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Introduction Human immunoglobulin is produced from plasma derived from blood donors. These drugs consist of antibodies that can protect against infections and are used to treat a wide variety of diseases, among others hereditary (primary) immunodeficiencies and deficiencies following other treatment or diseases (secondary), as well as autoimmune and inflammatory diseases. For some conditions, the treatment is lifesaving, while for other diseases alternative treatment options exist. In Norway, human immunoglobulin is used in the medical fields of immunology, hematology, neurology, rheumatology, skin diseases, pediatric and infectious disease, as well as treatment of malignancies and transplantation. The drugs are administered intravenously or subcutaneously. Some patients may receive repeated and lifelong treatment, for example in the case of primary immunodeficiency. For other conditions, for example the neurological disease Guillain-Barré syndrome, immunoglobulin is an acute treatment. In situations with limited supply, there may be a need to prioritize patients or patient groups. The availability of human immunoglobulin is limited and may be uncertain as its production depends on blood donations. Norway is not self-sufficient with human immunoglobulin, but depends to a large extent on donations in other countries, first and foremost in the USA. The costs are high and the use of these medicines is increasing in Norway and globally. Objective We aimed to conduct a scoping review of the clinical research literature on the efficacy of human immunoglobulin in a selection of diseases and conditions where these drugs are currently used in Norway. With this rapid health technology assessment, we mapped the consumption of and costs incurred by human immunoglobulin use in Norway. We further aimed to unveil possible variations in use by geographical regions and between clinical disciplines. Method We limited the scope of this health technology assessment to map the evidence base of efficacy in patients who receive human immunoglobulin in Norwegian medical practice. We developed a list of relevant diseases in co-operation with external experts. For the selected conditions, we searched for review literature (systematic reviews and health technology assessments) published during the past five years and for primary studies where we could not find reviews. We extracted data from the included reviews and present them in tables as the results were reported in the original reviews. We have not conducted our own analyses. We have not explicitly assessed the quality of the included reviews and studies. We have not made confidence judgements in the results. The Norwegian Institute of Public Health co-operated with The Norwegian Hospital Procurement Trust and calculated the consumption of human immunoglobulin in Norway. Here, we used data from Farmastat and Sykehusapotekenes legemiddelstatistikk, respectively. We analysed both consumption and costs on a national level from 2016 to 2020. To investigate possible geographical differences, we mapped consumption at county level. Here, we present both absolute figures and consumption relative to population size. We also gathered data from the innsatsstyrt finansiering («effort driven financing») database and calculated consumption in different medical fields. Results We included 63 systematic reviews and 4 primary studies that summarize the efficacy of immunoglobulin in conditions treated in Norway. For some diseases, efficacy has been explored in randomised controlled trials. For many conditions, research evidence is limited to cohort studies, case series and case reports. The consumption of human immunoglobulin has increased by 55 % between 2016 and 2020. Both intravenous and subcutaneous use is on the rise. From 2019 to 2020, this increase was lower than during the previous years. Data for 2021 point to a reduction in annual usage compared to 2020. Total consumption is up to three times higher in counties that use the largest volume of immunoglobulin (Nordland, Troms and Finnmark) compared with counties where their use is lowest (Trøndelag, Vestland) adjusted for population size. Human immunoglobulin is most used in the fields of hematology, neurology and immunology, which together made up for 87 % of all patients treated in 2020. Patients who received intravenous immunglobulin that year most frequently suffered from a hematological or neurological disease, primary or secondary immunodeficiency. Subcutaneous immunglobulin, which can be self-administered in outpatient treatment, is mostly used for immunological conditions. Discussion For many conditions where immunoglobulin is used as treatment, research evidence of its efficacy is insufficient. Many conditions are rare and to conduct robust effect studies can therefore be difficult. Both consumption of human immunoglobulin and costs associated with these medicines have increased substantially in Norway between 2016 and 2020. The increase from 2019 to 2020 was lower compared to previous years. Preliminary numbers for 2021 indicate a lower annual consumption than during the year of 2020 and may have been impacted by the COVID-19 pandemic. Less availability of blood donations globally may have contributed to the increase in costs. We expect the consumption of human immunoglobulin to increase further in years to come, for example among patients with immunodeficiencies following cancer treatment. In a possible future shortage of these drugs, there may not be enough human immunoglobulin available for all patients. This development is in line with the overall increasing usage in Scandinavia, in other European countries and globally. Our analyses show variable prescribing patterns for these drugs within Norway. We believe that regional differences in medical practice in part are due to the lack of national guidelines. If further efforts are to be taken in this domain, we believe it is necessary to include recommendations for use in addition to an assessment of research evidence. Existing international guidelines for their use rely heavily on clinical experience, among other factors. International guidelines can be adapted to the Norwegian context. If priority settings are to be developed, they should cover all relevant medical disciplines. Conclusion We found evidence of efficacy for diagnoses that are indicated for treatment with human immunoglobulin. We identified research on their efficacy also for diseases that at present are treated off-label, that is for unapproved indications. For such conditions, the evidence of efficacy is usually very limited. The consumption of human immunoglobulin in Norway has increased by 55 % between 2016 and 2020. Their costs have increased by 119 % during the same period. Immunoglobulin is mostly used within the medical disciplines of hematology, neurology and immunology. These medicines are not uniformly used throughout Norway. In the northernmost counties, total immunoglobulin consumption was almost three times as high as in counties with least usage during the past year.

Executive summary Background: Glaucoma is a substantial public health problem, with a large negative impact on quality of life and the utilization of health care resources. Glaucoma refers to a group of eye conditions with a characteristic pattern of progressive damage to the optic nerve. Raised intraocular pressure (IOP) is the best characterized risk-factor, but IOP can also be normal. Globally, glaucoma is considered the leading cause of irreversible vision loss and one of the leading causes of blindness overall. There are approximately 77,000 Norwegian individuals with a glaucoma diagnosis. The incidence is expected to increase because of demographic changes and because the disease can now be diagnosed at earlier stages than before. Minimally invasive glaucoma surgery (MIGS) represents a class of new surgical procedures and devices to address this issue. Experts suggest MIGS may result in shorter procedure and recovery times than traditional surgical procedures, and that MIGS make it possible to offer treatment at an earlier stage of glaucoma. The indications for each MIGS procedure depend on its mechanism of action and the individual patient’s target IOP and concomitant eye diseases. MIGS procedures and devices can be used alone or in conjunction with cataract surgery. The procedure is already offered in many public hospitals in Norway. Objective The objectives of this health technology assessment (HTA) were to: 1) supplement the evidence of (effectiveness and safety ) of MIGS in an HTA published by the Canadian Agency for Drugs and Technologies in Health (CADTH) in January, 2019, 2) conduct a health economic evaluation of MIGS from a Norwegian health care perspective, and 3) assess organizational and ethical aspects of MIGS in a Norwegian setting. Method: Clinical effectiveness and safety We have summarized CADTH’s HTA evidence of effectiveness and safety, and adapted CADTH’s methods in the conduct of our supplementary review of more recent studies. CADTH carried out systematic literature searches in August and November 2017, while our updated searches were carried out in August 2019 and