The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

Transkript

1 The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

2 Background 80 new cases a year in Sweden (Cancerregistret, 2013) 30-50% will develop metastases (Diener-West et al 2005, Kujala 2003) 50-70% will have isolated liver metastases (Diener-West et al 2005)

3 Survival after diagnose of metastatic disease Systematic screening (Gragoudas 1991) 1116 patients screened yearly with LFTs and lung x-ray Overall survival 4 months (145 patienter) COMS-trial (Diener-West 2005) 2320 patients screend yearly with LFTs Overall survival 6 months (739 patients) MSK (Rietchel 2005) All patients developing metastatic disease during 10 years Overall survival 12,5 months (119 patienter)

4 Treatments (median overall survival) Chemotherapeutic 6.7 months for temozolomide (Bedikian et al 2003) 10.6 months for BOLD (Kivelä et al 2003) Immunotherapy months for ipilimumab (Luke et al 2013) Targeted therapies months for selumetinib (Falchook 2012) Chemoembolization months (Sharma et al 2008) Intra-arterial fotemustine months (Leyvraz et al 2012) Liver resection - 14 months (Mariani et al 2009)

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9 Melphalan 1 mg/kg O 2 C

10 Retrospective study (Olofsson et al 2013) patients Uveal melanoma Isolated liver metastases, no extra-hepatic disease Age 59 years (18-77)

11 Morbidity/Mortality No postoperative mortality 3 major complications 2 respiratory insufficiency 1 perforated duodenal ulcer Median time ICU: 1 (1-38) days Median in hospital stay: 10 (3-43) days ( less than 7 days)

12 Response RECIST-criteria Independent radiologist CR 4 (12%) PR 19 (59%) SD 5 (15%) PD 6 (18%) Overall response 23 (71%)

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14 Swedish patient registry Uveal melanoma C69.3, C69.4 Liver metastases C78.7 n=135

15 Swedish patient registry Uveal melanoma C69.3, C69.4 Leverperfusion IHP n=28 Liver metastases C78.7 n=135 Kontroll No IHP n=107

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17 Swedish patient registry Uveal melanoma C69.3, C69.4 Leverperfusion IHP n=28 Liver metastases C78.7 n=135 Kontroll No IHP n=107

18 Swedish patient registry Uveal melanoma C69.3, C69.4 IHP n=28 Liver metastases C78.7 n=135 No IHP n=107 IHP n=28 Longest survivor n=28

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20 Studie The SCANDIUM trial The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

21 Studie Randomized, multicenter (Nordic countries) IHP vs BAC No crossover to IHP allowed

22 Studie Randomized, multicenter (Nordic countries) IHP vs BAC No crossover to IHP allowed Primary endpoint: Secondary endpoints: OS at 24 months PFS, HPFS, Respons, QoL and SAE 78 patients (50% vs 20% survival at 24 months) 5 year (15 pts. per year)

23 Studie Randomized, multicenter (Nordic countries) IHP vs BAC No crossover to IHP allowed Primary endpoint: Secondary endpoints: OS at 24 months PFS, HPFS, Respons, QoL and SAE 78 patients (50% vs 20% survival at 24 months) 5 year (15 pts. per year) Randomization, BAC and follow-up at local center IHP at Sahlgrenska, Göteborg

24 Studie Inclusion Criteria 1. Male or female aged above 18 years. 2. Signed and dated written informed consent before the start of specific protocol procedures. 3. Histologically or cytologically proven liver metastases of uveal melanoma. 4. Liver metastases measurable by CT/MRI (thorax and abdomen) according to RECIST version 1.1 with at least one unidimensional measurable lesion 10 mm. 5. ECOG performance status of 0 or No previous chemotherapy, radiotherapy, or biologic therapy for uveal melanoma metastases (ie first-line therapy) 7. Adequate hepatic function (defined as ASAT,ALAT, bilirubin <= 3*ULN and PK- INR <= 1.5) and no medical history of liver cirrhosis or portal hypertension

25 Studie Exclusion Criteria 1. More than 50% of the liver volume (measured by CT or MRI) replaced by tumour. 2. Evidence of extrahepatic disease by PET-CT 3. Life expectancy of less than 4 months 4. Pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study. 5. Active infection. 6. Ischemic cardiac disease or history of congestive heart failure with an LVEF < 40%. 7. COPD or other chronic pulmonary disease with PFT's indicating an FEV< 50% predicted for age. 8. Reduced renal function defined as S-Creatinine >=1.5xULN or Creatinine Clearance < 40 ml/min, calculated using the Cockroft and Gault formula. 9. Reduced blood leukocytes or platelets defined as LPK < 2.0x109/L and TPK <100x109/L 10. Use of live vaccines four weeks before or after the start of study. 11. Body mass index above 35.

