 - CENTERS PERFMING RADIOEMBOLIZATION IN ITALY... 84 APPENDIX 8 - SEARCH STRATEGY F THE SYSTEMATIC REVIEW OF ECONOMIC STUDIES... 85 APPENDIX 9 - LIST OF EXCLUDED STUDIES FROM THE ECONOMICS REVIEW... 89 APPENDIX 10 - LIST OF CONSULTED WEB SITES... 89 GLOSSARY... 91 7

Foreword This year Agenas has produced a HTA report on the use of Selective Internal Radiation Therapy (SIRT) for treatment of colorectal liver metastases on behalf of the Italian Ministry of Health. The HTA report was developed to answer the question: What is the impact on the Italian NHS of adding radioembolization with 90 Y-Microspheres on current treatments for patients with nonresectable liver metastases from primary colorectal cancer (CRC)?. The latest evidence on clinical effectiveness has been synthesized by a systematic review of literature. To describe the patterns of real use and expected expenditure of SIRT, Agenas carried out a survey involving nineteen Italian Centres which were probably performing SIRT. The results of the systematic review show that the evidence for the combination of SIRT with chemotherapy vs. chemotherapy alone for the treatment of colorectal liver metastases is limited, notwithstanding the publication in the next few years of large datasets from trials nearing completion. A more rational use of resources would involve concentration of all patients in a smaller number of qualified Hospitals doing higher volumes of SIRT and accruing experience with the technique. In addition, given the nature and stage of the disease in which patients are candidates for treatment, the cost of SIRT and the uncertainty surrounding its effects, the adoption of SIRT would be recommended in few selected cases. Fulvio Moirano Executive Director of Agenas 8

Prefazione Quest anno Agenas ha prodotto, su mandato del Ministero della Salute un report di HTA sull utilizzo della Selective Internal Radiation Therapy (SIRT) per il trattamento delle metastasi epatiche da carcinoma del colon-retto. Il report è stato sviluppato a partire dal seguente quesito: Qual è l impatto generato sul Sistema Sanitario Italiano se al trattamento corrente (chemioterapia) per metastesi epatiche da carcinoma coloroettale viene aggiunto anche quello di radioembolizzazione con 90 Y-Microspheres?. Le prove di efficacia clinica sono state sintetizzate mediante revisione sistematica della letteratura mentre, per la descrizione dell utilizzo nel contesto italiano e per il rilevamento dei costi è stata predisposta una survey presso tutti i centri italiani che utilizzano la SIRT. I risultati suggeriscono che le prove di efficacia dell utilizzo della SIRT per il trattamento delle metastasi epatiche da carcinoma del colon-retto sono molto limitate, sebbene diversi studi multicentrici siano in corso di svolgimento. Gli elevati costi possono essere contenuti solo mediante l adozione della SIRT in centri qualificati di alta specializzazione. Inoltre, considerata la natura e lo stadio della malattia in cui si trovano i pazienti candidati al trattamento, i costi della SIRT e l'incertezza che circonda i suoi effetti, l adozione del trattamento SIRT sarebbe consigliabile in pochissimi e selezionati casi. Fulvio Moirano Direttore Generale Agenas 9

Executive summary One-liner We assessed effectiveness, acceptability and costs of the combination of SIRT with chemotherapy vs. chemotherapy alone for the treatment of liver metastases from Colorectal cancer (CRC). Background CRC is one of the most frequent cancers in the western world, with a prevalence of 300,000 cases in Italy and 52,000 new diagnoses in 2012. Liver metastases from CRC develop in 50% of patients but only 25% of those are considered to have resectable metastases. The primary aim of treating CRC liver metastases is to decrease the lesions size and spread. Surgical resection is the treatment of choice for resectable colorectal metastases. For unresectable metastatic disease, systemic medical therapy (chemotherapy) is the first choice treatment, but local therapy such as loco-regional radiotherapy and ablative procedures, may be associated in an attempt to prolong survival or to palliate symptoms (e.g. pain). Radioembolization, also known as Selective Internal Radiation Therapy (SIRT) is a form of intra-arterial brachytherapy used to treat primary liver cancer and liver metastases. The potential benefits of radioembolization technology for CRC liver metastases treatment can be significant in terms of economical and organizational impact and important ethical implications such as patient s expectations and hopes. Objective To assess clinical effectiveness, acceptability, costs and organisational aspects of SIRT for the treatment of liver metastases from CRC. Methods For clinical effectiveness analysis we carried out a systematic review of literature, including studies on people aged 18-80 with non-resectable liver metastases from primary CRC. The Intervention assessed was SIRT using Yttrium-90 coated microspheres administered via the hepatic artery compared to chemotherapy at 2nd and later lines and excluding supportive therapy. We carried out a literature search on the following databases: MEDLINE, EMBASE, Cochrane Library, Health Technology Assessment websites, trial registries. We aimed to include HTA reports, systematic reviews and comparative prospective primary studies (trials and cohort studies) carried out from 1997 to date in English or Italian. 10

Data on study design, study population, SIRT and comparator outcomes were extracted. We assessed studies according to randomization, generation of the allocation sequence, allocation concealment, blinding and follow up. Interpretation of the studies results was carried out in terms of numerousness, quality and consistency. We performed a context analysis of the nineteen Italian Centres which were able to perform SIRT for the treatment of liver metastases from CRC. We adopted a questionnaire to collect data and information on diffusion, type of technology and resource used, data on clinical outcomes, patient selection and costs of procedure. We conducted a systematic review of the italian and international scientific literature to identify and describe the economic evaluation studies of SIRT for liver metastases from primary CRC. We carried out a cost analysis of SIRT technology using data collected from questionnaires. Finally, we used different sources of information to collect views and hopes of patients who used SIRT. Results We included one small open label randomized trial carried out on 46 patients. The study is small and its generalizability is unclear. In our survey the majority of hospitals provided SIRT in one session. Choice of number of sessions depended on cost and on extension of metastatic disease (unilobar, bilobar), reduction of technical complications potentially related to several sessions, different vascular supply of liver metastases and different response of each metastatic nodule to chemotherapy. Fifty percent of liver involvement is the highest acceptable threshold in all hospitals. An increasing number of Centers are employing SIRT early (2 nd or 3 rd line). Considering the therapeutic potential of SIRT, the impact of SIRT in Italy should be tested with a larger use of prospective studies, similarly to clinical strategies promoted by other countries. Moreover, our survey shows that the number of patient yearly treaded is relatively small with no more than 12 patients treated per year. We calculated the total cost of SIRT procedure by adding the costs of diagnostic work-up, treatment and follow up. The median cost is 15,229 euro ranging from 13,582 to 17,370. The costs of an individual dose of radioisotopes amounts to 10,000 euro. For the patients being able to undergo radioembolization means having a further chance. The attitude toward it is usually positive and the probable side effects are regarded as tolerable. Any future study comparing radioembolization with other therapies should always include QoL as a secondary outcome measured with standardized and internationally validated instruments. Recommendations We recommend that the results of completed and nearly completed trials currently still active, be reported at the earliest opportunity. A national resource optimization plan is needed. 11

Synthesis Clinical problem and target population Colorectal cancer (CRC) is one of the most frequent cancers in the western world, with a prevalence of 300,000 cases in Italy and 52,000 new diagnoses in 2012. Liver metastases from CRC develop in 50% of patients but only 25% of those are considered to have resectable metastases. The five-year survival rate after surgery is 20% to 40%. The primary aim of treating CRC liver metastases is to decrease the lesions size and spread. Surgical resection is the treatment of choice for resectable colorectal metastases. However, only 10 to 25 percent of patients with isolated liver metastases are eligible for resection because of anatomical constraints, inadequate hepatic functional reserve or concurrent medical co-morbidities such as poor performance status and cardiac failure. For unresectable metastatic disease, systemic medical therapy (chemotherapy) is the first choice treatment, but local therapy such as locoregional radiotherapy and ablative procedures, may be associated in an attempt to prolong survival or to palliate symptoms (e.g. pain). Radioembolization, also known as Selective Internal Radiation Therapy (SIRT), is a form of intraarterial brachytherapy used to treat primary liver cancer and liver metastases. Radioembolization uses glass (TheraSphere produced by MDS Nordion Inc.) or resin (SIR-Spheres produced by Sirtex Medical Inc.) microspheres including β-emitter 90Y. The potential benefits of radioembolization technology for CRC liver metastases treatment can be significant in terms of economical and organizational impact and important ethical implications such as patient s expectations and hopes. Objectives Objectives of this HTA report were: i) to assess the clinical effectiveness of SIRT; ii) to analyse the clinical use of SIRT in Italy; iii) to carry out a cost and organizational analysis on the use of SIRT iv) to collect information on patients expectations and quality of life with SIRT. Methods For clinical effectiveness analysis we carried out a systematic review of literature, including studies on people aged 18-80 with non-resectable liver metastases from primary CRC. The Intervention assessed was SIRT using Yttrium 90 coated microspheres administered via the hepatic artery compared to chemotherapy at 2 nd and later lines and excluding supportive therapy. 12

We carried out a literature search on the following databases: MEDLINE, EMBASE, Cochrane Library, Health Technology Assessment websites, trial registries. We aimed to include HTA reports, systematic reviews and comparative prospective primary studies (trials and cohort studies) carried out from 1997 to date in English or Italian. Data on study design, study population, SIRT and comparator outcomes were extracted. We assessed studies according to randomization, generation of the allocation sequence, allocation concealment, blinding and follow up. Interpretation of the studies results was carried out in terms of numerousness, quality and consistency. We performed a context analysis of the nineteen Italian Centres which were probably performing SIRT for the treatment of liver metastases from CRC. We adopted a questionnaire to collect data and information on diffusion, type of technology and resources used, data on clinical outcomes patient selection and costs of procedure. We conducted a systematic review of the Italian and international scientific literature to identify and describe the economic evaluation studies of SIRT for liver metastases from primary CRC. We carried out a cost analysis of SIRT technology using data collected from questionnaires. Finally, we used different sources of information to collect views and hopes of patients who used SIRT. First via Google search engine we identified websites, blogs and forums reporting narratives from patients with liver metastasis due to CRC who had or were going to have radioembolization. We then focused on primary studies which measured Quality of life with SIRT and collected some expert opinions. Results Systematic review We identified and extracted one small open label randomized trial carried out on 46 patients. The trial appeared to show a benefit in terms of shortening time to liver progression (TTLP) and time to progression (TTP) of the disease of around 3 months. The study is small and judgment on the generalizability of its results to the Italian setting is unclear in the light of the results of our national survey. No other studies fitting our inclusion criteria were identified. Context Analysis All responders performing SIRT are equipped with the appropriate technology such as CT, Angiography, PET-CT and SPECT and with all key professional figures required. Up to now SIRT in Italy was used as 1st-line in only about one fifth of all patients treated (21.2%), echoing the general opinion that chemotherapy still represents the best option as 1st-line treatment. The majority of hospitals (54.5%) preferred to provide SIRT in one session, while only two hospitals in two sessions and the remaining three of them in one or two sessions. Choice of number of sessions depended on not only cost but most importantly extension of metastatic 13

disease (unilobar, bilobar), reduction of technical complications potentially related to several sessions, different vascular supply of liver metastases and different response of each metastatic nodule to chemotherapy. Fifty percent of liver involvement is the highest acceptable threshold in all hospitals. On this basis the number of liver metastases doesn t seem to be a selection criterion. Overall, the current patient selection threshold is higher than the past. This is to guarantee the lowest risk of toxicity, the highest chances of response, the best quality of life and also cost containment. Centres chose how to employ SIRT essentially in function of ongoing protocols at their respective sites: however, in comparison with use of SIRT a few years ago, an increasing number of Centres are employing it in early therapeutic lines (2nd, 3rd). The increasing rates of responses observed in different subsets of patients allowed testing SIRT in patients who had received i.v. chemotherapy. Emerging SIRT Centres initially selected patients in more advanced lines of treatment, even for testing feasibility and safety at each respective clinical site. Considering the therapeutic potential of SIRT, in Italy the impact of SIRT should be tested with a larger use of prospective studies, similarly to clinical strategies promoted by other countries. Moreover our survey shows that the number of patient yearly treaded is relatively small with no more than 12 patients treated per year. Consequently a national resource optimization plan is needed. Cost Analysis The only study included in the effectiveness review did not have sufficient data on the effects for a cost-effectiveness analysis, as the results in terms of survival rate were not robust. Unfortunately, data on QALYs were also not available. For this reason only a cost analysis and a (partial) BIA were performed considering the real context data. During 2012 the number of patients that received SIRT was 25 (and 35 procedures). Data from the survey instead are not enough reliable to determine how many patients with liver metastases from CRC actually perform the diagnostic work up resulting not eligible for SIRT treatment. Literature searches did not provide information on this percentage, so we don t know how many additional costs should be considered in the budget analysis.we calculated the total cost of the SIRT procedure adding the costs of diagnostic work-up, treatment and follow up. The median cost is 15,229 Euros ranging from 13,582 to 17,370 Euros. The costs of an individual dose of radioisotopes amount to 10,000 euro. Total cost of the SIRT treatment in 2012 is 533,015 Euros (35 procedures).the total cost considering the minimum and maximum costs ranges from 393,878 to 503,730 Euros. 14

Patients views For patients being able to undergo radioembolization means having a further chance of surviving cancer. Thus the attitude toward this treatment is usually positive and its probable side effects are regarded as tolerable. We found only one study, although not a RCT, which measured QoL with standardized questionnaires. Authors of the study concluded that patients QoL did not get worst with SIRT. Any future study comparing radioembolization with other therapies should always include QoL as a secondary outcome measured with standardized and internationally validated instruments. Discussion The results of our systematic review show that the combination of SIRT with chemotherapy vs. chemotherapy alone for the treatment of colorectal liver metastases may have a potential benefit in terms of shortened time to liver progression (TTLP) and time to disease progression (TTDP) of around 3 months. However, these results come from the single trial identified in our systematic review with a limited number of participants. The results of our survey of harms of SIRT show that pain and fever are the most common adverse experiences reported. However, these events could be also be interpreted as a good response to the treatment because they may be induced by tumour necrosis. Our survey shows a scatter of many different Italian Hospital Centers performing SIRT on a small number of cases. In some cases these may have been part of study protocols for formal scientific investigations. This may explain the irregular pattern of provision of the therapy. A more rational use of resources would involve concentration of all patients in a smaller number of qualified Hospitals doing higher volumes of SIRT and accruing experience with the technique. The potential costs of SIRT should require an exhaustive and complete economic evaluation in terms of cost per outcome (survival and QALY) compared with standard interventions to guarantee the best evidence base for decision-making. Data from our context analysis showed a complexity of organization and management aspects due to the variety in professionals, skills, and equipment involved. Costs estimates from our survey reflect this complexity. The total costs per procedure estimated in this report (Euros 15,229) are higher than those reimbursed (using different codes) to hospital. The finding that 10 years after the approval of the technique for such a late and intractable form of cancer, evidence of its effects is thin and its effects on quality of life are almost unknown. Given the potential large costs of the intervention and the apparently promising nature of its effects on life, its quality and its acceptability to vulnerable patients, robust evidence is required. 15

Recommendations Evidence on the effectiveness of the use of SIRT for the treatment of liver metastases from colorectal carcinoma is very limited, although several multi-center studies are in progress. We recommend that the results of completed and nearly completed trials currently still active, be reported at the earliest opportunity. Ideally this could be done directly as preliminary summary results on the clinicaltrials.gov website. Given the nature and stage of the disease in which patients are candidates for treatment, the cost of the SIRT and the uncertainty surrounding its effects, the adoption of the SIRT treatment would be advisable in few selected cases to concentrate in few qualified high specialized centres. 16