November 2020. Searches were run in electronic medical databases, such as MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials, using peer-reviewed search strategies. Two reviewers independently selected studies meeting our inclusion criteria. Likewise, 8 Executive summary two reviewers independently judged the included studies’ risk of bias. One reviewer extracted predefined data, and another reviewer checked the data extraction. The primary outcome in CADTH’s HTA was quality of life, and intraocular pressure in the Norwegian Institute of Public Health (NIPH) HTA supplementary review. When possible, mean differences with 95 % confidence intervals were calculated, and effect estimates were pooled for similar comparisons. When pooling was not possible, findings were reported narratively. One reviewer assessed the certainty of the evidence with the GRADE approach, and a second reviewer checked the assessments. Health economic evaluation We based our health economic analysis on the previous HTA carried out by CADTH. We developed six different decision analytic cost-effectiveness models in TreeAge Pro, to estimate incremental cost utility rate (ICER). The models provide insight into costs, health effects, survival, and disease stage. The analysis was carried out from a modified Norwegian health care perspective. We have estimated absolute shortfall for patients with glaucoma. We handled uncertainties in model parameters by assigning probability distributions to the parameters and performing probabilistic sensitivity analysis (PSA), designed as a Monte Carlo simulation. We also performed one-way sensitivity analyses for each of the six models to explore potential impact of uncertainty in single parameters. In addition, we estimated the budget impact of introducing MIGS as a routine treatment option in Norway for patients with glaucoma. Organizational aspects In order to evaluate the organizational consequences related to the implementation of MIGS and a potential increase in volume of MIGS performed in Norwegian hospitals, we asked clinical experts from five of the state-run hospitals that perform MIGS in Norway, to answer a questionnaire regarding their present capacity and procedure used: patient selection, procedures and ongoing trials. Ethical perspectives We analysed central ethical implications of MIGS implementation, and the analysis was proceeded in three major steps: First, brief description of the situation, alternative actions and solutions, and the involved stakeholders. Second, analysis of the ethical challenges and possible consequences in terms of the four principles: benefit, harm, autonomy and justice. Results: Clinical effectiveness and safety CADTH HTA CADTH’s HTA included 35 publications from 32 studies; 10 randomized trials and 22 non-randomised studies. The evidence included 24 specific comparisons: one comparison of a MIGS versus another MIGS, six comparisons of a MIGS combined with cataract surgery versus cataract surgery alone, nine comparisons of a MIGS combined with cataract surgery versus filtration surgery combined with cataract surgery, six comparisons 9 Executive summary of a MIGS combined with filtration surgery versus filtration surgery alone, two comparisons of a MIGS versus pharmacotherapy, and one comparison of a MIGS versus laser therapy. CADTH’s authors considered all the included studies to have some risk of bias. As shown in the table below with summary of findings by comparison and outcomes (reproduced with kind permission from CADTH), there was largely no statistically significant difference between intervention and comparator and this can be explained because the heterogeneity in interventions and comparisons did not allowed pooling. . The evidence was considered very low or low certainty across comparisons and outcomes. NIPH supplementary review We identified and included eight studies (seven randomised trials and one non-randomised study) that compared a MIGS procedure alone or in combination with cataract surgery, with another MIGS procedure or non-MIGS procedures. None of the additional found studies could be pooled with study results in the CADTH HTA. As showed in the summary of findings table below, there was high-certainty evidence of lower IOP with Hydrus in combination with cataract surgery than with cataract surgery alone, and moderate-certainty evidence of lower unmedicated IOP with iStent inject in combination with cataract surgery than with cataract surgery alone. Otherwise, there was no or little difference between the MIGS and interventions in control groups, or the certainty of the evidence was too low to make a judgement. The evidence for the safety of MIGS was inconclusive across the comparisons, but there appeared to be little or no risk of complications associated with any of the treatment options. There also appears to be no standarized method to measure safety. 