26 Studie Follow-up The subjects will be followed for 2 years. Study visits will be at each center and performed at baseline, and after 3, 6, 12, 18 and 24 months. CT or MRI of liver (same modality as baseline examination) according to specified protocol Laboratory tests EQ5D-3L Quality of Life questionnaire

27 Studie Cross-over No cross-over from BAC to IHP allowed At progression, patients can cross-over from IHP to BAC

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30 scandium online

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32 SCANDIUM)Accrual)status) 80" 70" 11/78 patienter randomiserade 7 BAC 4 IHP 60" 50" 40" 30" 20" 10" 0" 2014" Mar" Maj" Jul" Sep" Nov" 2015" Mar" Maj" Jul" Sep" Nov" 2016" Mar" Maj" Jul" Sep" Nov" 2017" Mar" Maj" Jul" Sep" Nov" 2018" Mar" Maj" Jul" Sep" Nov"

33 Principal investigators and Sites Lars Ny Sahlgrenska University Hospital, Gothenburg Ingrid Ljuslinder Norrlands University Hospital, Umeå Johan Hansson Karolinska University Hospital, Stockholm Ulf Lönn Linköping University Hospital, Linköping Gustav Ullenhag Uppsala University Hospital, Uppsala Sara Kinhult Skåne University Hospital, Lund Jens Folke Kiilgaard Rigshospitalet, Köpenhamn, Danmark

34 Protocol amendment version Krav på cytologisk verifikation av levermetastaser innan behandling startas (men inte nödvändigtvis vid randomisering). 2. MR lever är den undersökningsmodalitet som föredras, CT lever går dock att använda för dom som inte har möjlighet. 3. MR/CT av lever ska vara maximalt 4 veckor gammal innan randomisering.

35 Protocol amendment version Vid baseline och uppföljning har vi lagt till analys av S-100, efter förslag om att detta möjligen skulle kunna vara en markör för respons.

36 Protocol amendment version Förändring avseende rapportering av AE i IHP gruppen, där nu endast grad III-V behöver rapporteras. 8. Förändringar i rapportering av SAE i båda grupper, där vi nu listat undantag relaterade till cancersjukdom. 9. Att patienter om möjligt ska genomgå IHP inom 4 veckor efter randomisering.

37 SAE #1 Man född 1935 I bakgrunden väsentligen frisk, viss etylöverkonsumtion kan ej uteslutas. Genomgår IHP Vid perfusion noteras två relativt likstora artärer där endast den större perfunderas. Postoperativt höga transaminaser som leder till exploration som dock visar normalt kärlflöde till levern. Utvecklar njursvikt postoperativt och får hemodialys. Leverfunktionen hämtar och allmäntillståndet förbättras. Utskrives till hemsjukhus, har nu inget dialysbehov och normal urinproduktion. Senaste MR visat PR.

38 SAE/SUSAR #2 Kvinna 1941 Hypertoni och övervikt. Genomgår IHP , tekniskt besvärligt, misstanke om intimaskada i huvudartären. En mindre artär till segment 2+3 stängs under perfusionen. Postoperativt höga transaminaser som sjunker, efter en vecka dock försämring med på nytt stigande leverprover. Exploreras pga peritonit och man finner dåligt arteriellt flöde till höger leverhalva, misstanke om dissektion. Utskrives till avdelning från IVA efter 2 dagar. Sista veckan trött och förhöjt bilirubin. Insjuknar med fekala kräkningar, aspirerar och får hjärtstillestånd som ej går att häva. Avlider.

39 The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases