LIVER DIRECTED THERAPY IN UVEAL MELANOMA- THE SOUTHAMPTON EXPERIENCE DR IOANNIS KARYDIS ASSOCIATE PROFESSOR IN MEDICAL ONCOLOGY UNIVERSITY OF SOUTHAMPTON AND SOUTHAMPTON UNIVERSITY HOSPITAL
UVEAL MELANOMA BACKGROUND Incidence 2-8/million in Europe 400-450 new cases / year in UK 50% will develop metastatic disease within 15 years Historic data: Median expected survival 4-6 months At 1 year post diagnosis of metastasis only 10-15% still alive without treatment
UVEAL MELANOMA AN ORPHAN DISEASE No molecular targeted treatments available Chemo-resistant (ORR<10 % even with combination regimes) Immunotherapies unproven
TARGETING THE LIVER 85-95% will develop liver metastases In >~ 50% liver is the only site of metastatic disease Less than 5-10% qualify for surgical resection Imaging often underestimates extent of disease Uncontrolled liver disease often behaves aggressively Immunotherapeutics less likely to work
LIVER DIRECTED THERAPIES Chemo- / Immuno- / Radioembolisation Ablation modalities Hepatic Perfusion
UVEAL MELANOMA IN SOUTHAMPTON 30-40 high risk UM patients a year referred for follow-up post treatment of primary tumour Direct referrals from UK and abroad for management of metastatic disease Ocular Melanoma Multidisciplinary team Interventional radiologists Medical Oncologists Hepatobiliary surgeons Perfusionists Anaestetists Nurse specialists
INTEGRATING LIVER DIRECTED AND SYSTEMIC MANAGEMENT Early diagnosis of metastatic disease Serial imaging 6 - monthly liver MRI Liver directed management Surgery Melphalan PHP / TACE SIRTS Systemic treatment Ipilimumab Anti PD-1 agents Clinical Trials
PERCUTANEOUS HEPATIC PERFUSION ( PHP ) Chemofiltration circuit Hepatic vein & IVC Isolation Hepatic Artery cannulation
WORK-UP FOR MELPHALAN PHP Accurate Staging Clinical Assessment Management plan MRI liver, whole body CT CPET testing OM MDT Staging laparoscopy Oncology & Anaesthetic Review Final consultation with patient
THE SOUTHAMPTON EXPERIENCE 25 patients received 43 cycles (median 2, range 1-4) 2 treatments abandoned on day of procedure due to unsuitable anatomy on angiography Median length of stay: 4 days range 3-8, though only 3 episodes were longer than 5 days
HEPATIC RESPONSE ASSESSMENT Best hepatic response (by liver MRI): Overall Response Rate (CR+PR): 37 % Disease control rate (CR+PR+SD): 83 % Median liver Progression Free Survival : 242 days Best liver Response Complete Response Partial Response Stable Disease >3months Progressive Disease N (%) 1 (4%) 8 (33%) 11 (46%) 4 (17%)
OUTCOMES Median Survival : 511 days (17 months) 12/25 patients still alive after a median of 315 days (~10.5 months) 1 year survival rate ~ 65% Progression Free Survival Median overall PFS ~ 182 days (~6 mo) Median liver PFS ~ 242 days (~8 mo) In 9/21 (~42%) cases systemic progression preceded liver progression.
COMPARATOR: PHASE III TRIAL Hepatic median PFS: Overall median PFS: Median OS: 242 vs 245 days 182 vs 186 days 511 vs 301 days From: Hughes et al, Ann Surg Onc Apr 2016, Vol 23, Issue 4, pp 1309 1319 Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases
WHAT ABOUT SIDE EFFECTS? Adverse Events UHS Phase III trial G3-4 Neutropenia 7/25 (28%) 60/70 (86%) Febrile neutropenia 2/25 (8%) 12/70 (17%) G3-4 Anaemia 10/25 (40%) 44/70 (63%) G3-4 Thrombocytopenia 7/25 (28%) 56/80 (80%) Cardiac arrhythmias 2/25 (8%) 4/70 (6%) Troponin rise 1/25 (4%) 6/70 (9%)
SEVERE NON-HAEMATOLOGICAL TOXICITIES No treatment related fatalities Immediate toxicities: Cardiovascular : 3/25 1 case of pulmonary oedema 2 cases of cardiac arrhythmias Vascular access complication : 2/25 1 case of intraabdominal haemorrhage 1 case of IVC thrombus (with subsequent PE) Late toxicities Thromboembolic (4/25) 3 cases of PE, 1 DVT diagnosed within 3 months of procedure 1 case of G3 fatigue
NON-HAEMATOLOGICAL MILD-MODERATE TOXICITIES Mild abnormalities in liver function tests common (32%) but resolve rapidly Other notable mild toxicities include: Nausea / Vomiting ( 12% & 8% respectively) Epigastric discomfort (12%) Constipation (8%) Mucositis/ Alopecia (4%)
HAEMATOLOGICAL TOXICITIES Immediate haematological toxicities common but easily manageable: Grade 1 2 3 4 Anaemia 4 (16%) 10 (40%) 10 (40%) 0 Thrombocytopenia 5 (20%) 11 (44%) 3 (12%) 4 (16%) Neutropenia 0 1(4%) 2 (8%) 5 (20%) 2 episodes of neutropenic sepsis were documented Platelet and blood transfusions were needed in 19 (76%) and 13 (52%) respectively, typically in the peri/immediate post-procedure setting There was 1 case of systemic coagulopathy (DIC) requiring extensive coagulation factor support
PROS/CONS OF M-PHP PROS: High hepatic disease control rates Generally well tolerated in appropriately selected patients CONS Risk of potentially life threatening complications Technically demanding & expensive BIG ISSUE Lack of concrete evidence of survival benefit/ superiority versus alternatives
FOCUS TRIAL WHY? Phase 3 trial allowed crossover -> survival benefit diluted, not statistically significant In the absence of evidence from randomised clinical trials NHS funding extremely unlikely Since then technique has improved New Immunotherapies have also arrived! <-> less effective in patients with uncontrolled liver disease * Is M-PHP superior to current alternatives? *
Randomised: Melphalan PHP vs alternative Standard of Care (TACE/immunotherapy/chemotherapy) Inclusion criteria Histologically proven & measurable liver metastatic disease No previous intra-arterial hepatic therapy No contraindication to Melphalan PHP
MELPHALAN CHEMOPERFUSION A TECHNIQUE AT CROSSROADS Appropriate patient selection and optimised perioperative management have resulted in improved side-effect profile Role in a rapidly developing field of alternative potentially complementary treatment approaches remains to be determined
SOUTHAMPTON PHP EXPERIENCE SUMMARY Melphalan PHP can be delivered safely by an experienced multidisciplinary team in the UHS Can provide significant benefits in a carefully selected group of patients as part of a multidisciplinary approach Further research is needed to establish its place in the context of new systemic and especially immunotherapeutic treatment Randomised Phase III study now open for recruitment!