10 Executive summary Summary of findings: Intraocular pressure (IOP) Effectiveness of MIGS for open-angle glaucoma in adults Patient or population: adults with open-angle glaucoma Intervention: MIGS alone or in combination with other procedure Comparison: other MIGS or other procedure Comparison Anticipated absolute effects* MD (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments Intraocular pressure [mm Hg] One MIGS procedure versus another MIGS procedure Hydrus vs 2x iStent MD 1.9 lower (2.91 lower to 0.89 lower) 148 (1 RCT) ⨁⨁◯◯ LOW a,b Follow-up: 12 months One MIGS procedure versus another procedure (non-MIGS) iStent+phaco vs phaco alone MD 1.9 lower (3.32 lower to 0.48 lower) 48 (1 observational study) ⨁◯◯◯ VERY LOW b,c Follow-up: 12 months iStent inject+phaco vs phaco alone MD 0.7 lower (1.27 lower to 0.13 lower) 570 (2 RCTs) ⨁⨁⨁◯ MODERATE a Follow-up: 24 months Hydrus+phaco vs phaco alone MD 1.8 lower (2.73 lower to 0.87 lower) 331 (1 RCT) ⨁⨁⨁⨁ HIGH Follow-up: 24 months Trab360+phaco vs phaco alone MD 2.8 lower (5.49 lower to 0.11 lower) 18 (1 RCT) ⨁◯◯◯ VERY LOW b,d Follow-up: 24 months Gold MicroShunt vs Ahmed glaucoma valve MD 0.7 lower (2.71 lower to 1.31 higher) 12 (1 RCT) ⨁◯◯◯ VERY LOW b,e Follow-up: 5 years iTrack+phaco vs filtration surgery+phaco MD 1.7 lower (3.29 lower to 0.11 lower) 59 (1 RCT) ⨁◯◯◯ VERY LOW b,f Follow-up: 12 months *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference; phaco: phacoemulsification (cataract surgery) GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Explanations a. Possible risk of performance bias in personnel b. Wide confidence interval and/or sub-optimal information size c. Serious bias due to confounding d. High risk of performance and detection bias. 11 Executive summary e. High risk of attrition bias; unclear risk of bias in most other domains. f. High risk of selection, performance and attrition bias; unclear risk of detection and reporting bias. Health economic evaluation The lifetime total cost per patient for glaucoma treatment ranged between NOK 30 000 and NOK 84 000 depending on the treatment strategy and patient’s baseline disease stage. The incremental quality adjusted life years (QALYs) for MIGS between comparators ranged between – 0.080 and 0.057. Organizational aspects MIGS surgery is done at many public hospitals in Norway in addition to a few private clinics. There is a lack of formalised indications for the use of MIGS in Norway. MIGS is suitable for outpatient surgery without hospital admission. Ophthalmologists need specific MIGS training to perform the surgery (certification). The MIGS-procedures have a shorter learning curve than traditional glaucoma surgery, and has in other countries also been implemented by non-glaucoma specialists / general cataract surgeons for this reason (i.e. some benefit in terms of regional accessibility in Norway can be expected). MIGS procedures require less follow-up than traditional surgery, so there may be fewer post-intervention controls per patient in the hospital. Finally, a better treatment option may also lead to more patients being operated. The need for glaucoma surgery may increase due to increased population growth in the relevant age group. Experts predict that the demand for MIGS procedures will increase annually from today to twice as many by 2024. Ethical perspectives There are potential benefits of MIGS. The central ethical concerns of MIGS implementation are, in terms of justice, to guarantee patients equal access to treatment, regardless of ability to pay, place of residence, social status, or cultural background. The challenges for patient autonomy seem manageable, if patients can be thoroughly informed about risks of and alternatives to a given MIGS procedure. Discussion: The strengths of CADTH’s and our health technology assessments include updated systematic searches in electronic databases, pre-specified inclusion and exclusion criteria, double independent screening of identified records, independent assessments of risk of bias in included studies, systematic data extraction and reporting, and assessments of the certainty of the evidence. We believe we have identified most eligiblie studies that were not included in CADTH’s HTA, thus providing a useful supplement. We had to make several assumptions to develop the six health economic models, leading to some uncertainty surrounding our economic results. MIGS is a heterogeneous group of devices with potentially different costs, risk profiles and relative treatment effects. We replicated the model from CADTH with respect to model structure and efficacy data. The input is adjusted according to Norwegian conditions. 