Sintesi Introduzione Il tumore del colon retto (CRC) è uno dei più frequenti nel mondo occidentale, con una prevalenza di 300.000 casi in Italia. Nel corso del 2012 sono attesi 52.000 nuovi casi. Le metastasi epatiche da CRC si sviluppano nel 50% dei pazienti ma sono resecabili solo nel 25%. Il tasso di sopravvivenza a cinque anni dopo l'intervento chirurgico è compreso tra il 20% e il 40%. L'obiettivo principale del trattamento delle metastasi epatiche da colon consiste nel ridurre la dimensione e la diffusione delle lesioni. La resezione chirurgica rimane il trattamento di elezione a cui può ricorrere solo dal 10 al 25 per cento dei pazienti a causa di vincoli anatomici, riserva funzionale epatica inadeguata, o comorbilità concomitanti quali l insufficienza cardiaca. Per la forma tumorale metastatica non resecabile, il trattamento di elezione è la terapia medica sistemica (chemioterapia) a cui possono essere associate terapie locali, come la radioterapia loco-regionale e le procedure ablative, nel tentativo di prolungare la sopravvivenza o per attenuare i sintomi (es. dolore). La radioembolizzazione, conosciuta anche come Selective Internal Radiation Therapy (SIRT), è una forma di brachiterapia usata per il trattamento dell epatocarcinoma e le metastasi epatiche. La SIRT utilizza microsfere di vetro (TheraSphere prodotto da MDS Nordion Inc.) o resina (SIR- Spheres prodotto da Sirtex Medical Inc.) e contengono 90Y che è un β-emettitore. I potenziali vantaggi della tecnologia di radioembolizzazione per il trattamento delle metastasi al fegato da CRC possono essere significativi in termini di impatto economico ed organizzativo oltre etico alimentando aspettative e speranze nel paziente. Obiettivi Gli obiettivi sono di: i) valutare l efficacia clinica della SIRT; ii) studiare le modalità di utilizzo clinico della SIRT in Italia; iii) effettuare un analisi dei costi e degli aspetti organizzativi; iv) raccogliere le informazioni sull aspettativa dei pazienti e la loro qualità di vita. Metodi Al fine di valutare l efficacia clinica è stata effettuata una revisione sistematica della letteratura, che include pazienti di età compresa tra 18-80 anni con metastasi epatiche da CRC non resecabili. Si sono presi in considerazione gli studi comparativi in cui si confrontano gli effetti della SIRT con microsfere di Ittrio-90 somministrate attraverso l'arteria epatica in pazienti dalla 2 a linea in poi 17

rispetto al trattamento con sola chemioterapia, escludendo il trattamento a scopo compassionevole. La ricerca bibliografica è stata effettuata utilizzando i seguenti database: MEDLINE, EMBASE, Cochrane Library e siti web di Health Technology Assessment e Clinical trial. Il criterio di selezione degli studi si è esteso a tutti i report HTA, revisioni sistematiche e studi primari comparativi (trial e di coorte) pubblicati dal 1997 ad oggi in italiano o in inglese. Da questi studi si sono estratte informazioni riguardanti il disegno, la popolazione, gli outcome della SIRT e del comparatore. Gli stessi sono stati valutati analizzando i criteri di randomizzazione, la sequenza di assegnazione, l occultamento della lista, la cecità e il follow-up. L'interpretazione dei risultati degli studi è stata effettuata in termini della loro numerosità, qualità e consistenza. Abbiamo effettuato un analisi di contesto sui diciannove centri italiani che utilizzano la SIRT e che potenzialmente potrebbero utilizzarla per il trattamento delle metastasi epatiche da CRC. Si è utilizzato un apposito questionario al fine di raccogliere dati e informazioni circa la diffusione, il tipo di tecnologia e di risorse utilizzate, i dati sugli esiti clinici selezione dei pazienti e i costi della procedura. Abbiamo condotto una revisione sistematica della letteratura scientifica italiana e internazionale per identificare e descrivere gli studi di valutazione economica della SIRT per il trattamento delle metastasi epatiche da CRC ed effettuato un'analisi dei costi della SIRT utilizzando i dati raccolti dai questionari. Infine, abbiamo utilizzato diverse fonti di informazione per raccogliere le opinioni e le aspettative dei pazienti che hanno utilizzato la SIRT. Dapprima, tramite il motore di ricerca Google, individuando e raccogliendo sui siti web, blog e forum, le narrazioni dei pazienti che avevano ottenuto o che sono in procinto di ricevere il trattamento. Successivamente ci siamo concentrati sugli studi primari che hanno misurato la qualità della vita con la SIRT e raccolto alcuni pareri di esperti. Risultati Revisione sistematica Abbiamo individuato ed estratto solo uno studio randomizzato effettuato su 46 pazienti. Il trial sembra mostrare un beneficio in termini di riduzione del tempo di circa 3 mesi della progressione epatica (TTLP) e del tempo alla progressione della malattia (TTP). Lo studio non è esteso e il giudizio sulla generalizzabilità dei suoi risultati nel contesto italiano non è così chiaro alla luce anche dei risultati rilevati dalla survey condotta. Non sono stati individuati altri studi che corrispondono ai nostri criteri di inclusione. 18