12 Executive summary It is important to ask whether the introduction of MIGS will lead to a change in Norwegian practice. According to our clinical experts, the impact on practice will be limited. Our health economic evaluation is consistent with other evaluations on health economics, among others the CADTH report, regarding uncertainty around estimates due to lack of data. Cost components may be different in different countries. To obtain high quality documentation for the myriad of possible MIGS comparisons, there is a need for more well-designed randomised trials, with larger numbers of participants and longer follow-up. Further, detailed micro-costing of MIGS procedures may allow for greater certainty in the true absolute and incremental costs of MIGS to better inform the potential economic value of MIGS. For patients and clinicians, it would be helpful if evidence-based guidelines were developed or applied to a Norwegian setting in addition to local and/or national registrers. Studies on the most used MIGS procedures in Norway (as iStent, Xen, Preserflo) are included, but might not be well documented in this report, as some relevant clinical comparisons have not been conducted yet (to our knowledge). The evaluation of effect and cost-effectiveness might therefore have some limits. Conclusion: MIGS with Hydrus Microstents combined with cataract surgery reduces intraocular pressure (IOP) at 24 months, compared to cataract surgery alone. MIGS with Hydrus Microstents probably reduces IOP at 12 months, compared to MIGS with 2x iStents. For other comparisons and outcomes, it is uncertain whether there is a difference in IOP reduction. Neither MIGS procedures nor alternative surgical strategies appear to be at high risk of adverse events, and it is uncertain whether complications occur more or less frequently in either category. Definitive conclusions on the cost-effectiveness of MIGS are uncertain, given the uncertainty in the analysis. The economic evaluation provided some scenarios where MIGS might be cost-effective, depending on comparator and disease stage. The clinical evidence on MIGS is limited. The main reason for this is the lack of comparative studies. Our health economic evaluation shows some scenarios where MIGS may be cost-effective, depending on comparator and disease stage. Our analysis puts individuals with glaucoma in severity class 1. Hovedbudskap: Denne metodevurderingen (HTA) oppsummerer og supplerer en kanadisk HTA fra 2019 om effekt og sikkerhet ved minimal-invasiv glaukomkirurgi (MIGS). Videre gjorde vi kost-nytteanalyser basert på den kanadiske HTAen, i tillegg til brukerperspektiv, organisatoriske og etiske vurderinger som er relevante i en diskusjon om hvorvidt MIGS bør være et rutinetilbud i norsk praksis. Det kanadiske kunnskapsgrunnlaget, som omfattet 32 studier og 24 sammenlikninger, var usikkert på grunn av svært lav til lav tillit til resultatene. Våre supplerende funn viser at: • MIGS med Hydrus Microstent kombinert med kataraktkirurgi reduserer intraokulært trykk (IOP) etter 24 måneder, sammenliknet med kataraktkirurgi alene (høy tillit til resultatet) • MIGS med iStent inject og kataraktkirurgi reduserer trolig IOP etter 24 måneder, sammenliknet med kataraktkirurgi alene (middels tillit til resultatet) • Det er usikkert hvorvidt det er noen forskjell i effekt mellom MIGS og kontrollgruppene for andre sammenligninger • Det ser ikke ut til å være noen betydelig forskjell mellom MIGS og kontrollgruppene i risiko for uønskede hendelser/skader • Total livstidskostnad per pasient for glaukombehandling ble estimert mellom 30 000 norske kroner og 83 000 norske kroner avhengig av behandlingsstrategi og sykdomsstadie ved start. Inkrementell QALY for MIGS sammenlignet med komparatorer var mellom – 0.080 og 0.057 • MIGS egner seg for poliklinisk kirurgi. Øyeleger må ha opplæring for å utføre MIGS. Det bør utvikles klare kriterier for pasientseleksjon. Eksperter predikerer en dobling av antall MIGS prosedyrer i 2024 enn antallet i dag • Kunnskapsgrunnlaget for effekt og sikkerhet om MIGS er begrenset. Hovedgrunnen er mangel på sammenliknende studier. Vår helseøkonomiske vurdering viser at MIGS kan være kostnadseffektive, avhengig av sammenliknng og sykdomsutvikling. Vår analyse setter individer med glaukom i gruppe for alvorlighetsgrad 1.

Hovedbudskap Det er faglig uenighet om hvordan svangerskap som har passert termin skal håndteres. Verdens helseorganisasjon anbefaler å tilby igangsetting av fødsel etter 41 fullgåtte uker. I denne systematiske oversikten har vi inkludert fire randomiserte studier for å vurdere effektene av å sette i gang fødsel ved 41 fullgåtte svangerskapsuker sammenliknet med avventende holdning fram til 42 fullgåtte svangerskapsuker. Kunnskapsgrunnlaget viser at fødselsinduksjon ved 41 svangerskapsuker (+ 0-2 dager) sammenliknet med avventende holdning til 42 svangerskapsuker (+ 0-2 dager): trolig reduserer dødfødsler, perinatale dødsfall og innleggelser i nyfødtintensivavdeling trolig gir en liten reduksjon i andel nyfødte med Apgar-skår < 7 etter 5 minutter muligens gir liten eller ingen forskjell når det gjelder asfyksi trolig ikke gir noen forskjell når det gjelder risiko for forløsning ved keisersnitt, forløsning ved vakuum eller tang eller postpartum blødning muligens gir en liten reduksjon i andel kvinner med perinealrifter grad 3 eller 4 Vi har middels tillit til de fleste resultatene. Igangsetting av fødsel ved 41 uker ser ut til å redusere risikoen for nyfødtkomplikasjoner, men ser ikke ut til å ha betydning for utfall hos kvinnene.

Key message Prostate cancer is one of the most common types of cancer and it affects an increasing number of mainly elderly men. Usually prostate cancer grows slowly and is initially confined to the prostate gland, where it may not cause serious harm. In advanced metastatic prostate cancer hormone therapy (medical and/or surgical) is the first choice of treatment. We aimed to summarise findings about the effectiveness of androgen suppression therapy, chemotherapy, radiation and radioactive treatment in addition to standard care (medical or surgical castration) for metastatic prostate cancer. We found seven reviews and supplied with two newer trials. Based on our summary of the findings: Maximal androgen blockade compared to monotherapy probably improves survival slightly at two years follow up improves survival at five years follow up Taxane-based chemohormonal therapy with standard care compared to standard care alone in hormone sensitive phase probably reduces prostate-cancer specific death may increase quality of life (one year follow up) may increase adverse events (four years follow up) Chemotherapy (prednisone plus cabazitaxel) plus standard care compared to other chemotherapy (prednisone plus mitroxantrone) plus standard care in castration-resistant patients probably reduces death during study (2.5 years) may make little or no difference on pain probably increases nausea probably reduces disease progression probably slightly reduces death Radiotherapy plus standard care compared to standard care alone probably make little or no difference on survival (at three years) increases urinary tract infection (at three to seven months) Radioactive treatment in addition to or compared to standard care we are not sure if radioactive treatment influence overall survival may slightly delay symptomatic skeletal events may slightly improve quality of life Docataxel, chemotherapy in addition to standard care may slightly increase survival Active treatment with noncytotoxic agents, abiraterone acetate plus prednisone and enzalutamide, and radium-223 dichloride (Ra-223) is associated with varying levels of improvement in health related quality of life.