Analisi di contesto Tutti i centri che effettuano la SIRT dispongono di tecnologie appropriate, come TAC, angiografo, PET-TC e SPECT e di tutte le figure professionali necessarie. Ad oggi, in Italia, la SIRT viene utilizzata in 1 a linea solo su un quinto di tutti i pazienti trattati (21,2%), e pertanto, in questa linea, la chemioterapia rappresenta ancora l'opzione migliore. La maggior parte degli ospedali (54,5%) preferisce somministrare il trattamento SIRT in un unica sessione, solo due centri in due e i restanti tre in una o due sedute. La scelta del numero di sedute dipende non solo dal costo, ma soprattutto dall'estensione delle metastasi (uni-lobare, bi-lobare), dalla riduzione delle complicazioni potenzialmente correlate alla somministrazione in diverse sessioni, dalla diversa vascolarizzazione delle metastasi epatiche e dalla diversa risposta di ogni nodulo metastatico alla chemioterapia. Il cinquanta per cento del coinvolgimento epatico è la soglia più alta di accettabilità utilizzata in tutti i centri. Sulla base di questo parametro il numero di metastasi epatiche non sembra essere un criterio di selezione. Complessivamente, l attuale soglia di selezione del paziente è superiore al passato. Questo al fine di garantire un più basso rischio di tossicità, le più alte probabilità di risposta, la migliore qualità di vita e anche il contenimento dei costi. I centri utilizzano la SIRT essenzialmente in funzione dei protocolli in uso nelle singole strutture: tuttavia, rispetto a qualche anno fa, un numero crescente di centri stanno impiegando l utilizzo della SIRT in linee terapeutiche sempre più precoci (2 a, 3 a ). L'aumento del tasso di risposta osservato nei diversi sottogruppi di pazienti ha consentito di testare la SIRT nei pazienti che avevano ricevuto la chemioterapia per via intravenosa. Inizialmente i centri selezionavano i pazienti in linee più avanzate di trattamento, anche per testare la fattibilità e di sicurezza della metodica nel proprio contesto. Considerando il potenziale terapeutico della SIRT, il suo impatto dovrebbe essere testato attraverso un uso più diffuso di studi prospettici, così come accade in altri paesi. Inoltre la nostra indagine mostra che il numero di pazienti trattati ogni anno è relativamente esigua, non più di 12 pazienti. Di conseguenza, si rende necessario un piano nazionale di ottimizzazione delle risorse. Analisi dei costi L'unico studio incluso nella revisione dell'efficacia non disponeva di dati utili alla conduzione dell analisi di costo-efficacia poiché i risultati in termini di sopravvivenza non erano robusti. Sfortunatamente non sono disponibile neppure dati sui QALY. Per questi motivi è stata eseguita solo un analisi dei costi e una (parziale) BIA utilizzando i dati reali provenienti dall analisi di contesto. Il numero di pazienti che hanno ricevuto il trattamento SIRT nel 2012 è pari a 25 (equivalenti a 35 procedure). Le informazioni ricavate dalla survey invece non sono stati sufficientemente affidabili per determinare quanti pazienti con metastasi epatiche da CRC 19