Hovedbudskap: Kronisk overvekt kan forårsake dårlig helse. Verdens helseorganisasjon definerer sykelig fedme som en kroppsmasseindeks ≥ 40 kg/m2 eller ≥ 35 kg/m2 hos pasienter med fedmerelatert sykdom. Behandlingsalternativer for sykelig fedme omfatter livsstils¬intervensjoner alene eller i kombinasjon med motivasjonsopphold, kirurgiske inngrep og medikamentell behandling. Vi søkte etter oppdaterte oppslagsverk og systematiske oversikter. Vi søkte ikke etter primærstudier. Vi har inkludert to systematiske oversikter som vårt kunnskapsgrunnlag for behandling av sykelig fedme. Oversiktene inkluderte sju sammenlikninger med effektmål for flere, men ikke alle, utfall vi var interessert i. Vi fant at sammenliknet med livsstilsintervensjoner alene: Gir trolig livsstilsintervensjoner kombinert med Roux-en-Y gastrisk bypassoperasjon større vektreduksjon etter 1, 2, 3, 4 og 5 år og trolig forebedrer endringer i triglyserider, blodtrykk, HBA1c i blodplasma og blodglukose etter 1 år Gir trolig livsstilsintervensjoner kombinert med legemiddelet naltrekson/bupropion større vektreduksjon etter 13 måneder Gir trolig livsstilsintervensjoner kombinert med legemiddelet liraglutid større vektreduksjon etter 13 måneder Gir muligens livsstilsintervensjoner kombinert med legemiddelet orlistat større vektreduksjon etter 1, 2 og 4 år Gir muligens livsstilsintervensjoner kombinert med sleeve gastrektomi større vektreduksjon etter 1, 2, 3, 4 og 5 år

Innledning Kolorektal kreft er blant de hyppigst forekommende krefttyper i Norge. De aller fleste tilfeller av kolorektal kreft utvikler seg fra godartede forstadier (adenomer) i tykktar‐ men, og det er langt bedre prognose ved lokalisert sykdom enn ved spredning. Det kan derfor være nyttig både å oppdage og fjerne adenomer, og å oppdage tilfeller av kolo‐ rektal kreft tidlig. Flere metoder er i bruk som screeningverktøy for kolorektal kreft. Denne kunnskaps‐ oppsummeringen er avgrenset til de tre mest brukte metodene: • Koloskopi (kikkertundersøkelse av hele tykktarmen) • Sigmoidoskopi (kikkertundersøkelse av nedre halvdel av tykktarmen) • Test for usynlig blod i avføringen (fekalt okkult blod‐testing – enten guaiacbasert, gFOBT, eller immunologisk påvisning av blod, iFOBT) Nasjonalt råd for kvalitet og prioritering i helsetjenesten drøftet i flere møter i 2010 om det burde innføres et nasjonalt screeningprogram for kolorektal kreft. Etter anbefaling fra Prioriteringsrådet ble det i 2012 startet en sammenliknende randomisert studie av to screeningmetoder: iFOBT og sigmoidoskopi. Metode I første omgang gjorde vi et enkelt søk etter relevante systematiske oversikter og fant en som nylig ble publisert (mars 2016). For å identifisere ev. andre systematiske over‐ sikter og randomiserte studier av nyere dato, gjorde vi systematiske søk i flere databa‐ ser, for perioden oktober 2015 til juni 2016. Etter at litteratursøket var ferdig og flere av analysene var utført, publiserte en ameri‐ kansk forskergruppen en systematisk oversikt, som vi også tok med i vurderingen. Vi valgte å utføre våre egne analyser for å beregne helsegevinst ved screening. Vi tok utgangspunkt i metaanalysene som var utført for en Cochrane‐oversikt fra 2013. Ved å legge til data fra nyere studier fikk vi oppdaterte effektestimater. For negative konsekvenser av screening og oppslutning om screeningprogrammene, rapporterer vi funnene som er presentert i tre systematiske oversikter, supplert med foreløpige funn fra pågående norske studier. Resultat Det foreligger overbevisende dokumentasjon fra flere store randomiserte studier som viser at screeningprogram, enten med gFOBT eller sigmoidoskopi, fører til færre døds‐ fall som følge av kolorektal kreft – hhv. 14 % (95 % KI 6 til 22 %) og 27 % (95 % KI 20 til 34 %) relativ risikoreduksjon. Sigmoidoskopi‐screening reduserer dessuten antall nye tilfeller av kolorektal kreft med 22 % (95 % KI 18 til 26 %), mens en slik effekt ikke er vist for gFOBT (2 % relativ risikoreduksjon; 95 % KI fra 10 % reduksjon til 6 % øk‐ ning). Usikkerheten rundt effektestimatene gjør at vi ikke kan slå fast at den ene meto‐ den er bedre enn den andre når det gjelder å forebygge dødsfall som følge av kolorektal kreft. Vi fant ikke god dokumentasjon for helseeffekter av iFOBT eller koloskopi som screeningmetode. Hvorvidt screening for kolorektal kreft innvirker på den totale dødeligheten er fremde‐ les uavklart. Dette kan skyldes at det trengs et enda større datagrunnlag for å påvise en effekt på dødeligheten totalt sett, ettersom dødsfall som skyldes kolorektal kreft utgjør en relativt liten andel av alle dødsfall. Alternativt kan det skyldes at screening også har negative effekter som veier opp for nedgangen i antallet som dør av kolorektal kreft. Vi sammenliknet hyppigheten av dødsfall som ikke skyldtes kolorektal kreft, og fant ikke tegn til at screening medfører økt risiko dødsfall av annen årsak. Det er vist at screening medfører en liten, men reell fare for alvorlige hendelser, i første rekke knyttet til fjerning av adenomer (og andre tarmpolypper) ved koloskopiundersø‐ kelse. Dokumentasjonen er for svak til å trekke konklusjoner om andre mulige negative konsekvenser, for eksempel psykologiske effekter. Diskusjon Det er ikke uten videre lett å forutsi de helsemessige konsekvensene av å innføre et screeningprogram i Norge. I 2014 ble det registrert 567 dødsfall som følge av ondartet svulst i tykktarm, endetarm og endetarmsåpning i aldersgruppen 55 til 74 år, i Norge. Dersom vi legger dette tallet til grunn og anvender de effektestimatene vi har kommet fram til, vil screening med sigmoidoskopi eller gFOBT føre til at hhv. 139 (95 % KI 113 til 193) og 79 (95 % KI 34 til125) færre i denne aldersgruppa dør av kolorektal kreft, per år. Dersom vi videre antar at et nasjonalt screeningprogram i ordinær drift hvert år inviterer 70 000 fra ett årskull, at 55 % møter opp, og at 10 % av disse henvises videre etter den første screeningen, så tilsvarer dette 3850 oppfølgingskoloskopier. Det er noe usikkerhet knyttet til omfanget av negative konsekvenser av deltakelse i denne type screeningprogram. Vi kan ikke slå fast at den ene screeningmetoden er mer effektiv enn den andre med tanke på å forebygge dødsfall som følge av kolorektal kreft. Konklusjon God dokumentasjon tilsier at screeningprogram med gFOBT eller sigmoidoskopi vil føre til færre dødsfall som følge av kolorektal kreft. Sigmoidoskopscreening vil også re‐ dusere forekomsten av sykdommen. Alvorlige komplikasjoner som følge av screen‐ ingen forekommer, men er sjeldne.

Nasjonalt kunnskapssenter for helsetjenesten ble bedt av Sosial- og helsedirektoratet om å vurdere innhentet og tilsendt dokumentasjon som gjelder effekten av manuelle behandlingsformer. Manuelle behandlingsformer som omhandles er behandling gitt av manuellterapeuter, osteopater og naprapater. Kiropraktikk er omhandlet der kiropraktikere er beskrevet i artiklene. Vi ble også bedt om å gjøre nye litteratursøk om effekten av naprapatisk og osteopatisk behandling.